Download CHAPTER 1 Synthesis of amides using Lewis acid catalyst: Iodine

CHAPTER 1
Synthesis of amides using Lewis acid catalyst: Iodine
catalyzed Ritter reaction
Part-1
Chemistry of Lewis acids and amides
1
1.1.1. General overview of Lewis acids
Acid and base reactions are of tremendous importance in organic chemistry,
as they are also in inorganic and biochemistry. In 1884, Svante A. Arrhenius defined
acids as substances dissociating into protons (H+) and the corresponding anions (A‐)
in an aqueous medium.1 Correspondingly, bases were characterized as substances
dissociating into hydroxy‐anions (OH‐) and its respective cations (C+). Clearly this
concept is restricted to acids and bases like HBr or KOH in water. In 1923 Johannes
N. Brønsted and Thomas M. Lowry independently elaborated the extension of the
acid‐base
theory by defining
acids as proton‐(H+)‐donors
and bases as
proton‐acceptors, no longer restricting the concept to specific substance classes or
2
solvents.2 Following these ideas, a number of reactions could be interpreted
accordingly.
Since many reactions
do not involve
direct proton transfers,
the
generalization of the acid base definition by Gilbert N. Lewis in 1938, was an
important
step for the understanding
of chemical
compounds
and their
transformations.3 A Lewis acid is a compound with electron demand, (i.e.) having an
unoccupied orbital which is able to accept an electron pair. On the other hand a
Lewis base donates an electron‐pair from an occupied orbital. The reaction products
of Lewis acids and bases are Lewis adducts, bound through a coordinative (or
dative) bond. By joining the two concepts it becomes clear, that a Brønsted acid is a
compound consisting of a Lewis base and a proton. This leaves the proton as the
smallest of all Lewis acids, bearing free space in its 1s‐orbital.
Further refined by Ralph G. Pearson in 1963, Lewis acids and bases are
categorized into hard and soft acids and bases (HSAB‐concept).4 This approach
3
describes the quality of a bond in a Lewis adduct by consideration of atomic or ionic
radii, charge distribution and polarizability.
Accordingly, moieties of small size, high charge density and high polarizing
potential are considered “hard”, whereas large radii, low charge densities and low
polarizing potential characterize “soft” acids or bases. The association of hard acids
with hard bases, and soft acids with soft bases is preferred. This preference is based
on the bond character present in these combinations. A bond between a hard acid
and a hard base, as in NaCl, has an ionic character, whereas the bond between a soft
acid and a soft base results in a combination exhibiting a covalent bond character.
With these concepts a manifold of chemical reactions and compounds can be
qualitatively described. Especially for the understanding of structure and reactivity
of transition metal complexes, the HSAB‐concept is of very high value (Scheme
1.1).
LA
+
LA
LB
LB
LA
LB
LA
LB
Lewis ad du ct bind ing through
a coo rdinative (d ative ) bond
Examples:
H
OH
+
H 2O
F3B
+
OEt2
BF3 OEt 2
Cl4Si
+
OC(CH3 )2
Cl4 SiH
OC(CH3 )2
Hard acids: BF3 +, H +, Na +, K+, Fe3+, Mg2+; Hard bases: OH-, F- , Cl-, NH3 , NR 3
Sof t acids: BH 3, pd 2+, Au+, Cu+, SiCl4; Soft bases: RSH, CN -, R2 S, R 3P,CO
LA=Lewis acid, LB=Lewis base
4
Scheme 1.1: Interaction of Lewis acids and Lewis bases and the HSAB‐categorization.
A great potential of Lewis acids is their application in the activation of
molecules bearing Lewis basic sites. Thus Lewis acids play a key role for the
activation of σ‐and π‐systems. The formation of σ‐complexes is present in the
activation of substrates such as carbonyl compounds or imines.5 Due to the
interaction of the lowest unoccupied molecular orbital (LUMO) of the Lewis acid
with the highest occupied molecular orbital (HOMO) of the Lewis base, adjacent
bonds get polarized and a nucleophilic attack from external or internal nucleophiles
is facilitated. This mode of action can be summarized in a commonly accepted
catalytic cycle which accounts for this activation mode, “Lewis acid catalysis”
(Scheme 1.2).
LA
S
P
activation
libe ration
LA
LA
P
Lewis adduct
(intermediate II)
S
Lewis addu ct
(intermediate I)
transformation
Scheme 1.2: General reactive principle of Lewis acid catalysis.
Together with Lewis base activation, Brønsted acid activation and Brønsted
base activation it represents the pillars of asymmetric catalysis.6 However,
Lewis acid activation is not restricted to σ‐electron donors. Some Lewis acids
5
are very powerful catalysts for the activation of π‐electron‐systems as well. By
these interactions, nucleophilic attacks on allenes, alkenes and alkynes can be
efficiently triggered. Usually these catalysts are complexes bearing a “soft” metal
center.7
σ‐Lewis acids
Some archetypical Lewis acids for σ‐donor activations are group 3‐ and
4‐element halides, such as BF3, AlCl3, SnCl4 or SiCl4. Many other σ‐Lewis acids are
based on transition metals, such as TiCl4 and FeCl3. Based on the periodic table, a
vaguely defined borderline between (transition)‐metal and (transition)‐metal‐free
Lewis acids can be drawn. As a common example from the main group elements,
AlCl3 finds its application for various purposes.8 One important example is the
Friedel‐Crafts alkylation (see scheme 1.3). This reaction, first reported in 1877 by
French chemist Charles Friedel and American chemist James Crafts, is an
electrophilic aromatic substitution, occurring through an addition‐elimination
mechanism.9 The role of the Lewis acid is the interaction of its empty orbital with a
lone pair of electrons on chlorine. This interaction polarizes the halogen‐carbon
bond in RCl and results in a higher electrophilicity on carbon. Subsequently a
nucleophilic attack by the aromatic ring takes place. Upon rearomatization via
elimination of a proton, the product and the catalyst are liberated.
6
CH 3
AlCl3
R
HCl +
Me
H
R
Cl
Cl
Cl
Cl
Al Cl
Cl
AlCl3
Scheme 1.3: Mechanism of the Friedel‐Crafts alkylation of benzene
π‐Lewis acids
As already mentioned, the activation of multiple carbon‐carbon bonds is
another domain of Lewis acid catalysis. Here the π‐systems of, for example, allenes,
alkenes and alkynes are activated. An extremely important reaction using this
slightly different mode of action is the Ziegler‐Natta polymerization of ethylene or
propylene.10
Z iegler-Aufbau:
R
n+1
Al
R
R
Al
R
R
(
Al
R
7
)n
Scheme 1.4: The Ziegler‐Aufbau reaction.
In early studies Ziegler developed the so‐called Aufbau‐reaction (Aufbau
(Ger.) = assembly), the multiple insertion of ethylene into the carbon‐aluminium
bond of trialkylaluminium compounds (Scheme 1.4).
1.1.2. Application of Lewis acid catalysts in organic synthesis
The use of Lewis acids in organic synthesis, especially in catalysis is one of
the most rapidly developing fields in synthetic organic chemistry. In addition, Lewis
acid catalysis is one of the key technologies for asymmetric synthesis, and
combinatorial chemistry as well as for large-scale production. Lewis-acid (LA)catalyzed reactions are of great interest because of their unique reactivities
and selectivities and mild reaction conditions used. A wide variety of reactions
using Lewis acids have been developed, and they have been applied to the
synthesis of natural and unnatural compounds. Some of the examples are given
below.
8
Alkylation reactions
Friedel-Crafts alkylations are of great interest due to their importance and
common use in synthetic and industrial chemistry. In 1887 Charles Friedel and
James Mason Crafts11 isolated amylbenzene after the treatment of amyl chloride
with AlCl3 in benzene (Scheme 1.5). This was not only one of the first descriptions
of a Lewis acid used in organic synthesis but also the first example of what as later
to be called Friedel-Crafts alkylation after its inventors.
+
Cl
AlCl3
-HCl
Scheme 1.5: Friedel-Crafts alkylation of amyl chloride with benzene
Over the intervening years many other Lewis acids including BF3, BeCl2,
TiCl4, SbCl5 and SnCl4 have been described as catalysts for the FC alkylation.12
Acylation reactions
Friedel–Crafts acylation is the acylation of aromatic rings with an acyl
chloride or acid anhydride using FeCl3 or AlCl3 as a strong Lewis acid catalyst.
Reaction conditions are similar to the Friedel–Crafts alkylation as mentioned above.
O
RCOCl or (RCO) 2O
R
FeCl3
Scheme 1.6: Friedel–Crafts acylation of benzene with acylchloride
The aldol reactions
The Lewis acid-catalyzed aldol reaction of silyl enol ethers, commonly
known as the Mukayama aldol reaction, was first reported in the early seventies.13
The titanium-tetrachloride was also used as Lewis acid catalyst for the cross-aldol
reactions.14Kobayashi reported15 the first Lewis acid catalyzed cross-aldol reaction
9
in aqueous solution. He examined the effects of lanthanide triflates in the reaction of
several silyl enol ethers with benzaldehyde.
