Short, efficient syntheses of pyrrole α-amides

Article abstract of DOI:10.1080/00397910802323130

We report an inexpensive method for producing a diverse array of pyrrole amides on a large scale and in good yield. The synthetic sequence allows for the preparation of a number of pyrrole amide derivatives in excellent to moderate yields from commercially available compounds. The diketene adduct, in the presence of an amine nucleophile, provides an excellent method for acetoacetylation. For diversity and versatility, a second method utilizing Meldrum's acid was successfully employed for the preparation of additional acetoacetamide derivatives. Using the Knorr pyrrole synthesis, pyrrole amides were readily prepared from the oxime of the acetoacetamides. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802323130

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Short, Efficient Syntheses of
Pyrrole α-Amides
Michael T. Huggins a , Patrick S. Barber a , David
Florian a & William Howton a
a Department of Chemistry, University of West
Florida, Pensacola, Florida, USA
Version of record first published: 31 Oct 2008
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William Howton (2008): Short, Efficient Syntheses of Pyrrole α-Amides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:23, 4226-4239
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Synthetic Communications1, 38: 4226–4239, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802323130
Short, Efficient Syntheses of Pyrrole a-Amides
Michael T. Huggins, Patrick S. Barber, David Florian,
and William Howton
Department of Chemistry, University of West Florida, Pensacola,
Florida, USA
Abstract: We report an inexpensive method for producing a diverse array of pyr-
role amides on a large scale and in good yield. The synthetic sequence allows for
the preparation of a number of pyrrole amide derivatives in excellent to moderate
yields from commercially available compounds. The diketene adduct, in the pre-
sence of an amine nucleophile, provides an excellent method for acetoacetylation.
For diversity and versatility, a second method utilizing Meldrum’s acid was suc-
cessfully employed for the preparation of additional acetoacetamide derivatives.
Using the Knorr pyrrole synthesis, pyrrole amides were readily prepared from
the oxime of the acetoacetamides.
Keywords: Diketene, Knorr pyrrole synthesis, Meldrum’s acid, pyrrole amide,
synthesis
INTRODUCTION
Pyrrole amides are well known for their biological activity, and many are
presently either being used or pursued as herbicides,[1] cancer treat-
ments,[2] or inhibitors of numerous enzymes.[3–5] In addition, the pyrrole
amide motif has also been used by several research groups to develop
receptors for anions.[6–11] In general, there have been many methods used
to prepare the pyrrole amide moiety, but most have started from easily
accessible pyrrole esters that can be synthesized via numerous routes.
Received May 18, 2008.
Address correspondence to Michael T. Huggins, Department of Chemistry,
University of West Florida, 11000 University Parkway, Pensacola, FL 325140.
E-mail: mhuggins@uwf.edu
4226

Short, Efficient Syntheses of Pyrrole a-Amides
4227
Figure 1. Target molecules.
These methods are typically performed on a small scale (usually a few
grams at most), often result in low yields, and can require extensive
purification to obtain pure products.
We are interested in using the pyrrole amide motif for a wide range of
potential applications that require the ability to control the substituents
on all positions of the pyrrole. Specifically, we are interested in develop-
ing a synthetic procedure that allows for control of the substituents on
the pyrrole core as well as the amide; see Fig. 1. There have been only
a few reports showing the preparation of the pyrrole core with the amide
group already in place.[12–15] Each used acetoacetamides under Knorr
pyrrole synthesis conditions[14,16] to prepare the pyrrole a-amides. How-
ever, these reports did not explore the potential for controlling the diver-
sity of the substituents on either the pyrrole core or the amide moiety. In
the following, we report our results in developing this synthetic route to
produce a wide array of pyrrole amide derivatives, which results in the
ability to control the functionality on the pyrrole core.
RESULTS AND CONCLUSIONS
Our initial efforts used three commercially available acetoacetamide deri-
vatives to probe the versatility of the synthetic route. Reaction of the ter-
tiary and secondary acetoacetamides 1a and 1b with sodium nitrite in
acetic acid gave the corresponding oximes 2a and 2b in high yields,
92% and 79% respectively. Unfortunately, all attempts at using the pri-
mary acetoacetamide 1c failed to produce the desired oxime derivative.
Reaction of oximes 2a and 2b under Knorr conditions with three differ-
ent b-dicarbonyl derivatives resulted in moderate to high yields of the
various pyrrole aꢀamide derivatives 3a–f, see Scheme 1. Generally, the
observed yields were lower when using the oxime of the tertiary amide,
2a. The conditions for both steps of the reaction sequence are amenable
to being performed on a relatively large scale (50 þ g).
For this method to be truly versatile, we needed to develop a method
for preparing pyrrole a-amide analogs with control of the N-alkyl

