Download Efficient hydrogenation of organic carbonates, carbamates and

ARTICLES
PUBLISHED ONLINE: 22 JULY 2011 | DOI: 10.1038/NCHEM.1089
Efficient hydrogenation of organic carbonates,
carbamates and formates indicates alternative
routes to methanol based on CO2 and CO
Ekambaram Balaraman1, Chidambaram Gunanathan1, Jing Zhang1, Linda J. W. Shimon2
and David Milstein1 *
Catalytic hydrogenation of organic carbonates, carbamates and formates is of significant interest both conceptually and
practically, because these compounds can be produced from CO2 and CO, and their mild hydrogenation can provide
alternative, mild approaches to the indirect hydrogenation of CO2 and CO to methanol, an important fuel and synthetic
building block. Here, we report for the first time catalytic hydrogenation of organic carbonates to alcohols, and carbamates
to alcohols and amines. Unprecedented homogeneously catalysed hydrogenation of organic formates to methanol has also
been accomplished. The reactions are efficiently catalysed by dearomatized PNN Ru(II) pincer complexes derived from
pyridine- and bipyridine-based tridentate ligands. These atom-economical reactions proceed under neutral, homogeneous
conditions, at mild temperatures and under mild hydrogen pressures, and can operate in the absence of solvent with no
generation of waste, representing the ultimate ‘green’ reactions. A possible mechanism involves metal–ligand cooperation
by aromatization–dearomatization of the heteroaromatic pincer core.
T
he hydrogenation of polar bonds, in particular organic carbonyl
groups, has captured much attention during the past four
decades1–3, mainly due to its synthetic significance as an environmentally benign approach to fundamental synthetic building
blocks such as alcohols and amines. Much progress has been
made in the hydrogenation of ketones and aldehydes and, more
recently, rare examples of the significantly more difficult hydrogenation of esters4,5 and amides6,7 have also been reported. However, the
hydrogenation of organic carbonates and carbamates remains a
major challenge. Indeed, as far as we know, catalytic hydrogenation
of these important families of compounds has never been reported,
be it under heterogeneous or homogeneous catalysis. In fact, organic
carbonates have been used as solvents in catalytic hydrogenation
reactions8. Moreover, the popular amine protecting groups, benzyl
carbamates, undergo deprotection by heterogeneous hydrogenation,
which involves cleavage of the benzyl–O bond, but with the
carbonyl group not being reduced 9. In addition, hydrogenation of
cyclic N-acylcarbamates leads to cleavage of the C–N bond
without affecting the carbamate group10.
Hydrogenation of carbonates and carbamates is of considerable
interest conceptually and practically, because these compounds can
be readily formed from CO2 or from CO, and their mild
hydrogenation would effectively mean indirect hydrogenation of the
latter compounds to methanol. In addition, mild hydrogenation of
methyl formate, which can be produced from CO2 or CO, is of great
interest as an alternative route to the conversion of these gases to
methanol. Heterogeneously catalysed hydrogenation of methyl formate
under high pressure and temperature has been reported11,12, but we
are unaware of reports of homogeneously catalysed hydrogenations.
Attempts at homogeneous hydrogenations of formate esters resulted
in decomposition to CO and alcohol, with no methanol formation13.
Methanol is industrially produced from syngas at high temperatures (250–300 8C) and high pressures (50–100 atm) using a
copper-zinc-based oxide catalyst14,15. In contrast, the carbonylation
of methanol to methyl formate16,17 or oxidative carbonylation to
dimethyl carbonate18,19 occurs under relatively mild conditions,
and their mild hydrogenation could provide a desirable route to
methanol (Fig. 1).
Production of methanol from CO2 by direct hydrogenation
under mild conditions is an attractive goal, but a practical catalytic
process has not yet been developed20–22. On the other hand, efficient
transformation of CO2 to formic acid and its derivatives (for
example, methyl formate) is known and well investigated23–29.
Heterogeneous hydrogenation of methyl formate to methanol in
the gas phase30–33 as well as the liquid phase using a semi batch
a CO
+ MeOH
MeOH
CO2 + H2
b
CO
2H2
O
H
1/2 O2
+ 2 MeOH
MeO
CO2 + 2 MeOH
OMe
O
–H2O
c
2 MeOH
3H2
3 MeOH
OMe
O
3H2
MeOH
CO2
R
NH2
R
N
H
OMe
–
R
2 MeOH
NH2
Figure 1 | Alternative routes to methanol based on methyl formate,
dimethyl carbonate and organo-carbamates. a, Synthesis of methyl formate
either from CO or CO2 followed by hydrogenation. b, Synthesis of dimethyl
carbonate either from CO or CO2 followed by unprecedented hydrogenation.
c, Synthesis of organo-carbamates from CO2 followed by
unprecedented hydrogenation.
1
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel, 2 Department of Chemical Research Support, The Weizmann
Institute of Science, Rehovot, 76100, Israel. *e-mail: [email protected]
NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry
© 2011 Macmillan Publishers Limited. All rights reserved.
609
ARTICLES
NATURE CHEMISTRY
reactor34 has been reported at elevated temperatures, with low
selectivity. However, this method suffers from side reactions such
as the formation of CO by-product from the decomposition of
methyl formate, making it less attractive.
The synthesis of dimethyl carbonate from CO2 is well documented35,36, but to the best of our knowledge the hydrogenation of organic
carbonates (such as dimethyl carbonate) to methanol remains
unknown25,37. Methods for the synthesis of methyl carbamates
from CO2 , methanol and amines have also been reported36,38,39.
Thus, catalytic hydrogenation of the organic carbonates, carbamates
and formates to methanol under mild conditions could provide an
indirect method to obtain methanol from CO2 and from CO (Fig. 1).
We have developed several reactions catalysed by pincer complexes
based on pyridine4,40–46 and acridine backbones47,48, including the
hydrogenation of esters4 catalysed by 1 and, very recently, selective
hydrogenation of amides7 to the corresponding alcohols and amines
by cleavage of the C–N bond under homogeneous conditions, catalysed by bipyridine-based pincer complex 2. These reactions are
thought to involve a new mode of metal–ligand cooperation based
on ligand aromatization–dearomatization, which has also led to consecutive water splitting promoted by complex 1 (ref. 49).
tBu
tBu
H
N
tBu
Ru
N
N
P
1
tBu
CO
2
H
H
tBu
tBu
N
P
tBu
Ru
N
P
Ru
N
CO
N
H
CO
3
H
P
tBu
Ru
N
Cl
CO
4
Here we report the first examples of catalytic hydrogenation of
organic carbonates to alcohols and organic carbamates to alcohols
and amines, and homogeneously catalysed hydrogenation of alkyl
formates to methanol and the corresponding alcohols. The reactions
are selective, proceed efficiently under mild, neutral conditions, have
high turnover numbers, and generate no waste. In addition, they
also proceed very efficiently under solvent-free conditions. These
new reactions provide interesting alternatives for the mild hydrogenation of CO2 and CO to methanol, which is a timely topic in
the context of the ‘methanol economy’50. Some key mechanistic
insight is also provided.
Results and discussion
610
Table 1 | Hydrogenation of dimethyl carbonate to methanol.
O
MeO
OMe
1 or 2
+ 3H2
Entry
Cat.
Solvent
pH2
1†
2†
3‡
4§
5}
6}
1
1
2
2
2
2
1,4-dioxane
1,4-dioxane
THF
THF
Neat
Neat
40
60
10
50
10
10
3 MeOH
Δ
Time
(h)
3.5
1
48
14
2
8
Conv.
(%)*
.99
.99
96
89
89
.99
Yield
(%)*
.99
.99
96
88
89
.99
TON
2,500
2,500
960
4,400
890
.990
*Yields of methanol and conversion of dimethyl carbonate were determined by gas chromatography
(GC) using m-xylene as an internal standard. †Complex 1 (0.01 mmol), dimethyl carbonate
(25 mmol) and 1,4-dioxane (20 ml) were heated in a Parr apparatus at 145 8C. ‡Complex 2
(0.01 mol) and dimethyl carbonate (10 mmol) were heated in a Fischer-Porter tube at 110 8C.
§
Complex 2 (0.005 mmol), dimethyl carbonate (25 mmol) and dry THF (5 ml) were heated in an
autoclave at 110 8C. }Complex 2 (0.01 mmol) and dimethyl carbonate (10 mmol) were heated at
100 8C.
of dimethyl carbonate with H2 (10 atm) at 110 8C in
tetrahydrofuran (THF) for 48 h yielded 96% of methanol (Table 1,
entry 3). It is quite remarkable that this novel hydrogenation
reaction can proceed under such mild pressure (10 atm) and with
high TON (960). Even higher TONs (4,400) were obtained using
complex 2 as a catalyst with 50 atm of dihydrogen (Table 1, entry 4).
Remarkably, the hydrogenation of dimethyl carbonate proceeds
smoothly under solvent-free conditions with catalyst 2. Thus,
performing the reaction at 100 8C resulted in 89% conversion of
dimethyl carbonate to methanol after 2 h, and quantitative
conversion was observed after 8 h (Table 1, entries 5 and 6). This
represents an ultimate green transformation—no solvent, no waste,
complete selectivity, quantitative yield and under very mild conditions.
Complex 2 also efficiently catalyses the hydrogenation of other
organic carbonates to the corresponding alcohols. For example,
diethyl carbonate was selectively hydrogenated to ethanol (91%)
and methanol (89%) after 8 h in almost complete conversion
(93%) and with a good TON (910, based on ethanol). The
Table 2 | Hydrogenation of methyl carbamates to methanol
and amines.
O
N
H
R
Entry
OMe
2
+ 3H2
Carbamate
2 MeOH
Δ
–
R
NH2
Amine
Alcohol Yield*
O
1
N
H
O
N
H
97
MeOH
98
MeOH
94
NH2
OMe
MeO
MeOH
NH2
OMe
2
Catalytic hydrogenation of organic carbonates. Complexes 1 and 2
were investigated as catalysts for the catalytic hydrogenation of
organic carbonates to alcohols. Dimethyl carbonate was selected as
a benchmark substrate for the hydrogenation reactions. Thus,
treatment of dimethyl carbonate (25 mmol) with dihydrogen
(40 atm) at 145 8C for 3.5 h with a catalytic amount of 1
(0.01 mmol), using 1,4-dioxane as solvent, resulted in complete
conversion with selective formation of methanol, with a turnover
number (TON) of 2,500 (Table 1, entry 1). With 60 atm of H2 ,
quantitative formation of methanol was observed even after
1 h (TOF ¼ 2,500 h21), with corresponding consumption of
dihydrogen (Table 1, entry 2). Using catalyst 2 (0.1 mol%), reaction
DOI: 10.1038/NCHEM.1089
MeO
O
3
Pentyl
N
H
OMe
NH2
Complex 2 (0.01 mmol), carbamate (1 mmol), H2 (10 atm) and dry THF (2 ml) were heated in a
Fischer-Porter tube at 110 8C (bath temperature). *Yields of product (based on MeOH) were
analysed by GC using m-xylene as an internal standard.
NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry
© 2011 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY
ARTICLES
DOI: 10.1038/NCHEM.1089
Catalytic hydrogenation of carbamates. In still another
unprecedented reaction, complex 2 catalyses the hydrogenation of
methyl carbamates to methanol and the corresponding amines.
Thus, heating a solution of methyl N-benzyl carbamate
(1.0 mmol) and dihydrogen (10 atm) with a catalytic amount of
complex 2 (0.01 mmol) at 110 8C in THF for 48 h selectively
yielded methanol and benzylamine in quantitative yields. Other
examples are listed in Table 2.
Remarkably, benzyl carbamates were also selectively hydrogenated to yield methanol, the corresponding amines and benzyl
alcohol, without cleavage of the benzyl–O bond. Thus, upon treatment of benzyl morpholine-4-carboxylate with H2 (10 atm) at
110 8C in dry THF for 52 h with a catalytic amount of 2
(1 mol%), 88% of benzyl alcohol, 87% of morpholine and 81% of
methanol were obtained (Fig. 2a). It is important to note that in
the hydrogenolysis of benzyl carbamates, used for deprotection of
carbamate-N functional groups catalysed by Pd/C, the deprotected
amine and free CO2 (via a carbamic acid intermediate) are formed 9.
The reaction occurs by cleavage of the benzyl–O bond, but the carbonyl group is not reduced, unlike the benzyl carbamate hydrogenation reported here (Fig. 2b).
complexes 1–4 as catalysts. Reaction of methyl formate and
dihydrogen (7 atm) catalysed by 1 (0.1 mol%) at 145 8C in 1,4dioxane yielded 71% of methanol after 30 h (Table 3, entry 1).
Performing the reaction under 9 atm of H2 resulted in complete
conversion of methyl formate to methanol after 36 h with complete
selectivity (Table 3, entry 2). Using a lower temperature, complex
1 (0.01 mmol) was heated with methyl formate (15 mmol) and
dihydrogen (10 atm) at 110 8C in THF for 48 h to yield 77% of
methanol (Table 3, entry 3). With catalyst 2, under the same
conditions (methyl formate/2 ¼ 1,500/1, 10 atm of H2 , 110 8C in
THF for 48 h), 96% conversion of methyl formate into methanol was
observed (Table 3, entry 4). Importantly, GC analysis of the reaction
mixtures indicated the absence of CO, which is a problematic
by-product in heterogeneously catalysed hydrogenation of methyl
formate35–39. Using 50 atm of H2 , even higher TONs (Table 3, entries
5 and 6) were achieved (up to 4,700) using complex 2. Notably, the
air-stable hydrido chloride complex7 4 in the presence of one
equivalent of base (relative to Ru) also efficiently catalysed the
hydrogenation of methyl formate; in this reaction the actual catalyst
2 is generated in situ by deprotonation of 4. Thus, upon heating a
THF solution of complex 4 (0.01 mmol) with KOtBu (0.01 mmol)
and methyl formate (15 mmol) at 110 8C under H2 (10 atm) for
48 h, methanol was formed in 91% yield (Table 3, entry 8). No
reaction took place in the absence of base (Table 3, entry 9).
Importantly, hydrogenation of methyl formate is efficiently catalysed
by 2 under solvent-free conditions, as in the case of dimethyl
carbonate. Thus, heating a solution of methyl formate (10 mmol)
and a catalytic amount of 2 (0.01 mmol) at 80 8C under H2 (10 atm)
resulted in quantitative conversion of methyl formate selectively
to methanol after 8 h, with the corresponding consumption of
dihydrogen (Table 3, entry 10). Like in the case of dimethyl
carbonate, this is an ultimate green transformation—no solvent, no
waste, complete selectivity, quantitative yield, and under very mild
conditions. Under the same solvent-free conditions, catalyst 1 is less
effective and affords only 16% conversion of methyl formate.
Hydrogenation of other formate esters also proceeds efficiently.
Thus, reaction of ethyl formate with H2 (10 atm) at 110 8C in
THF for 48 h catalysed by 2 (formate/2 ¼ 1,500/1) resulted in
92% of ethanol and 91% of methanol without formation of CO or
ethyl acetate. In the same way, hydrogenation of n-butyl formate
catalysed by 2 resulted in 86% conversion and selectively yielded
methanol (82%) and n-butanol (84%).
