Remarkable solvent effect in Barton-Zard pyrrole synthesis: application in an efficient one-step synthesis of pyrrole derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.05.167

A unique solvent effect encountered in the Barton-Zard pyrrole synthesis was exploited to develop an efficient synthesis of pyrrole-2-esters. The chemistry was extended to a one-pot synthesis of pyrrole-2,4-dicarboxylates.

Full text of DOI:10.1016/j.tetlet.2006.05.167

Tetrahedron Letters 47 (2006) 5481–5484
Remarkable solvent effect in Barton–Zard pyrrole
synthesis: application in an efficient one-step synthesis
of pyrrole derivatives
a,
a
a
*
Apurba Bhattacharya, Sankara Cherukuri, Robert Erik Plata,
a
a
b
Nitinchandra Patel, Victoriano Tamez, Jr., John A. Grosso,
b
b
Michael Peddicord and Venkatapuram A. Palaniswamy
a
Department of Chemistry, Texas A&M University-Kingsville, Kingsville, TX 78363, United States
Bristol Myers Squibb Co., One Squibb Drive, PO Box 191, New Brunswick, NJ 08903-0191, United States
b
Received 20 December 2005; revised 22 May 2006; accepted 30 May 2006
Available online 16 June 2006
Abstract—A unique solvent effect encountered in the Barton–Zard pyrrole synthesis was exploited to develop an efficient synthesis
of pyrrole-2-esters. The chemistry was extended to a one-pot synthesis of pyrrole-2,4-dicarboxylates.
ꢀ
2006 Elsevier Ltd. All rights reserved.
As part of our ongoing industry-university collaborative
research program directed towards developing efficient
processes for pharmaceutical intermediates, we needed
an expeditious entry into a diverse spectrum of 3,4-
tant-mediated solvent-free conditions recently developed
in our laboratories. Acylation of nitroalcohols in the
4
presence of catalytic amount of amberlyst IR-120 ion-
exchange resin (60 ꢁC, 1 h) affords b-acetoxy-nitro deriv-
atives (>95% yield) after filtration of the resin, followed
by aqueous sodium carbonate wash. The crude product
was carried forward into the Barton–Zard condensation
without any further purification. Resin catalysis is
superior in efficiency to the existing H SO -catalyzed
1
disubstituted pyrrole-2-esters (1). The most advanta-
geous and conceptually unique synthesis developed by
Barton and Zard involves condensation of nitroolefins
or b-acetoxy-nitro derivatives with a-isocyanoacetates
in the presence of a non-ionic base, such as 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) and guanidine (Table 1).
Despite its attractiveness, the method is often compli-
2
4
acylation, which is cumbersome and low yielding.
Furthermore, the product needed to be isolated by high
2
2d,5
cated by poor yields and unwanted by-products. A po-
vacuum distillation.
Initial Barton–Zard condensa-
tential improvement has been reported by Varkade that
uses proazaphosphotranes as a non-ionic superbase,
however, that option for a base, while recyclable, must
tions with ethyl isocyanoacetate and 4-acetoxy-3-nitro-
hexane as representative examples under established
conditions (DBU, tetrahydrofuran (THF)-isopropanol),
followed by aqueous work-up, produced the desired
ethyl 3,4-diethylpyrrole-2-carboxylate in 38% yield, as
3
be prepared independently. Herein we report a significant
improvement in the Barton–Zard protocol by exploiting
a unique and serendipitous solvent effect discovered in
the nitroalkene–isocyanoacetate condensations.