4228
M. T. Huggins et al.
Scheme 1. Preparation of pyrrole amides from commercially available
acetoacetamides.
substituents as well as substituents on the entire pyrrole core. Achieving
diversity of N-alkyl substituents requires the ability to make acetoaceta-
mides with varying N-alkyl substituents. Currently, there are several syn-
thetic routes in the literature for preparing acetoacetamides: Meldrum’s
acid[17,18] or diketene[19–21] (commonly used as a diketene acetone adduct)
are two of the most commonly used precursors. Reaction of the diketene
adduct 4 and various primary amines[21] resulted in acceptable to excel-
lent yields, 52–93%, of the corresponding acetoacetamide derivative
(Scheme 2). For most cases, use of dry xylenes was the preferred solvent.
In a few instances, use of dimethylformamide (DMF) as the solvent
resulted in higher yields and easier isolation of the desired product.
Most of these acetoacetamide derivatives were easily converted into
their corresponding pyrrole amide derivatives 7a–d in respectable yields
(Table 1). Fortunately, it was determined that the oxime formation and
Knorr pyrrole synthesis sequence can be performed in one pot, which
greatly increased the overall yield. For example, the stepwise preparation
of pyrrole 7a resulted in an overall yield of 29% from the acetoacetamide,
Scheme 2. Preparation of acetoacetamide derivatives from diketene adduct.

Short, Efficient Syntheses of Pyrrole a-Amides
4229
Table 1. Synthesis of pyrrole derivatives from acetoacetamides prepared from
diketene adduct 4
R
R0
Yield (%)
5a
5a
5a
5b
5c
5d
5e
C4H7
C4H7
C4H7
2-pyridyl
4-ClC6H4
CH3
CH3
OEt
ꢁ6a 51%
ꢁ
7a 57%
7a 57%
7b 58%
ꢁꢁ
6b 35%
6c 52%
ꢁ
OEt
OEt
7c 34%
7d 56%
ꢁꢁ
3-CH3OC6H4
4-NO2C6H4
6d 75%
ꢁReaction was conducted via one-pot reaction sequence.
ꢁꢁReaction failed give the desired product.
while the same compound was prepared in 57% overall yield when the
crude oxime reaction mixture was used directly in the pyrrole synthesis.
Isolation of the oxime intermediates typically resulted in loss of product,
which was mainly responsible for the decrease in yields. With this one-pot
method, care must be taken with the quantities of the sodium nitrite and
b-keto derivative used in the reactions. A large excess of either material
occasionally resulted in the formation of additional pyrrole products,
which are difficult to separate from the desired product. This was parti-
cularly evident when using ethyl acetoacetate as the b-keto derivative.
The 4-nitrophenyl and 2-pyridyl derivatives both failed to yield the
desired pyrrole amides; in both cases there were indications of these moi-
eties being reduced under the Knorr pyrrole synthesis condition, zinc in
hot acetic acid. Additionally, the 4-chlorophenyl derivative, 7c, suffered
from limited solubility, which was responsible for the low yield.
Use of the acetoacetamide derivatives prepared from diketene-
acetone adduct resulted in pyrroles with methyl groups at the 3- and 5-
positions. Unfortunately, this can lead to limited solubility of the desired
pyrrole products, as noted in attempts to prepare the 4-chlorophenyl
amide analog, 7c. Therefore, we sought a method for preparing analogs

