Download Zinc Alkyls in Organic Synthesis

Zinc Alkyls in Organic Synthesis
Zinc alkyls, including diethylzinc (DEZ), were first synthesized by Frankland in the 1800’s.[1] It was not
until the 1970’s that chemists found a series of their special utility. Work to that period was reviewed by
Furukawa and Kawabata.[2] In recent years, interest in zinc alkyls increased significantly as synthetic
organic chemists found the exceptional efficiency with which these reagents perform certain asymmetric
organic transformations. That zinc alkyls, especially DEZ, have made a substantial inroad into synthetic
chemistry is evidence by their use in commercial manufacture of leading active pharmaceutical
ingredients (API).
Akzo Nobel Functional Chemicals B.V. has pioneered the large-scale manufacturing process for zinc
alkyls and has been producing commercially in our Deer Park, Texas plant since the 1960’s. We are now
the world’s largest manufacturer of zinc alkyls. Table 1 lists major commercial and developmental
dialkylzinc compounds from AkzoNobel. In this technical bulletin, we describe the applications of
diethylzinc (DEZ) and other dialkylzinc compounds in organic synthesis. A separate technical bulletin
details the properties of zinc alkyls.[3]
Table 1.
Properties of AkzoNobel Zinc Alkyls
Zinc Alkyl
NPL*), %
(solvent)
Acronym
CAS no.
Molecular
formula
Formula
weight
Boiling point,
°C at mm Hg
Dimethylzinc
DMZ
544-97-8
(CH3)2Zn
95.45
44 at 760
13 (toluene), Developmental
21 (THF)
Diethylzinc
DEZ
557-20-0
(C2H5)2Zn
123.50
118 at 760
23(hexane),
22 (toluene)
Commercial
DNPZ
628-91-1
(n-C3H7)2Zn
151.55
48 at 10
31 (heptane)
Research
Di-n-propylzinc
Diisopropylzinc
DIPZ
625-81-0
(i-C3H7)2Zn
151.55
96 at 40
Di-n-butylzinc
DNBZ
1119-90-0
(n-C4H9)2Zn
179.60
45 at 2
Availability
Research
29 (heptane)
Research
Diisobutylzinc
DIBZ
1854-19-9
(i-C4H9)2Zn
179.60
34 at 3
Research
Di-sec-butylzinc
DSBZ
7446-94-8
(sec-C4H9)2Zn
179.60
56 at 4
Research
Di-t-butylzinc
DTBZ
16636-96-7
(t-C4H9)2Zn
179.60
34 at 12
Research
Diphenylzinc
DPHZ
1078-58-6
(C6H5)2Zn
219.6
280 at 760
Research
Dicyclohexylzinc
DCHZ
15658-08-9
(C6H11)2Zn
231.69
64 at 0.0001
Research
)
* NPL (Non-Pyrophoric Limit) determined by paper-char test.[3]
OMS 06.389.02/August 2008
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With more than 60 commercial and developmental alkyls of aluminum, magnesium, boron and zinc,
Akzo Nobel Functional Chemicals B.V. is a world leader in manufacturing and distributing metal alkyls.
Our infrastructure includes manufacturing plants in Deer Park, Texas and Rotterdam, the Netherlands
and blending/transfilling facilities in Tianjin (China), Mahad (India), and Paulinia (Brazil).
While majority of our products go to the polyolefin industry, many of them have found increasing
applications in the pharmaceutical industry, owing to their unique properties and versatile functions in
organic synthesis. In addition, the improved know-how in safe handling of these previously perceived
‘dangerous’ materials has ensured pure and consistent metal alkyls to be readily available in commercial
quantities. Today, several metal alkyls of Akzo Nobel Functional Chemicals B.V. are used by world’s
leading pharmaceutical companies to make active pharmaceutical ingredients (APIs). We invite you to
visit www.akzonobel.com/polymer to learn more.