Homogeneous hydrogenation of alkyl formates. Finally, we
examined the possibility of homogeneous hydrogenation of alkyl
formates to methanol and the corresponding alcohols using
Mechanistic studies of the hydrogenation of organic carbonates
and formates. The mechanism of these unusual hydrogenation
reactions is of interest. As we reported, the trans-dihydride 3 is
O
Cat. 2
a
O
Ph
O
3H2
Ph
CH2OH +
+ MeOH
N
H
N
O b
O
Pd/C
H2
Ph
CH3
+
+ CO2
N
H
Figure 2 | Hydrogenation of a benzyl carbamate. a, Unprecedented
hydrogenation to methanol, amine and benzyl alcohol catalysed by 2.
b, A common amine deprotection by heterogeneous hydrogenation of benzyl
carbamate with cleavage of the benzyl–O bond and liberation of free CO2.
reaction was performed under solvent-free conditions under mild
pressure ( pH2 ¼ 10 atm) and low temperature (100 8C). In none
of these hydrogenations did we observe any formation of
alkyl formates.
Table 3 | Homogeneously catalysed hydrogenation of methyl formate to methanol.
O
H
Entry
1
2
3
4
5†
6†
7
8‡
9
10§
Cat.
1
1
1
2
2
2
3
4
4
2
Solvent
1,4-dioxane
1,4-dioxane
THF
THF
THF
THF
THF
THF
THF
Neat
OMe
+ 2H2
Temp. (88 C)
145
145
110
110
110
110
110
110
110
80
pH2
7
9
10
10
50
50
10
10
10
10
Cat.
Δ
2 MeOH
Time (h)
30
36
48
48
8
14
48
48
48
8
Conv. (%)*
72
.99
78
96
87
94
84
93
–
99
Yield (%)*
71
99
77
96
85
94
81
91
–
98
TON
710
990
1,155
1,440
4,250
4,700
1,215
1,365
–
980
Complexes 1, 2, 3 or 4 (0.01 mmol), methyl formate (10 mmol for entries 1–2; 15 mmol for entries 3–4, 7–9), H2 and dry solvent (2 ml) were heated in a Fischer-Porter tube at the specified (oil bath) temperature.
*Yields of methanol and conversion of methyl formate were analysed by GC using m-xylene as an internal standard. †Complex 2 (0.005 mmol), methyl formate (25 mmol), and THF (5 ml) were heated under H2
pressure in an autoclave. ‡One equiv (relative to Ru) of KOtBu was used. §Complex 2 (0.01 mmol) and methyl formate (10 mmol) were used neat.
NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry
© 2011 Macmillan Publishers Limited. All rights reserved.
611
ARTICLES
NATURE CHEMISTRY
dimethyl carbonate to deliver methyl formate, the in situ generated
complex 1 (in the absence of dihydrogen) reacts further with excess
of dimethyl carbonate, leading to 5 (see Supplementary Information
for reaction of 1 with dimethyl carbonate) by the decomposition of
dimethyl carbonate to methanol, CO and H2 (note that no CO was
observed in the catalytic hydrogenation reactions, because 1 reacts
with H2 to form 3).
Analogous stepwise hydrogenation was also observed for the case of
methyl formate. Upon reaction of methyl formate (2.5 equiv.) with 3
at room temperature, formation of methanol and a complex tentatively
assigned as a formaldehyde Ru(II) intermediate 6 was observed after
10 min (Fig. 4b)51. The aldehyde proton of 6 appears as a singlet at
9.21 ppm (0.5 ppm downfield relative to free formaldehyde, which
appears at 8.73 ppm in toluene-d8). After prolonged standing at
room temperature (6 h), the signal of 6 slowly diminished, together
with the formation of the fully characterized, methoxy Ru(II) species 7,
which was independently prepared by the addition of methanol to
complex 1 (see Supplementary Information).
On the basis of the above results and the metal–ligand
cooperation by aromatization–dearomatization prevalent in the
chemistry of pincer complexes 1 (ref. 44) and 2 (ref. 7), we
propose a possible mechanism for the hydrogenation of dimethyl
carbonate and methyl formate catalysed by 1 (Fig. 5), although
more studies are needed for mechanistic interpretation. Initially,
dihydrogen addition by metal–ligand cooperation to complex 1
results in aromatization, to form the coordinatively saturated,
trans-dihydride complex 3, as previously observed4. Subsequent
hydride transfer to the carbonyl group of the carbonate ligand
can lead to intermediate A. This process may involve direct
hydride attack on the ester or alternatively dissociation of the
pyridyl arm to provide a site for dimethyl carbonate coordination.
Deprotonation of the benzylic arm by the adjacent methoxy
group can result in liberation of methanol and the formation of a
dearomatized intermediate B, bearing a coordinated methyl
formate. Dihydrogen addition to B (which may also involve
amine arm opening), followed by hydride transfer to methyl
formate, can generate a intermediate C. Deprotonation of the
benzylic arm by the methoxy group can generate the product
methanol and a formaldehyde intermediate 6, which undergoes
hydrogenation to the characterized methoxy intermediate 7.
Methanol liberation from complex 7 regenerates catalyst 1.
Similarly, in the case of hydrogenation of methyl formate, reaction with the dihydride 3 can give intermediate C. Deprotonation
P3
1HB
O1
C1
RU1
N1
DOI: 10.1038/NCHEM.1089
1HA
N2
Figure 3 | X-ray structure of complex 3 (50% probability level). Hydrogen
atoms (except hydrides) are omitted for clarity. Selected bond distances (Å)
and angles (deg): Ru1–N1 2.101 (3), Ru1–N2 2.251 (3), Ru1–P3 2.252 (1),
Ru1–C1 1.821 (4), H1A–Ru1 1.71 (4) Å, (H1B–Ru1 was not refined). N1–Ru1–C1
175.0 (2), N1–Ru1–P3 82.6 (1), N1–Ru1–N2 78.0 (1), N2–Ru1–P3 160.6 (1),
N2–Ru1–C1 104.8 (2), C1–Ru1–P3 94.6 (1).
formed by treatment of the dearomatized 1 with dihydrogen4. A
single-crystal X-ray diffraction study of 3 (Fig. 3) reveals a
distorted octahedral geometry around the ruthenium centre, with
the CO ligand coordinated trans to the pyridyl nitrogen atom.
Complex 3 also catalyses the hydrogenation of methyl formate to
methanol (Table 3, entry 7).
Reaction of the trans-dihydride 3 with dimethyl carbonate
(2.5 equiv.) in toluene-d8 in a sealed NMR tube at 50 8C resulted
in the formation of free methyl formate and methanol in 5 min, as
observed by 1H NMR, together with the fully characterized, new
dearomatized dicarbonyl complex 5 (Fig. 4a and Supplementary
Information). Presumably, after reaction with one equivalent of
a
tBu
H
N
P
tBu
Ru
N
H
CO
O
2
MeO
O
OMe
Δ, –H2, –CO
H
N
H
+
OMe
2MeOH
+
tBu
P
tBu
Ru
N
CO
CO
5
3
H
b
H
N
tBu
Ru
N
H
3
CO
tBu
O
N
P
H
CH3
H
O
tBu
OMe
tBu
Ru
N
H
tBu
CO
O
N
P
+
MeOH
P
tBu
Ru
N
H
MeOH
1
CO
7
6
Figure 4 | Reactivities of the saturated Ru(II)–trans-dihydride complex 3, suggesting its intermediacy in the catalytic hydrogenation mechanism. a,
Reaction with dimethyl carbonate leads to methyl formate, methanol and complex 5. b, Reaction of complex 3 with methyl formate resulted in methanol,
formaldehyde intermediate 6 and methoxy intermediate 7.
612
NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry
© 2011 Macmillan Publishers Limited. All rights reserved.
NATURE CHEMISTRY
ARTICLES
DOI: 10.1038/NCHEM.1089
Me
O
MeO
H2
H
N
OMe
MeOH
PtBu2
N
Ru
N
Et2
H
O
PtBu2
H2
Ru
CO
N
Et2
CO
H
3
7
H H OMe
N
O
H
OMe
PtBu2
N
N
Et2
CO
H
PtBu2
N
Ru
Ru
N
Et2
H
H
N
MeOH
CO
N
Et2
PtBu2
N
H
O
B
CO
OMe
PtBu2
MeOH
Ru
CO
H
HH
Ru
N
Et2
PtBu2
6
OMe
O
O
Ru
1
A
H
H2
N
Et2
CO
H
C
Figure 5 | Postulated mechanism for novel, homogeneous hydrogenation of dimethyl carbonate and methyl formate to methanol catalysed by complex 1.
The mechanism involves metal–ligand cooperation by aromatization–dearomatization of the heteroaromatic pincer ligand and hydride transfer to the
carbonyl group.
of the benzylic arm by the methoxy group (as with intermediate B in
the case of dimethyl carbonate) leads to methanol and intermediates
6 and 7, as indicated experimentally (Fig. 4b). Further mechanistic
studies are in progress.
In conclusion, for the first time, selective hydrogenations of
the CO2 (and CO)-derived organic carbonates, formates and carbamates to methanol were demonstrated using soluble, well-defined
metal complexes as catalysts. The reactions, catalysed by PNN
complexes 1–3, proceed efficiently and selectively under mild,
neutral conditions using mild hydrogen pressure, without the
generation of any waste or by-products (such as CO) and with
high TONs. Moreover, the reactions proceed very well also in
absence of solvent, as demonstrated for the cases of dimethyl carbonate and methyl formate, representing ultimate ‘green’ reactions.
A postulated mechanism involving metal–ligand cooperation is
supported by stoichiometric reactions of dimethyl carbonate and
methyl formate with dihydride complex 3. The high efficiency
and selectivity of these new, environmentally benign reactions
provide mild, indirect routes to methanol from CO2 and CO
via hydrogenation of dimethyl carbonate, methyl formate and
methyl carbamates.
Received 21 February 2011; accepted 10 June 2011;
published online 22 July 2011
References
1. Ito, M. & Ikariya, T. Catalytic hydrogenation of polar organic functionalities
based on Ru-mediated heterolytic dihydrogen cleavage. Chem. Commun.
43, 5134–5142 (2007).
2. Clapham, S. E., Hadzovic, A. & Morris, R. H. Mechanisms of the
H2-hydrogenation and transfer hydrogenation of polar bonds catalyzed by
ruthenium hydride complexes. Coord. Chem. Rev. 248, 2201–2237 (2004).
3. O, W. W. N., Lough, A. J. & Morris, R. H. The hydrogenation of molecules with
polar bonds catalyzed by a ruthenium(II) complex bearing a chelating
N-heterocyclic carbene with a primary amine donor. Chem. Commun. 46,
8240–8242 (2010) and references therein.
4. Zhang, J., Leitus, G., Ben-David, Y. & Milstein, D. Efficient homogeneous
catalytic hydrogenation of esters to alcohols. Angew. Chem. Int. Ed. 45,
1113–1115 (2006).
5. Saudan, L. A., Saudan, C. M., Debieux, C. & Wyss, P. Dihydrogen reduction of
carboxylic esters to alcohols under the catalysis of homogeneous ruthenium
complexes: high efficiency and unprecedented chemoselectivity. Angew. Chem.
Int. Ed. 46, 7473–7476 (2007) and references therein.
6. Núñez Magro, A. A., Eastham, G. R. & Cole-Hamilton, D. J. The synthesis of
amines by the homogeneous hydrogenation of secondary and primary amides.
Chem. Commun. 43, 3154–3156 (2007).
7. Balaraman, E., Gnanaprakasam, B., Shimon, L. J. W. & Milstein, D. Direct
hydrogenation of amides to alcohols and amines under mild conditions.
J. Am. Chem. Soc. 132, 16756–16758 (2010).
8. Schaffner, B., Schaffner, F., Verevkin, S. P. & Borner, A. Organic carbonates as
solvents in synthesis and catalysis. Chem. Rev. 110, 4554–4581 (2010).
9. Kocienski, P. J. Protecting Groups 3rd edn (Thieme, 2005).
10. Ito, M., Koo, L. W., Himizu, A., Kobayashi, C., Sakaguchi, A. & Ikariya, T.
Hydrogenation of N-acylcarbamates and N-acylsulfonamides catalyzed
by a bifunctional [Cp*Ru(PN)] complex. Angew. Chem. Int. Ed. 48,
1324–1327 (2009).
11. Gormley, R. J., Rao, V. U. S. & Soong, Y. Methyl formate hydrogenolysis for
low-temperature methanol synthesis. Appl. Catal. A 87, 81–101 (1992) and
references therein.
12. Iwasa, N., Terashita, M., Arai, M. & Takezawa, N. New catalytic functions of Pd
and Pt catalysts for hydrogenolysis of methyl formate. React. Kinet. Catal. Lett.
74, 93–98 (2001) and references therein.
13. Grey, R. A., Pez, G. P. & Wallo, A. Anionic metal hydride catalysts. 2. Application
to the hydrogenation of ketones, aldehydes, carboxylic acid esters, and nitriles.
J. Am. Chem. Soc. 103, 7536–7542 (1981).
14. Bart, J. C. J. & Sneeden, R. P. A. Copper-zinc oxide-alumina methanol catalysts
revisited. Catal. Today 2, 1–124 (1987).
15. Ertl, G., Knözinger, H., Schüth, F. & Weitkamp, J. Handbook of Heterogeneous
Catalysis 3rd edn, Ch. 13.13 (Wiley-VCH, 2008).
16. Lee, J. S., Kim, J. C. & Kim, Y. G. Methyl formate as a new building block in C1
chemistry. Appl. Catal. 57, 1–30 (1990).
17. Girolamo, M. D. et al. Methanol carbonylation to methyl formate catalyzed by
strongly basic resins. Catal. Lett. 38, 127–131 (1996).
18. Delledonne, D., Rivetti, F. & Romano, U. Oxidative carbonylation of methanol to
dimethyl carbonate (DMC): a new catalytic system. J. Organomet. Chem. 448,
C15–C19 (1995).
19. Delledonne, D., Rivetti, F. & Romano, U. Developments in the production and
application of dimethyl carbonate. Appl. Catal. A 221, 241–251 (2001).
20. Ma, J. et al. A short review of catalysis for CO2 conversion. Catal. Today 148,
221–231 (2009).
21. Jiang, Z., Xiao, T., Kuznetsov, V. L. & Edwards, P. P. Turning carbon dioxide into
fuel. Phil. Trans. R. Soc. A 368, 3343–3364 (2010).
NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry
© 2011 Macmillan Publishers Limited. All rights reserved.
613
ARTICLES
NATURE CHEMISTRY
22. Jessop, P. G., Ikariya, T. & Noyori, R. Homogeneous hydrogenation of carbon
dioxide. Chem. Rev. 95, 259–272 (1995).
23. Leitner, W. Carbon dioxide as a raw material: the synthesis of formic acid and its
derivatives from CO2. Angew. Chem. Int. Ed. 34, 2207–2221 (1995).
24. Jessop, P. G., Joó, F. & Tai, C. C. Recent advances in the homogeneous
hydrogenation of carbon dioxide. Coord. Chem. Rev. 248, 2425–2442 (2004).
25. Federsel, C., Jackstell, R. & Beller, M. State-of-the-art catalysts for hydrogenation
of carbon dioxide. Angew. Chem. Int. Ed. 49, 6254–6257 (2010).
26. Jessop, P. G., Hsiao, Y., Ikariya, T. & Noyori, R. Homogeneous catalysis in
supercritical fluids: hydrogenation of supercritical carbon dioxide to formic acid,
alkyl formates, and formamides. J. Am. Chem. Soc. 118, 344–355 (1996).
27. Yu, K. M. K., Yeung, C. M. Y. & Tsang, S. C. Carbon dioxide fixation into
chemicals (methyl formate) at high yields by surface coupling over a
Pd/Cu/ZnO nano catalyst. J. Am. Chem. Soc. 129, 6360–6361 (2007).
