Practical one-pot syntheses of ethyl 4-substituted-1 H-pyrrole-3- carboxylates from aldehydes

Article abstract of DOI:10.1021/op7002826

Ethyl 4-substituted-1H-pyrrole-3-carboxylates were prepared in a one-pot manner starting from aromatic or aliphatic aldehydes via a Horner-Wadsworth- Emmons reaction and subsequent reaction with tosylmethylisocyanide (TosMIC) in the presence of sodium tert-amylate in toluene. Judicious selection of base and solvent led to the use of a single solvent, i.e., toluene, for reactions as well as for crystallization to render the one-pot process more practical and greener than the stepwise version. hisin@ lels.com.

Full text of DOI:10.1021/op7002826

Organic Process Research & Development 2008, 12, 291–293
Technical Notes
Practical One-Pot Syntheses of Ethyl 4-Substituted-1H-Pyrrole-3-Carboxylates from
Aldehydes†
Jay Hyok Chang and Hyunik Shin*
Chemical DeVelopment DiVision, LG Life Sciences, Ltd./R&D, 104-1, Moonji-dong, Yusong-gu, Daejeon 305-380, Korea
Scheme 1
Abstract:
Ethyl 4-substituted-1H-pyrrole-3-carboxylates were prepared in
a one-pot manner starting from aromatic or aliphatic aldehydes
via a Horner-Wadsworth-Emmons reaction and subsequent
reaction with tosylmethylisocyanide (TosMIC) in the presence of
sodium tert-amylate in toluene. Judicious selection of base and
solvent led to the use of a single solvent, i.e., toluene, for reactions
as well as for crystallization to render the one-pot process more
practical and greener than the stepwise version.
In search of a potent and selective farnesyltransferase (FTase)
inhibitor, our discovery team identified LB42908 (1) having
an ethyl 4-(1-naphthyl)-1H-pyrrole-3-carboxylate fragment as
a development candidate1 (Scheme 1). For its expeditious
development, it became prerequisite to set up a large-scale viable
synthesis of the pyrrole fragment 2a and its coupling partner
3.2 Herein, we describe a practical and green, one-pot prepara-
tion of 2a from aldehyde 5a.3
In the literature there are limited synthetic methods for the
construction of this class of compounds. Most frequently
reaction of R,ꢀ-unsaturated ester with tosylmethylisocyanide
(TosMIC) in the presence of base is used as developed by van
Leusen et al.4 Alternatively, reaction of ꢀ-aminoacrylate with
R-aminoarylketone5 or Michael addition of ꢀ-aminoacrylate
towards nitroalkene followed by Nef reaction,6 or oxidation of
pyrrolidine by excess manganese dioxide7 could be a possible
route towards 4-substituted-1H-pyrrole-3-carboxylates. Based
on readily accessible starting materials, R,ꢀ-unsaturated ester
and TosMIC, a modified version of the first method was
investigated for the synthesis of pyrrole compounds via two
separate steps: (1) conversion of an aldehyde to an R,ꢀ-
unsaturated ester with triethylphosphonoacetate in the presence
of lithium chloride and DBU in acetonitrile and (2) its reaction
with TosMIC in the presence of potassium tert-butoxide in THF
(Scheme 2). However, we quickly realized that this route was
Scheme 2
† This paper is dedicated to Dr. Hokoon Park on the occasion of his 61st
birthday.
* To whom correspondence should be addressed. E-mail: hisin@
lgls.com. Telephone: 82-42-8662471. Fax: 82-42-8665754.
(1) Lee, H.; Lee, J.; Lee, S.; Shin, Y.; Jung, W.; Kim, J.-H.; Park, K.;
Kim, K.; Cho, H. S.; Ro, S.; Lee, S.; Jeong, S. W.; Choi, T.; Chung,
H.-H.; Koh, J. S. Biorg. Med. Chem. Lett. 2001, 11, 3069.
(2) (a) For the synthesis of 3, please refer to: (a) ref 1. (b) Chang, J. H.;
Lee, K. W.; Nam, D. H.; Kim, W. S.; Shin, H. Org. Process Res. DeV.
2002, 6, 674.
not viable for a large-scale operation because water-miscible
solvents, acetonitrile and THF, should be removed for efficient
extractive workups, thus increasing effluent as well as the
number of operations such as distillations. These shortcomings
led us to consider a one-pot synthesis which not only obviates
a number of operations but also reduces the amount of effluent.
To this end, we ran the Horner-Wadsworth-Emmons reaction
of aldehyde 5a with sodium tert-butoxide in DME to form 4a,
into which TosMIC and additional sodium tert-butoxide was
added to provide pyrrole 2a. After the addition of water and
toluene, most of DME was removed by distillation, and the
organic phase was separated at 80 °C. Crystallization from
toluene afforded highly pure product 2a. Although this change
is superior to the stepwise version, there is still room for further
(3) The content of this paperhas been published as a part of patent. See:
Shin, H.; Oh, S. T.; Chang, J. H.; Lee, K. U. WO 01/62727, 2001.
(4) (a) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen,
D. Tetrahedron Lett. 1972, 5337. (b) Pavri, N. P.; Trudell, M. L. J.
Org. Chem. 1997, 62, 2649. (c) For the use of benzotriazol-1-yl-methyl
isocyanide (BetMIC) as a TosMIC surrogate, see Katritzky, A. R.;
Cheng, D.; Musgrave, P. Heterocycles 1997, 44, 67.
(5) Alberola, A.; Andres, J. M.; Gonzalez, A.; Pedrosa, R.; Vicente, M.
J. Chem. Soc., Perkin Trans. 1 1990, 2681.
(6) Trautwein, A. W.; Jung, G. Tetrahedron Lett. 1998, 39, 8263.
(7) Menasra, H.; Kedjadja, A.; Debaches, A.; Rhouati, S.; Belfaitah, A.
Synth. Commun. 2005, 35, 2779.
10.1021/op7002826 CCC: $40.75
Published on Web 02/29/2008
2008 American Chemical Society
Vol. 12, No. 2, 2008 / Organic Process Research & Development
•
291