4230
M. T. Huggins et al.
Scheme 3. Synthesis of pyrrole derivatives from Meldrum’s acid.
that would allow changing the 3-methyl group to other alkyl and aryl
substituents. Use of 4-substituted acetoacetamide derivatives provides
access to modification at the 3-position of the pyrrole ring. Reaction of
the Meldrum’s acid, 8, with an appropriate acid chloride[22] followed by
addition of a corresponding amine allows for relatively easy preparation
of the desired 4-substituted acetoacetamide derivatives. Specifically, reac-
tion of Meldrum’s acid with butanoyl chloride resulted in a 90% yield of
the desired acylated Meldrum’s acid product, 9 (Scheme 3). Aminolysis
of 9 performed in anhydrous benzene resulted in good yields (53–96%)
of the corresponding 3-oxo-hexanamide derivatives 10a–c. Using the pre-
viously discussed Knorr pyrrole synthesis method, the corresponding
pyrrole analogs 11a–c were prepared in 31–47% yield, over two synthetic
steps. In the best case (11b), the synthesis resulted in a 41% overall yield
of the pyrrole (four total synthetic steps).
CONCLUSIONS
In this article, we present our results for the preparation of pyrrole
a-amide derivatives. The synthetic routes allow for controlling the substi-
tuents on the pyrrole core as well as modification of the amide substitu-
ents. Preparation of the required acetoacetamide derivatives from either
the diketene adduct or Meldrum’s acid provides the flexibility in adjusting

Short, Efficient Syntheses of Pyrrole a-Amides
4231
substituents on pyrrole and amide moieties. In addition, these methods
allow for the production of relatively large quantities of pyrrole a-amide
derivatives in good yield and in short facile synthesis (three to four syn-
thetic steps). The synthetic procedures used in the preparation of the
pyrrole a-amides are amenable to scale-up. Successful syntheses have
been carried out to produce as much as 40 g of the resulting pyrrole
a-amide derivatives.
EXPERIMENTAL PROCEDURES
General Methods
Nuclear magnetic resonance (NMR) spectra were measured in CDCl3,
unless otherwise noted, with tetramethylsilane (TMS) as internal refer-
ence standard using a Varian 300-MHz MercuryPlus NMR. Chemical
shifts are reported in d (ppm) referenced to TMS. The reported melting
points are uncorrected. Meldrum’s acid was purchased from Acros and
recrystallized from toluene. Xylenes and benzene were dried over phos-
phorus pentachloride and freshly distilled. UltraDry DMF was pur-
chased from Acros. All other solvents and materials were purchased
from common sources and used as received.
General Synthetic Procedures
Method A1: Preparation of Acetoacetamide Derivatives[21]
A solution of an amine (20 mmol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-
one (20 mmol) in 10 mL of dry xylenes was placed in a 50-mL Erlenmeyer
flask equipped with magnetic stirring. The flask was immersed in a pre-
heated oil bath at 150 ꢂC and stirred vigorously for 30 min. Upon cooling
to room temperature, the product precipitated. The product was collected
via vacuum filtration and recrystallized in hot xylenes.
Method A2: Preparation of Acetoacetamide Derivatives
A solution of an amine (20 mmol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-
one (20 mmol) in 10 mL of DMF was placed in a 50-mL Erlenmeyer flask
equipped with magnetic stirring. The flask was immersed in a preheated
oil bath at 150 ꢂC and stirred vigorously for 30 min. Upon cooling, the
solution was poured into brine (300 mL) and extracted with methylene

