Malonic ester amide synthesis: An efficient methodology for synthesis of amides

Article abstract of DOI:10.1080/00397911.2012.717671

A general methodology malonic ester amide synthesis has been demonstrated, which uses α-substituted/unsubstituted diethyl malonates for the decarboxylative acylation of various aromatic/heteroaromatic primary/secondary amines to form one-carbon homologated amides, thus providing easy access to amides with odd/even chain lengths and an array of substituents on the alkyl/aryl part while avoiding use of acyl chlorides or peptide coupling reagents. Copyright

Full text of DOI:10.1080/00397911.2012.717671

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Malonic Ester Amide Synthesis: An
Efficient Methodology for Synthesis of
Amides
Pankaj S. Mahajan a , Jyoti P. Mahajan a & Santosh B. Mhaske a
a National Chemical Laboratory (CSIR-NCL) , Division of Organic
Chemistry , Pune , India
Accepted author version posted online: 26 Mar 2013.Published
online: 03 Jun 2013.
To cite this article: Pankaj S. Mahajan , Jyoti P. Mahajan & Santosh B. Mhaske (2013): Malonic Ester
Amide Synthesis: An Efficient Methodology for Synthesis of Amides, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:18, 2508-2516
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Synthetic Communications1, 43: 2508–2516, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.717671
MALONIC ESTER AMIDE SYNTHESIS: AN EFFICIENT
METHODOLOGY FOR SYNTHESIS OF AMIDES
Pankaj S. Mahajan, Jyoti P. Mahajan, and Santosh B. Mhaske
National Chemical Laboratory (CSIR-NCL), Division of Organic
Chemistry, Pune, India
GRAPHICAL ABSTRACT
Abstract A general methodology ‘‘malonic ester amide synthesis’’ has been demonstrated,
which uses a-substituted/unsubstituted diethyl malonates for the decarboxylative acylation
of various aromatic/heteroaromatic primary/secondary amines to form one-carbon homo-
logated amides, thus providing easy access to amides with odd/even chain lengths and an
array of substituents on the alkyl/aryl part while avoiding use of acyl chlorides or peptide
coupling reagents.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Amide synthesis; aromatic amines; condensation; decarboxylation; diethyl
malonates
INTRODUCTION
Amide bond formation is one of the most important and regularly utilized
reactions in organic synthesis.[1–4] It is used in the synthesis of 65% of the drug can-
didates surveyed[5] and 16% of industrial processes investigated.[6] Amides are
present in more than 50% of reported medicinal compounds. Constable et al.[5] ident-
ified amide bond formation as one of the most utilized transformation in the phar-
maceutical industry and also emphasized that it is one of 12 very high priority
research areas. Diethyl malonate (DEM), found in fruits such as grapes, pineapples,
and strawberries, is extensively used in the famous reaction, malonic ester synthesis
(MES); however, application of a-substituted=unsubstituted DEM for the synthesis
of amides never emerged as a general and efficient methodology. In this context, we
Received July 13, 2012.
Address correspondence to Santosh B. Mhaske, National Chemical Laboratory (CSIR-NCL),
Division of Organic Chemistry, Pune 411 008, India. E-mail: sb.mhaske@ncl.res.in
2508

MALONIC ESTER AMIDE SYNTHESIS
2509
herein report a general methodology, malonic ester amide synthesis (MEAS), for
the synthesis of various amides.
Acetic acid, acetic anhydride, or acetyl chlorides are commonly used in the
presence of base or acid catalysts to form corresponding amides. Long-chain substi-
tuted amides are usually formed via a reaction of activated carboxylic acid with an
amine. The best known method, the Schotten–Baumann reaction, involves conver-
sion of the acid to acid chlorides. A survey reveals[5] that 44% of the amide drug can-
didates are prepared from acid chloride intermediates. Carboxylic acids are also
activated with a variety of catalysts, which include Lewis acids or peptide coupling
agents. Approximately 36% of the amide bond-forming reactions in pharmaceutical
industries are carried out by means of peptide coupling reagents.[5] Several other
approaches for the amide bond formation including enzymatic catalysis,[7] metal
catalysis,[8] activated carboxylic esters,[9] and S-nitrosothioacids[10] are also known.
Every methodology has its own advantages=drawbacks, and despite a number of
precedents, in view of its significance,[1] new methodologies for amide bond
[1,5,6]
formation are always desired
and it is of contemporary interest.[2–4,11–15]
RESULTS AND DISCUSSION
We were trying to develop a methodology for the synthesis of indole alka-
loid[16] of type 3 starting from the substrate of type 2[17] using intramolecular
copper-catalyzed a-arylation of malonates.[18] We observed the formation of
N-acetylated product 1 instead of alkaloid 3 in a reasonable yield (Scheme 1).
Presented herein is the exploration of the serendipitous observation as a general
methodology for amide bond formation.
The decarboxylation observed at milder conditions (Scheme 1) was well studied
to identify the exact catalyst that is playing the role in this transformation. Forma-
tion of amide 1 was not observed even after heating the reaction mixture at 100 ꢀC
for several hours without the addition of any of the mentioned additives. It was
found that the reaction using only CuI or 2-picolinic acid did not furnish amide 1,
but it was observed when Cs2CO3 was used in the reaction. Heating the reaction mix-
ture containing 2-chloroaniline (4) and DEM (5) at 150 ꢀC without any base for 12 h
showed complete consumption of the amine (4), and the two new spots were isolated
and characterized as intermediate 2 and the N-acetylated product 6 in ꢁ1:1 ratio
(Scheme 2). This experiment suggested that the decarboxylation can also be done
at higher temperature without the use of Cs2CO3, but then it requires longer reaction
time (incomplete consumption of intermediate 2) and also gives lower yield. In one
of the experiments, evaporating off DEM after consumption of amine (4) and neat
heating of the residue containing compounds 2 and 6 shows complete disappearance
Scheme 1. Indole methodology attempted and its result reactions conditions: (a) CuI (0.10 equiv.),
2-picolinic acid (0.20 equiv.), Cs2CO3 (3.00 equiv.), 1,4-dioxane, rt to 70 ꢀC, 4 h.