2
d
reported earlier. Commercial THF is stabilized with
trace amounts of the radical inhibitor, butylated
hydroxytoluene (BHT), to prevent the formation and/
6
Our improved process for the preparation of the pyrrole
derivatives via the corresponding nitroolefins is outlined
in Table 1. Nitroaldols were prepared in >90% yield by
addition of nitroalkanes with aldehydes under surfac-
or accumulation of THF–peroxide. It occurred to us
that BHT, being a radical inhibitor, could potentially
interfere with the condensation process, thereby lower-
7
ing the yield which proved to be the case. Further inves-
tigations revealed that when THF–isopropanol was
replaced with distilled THF or tert-butyl methyl ether
(MTBE), neither of which contains a stabilizer, under
otherwise identical conditions, the reaction was faster
*
Corresponding author. Tel.: +1 361 593 2664; fax: +1 361 593
597; e-mail: kfab002@tamuk.edu
3
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.167

5482
A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 5481–5484
Table 1. Preparation of 3,4-dialkylpyrrole-2-carboxylates from nitroalcohols
Ac O, 60 ºC
DBU,
2
R1
R2
IR-120 Resin (cat)
R1
R2
MTBE, 20 ºC
R1
R2
NO2
CNCH COOEt
2
R1
R2
(>95%)
(>95%)
HO
NO2
AcO
NO2
EtOOC
N
H
Nitroalcohol
ß-Acetoxy-nitro derivative
Nitroolefin
1
Entry
R
1
R
2
% Yield 1 (over 3 steps)
1
2
3
4
5
6
Me–
Et–
n-Pr–
Et–
n-Pr–
n-Pr–
Me–
Et–
n-Pr–
Me–
Et–
94
96
93
92
93
91
Me–
(
cf. 2 h from 4 h), cleaner, and the product was obtained
(43 g) and concd HCl (222 g) and the stirred mixture
was warmed to 35–40 ꢁC and allowed to settle. The
MTBE solution containing the product was washed with
saturated aqueous sodium bicarbonate solution (600 g).
Evaporation of the solvent in vacuo produced 322.2 g
in near quantitative yield (98–100%). Control experi-
ments conducted by adding trace amounts of BHT
(
100 ppm) to the above solvents again resulted in lower
yield (ca. 45–50%) of the product 3,4-diethylpyrrole-2-
carboxylate. We have not carried out detailed mechanis-
tic studies and further work is warranted to gain better
understanding in this process. However, replacing
THF with MTBE in the process offers an additional
advantage from commercial standpoint since MTBE,
unlike distilled THF, can be stored for an indefinite
period. A typical experimental procedure is as follows:
under nitrogen, acetic anhydride (345.23 g, 3.38 mol)
was added to a stirred mixture of 3-nitro-4-hexanol
8
(100% yield) of ethyl 3,4-diethylpyrrole-2-carboxylate.
Exploiting the ability of acetylenic esters (2) to act as
Michael acceptors coupled with the propensity of the
initial adduct (3) to cyclize, the above isocyanoacetate
condensation protocol was extended to an efficient,
one-pot synthesis of pyrrole-2,4-dicarboxylate deriva-
9
tives (4). The optimal conditions to effect the transfor-
mation involves treating a mixture of the acetylenic
esters (1 equiv) and ethyl isocyanoacetate (1 equiv) with
KH (1.4 equiv) as an irreversible base in MTBE (10 mL/
g of isocyanoacetate) for 4–20 h at 20 ꢁC producing the
pyrrole derivatives (4) in good to excellent yields (Table
(
1:1 diastereomeric mixture, 246.3 g, 1.7 mol) and
Amberlite IR-(120) plus cation exchange resin (18.7 g)
over a period of 1 h maintaining the batch-temperature
between 55 and 65 ꢁC. The reaction mixture was stirred
at 60 ꢁC for another hour. The mixture was cooled to
room temperature, filtered, washed with an aqueous
solution of sodium carbonate (1380 g of 2 M solution)
and dried over molecular sieves to produce 311.8 g of
1
0
2). A typical experimental procedure is as follows: a
suspension of potassium hydride (0.49 g, 12.4 mmol)
in MTBE (10 mL) was added to a stirred mixture of
ethyl 2-butynoate (1.0 g, 8.9 mmol) and ethyl iso-
cyanoacetate (1 g, 8.9 mmol) in MTBE (10 mL) and
4
-acetoxy-3-nitrohexane (yield 98%) and was carried to
1
1
the next step without any further purification. In the
next step, under nitrogen, DBU (498.3 g, 3.3 mol) was
added to a stirred mixture of 4-acetoxy-3-nitrohexane
the reaction mixture was stirred at 22 ꢁC for 4 h.