28. Federsel, C. et al. A well-defined iron catalyst for the reduction of bicarbonates
and carbon dioxide to formates, alkyl formates, and formamides. Angew. Chem.
Int. Ed. 49, 9777–9780 (2010).
29. Tanaka, R., Yamashita, M. & Nozaki, K. Catalytic hydrogenation of
carbon dioxide using Ir(III)–pincer complexes. J. Am. Chem. Soc. 131,
14168–14169 (2009).
30. Evans, J. W., Casey, P. S., Wainwright, M. S., Trimm, D. L. & Cant, N. W.
Hydrogenolysis of alkyl formates over a copper chromite catalyst. Appl. Catal.
7, 31–41 (1983).
31. Monti, D. M., Cant, N. W., Grimm, D. L. & Wainwright, M. S. Hydrogenolysis
of methyl formate over copper on silica. J. Catal. 100, 28–38 (1986).
32. Gormley, R. J., Rao, V. U. S. & Soong, Y. Methyl formate hydrogenolysis for
low-temperature methanol synthesis. Appl. Catal. A 87, 81–101 (1992) and
references therein.
33. Iwasa, N., Terashita, M., Arai, M. & Takezawa, N. New catalytic functions of Pd
and Pt catalysts for hydrogenolysis of methyl formate. React. Kinet. Catal. Lett.
74, 93–98 (2001) and references therein.
34. Monti, D. M., Kohler, M. A., Wainwright, M. S., Trimm, D. L. & Cant, N. W.
Liquid phase hydrogenolysis of methyl formate in a semi batch reactor.
Appl. Catal. 22, 123–136 (1986).
35. Sakakura, T. & Kohno, K. The synthesis of organic carbonates from carbon
dioxide. Chem. Commun. 45, 1312–1330 (2009).
36. Sakakura, T., Choi, J. C. & Yasuda, H. Transformation of carbon dioxide.
Chem. Rev. 107, 2365–2387 (2007).
37. Federsel, C., Jackstell, R., Boddien, A., Laurenczy, G. & Beller, M. Rutheniumcatalyzed hydrogenation of bicarbonate in water. ChemSusChem. 3,
1048–1050 (2010).
38. Abla, M., Choi, J. C. & Sakakura, T. Halogen-free process for the conversion of
carbon dioxide to urethanes by homogeneous catalysis. Chem. Commun. 37,
2238–2239 (2001).
39. Abla, M., Choi, J. C. & Sakakura, T. Nickel-catalyzed dehydrative transformation
of CO2 to urethanes. Green Chem. 6, 524–525 (2004).
40. Zhang, J., Leitus, G., Ben-David, Y. & Milstein, D. Facile conversion of alcohols
into esters and dihydrogen catalyzed by new ruthenium complexes. J. Am. Chem.
Soc. 127, 10840–10841 (2005).
614
DOI: 10.1038/NCHEM.1089
41. Gunanathan, C., Ben-David, Y. & Milstein, D. Direct synthesis of amides from
alcohols and amines with liberation of H2. Science. 317, 790–792 (2007).
42. Gnanaprakasam, B., Zhang, J. & Milstein, D. Direct synthesis of imines from
alcohols and amines with liberation of H2. Angew. Chem. Int. Ed. 49,
1468–1471 (2010).
43. Gnanaprakasam, B., Ben-David, Y. & Milstein, D. Ruthenium pincer-catalyzed
acylation of alcohols using esters with liberation of hydrogen under neutral
conditions. Adv. Syn. Cat. 352, 3169–3173 (2010).
44. Milstein, D. Discovery of environmentally benign catalytic reactions of alcohols
catalyzed by pyridine-based pincer Ru complexes, based on metal–ligand
cooperation. Top. Catal. 53, 915–923 (2010).
45. Langer, R., Leitus, G., Ben-David, Y. & Milstein, D. Efficient hydrogenation
of ketones catalyzed by an iron pincer complex. Angew. Chem. Int. Ed. 50,
2120–2124 (2011).
46. Gnanaprakasam, B. & Milstein, D. Synthesis of amides from esters and amines
with liberation of H2 under neutral conditions. J. Am. Chem. Soc. 133,
1682–1685 (2011).
47. Gunanathan, C. & Milstein, D. Selective synthesis of primary amines directly
from alcohols and ammonia. Angew. Chem. Int. Ed. 47, 8661–8664 (2008).
48. Gunanathan, C., Shimon, L. J. W. & Milstein, D. Direct conversion of alcohols
to acetals and H2 catalyzed by an acridine-based ruthenium pincer complex.
J. Am. Chem. Soc. 131, 3146–3147 (2009).
49. Kohl, S. W. et al. Consecutive thermal H2 and light-induced O2 evolution from
water promoted by a metal complex. Science 324, 74–77 (2009).
50. Olah, G. A., Geoppert, A. & Surya Prakash, G. K. Beyond Oil and Gas: The
Methanol Economy (Wiley-VCH, 2006).
51. Huang, Y. H. & Gladysz, J. A. Aldehyde and ketone ligands in organometallic
complexes and catalysis. J. Chem. Educ. 65, 298–303 (1988).
Acknowledgements
This research was supported by the European Research Council under the FP7 framework
(ERC no. 246837), by the Israel Science Foundation, and by the MINERVA Foundation.
D.M. is the Israel Matz Professorial Chair of Organic Chemistry.
Author contributions
E.B. carried out catalytic experiments, mechanistic studies and contributed to writing the
manuscript. C.G. carried out catalytic experiments and contributed to writing the
manuscript. J.Z. prepared and crystallized complex 3. L.J.W.S. conducted the X-ray
structural study of complex 3. D.M. carried out the design and direction of the project
and contributed to writing the manuscript.
Additional information
The authors declare no competing financial interests. Supplementary information
accompanies this paper on www.nature.com/naturechemistry, including synthesis and
X-ray structural determination of 3, mechanistic stoichiometric reactions, general
procedures for the catalytic hydrogenation reactions, and cif file for 3 (CCDC #826775)
and chemical compound information accompanies this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to D.M.
NATURE CHEMISTRY | VOL 3 | AUGUST 2011 | www.nature.com/naturechemistry
© 2011 Macmillan Publishers Limited. All rights reserved.
Communications
DOI: 10.1002/anie.201106612
Hydrogenation
Unprecedented Catalytic Hydrogenation of Urea Derivatives to
Amines and Methanol**
Ekambaram Balaraman, Yehoshoa Ben-David, and David Milstein*
Catalytic hydrogenation of polar bonds, in particular organic
carbonyl groups, has captured considerable attention, because
it provides environmentally benign approaches to synthetically important building blocks, such as alcohols and amines.[1]
The ease of hydrogenation of carbonyl groups, in which
hydride transfer to the carbonyl carbon is involved, generally
corresponds to the electrophilicity of this carbon. The lower
electrophilicity of the carbonyl group, as a result of resonance
effects involving alkoxy or amido groups, makes hydrogenations of esters,[2] amides,[3] and even more so, carbonic acid
derivatives, such as organic carbonates, carbamates and urea
derivatives, very difficult (Figure 1). The common trend in the
reactivity of polar carbonyl groups towards hydrogenation
reactions
is
RC(O)H > RC(O)R’ @ RC(O)OR’ >
RC(O)NR2’ @> ROC(O)OR’ > ROC(O)NR2’ >
Figure 1. Resonance forms of urea derivatives.
R2NC(O)N2R’,[3d] urea derivatives being the most challenging. Indeed, as far as we know, catalytic hydrogenation of urea
derivatives has never been reported, be it under heterogeneous or homogeneous catalysis. In fact, alkyl urea compounds have been used as solvents in catalytic hydrogenation
reactions. For example, rhodium-catalyzed hydrogenation of
carbon monoxide to ethylene glycol under very high pressure
(p(H2) = 200 bar) and at elevated temperature (200 8C) using
N,N,N’,N’-tetramethylurea (TMU) as an inert solvent was
reported.[4] In addition, sugar-urea-salt melts were used as
“green solvents” for Rh-catalyzed hydrogenation reactions
and found to be sustainable reaction media.[5]
[*] Dr. E. Balaraman, Y. Ben-David, Prof. D. Milstein
Department of Organic Chemistry
The Weizmann Institute of Science, 76100 Rehovot (Israel)
E-mail: [email protected]
Homepage: http://www.weizmann.ac.il/Organic_Chemistry/milstein.shtml
[**] This research was supported by the European Research Council
under the FP7 framework, (ERC number 246837), by the Israel
Science Foundation, by the MINERVA Foundation, and by the
Kimmel Center for Molecular Design. D.M. is the holder of the Israel
Matz Professorial Chair of Organic Chemistry.
Supporting information, including the general procedure for the
catalytic hydrogenation reactions and spectroscopic data for
synthesized urea derivatives, for this article is available on the
WWW under http://dx.doi.org/10.1002/anie.201106612.
11702
Notably, alkyl and aryl urea compounds are readily
synthesized from reactions of amines with CO2 in the
presence of various catalysts, such as 1,8-diazabicyclo[5.4.0]undec-7-ene,[6] CsOH,[7] Cs2CO3,[8] Au/polymers,[9]
[Bmim]OH[10] or KOH/PEG1000,[11] and by using ionic
liquids, N-methylpyrrolidone, and supercritical carbon dioxide as solvents. Transition-metal-catalyzed synthesis of urea
derivatives was also reported.[12] Recently, Zhao et al.
reported the synthesis of dialkyl urea derivatives from CO2
and amines in the absence of any catalysts, organic solvents, or
other additives.[13] In this context, mild hydrogenation of urea
derivatives to methanol is very attractive, as it would
represent a mild, two-step hydrogenation of CO2 to methanol,
which is of intense current interest with regard to hydrogen
storage and “methanol economy”.[14, 15] Direct, heterogeneously catalyzed hydrogenation of CO2 to methanol requires
harsh conditions of temperature and pressure and suffers
from the formation of byproducts such as CO, hydrocarbons,
and higher alcohols, making this approach difficult.[16] Moreover, the direct hydrogenation of urea derivatives to the
corresponding amines and methanol can also provide an
alternative approach for amine protection chemistry,[17]
because amines can be protected as urea derivatives by
treatment with nontoxic, abundant CO2 under mild conditions.
We have developed several unique reactions catalyzed by
tridentate PNN and PNP Ru(II) pincer complexes based on
pyridine[2a, 18–19] and acridine[20] backbones. These complexes
show a new mode of metal–ligand cooperation based on
ligand aromatization–dearomatization, which has led to a
number of bond activation processes.[21]
Recently, hydrogenation of amides[3c] to
the corresponding alcohols and amines
by selective cleavage of the C N bond
under homogeneous conditions, catalyzed by the bipyridine-based pincer
complex 1 (Figure 2) was developed.
An analogous NHC complex is effective
in hydrogenation of nonactivated esters Figure 2. Bipyridylbased PNN Ru(II)
to the corresponding alcohols under pincer complex 1.
mild conditions.[2f] Complex 1 effectively catalyzes also the novel hydrogenation of organic carbonates to alcohols, organic carbamates to methanol and amines, and alkyl formates to
methanol and alcohols, which are of current interest with
regard to mild stepwise CO2 hydrogenation to methanol.[22]
Here we report the first example of catalytic hydrogenation of urea derivatives. Selective formation of methanol
and the corresponding amines takes place by the double
cleavage of the robust C N bonds under mild, neutral
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11702 –11705
Scheme 1. Hydrogenation of urea derivatives to methanol and amines.
conditions and with no generation of waste, using catalyst 1
(Scheme 1).
1,3-Dimethylurea was selected as a benchmark substrate
for the study of hydrogenation of alkyl ureas catalyzed by
complex 1. Treatment of 1,3-dimethylurea (1 mmol) and a
catalytic amount of complex 1 (1 mol %) with H2 (10 atm) at
110 8C in anhydrous THF resulted in 41 % conversion of
dimethylurea to yield methanol (35 % by GC) and methylamine after 48 h (Table 1, entry 1). The gaseous amine was
characterized by GC-MS of the gas phase of the reaction
mixture and not quantified. A longer reaction time and higher
Table 1: Hydrogenation of 1,3-dimethylurea to methanol and methylamine catalyzed by 1.
Entry Catalyst 1
[mol %]
Reaction conditions[a]
p(H2) [atm] t [h] Conversion [%][b] Yield of
MeOH [%][b,c]
1
2
3
4
1
1
1
2
10
10
13.6
13.6
48
72
72
72
41
53
61
96
35
52
57
93
[a] Complex 1, 1,3-dimethylurea (1 mmol), H2, and anhydrous THF
(2 mL) were heated in a Fischer–Porter tube (100 mL) at 110 8C (bath
temperature) for the specified time. [b] Conversion of 1,3-dimethylurea
and yields of methanol were determined by GC using m-xylene as an
internal standard. [c] MeNH2 was detected in the gas phase (as well as in
liquid phase) by GC-MS and not quantified.
hydrogen pressure resulted in improved conversion of
dimethylurea and yield of methanol (Table 1, entries 2 and
3). Performing the same reaction under 13.6 atm of H2 and
2 mol % of catalyst resulted in a 93 % yield of methanol after
72 h (Table 1, entry 4).
Various alkyl and aryl urea derivatives were subjected to
hydrogenation at 13.6 atm of hydrogen (Table 2). Hydrogenation of 1,3-dihexylurea yielded methanol and 1-hexylamine in 83 and 87 % yields, respectively, after 72 h (Table 2,
entry 2). As expected, the activated urea, 1,3-bis(2-methoxyethyl)urea gave almost quantitative conversion to methanol
and 2-methoxyethylamine upon hydrogenation (Table 2,
entry 3). Dibenzylurea derivatives underwent hydrogenation
in moderate yields (Table 2, entries 5–7), giving methanol,
benzyl amines, as well as trace amounts of the corresponding
benzyl formamides (detected by GC-MS). Fluoro-dibenzylurea did not undergo defluorination during the hydrogenation (Table 2, entry 7). The hydrogenation of 1,3-diarylurea
Angew. Chem. Int. Ed. 2011, 50, 11702 –11705
derivatives proceeded very smoothly to yield methanol and
the corresponding aniline derivatives (Table 2, entries 8 and
9). Thus, upon heating a THF solution of 1 (0.02 mmol) and
1,3-diphenylurea (1 mmol) at 110 8C under H2 (12 atm),
complete conversion took place to selectively form methanol
and aniline in 90 % and 95 % yields, respectively (Table 2,
entry 8). Performing the same reaction with a lower catalyst
loading (1 mol % of 1) gave moderate yields of methanol
(63 %) and aniline (69 %). Even the more sterically hindered
tetra-substituted urea derivatives were selectively hydrogenated to yield methanol and the corresponding secondary
amines. Thus, heating a THF solution containing 1,1’,3,3’tetramethylurea (1 mmol) and a catalytic amount of complex 1 (2 mol %) under hydrogen pressure (13.6 atm) at
110 8C for 72 h resulted in a 53 % conversion of tetramethylurea (TMU) to methanol (46 %) and N,N’-dimethylamine
(Table 2, entry 10); the lower conversion is probably a result
of steric reasons. In the case of bis(pentamethylene)urea,
63 % yield of methanol, and 57 % of piperidine (Table 2,
entry 11) were obtained. Traces of the corresponding dialkyl
formamides were also observed in these cases. Although
moderate yields were obtained for the hydrogenation of tetrasubstituted urea, these compounds have been used as inert
polar solvents for hydrogenation reaction under very high
hydrogen pressure, without undergoing hydrogenation.[4]
The observation of traces of formamides (Table 2,
entries 5–6 and 10–11) suggests a stepwise hydrogenation
reaction, in which a formamide along with one equivalent of
amine is initially formed by the cleavage of a C N bond,
followed by fast hydrogenation of the formamide, which does
not accumulate.[23] In support of faster hydrogenation of
formamides as compared with the starting urea derivatives,
heating a THF solution of complex 1 (0.02 mmol), bis(pentamethylene)urea and N-formylmorpholine (1 mmol each) at
110 8C for 12 h under H2 (13.6 atm), resulted in almost
complete conversion of N-formylmorpholine (to 89 % yield
of morpholine and 93 % yield of methanol) and very low
conversion (< 2 %) of bis(pentamethylene)urea (to piperidine and methanol; Scheme 2). In addition, partial hydrogenation of bis(pentamethylene)urea did not lead to accu-
Scheme 2. Competitive hydrogenation of formamide- and urea- derivatives (conversion of N-formylmorpholine = 95 %, conversion of bis(pentamethylene)urea 2 %).
mulation of the corresponding formamide; only methanol and
piperidine (31 % and 37 % yields, respectively) were formed
after 36 h under 13.6 atm of H2 and 2 mol % of catalyst 1.