2510
P. S. MAHAJAN, J. P. MAHAJAN, AND S. B. MHASKE
Scheme 2. Initial optimization studies for amide formation.
of the intermediate 2, but the yield of the amide 6 reduces drastically with the
formation of several other side products, which results in a poor-quality dark-
colored product. When the mixture containing 2, 6, and DEM was heated
(100 ꢀC) in the presence of Cs2CO3 we got a quantitative yield of amide 6
(Scheme 2). Use of several other organic=inorganic bases instead of Cs2CO3 gave
either poor conversion or a complex reaction mixture.
Further optimization studies using several permutations and combinations
provided a better reaction condition, wherein the reaction mixture containing the
amine (1.00 eq.) and DEM was heated (100–130 ꢀC) until complete consumption
(0.5–3 h) of amine followed by the addition of Cs2CO3 (3.00 eq.) at 100 ꢀC and heat-
ing for another 1–3 h at the same temperature. Although the overall process has been
observed occasionally[19–23] in fragmented forms previously in the literature using
varying conditions and has been used in several industrial applications, generaliza-
tion studies on its usefulness for amide synthesis have never been reported.
The optimized reaction condition was applied to various aromatic, hetero-
aromatic, and aliphatic amines to study the reactivity pattern and generalization
of the developed protocol. The methodology worked very well for aromatic=
hetero-aromatic amines as seen in Table 1. Quantitative yield of corresponding
amide in the case of 4-nitroaniline (Table 1, entry 3) and 70–75% yields in the case
of aniline (Table 1, entry 1), p-toludine (Table 1, entry 2), and 3,4,5-trimethoxy ani-
line (Table 1, entry 4) were obtained. In the case of halogen-substituted substrates,
we have observed that 2-chloroaniline (Table 1, entry 5) gave better yield than
2-iodoaniline (Table 1, entry 6), plausibly because of the steric reasons and tenacity
of iodo compounds to decompose at higher temperature. p-Phenylenediamine
(Table 1, entry 7) gave good yield as expected. Application of the protocol to an acid
labile substrate (Table 1, entry 8) provided very good yield, which shows that this
protocol can be used for such substrates too. However, in the case of base labile sub-
strate (Table 1, entry 9) we have not observed any expected compound formation,
but a trace amount of the same product as observed in the case of entry 7
(Table 1) was detected. Our study on amide formation of aromatic amine in the pres-
ence of competing phenolic -OH moiety (Table 1, entry 10) showed 100% selectivity
and only the expected N-acetamide product was obtained in good yields.
The product of entry 10 (Table 1) is a widely used over-the-counter antipyretic
and analgesic drug, Paracetamol, which is industrially prepared by acetylation of
4-aminophenol using acetic anhydride. In the case of amino-alcohol (Table 1, entry
11) along with the expected amide product a DEM transesterified (but not decar-
boxylated) product was also observed. After completion of the reaction, methanol

MALONIC ESTER AMIDE SYNTHESIS
2511
Table 1. Amide formation of various amines using DEM
Entry
Product
Yield (%)
1
2
3
70
75
98
4
74
5
6
98
66
7
8
71
87
–
9
10
11
72
57
12a
13
87
65
14
15
92
90
aSingle step, 120 ꢀC, 1 h (Cs2CO3 was not necessary, self-catalyzed).