The resulting mixture was acidified to pH 3 using 1 N
HCl. The organic layer containing the produce was sep-
arated from the aqueous layer and the aqueous layer
was extracted with two 25 mL portions of MTBE. The
combined organic extracts were washed with brine solu-
tion (2 · 10 mL), dried over magnesium sulfate, and
evaporation of the solvent in vacuo produced 1.6 g of
(
311.2 g, 1.7 mol), MTBE (363.8 g) and ethyl iso-
cyanoacetate (187.1 g, 1.7 mol) over a period of 85 min
maintaining a temperature of 10–20 ꢁC. The reaction
mixture was stirred at 20 ꢁC for 2 h. To the stirred mix-
ture was added MTBE (540 g), water (614 g), NaCl
Table 2. Preparation of pyrrole-2,4-dicarboxylate derivatives from acetylenic esters
CNCH COOEt,
KH, MTBE, 20 ºC
2
COOEt
R3
COOEt
R3
R3
COOEt
EtOOC
N
H
EtOOC
2
N
3
4
a
Entry
R
3
Time (h)
% Conversion (% Yield 4)
1
2
3
4
5
Me–
H–
Ph–
n-Pr–
Et–
5
4
20
5
100 (78)
100 (84)
100 (81)
100 (85)
100 (91)
5
a
Conversion based on GC and HPLC.

A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 5481–5484
5483
1
3
3
-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester
7.54 (dd, J = 1.6, 3.2, 1H), 12.51 (s, 1H, NH);
C
(
78%).
NMR (100.6 MHz, CD OD): d 14.2 (·2), 59.4, 60.1,
3
1
15.1, 116.6, 123.4, 127.8, 159.9, 163.2. 3-Phenyl-1H-
In summary, we have exploited a unique solvent effect
encountered in Barton–Zard synthesis to develop an
efficient and operationally simple process for 3,4-disubsti-
tuted pyrrole-2-esters. The isocyanoacetate condensation
was also extended to a simple, one-step, conceptually
distinct methodology for the synthesis of pyrrole-2,4-
pyrrole-2,4-dicarboxylic acid diethyl ester (entry 3, Table
1
2): H NMR (600.13 MHz, DMSO-d ): d 1.00 (t,
6
J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H), 3.99 (q,
J = 7.2 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 7.21–7.28
1
3
(m, 5H), 7.56 (s, 1H), 12.44 (s, 1H, NH); C NMR
(100.6 MHz, DMSO-d ): d 13.7, 13.9, 59.0, 59.6, 115.5,
6
1
2
dicarboxylate derivatives.
120.4, 126.5, 126.6 (·2), 127.6, 130.2 (·2), 131.5, 134.0,
1
60.0, 163.0. 3-Propyl-1H-pyrrole-2,4-dicarboxylic acid
1
Selected NMR data. 3,4-Dimethyl-1H-pyrrole-2-carbox-
diethyl ester (entry 4, Table 2): H NMR (400.13
1
ylic acid ethyl ester (entry 1, Table 1): H NMR (CDCl ,
MHz, DMSO-d ): d 0.86 (t, J = 7.5 Hz, 3H), 1.24
3
6
6
00.1 MHz) d 1.35 (t, 3H, J = 7.2 Hz), 2.01 (s, 3H,), 2.27
(t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.48 (sextet,
J = 7.5 Hz, 2H), 2.98 (t, J = 7.5 Hz, 2H), 4.17 (q, J =