OH
OSiMe3
CHO
O
Yb(OTf) 3 (10 mol%)
+
H2 O-THF , RT
Scheme 1.7: Lewis acid-catalyzed aldol reaction of silyl enol ether
Allylation reactions
The synthesis of homoallylic alcohols via Lewis acid-catalyzed reaction of
organo-metallic reagents with a carbonyl compound has been widely studied.16 The
first example of such a Lewis acid-catalyzed allylation reaction in aqueous medium
was again reported by Kobayashi.17 In smooth reaction under the influence of 5
mol% of Sc(OTf)3, tetra allyltin reacted with several ketones and aldehydes. The
much cheaper Yb(OTf)3 was also used effectively and the Lewis acid could be reused without loss of activity.18
OH
CHO
+
Br
Sc(OTf) 3 (5 mol%)
H2 O, RT
Scheme 1.8: Lewis acid-catalyzed allylation reaction of benzaldehyde with allylbromide
Diels-Alder Reaction
Davies et al.19
developed aluminum chloride induced reaction between
cyclopentadiene and α,β-unsaturated aldehydes resulting in the stereoselective
formation of the products of a formal [4 + 3] cycloaddition. The reaction proceeded
by a tandem Diels-Alder reaction/ring expansion. They also reported MeAlCl2 –
catalyzed hetero Diels-Alder reaction.20
10
R2
AlCl3
R1
+
R2
21-90%
O
O
R1
Scheme 1.9: Lewis acid-catalyzed Diels-Alder reaction of cyclopentadiene and α,β-unsaturated
aldehyde
Rearrangement
Lambert et al.21 have developed a new Lewis acid-catalyzed [3,3]Sigmatropic rearrangement and Allenote-Claisen rearrangement between benzyl 2,3pentadienoate and allyl pyrrolidines using Lewis acid catalyst.
Me
Me
C
CO 2Bn
Me
N
NR 2
Lewis Acid
+
CH 2 Cl 2
Me
CO2 Bn
syn
Scheme 1.10: Lewis acid-catalyzed Rearrangement
Yb(OTf)3, Sn(OTf)2, Cu(OTf)2, TiCl4, AlCl3, FeCl3, Zn(OTf)2 were also
used as Lewis acid catalysts for this transformation.
Halogenations
Yamamoto et al.22 have reported asymmetric chlorination of ketones using
ZrCl4 as a Lewis acid catalyst.
OSi
OSi
Cl
ZrCl4
CH2 Cl2, -78 ºC
OSi
O Si
ZrCl 4
Cl
( )n
( )n
Scheme 1.11: Lewis acid-catalyzed halogenation
11
Hintermann, and Tongni, have developed chiral Lewis acid catalyzed
asymmetric chlorination and bromination.23
O
O
O
R1
N X
+
OR2
O
Me
5mol% A
R1
MeCN
O
O
O
Nph-1
X Me
OR2
Nph-1
O
Cl
1-Nph
O
1-Nph
Ti
MeCN Cl NCMe
O
X=Cl, Br
A
Scheme 1.12: Lewis acid-catalyzed bromination
Oxidation
Michel Vatele et al.24 developed the method for the oxidative rearrangement
of tertiary allylic alcohols. Most of tertiary allylic alcohols studied were oxidized to
their corresponding transposed carbonyl derivatives in excellent to fair yields by
reaction with TEMPO in combination with PhIO and Bi(OTf)3 or copper(II)
chloride in the presence of oxygen.
R2
H
Bi(OTf) 3/PHIO
OH
R
1
R4
R3
TEMPO , CH2 Cl2
R4
O
R1
R3
2
R
Scheme 1.13: Lewis acid-catalyzed oxidative rearrangement of tertiary allylic alcohol
Reduction
Stephan et al.25 have found that the Lewis acid B(C6F5)3 efficiently catalyzed
the direct hydrogenation of imines and the reductive ring-opening of aziridines with
H2 under mild conditions; addition of a bulky phosphine allows the reduction of
protected nitriles.
R1
R2
5mol%, B(C6 H6 )3
N
R3
H2
R1
R2
NH
H
R3
Scheme 1.14: Lewis acid-catalyzed reduction reaction of imines
12
Addition reaction (Michael addition)
Feringa et al.26 observed that the large range of β-keto esters reacted
efficiently with various β-unsubstituted enones in the presence of a catalytic amount
of Yb(OTf)3, to give corresponding product with good yield.
O
O
R1
O R2
R 2O
R
Yb(OTf) 3
+
H 2O
O
R
O
O
R1
O
Scheme 1.15: Lewis acid-catalyzed Michael addition of β-keto esters with β-unsubstituted enones
Mannich-type reaction
For the synthesis of β-amino ketones the Mannich reaction is one of the most
attractive processes.
A Lewis acid-catalyzed Mannich reaction can be carried out
conveniently in aqueous solution.27 An aldehyde, an amine and a vinyl ether reacted
in THF/water mixture in the presence of 10 mol% of Yb(OTf)3, to give β-amino
ketone in 55-100% yield.
2
OMe
R 1CHO + R 2NH 2
+
R3
10 mol%, Yb(OT f)3
THF/H2 O
R
NH
R1
O
R3
Scheme 1.16: Lewis acid-catalyzed Mannich-type reaction
1.1.3. General introduction of amides
The amides are a group of organic compounds derived from carboxylic acids
and nitrogen compounds, like ammonia and amines providing compounds that
contain the -CONH2, -CONHR, or -CONR2 groups. They have the ability to bond
very strongly to themselves, at other amide sites down the chain, or different chains
with amides through hydrogen bonding between the oxygen and the hydrogen from
the NH group elsewhere. These are very strong intermolecular bonds.
13
Amide bonds play a major role in the elaboration and composition of
biological systems, representing for example the main chemical bonds that
link amino acid building blocks together to give proteins. Hermann Fischer
discovered the peptide bond (Amide bond) and won the Nobel Prize for Chemistry
in 1902 for groundbreaking work on the structure and properties of purines and
sugars.
The structure of amides
Amides are made by a chain of carbon atoms with one as a carbonyl bonded
to an amine group, which is then bonded to the next carbon to continue the chain.
O
O
R
N
R
R
H
N
R
H
A
B
Scheme 1.17: Structure of amide
The lone pair of electrons on the nitrogen is delocalized into the carbonyl,
thus forming a partial double bond between N and the carbonyl carbon.
Consequently the nitrogen in amides is not pyramidal. It is estimated that acetamide
is described by resonance structure A for 62% and by B for 28%.28
1.1.4. Amide Formation
One or more of the hydrogens of the ammonia are replaced with organic acid
groups to produce primary, secondary, or tertiary amide. Primary amides are
prepared by reacting ammonia or amines with acid chlorides, anhydrides, or esters.
Secondary and tertiary amides are prepared by reacting primary amides or nitriles
with organic acids.
Amides are commonly synthesized via reactions of a carboxylic acid with an
amine.
14
O
R
OH +
H
H
N
O
R
R
N
H
R + H O
2
Scheme 1.18: Amide Synthesis
Many methods are known for driving the unfavorable equilibrium to
the right, because the unification of these two functional groups does not
occur spontaneously at ambient temperature, with the necessary elimination of water
only taking place at high temperatures (e.g. >200 ºC),29 conditions typically
detrimental to the integrity of the substrates. For this reason, it is usually necessary
to first activate the carboxylic acid, a process that usually takes place by converting
the –OH of the acid into a good leaving group prior to treatment with the amine
(Scheme 1.19).
O
R
O
activation
OH
R
1
R
H
N
R2
Act
O
R
N
R1
R2
Scheme-1.19: Principle of the activation process for amide-bond formation.
In order to activate carboxylic acids, one can use so-called coupling reagents,
which act as stand-alone reagents to generate compounds such as acid chlorides,
(mixed) anhydrides, carbonic anhydrides or active esters.
For the most part, these reactions involve "activating" the carboxylic acid
and the best known method, the Schotten-Baumann reaction which involves
conversion of the acid to the acid chlorides.
O
R
O
activation
OH
R
O
R1 NH 2
Cl
NaO H
Scheme 1.20: Schotten-Baumann reaction
15
R
N
H
R1
Many reviews on coupling reagents have been published.30–36 For example
DCC,37 HOBt,38,39 DIC40
HOAT,41 etc
42
have been effectively employed for this
purpose.
Amide can be synthesized from ketone with hydrogen azide using acid
catalyst (Schmidt Reaction).
O
R1
R
O
HN 3
H 2SO 4
R
NHR1
Scheme 1.21: Schmidt Reaction
The use of magnesium nitride as a convenient source of ammonia allows a
direct transformation of esters to primary amides. Methyl, ethyl, isopropyl, and tertbutyl esters are converted to the corresponding carboxamides in good yields.43
O
R
O
Mg3 N 2
OR
1
MeOH, 80 º C
R
NH2
R= alkyl o r ar yl
R 1= Me, Et, i- Pr, t-Bu
Scheme 1.22: Amide formation from esters
Gunanathan, et al.44 have prepared amides from amines and alcohols under mild
pressure and neutral, homogeneous conditions using a dearomatized bipyridyl-based
PNN Ru(II) pincer complex as a catalyst.
H
R
H
OH
+
R
1
H
NH
P
N Ru
CO
N
H
Toluene, Ref lux, -2H2
O
R
N
H
R1
Scheme 1.23: Synthesis of amides from amine and alcohol
16
1.1.5. Applications of amides
Usesinorganicsynthesis
Recently, Matthias Beller and co-worker reported45 amine can be prepared
from amide using zinc acetate as catalyst.
O
R
N
R2
Zn(OAc) 2
R
N
R1
R2
Sila ne s, RT
R1
Scheme 1.24: Synthesis of amine from amides
Since Nahm and Weinreb first reported the use of N-methoxy-N-methylamides
as carbonyl equivalents, this functional group has rapidly become popular in organic
synthesis. The ease of preparation, the limitation of side reactions during
nucleophilic addition, and the selective reduction of this moiety to aldehydes has
propelled it to the forefront of synthetic utility.