4232
M. T. Huggins et al.
chloride (2 ꢃ 50 mL). The combined organic extracts were washed with
water (2 ꢃ 50 mL), 10% HCl (2 ꢃ 50 mL), and saturated sodium bicarbo-
nate (50 mL) and dried over anhydrous sodium sulfate. After decanting
from the drying agent, the solvent was removed by rotary evaporation,
yielding the desired product.
Method B (Preparation of Oxime Derivatives)
A solution of acetoacetamide (20 mmol) in acetic acid (50 mL) was placed
in a round-bottomed flask equipped with magnetic stirring and placed in
an ice water bath. An excess of sodium nitrite (ꢄ 40 mmol) dissolved in a
minimal amount of water was added dropwise over a 15-min period. The
resulting solution was stirred for 2 h in an ice water bath followed by an
additional hour of stirring at room temperature. If the product precipi-
tated from the reaction mixture, then the product was collected via
vacuum filtration. Otherwise, the resulting reaction mixture was diluted
with water (200 mL) and extracted with methylene chloride (2 ꢃ 50 mL).
The combined organic extracts were washed with water (2 ꢃ 50 mL),
10% HCl (2 ꢃ 50 mL), and saturated sodium bicarbonate (50 mL) and
dried over anhydrous sodium sulfate. After decanting, the solvent was
the removed by rotary evaporation to yield the desired product. Crude
products were used directly without further purification.
Method C (Pyrrole Synthesis)
A solution of oxime (20 mmol) in acetic acid (50 mL) was placed in a
three-neck, round-bottom flask equipped with a condenser and magnetic
stirrer. The dione (20 mmol) was added along with a slow addition of
excess zinc dust (ꢄ 80 mmol) to maintain a temperature of 80–85 ꢂC.
After the addition was completed, the resulting solution was heated at
reflux for 2 h. The hot reaction mixture was poured into ice water
(1500 mL) and allowed to crystallize overnight in the refrigerator. The
solid product was collected via suction filtration and recrystallized from
methanol=water to give the desired product.
Method D (One-Pot Pyrrole Synthesis)
A solution of acetoacetamide (20 mmol) in acetic acid (50 mL) was placed
in a three-neck, round-bottom flask equipped with a condenser and
magnetic stirrer and placed in an ice water bath. An excess of sodium

Short, Efficient Syntheses of Pyrrole a-Amides
4233
nitrite (ꢄ 40 mmol) dissolved in a minimal amount of water was added
dropwise over a 15-min period. The resulting solution was stirred for
2 h in an ice water bath followed by an additional hour of stirring at room
temperature. The dione (20 mmol) was added all at once, followed by the
slow addition of excess zinc dust (ꢄ80 mmol) such that the temperature
was maintained at 80–85 ꢂC. Upon completion of the addition, the reac-
tion mixture was heated at reflux for 2 h. The hot solution was poured
into ice water (1500 mL) and allowed to crystallize overnight in the refrig-
erator. The solid product was collected via suction filtration and recrys-
tallized from methanol=water to give the desired product. Analytically
pure samples were prepared either by multiple recrystallizations or radial
chromatography (CH2Cl2=CH3OH).
Method E (Aminolysis of Acyl Meldrum’s Acid Derivative, 9)[22,23]
A solution of the corresponding amine (20 mmol) and a slight excess
of freshly prepared acyl Meldrum’s acid derivative[22,24] (22 mmol) in
100 mL of anhydrous benzene was heated at reflux for 4 h. The solvent
was removed by rotary evaporation to yield the desired crude product.
The crude product was used in the respective pyrrole synthesis without
further purification.
Data
4-Acetyl-N,N-diethyl-3,5-dimethyl-1H-pyrrole-2-carboxamide (3a)
The crude product was recrystallized from methanol and water and dried
in vacuo to yield 3.3 g (70%) of pure product. It had a mp of 175–179 ꢂC
(lit.[12] ¼ 173–174ꢂ); 13C NMR (75 MHz, CDCl3) d 13.09, 13.38, 14.57,
30.75, 41.11, 120.29, 120.91, 121.83, 137.17, 165.12, 195.07 ppm;
1H NMR (300 MHz, CDCl3) d 1.06 (t, 6H, 7.0 Hz), 2.15 (s, 3H), 2.27
(s, 3H), 2.29 (s, 3H), 3.41 (q, 4H, 7.0 Hz), 11.00 (bs, 1H) ppm.
4-Carboethoxy-N,N-diethyl-3,5-dimethyl-1H-pyrrole-2-carboxamide
(3b)
The crude product was recrystallized from methanol and water and dried
in vacuo to yield 3.5 g (66%) of pure product. It had a mp of 108–110 ꢂC;
13C NMR (75 MHz, CDCl3) d 12.93, 13.76, 13.94, 14.69, 41.36, 59.34,
1
111.15, 121.81, 121.84, 138.28, 165.52, 166.2 ppm; H NMR (300 MHz,