Diethylzinc (DEZ) in Organic Synthesis
Of the many zinc alkyls that have been synthesized, diethylzinc (DEZ), is the most commonly used. It
has found applications in a variety of organic transformations, including those of asymmetric nature. Like
most zinc alkyls, DEZ is an easily handled low viscosity liquid that is conveniently miscible in most
hydrocarbon solvents. This section is devoted to applications of DEZ, organized by classes of
transformations. It is believed that some of the examples below are the actual chemistry used in the
synthesis of major API’s.
Cyclopropanation
The most well-known application of DEZ in organic synthesis is arguably the Simmons-Smith
cyclopropanation. The pioneering work of Simmons and Smith used zinc dust in combination with
diiodomethane (CH2I2) to convert alkenes to cyclopropanes.[4] In that methodology, CH2I2 is first reacted
with Zn to form the active reagent ICH2ZnI, which coordinates with the olefin to form a cyclic bond. Later,
Furukawa and Kawabata found that replacing the zinc dust with a more convenient DEZ renders the
reaction much more rapid.[2] They suggested that the reaction of DEZ and CH2I2 forms the active
reagent ICH2ZnCH2CH3 and byproduct CH3CH2I. Their work also provided evidence that
cyclopropanation in the presence of DEZ and CH2I2 proceeds stereo specifically, i.e. cis-alkenes give rise
to syn-cyclopropanes and trans-alkenes yield anti-cyclopropanes.
R1
R2
R1
R2
H
H
DEZ, CH2I2
H
H
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Those workers further demonstrated a potentially useful variation using substituted diiodomethane in
place of diiodomethane. With DEZ, the technique provided cyclopropanation with concomitant addition
of a third substituent.[5] Tri-substituted cyclopropanes were therefore synthesized. The authors
suggested that the nature of substituents on the starting alkene determines the relative position of the
third substituent. The workers also noted that the reaction proceeds by electrophilic addition,
preferentially giving the thermodynamically less stable yet synthetically more interesting syn-isomer.
Alkenes containing hydroxyl groups, however, yielded primarily the anti-isomer. In addition to linear
alkenes, these workers successfully cyclopropanated a wide range of substrates, including cycloalkene,
norbornene, cycloalkenyl ether and furan.
R1
DEZ, R3CHI2
H
R2
R1
R2
H
H
H
R3
H
R3 = CH3, Ar, CH2X
In the study of epothilone synthesis, Danishefsky found DEZ to be effective in cyclopropanation within a
complex chemical environment.[6] In this case, the alkene substrate was part of a cyclic vinyl ether. The
conversion was performed in diethylether solvent at 25°C and gave a yield of 93%.
H
CH3
CH3
O
O
DEZ, CH2I 2
ether, 25 C
PhH2CO
PhH2CO
OH
CH3
OH
CH3
CH3
CH3
Similarly, Bristol-Myers Squibb scientists demonstrated that cyclopropanation could be accomplished on a
substituted pyrroline.[7] The methodology involved forming the DEZ/CH2I2 reagent in methylene
chloride/dimethylether solvent and was applied in the synthesis of cyclopropyl-fused pyrrolidine
derivatives.
O
1. DEZ/toluene
2. CH2I2
N
O
N
CH2Cl2, DME
-30 C
O
O
CONH2
CONH2
Merck chemists showed that CH2I2 may be replaced by similar analogues. They accomplished
cyclopropanation of a terminal olefin using DEZ in toluene, but with 1,2-dichloroethane and
chloroiodomethane.[8] Advantages of these reagents with the more conventional reagent, DEZ and
CH2I2, were not discussed.
OH
1. DEZ/toluene
2. 1,2-dichloroethane
3. CH2ClI
0 C, 3 hrs
OH
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Asymmetric Additions to Aldehydes and Ketones
DEZ is also useful in catalytic asymmetric addition to aldehydes or ketones forming chiral secondary or
tertiary alcohols. These reactions typically involve an amine or a sulfonamide ligand in combination with
tetraisopropyl titanate (TIPT). The added substituent comes from zinc alkyls such as DEZ or
dimethylzinc (DMZ).