O
M
O
LAH( or) DIBAL-H
OM e
R1
N
R2
Me
M = Li,Al
R
N
Me
O Me
R2 M
R1
R2
R 1 = alkyl, aryl, alkenyl, alkynyl.
heteroaryl
R2 = alkyl, aryl,alkenyl, alkynyl.
heteroary
H 3O
O
OMe
N
Me
M = Li,Mg
H3 O
O
R
M
O
H
Scheme 1.25: Synthesis of ketone and aldehyde from amides
R
R
The main synthetic use of Weinreb amides derives from their reactivity toward
nucleophiles. They can be useful for the addition of Grignard or alkyllithium reagents to
produce ketones. Other advantages are seen in the selective reduction of the Weinreb
amides to the corresponding aldehydes. The chelating ability of the amides provides a
stable intermediate that does not form the aldehyde until aqueous workup. This prevents
17
the over reduction commonly seen with other functionalities. Several reviews and
numerous articles on the utility of Weinreb amides have been published.46
Schroeder et al.47 synthesized 1,5-disubstituted tetrazoles from amides using
diisopropyl azodicarboxylate (DIAD), diphenylphosphoryl azide (DPPA), and
diphenyl-2-pyridyl phosphine in THF.
DPPA
O
R
NH
(2-pyridyl)PPh2
N
DIAD, THF
N
N
N
Scheme 1.26: Synthesis of tetrazole from amide
The amides such as dimethylacetamide, dimethylformamide, formamide,
N-methylformamide,
methylpyrrolidone,
2-pyrrolidone
and N-vinylpyrrolidone
are often used as very useful common solvents in organic synthesis.
Several
articles and many reviews are available in literature regarding the use of amides
as starting materials or intermediates for the synthesis of several bioactive
molecules.
Usesinmedicinalchemistry
Amide bonds are not limited to biological systems and are indeed present in
a huge array of molecules, including major marketed drugs. For example,
Atorvastatin,48 the top selling drug worldwide since 2003, blocks the production of
cholesterol, contains an amide bond (Fig. 1.1), as do Lisinopril49 (inhibitor of
angiotensin
converting
enzyme),
Valsartan50
(blockade
of
angiotensin-II
receptors),51 and Diltiazem (calcium channel blocker used in the treatment of angina
and hypertension).52
18
HO
H 2N
COO H
OH
O
F
N
CO2 H
N
NH
HO2 C
H
H
N
O
Atorvastatin
Lisinopril
O
H 3CO
N
O
CO 2H
H
O
H
O
S
N
HN N
N
N
N
Valsartan
Diltiazem
Figure 1.1: Examples of top drugs containing an amide bond.
Acetaminophen or Paracetamol, an amide is used as analgesic (pain-killer)
and antipyretic (fever reducer). It is commonly used for the relief of headaches,
other minor aches and pains, and is a major ingredient in numerous cold and flu
remedies. Another amide analgesic Phenacetin was introduced in 1887 by Harmon
Northrop Morse. It was one of the first synthetic fever reducers to go on the market.
It is also known historically to be one of the first non-opioid analgesics without antiinflammatory properties. Phenacetin was used in products such as Empirin and APC
(aspirin, phenacetin, and caffeine) tablets.
H
N
HO
H
N
O
O
Paracetamol
Phenacetin
19
O
O
H
N
N
N
O
DEET
Lidocaine
Figure 1.2: Amides with biological activity
Other
commercially
used
amides
include
N,N-dimethyl-m-toluamide
(DEET) which is used as insect repellant and is intended to be applied to the skin or
to clothing, and is primarily used to repel mosquitoes. Lidocaine (Xylocaine) and
dibucaine (Nupercaine) were used as common local anesthetic and antiarrhythmic
drugs. Lidocaine is used topically to relieve itching, burning and pain from skin
inflammations, injected as a dental anesthetic or as a local anesthetic for minor
surgeries.
Uses in industry
Amides are used widely in industry. Amides are found in the plastic and
rubber industry, paper industry, water and sewage treatment and colour, in crayons,
pencils and inks. Acrylamide and polyacrylamide are the products most widely used
in these industries. However, acryl amide is a carcinogen, so can only be used if the
chemicals are not intended for consumption. Polyacrylamide is used in its place,
mainly therefore, in the treatment of drinking water and sewage, as these are
intended for consumption.
CH 2
CH
C
NH 2
n
Polyacrylamide
O
O
C
O
O
C N
H
NH2 ]
Acryl amide
Polyamides
Figure 1.3: Example of acrylamides and Polyamides
20
N
H n
Acryl amides are a family of nylons, including Nomex and Kevlar. Kevlar, a
form of polyamide is a very strong material which is about five times as strong as steel,
weight for weight. It is used in composites for boat construction, in manufacture of
bulletproof vests, and in lightweight mountaineering ropes and skis and racquets.
Nylons are polyamides, first produced on February 28, 1935, by Wallace
Carothers at DuPont's research facility at the DuPont Experimental Station. It was
used for various purposes. Apart from textiles for clothing and carpets, nylon is also
used to make tyre cords.
1.1.6. Lewis acids catalyzed amide formation reactions
Yadav et al.53 have used FeCl3 as Lewis acid catalyst for the synthesis of
C-glycosyl amides from isocyanides in good yields with α-selectivity. The use of
FeCl3 makes this method simple, convenient and cost-effective. This is the first
report on carbon-Ferrier rearrangement using isonitriles as nucleophiles.
O
O
RO
+
FeCl3
R-NC
RO
CH 2Cl2, RT
RO
O
N
H
R
RO
OR
Scheme 1.27: FeCl3 catalyzed amide synthesis
Jae Nyoung Kim and co-workers reported InCl3 has efficiently catalyzed the
synthesis of amides from nitriles.54 The reaction was carried out in toluene at
refluxing temperature with the aid of acetaldoxime as an effective water surrogate to
produce amides in high yields.
O
H
Ph-CN + H C
3
N
OH
InCl 3 ,(5 mol%)
Tolune, ref lux
Ph
Scheme 1.28: InCl3 catalyzed amide synthesis
21
N
H
H
Recently, rare-earth metal triflates have enjoyed extensive applications in a
variety of Lewis acid catalyzed organic reactions. Kumar and co-workers developed
Yb(OTf)3-catalyzed amidoalkyl naphthols from aldehyds in ionic liquids.55
R'
+ R'
R
HN
CHO
O
OH
Yb(OTf) 3
NH 2 +
[bmim] [BF4 ]
R"
R
Scheme 1.29: Yb(OTf)3 catalyzed amide synthesis
22
O
R"
CHAPTER 1
Synthesis of amides using Lewis acid catalyst: Iodine
catalyzed Ritter reaction
Part-2
Iodine-catalyzed synthesis of amides from nitriles via Ritter
reaction
23
1.2.1 Introduction
During the last several decades, Lewis acid catalyzed carbon-nitrogen bond
formation has been extensively studied for organic synthesis. Amide formation
reaction between nitriles and alcohols or alkenes is one of the most important
methods for forming new carbon-nitrogen bond.
1.2.1.1. Ritter reaction
In 1948, J.J. Ritter and P.P. Minieri reported that, treatment of nitriles with
alkenes or tertiary alcohols under acidic conditions resulted in the formation of Ntert-alkylamides (scheme 1.30).56 The formation of
N-alkyl carboxamides from
aliphatic or aromatic nitriles and carbocations is known as the Ritter reaction. Since
its discovery, the Ritter reaction has enjoyed an enormous success and is widely
used for the preparation of acyclic amides as well as heterocycles (e.g. lactams,
oxazolines, etc.). The general features of this reaction are i) the carbocation can be
generated in variety of ways from tertiary, secondary, or benzylic alcohols, alkenes
or alkyl halides; ii) the classical reaction conditions involve the dissolution of the
nitrile substrate in the mixture of acetic acid and concentrated sulfuric acid followed
by the addition of the alcohol or alkene at slightly elevated temperature (50-100 ºC);
iii) alcohols that are easily ionized (e.g. 2˚, and 3˚ alcohols, benzylic alcohols) give
the best results; iv) besides protic acids, Lewis acids (e.g. SnCl4, BF3.OEt2, AlCl3,
etc.) have been successfully employed in the Ritter reaction to generate the required
carbocations; v) the structure of the nitrile compound can be varied widely and most
of the substrates containing a cyano group will undergo the reaction, so, for
example, besides aliphatic and aromatic nitriles, compounds like cyanogen and
cyanamide will also react; and vi) the nitrile substrate may not contain acid sensitive
24
functional groups that would be destroyed under the strongly acid conditions, but
modifications (Ritter-type reactions) that proceed under neutral conditions expanded
the scope of the substrates.
R1
R2
R2
+ R CN
R1
R3
OH
+ R CN
H 2SO 4 /AcO H
H 2O
O
R
N
H
R
1
R2
Me
R1
O
H2 SO4 / AcOH
H2O
R
N
H
R2
R3
Scheme 1.30: Ritter reaction
The Ritter reaction is most useful in the formation of new carbon-nitrogen
bonds, especially in the formation of amides in which the nitrogen has a tertiary alkyl
group. Real world applications include Merck’s industrial-scale synthesis of anti-HIV
drug Crixivan (indinavir);57 the production of the falcipain-2 inhibitor PK 11195; the
synthesis of the alkaloid aristotelone;58 and synthesis of Amantadine, an antiviral and
antiparkinsonian drug.59 Other applications of the Ritter reaction include synthesis of
dopamine receptor ligands and production of amphetamine from allylbenzene.60
1.2.1.2. Iodine
Iodine was discovered in 1811 by French chemist Bernard Courtois (17771838). Iodine is one of the most abundant elements and its toxicity is relatively low. The
element occurs primarily in seawater and in solids formed when seawater evaporates. It
also exist in nature from many sources such as iodide ions in brines, as an impurity in
chile saltpeter and main natural source of iodine is kelp (2000kg seaweed=1kg iodine).