2512
P. S. MAHAJAN, J. P. MAHAJAN, AND S. B. MHASKE
was added, and the reaction mixture was stirred at room temperature for 0.5 h to
obtain exclusively the expected product in 57% yield. We also studied the acetylation
reaction on hetero-aromatic amines. 2-Aminopyridine (Table 1, entry 12) gave an
interesting result, wherein we could get the amide directly in a short time without
the need for Cs2CO3. This indicates that the substrate itself catalyzed the further dec-
arboxylation reaction. In view of this observation, attempts to optimize the protocol
using pyridine or dimethylaminopyridine (DMAP) as a base did not work well.
Further detailed studies on this novel organocatalytic process are warranted. Our
methodology also worked well with a multisubstituted thioheterocyclic amine
(Table 1, entry 13). Studies on the secondary amine also showed good results. Thus,
diphenylamine (Table 1, entry 14) and N-methylaniline (Table 1, entry 15) provided
corresponding amides in excellent yield proving the generality of the method for
acetylation of variety of aromatic=heteroaromatic primary and secondary amines.
However, our attempts to extend the MEAS protocol to aliphatic amines under
the same conditions were not fruitful. The high reactivity of these aliphatic amines
toward the ester moiety even at room temperature might be the cause, which plausi-
bly leads to the formation of several other side products at higher temperature.
Further studies in search of appropriate protocol for aliphatic amines are in progress.
Table 2. Amide formation using a-substituted DEM
Entry
a-Substituted DEMa
Product
Yield (%)
1
2
62
70
3
60
68
91
4b
5c
6
7
85
90
aa-Substituted DEM was purchased or prepared.[18,26–30]
bStep 1, 12 h. Step 2, 5 h.
cSingle step, 120 ꢀC, 1 h (Cs2CO3 was not required, self-catalyzed).

MALONIC ESTER AMIDE SYNTHESIS
2513
Scheme 3. Plausible mechanism for the MEAS methodology.
The MEAS methodology using DEM worked well with aromatic=
heteroaromatic amines (Table 1); hence, we decided to broaden the scope by using
a-substituted DEMs to prepare amides with a variety of one-carbon homologated acyl
groups. Similar to the reaction pattern observed with DEM (Table 1, entries 1 and 2),
aniline and p-toluidine reacted with a-methyl DEM, providing satisfactory yields
(Table 2, entries 1 and 2). Contrary to the observation in Table 1 (entry 3), reaction
of 4-nitro aniline with a-ethyl DEM provided lower yield. The reaction of 4-chloro ani-
line with a-butyl DEM (Table 2, entry 4) provided the expected amide in 68% yield.
The plausible side reaction of malondiamide[24,25] formation might have contributed
to the lower yield. With reasonable results in hand for a-methyl, a-ethyl, and a-butyl
DEM, we decided to try our method on a longer chain a-substituted DEM.
We got very good yields (Table 1, entry 13) using 2-amino pyridine and DEM,
without the need for Cs2CO3. Hence we used the same amine for the reaction with
a -decyl DEM, and interestingly in this case also we obtained the same results and
very good yield (Table 2, entry 5). The reaction of aniline with a-benzyl DEM
(Table 2, entry 6) and a-phenyl DEM (Table 2, entry 7) gave excellent yields as com-
pared to a-methyl DEM (Table 2, entry 1), probably because of the extended
electron-withdrawing resonance and inductive effect of the benzene ring. A plausible
mechanism for MEAS is depicted in Scheme 3.
CONCLUSION
In conclusion, MEAS, a general and efficient methodology for amide bond for-
mation has been demonstrated. It provides easy access to amides with odd=even chain
lengths. Synthesis of amides with odd chain lengths is particularly important and
noteworthy because most of the naturally occurring long-chain alcohols=acids (which
are commonly used as starting materials) have even chain length. We believe that
the MEAS methodology might become a suitable alternative in industries that are
currently using acyl chlorides = anhydrides = peptide coupling reagents for this
transformation. This method may potentially be useful for the preparation of polya-
mides. The work to improve the MEAS methodology in terms of broader substrate