For conversion of ketones to optically active tertiary alcohols, Walsh discovered a bis-sulfonamide diol
ligand and its use along with TIPT and DEZ. The combination was shown to yield tertiary alcohols with a
remarkable enantioselectivity, up to 99% enantiomeric excess (ee).[9] Diphenylzinc (DPHZ) was also
shown to be effective in this type of reaction. The authors suggested that these results are superior to
that from other DEZ additions which use dimethylamino isoborneol (DAIB) or a camphor-based
hydroxysulfonamide ligand. Walsh demonstrated the effectiveness of his technique with a wide array of
substituent groups on the ketone, e.g. alkyl, halogenated alkyl, phenyl, and alkoxy phenyl. Other
interesting zinc alkyls, e.g. di-n-butylzinc, dicyclohexylzinc, were not evaluated.
R32Zn (1.6 eq.)
Ti(O-iPr)4 (1.2 eq.)
bis-sulfoneamide diol ligand
O
R1
R2
HO R3
hexane/toluene, RT, 16-48 hrs.
R1
R2
up to 99% ee
Walsh’s catalytic enantioselective method was also applied to asymmetric addition to cyclic
-unsaturated ketones.[10] Various substituted cyclic enones were examined with both DEZ and DMZ.
Yield of the tertiary alcohol were reported to be in the 20-84% range with enantioselectivity in the 95-99%
range for most substrates.
O
R1
OH
Ti(OiPr)4
ZnR2
Ligand
R
R1
hexane/toluene
RT
n
n
In that work, introducing oxygen during the reaction led to tandem addition and epoxidation of the olefin
to form epoxy alcohols. This addition procedure also yielded high enantioselectivity (97-99%), with epoxy
alcohols being formed as single diastereomers.
O
R1
n
Ti(OiPr)4
ZnR2
Ligand
hexane/toluene
RT
OH
R
R1
O2
0 C to RT
O
n
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For asymmetric addition to aldehydes, Noyori discovered that DEZ in combination with DAIB is effective.
The transformation to secondary alcohols was performed with excellent enantioselectivity.[11] In that
work, DEZ was used to alkylate substituted benzaldehydes, forming chiral secondary alcohols. Liu et al.
later used a aminonaphthol chiral ligand to achieve extraordinarily high yield and selectivity.[12] There,
the reaction using DEZ in hexane and 15 mol% of the chiral ligand gave 97% yield with 99.8% ee.
OH
CHO
DEZ/hexane
10 mol% ligand
RT, 24 hrs
R
R
up to 97% yield and 99.8% ee
Other Addition Reactions
Zinc alkyls have also found utility in synthesis of allylic amines and alcohols. These allylic species are
useful intermediates in API manufacturing. A review of the literature indicates that such compounds are
readily synthesized using alkenyl organozinc reagents. Those reagents are typically formed by the
reaction of a suitable alkyne with Cp2ZrHCl, followed by a reaction with DMZ. The resulting compound is
a methyl vinylzinc reagent. In that methodology, DMZ and DEZ are often equally effective.
Wipf and co-workers showed that such a vinylzinc intermediate may be reacted with imines to obtain
allylic amines.[13] When CH2I2 is used as the solvent, C-cyclopropylamines or homoallylic amines
resulted depending on the order of addition.
1. Cp2ZrHCl
R1
MeZn
R1
2. DMZ
R2
NR3
R2
CH2I2
NR3
+
+
CH2I2
R2
NR3
NHR3
NHR3
NHR3
R1
R2
R2
R1
R2
R1
anti(major) syn(minor)
anti(major) syn(minor)
Li and Walsh employed a similar reagent along with the above mentioned bis-sulfonamide diol ligand to
accomplish asymmetric vinylation of ketones.[14] Here, the ligand and TIPT were first added to the
organozinc reagent, followed by addition of the prochiral ketone. The reaction proceeded at room
temperature, giving yield and enantioselectivity of allylic alcohols of greater than 90% for most
substrates tested.