4234
M. T. Huggins et al.
CDCl3) d 1.17 (t, 7.0 Hz, 6 H), 1.34 (t, 7.0 Hz, 3 H), 2.25 (s, 3 H), 2.39 (s, 3
H), 3.53 (q, 7.0 Hz, 4 H), 4.26 (q, 7.0 Hz, 2 H), 10.59 (bs, 1 H) ppm; IR
(KBr) 779, 1267, 1605, 1698, 2976, 3242 cmꢀ1; MS (EIþ) 72, 167, 194
(base peak), 266 m=z. HR-MS (EIþ) C14H22N2O3, calcd. 266.1630 amu;
found 266.1632 amu.
N2,N2Diethyl-3,5-dimethyl-N4-phenyl-1H-pyrrole-2,4-dicarboxamide
(3c)
The crude product was recrystallized from water and methanol and dried
in vacuo to yield 6.45 g (40.5%) of pure product. It had a mp of 149–
156 ꢂC; 13C NMR (75 MHz, CDCl3) d 11.68, 12.42, 13.49, 41.12,
116.34, 118.05, 119.96, 121.82, 123.65, 128.74, 133.05, 138.56, 165.02,
1
165.27 ppm; H NMR (300 MHz, CDCl3) d 1.15 (t, 6H, 7.0 Hz), 2.23
(s, 6H), 3.5 (q, 4H, 7.0 Hz), 7.06 (t, 1H, 7.0 Hz), 7.28 (t, 2H, 7.5 Hz),
7.63 (d, 2H, 8.0 Hz), 7.83 (bs, 1 Hz), 10.59 (bs, 1H) ppm; IR (KBr) 759,
1441, 1598, 1638, 3249, cmꢀ1; MS (EIþ) 148, 221 (base peak),
313 m=z. HR-MS (EIþ) C18H23N3O2 calcd. 313.1790 amu; found
313.1793 amu.
4-Acetyl-3,5-dimethyl-N-phenyl-1H-pyrrole-2-carboxamide (3d)
The crude product was recrystallized from methanol and water and dried
in vacuo to give 28.6 g (93%) of pure product. It had a mp of 235–238 ꢂC
(lit.[25] ¼ 237–238 ꢂC); 13C NMR (75 MHz, DMSO) d 12.54, 14.65, 31.19,
119.77, 121.93, 122.09, 123.22, 125.13, 128.72, 136.80, 139.20, 159.84,
1
194.41 ppm; H NMR (300 MHz, DMSO) d 2.38 (s, 3H), 2.49 (s, 6H),
7.07 (t, 1H, 7.0 Hz), 7.34 (t, 2H, 7.5 Hz), 7.67 (d, 2H, 7.5 Hz), 9.58 (bs,
1H), 11.68 (bs, 1H) ppm.
Ethyl 2,4-dimethyl-5-(phenylcarbamoyl)-1H-pyrrole-3-carboxylate (3e)
The crude product was recrystallized from methanol and water and dried
in vacuo to give 11.49 g (82%) of pure product. It had a mp of 182–185 ꢂC
(lit.[25] ¼ 178–179 ꢂC); 13C NMR (75 MHz, DMSO) d 11.90, 13.70, 14.35,
58.84, 111.76, 119.75, 121.90, 123.18, 125.88, 128.69, 137.36, 139.18,
159.65, 164.87 ppm; 1H NMR (300 MHz, DMSO) d 1.28 (t, 3H,
7.0 Hz), 2.45 (s, 3H), 2.48 (s, 3H), 4.19 (q, 2H, 7.0 Hz), 7.06 (t, 1H,
7.5 Hz), 7.33 (t, 2H, 8.5 Hz), 7.66 (d, 2H, 8.5 Hz), 9.52 (bs, 1H), 11.71
(bs, 1H) ppm.