World demand for iodine and organic iodine compounds is as follows: X-ray
contrast media (21 %), disinfectants and biocides (20 %), medium of organic reactions
(19 %), medicines and pharmaceuticals (16 %), animal feeds (9 %), herbicides (4 %),
and photographics (3 %). Chemical functional ability of iodine as disinfectant or biocide
25
comes from the oxidizing ability of iodine itself, especially for SH groups to disulfides,
iodination of aromatic rings in tyrosine and histidine in proteins. Thus, iodine is one of
the most simple, less expensive, less toxic oxidants. Today, iodine is an old reagent;
however, in view of various functionalizing abilities, it is important as an
environmentally benign reagent for organic functional group conversions. The reports
on the recent synthetic utility of iodine in organic synthesis are discussed in the
literature section.
1.2.2. Review of literature
1.2.2.1. Ritter reactions
To date several methods have been reported in literature for synthesis of
amides via Ritter reaction using various catalysts.
Barton et al. (1974)61: N-alkylated amides were prepared from nitrile and
alcohols. Chlorodiphenylmethylium hexachloroantimonate was used as catalyst for
the activation of primary and secondary alcohols.
R1
OH
+ RCN
1) Ph2 CClSbCl6
R1
H
N
2) H 2O
R
O
Scheme 1.31
Martinez et al. (1989)62: They synthesized amide from alcohols and nitriles.
Here they have used triflic anhydride for activation of alcohols to obtain good yield.
R2
R1
R3
OH
+ RCN
1) Tf 2O, CH 2 Cl2
R1
2) NaHCO 3
R2
H
N
R3
R
O
Scheme 1.32
Lebedev et al. (2002)63: N-Primary-alkyl amides were obtained by a Ritter-type
reaction of nitriles with lower primary alcohols or their esters in the presence of acid.
26
1) alkyl donor, acid
RCN
1
R
2) H 2O
H
N
R
O
Acids: H 2SO4 , PPA, Tf OH,ClSO3H
alkyl donors: MeCO OR 1, B(OR)3 , R1 SO2 Me, OP(OR)3
Scheme 1.33
Reddy et al. (2003)64: Aromatic and aliphatic nitriles react with tert-butyl
acetate in the presence of a catalytic amount of sulfuric acid to give the
corresponding N-tert-butyl amides in excellent yields.
O
CN
+
X
O
Me
H2 SO4 (cat)
O
Me
Me
N
H
42 °C
Me
X
X : H, OMe, CF3, CF3O, CO 2Me, F, Br, SMe
Ar : phenyl, naphthyl, pyridyl and thiophenyl
Scheme 1.34
Jaouen et al. (1981)65: Benzyl alcohol derivatives reacted with nitriles in the
presence of chromium tricarbonyl complexes to give corresponding amides and the
complex provided stereochemical controlled product.
R CN
OH
H2SO 4
R
OC
Cr
CO
CO
R1
R1
HO
2
O
R
R : Me, OMe, H,
R1 : H, Me, Ph
R2 : Me, Ph
OC
Cr
CO
HN
CO
O
Me
MeCN
H2SO4
OC
Cr
Cr
OC CO CO
CO CO
racemic mixture
89 % Yield
optically pure
Scheme 1.35
27
R2
Warren et al. (2002)66: They reported electrophilic activation of Ritter
reaction for alkenes with nitriles.
O
R
M eCN
E
+ E
R
HN
H2 O
E
Me
E
R
+ R
H
N
Me
O
Scheme 1.36
Lewisacidcatalyzed Ritterreactions:
Callens et al. (2006)67: N-tert-Alkyl and aryl amides were obtained by a
Ritter reaction of various nitriles with tertiary alcohols in the presence of a catalytic
amount of bismuth triflate.
RCN + HO
Me
Me
Me
1) Bi(OTf) 3
Me
Me
Me
2) H 2O
O
N
H
R
R= alkyl, aryl
Scheme 1.37
Reymond and Cossy et al. (2009)68:
A safe and inexpensive synthesis of
amides, from benzylic alcohols and nitriles and from t-butyl acetate and nitriles,
using a Ritter reaction catalyzed by FeCl3·6H2O was described.
O
FeCl3 .6H2 O
RCN
t-BuOAc, H2 O, 150 °C
OH
RCN +
Ar
R1
R
N
H
NHCOR
FeCl3 .6H2 O
H 2O , 150 °C
t-Bu
Ar
R1
Scheme 1.38
Varma et al. (2008)69: They have developed an atom-economic solvent-free
synthesis of amides by the Ritter reaction of alcohols and nitriles under microwave
28
irradiation. This green protocol was catalyzed by solid-supported Nafion®NR50 with
improved efficiency and reduced waste production.
OH
CN
O
Nafion®NR50
+
R1
N
H
MW, 130 °C
1
R2
R
R2
R 1= H, OMe, Cl
R 2= H, Cl, Me, O Me, naphthyl, etc
Scheme 1.39
Tamaddon et al. (2007)70: Tertiary alcohols as well as primary and
secondary benzylic alcohols react efficiently with nitriles to give the corresponding
amides in good to excellent yields in the presence of P2O5/SiO2 (60% w/w).
R C N + R1 O H
O
P2O5/SiO2 (60% w/w)
Heat or MW
R
1
N R
H
R 1= Ph, t-Bu
R= Ph, Me, C=C,
Scheme 1.40
1.2.2.2. Iodine catalyzed transformations
Iodine has been attracting much attention in synthetic organic chemistry since its
discovery in 1811. It is the weakest oxidizer among the halogens and a poor electrophile
that often needs the assistance of strong acid. Iodine has several advantages over the
vast majority of the other Lewis-acid catalysts, especially the metallic catalysts. Its
catalytic potential is intriguingly broad.
Many Iodine-catalyzed transformations have been reported in literature. The
reports on the recent synthetic utility of iodine in organic synthesis are discussed below.
In the C–C bond formation reactions
A mild, metal-free, and environmentally benign iodine-promoted regioselective
C−C and C−N bonds formation of N-protected indole derivatives giving 2,3′-biindoles
29
and 4-(1H-indol-2-yl)morpholines
has been successfully demonstrated. Various
bioactive 2, 3′-biindoles and 4-(1H-indol-2-yl) morpholines, bearing electron-rich to
moderately electron-poor substituents, can be prepared in moderate to good yields.71
1equiv I 2
R1
R1
NaHCO 3, Rt
N
R2
N
N
R2
R1
R 1= H, M e, Br, OMe
R 2= H, M e, allyl, Bn
HN
R1
N
R2
O
I 2 , Cs 2CO3, Rt
R1
O
N
N
R2
R2
Scheme 1.41: Iodine catalyzed carbon-carbon bond formation
Intramolecular cyclization of enamines
The synthesis of 3H-indoles was achieved via the iodine-mediated
intramolecular cyclization of enamines. A wide variety of 3H-indole derivatives
bearing multifunctional groups were obtained in good to high yields under transition
metal-free reaction conditions.72
R3
R2
N
H
R1
R
R 3 R2
I2
R1
R
base
N
Scheme 1.42: Iodine catalyzed indole synthesis
Treatment of olefins bearing an active methylene group, such as allyl ethyl
malonate and α-alkenyl β-ketoesters with iodine in benzene or CH2Cl2 results in
fused cyclopropane lactone and fused cyclopropane β-ketoester respectively.73
O
O
O
OEt
I 2 (1.2 equiv)
K2 CO 3 (2.4 equ iv)
T oluene
O
O
EtO2 C
I 2 (4 equiv)
O
OEt
Et3 N (2 .5 equ iv)
M g(ClO4 )2 (2.0 equiv
O
O
CO 2Me
CH2 Cl2 , rt
Scheme 1.43: Iodine catalyzed fused cyclopropane lactone synthesis
30
Iodine as acetylation catalyst
While the catalytic activity of iodine in the acetylation of alcohols with
acetic anhydride was being studied by Deka and co-workers,74 the following
conversion was observed in more than 90% yield in a short reaction time.
RCHO + Ac 2O
I2
RCH(O Ac) 2
CHCl3
R = alkyl, aryl
Scheme 1.44: Iodine catalyzed acetylation
Protection of carboxylic acids as esters using iodine catalyst
Carboxylic acids with a catalytic amount of iodine in methanol provides the
corresponding methyl esters smoothly.75 The reaction is not possible with acidic
aromatic carboxylic acids and iodine is assumed to oxidize methanol partly during
the course of this reaction.
I2 (1.0 equiv)
R COOH
R COOM e
MeOH,
Scheme 1.45: Iodine catalyzed ester synthesis
Iodine in one-pot three-component synthesis
Iodine has been found to be an effective catalyst for one-pot synthesis of
homoallyl benzyl ethers under mild reaction conditions.76 Various homoallyl benzyl
ethers were synthesized in moderate to high yields by three-component condensation
of aldehydes, benzyloxytrimethylsilane, and allyltrimethylsilane in presence of
iodine (10 mol %) in dichloromethane at 0 °C.