Stepwise hydrogenation was also observed by us in the
hydrogenation of organic carbonates to methanol.[22]
In conclusion, hydrogenation of urea derivatives to the
corresponding amines and methanol was achieved for the first
time. The reaction is selectively catalyzed by a bipyridine-
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
11703
Communications
Table 2: Hydrogenation of urea derivatives to amines and methanol catalyzed by complex 1.[a]
Entry
Urea derivative
MeOH (yield [%][b])
Product
Amine
Yield [%][b]
1[c]
89
2
83
87
3
94
97
4
73
79
5[d]
61
60
6[d]
67
71
7
58
59
8[e]
90
63[f ]
95
69[f ]
9[e]
93
87
10[c,d]
46
11[d]
63
(CH3)2NH
57
[a] Complex 1 (0.02 mmol), urea derivative (1 mmol), H2 (13.6 atm) and anhydrous THF (2 mL) were heated in a Fischer–Porter tube (100 mL) at
110 8C (bath temperature) for 72 h (most of the reactions were repeated twice). [b] Yields of products were determined by GC (using 1 mmol of mxylene as an internal standard). [c] The amines n-propylamine and Me2NH (entries 1 and 10, respectively) were analyzed in the gas phase (as well as in
the liquid phase) by GC-MS and not quantified. [d] The corresponding formamides (entries 5–6 and 10–11) were observed by GC-MS and not
quantified. [e] p(H2) = 12 atm. [f] Complex 1 (0.01 mmol), 1,3-diphenylurea (1 mmol), H2 (13.6 atm), and anhydrous THF (2 mL) were heated at
110 8C for 72 h.
based PNN Ru(II) pincer complex under mild hydrogen
pressure and neutral reaction conditions. As alkyl and aryl
urea derivatives are readily obtained from CO2 and amines,
their hydrogenation offers an environmentally benign, mild,
atom economical approach to the indirect transformation of
CO2 to methanol, which is of intense current interest with
regard to hydrogen storage and “methanol economy”.
Received: September 17, 2011
Published online: November 3, 2011
11704
www.angewandte.org
.
Keywords: catalysis · hydrogenation · methanol ·
pincer complexes · urea derivatives
[1] a) S. E. Clapham, A. Hadzovic, R. H. Morris, Coord. Chem. Rev.
2004, 248, 2201 – 2237; b) M. Ito, T. Ikariya, Chem. Commun.
2007, 5134 – 5142; c) O. W. W. N, A. J. Lough, R. H. Morris,
Chem. Commun. 2010, 46, 8240 – 8242.
[2] a) J. Zhang, G. Leitus, Y. Ben-David, D. Milstein, Angew. Chem.
2006, 118, 1131 – 1133; Angew. Chem. Int. Ed. 2006, 45, 1113 –
1115; b) L. A. Saudan, C. M. Saudan, C. Debieux, P. Wyss,
Angew. Chem. 2007, 119, 7617 – 7620; Angew. Chem. Int. Ed.
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11702 –11705
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
2007, 46, 7473 – 7476; c) S. Takebayashi, S. H. Bergens, Organometallics 2009, 28, 2349 – 2351; d) W. Kuriyama, Y. Ino, O. Ogata,
N. Sayo, T. Saito, Adv. Synth. Catal. 2010, 352, 92 – 96; e) Y. Ino,
W. Kuriyama, O. Ogata, T. Matsumoto, Top. Catal. 2010, 53,
1019 – 1024; f) E. Fogler, E. Balaraman, Y. Ben-David, G. Leitus,
L. J. W. Shimon, D. Milstein, Organometallics 2011, 30, 3826 –
3833, and references therein; g) Y. Sun, C. Koehler, R. Tan, V. T.
Annibale, D. Song, Chem. Commun. 2011, 47, 8349 – 8351.
a) A. A. NfflÇez Magro, G. R. Eastham, D. J. Cole-Hamilton,
Chem. Commun. 2007, 3154 – 3156; b) E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon, D. Milstein, J. Am. Chem. Soc.
2010, 132, 16756 – 16758; c) M. Ito, T. Ootsuka, R. Watari, A.
Shiibashi, A. Himizu, T. Ikariya, J. Am. Chem. Soc. 2011, 133,
4240 – 4242; d) J. M. John, S. H. Bergens, Angew. Chem. 2011,
123, 10561 – 10564; Angew. Chem. Int. Ed. 2011, 50, 10377 –
10380.
Y. Ohgomori, S. Mori, S. Yoshida, Y. Watanabe, J. Mol. Cat.
1987, 40, 223 – 228.
G. Imperato, S. Hçger, D. Lenoir, B. Kçnig, Green Chem. 2006,
8, 1051 – 1055.
C. F. Cooper, S. J. Falcone, Synth. Commun. 1995, 25, 2467 –
2474.
F. Shi, Y. Q. Deng, T. L. SiMa, J. J. Peng, Y. L. Gu, B. T. Qiao,
Angew. Chem. 2003, 115, 3379 – 3382; Angew. Chem. Int. Ed.
2003, 42, 3257 – 3259.
A. Ion, V. Parvulescu, P. Jacobs, D. De Vos, Green Chem. 2007, 9,
158 – 161.
F. Shi, Q. H. Zhang, Y. B. Ma, Y. D. He, Y. Q. Deng, J. Am.
Chem. Soc. 2005, 127, 4182 – 4183.
T. Jiang, X. M. Ma, Y. X. Zhou, S. G. Liang, J. C. Zhang, B. X.
Han, Green Chem. 2008, 10, 465 – 469.
D. L. Kong, L. N. He, J. Q. Wang, Synlett 2010, 1276 – 1280.
a) J. Fournier, C. Bruneau, P. H. Dixneuf, S. Lecolier, J. Org.
Chem. 1991, 56, 4456 – 4458; b) C. Tai, M. J. Huck, E. P.
McKoon, T. Woo, P. G. Jessop, J. Org. Chem. 2002, 67, 9070 –
9072.
C. Wu, H. Cheng, R. Liu, Q. Wang, Y. Hao, Y. Yu, F. Zhao, Green
Chem. 2010, 12, 1811 – 1816.
a) G. A. Olah, A. Goeppert, G. K. S. Prakash, Beyond Oil and
Gas: The Methanol Economy, Wiley-VCH, Weinheim, 2006;
b) G. A. Olah, Angew. Chem. 2005, 117, 2692 – 2696; Angew.
Chem. Int. Ed. 2005, 44, 2636 – 2639; c) G. A. Olah, A. Goeppert,
G. K. S. Prakash, J. Org. Chem. 2009, 74, 487 – 498.
M. Cokoja, C. Bruckmeier, B. Rieger, W. A. Herrmann, F. E.
Khn, Angew. Chem. 2011, 123, 8662 – 8690; Angew. Chem. Int.
Ed. 2011, 50, 8510 – 8537.
Recent reviews including hydrogenation of CO2 to MeOH: see
a) X. Liu, G. Q. Lu, Z. Yan, J. Beltramini, Ind. Eng. Chem. Res.
2003, 42, 6518 – 6530; b) J. Ma, N. N. Sun, X. L. Zhang, N. Zhao,
F. Xiao, F. K. Mao, W. Wei, Y. Sun, Catal. Today 2009, 148, 221 –
231; c) W. Wang, S. Wang, X. Ma, J. Gong, Chem. Soc. Rev. 2011,
40, 3703 – 3727.
Angew. Chem. Int. Ed. 2011, 50, 11702 –11705
[17] P. J. Kocienski, Protecting Groups, 3rd ed., Thieme, Stuttgart,
2005.
[18] For recent reviews: see a) D. Milstein, Top. Catal. 2010, 53, 915 –
923; b) C. Gunanathan, D. Milstein, Top. Organomet. Chem.
2011, 37, 55 – 84; c) C. Gunanathan, D. Milstein, Acc. Chem. Res.
2011, 44, 588 – 602.
[19] a) J. Zhang, M. Gandelman, L. J. W. Shimon, D. Milstein,
Organometallics 2004, 23, 4026 – 4033 (acceptorless dehydrogenation of secondary alcohols to ketones and hydrogen); b) J.
Zhang, G. Leitus, Y. Ben-David, D. Milstein, J. Am. Chem. Soc.
2005, 127, 10840 – 10841 (dehydrogenative coupling of primary
alcohols to esters with liberation of H2); c) J. Zhang, M.
Gandelman, L. J. W. Shimon, D. Milstein, Dalton Trans. 2007,
107 – 113 (dehydrogenation of alcohols); d) C. Gunanathan, Y.
Ben-David, D. Milstein, Science 2007, 317, 790 – 792 (novel
coupling of alcohols and amines to form amides and H2); e) B.
Gnanaprakasam, Y. Ben-David, D. Milstein, Adv. Synth. Catal.
2010, 352, 3169 – 3173 (acylation of alcohols using esters with
extraction of hydrogen); f) B. Gnanaprakasam, D. Milstein, J.
Am. Chem. Soc. 2011, 133, 1682 – 1685 (amide synthesis from
esters and amines); g) B. Gnanaprakasam, J. Zhang, D. Milstein,
Angew. Chem. 2010, 122, 1510 – 1513; Angew. Chem. Int. Ed.
2010, 49, 1468 – 1471 (dehydrogenative coupling of alcohols and
amines to form imines with liberation of H2 and H2O).
[20] a) C. Gunanathan, L. J. W. Shimon, D. Milstein, J. Am. Chem.
Soc. 2009, 131, 3146 – 3147 (direct conversion of alcohols to
acetals and H2); b) C. Gunanathan, D. Milstein, Angew. Chem.
2008, 120, 8789 – 8792; Angew. Chem. Int. Ed. 2008, 47, 8661 –
8664 (selective synthesis of primary amines directly from
alcohols and ammonia).
[21] a) S. W. Kohl, L. Weiner, L. Schwartsburd, L. Konstantinovski,
L. J. W. Shimon, Y. Ben-David, M. A. Iron, D. Milstein, Science
2009, 324, 74 – 77 (consecutive light-induced splitting of water to
dihydrogen and dioxygen); b) E. Khaskin, M. A. Iron, L. J. W.
Shimon, J. Zhang, D. Milstein, J. Am. Chem. Soc. 2010, 132,
8542 – 8543 (N H activation of amines and ammonia); c) C.
Gunanathan, B. Gnanaprakasam, M. A. Iron, L. J. W. Shimon,
D. Milstein, J. Am. Chem. Soc. 2010, 132, 14763 – 14765
(activation of H2 and NH3 by an acridine-based PNP Ru(II)
complex).
[22] E. Balaraman, C. Gunanathan, J. Zhang, L. J. W. Shimon, D
Milstein, Nat. Chem. 2011, 3, 609 – 614.
[23] Heating a THF solution containing N-formylmorpholine
(1 mmol) and a catalytic amount of complex 1 (2 mol %) under
hydrogen pressure (13.6 atm) using a pressure vessel at 110 8C
for 12 h resulted in quantitative conversion of N-formylmorpholine to methanol (91 %) and morpholine (95 %) without
decarbonylation of the formyl group. Thus, under our reaction
conditions the formamides undergo hydrogenation more readily
than urea derivatives. See also Ref. [3b].
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
11705
Published on Web 11/04/2010
Direct Hydrogenation of Amides to Alcohols and Amines under Mild
Conditions
Ekambaram Balaraman,† Boopathy Gnanaprakasam,† Linda J. W. Shimon,‡ and David Milstein*,†
Department of Organic Chemistry and Department of Chemical Research Support, Weizmann Institute of Science,
RehoVot, 76100, Israel
Received September 5, 2010; E-mail: [email protected]
Abstract: The selective, direct hydrogenation of amides to the
corresponding alcohols and amines with cleavage of the C-N
bond was discovered. The expected products of C-O cleavage
are not formed (except as traces in the case of anilides). The
reaction proceeds under mild pressure and neutral, homogeneous
conditions using a dearomatized, bipyridyl-based PNN Ru(II)
pincer complex as a catalyst. The postulated mechanism involves
metal-ligand cooperation by aromatization-dearomatization of
the heteroaromatic pincer core and does not involve hydrolytic
cleavage of the amide. The simplicity, generality, and efficiency
of this environmentally benign process make it attractive for the
direct transformations of amides to alcohols and amines in good
to excellent yields.
Reduction of carboxylic acids and their derivatives plays an
important role in organic synthesis, in both laboratory and industrial
processes. Traditionally, the reduction is performed using stochiometric
amounts of hydride reagents, generating stochiometric amounts of
waste.1 A much more attractive, atom-economical approach is a
catalytic reaction using H2; however, hydrogenation of carboxylic acid
derivatives under mild conditions is a very challenging task,2 with
amides presenting the highest challenge among all classes of carbonyl
compounds. Very few examples of the important hydrogenation of
amides to amines, in which the C-O bond is cleaved with the liberation
of water (Scheme 1), were reported.3 C-O cleavage of amides can
also be affected with silanes as reducing agents.4 In addition, the
interesting hydrogenation of cyclic N-acylcarbamates and N-acylsulfonamides, which involves cleavage of the C-N bond, but does not
form amines, was recently reported by Ikariya.5 On the other hand, to
the best of our knowledge, selective, direct hydrogenation of amides
to form amines and alcohols has not been reported.6 Amines and
alcohols are used extensively in the chemical, pharmaceutical, and
agrochemical industries.7 Design of such a reaction is conceptually
challenging, since the first mechanistic step in amide hydrogenation
is expected to be H2 addition to the carbonyl group to form a very
unstable hemiaminal which, in the case of primary or secondary
amides, spontaneously liberates water to form an imine; further
hydrogenation of the imine then leads to amine formation (Scheme
1). This is the basis of the amide hydrogenation mentioned above.
For amine and alcohol formation, cleavage of the C-N bond in
preference to the C-O bond would be required.
We have recently developed new catalytic reactions of alcohols,
based on a new mode of metal-ligand cooperation, involving
aromatization-dearomatization of pyridine-8 and acridine-derived9
pincer ligands. The dearomatized pyridine-based PNN Ru complex
†
‡
Department of Organic Chemistry.
Department of Chemical Research Support.