Short, Efficient Syntheses of Pyrrole a-Amides
4235
3,5-Dimethyl-N,N’-diphenyl-1H-pyrrole-2,4-dicarboxamide (3f)
The crude product was recrystallized from methanol and water and dried
in vacuo to yield 12.3 g (79%). It had a mp of 236–240 ꢂC (lit.[26] ¼ 237–
240 ꢂC); 13C NMR (75 MHz, CDCl3) d 11.96, 13.01, 120.01, 120.25,
12.45, 121.59, 123.83, 123.90, 124.86, 129.31, 129.40, 132.84, 139.77,
140.11, 160.30, 164.97 ppm; 1H NMR (300 MHz, DMS0-d6) d 2.37
(s, 3H), 2.41 (s, 3H), 7.04 (m, 2H), 7.31 (m, 4H), 7.66 (m, 4H), 9.38
(bs, 1H), 9.62 (bs, 1H), 11.45 (bs, 1H) ppm.
4-Acetyl-N-butyl-3,5-dimethyl-1H-pyrrole-2-carboxamide (7a)
The crude product was recrystallized from methanol and water and dried
in vacuo to give 2.5 g (57%) of pure product. It had a mp of 158–161 ꢂC;
13C NMR (75 MHz, CDCl3) d 12.83, 13.89, 15.18, 20.30, 31.44, 31.95,
39.58, 121.94, 122.30, 123.02, 136.97, 162.28, 195.73 ppm; 1H NMR
(300 MHz, CDCl3) d 0.95 (t, 3H, 7.5 Hz), 1.40 (m, 2H), 1.60 (m, 2H),
2.43 (s, 3H), 2.54 (s, 6H), 3.54 (q, 2H, 7.0 Hz), 5.87 (t, 1H, 5.0 Hz),
10.72 (bs, 1H) ppm; IR (KBr) 1412, 162, 1639, 3241, 3272 cmꢀ1; Anal.
calcd. for C13H20N2O2: C, 66.07; H, 8.53; N; 11.85. Found: C, 65.96;
H, 8.34; N; 11.88.
Ethyl 5-(butylcarbamoyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (7b)
The crude product was recrystallized from methanol and water and dried
in vacuo to give 8.9 g (58%) of pure product. It had a mp of 145–148 ꢂC;
13C NMR (75 MHz, CDCl3) d 12.00, 13.97, 14.12, 14.35, 20.10, 31.76,
39.35, 59.36, 117.91, 121.74, 122.47, 138.07, 162.15, 165.78 ppm; 1H
NMR (300 MHz, CDCl3) d 0.95 (t, 3H, 7.5 Hz), 1.35 (t, 3H, 7.0 Hz),
1.39 (m, 2H), 1.59 (m, 2H), 2.50 (s, 3H), 2.55 (s, 3H), 3.45 (q, 2H,
6.5 Hz), 4.28 (q, 2H, 7.0 Hz), 5.78 (bs, 1H), 9.97 (bs, 1H) ppm; IR
(KBr) 1091, 1262, 1650, 1689, 3262 cmꢀ1. Anal. calcd. for C14H22N2O3:
C, 63.13; H, 8.33; N; 10.52. Found: C, 63.02; H, 8.11; N; 10.37.
Ethyl 5-[(4-chlorophenyl)carbamoyl]-2,4-dimethyl-1H-pyrrole-
3-carboxylate (7c)
The crude product was recrystallized from methanol and water and dried
in vacuo to give 1.23 g (34%) of pure product. It had a mp of 248–249 ꢂC
(lit.[27] ¼ 250–251 ꢂC); 13C NMR (75 MHz, CDCl3) d 12.36, 14.49, 14.59,
59.76, 113.45, 121.69, 123.81, 129.25, 129.62, 136.32, 138.93, 159.97,