O
R
H
+
OSiMe3
+
SiMe3
I 2 (10 mol%)
DCM, 0 °C
O
R
Scheme 1.46: Iodine catalyzed homoallyl benzyl ether synthesis
31
Iodine catalyzes efficiently the three-component condensation of aldehydes,
benzyl carbamate, and allyltrimethylsilane to afford the corresponding protected
homoallylic amines in excellent yields.77
O
R
H
+ Cbz NH2
SiMe3
+
NHCbz
I2 (10%), CH3 CN
R
RT
Scheme 1.47: Iodine catalyzed homoallylic amines synthesis
Iodine-catalyzed oxidation reactions
Aromatic and aliphatic thiols can be smoothly oxidized to the corresponding
disulfides by iodine in the presence of pyridine at room temperature as shown in
Scheme 1.48.78
RSH
I 2, pyridine
rt
RSSR
Scheme1.48: Iodine catalyzed oxidation
Yadav et al.79 demonstrated the aromatization of 4-substituted Hantzsch 1,4dihydropyridines to the corresponding pyridines in high yields by iodine in
methanol.
R
R
ErO2C
Me
CO2Et
N
H
Me
I2 (1.0 equiv)
M eOH
ErO2 C
Me
CO2 Et
N
Me
Scheme 1.49: Iodine catalyzed aromatization
Jun Ji and co-workers reported,80 the electrophilic substitution reactions of
indoles with various aromatic aldehydes using a catalytic amount of I2 under
solvent-free conditions. The corresponding bis(indolyl)methanes were obtained in
excellent yields.
32
Ar H
+ Ar C HO
N
H
I2
r.t., So lve nt F re e
N
H
N
H
Scheme 1.50: Iodine catalyzed bis(indolyl)methane synthesis
Panneer Selvam et al. have described a convenient and efficient one-pot
synthesis of substitutedamidophenols using iodine as catalyst at room temperature
under neat condition.81
O H NHAc
CHO
OH
R
I2 (4 mol%)/ CH3 CN
+
R1
AcCl, rt,
R1
R
Scheme 1.51: Iodine catalyzed amidophenol synthesis
Iodine was established as a good mediator and reagent in organic synthesis.82
For a long time iodine has been recognized as a good catalyst and reagent in
carbohydrate chemistry also.83 Recently Marjan Jereb et al.84 reported many
transformations of molecules containing oxygen functional groups using iodine as
catalyst.
1.2.3. Present work
In recent years there has been considerable interest in the one-pot reaction
using Lewis acid as catalyst due to their diversity, efficiency and rapid access to
complex and highly functionalized organic molecules. Pioneering work by several
research groups in this area has already established the versatility and uniqueness of
one-pot synthetic protocols as a powerful methodology for the synthesis of diverse
structural scaffolds required in the search of novel therapeutic molecules. In the past
decade there have been tremendous developments in the iodine catalyzed one-pot
reactions and great efforts have been paid to find and develop newer methodologies.
33
Several iodine catalyzed transformations have been reported in literature
using alcohols such as benzyl, allyl, and propargyl alcohols as starting materials that
reacted with various nucleophiles in the presence of 2-20 mol % of I2 to form the
corresponding products. The property of iodine to catalyze the elimination of water
from hydroxy compounds has been known for almost a century85 while primary and
secondary benzylic alcohols furnished ethers at elevated temperatures under solvent
free reaction conditions. Benzylic and aliphatic alcohols were converted into nitriles
in the presence of a twofold excess of iodine in aqueous NH4OAc and many such
transformations were reported but there is no report found in literature for the
synthesis of amides from alcohols and nitriles using iodine as catalyst. Therefore, we
have planned to study the iodine catalyzed Ritter reaction for the synthesis of
amides. In this work, we have developed a simple and practical method for the
synthesis of amides and N-tert-butyl amides starting from nitriles and alcohols
(Scheme 1.52).
O
OH
R
R1
HN
+
R1 -CN
I2 (20 mol %)
R
H2O (2 equiv), 110 ºC
(I,II,III)
O
O
O
I2 (20 mol %)
+ R-CN
H2 O (2 equiv), 110 ºC
R
N
H
R = R 1= alkyl, aryl
Scheme 1.52: Iodine catalyzed Ritter reaction
1.2.4. Results and discussion
The activation of alcohols to generate the carbocation is thought to be
difficult due to the poor leaving ability of the -OH group in the absence of any
catalyst. In the present study, alcohols I–IV and the tert-butyl acetate were used
34
with a variety of aromatic/aliphatic nitriles for the synthesis of the corresponding
amides.
Reaction of 1-phenylethanol (I) with acetonitrile was taken as a model
reaction to optimize the reaction conditions.
After several trials, iodine with two equivalents of water was found to be the
best to provide the desired amide in good yield. To optimize other reaction
conditions, the reaction was performed using different solvents and toluene was
found to be superior to others. The reaction was also monitored to find out the
influence of different concentration of the catalyst using toluene as solvent and 20
mol% of iodine was found to be the optimum. To find out the optimum temperature,
the reaction was carried out at different temperatures and even at reflux conditions
the conversion was found to be only 50% and this prompted us to study the reaction
using sealed tubes. The reaction worked in a much better way at 110 ˚C in a sealed
tube (Table 1.1).
Table 1.1 Iodine - catalyzed Ritter reaction of I with MeCN in different solvents.
O
OH
CH 3
CH3
HN
+ CH 3CN
I
I2 (20 mol %)
CH 3
H2O (2 equiv),
Entry
1
Solventa
MeNO2
Temp (˚C )
100
Time (h) Conversion (%)b
8
50
2
MeNO2
50
8
10
-
3
Toluene
110
4
100
85
4
Xylene
150
4
100
80
5
THF
80
6
30
-
a
Alcohol I (1 mmol ), nitrile (1.1 mmol), solvent (10 volume), sealed tube
b
Conversion of I monitored by LC-MS
c
Isolated yield
35
Yield (%)c
-
The conditions described in the entry 3 of Table 1.1 were found to be
suitable for the synthesis of various other amides in good yields, and the results are
summarized in Tables 1.2 and 1.3.
The generality and scope of this protocol was evaluated for both aromatic
and aliphatic alcohols, and a variety of nitriles. In all these cases, the Ritter reaction
proceeded and yielded the desired amides in good to excellent yields including some
novel amides (entries 3, 7, 9, 10, 11, 15, 19). When secondary benzyl or tert-butyl
alcohols are used as substrates, amides are produced in good yields. On the other
hand primary benzyl alcohol on treatment with phenyl cyanide under the same
conditions, disappointingly, resulted in a very low conversion (10%).
Table 1.2 Ritter reaction of various alcohols and nitriles catalyzed by iodine
O
OH
R
R1
HN
+
R1 -CN
I2 (20 mol %)
R
H2 O (2 equiv), 110 ºC
Time
(h)b
Yield
(%)c
1
4.0
8568
2
4.0
8468
3
4.0
60†
5.0
6286
Entrya
Alcohol
Nitrile
Amide
4
36
5
5.0
6487
4.0
7588,89
O
HN
6
6
3.0
91†
6.0
4490
4.0
66 †
4.0
88 †
6.0
82†
12
5.0
8068
13
6.0
8568
5.0
6051
6.0
70†
7
Br
OH
8
II
Br
OH
9
II
Br
OH
10
II
Br
OH
O
Br HN
11
II
14
11
CN
Cl
15
37
16
6.0
6691,92
17
5.0
9593
18
6.0
4091
7.0
76 †
20
8.0
6064
21
8.0
6364
F
O
HN
19
19
a
alcohol (1 mmol ), Nitrile (1.1 mmol), Solvent ( 10 volume), 110 ˚C, sealed tube
Reactions were monitored by LC-MS
c
Isolated yield
†
Novel compounds
b
1.2.5. Plausible mechanism
In the mechanism proposed, we invoke the formation of ether as suggested in
70
the Ritter reaction of alcohols catalyzed by FeCl3. 6H2O.
The ether leads to the
formation of carbocation which attacks the nitrile to give the amide. When the
reaction was carried out in the absence of water, it has been observed that, ether B
was the major product and no amide was formed. While ether formation was
observed at low temperatures (60 ˚C), at higher temperatures (110 ˚C) amide was
found to be the only product (Scheme 1.53).
38
OH
I2 (20 mol %)
O
MeCN,
110 oC
B
I 2 (20 mol%),
H 2O (2 equiv)
MeCN, 60 oC
I
NHAc
1
Scheme 1.53
In one of the experiments, ether B was isolated and confirmed by NMR. The
plausible mechanism for the iodine catalyzed Ritter reaction is given in Scheme
1.54. It is presumed that iodine catalyzes the reaction as a mild Lewis acid.71 The
molecular iodine is believed to activate the alcoholic OH to give intermediate A,
which on combination with another alcohol molecule yields the ether B. In the
presence of iodine, B may afford C which may then be converted to the carbocation
D. The attack of the carbocation on the nitrile followed by water addition may
provide the amide.
I2
Ph
Ph
I
I2
OH
OH
O
B
Ph
Ph
I
I2
Ph
O
Ph
A
I2
Ph
C
MeCN
O
HN
D
Me
H2O
Ph
N
Ph
1
C
Me
E
Scheme 1.54
Next, we turned our attention to the synthesis of N-tert butyl amides from
tert- butyl acetate and nitriles under the reflux conditions. As the yields with the
tert-butyl alcohol are less, tert-butyl acetate has been used as the carbocationic
source. In an earlier report, synthesis of tert-butyl amides has been achieved using
H2SO4 and acetic acid at room temperature54 where they describe the convenient
39
synthesis of only the tert-butyl amides but the present protocol can be effectively
used for the synthesis of both benzyl and tert-butyl amides.