2514
P. S. MAHAJAN, J. P. MAHAJAN, AND S. B. MHASKE
scope, lower temperature, and less reaction time by developing a suitable
2-aminopyridine-based organocatalyst is under way.
EXPERIMENTAL
General Procedure
A two-neck, round-bottom flask (equipped with a distillation condenser and a
magnetic stirring bar) contained a mixture of amine (1 eq.) and DEM=a-substituted.
(To avoid the use of excess a-substituted DEM from economical point of view, only
10–20 eq. can be used and in the second step a small amount of 1,4-dioxane, just suf-
ficient to avoid thick slurry formation, can be added. The results of both ways were com-
parable). DEM was heated (100–130ꢀC) until complete consumption (0.5–3 h) of the
starting amine. The reaction mixture was allowed to cool down to 100ꢀC, and Cs2CO3
(3 eq.) was added [Cs2CO3 was not required for entry 12 (Table 1) and entry 5 (Table 2)].
Heating at 100ꢀC was continued until for 1–3 h until complete disappearance of
the intermediate. Reaction progress was monitored by thin-layerchromatography.
N-(3,4,5-Trimethoxyphenyl)acetamide (CAS: 4304–24–9, Table 1,
Entry 4)[31]
Mp 140–142 ꢀC; IR (Nujol) nmax 1212, 1695, 1758, 3395 cmꢂ1 1H NMR
;
(DMSO-d6, 200 MHz, ppm): d 2.00 (s, 3H), 3.60 (s, 3H), 3.72 (s, 6H), 6.94 (s, 2H),
9.84 (bs, 1H); 13C NMR (DMSO-d6, 50 MHz, ppm): d 24.3, 55.9, 60.3, 97.0,
133.5, 135.8, 153.0, 168.5; ESIMS (m=z): 248 (M þ Na).
N-(3-Cyano-5-propylthiophen-2-yl)acetamide (Table 1, Entry 13)
Mp 108–110 ꢀC; IR (Nujol) nmax 1693, 2220, 3225, 3280 cmꢂ1 1H NMR
;
(CDCl3, 400 MHz, ppm): d 0.96 (t, J ¼ 7.1 Hz, 3H), 1.62–1.73 (m, 2H), 2.29 (s,
3H), 2.68 (t, J ¼ 7.5 Hz, 2H), 6.61 (s, 1H), 9.11 (bs, 1H); 13C NMR (CDCl3,
100 MHz, ppm): d 13.5, 22.9, 24.3, 31.4, 91.2, 115.0, 119.6, 137.6, 148.1, 167.2;
ESIMS (m=z): 207 (Mꢂ1). Anal. calcd. for C10H12N2OS: C, 57.67; H, 5.81; N,
13.45. Found: C, 57.95; H, 5.68, N, 13.24.
N-(4-Nitrophenyl)butyramide (CAS: 54191–12–7, Table 2, Entry 3)[32]
1
Mp 143–145 ꢀC; IR (Nujol) nmax 1676, 3148, 3269 cmꢂ1; H NMR (CDCl3,
500 MHz, ppm): d 1.03 (t, J ¼ 7.32 Hz, 3H), 1.75–1.79 (sext., J ¼ 7.5, 2H), 2.41 (t,
J ¼ 7.33 Hz, 2H), 7.62 (bs, 1H), 7.73 (d, J ¼ 9.1 Hz, 2H), 8.21 (d, J ¼ 9.1 Hz, 2H);
13C NMR (CDCl3, 125 MHz, ppm): d 13.7, 18.8, 39.7, 119, 125.1, 143.4, 143.8,
171.6; ESIMS (m=z): 207 (Mꢂ1).
N-(4-Chlorophenyl)hexanamide (CAS: 95843–76–8, Table 2,
Entry 4)[33]
Mp 101–103 ꢀC; IR (Nujol) nmax 1654, 1706, 3302, 3412 cmꢂ1
;
1H NMR
(CDCl3, 500 MHz, ppm): d 0.91 (t, J ¼ 7.0 Hz, 3H), 1.30–1.40 (m, 4H), 1.69–1.78

MALONIC ESTER AMIDE SYNTHESIS
2515
(m, 2H), 2.35 (t, J ¼ 7.8 Hz, 2H), 7.28 (d, J ¼ 8.8 Hz, 2H), 7.27 (s, 1H), 7.46 (d,
J ¼ 8.86 Hz, 2H); 13C NMR (CDCl3, 125 MHz, ppm): d 13.9, 22.4, 25.2, 31.4,
37.7, 121.0, 128.9, 129.1, 136.5, 171.5.
SUPPORTING INFORMATION
1
Full experimental detail, copies of H and 13C, and DEPT NMR spectra and
literature references for known compounds can be found via the Supplementary
Content section of this article’s web page.
ACKNOWLEDGMENTS
P. S. M. and J. P. M. thank the Council of Scientific and Industrial Research
(CSIR), New Delhi, for the research fellowship. S. B. M. thanks the Department of
Science and Technology (DST), New Delhi for the Ramanujan fellowship award and
DST-Science and Engineering Research Council (SERC) Fast-Track project
research grant. S. B. M. also thanks CSIR, New Delhi, and S. Pal, director, National
Chemical Laboratory Pune, for providing the infrastructure, constant support, and
encouragement.
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