16756
9
J. AM. CHEM. SOC. 2010, 132, 16756–16758
Scheme 1. General Scheme for Hydrogenation of Amides
1 (Figure 1) efficiently catalyzes the dehydrogenative coupling of
alcohols to form esters,8b,d,h the hydrogenation of esters to alcohols
under mild conditions,8c,h and the novel coupling of alcohols and
amines to form amides and H2.8e,h The dearomatized PNP complex
2 is an efficient catalyst for the dehydrogenative coupling of alcohols
and amines to form imines.8f Complex 1 is also effective in N-H
activation10 and in the unique light-induced splitting of water to
hydrogen and oxygen.11
Figure 1. Dearomatized Ru-pincer complexes.
We have now prepared the new, dearomatized, bipyridine-based
pincer complex 3. Remarkably, 3 efficiently catalyzes the selective
hydrogenation of amides to form amines and alcohols (eq 1). The
reaction proceeds under mild pressure and neutral conditions, with
no additives being required. Since the reaction proceeds well under
anhydrous conditions, hydrolytic cleavage of the amide is not
involved in this process.
Reaction of the new, electron-rich tridentate ligand, BPy-tPNN
(5),12 with [RuHCl(PPh3)3(CO)] in THF at 65 °C for 8 h results in
substitution of the PPh3 ligands to yield the hydrido chloride pincer
complex 4.12 The fully characterized 4 gives rise to a singlet at
107.01 ppm in the 31P{1H}NMR spectrum, and the hydride ligand
appears as a doublet at -15.26 ppm (2JPH ) 24.6 Hz) in the 1H
NMR spectrum. The “arm” methylene protons give rise to signals
at 3.06 and 3.75 ppm (2JHH ) 16.8 Hz and 2JPH ) 10.2 Hz). The
carbonyl ligand appears as a doublet at 207.37 ppm (JPC ) 15.0
10.1021/ja1080019  2010 American Chemical Society
COMMUNICATIONS
Table 1. Hydrogenation of Amides to Alcohols and Amines
Selectively Catalyzed by BPy-PNN-Ru(II) Pincer Complex 3a
Figure 2. X-ray structure of complex 4 (50% probability level). Hydrogen
atoms (except hydride) were omitted for clarity. Selected bond distances
(Å): Ru1-N1 2.124(2), Ru1-N2 2.086(2), Ru1-P1 2.2859(7), Ru1-C20
1.861(3). Selected angles (deg): N2-Ru1-C20 173.34(10), N2-Ru1-H1
86.4(9), Cl1-Ru1-H1 170.4(9), N1-Ru1-P1 159.65(6).
Hz) in the 13C{1H}NMR spectrum. The structure of 4 was confirmed
by a single-crystal X-ray diffraction study (Figure 2), which reveals
a distorted octahedral geometry around the ruthenium center, with
the CO ligand coordinated trans to the central nitrogen atom of
the pincer system and the hydride trans to the chloride.
Deprotonation of complex 4 with KOtBu at -32 °C gave the
dearomatized, coordinatively unsaturated complex 3 in 94% yield (see
Supporting Information (SI)). The hydride ligand of the resulting
complex 3 exhibits a doublet at -20.93 ppm (2JPH ) 25.0 Hz) in the
1
H NMR spectrum. The “arm” vinylic proton appears as a singlet at
3.36 ppm and a doublet at 66.56 ppm (JPC ) 48.8 Hz) in the 13C{1H}
NMR spectrum, indicating formation of an anionic PNN system. The
CO ligand absorbs at 1907 cm-1 in the IR spectrum.
We have reported the dehydrogenative coupling of alcohols with
amines to form amides, catalyzed by complex 1, with liberation of
hydrogen gas.8e,h,13,14 Exploring whether it might be possible to reverse
this reaction by the application of H2 pressure, complexes 1-4 were
tested as catalysts for the hydrogenation of amides. Thus, upon
treatment of N-benzyl-2-methoxyacetamide with H2 (10 atm) at 110
°C (bath temperature) in dry THF for 48 h with a catalytic amount of
1 (1 mol %), 63% of 2-methoxyethanol and 62% of benzyl amine
were obtained. Performing the reaction at 140 °C using 1,4-dioxane
as solvent did not significantly improve the yield (alcohol yield 66%).
Although a modest yield was obtained, it was significant that the
reaction was selective and the corresponding secondary amine was
not formed. Under the same conditions complex 2 was inactive.8c
Importantly, employing complex 3 (1 mol %) as catalyst, hydrogenation of N-benzyl-2-methoxyacetamide under identical conditions (THF,
110 °C) resulted in considerably higher yields of 89% 2-methoxyethanol and 90% benzyl amine (Table 1, entry 1), with C-O
hydrogenolysis not taking place at all. Of practical significance, the
air-stable complex 4 (stable in air for at least 2 days) in the presence
of 1 equiv (relative to Ru) of base also efficiently catalyzes the
hydrogenation of amides to alcohols and amines, by generation of the
catalyst 3 in situ. Thus, upon heating a THF solution of 4 (0.01 mmol)
with KOtBu (0.01 mmol) and N-benzyl-2-methoxyacetamide (1 mmol)
at 110 °C under H2 (10 atm) for 48 h, 80% of alcohol and 82% of
amine were formed. No reaction took place in the absence of base.
Hydrogenation of N-hexyl-2-methoxyacetamide catalyzed by 3 yielded
2-methoxy ethanol and hexyl amine in 91% and 90% yields,
respectively (entry 2). Interestingly, N-hexyl-3-methyloxetane-3-carboxamide underwent hydrogenation to the alcohol and amine without
hydrogenolysis of the strained oxetane ring (entry 3). The heterocyclic
amide, N-hexylfuran-2-carboxamide, was hydrogenated to yield 69%
of furfuryl alcohol and 68% of hexylamine (entry 4). The aromatic
nonactivated amide, N-benzylbenzamide, was hydrogenated to benzyl
a
Complex 1, 2, or 3 (0.01 mmol), amide (1 mmol), H2 (10 atm), and
dry THF (2 mL) were heated in a Fischer-Porter tube at 110 °C (bath
temperature) for 48 h. b Yields of products were analyzed by GC
(m-xylene as internal standard). c 1,4-Dioxane (2 mL) at 140 °C. d 1
equiv (relative to Ru) of base was used. e The amines (EtNH2 and
MeNH2 for entries 6 and 7 respectively) were analyzed in the gas phase by
GC-MS. f In the reactions involving anilide derivatives (entries 9-12), trace
amounts of the corresponding secondary amines were detected by GC-MS.
g
0.5 mmol of bis-amide was used. h Yield after 32 h.
J. AM. CHEM. SOC.
9
VOL. 132, NO. 47, 2010 16757
COMMUNICATIONS
alcohol and benzyl amine (entry 5) in a lower yield (57%), probably
because of steric reasons. Significantly, the aliphatic nonactivated amides,
N-ethylacetamide and N-methylpropionamide, also underwent hydrogenation to yield the corresponding alcohols and amines (71% of ethanol and
ethylamine for entry 6 and 68% of n-propanol and methylamine for entry
7). The product gaseous amines were characterized by GC-MS of the gas
phase and not quantified. Anilide derivatives were converted into their
corresponding alcohols and aniline in excellent yields (91-95%; entries
9-12) along with trace amounts of the secondary amines (detected by
GC-MS) under similar conditions. The reaction is also effective for bisamides. Thus, N,N′-(ethane-1,2-diyl)bis(2-methoxyacetamide) (0.5 mmol)
was hydrogenated selectively to diamine (77%) and alcohol (78%) using
catalyst 3 without formation of monoamine-monoamide (entry 13).15
Noteworthy, tert-amides also underwent hydrogenation almost quantitatively to yield alcohols and secondary amines in equivalent amounts
(entries 14-16). Gratifyingly, heating a solution of N-formymorpholine
(1 mmol) and complex 3 in THF at 110 °C yielded after 32 h 97% of
methanol and 98% of morpholine, formyl decarbonylation not being
observed. These results highlight the substantial scope of the selective
hydrogenation of amides catalyzed by 3, or by the air-stable 4 with an
equivalent of base (which generates 3 in situ).
Figure 3. Postulated mechanism for hydrogenation of amides to amines
and alcohols catalyzed by complex 3.
On the basis of the above results and the known chemistry of the
pincer complexes 1 and 28,10 we propose the mechanism depicted in
Figure 3. Initially, dihydrogen addition by metal-ligand cooperation8,10,16
to complex 3 results in aromatization, to form the coordinatively
saturated, trans dihydride complex A, as reported for complex 1.8c
Decoordination of the pyridyl “arm” can provide a site for amide
coordination, to give the intermediate B. Subsequent hydride transfer
to the carbonyl group of the amide ligand leads to a hemiaminoxy
intermediate C, with no formation of free hemiaminal. Deprotonation
of the benzylic arm by the adjacent NH group leads to the amine
product and a dearomatized intermediate D, bearing a coordinated
aldehyde. H2 addition to D forms the aromatic dihydride E, followed
by hydride transfer to the aldehyde to generate the alkoxy intermediate
F. Deprotonation of the benzylic arm by the alkoxy ligand generates
the product alcohol and regenerates catalyst 3. The overall process
does not involve a change in the metal oxidation state. We postulate
that key to the success of this process is that it does not involve
intermediacy of free hemiaminal, avoiding water elimination to give
an imine and, subsequently, a secondary amine.
16758
J. AM. CHEM. SOC.
9
VOL. 132, NO. 47, 2010
In conclusion, amides can be selectively and directly hydrogenated to alcohols and amines (including under anhydrous conditions)
for the first time. The reaction proceeds under mild pressure and
neutral, homogeneous conditions using a BPy-PNN-Ru(II) hydride
pincer catalyst and dihydrogen by a mechanism involving
metal-ligand cooperation. This new catalytic protocol exhibits a
broad substrate scope providing a variety of amines and alcohols
in good to excellent yields.17 The analogous Py-PNN complex 1
is less efficient. The reasons for this are being explored.
Acknowledgment. This research was supported by the European
Research Council under the FP7 framework (ERC No 246837), by
the Israel Science Foundation, and by the Helen and Martin Kimmel
Center for Molecular Design. D.M. is the holder of the Israel Matz
Professorial Chair of Organic Chemistry.
Supporting Information Available: Experimental procedures and
X-ray data for complex 4 in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Seyden-Penne, J. Reductions by the Alumino and Borohydrides in Organic
Synthesis, 2nd ed.; Wiley-VCH: New York, 1997.
(2) (a) Rylander, P. M. Hydrogenation Methods; Academic Press: London,
1985. (b) Hartwig, J. Organotransition Metal Chemistry; University Science
Books: Sausalito, CA, 2010; pp 651-655.
(3) (a) Hirosawa, C.; Wakasa, N.; Fuchikami, T. Tetrahedron Lett. 1996, 37, 6749.
(b) Núñez Magro, A. A.; Eastham, G. R.; Cole-Hamilton, D. J. Chem.
Commun. 2007, 3154. (c) Beamson, G.; Papworth, A. J.; Philipps, C.; Smith,
A. M.; Whyman, R. AdV. Synth. Catal. 2010, 352, 869. (d) Beamson, G.;
Papworth, A. J.; Philipps, C.; Smith, A. M.; Whyman, R. J. Catal. 2010,
269, 93.
(4) (a) Fernandes, A. C.; Romao, C. C. J. Mol. Catal. A 2007, 272, 60. (b)
Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc.
2010, 132, 1770.
(5) Ito, M.; Koo, L. W.; Himizu, A.; Kobayashi, C.; Sakaguchi, A.; Ikariya,
T. Angew. Chem., Int. Ed. 2009, 48, 1324.
(6) Catalytic hydrogenation of amides to amines (Via C-O cleavage, generating
water) can be accompanied by hydrolytic C-N cleavage as a side reaction,
presumably resulting from catalytic hydrolysis of the amides to acids and
amines, followed by hydrogenation of the acids to alcohols: see refs 3b,c.
(7) (a) Lawrence, S. A. Amines: Synthesis, Properties and Applications;
Cambridge University Press: Cambridge, 2005. (b) Ricci, A. Amino Group
Chemistry: From Synthesis to the Life Sciences; Wiley-VCH: Weinheim,
2008. (c) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.;
Pavan Kumar, K. V. P. Chem. ReV. 2009, 109, 2551.
(8) (a) Zhang, J.; Gandelman, M.; Shimon, L. J. W.; Milstein, D. Organometallics 2004, 23, 4026. (b) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein,
D. J. Am. Chem. Soc. 2005, 127, 10840. (c) Zhang, J.; Leitus, G.; BenDavid, Y.; Milstein, D. Angew. Chem., Int. Ed. 2006, 45, 1113. (d) Zhang,
J.; Gandelman, M.; Shimon, L. J. W.; Milstein, D. Dalton Trans. 2007,
107. (e) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790. (f) Gnanaprakasam, B.; Zhang, J.; Milstein, D. Angew. Chem., Int.
Ed. 2010, 49, 1468. (g) Schwartsburd, L.; Iron, M. A.; Konstantinovski, Y.;
Diskin-Posner, Y.; Leitus, G.; Shimon, L. J. W.; Milstein, D. Organometallics 2010,
29, 3817. (h) Milstein, D. Top. Catal. 2010, 53, 915.
(9) (a) Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2009,
131, 3146. (b) Gunanathan, C.; Milstein, D. Angew. Chem., Int. Ed. 2008,
47, 8661. (c) Gunanathan, C.; Gnanaprakasam, B.; Iron, M. A.; Shimon,
L. J. W.; Milstein, D. J. Am. Chem. Soc. 2010, 132, 14763.
(10) Khaskin, E.; Iron, M. A.; Shimon, L. J. W.; Zhang, J.; Milstein, D. J. Am.
Chem. Soc. 2010, 132, 8542.
(11) Kohl, S. W.; Weiner, L.; Schwartsburd, L.; Konstantinovski, L.; Shimon,
L. J. W.; Ben-David, Y.; Iron, M. A.; Milstein, D. Science 2009, 324, 74.
(12) See SI for full details.
(13) Coupling of alcohols with amines to form amides and H2 reported after
our publication (ref 8e): (a) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am.
Chem. Soc. 2008, 130, 17672. (b) Zhang, Y.; Chen, C.; Ghosh, S. C.; Li,
Y.; Hong, S. H. Organometallics 2010, 29, 1374.
(14) Coupling of alcohols with amines to form amides using hydrogen
acceptors: (a) Zweifel, T.; Naubron, J. V.; Grützmacher, H. Angew. Chem.,
Int. Ed. 2009, 48, 559. (b) Watson, A. J. A.; Maxwell, A. C.; Williams,
J. M. J. Org. Lett. 2009, 11, 2667.
(15) The fact that the monoamine-monoamide was not observed, while some
starting diamide was still present, suggests that it reacts faster than the
diamide, perhaps as a result of coordination of the amine group.
(16) (a) Grützmacher, H. Angew. Chem., Int. Ed. 2008, 47, 1814. (b) van der
Vlugt, J. I.; Reek, J. N. H. Angew. Chem., Int. Ed. 2009, 48, 8832.
(17) Complex 3 catalyzes also amide formation by dehydrogenative coupling
of alcohols with amines: Balarman, E.; Milstein D. to be published.