Though the reaction was carried out at high temperature (110 ˚C), our
method avoids the use of corrosive H2SO4 and uses only catalytic amount of iodine.
Therefore this is an eco-friendly reaction. This reaction is useful to prepare bulky
amides, which may be useful in the preparation of the hindered amines by
hydrolysis.61
O
O
O
I2 (20 mol %)
+ R-CN
R
H2O (2 equiv), 110 ºC
N
H
Scheme 1.55
The scope of this reaction was investigated by examining a variety of nitriles
and in most of the cases, using the same conditions, the reaction proceeded smoothly
in a few hours with good yields and the results are summarized in Table 1.3.
Table 1.3 Ritter reaction of various nitriles with tert-butyl acetate catalyzed by
iodine
O
+
O
Entrya
Nitrile
ArCN
O
I 2 (20 mol %)
H 2 O (2 eq uiv), 110 ºC
Amide
Ar
N
H
Time (h)
Yield (%)c
6.0
6564
6.0
4496
5.0
87†
O
1
CN
N
H
20
O
2
CN
N
H
Cl
Cl
22
O
3
CN
N
H
23
40
O
4
O2N
O 2N
CN
N
H
7.0
81†
6.0
86†
6.0
7294
6.0
8664
4.0
8364
6.0
80†
5.0
8295
24
O
CN
5
MeO
NO 2
N
H
MeO
NO 2
25
O
6
N
N
CN
N
H
26
O
7
CN
N
H
CF 3
F3 C
27
O
8
CN
N
H
Me O
MeO
28
H
N
CN
9
O
F
F
29
H
N
CN
10
Br
O
Br
30
a
Nitrile (1.1 mmol), tert-butyl acetate (2 mmol ), Solvent ( 10 volume), 110 ˚C,
Reactions were monitored by LC-MS
c
Isolated yield after column chromatography
†
Novel compounds
b
1.2.6. Conclusion
In conclusion we have developed a simple, convenient and efficient protocol
for the synthesis of amides and N-tert-butyl amides from alcohols, tert-butyl acetate
and nitriles by Ritter reaction using catalytic amount of iodine in a sealed tube. This
catalytic reaction is an inexpensive and eco-friendly process.
41
1.2.7. Experimental section
General experimental procedure for the synthesis of amides: A mixture of
alcohol (1 mmol), nitrile (1.1 mmol), iodine (20 mol%) and water (2 equiv) were
placed in a sealed tube and heated to 110 ˚C for the appropriate time as mentioned in
Table 1.2. After completion of the reaction (reaction monitored by TLC), saturated
sodium thiosulfate in water was added and extracted with EtOAc. The organic layer
was separated and washed with water, brine and dried over sodium sulfate,
concentrated to furnish the desired amides. When ever necessary, the obtained
amides were purified by crystallization using petroleum ether/ethyl acetate (8:2).
General experimental procedure for the synthesis of tert-butyl amides: A
mixture of tert-butyl acetate (2 equiv), nitrile (1 mmol), iodine (20 mol%) and water
(2 equiv) were placed in a RB flask and heated to110 ˚C for the appropriate time as
mentioned in Table 1.3. After completion of the reaction (reaction monitored by
TLC), saturated sodium thiosulfate in water was added and extracted with EtOAc,
the organic layer was separated and washed with water, brine and dried over sodium
sulfate and concentrated. The obtained tert-butyl amides were purified by flash
chromatography.
1.2.8. Characterization of the products
Melting points, IR, LC-MS and 1H,
13
C, NMR, data of some unknown
compounds are given below. All other known compounds data were cross checked
with reported data in literature.
4-Isopropyl-N-(1-phenylethyl)benzamide (3): Off-white solid. Isolated yield:
60%, mp 129-130 ˚C. IR (neat): 3335, 1632 cm-1.1H NMR (DMSO-d6): δ (ppm)
8.73 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H) 7.3-87.41 (m, 2H), 7.30–7.34 (m,
42
4H), 7.20-7.24 (m, 1H), 5.18 (m, 1H), 2.96 (m, 1H), 1.48 (d, J=7.2 3H), 1.23 (d, J =
6.8 Hz, 6H).
13
C NMR (DMSO-d6): δ 165.93, 152.18, 145.51, 132.70, 128.66,
127.98, 126.99, 126.55, 126.50, 48.81, 33.83, 24.14, 22.75. MS: m/z Calcd for
C18H21NO: 267.16; Found: 268.2 (M+). Anal. Calcd for C18H21NO: C, 80.86; H,
7.92; N, 5.24; O, 5.98%. Found: C, 80.80; H, 7.99, N, 5.22%.
2-(4-Bromophenyl)-N-(1-phenylethyl)acetamide (7): Isolated yield: 91%, mp
111-112 ˚C. IR (neat): 3285, 1644 cm-1.1H NMR (DMSO-d6): δ (ppm) 8.56 (d, J =
7.6 Hz, 1H), 7.49 (m, 1H), 7.29–7.33 (m, 4H), 7.20-7.20 (m, 3H), 4.92 (m, 1H), 3.44
(s, 2H), 1.36 (d, J = 6.8 Hz, 3H).
13
C NMR (DMSO-d6): δ 169.17, 145.02, 136.37,
131.71, 131.48, 128.71, 127.09, 126.38, 119.98, 48.43, 42.01, 22.97. MS: m/z Calcd
for C14H16BrNO: 318.22; Found: 320 (M+2). Anal. Calcd for C14H16BrNO: C,
60.39; H, 5.07; Br, 25.11; N, 4.40; O, 5.03%. Found: C, 60.37; H, 5.09; N, 4.25%.
N-(1-(2-Bromophenyl)ethyl)benzamide (9): White solid. Isolated yield: 66%, mp:
168-169 oC. IR (neat): 3296, 1630 cm-1. 1H NMR (DMSO-d6): δ (ppm) 8.98 (d, J =
7.2 Hz, 1H), 7.89–7.91 (m, 2H), 7.53-7.60 (m, 3H), 7.47–7.50 (t, 2H), 7.36–7.39 (t,
1H), 7.16–7.20 (m, 1H), 5.4 (m, 1H) 1.45 (d, J = 7.2 Hz, 3H).
13
C NMR (DMSO-
d6): δ 166.11, 144.60, 134.78, 132.94, 131.74 129.10, 128.70, 128.53, 127.90,
127.46, 122.48, 49.06, 21.53. MS: m/z Calcd for C15H14 BrNO: 304.18; Found: 330
(M+2).Anal. Calcd for C15H14BrNO: C, 59.23; H, 4.64; N, 4.60; O, 5.26%. Found:
C, 59.20; H, 4.67; N, 4.55%.
N-(1-(2-Bromophenyl)ethyl)-4-isopropylbenzamide
(10):
-1
White
solid.Isolated
1
yield: 88%, mp: 183-184 ˚C. IR (neat): 3337, 1632 cm . H NMR (DMSO-d6): δ
(ppm) 8.98 (d, J = 7.6 Hz, 1H), 7.852 (d, J = 8.0 Hz 2H), 7.52-7.59 (m, 2H), 7.33–
7.38 (m, 3H), 7.15–7.19 (m, 1H), 5.36-5.40 (m, 1H), 2.5–2.51 (m, 1H) 1.44 (d, J =
43
6.8 Hz 3H), 1.23 (d, J = 6.8 Hz, 6H).
13
C NMR (DMSO-d6): δ 166.04, 152.33,
144.71, 132.91, 132.47, 129.03, 128.47, 128.05, 127.46, 126.57, 122.50, 49.02,
33.85, 24.14, 21.54. MS: m/z Calcd for C18H20BrNO: 345.07; Found: 346 (M+).
Anal. Calcd for C15H14BrNO: C, 62.44; H, 5.82; Br, 23.08; N, 4.05; O, 4.62%.
Found: C, 62.40; H, 5.84; Br, 23.10; N, 4.0%.
N-(1-(2-Bromophenyl)ethyl)-2-phenylacetamide (11): White solid. Isolated yield:
-1 1
82%, mp: 158–159 ˚C. IR (neat): 3236, 1638 cm . H NMR (DMSO-d6): δ (ppm)
8.74 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz 1H), 7.14–7.41 (m, 8H), 5.09-5.16 (m,
1H), 3.4 (s, 2H), 1.32 (d, J = 6.8 Hz, 3H).
13
C NMR (DMSO-d6): δ 169.67, 144.28,
136.75, 132.95,129.44, 129.08, 128.60, 128.42, 127.24, 126.76, 122.45, 48.43,
42.65, 21.75. MS: m/z Calcd for C16H16BrNO: 318.21; Found: 320 (M+2). Anal.
Calcd for C15H14BrNO: C, 60.39; H, 5.07; Br, 25.11; N, 4.40; O, 5.06%. Found: C,
60.28; H, 5.12; N, 4.2%.
N-Benzhydryl-4-isopropylbenzamide (15): White solid. Isolated yield: 70%, mp:
166–168 ˚C. IR (neat): 3333, 2959, 1493 cm-1. 1H NMR (DMSO-d6): δ (ppm) 9.21
(d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.33–7.39 (m, 10H), 7.25–7.30 (m,
2H), 6.4 (d, J = 8.8 Hz, 1H), 2.96 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H).