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Cp2ZrHCl
+
R3
R3
Cp2ClZr
DMZ
R3
R1R2CO
Ti(O-iPr)4 (1.2 eq.)
bis-sulfoneamide diol ligand
R1
R3
MeZn
HO
R2
Walsh and co-workers also demonstrated an interesting variation to this technique. Here, (Z)-trisubstituted allylic alcohols were synthesized in a one-pot coupling reaction.[15] The synthesis involved
first reacting a bromoalkyne with dialkylborane generated in situ, e.g. from triethylborane (Et3B) and
borane dimethylsulfide (BH3 SMe2), followed by reactions with DEZ and aldehyde. The (Z)-tri-substituted
allylic alcohol product was isolated in 73% yield.
1
Br
R
1. R22BH, 0 C
2. DEZ, -78 C
3. R3CHO
OH
3
R1
R
R2
A slight modification of this methodology led to the formation of an epoxy alcohol.[16] Whereas the
classic Sharpless asymmetric epoxidation employs TIPT, t-butylhydroperoxide (TBHP) and diethyl
tartrate (DET) or isopropyl tartrate (DIPT),.[17] Walsh and co-workers used a zinc alkoxide intermediate
from an alkyne, morpholino isoborneol (MIB) ligand, DEZ and aldehyde. Upon introducing oxygen in the
presence of TIPT and DIPT, they obtained epoxy alcohols with high enantiomeric purity and good yield.
R1
1. Cy2BH
2. (-)-MIB, 4 mol%
3. DEZ, -10 C
4. R'CHO
R'
OZnEt
OH
5. O2
R
6. TIPT,
(+)-DIPT
R'
68-92% yield
77-98% ee
up to 4.5:1 d.r.
R
O
In a remarkably creative technique, DEZ formed the basis for an organozinc reagent used in a ketone
alkynylation reaction. The reagent facilitated an asymmetric addition with exceptional yield and
selectivity.[18]
DEZ, or equally effectively DMZ, was reacted with a chiral auxiliary (1R,2S)-N-pyrrolodinylnorephedrine,
giving a chiral zinc alkoxide. Transmetallation of this zinc alkoxide with a suitable Grignard, in this case a
cyclopropyl alkynyl-MgCl, provided the desired organozinc reagent. The reagent was reacted with the
ketoaniline substrate to prompt the desired alkynylation.
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OH
Ph
1. CF3 CHOH
Zn
Ph
OEt
Zn
MgCl
2. DEZ
N
N
N
H3C
OEt
O
O
Ph
[1]
H3C
H3C
Cl
Cl
CF3
O
1 M Citric Acid
[1] +
15 hrs
OH
CF3
95.3% yield
99.2% ee
NH2
NH2
Using the same reagent as in Simmons-Smith cyclopropanation, DEZ/CH2I2, Macdonald accomplished
C-alkylation of phenol. Whereas typical reagents would alkylate at the oxygen site, this reaction yielded
ortho-methylation.[19] This synthetic method, relevant to accessing phenolic natural products, was
successfully applied to a series of phenol compounds.
OH
OH
CH3
DEZ, CH2I2
Toluene Reflux
The combination of DEZ and CH2I2 was shown by Zercher and co-workers to be useful in another
noteworthy application. In this procedure, the reagent was used to extend the chain length of -keto
esters by one carbon atom, forming -keto esters.[20] The authors proposed that a cyclopropyl
intermediate may be involved. Depending on the subsequent reactant used, a variety of -keto esters
could be obtained. Immediate quenching yielded simple chain extension, whereas further reaction with I 2
and 1,8-diazobicyclo[5.4.0].undec-7-ene (DBU) inserted an olefin function. Alternatively, reaction with an
aldehyde inserted an alcohol side chain.
O
OR
1. I2
2. DBU
Et
R'
O
Zn
O
R'
O
OR
O C
O
O
O
DEZ
CH2I2
NH4 Cl
OR
R'
R'
OR
O
H
R"CHO
R"
OH
O
OR
R'
O
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Work-Up
The work-up procedure of reactions involving DEZ is similar to those of other reactions employing
organometallic reagents. It includes quenching with aqueous salt solution, extraction with an organic
solvent, drying of the organic fraction, concentration in vacuo, and purification. Other variations may be
similarly effective depending on the chemistry under consideration. See the work of Walsh, Tan,
Macdonald, Danishefsky, and Zercher for details.