JA1080019
View Online / Journal Homepage / Table of Contents for this issue
ChemComm
Dynamic Article Links
Cite this: Chem. Commun., 2012, 48, 1111–1113
COMMUNICATION
www.rsc.org/chemcomm
Efficient hydrogenation of biomass-derived cyclic di-esters to 1,2-diolsw
Downloaded by Weizmann Institute of Science on 06 January 2012
Published on 31 October 2011 on http://pubs.rsc.org | doi:10.1039/C1CC15778G
Ekambaram Balaraman, Eran Fogler and David Milstein*
Received 18th September 2011, Accepted 12th October 2011
DOI: 10.1039/c1cc15778g
The unprecedented homogeneous hydrogenation of cyclic
di-esters, in particular biomass-derived glycolide and lactide,
to the corresponding 1,2-diols is catalyzed by Ru(II) PNN (1)
and Ru(II) CNN (2) pincer complexes under mild hydrogen
pressure and (in the case of 1) neutral conditions. No racemization
was observed when a chiral di-ester was used.
The hydrogenation of esters to alcohols is an important
transformation and remains a challenging task in the context
of ‘‘green and sustainable chemistry (GSC)’’.1 There are
relatively few examples of catalytic hydrogenation of esters
to alcohols under mild conditions,1,2 which is a difficult process
due to the relatively low hydridophilicity (electrophilicity) of the
ester carbonyl functionality.2h,3 The complete catalytic hydrogenation of cyclic di-esters to the corresponding 1,2-diols,
which is expected to be even more difficult, has never been
reported, be it under heterogeneous or homogeneous conditions.
The activated ester dimethyl oxalate (DMO) is the most
widely reported benchmark substrate employed in studies of
homogeneously catalyzed ester hydrogenation to produce
1,2-diols.4 The majority of these reports describe only partial
hydrogenation (to methyl glutamate) rather than the complete
hydrogenation (to ethylene glycol) whilst complete hydrogenation requires high pressures and high temperatures. For
example, Matteoli et al.4b reported the homogeneous hydrogenation of oxalates to ethylene glycol (EG) with 82% yield under
a H2 pressure of B200 atm at 180 1C using Ru(CO)2(Ac)2(PBu3)
(Ac = acetate) as a catalyst. Elsevier et al. applied Ru-based
homogeneous catalysts in the hydrogenation of dimethyl oxalate;
an EG yield of 95% was obtained under B70 atm of H2 at
100 1C.4c Homogeneous hydrogenation of chiral methyl lactate to
propylene glycol was reported by Ino et al. using ruthenium
hydrido borohydride complexes based on bidentate phosphorus
and diamine ligands under P(H2) E 50 atm with 30–45%
yield.2f–g Ito et al. reported the Ru-catalyzed enantioselective
hydrogenation of racemic lactones to chiral diols via dynamic
kinetic resolution at 100 1C under 50 atm H2 in 2-propanol
containing 25 mol% of KOtBu.2h A few cases of catalytic hydrogenations of lactones to diols were reported.1b,2d–e,h,5 Here we
Department of Organic Chemistry, The Weizmann Institute of
Science, Rehovot 76100, Israel.
E-mail: [email protected]; Fax: +972 9346569;
Tel: +972 9342599
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1cc15778g
This journal is
c
The Royal Society of Chemistry 2012
report the first catalytic hydrogenation of cyclic di-esters to the
corresponding 1,2-diols.
Glycolides and lactides are important classes of cyclic di-esters
(di-lactones), produced from biomass sources such as glycolic
acid (derived from sugar cane) and lactic acid (from fermentation
of glucose), via self-esterification, and their efficient hydrogenation
can provide a mild approach to 1,2-diols, which are important
synthetic building blocks.6
Simple 1,2-diols, such as ethylene glycol (EG) and propylene
glycol (PG) are utilized as high value-added specialty chemical
intermediates, in the manufacture of biodegradable polyester
fibers, unsaturated polyester resins, antifreeze, pharmaceuticals
and other important products.7 Currently, these two vicinal
diols are industrially produced from petroleum-derived ethylene
and propylene via hydration of their corresponding epoxy
alkanes under forcing conditions.8 However, as crude oil
resources become limited, substitutes for petroleum feedstocks
are increasingly sought after; as such, the synthesis of 1,2-diols
from biomass-derived compounds is of great interest.9 Such
alternative methods which are selective, environmentally benign,
and proceed under mild reaction conditions with stable, welldefined catalysts are very desirable.
In studies towards the development of ‘green’, atom-economical
approaches for various catalytic organic transformations,10 we
have developed the acceptorless dehydrogenation of alcohols,11a
dehydrogenative coupling of primary alcohols to esters,11b,c
direct amidation of alcohols with amines,11d acylation of alcohols
using esters,11e amide synthesis from esters and amines,11f and
imines from alcohols and amines11g with liberation of molecular
hydrogen, and mild hydrogenation of non-activated esters.2c
These reactions are catalyzed by pyridine-based PNN [2-(di-tertbutylphosphinomethyl)-6-(diethylaminomethyl)pyridine] and
PNP [2,6-bis(di-tert- butylphosphinomethyl)pyridine] pincertype Ru(II) complexes. We have also reported the hydrogenation
of ketones12a and hydrogenation of CO2 and bicarbonate to
formate salts using PNP–Fe pincer complexes.12b Recently, we
illustrated the selective hydrogenation of amides to the corresponding alcohols and amines by C–N bond activation under
mild conditions, catalyzed by the new bipyridine-based pincer
complex 1.13 Complex 1 also effectively catalyzes the hydrogenations
of CO2– and CO– derived organic carbonates, formates and
carbamates to form methanol.14 The recently synthesized analogous
N-heterocyclic carbene complex 2 efficiently catalyzes the hydrogenation of simple esters to the corresponding alcohols.2i Here
we report that the biomass-derived glycolide and lactide
can selectively and efficiently be hydrogenated to the corresponding
Chem. Commun., 2012, 48, 1111–1113
1111
View Online
Table 2 Catalytic hydrogenation of lactide to propylene glycola
Solvent p(H2)/atm Time/h Yieldb (%)
Entry Catalyst Lactide
1
2
3c
4e
1
1
1
2
Meso
THF
Chiral (S,S) THF
Chiral (S,S) THF
Chiral (S,S) THF
10
10
50
50
48
48
12
12
87
82
91(73)d
67
Downloaded by Weizmann Institute of Science on 06 January 2012
Published on 31 October 2011 on http://pubs.rsc.org | doi:10.1039/C1CC15778G
a
Fig. 1 Bipyridine-based PNN (1) and CNN-Ru(II) (2) pincer
complexes.
1,2-diols under very mild conditions, with no generation
of waste.
The cyclic di-ester of glycolic acid, glycolide, was chosen as
a model substrate for the hydrogenation of cyclic di-esters
catalyzed by complexes 115 and 22i (Fig. 1). Heating a 1,4-dioxane
solution containing glycolide (1 mmol) and 1 mol% of
complex 1 under mild hydrogen pressure (6 atm) at 135 1C
(bath temperature) for 36 h resulted in formation of ethylene
glycol (EG) as the only product in 61% yield (Table 1, entry 1),
with 67% conversion of the glycolide. After removal of the solvent,
the obtained crude viscous liquid was analyzed by ESI (electrospray ionization mass spectrometry), showing no formation of
polymeric material.
Performing the same reaction under similar conditions using
10 atm of H2 resulted after 36 h in 88% of ethylene glycol
(Table 1, entry 2). Optimization studies revealed that lower
reaction temperatures could be employed using THF as
solvent. Thus, heating complex 1 (0.01 mmol) with glycolide
(1 mmol) and dihydrogen (10 atm) at 110 1C in 3 mL of dry
THF for 48 h in a Fisher–Porter tube yielded 93% of ethylene
Scheme 1 Catalytic hydrogenation of glycolide to ethylene glycol.
Table 1 Catalytic hydrogenation of glycolide to ethylene glycol (EG)
according to Scheme 1a
Entry Catalyst Solvent
p(H2)
Yield of
Temp. (1C) (atm) Time/h EGb (%)
1
2
3
4c
5d
6
135
135
110
110
110
110
1
1
1
1
2
2
1,4-Dioxane
1,4-Dioxane
THF
THF
THF
THF
6
10
10
50
10
10
36
36
48
12
48
48
61
88
93
85
58
0
a
Catalyst (0.01 mmol), glycolide (1 mmol), H2 and dry solvent (3 mL)
were heated in a Fischer–Porter tube at the specified (oil bath)
temperature. b Yields of ethylene glycol were determined by GC using
m-xylene as an internal standard. c Complex 1 (0.02 mmol), glycolide
(10 mmol) and THF (5 mL) were heated under H2 pressure in a highpressure reactor. d One equivalent (relative to Ru) of KOtBu was
added.
1112
Chem. Commun., 2012, 48, 1111–1113
Catalyst (0.01 mmol), meso or chiral lactide (1 mmol), H2 and dry
THF (3 mL) were heated in a Fischer–Porter tube at 110 1C (oil bath
temperature). b Yields of propylene glycol were analyzed by GC using
m-xylene as an internal standard. c Complex 1 (0.02 mmol), L-lactide
(10 mmol) and THF (5 mL) were heated under H2 pressure in a highpressure reactor. d Isolated yield. e One equivalent (relative to Ru) of
KOtBu was used.
glycol (Table 1, entry 3). Higher rates were obtained at higher
pressure; heating a THF solution of glycolide (10 mmol) and a
catalytic amount of complex 1 (0.02 mmol) at 110 1C under H2
(50 atm) using a high pressure reactor resulted after 12 h in the
selective formation of ethylene glycol in 85% yield (turnover
number 425) (Table 1, entry 4).
The bipyridine-based N-heterocyclic carbene complex 22i,16
in the presence of one equiv. of base (relative to Ru) also
catalyzed the hydrogenation of gylcolide to ethylene glycol.
Upon heating a THF solution of complex 2 (0.01 mmol) with
KOtBu (0.01 mmol) and gylcolide (1 mmol) at 110 1C under
H2 (10 atm) for 48 h, 58% of ethylene glycol was formed
(Table 1, entry 5). The reaction likely proceeds via the in situ
deprotonation of 2 to generate a dearomatized complex2i
which is the actual catalyst. In the absence of base, no reaction
was observed (Table 1, entry 6). Notably, in none of these
hydrogenation reactions did we observe (by GC and GC-MS)
any formation of partially hydrogenated products, even after
shorter reaction times.
The optimized catalytic conditions were employed in the
hydrogenation of lactide, the ester derivative of lactic acid
(a glucose fermentation product). Thus, upon hydrogenation
of meso-lactide with H2 (10 atm) at 110 1C in THF for 48 h
with 1 mol% of 1, propylene glycol (1,2-propanediol) was
obtained selectively in 87% yield (Table 2, entry 1).
Significantly, the hydrogenation of the chiral L-lactide catalyzed
by complex 1 yielded optically pure (S)-(+)-1,2-propanediol
as the sole product, without racemization even under high
pressure (Scheme 2). Thus, treatment of a THF solution (5 mL)
of L-lactide (10 mmol) with dihydrogen (50 atm) at 110 1C for 12 h
with a catalytic amount of 1 (0.02 mmol) selectively yielded 91%
of (S)-(+)-1,2-propanediol (Table 2, entry 3). After removal of the
solvent under reduced pressure, the reaction mixture was passed
through a short silica gel bed and the 1,2-diol was eluted with
CH2Cl2 : MeOH (10 : 1) and concentrated under vacuum to yield
73% of the optically pure 1,2-propanediol. The optical rotation of
Scheme 2 Hydrogenation of optically active L-lactide to (S)-(+)1,2-propanediol.
This journal is
c
The Royal Society of Chemistry 2012
Downloaded by Weizmann Institute of Science on 06 January 2012
Published on 31 October 2011 on http://pubs.rsc.org | doi:10.1039/C1CC15778G
View Online
the isolated 1,2-propanediol (([a]D22 = +27.51, in CHCl3) was
essentially the same as reported in the literature (+26.91).17
Complex 2 (0.2 mol%) in the presence of one equiv. of base
(relative to Ru) also catalyzed the hydrogenation of L-lactide to
optically pure 1,2-propanediol under the same conditions in 67%
yield. Thus, under these experimental conditions, no racemization
took place.17,18
In conclusion, for the first time, complete hydrogenation of
cyclic di-esters was accomplished. The biomass-derived glycolide
and lactide were selectively hydrogenated to the corresponding
1,2-diols, catalyzed by well-defined electron rich bipyridine-based
PNN and CNN Ru(II) pincer complexes. This offers an environmentally benign, atom economic approach to the indirect transformation of biomass to important synthetic building blocks,
ethylene glycol and propylene glycol. The reactions proceed under
mild, neutral homogeneous conditions (in the case of the CNN
complex, in the presence of catalytic base). Significantly, no
racemization took place when a chiral di-ester was used.
This research was supported by the European Research
Council under the FP7 framework (ERC No 246837), by the
Israel Science Foundation, by the MINERVA Foundation
and by the Helen and Martin Kimmel Center of Molecular
Design. D.M. holds the Israel Matz Professorial Chair of
Organic Chemistry.
4
5
6
7
8
9
10
Notes and references
1 (a) S. E. Clapham, A. Hadzovic and R. H. Morris, Coord. Chem.
Rev., 2004, 248, 2201–2237; (b) M. Ito and T. Ikariya, Chem.
Commun., 2007, 5134–5142; (c) W. W. N. O, A. J. Lough and
R. H. Morris, Chem. Commun., 2010, 46, 8240–8242.
2 (a) H. T. Teunissen and C. J. Elsevier, Chem. Commun., 1998,
1367–1368 (aromatic and aliphatic esters were hydrogenated in
hexafluoropropan-2-ol using in situ prepared ruthenium complexes
at 86 atm of H2 under basic conditions); (b) K. Nomura, H. Ogura
and Y. Imanishi, J. Mol. Catal. A: Chem., 2002, 178, 105–114 (methyl
phenylacetate was hydrogenated to a mixture of PhCH2CH2OH and
PhCH2CO2CH2CH2Ph using in situ prepared Ru catalyst and zinc
under 20 atm of H2); (c) J. Zhang, G. Leitus, Y. Ben-David and
D. Milstein, Angew. Chem., Int. Ed., 2006, 45, 1113–1115;
(d) L. A. Saudan, C. M. Saudan, C. Debieux and P. Wyss, Angew.
Chem., Int. Ed., 2007, 46, 7473–7476 (catalyzed by Ru N,P complexes,
P(H2) = 50 atm under very basic conditions (catalyst/base = 1/100);
(e) S. Takebayashi and S. H. Bergens, Organometallics, 2009, 28,
2349–2351; (f) W. Kuriyama, Y. Ino, O. Ogata, N. Sayo and T. Saito,
Adv. Synth. Catal., 2010, 352, 92–96; (g) Y. Ino, W. Kuriyama,
O. Ogata and T. Matsumoto, Top. Catal., 2010, 53, 1019–1024;
(h) M. Ito, T. Ootsuka, R. Watari, A. Shiibashi, A. Himizu and
T. Ikariya, J. Am. Chem. Soc., 2011, 133, 4240–4242; (i) E. Fogler,
E. Balaraman, Y. Ben-David, G. Leitus, L. J. W. Shimon and
D. Milstein, Organometallics, 2011, 30, 3826–3833; (j) Y. Sun,
C. Koehler, R. Tan, V. T. Annibale and D. Song, Chem. Commun.,
2011, 47, 8349–8351.
3 (a) A. J. McAlees and R. McCrindle, J. Chem. Soc., 1969,
2425–2435; (b) F. A. Carey and R. J. Sundberg, Advanced
This journal is
c
The Royal Society of Chemistry 2012
11
12
13
14
15
16
17
18
Organic Chemistry, Kluwer Academic/Plenum, New York,
4th edn, 2000.