13
C NMR
(DMSO-d6): δ 166.35, 152.38, 142.89, 132.52, 128.52, 128.28, 127.41, 126.56,
56.75, 33.86, 24.13. MS: m/z Calcd for C23H23NO: 329.4; Found: 330 (M+). Anal.
Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25; O, 4.86%. Found: C, 83.98; H,
7.09; N, 4.21%.
N-Benzhydryl-2-(3-fluorophenyl) acetamide (19): White solid. Isolated yield:
76%, mp: 147–148 ˚C. IR (neat): 3293, 1650 cm-1. 1H NMR (DMSO-d6): δ (ppm)
9.07 (d, J = 8.8 Hz, 1H), 7.34-7.37 (m, 5H), 7.24–7.32 (m, 6H), 7.04–7.13 (m, 3H),
44
6.12 (d, J = 8.4 Hz, 1H), 3.60 (s, 2H),
13
C NMR (DMSO-d6): δ 169.32, 163.69,
161.28, 142.86, 139.64, 139.57, 130.4, 128.83, 127.81, 127.43, 125.63, 116.3, 113.7,
113.49, 56.56, 42.17. MS: m/z Calcd for C23H23NO: 319.37; Found: 320.2 (M+).
Anal. Calcd for C23H23NO: C, 78.98; H, 5.68; F, 5.95; N, 4.39; O, 5.01%. Found: C,
78.76; H, 5.73; N, 4.21%.
N-tert-butyl-4-isopropylbenzamide (23): White solid. Isolated yield: 87 %, mp:
148-149 ˚C. IR (neat): 3333, 1633 cm-1. 1H NMR (DMSO-d6): δ (ppm) 7.70–7.72
(m, 2H), 7.6 (s, 1H), 7.30-7.28 (m, 1H), 2.90-2.96 (m, 1H), 1.37 (s, 9H), 1.22 (d, J =
8.0 6H).
13
C NMR (DMSO-d6): δ 166.76, 151.67, 134.10, 127.90, 126.32, 51.10,
33.78, 29.08. 24.17. MS: m/z Calcd for C14H21NO: 219.32; Found: 220.2 (M+).
Anal. Calcd for C14H21NO: C, 76.67; H, 9.65; N, 6.39; O, 7.29%. Found: C, 76.12;
H, 9.83; N, 6.2%.
N-tert-butyl-2-methyl-5-nitrobenzamide (24): White solid. Isolated yield: 81%, mp:
100–102 ˚C. IR (neat): 3386, 1650 cm-1. 1H NMR (DMSO-d6): δ (ppm) 8.15-8.18 (m,
2H), 8.02 (s, 1H), 7.54 (d, J = 8.4 1H), 2.43 (s, 3H), 1.38 (s, 9H). 13C NMR (DMSO-d6):
δ 167.15, 145.63, 143.81, 139.78, 132.07, 123.81, 122.04, 51.47, 28.86, 19.70. MS: m/z
Calcd for C12H16N2O3: 236.27; Found: 237.0 (M+). Anal. Calcd for C12H16N2O3: C,
61.00; H, 6.83; N, 11.86; O, 20.32%. Found: C, 61.12; H, 7.55; N, 11.74%.
N-tert-butyl-4-methoxy-2-nitro-benzamide (25): White solid. Isolated yield: 86%, mp:
101–102 ˚C. IR (neat): 3232, 1626 cm-1. 1H NMR (DMSO-d6): δ (ppm) 8.13 (s, 1H),
7.47–7.52 (m, 2H), 7.27–7.30 (m, 1H), 3.87 (s, 3H), 1.34 (s, 9H). 13C NMR (DMSO-d6):
δ 165.31, 160.24, 148.63, 130.85, 126.47, 119.02, 109.36, 56.59, 51.31, 28.71. MS: m/z
Calcd for C12H16N2O4: 252.26; Found: 253.2 (M+). Anal. Calcd for C12H16N2O4: C, 57.13;
H, 6.39; N, 11.10; O, 25.37%. Found: C, 57.05; H, 6.45; N, 11.13%.
45
N-tert-butyl-2-(3-fluorophenyl)acetamide (29): White solid. Isolated yield: 86%,
mp: 105–106 ˚C. IR (neat): 3280, 1644 cm-1. 1H NMR (DMSO-d6): δ (ppm) 7.73 (s,
1H), 7.30–7.36 (m, 1H), 7.02–7.08 (m, 3H), 3.38 (s, 2H), 1.25 (s, 9H).
13
C NMR
(DMSO-d6): δ 169.48, 163.68, 161.26, 140.21, 130.38, 125.47, 116.15, 113.48,
50.55, 43.02, 28.90. MS: m/z Calcd for C12H16FNO: 209.26; Found: 210.2 (M+).
Anal. Calcd for C12H16FNO: C, 68.88; H, 7.71; F, 9.08; N, 6.69; O, 7.65%. Found:
C, 68.92; H, 7.67; N, 6.65%.
46
1.2.8.1. Spectras
O
HN
1
H NMR (400 MHz, DMSO-d6) of Compound 3
O
HN
13
C NMR (100 MHz, DMSO-d6) of Compound 3
47
Br
O
HN
1
H NMR (400 MHz, DMSO-d6) of compound 7
Br
O
HN
13
6
C NMR (100 MHz, DMSO-d ) of compound 7
48
O
Br HN
1
H NMR (400 MHz, DMSO-d6) of compound 9
O
Br HN
13
6
C NMR (100 MHz, DMSO-d ) of compound 9
49
O
Br HN
1
H NMR (400 MHz, DMSO-d6 ) of compound 10
O
Br HN
13
C NMR (100 MHz, DMSO-d 6) of compound 10
50
O
N
H
1
H NMR 400 MHz, DMSO-d6) of compound 15
O
N
H
13
6
C NMR (100 MHz, DMSO-d ) of compound 15
51
F
O
HN
1
H NMR (400 MHz, DMSO-d6 ) of compound 19
F
O
HN
13
6
C NMR (100 MHz, DMSO-d ) of compound 19
52
O
N
H
1
H NMR (400 MHz, DMSO-d6 ) of compound 23
O
N
H
13
6
C NMR 100 MHz, DMSO-d ) of compound 23
53
O
O2 N
1
N
H
H NMR (400 MHz, DMSO-d6 ) of compound 24
O
O2 N
13
N
H
6
C NMR (100 MHz, DMSO-d ) of compound 24
54
O
MeO
1
N
H
NO2
H NMR (400 MHz, DMSO-d6 ) of compound 25
O
N
H
NO2
MeO
13
6
C NMR (100 MHz, DMSO-d ) of compound 25
55
H
N
O
F
1
H NMR (400 MHz, DMSO-d6 ) of compound 29
H
N
O
F
13
6
C NMR (100 MHz, DMSO-d ) of compound 29
56
O
Br HN
57
O
HN
58
1.3. References
1.
Arrhenius, S. A. in PhD‐Thesis, Norstedt, P. A. Stockholm, 1884.
2.
(a) Lowry, T. M. J. Soc. Chem. Ind. 1923, 42, 1048. (b) Brönsted, J. N. Recl. Trav. Chim.
Pay. B. 1923, 42, 718.
3.
(a) Lewis, G. N. J. Franklin Inst. 1938, 226, 293. (b) Lewis, G. N.; Seaborg, G. T. J. Am.
Chem. Soc. 1939, 61, 1886.
4.
Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533.
5.
Engberts, J. B. F. N.; Feringa, B. L.; Keller, E.; Otto, S. Recl. Trav. Chim. Pay. B. 1996, 115,
457.
6.
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
7.
Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
8.
Helmboldt, O.; Keith Hudson, L.; Misra, C.; Wefers, K.; Heck, W.; Stark, H.; Danner, M.;
Rösch, N. in Ullmann's Encyclopedia of Industrial Chemistry, Wiley‐VCH Verlag GmbH &
Co. KGaA, 2000.
9.
Friedel, C.; Crafts, J. M.; Hebd. C. R. Séances Acad. Sci. 1887, 84, 1392.
10. (a) Ziegler, K.; Holzkamp, E.; Breil, H.; Martin, H. Angew. Chem., Int. Ed. 1955, 67, 541. (b)
Natta, G. Angew. Chem. 1964, 76, 553.
11. Friedel, C.; Crafts, J. M. J. Chem. Soc. 1877, 32, 725.
12. Rueping, M.; Nachtsheim, B. J. Beilstein. J. Org. Chem. 2010, 6, 6.
13. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. (b) Mukayama, T.;
Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
14. (a) Kobayashi, S. Chem. Lett. 1991, 2187. (b) Kobayashi, S. Hachiya, I. J. Org. Chem. 1994,
59, 3590.
15. Kobayashi, S. Chem. Lett. 1991, 2087.
16. Yamamoto, Y.; Asoa, N. Chem. Rev. 1993, 93, 2207.
17. Hachiya, I.; Kobayashi, S. J. Org. Chem. 1993, 58, 6958.
18. Kobayashi, S.; Hachiya, I.; Yamanoi, Y. Bull. Chem. Soc. Jpn. 1994, 67, 2342.
19. (a) Davies, H. M. L.; Dai, X. J. Am .Chem. Soc. 2004, 126, 2692. (b) Niess, B.; Hoffmann, H.