In general, the reaction mixtures can be quenched with an aqueous solution of NH4Cl (either dilute or
saturated), NaHCO3, or water. In most cases, it is advisable to cool the mixture to 0°C prior to quenching.
The cooling allows a better control of the highly exothermic reaction between water and DEZ. Extraction
can be performed with ethers or aliphatic solvents. The organic layer is usually dried with Na2SO4 or
MgSO4. After separating the dried organic layer, the solvent is removed by vacuum. At this point, the
product is typically in an oil form. The concentrated product is then purified by column chromatography or
HPLC.
Reactions of Other Zinc Alkyls
Dimethylzinc (DMZ) has been used in similar ways as DEZ in organic reactions. Because DMZ is highly
volatile (bp 44°C), accurate addition of the reagent into the reaction mixture can be difficult. When the
reaction mixture is not cooled to a low temperature, a portion of the DMZ added will vaporize into the
headspace, rendering it unavailable for reaction. This vaporization makes stoichiometric additions tricky.
When DMZ or DEZ give identical results, the less volatile DEZ may be preferred.
As with DEZ, DMZ is most commonly used in alkylation-addition reactions. Reetz and Westermann
showed that direct geminal alkylation of ketones may be performed using DMZ with alkyl lithium and
TiCl4.[21] In that work, the side chain n-alkyl group of tetrahydrocannabinoid was replaced with a tertiaryalkyl group. The product was noted to be pharmacologically interesting. In this procedure, the alkyl
lithium was first mixed with the substrate ketone. The resulting lithium alcoholate was further reacted
with DMZ and TiCl4 to effect the desired alkylation. The product therefore received one alkyl group from
the alkyl lithium and the other from DMZ.
H3CO
OCH3
H3 CO
OCH3
OCH3
1. DMZ
2. TiCl4
R2Li
CH2 Cl2 , - 40 C
hexane, - 40 C
R1
R1
H3 CO
OLi
R1
CH3
O
R2
R2
Further to DMZ and DEZ, other dialkylzinc compounds worth noting are diphenylzinc (DPHZ) and di-tbutylzinc (DTBZ). These zinc alkyls were used in Cu-catalyzed reactions reported by Johnson.[22]
OMS 06.389.02/August 2008
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In that work, DPHZ and DTBZ were used in eletrophilic amination reactions. These zinc alkyls were
particularly effective in replacing the alkoxy group, resulting in tertiary amines.
O
N
+ (Ph)2Zn
91%
CuCl2 (2.5 mol%)
O
N
OBz
Ph
THF, 15 min
+ (t-Bu)2Zn
O
N
t-Bu
99%
As noted above, specially synthesized organozinc reagents are highly effective in certain
transformations. Typically, organo-magnesium or -lithium reagents are transmetallated with dialkylzinc to
form the desired reagent. Noyori and co-workers assembled a prostaglandin analogue by sequentially
linking side chains to 2-cyclopentenone.[23] In that synthesis, equimolar amounts of cyclopentenone,
vinylic lithium and DMZ were mixed, followed by addition of methyl 6-formylhexanoate. The result was a
three-component coupling with 82-92% yield and 10:1 selectivity of 7S/7R. DMZ was suggested to be
critical in effecting the consecutive linking with the initial step being the reaction of DMZ with vinylic
lithium to form a lithium methyl/vinyl mixed zincate.
HO
O
O
O
COOCH3
H
+
OTBMDS
COOCH3
DMZ
Li
OTBMDS
OTBMDS
OTBMDS
82-92% yield, 7S/7R=10:1
Properties, Safety and Handling of Zinc Alkyls
For properties, safety and handling of zinc alkyls, readers are recommended to review our separate
technical bulletin that addresses the subject in detail.[3] Briefly, zinc alkyls are typically clear, colorless
liquids and are miscible in all proportions with saturated aliphatic hydrocarbons. Many of the lower zinc
alkyls, such as DMZ and DEZ are highly pyrophoric. Nonpyrophoric limits for selected solutions of zinc
alkyls are provided in Table 1. Both neat and solutions of zinc alkyls react violently with water. Zinc
alkyls should be handled under an inert atmosphere. Nitrogen (oxygen and water content typically < 5
ppm) is used at AkzoNobel.