(a) R. A. Grey, G. P. Pez and A. Wallo, J. Am. Chem. Soc., 1981,
103, 7536–7542; (b) U. Matteoli, G. Menchi, M. Bianchi,
P. Frediani and F. Piacenti, J. Organomet. Chem., 1995, 498,
177–186; (c) M. C. van Engelen, H. T. Teunissen, J. G. de Vries
and C. J. Elsevier, J. Mol. Catal. A: Chem., 2003, 206, 185–192 and
references therein; (d) B. Boardman, M. J. Hanton, H. van Rensburg
and R. P. Tooze, Chem. Commun., 2006, 2289–2291.
Y. Hara, H. Inagaki, S. Nishimura and K. Wada, Chem. Lett.,
1992, 1983–1986.
Heterogeneous hydrogenation of lactic acid to propylene glycol:
(a) R. D. Cortright, M. Sanchez–Castillo and J. A. Dumesic, Appl.
Catal., B, 2002, 39, 353–359 (Using 10 wt% of Cu/SiO2 as catalyst
at 200 1C and 0.72 MPa of hydrogen pressure, achieving 1,2propanediol with 88% selectivity, in addition to 2-hydroxy
propionaldehyde (3%), propionic acid (6%) and propyl alcohol
(3%) as by-products under vapor-phase conditions); (b) A. Primo,
P. Concepción and A. Corma, Chem. Commun., 2011, 47,
3613–3615 (Reaction conditions: 0.4 mol% of Ru (0.64%)/TiO2,
T = 150 1C, P(H2) = 32 bar, t E 18 h. The yield of propylene
glycol was B87%).
(a) G. H. Xu, Y. C. Li and H. J. Wang, Ind. Eng. Chem. Res., 1995,
34, 2371–2378; (b) J. Lauridsen, J. Am. Oil Chem. Soc., 1976, 53,
400–405.
T. Haas, B. Jaeger, R. Weber and S. F. Mitchell, Appl. Catal., A,
2005, 280, 83–88.
Heterogeneous hydrogenolysis of glycerol to propylene glycol and
ethylene glycol: (a) A. Yin, X. Guo, W. Dai and K. Fan, Green
Chem., 2009, 11, 1514–1516; (b) J. Zhou, L. Guo, X. Guo, J. Mao
and S. Zhang, Green Chem., 2010, 12, 1835–1843.
For recent reviews: see (a) D. Milstein, Top. Catal., 2010, 53,
915–923; (b) C. Gunanathan and D. Milstein, Top. Organomet.
Chem., 2011, 37, 55–84; (c) C. Gunanathan and D. Milstein, Acc.
Chem. Res., 2011, 44, 588–602.
(a) J. Zhang, M. Gandelman, L. J. W. Shimon and D. Milstein,
Organometallics, 2004, 23, 4026–4033; (b) J. Zhang, G. Leitus,
Y. Ben-David and D. Milstein, J. Am. Chem. Soc., 2005, 127,
10840–10841; (c) J. Zhang, M. Gandelman, L. J. W. Shimon and
D. Milstein, Dalton Trans., 2007, 107–113; (d) C. Gunanathan,
Y. Ben-David and D. Milstein, Science, 2007, 317, 790–792;
(e) B. Gnanaprakasam, Y. Ben-David and D. Milstein, Adv. Synth.
Catal., 2010, 352, 3169–3173; (f) B. Gnanaprakasam and
D. Milstein, J. Am. Chem. Soc., 2010, 133, 1682–1685;
(g) B. Gnanaprakasam, J. Zhang and D. Milstein, Angew. Chem.,
Int. Ed., 2010, 49, 1468–1471.
(a) R. Langer, G. Leitus, Y. Ben-David and D. Milstein, Angew.
Chem., Int. Ed., 2011, 50, 2120–2124; (b) R. Langer, Y. DiskinPosner, G. Leitus, L. J. W. Shimon, Y. Ben-David and D. Milstein,
Angew. Chem., Int. Ed., 2011, 50, 9948–9952.
E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon and
D. Milstein, J. Am. Chem. Soc., 2010, 132, 16756–16758.
E. Balaraman, C. Gunanathan, J. Zhang, L. J. W. Shimon and
D. Milstein, Nat. Chem., 2011, 3, 609–614.
Complex 1 also catalyzes the hydrogenation of simple non-activated
esters to the corresponding alcohols. Unpublished results.
Complex 2 is stable at 35 1C for about 3 months (under atmosphere
of N2) and stable at room temperature for about 4 days under open
air without decomposition. See ESIw for more details.
See ESIw for full details.
Minor racemization (B6%) was reported in the hydrogenation of
methyl L-lactate (ref. 2f–g).
Chem. Commun., 2012, 48, 1111–1113
1113
Communications
DOI: 10.1002/anie.201105876
Homogeneous Catalysis
Synthesis of Peptides and Pyrazines from b-Amino Alcohols through
Extrusion of H2 Catalyzed by Ruthenium Pincer Complexes: LigandControlled Selectivity**
Boopathy Gnanaprakasam, Ekambaram Balaraman, Yehoshoa Ben-David, and
David Milstein*
Peptides constitute one of the most important families of
compounds in chemistry and biology. Short peptides have
found intriguing biological and synthetic applications. For
example, the conformational rigidity of cyclic peptides makes
them attractive for drug discovery and biomedical research.[1]
Several cyclic peptides that show intriguing biological activity
are found in nature.[2] Cyclic peptides have been discovered
that are novel antibiotics,[3] enzyme inhibitors,[4] and receptor
antagonists. Among them are the smallest cyclopeptides, 2,5diketopiperazines derivatives, which are commonly found as
natural products.[5] These compounds exhibit high-affinity
binding to a large variety of receptors and show a broad range
of biological acitivities,[6] including antimicrobial, antitumoral, antiviral, and neuroprotective effects. 2,5-diketopiperazine derivatives are synthesized in solution or on the solid
phase from commercially available and appropriately protected chiral a-amino acids in processes that are usually not
atom-economical and generate considerable amounts of
waste. Large libraries of cyclic peptides are accessible through
solid-phase split-and-pool synthesis,[7] and various methods
were developed for their syntheses.[8] Very recently, the
synthesis of diketopiperazines from amino acids under
microwave irradiation was reported.[9] Green, atom-economical methods for the generation of peptides are highly
desirable.
We have developed several reactions catalyzed by PNN
and PNP RuII pincer complexes based on pyridine,[10, 11]
bipyridine,[12, 13] and acridine[14] and have discovered a new
mode of metal–ligand cooperation[15] based on ligand aromatization–dearomatization.[16] For example, the PNN RuII
pincer complex 1 (Scheme 1) catalyzes the direct synthesis
of amides from alcohols and amines with liberation of H2[17]
(Scheme 2, Eq. (1)). Several reports on amide formation by
[*] Dr. B. Gnanaprakasam, Dr. E. Balaraman, Y. Ben-David,
Prof. D. Milstein
Department of Organic Chemistry
Weizmann Institute of Science
76100 Rehovot, (Israel)
E-mail: [email protected]
Homepage: http://www.weizmann.ac.il/Organic_Chemistry/milstein.shtml
[**] This research was supported by the European Research Council
under the FP7 framework, (ERC No 246837), by the Israel Science
Foundation, and by the MINERVA Foundation. D.M. is the holder of
the Israel Matz Professorial Chair of Organic Chemistry.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105876.
12240
Scheme 1. PNN- and PNP-type pincer ruthenium complexes.
Scheme 2. Reactions of alcohols with amines catalyzed by complexes
1–3.
dehydrogenative coupling of amines with alcohols appeared
later.[18] Unlike complex 1, the analogous PNP complex 2 (or
complex 3 in the presence of an equivalent of base) catalyzes
the coupling of amines with alcohols to form imines rather
than amides with liberation of H2 and H2O (Scheme 2,
Eq. (2)).[19]
Herein we report a novel method for peptide synthesis,
which involves dehydrogenative coupling of b-amino alcohols
with extrusion of H2 catalyzed by complex 1. This environmentally benign and atom-economical reaction proceeds
under neutral reaction conditions without the use of toxic
reagents, activators, condensing agents, or other additives.
With the analogous PNP complex 2, a strikingly different
reaction takes place, which leads to pyrazines with extrusion
of H2 and H2O.
Initially, we were interested to see whether coupling of bamino alcohols with amines can be accomplished and whether
racemization would be involved. Reaction of (S)-2-amino-3phenylpropan-1-ol (4), benzylamine, and 1 mol % of the
catalyst 1 in toluene at reflux for six hours led to (S)-2-aminoN-benzyl-3-phenylpropanamide 5 in 58 % yield[20a] after
column chromatography (Scheme 3). The specific rotation
of amide 5 obtained from the catalysis is essentially the same
as reported[20b] (+ 16.08). The neutral reaction conditions
likely help to prevent racemization.
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244
Table 1: Synthesis of cyclic dipeptides from b-amino alcohols catalyzed
by complex 1.[a]
Entry
Scheme 3. Amidation of (S)-2-amino-3-phenylpropan-1-ol (4) with benzylamine catalyzed by 1.
Scheme 4. Peptide formation by dehydrogenative coupling of b-amino
alcohols.
Next, we explored the self-reactions of b-amino alcohols.
In principle, dehydrogenative coupling of b-amino alcohols
can lead to formation of both cyclic and linear peptides
(Scheme 4). Heating a 1,4-dioxane solution containing (S)(+)-2-amino-1-propanol (2 mmol) and 1 (1 mol %) to reflux
for 19 h in argon atmosphere resulted in 90 % conversion of
the amino alcohol, as determined by GC–MS. Solvent
evaporation, dilution of the residue with CH2Cl2, separation
of an insoluble solid by filtration, and drying under vacuum
gave 72 % poly(alanine) 6 (R = Me in Scheme 4) containing a
minor quantity of the cyclic dimer 3,6-dimethylpiperazine2,5-dione 7 a[21] (R = Me in Scheme 4, Table 1, entry 1). The
products were characterized by NMR spectroscopy and mass
spectrometry. The characteristic peak at 174.9 ppm in the
13
C{1H} NMR spectrum of 6 indicates the presence of a
carbonyl group. The specific rotation of the product in acetic
acid was 1058. The ESI mass spectrum revealed the
formation of a linear polypeptide sequence. The peak with
the highest mass-to-charge ratio found by MALDI-TOF
spectrometry was at m/z 1644, which corresponds to 23
monomer units (see the Supporting Information).
Interestingly, larger substituents in a-position to the
amine group lead to the formation of the corresponding
cyclic dipeptides as the only products under the same reaction
conditions. Thus, a 1,4-dioxane solution of (S)-2-amino-4methylpentan-1-ol heated to reflux with complex 1 (1 mol %)
led to isolation of the cyclic dipeptide 3S,6S-3,6-diisobutylpiperazine-2,5-dione (7 b) in 64 % yield after workup
(Table 1, entry 2).[22] The product structure was confirmed
by NMR spectroscopy and mass spectrometry (see the
Supporting Information). The optical rotation (½a20
D ¼478)
was very close to the reported value (438), thus indicating
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244
b-Amino alcohol
Yield[b] [%]
Peptide
1
6
72[c]
2
7b
64
3
7c
72
4
7d
78
5
7e
72
6
7f
92
7
7g
99
[a] Complex 1 (0.02 mmol), amino alcohol (2 mmol), and 1,4-dioxane
(2 mL) were heated to reflux in argon (oil bath temperature of 135 8C) for
19 h. [b] Yield of isolated product. [c] Including a minor amount of the
dipeptide 7 a.
that no racemization had taken place.[23] A lower yield of 7 b
(52 %) was obtained in toluene as a solvent. Similarly, the use
of benzene as a solvent resulted in 48 % yield after 26 h. The
melting point of the cyclic dipeptide 7 b was 272 8C, as
reported.[23]
In contrast to traditional peptide syntheses, which include
both solid- and solution-phase methods and produce waste,
during this reaction only H2 is formed as a by-product.
Activated esters or carboxylic acids or the use of microwave
conditions are not required.
To explore the synthetic utility of this reaction, various bamino alcohols were studied. A 1,4-dioxane solution containing (2S,3S)-2-amino-3-methylpentan-1-ol (2 mmol) and catalyst 1 (0.02 mmol) was heated to reflux for 19 h and then
cooled to room temperature; subsequently the solid product
precipitated, was filtered off, and was dried under vacuum to
give pure 3-(sec-butyl)-6-(sec-butyl)piperazine-2,5-dione 7 c
in 72 % yield (Table 1, entry 3). The structure was confirmed
by NMR spectroscopy and mass spectrometry. Under the
same conditions, (S)-2-amino-3-methylbutan-1-ol yielded an
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
12241
Communications
insoluble solid, which precipitated from the reaction mixture
and was isolated by filtration and dried under vacuum to give
78 % of (3S,6S)-3,6-diisopropylpiperazine-2,5-dione 7 d
(Table 1, entry 4). The optical rotation of the pure product
(528) was essentially the same as reported[24] (54.88). Thus,
under the described experimental conditions, no racemization
took place.
The reaction of (S)-2-amino-3-phenylpropan-1-ol and 1 in
1,4-dioxane at reflux led to 90 % conversion and isolation of
the
corresponding
(3S,6S)-3,6-dibenzylpiperazine-2,5dione[24] 7 e in 72 % yield without racemization (Table 1,
entry 5 and the Supporting Information). The reaction of 2amino-2-methylpropan-1-ol under the same conditions gave
100 % conversion with isolation of the corresponding cyclic
dipeptide 3,3,6,6-tetramethylpiperazine-2,5-dione 7 f in 92 %
yield (Table 1, entry 6).
Tricyclic ring systems represent an important structural
motif in many naturally existing alkaloids. Such a ring system
was readily achieved when (S)-pyrrolidin-2-yl-methanol was
employed in the new cyclopeptidation reaction. Thus, heating
a 1,4-dioxane solution of (S)-pyrrolidin-2-yl-methanol at
reflux in the presence of catalyst 1 led to 100 % conversion
of the starting material as determined by GC–MS. After
solvent evaporation and subsequent hexane addition to the
crude solid, the solid was isolated by filtration and washed
with hexane to give optically pure (5aS,10aS)-octahydrodipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione[23] 7 g in 99 % yield
(Table 1, entry 7).
Pyrazines are biologically important organic compounds
and their synthesis[25] is of industrial significance. Interestingly, when RuII PNP complex 2 or 3 in the presence of an
equivalent amount of base was used as catalyst, an entirely
different reaction took place, which led to pyrazine derivatives of b-amino alcohols rather than to diketopiperazines
(Scheme 5). Thus, a toluene solution of isoleucinol with
Scheme 5. Synthesis of pyrazines from b-amino alcohols.
complex 2 (1 mol %) was heated to vigorous reflux in argon
for 24 h, while the reaction progress was monitored by GC–
MS, which showed complete conversion of isoleucinol. The
solvent was evaporated under vacuum and the residue was
purified by silica-gel column chromatography to afford 2,6diisobutylpyrazine 8 a in 53 % yield (Table 2, entry 1). In
refluxing 1,4-dioxane, 40 % conversion of the starting material was observed, yielding 15 % of the product 8 a after 24 h.