M. R. Angew. Chem. Int. Ed. 2005, 44, 26.
20. Davies, H. M. L.; Dai, X. J. Org. Chem. 2005, 70, 6680.
21. Lambert. T. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 13646.
59
22. Zhang, Y.; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038.
23. Hintermann, L.; Tongni, A. Helv, Chim. Acta, 2000, 83, 2425.
24. Vatele, M. J. Tetrahedron 2010, 66, 904.
25. Preston, A.; Jurca, C. T; Stephan, D. W. Chem. Commun. 2008, 1701.
26. Keller, E.; Feringa, B. L. Tetrahedron Lett. 1996, 37, 1879.
27. Kobayashi, S.; Ishitani, C J. Chem. Soc. Chem. Commum. 1995, 1379.
28. Carl R. Kemnitz C. R.; Loewen, M. J. J. Am. Chem. Soc. 2007, 129, 2521.
29. Jursic, B.S.; Zdravkovdki, Z. Synth. Commun. 1993, 23, 2761.
30. Bodanszky, M. Int. J. Pept. Protein. Res. 1985, 25, 449.
31. Bodanszky, M. Int. J. Pept. Protein. Res. 1992, 5, 134.
32. Han, S. Y.; Kim, Y. K. Tetrahedron 2004, 60, 2447.
33. Humphrey, J. M.; Chamberlin, A. R.; Chem. Rev. 1997, 97, 2243.
34. Katritzky, A. R.; Suzuki, K; Singh, S. K. Arkivoc, 2004, 12.
35. Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827.
36. Najera, C. Synlett 2002, 1388.
37. Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.
38. Koenig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
39. Koenig, W.; Geiger, R. Chem. Ber. 1970, 103, 2024.
40. Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589.
41. Carpino, L. A.; J. Am. Chem. Soc. 1993, 115, 4397.
42. EricValeur, W.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
43. Veitch, G. E.; Bridgwood, K. L.; Ley, S. V. Org. Lett. 2008, 10, 3623.
44. Gunanathan, C; Ben-David, Y; Milstein, D, Science 2007, 317, 790.
45. Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770.
46. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
47. Schroeder, G. M; Marshall, S; Wan, H; Purandare, A. V. Tetrahedron Lett. 2010, 51, 404.
48. Graul, A.; Castaner, J.; Drugs Future, 1997, 22, 956.
49. Patchett, A. A. J. Med. Chem. 1993, 36, 2051.
50. Gasparo, M. D.; Whitebread, S.; Pept, R. 1995, 59, 303.
51. Ananthanarayanan, V. S.; Tetreault, S.; Saint-Jean, A. J. Med. Chem. 1993, 36, 1324.
52.
Morse, H. N. "Ueber eine neue Darstellungsmethode der Acetylamidophenole". Berichte der
deutschen chemischen Gesellschaft, 1878, 11 232.
53. Yadav, J. S.; Subba Reddy B. V.; Narasimha Chary, D; Madavi, C.; Kunwar, A. C.
Tetrahedron Lett. 2009, 50, 81.
54. Sun Kim, E.; Seung Lee, H.; Hwan Kim, S.; Nyoung Kim, J. Tetrahedron Lett. 2010, 51,
1589.
55. Anil kumar, Sudershan Rao, M.; Israr Ahmad, Bharti Khungar, Can. J. Chem. 2009, 87, 714.
56. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. (b) Ritter, J. J.; Kalish, J. J.
Am. Chem. Soc, 1948, 70, 4048.
60
57.
Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry; Oxford Press: New
York, 2001.
58. Vardanyan, R.; Hruby, V. J. Synthesis of Essential Drugs, 1st Ed. Amsterdam: Elsevier,
2006,137.
59.
Kurti, L.; Czako, B. Strategic Applications of Named in Organic Synthesis. Burlington, MA
Elsevier Academic Press. 2005.
60. Fujisawa, Deguchi, Chemical Abstracts 1958, 52, 11965.
61. Barton, D. H. R.; Magnus, P. D.; Garbarino, J. A.; Young, R. N. J. Chem. Soc. Perkin Trans.
1974, 1, 2101.
62.
García Martínez, A.; Alvarez, R. M.; Teso Vilar, E.; García Fraile, A.; Hanack, M.;
Subramanian, L. R.; Tetrahedron Lett. 1989, 30, 581.
63. Lebedev, M. Y.; Erman, M. B.; Tetrahedron Lett. 1989, 43, 1397.
64. Reddy, K. L.; Tetrahedron Lett. 2003, 44, 1453.
65. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78.
66.
Eastgate, M. D.; Fox, D. J.; Morley, T. J.; Warren, S. Synthesis 2002, 2124. and references
therein.
67. Callens, E.; Burtonb, A. J.; Barretta, A. G. M. Tetrahedron Lett. 2006, 47, 8699.
68. Anxionnat, B.; Guerinot, A.; Reymond, S.; Cossy, J. Tetrahedron Lett. 2009, 50, 3470.
69. Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 2661.
70. Tamaddon, F.; Khoobi, M.; Keshavarz, E. Tetrahedron Lett. 2007, 48, 3643.
71. Li, X. Y.; Ji, K. G.; Wang, H. X.; Ali, S.; Liang, Y. M. J. Org. Chem. 2011, 76, 744.
72. He, Z.; Li, H.; Li, Z. J. Org. Chem. 2010, 75, 4636.
73.
(a) Toke, L.; Szabo, G. T.; Hell, Z.; Toth, G. Tetrahedron Lett. 1990, 31, 7501. (b) Toke, L.;
Hell, Z.; Szabo, G. T.; Toth, G.; Bihari, M.; Rockenbauer, A. Tetrahedron 1993, 49, 5133. (c)
Faigl, F.; Devenyi, T.; Lauko, A.; Toke, L. Tetrahedron 1997, 53, 13001. (d) Hell, Z.; Finta,
Z.; Grunvald, T.; Bocskei, Z.; Balan, D.; Keseru, G. M.; Toke, L. Tetrahedron 1999, 55, 1367.
(e) Yang, D.; Gao, Q.; Lee, C.; Cheung, K. Org. Lett. 2002, 4, 3271.
74. Deka, N.; Dipok J.; Kalita, J.; Borah, R.; Jadab C. Sarma, J. Org. Chem. 1997, 62, 1563.
75.
(a) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Tetrahedron Lett. 2002, 43, 879. (b)
Chavan, S. P.; Kale, R. R.; Shivasankar, K.; Chandake, S. I.; Benjamin, S. B. Synthesis 2003,
2695.
76. Kataki, D.; Phukan, P. Tetrahedron Lett. 2009, 50, 1958.
77. Phukan, P. J. Org. Chem. 2004, 69, 4005.
78.
(a) Higuchi, T.; Gensch, K. H. J. Am. Chem. Soc. 1966, 88, 5486. (b) Gensch, K. H.; Pitman,
I. H.; Higuchi, T. J. Am. Chem. Soc. 1968, 90, 2096. (c) Young, P. R.; Hsieh, L. J. Am. Chem.
Soc. 1978, 100, 7122. (d) Young, P. R.; Hou, K. C. J. Org. Chem. 1979, 44, 947. (e) Eiki, T.;
Tagaki, W. Chem. Lett. 1980, 1063. (f) Doi, J. T.; Musker, W. K.; Leeuw, D. L.; Hirschon, A.
S. J. Org. Chem. 1981, 46, 1239. (g) Doi, J. T.; Musker, W. K. J. Am. Chem. Soc. 1981, 103,
1159.
61
79. Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.; Reddy, G. S. K. K. Synthesis 2000, 1532.
80. Ji, S. J.; Wang, S. Y.; Zhang, Y.; Loh, T. P. Tetrahedron Lett. 2004, 60, 2051.
81. Selvam, N. P.; Perumal, P. T. Tetrahedron Lett. 2008, 64, 2972.
82. Togo, H.; Iida, S. Synlett 2006, 2159.
83. Vaino, A. R.; Szarek, W. A. Adv. Carbohydr. Chem. Biochem. 2001, 56, 9.
84. Jereb M.; Vrazic, D.; Zupan, M. Tetrahedron 2011, 67, 1355.
85. (a) Hibbert, H. J. Am. Chem. Soc. 1915, 37, 1748. (b) Reeve, W.; Reichel, D. M. J. Org.
Chem. 1972, 37, 68. (c) Conant, J. B.; Tuttle, N. Org. Synth. 1941, 1, 345.
86. Ramesh naidu, V.; Kim, M. C.; Suk, J-M.; Kim, H-J.; Lee, M.; Sim, E.; Jeong, K-S.Org. Lett.
2008, 10, 5373.
87. Suttsuo, F.; Kato, K.; Mukaiyama, T. Chemistry Lett. 2008, 37, 506.
88. Luigino, T.; Emanuela, P.; Valentina, S.; Piera, T. Tetrahedron: Asymmetry 2009, 20, 368.
89. Nordstrom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672.
90. Stemmler, R. T.; Bolm, C. Tetrahedron Lett. 2007, 48, 6189.
91. Vincent, A. C.; Sci, F. P.; Nigeria, U.; Nigeria, N. J. Chem and Eng data. 1984, 29, 231.
92. Tignibidina, L. G.; Filimonov, U. D.; Pustovotitiv, A. V.; Gorshkova, V. K.; Saratikov, A. S.;
Krasnov, V. A. Khimiko-Farmatsevticheskii zhurnal. 1989, 23, 1455.
93. Salehi, P.; Khodaei, M.M.; Zolfigol, M.A.; Keyvan, A. Synth. Commun. 2001, 31, 1947.
94. Londregan, A.; T. Storer, G.; Wooten, C.; Yang, X.; Warmus, J. Tetrahedron Lett. 2009, 50,
1986.
95. Deganan, W. M.; Shoemaker, C. J. J. Am. Chem. Soc. 1946, 68, 104.
96. Wan, X.; Ma, Z.; Li, B.; Zang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128,
7416.
62