7.0 Hz, 2H), 4.24 (q, J = 7.0 Hz, 2H), 7.42 (d, J =
1
3
(
(
s, 3H), 4.31 (q, 2H, J = 7.2 Hz), 6.67 (s, H2); C NMR
CDCl , 150.9 MHz) d (9.8, 10.2), 14.4, 59.8, 119.1,
3
1
3
1
20.4, 120.3, 126.5, 162.0. 3,4-Diethyl-1H-pyrrole-2-car-
2.6 Hz, 1H), 12.08 (s, 1H, NH); C NMR (100.6
1
boxylic acid ethyl ester (entry 2, Table 1): H NMR
CDCl , 600.1 MHz) d 1.14 (t, 3H, J = 7.4 Hz), 1.19 (t,
MHz, DMSO-d ): d 13.9, 14.2 (·2), 24.0, 26.4, 59.0,
6
(
59.6, 114.7, 120.0, 127.7, 133.4, 160.5, 163.6. 3-Ethyl-
1H-pyrrole-2,4-dicarboxylic acid diethyl ester (entry 5,
3
3
H, J = 7.7 Hz), 1.35 (t, 3H, J = 7.2 Hz), 2.45 (q, 2H,
1
J = 7.4 Hz), 2.75 (q, 2H, J = 7.3 Hz), 4.31 (q, 2H,
J = 7.1 Hz), 6.67 (d, J = 2.6 Hz); C NMR (CDCl3,
1
1
Table 2): H NMR (400.13 MHz, DMSO-d ): d 1.15
6
1
3
(t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H), 1.31 (t,
J = 7.5 Hz, 3H), 2.99 (q, J = 7.5 Hz, 2H), 4.18 (q, J =
7.1 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 7.42 (d, J =
50.9 MHz) d (14.5, 14.9, 15.5), (18.0, 18.1), 59.8,
18.7, 119.2, 126.8, 132.5, 161.6. 3,4-Dipropyl-1H-pyr-
1
13
role-2-carboxylic acid ethyl ester (entry 3, Table 1): H
2.6 Hz, 1H), 12.04 (br s, 1H, NH); C NMR (100.6
NMR (CDCl , 600.1 MHz) d 0.96 (t, 6H, J = 7.4 Hz),
MHz, DMSO-d ): d 15.01, 14.1 (·2), 27.62, 59.9,
3
6
1
.34 (t, 3H, J = 7.1 Hz), 1.55 (m, 4H), 2.39 (t, 2H,
60.53, 115.3, 120.5, 128.54, 136.2, 161.3, 164.44.
J = 7.7 Hz), 2.69 (t, 2H, J = 7.7 Hz), 4.30 (q, 2H,
1
3
J = 7.1 Hz), 6.67 (d, J = 2.8 Hz); C NMR (CDCl3,
1
50.9 MHz) d (14.0, 14.1, 14.3), (23.6, 24.3), (26.9,
6.9), 59.7, 118.8, 119.9, 125.2, 131.0, 161.7. 3-Ethyl-4-
Acknowledgements
2
methyl-1H-pyrrole-2-carboxylic acid ethyl ester (entry
Financial support provided by the Petroleum Research
Fund (PRF), National Institute of Health (NIH), Welch
Foundation, and Bristol Myers Squibb Corporation is
gratefully acknowledged.
1
4
, Table 1): H NMR (CDCl , 600.1 MHz) d 1.16 (t,
3
3
H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.1 Hz), 2.28 (s), 2.42
(
q, 2H, J = 7.4 Hz), 4.31 (q, 2H, J = 7.2 Hz), 6.68 (d,
1
3
J = 2.8 Hz); C NMR (CDCl , 150.9 MHz) d 10.1
3
(
Ethyl-3-propyl-1H-pyrrole-2-carboxylic acid ethyl ester
14.4, 14.4), 18.1, 59.8, 119.1, 119.3, 127.3, 162.0. 4-
References and notes
1
(
entry 5, Table 1): H NMR (CDCl , 600.1 MHz) d
3
0
.95 (t, 3H, J = 7.2 Hz), 1.18 (t, 3H, J = 7.6 Hz), 1.35
1
. The program was aimed at giving the BS/MS level
students exposure to pharmaceutical process R&D in an
academic setting. Chemical and Engineering News; Educa-
tion Concentrate, 2001, p 41.