The 1H NMR spectrum exhibits the characteristic aromatic
CH signals at 8.27 ppm, and GC–MS confirms the expected
molecular weight. The same reaction conducted in open air
atmosphere in the presence of complex 2 resulted in isolation
of 8 a in 48 % yield. The reaction of isoleucinol in air using
complex 3 in the presence of one equivalent of base (relative
12242
www.angewandte.org
Table 2: Synthesis of pyrazines from b-amino alcohols catalyzed by
complex 2.[a]
Entry
b-Amino alcohols
Yield[b] [%]
Pyrazines
1
8a
53
(48)[c]
2
8b
35
3[d]
8c
38
4
8d
45
[a] Complex 2 (0.02 mmol), an amino alcohol (2 mmol), and toluene
(2 mL) were heated at vigorous reflux (oil bath temperature 165 8C for
24 h). [b] Yield of isolated product. [c] Reaction performed in air (see the
Supporting Information for details). [d] Heated in absence of solvent (oil
bath temperature at 165 8C).
to Ru) under the same reaction conditions resulted in
isolation of 8 a in 50 % yield. The similar yields of 8 a obtained
after reaction in argon and in air indicate that air does not
play a role as oxidant in the dehydrogenation of the presumed
intermediate 1,4-dihydropyrazine to form the pyrazine. Significantly, no cyclic dipeptide was obtained under these
conditions. Similar results were obtained with other amino
alcohols. Thus, toluene solutions of (S)-2-amino-3-methylbutan-1-ol, (S)-2-amino-4-methylpentan-1-ol, and (S)-2-amino2-phenylethanol were heated at vigorous reflux (bath temperature 165 8C) for 24 h while the reaction progress was
monitored by GC–MS. After complete disappearance of the
amino alcohol, the crude product was purified by column
chromatography to give the corresponding pyrazine products
8 b–d[26, 27] (Table 2).
Although mechanistic studies have not been carried out,
we believe that first, OH activation of the alcohol by
complexes 1 or 2 results in aromatization of the pincer
complex. Then H2 liberation leads to the formation of a
coordinated aldehyde complex. A sequence involving nucleophilic attack by the amine group of a second amino alcohol
molecule on the aldehyde, which is coordinated to the PNN
complex 1, would eventually result in a peptide. In the case of
the bulky PNP complex 2, which lacks a hemilabile amine
“arm”, dissociation of the aldehyde and attack on it by the
amino alcohol take place in solution, resulting in an imine (by
water liberation from a hemiaminal), eventually leading to a
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244
pyrazine after aromatization of a presumed 1,4-dihydropyrazine intermediate.
In summary, a new method for peptide-bond formation, in
particular selective formation of cyclic dipeptides, and of
poly(alanine), was developed using dehydrogenative selfcoupling of b-amino alcohols. The reactions are catalyzed by
the dearomatized PNN complex 1 and lead to a variety of
biologically important cyclic dipeptides. In striking contrast,
the closely related dearomatized PNP complex 2 selectively
catalyzes the dehydrogenative coupling of b-amino alcohols
to form pyrazines. These unprecedented reactions proceed
under neutral reaction conditions and generate no waste,
thereby representing a clear departure from traditional
synthetic methodology.
Received: August 19, 2011
Revised: October 4, 2011
Published online: October 26, 2011
[9]
[10]
[11]
[12]
.
Keywords: dehydrogenation · homogeneous catalysis ·
peptides · pyrazines · ruthenium
[13]
[14]
[1] S. Liu, W. Gu, D. Lo, X. Ding, M. Ujiki, T. E. Adrian, G. A. Soff,
R. B. Silverman, J. Med. Chem. 2005, 48, 3630 – 3638.
[2] Y. Hamada, T. Shioiri, Chem. Rev. 2005, 105, 4441 – 4482.
[3] For examples see: a) S. Fernandez-Lopez, H. S. Kim, E. C. Choi,
M. Delgado, J. R. Granja, A. Khasanov, K. Kraehenbuehl, G.
Long, D. A. Weinberger, K. M. Wilcoxen, M. R. Ghadiri, Nature
2001, 412, 452 – 456; b) R. M. Kohli, C. T. Walsh, M. D. Burkart,
Nature 2002, 418, 658 – 661; c) C. Qin, X. Bu, X. Zhong, N. L. J.
Ng, Z. J. Guo, J. Comb. Chem. 2004, 6, 398 – 406; d) V. Dartois, J.
Sanchez-Quesada, E. Cabezas, E. Chi, C. Dubbelde, C. Dunn, J.
Granja, C. Gritzen, D. Weinberger, M. R. Ghadiri, T. R.
Parr, Jr., Antimicrob. Agents Chemother. 2005, 49, 3302 – 3310.
[4] For examples see: a) J. D. McBride, H. N. Freeman, G. J.
Domingo, R. J. Leatherbarrow, J. Mol. Biol. 1996, 259, 819 –
827; b) J. Eichler, A. W. Lucka, C. Pinilla, R. A. Houghten,
Mol. Diversity 1996, 1, 233 – 240; c) D. R. March, G. Abbenante,
D. A. Bergman, R. R. Brinkworth, W. Wickramasinghe, J.
Begun, J. L. Martin, D. P. Fairlie, J. Am. Chem. Soc. 1996, 118,
3375 – 3379; d) T. Bratkovič, M. Lunder, T. Popovic, S. Kreft, B.
Turk, B. Strukelj, U. Urleb, Biochem. Biophys. Res. Commun.
2005, 332, 897 – 903.
[5] C. Prasad, Peptides 1995, 16, 151 – 164.
[6] a) Recent review: M. B. Martins, I. Carvalho, Tetrahedron 2007,
63, 9923 – 9932; b) D. R. Houston, B. Synstad, V. G. H. Eijsink,
M. J. R. Stark, I. M. Eggleston, D. M. F. van Aalten, J. Med.
Chem. 2004, 47, 5713 – 5720; c) C. J. M. Graz, G. D. Grant, S. C.
Brauns, A. Hunt, H. Jamie, P. J. Milne, J. Pharm. Pharmacol.
2000, 52, 75 – 82; d) K. R. C. Prakash, Y. Tang, A. P. Kozikowski,
J. L. Flippen-Anderson, S. M. Knoblach, A. I. Faden, Bioorg.
Med. Chem. 2002, 10, 3043 – 3048.
[7] a) K. S. Lam, S. E. Salmon, E. M. Hersh, V. J. Hruby, W. M.
Kazmierski, R. J. Knapp, Nature 1991, 354, 82 – 84; b) R. A.
Houghten, C. Pinilla, S. E. Blondelle, J. R. Appel, C. T. Dooley,
J. H. Cuervo, Nature 1991, 354, 84 – 86; c) A. Furka, F.
Sebestyen, M. Asgedom, G. Dibo, Int. J. Pept. Protein Res.
1991, 37, 487 – 493.
[8] a) P. M. J. Fischer, J. Pept. Sci. 2003, 9, 9 – 35; b) C. J. Dinsmore,
D. C. Beshore, Tetrahedron 2002, 58, 3297 – 3312; c) I. L. Rodionov, L. N. Rodionova, L. K. Baidakova, A. M. Romashko, T. A.
Balashova, V. T. Ivanov, Tetrahedron 2002, 58, 8515 – 8523; d) S.
Rajappa, M. V. Natekar, Adv. Heterocycl. Chem. 1993, 57, 187 –
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
829; e) T. Ueda, M. Saito, T. Kato, N. Izumiya, Bull. Chem. Soc.
Jpn. 1983, 56, 568 – 572; f) K. Suzuki, Y. Sasaki, N. Endo, Y.
Mihara, Chem. Pharm. Bull. 1981, 29, 233 – 237; g) J. Eriksson,
P. I. Arvidsson, O. Davidsson, Chem. Eur. J. 1999, 5, 2356 – 2361;
h) S. Lee, T. Kanmera, H. Aoyagi, N. Izumiya, Int. J. Pept.
Protein Res. 1979, 13, 207 – 217.
K. A. Nonappa, M. Lahtinen, E. Kolehmainen, Green Chem.
2011, 13, 1203 – 1209.
a) J. Zhang, G. Leitus, Y. Ben-David, D. Milstein, J. Am. Chem.
Soc. 2005, 127, 10840 – 10841; b) J. Zhang, G. Leitus, Y. BenDavid, D. Milstein, Angew. Chem. 2006, 118, 1131 – 1133;
Angew. Chem. Int. Ed. 2006, 45, 1113 – 1115; c) B. Gnanaprakasam, Y. Ben-David, D. Milstein, Adv. Synth. Catal. 2010, 352,
3169 – 3173; d) B. Gnanaprakasam, D. Milstein, J. Am. Chem.
Soc. 2011, 133, 1682 – 1685.
a) J. Zhang, M. Gandelman, L. J. W. Shimon, D. Milstein,
Organometallics 2004, 23, 4026 – 4033; b) J. Zhang, M. Gandelman, L. J. W. Shimon, D. Milstein, Dalton Trans. 2007, 107 – 113.
a) E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon, D.
Milstein, J. Am. Chem. Soc. 2010, 132, 16756 – 16758; b) E.
Balaraman, C. Gunanathan, J. Zhang, L. J. W. Shimon, D
Milstein, Nat. Chem. 2011, 3, 609 – 614.
E. Fogler, E. Balaraman, Y. Ben-David, G. Leitus, L. J. W.
Shimon, D. Milstein, Organometallics 2011, 30, 3826 – 3833.
a) C. Gunanathan, L. J. W. Shimon, D. Milstein, J. Am. Chem.
Soc. 2009, 131, 3146 – 3147; b) C. Gunanathan, D. Milstein,
Angew. Chem. 2008, 120, 8789 – 8792; Angew. Chem. Int. Ed.
2008, 47, 8661 – 8664.
For recent reviews see: a) D. Milstein, Top. Catal. 2010, 53, 915 –
923; b) C. Gunanathan, D. Milstein, Top. Organomet. Chem.
2011, 37, 55 – 84; c) C. Gunanathan, D. Milstein, Acc. Chem. Res.
2011, 44, 588 – 602.
For examples see: a) S. W. Kohl, L. Weiner, L. Schwartsburd, L.
Konstantinovski, L. J. W. Shimon, Y. Ben-David, M. A. Iron, D.
Milstein, Science 2009, 324, 74 – 77; b) E. Khaskin, M. A. Iron,
L. J. W. Shimon, J. Zhang, D. Milstein, J. Am. Chem. Soc. 2010,
132, 8542 – 8543; c) C. Gunanathan, B. Gnanaprakasam, M. A.
Iron, L. J. W. Shimon, D. Milstein, J. Am. Chem. Soc. 2010, 132,
14763 – 14765.
C. Gunanathan, Y. Ben-David, D. Milstein, Science 2007, 317,
790 – 792.
a) L. U. Nordstrøm, H. Vogt, R. Madsen, J. Am. Chem. Soc.
2008, 130, 17 672 – 17 673; b) T. Zweifel, J. V. Naubron, H.
Grtzmacher, Angew. Chem. 2009, 121, 567 – 571; Angew.
Chem. Int. Ed. 2009, 48, 559 – 563; c) A. J. A. Watson, A. C.
Maxwell, J. M. J. Williams, Org. Lett. 2009, 11, 2667 – 2670;
d) S. C. Ghosh, S. Muthaiah, Y. Zhang, X. Xu, S. H. Hong, Adv.
Synth. Catal. 2009, 351, 2643 – 2649; e) K. Shimizu, K. Ohshima,
A. Satsuma, Chem. Eur. J. 2009, 15, 9977 – 9980; f) Y. Zhang, C.
Chen, S. C. Ghosh, Y. Li, S. H. Hong, Organometallics 2010, 29,
1374 – 1378; g) S. Muthaiah, S. C. Ghosh, J.-E. Jee, C. Chen, J.
Zhang, S. H. Hong, J. Org. Chem. 2010, 75, 3002 – 3006; h) H.
Zeng, Z. Guan, J. Am. Chem. Soc. 2011, 133, 1159 – 1161.
B. Gnanaprakasam, J. Zhang, D. Milstein, Angew. Chem. 2010,
122, 1510 – 1513; Angew. Chem. Int. Ed. 2010, 49, 1468 – 1471.
a) The dimerized product 7 e (35 %) was also isolated as an
insoluble material after the reaction; b) A. Basso, L. Banfi, R.
Riva, G. Guanti, J. Org. Chem. 2005, 70, 575 – 579.
V. A. Basyuk, T. Y. Gromovoi, A. A. Chuiko, V. A. Soloshonok,
V. P. Kukhar, Synthesis 1992, 449 – 451.
After isolation of 7 b the solvent of the filtrate was evaporated
and the residue was analyzed by 13C NMR spectroscopy; the
spectrum revealed an uncharacterized product lacking a C=O
group, thereby indicating the absence of other diastereomers of
7 b.
V. A. Basyuk, T. Y. Gromovoi, A. A. Chuiko, V. A. Soloshonok,
V. P. Kukhar, Dokl. Akad. Nauk SSSR 1991, 318, 905 – 906.
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
12243
Communications
[24] L. Prez-Picaso, J. Escalante, H. F. Olivo, M. Y. Rios, Molecules
2009, 14, 2836 – 2849.
[25] a) J. S. Dickschat, H. Reichenbach, I. Wagner-Dçbler, S. Schulz,
Eur. J. Org. Chem. 2005, 4141 – 4153; b) T. Chiba, H. Sakagami,
M. Murata, M. Okimoto, J. Org. Chem. 1996, 60, 6764 – 6770;
c) W.-Y. Su, J. F. Knifton, US patent No. 4788289, 1988; d) C. D.
Chang, P. D. Perkins, US patent No. 4855431, 1989; e) M.
Chaignaud, I. Gillaizeau, N. Ouhamou, G. Coudert, Tetrahedron
2008, 64, 8059 – 8066; f) L. Benati, R. Leardini, M. Minozzi, D.
Nanni, P. Spagnolo, S. Strazzari, G. Zanardi, G. Calestani,
Tetrahedron 2002, 58, 3485 – 3492; g) T. Utsukihara, H. Nakamura, M. Watanabe, C. A. Horiuchi, Tetrahedron Lett. 2006, 47,
9359 – 9364; h) Y. Okada, H. Taguchi, Y. Nisbiyama, T. Yokoi,
Tetrahedron Lett. 1994, 35, 1231 – 1234; i) J. Albaneze-Walker,
M. Zhao, M. D. Baker, P. G. Dormer, J. McNamara, Tetrahedron
12244 www.angewandte.org
Lett. 2002, 43, 6747 – 6750; j) J. U. Jeong, S. C. Sutton, S. Kim,
P. L. Fuchs, J. Am. Chem. Soc. 1995, 117, 10157 – 10158; k) C.
Guo, S. Bhandaru, P. L. Fuchs, J. Am. Chem. Soc. 1996, 118,
10672 – 10673; l) C. Y. Zhang, J. M. Tour, J. Am. Chem. Soc.
1999, 121, 8783 – 8790; m) F. Palacios, A. M. O. de Retana, J. I.
Gil, R. L. de Munain, Org. Lett. 2002, 4, 2405 – 2408; n) G.
Buechi, J. Galindo, J. Org. Chem. 1991, 56, 2605 – 2606; o) F.
Freeman, D. S. H. L. Kim, J. Org. Chem. 1992, 57, 550 – 552;
p) C. H. Heathcock, S. C. Smith, J. Org. Chem. 1994, 59, 6828 –
6839; q) N. Pl, A. Turck, K. Couture, G. Quguiner, J. Org.
Chem. 1996, 60, 3781 – 3786; r) D. F. Taber, P. W. DeMatteo,
K. V. Taluskie, J. Org. Chem. 2007, 72, 1492 – 1494.
[26] The remaining starting material was converted into uncharacterized products.
[27] Pyrazine 8 d see Ref. [25e].
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244