4236
M. T. Huggins et al.
1
165.62 ppm; H NMR (300 MHz, CDCl3) d 1.37 (t, 3H, 7.0 Hz), 2.48
(s, 3H), 2.69 (s, 3H), 4.30 (q, 2H, 7.0 Hz), 7.31 (m, 2H), 7.54 (m, 3H),
9.96 (bs, 1H) ppm.
Ethyl 5-[(3-methoxyphenyl)carbamoyl]-2,4-dimethyl-
1H-pyrrole-3-carboxylate (7d)
The crude product was recrystallized from methanol and water and dried
in vacuo to give 5.5 g (56%) of pure product. It had a mp of 140–143 ꢂC
(lit.[27] ¼ 141–143 ꢂC); 13C NMR (75 MHz, CDCl3) d 12.31, 14.35, 14.55,
55.46, 59.68, 106.47, 110.21, 112.68, 113.20, 121.90, 123.77, 129.89,
138.87, 139.10, 160.19, 160.34, 165.75 ppm; 1H NMR (300 MHz, CDCl3)
d 1.36 (t, 3H, 7.0 Hz), 2.47 (s, 3H), 2.69 (s, 3H), 3.81 (s, 3H), 4.30 (q, 2H,
7.0 Hz), 6.69 (m, 1H), 7.06 (m, 1H), 7.32 (m, 1H), 7.59 (s, 1H), 10.31 (bs,
1H) ppm.
4-Acetyl-N-butyl-5-methyl-3-propyl-1H-pyrrole-2-carboxamide (11a)
The crude product was recrystallized in methanol and water and dried in
vacuo to yield 1.5 g (47%). It had a mp of 85–88 ꢂC; 13C NMR (75 MHz,
CDCl3) d 13.82, 14.43, 15.32, 20.26, 24.52, 28.51, 31.34, 31.77, 39.47,
121.77, 122.89, 127.89, 136.95, 162.20, 195.33 ppm; 1H NMR
(300 MHz, CDCl3) d 0.96 (t, 3H, 7.0 Hz), 1.02 (t, 3H, 7.0 Hz), 1.41
(m, 4H), 1.61 (m, 4H), 2.43 (s, 3H), 2.53 (s, 3H), 2.90 (m, 2H), 3.45 (q,
2H, 7.0 Hz), 5.84 (broad triplet, 1H, 4.8 Hz), 10.06 (bs, 1H) ppm; IR
(KBr) 1071, 1262, 1416, 1634, 2932, 3241 cmꢀ1; MS (EIþ) 176, 192,
249, 264 (base peak) m=z. HR-MS (EIþ) C15H24N2O2 calcd.
264.1838 amu; found 264.1833 amu.
4-Acetyl-N-(4-chlorophenyl)-5-methyl-3-propyl-1H-pyrrole-2-
carboxamide (11b)
The crude product was recrystallized in methanol and water and dried in
vacuo to yield 0.83 g (44%) of pure product. It had a mp of 155–156 ꢂC.
13C NMR (75 MHz, CDCl3) d 14.55, 15.52, 24.65, 28.55, 31.43, 121.48,
1
121.58, 122.83, 129.28, 129.70, 136.21, 137.77, 160.09, 195.42 ppm; H
NMR (300 MHz, CDCl3) d 1.08 (t, 3H, 7.0 Hz) 1.71 (m, 2H), 2.44 (s,
3H), 2.49 (s, 3H), 3.04 (t, 2H, 8.0 Hz), 7.31 (d, 2H, 8.5 Hz), 7.50 (d,
3H, 8.5 Hz), 7.68 (bs, 1H), 10.43 (bs, 1H) ppm; IR (KBr) 826, 1065,
1337, 1490, 1626, 2950, 3245 cmꢀ1; MS (EIþ) 127, 192 (base peak),

Short, Efficient Syntheses of Pyrrole a-Amides
4237
318 m=z. HR-MS (EI þ) C17H19N2O2Cl calcd. 318.1135 amu; found
318.1132 amu.
4-Acetyl-N,N-diisopropyl-5-methyl-3-propyl-1H-pyrrole-2-carboxamide
(11c)
The crude product was recrystallized from methanol and water and dried
in vacuo to yield 0.62 g (31%) of pure product. It had a mp of 177–179 ꢂC.
13C NMR (75 MHz, CDCl3) d 14.49, 15.19, 21.17, 24.36, 28.45, 30.99,
48.90, 120.19, 123.44, 123.87, 136.45, 166.13, 195.38 ppm; 1H NMR
(300 MHz, CDCl3) d 0.89 (t, 3H, 7.0 Hz), 1.42 (d, 12H, 6.5 Hz), 1.49
(m, 2H), 2.31 (s, 3H), 2.37 (s, 3H), 2.63 (m, 2H) 3.87 (t, 2H, 6.0 Hz)
10.56 (bs, 1H) ppm; IR (KBr) 965, 1317, 1441, 1611, 1636, 2973,
3198 cmꢀ1. Anal. calcd. for C17H28N2O2: C, 69.83; H, 9.65; N; 9.58:
Found: C, 69.87; H, 9.40; N; 9.45.
ACKNOWLEDGMENTS
M. T. H. thanks the American Chemical Society’s Petroleum Research
Fund (PRF 44304-GB4) and the University of West Florida (UWF)
Research Foundation for their generous support of this work. P. S. B.
was a Morelli-Quinteros Undergraduate Research Fellow. D. F. was a
Project SEED summer I and II student at UWF and thanks the American
Chemical Society for its support.
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