Zinc alkyls are generally light-sensitive. Samples stored in clear glass bottles often become turbid within
a few days at ambient temperature. Analysis of wt% Zn is performed by standard analytical methods
using the hydrolyzate of the zinc alkyl. Gas chromatography (GC) may also be used to assess the purity
of zinc alkyls, by analyzing hydrocarbons produced upon hydrolysis.
OMS 06.389.02/August 2008
Page 9 of 10
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
a) E. Frankland, Liebigs Ann. Chem., 71, 171 (1848), b) E. Frankland, J. Chem. Soc., A, 2, 263
(1849) and c) E. Frankland, J. Chem. Soc., A, 3, 44 (1850).
J. Furukawa and N. Kawabata, Adv. Organomet. Chem., 12, 83 (1974).
Properties of Zinc Alkyls from AkzoNobel, Technical Bulletin from Akzo Nobel Functional
Chemicals B.V., (2003).
M. B. Smith and J. March, March’s Advanced Organic Chemistry, 5th Ed., Wiley, New York (2001),
Ch.15 and references therein.
J. Nishimura, N. Kawabata, and J. Furukawa, Tetrahedron, 25, 2647 (1969).
P. Bertinato, E. J. Sorensen, D. Meng, and S. J. Danishefsky. J. Org. Chem., 61, 8000 (1996).
W.O. Patent Application 2004/052850 A2 (Bristol-Myers Squibb, 2004).
U.S. Patent 6,610,692 B1 (Merck, 2003).
a) U.S. Patent 6,660,884 B2 (U. of Pennsylvania, 2003), b) S.-J. Jeon, H. Li, C. Garcia, L. K.
LaRochelle and P. J. Walsh, J. Am. Chem. Soc., 70, 448 (2005), c) C. Garcia, L. K. LaRochelle
and P. J. Walsh, J. Am. Chem. Soc., 124, 10970 (2002), and d) C. Garcia and P. J. Walsh, Org.
Lett., 5, 3641 (2003).
S. J. Jeon and P. J. Walsh, J. Am. Chem. Soc., 125, 9544 (2003).
M. Kitamura, S. Suga, K. Kawai and R. Noyori, J. Am. Chem. Soc., 108, 6071 (1986).
D.-X. Liu, L. C. Zhang, Q. Wang, C.-S. Da, Z.-Q. Xin, R. Wang, M. C. K. Choi and A. S. C. Chan,
Org. Lett., 3, 2733 (2001).
P. Wipf, C. Kendall and C. R. J. Stephenson, J. Am. Chem. Soc., 125, 761 (2003).
H. Li and P. J. Walsh, J. Am. Chem. Soc., 126, 6538 (2004).
Y. K. Chen, P. J. Walsh, J. Am. Chem. Soc., 126, 3702 (2004).
A. E. Lurain, P. J. Carroll and P. J. Walsh, J. Org. Chem., 70, 1262 (2005).
Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune and K. B. Sharpless, J. Am. Chem.
Soc., 109, 5765 (1987).
L. Tan, C. Chen, R. D. Tillyer, E. J. J. Grabowski and P. J. Reider, Angew. Chem. Int. Ed., 38, 711
(1999).
E. K. Lehnert, J. S. Sawyer and T. L. Macdonald, Tetrahedron Lett., 30, 5215 (1989).
J. B. Brogan and C. K. Zercher, J. Org. Chem., 62, 6444 (1997).
M. T. Reetz and J. Westermann, J. Org. Chem., 48, 254 (1983).
A.M. Berman and J. S. Johnson, J. Am. Chem. Soc., 126, 5680 (2004).
M. Suzuki, Y. Morita, H. Koyano, M. Koga and R. Noyori, Tetrahedron, 46, 4809 (1990).
All information concerning this product and/or suggestions for handling and use contained herein are offered in good faith and are believed to be reliable. AkzoNobel
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