(
t, 3H, J = 7.2 Hz), 1.54 (m, 2H), 2.44 (q, 2H,
J = 7.4 Hz), 2.70 (t, 2H, J = 7.9 Hz), 4.30 (q, 2H,
J = 7.2 Hz), 6.68 (d, J = 3.0 Hz); C NMR (CDCl3,
1
3
1
1
1
1
50.9 MHz) d (14.2, 14.4, 14.7), 18.0 (24.3, 26.9), 59.7,
2. (a) Barton, D. H. R.; Kervagore, J.; Zard, S. Tetrahedron
990, 21, 7587–7598; (b) Barton, D. H. R.; Zard, S. J.
1
18.9, 119.1, 127.2, 130.8, 161.7. 4-Methyl-3-propyl-
H-pyrrole-2-carboxylic acid ethyl ester (entry 6, Table
Chem. Soc., Chem. Commun. 1985, 1098–1100; (c) Ono,
N.; Maruyama, K. Bull. Chem. Soc. Jpn. 1988, 61, 4470–
1
): H NMR (CDCl , 300.1 MHz) d 0.96 (t, 3H,
3
4
472; (d) Sessler, J. L.; Mozattari, A.; Johnson, M. Org.
J = 7.4 Hz), 1.37 (t, 3H, J = 7.1 Hz), 1.56 (m, 2H,
J = 7.5 Hz), 2.04 (s, 3H), 2.72 (t, 2H, J = 7.6 Hz), 4.32
Syn. 1991, 70, 68–77.
3
. Kisanga, P. B.; Verkade, J. G. Tetrahedron 2001, 57, 467–
(
q, 2H, J = 7.1 Hz), 6.67 (d, 1H, J = 2.9 Hz), 8.77 (br,
4
75, and references cited therein.
1
3
1
2
H). C NMR (CDCl , 75.5 MHz) d 10.0, 14.1, 14.5,
3
4. Bhattacharya, A.; Purohit, V. C.; Rinaldi, F. Org. Proc.
Res. Dev. 2003, 7, 254–258.
3.9, 26.9, 59.8, 119.0, 120.2, 120.2, 131.5, 161.6. 3-
Methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester
(
5. Ono, N.; Maruyama, K. Chem. Lett. 1988, 1511–1514.
6. Mahn, W. J. Academic Laboratory Chemical Hazards
Guidebook; Nostrand Reinhold: New York, 1990.
1
entry 1, Table 2): H NMR (600.13 MHz, CD OD):
3
d 1.32 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H),
.54 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 4.31 (q,
7
8
9
. For radical character in cycloaddition processes, see:
Firestone, R. A. Tetrahedron 1977, 33, 3009–3039.
. The reaction was scaled up to provide initial supply of
materials.
. For silver acetate catalyzed cycloaddition of isocyano-
acetates, see: (a) Grigg, R.; Lansdell, M. I.; Thornton-Pett,
M. Tetrahedron 1999, 55, 2025–2044, and references cited
therein; (b) Kamijo, S.; Kanazawa, C.; Yamamoto, Y.
Tetrahedron Lett. 2005, 46, 2563–2566.
2
1
3
J = 7.2 Hz, 2H), 7.43 (s, 1H); C NMR (100.6 MHz,
CD OD): d 11.5, 14.7 (·2), 60.7, 61.2, 117.1, 121.9,
3
1
28.7, 130.9, 162.7, 166.6. 1H-Pyrrole-2,4-dicarboxylic
1
acid diethyl ester (entry 2, Table 2): H NMR
600.13 MHz, CD OD): d 1.24 (t, J = 7.2 Hz, 3H),
(
3
1
.27 (t, J = 7.2 Hz, 3H), 4.18 (q, J = 7.2 Hz, 2H), 4.24
(
q, J = 7.2 Hz, 2H), 7.04 (dd, J = 2.0, 2.0 Hz, 1H),

5484
A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 5481–5484
1
1
0. Adding trace amounts (100 ppm) of BHT to MTBE in this
12. For all the known compounds, GCMS analysis (Shimadzu
QP5050A) in the EI mode provided similarity index match
of >90% compared to the authentic samples in the NIST-
98 database.
case also resulted in low yield of the product.
1. KH, purchased as a suspension in mineral oil, was washed
repeatedly with hexanes and dried under vacuum.