Table 1. Substrate scope of one-pot pyrrole synthesis
any chromatographic separation. Compounds 2b, 2d, and 2g
(entries 2, 4, and 7) were purified by column chromatography.
Aliphatic aldehydes are also acceptable substrates for our
protocol: trimethylacetaldehyde and isovaleraldehyde (entries
8 and 9) were converted to corresponding pyrroles 2 h and 2i
in 23% and 53% yield, respectively.
In summary, by considering both operational efficiency as
well as reduction of effluent, we devised a one-pot process
towards ethyl 4-substituted-1H-pyrrole-3-carboxylates which
features the use of a single solvent, i.e., toluene, for both
reactions and crystallization.
Experimental Section
Solvents and reagents were obtained from commercial
sources and used without further purification. NMR spectra were
obtained on a Jeol 500 MHz spectrometer. HPLC analyses were
carried out on a Hewlett-Packard 1100 system and a Waters
490E detector and 616 pump system. Mass spectra were
collected using a Finnigan LCQ mass spectrometer system and
a Jeol JMX-700 mass spectrometer.
Ethyl 4-(1-Naphthyl)-1H-pyrrole-3-carboxylate (2a).1-Naph-
thaldehyde (2.8 kg, 18 mol) and triethylphosphonoacetate (4.04
kg, 18 mol) were introduced into a 50 L reactor and diluted
with 18 L of toluene. The reaction mixture was cooled to about
0-5 °C, and sodium tert-amylate (2.38 kg, 21.6 mol) was added
slowly in order to maintain the reaction temperature below 20
°C. After the addition was completed, the reaction mixture was
stirred for 1 h at ambient temperature and cooled to 0-5 °C.
TosMIC (3.69 kg, 18.9 mol) and sodium tert-amylate (2.38 kg,
21.6 mol) were added slowly in sequence, maintaining the
reaction temperature below 20 °C. After the addition was
completed, the reaction mixture was stirred for 5 h at ambient
temperature, and 25 L of distilled water was added. The
resulting mixture was heated at about 80 °C, and the organic
layer was separated and washed once again with 25 L of
distilled water at the same temperature. Roughly one-third of
the separated organic layer was subjected to azeotropic distil-
lation to remove the residual moisture. Then, the concentrate
was cooled to about 50 °C with slow stirring. After the crystal
was precipitated, the reaction temperature was further lowered
to 25 °C and stirring was continued for 15 h. The formed solid
was filtered, washed twice with 3 L of toluene and dried with
nitrogen purge to give 2.96 kg (HPLC Purity 96% PAR, Yield
62%) of 2a as a white solid. Physical and spectral data: mp
164-165 °C; 1H NMR (500 MHz, CDCl3) δ 8.65 (s, br, 1H),
7.80 (m, 3H), 7.59 (dd, J ) 3.2, 2.3 Hz, 1H), 7.41 (m, 4H),
6.79 (t, J ) 2.3 Hz, 1H), 3.91 (q, J ) 6.9 Hz, 2H), 0.71 (t, J
) 6.9 Hz, 3H), 13C NMR (125 MHz, CDCl3) δ 165.2, 133.8,
133.51, 133.50, 128.0, 127.5, 127.3, 126.7, 125.5, 125.4, 125.2,
124.7, 123.9, 119.3, 115.9, 59.5, 13.7.
a Except 2a, all the reactions were tested with 5 mmol of aldehydes. b At the
first step, sticky oil was formed as reaction progressed to make stirring difficult.
c Yield using MeTHF as a solvent; homogeneous reaction mixture was observed.
d Although products solidified in toluene, they were purified by column
chromatography.
improvement if we could use toluene as a solvent for the
reactions as well as for recrystallization.8 However, it was found
that the Horner-Wadsworth-Emmons reaction of aldehyde 5a
in toluene with sodium tert-butoxide as a base was very
sluggish. We speculated that the slow reaction might be caused
by low solubility of sodium tert-butoxide in toluene and an
alternative base having better solubility profile would solve this
problem. Happily, replacement of sodium tert-butoxide with
sodium tert-amylate9 caused smooth conversion to R,ꢀ-unsatur-
ated ester 4a as well as to pyrrole 2a. At the end of reaction,
water was added, phases were separated at 80 °C, the organic
phase was cooled, and product was filtered to provide highly
pure (better than 95% by HPLC) 2a as a crystalline solid.
To test the generality of the established method, we tested
various aromatic aldehydes substituted by electron-withdrawing
and -donating groups, revealing that electronic influence was
negligible (Table 1). Products 2a, 2c, 2e, and 2f (entries 1, 3,
5, and 6) were isolated as a good solid from toluene without
Ethyl 4-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (2b):
1H NMR (500 MHz, CDCl3) δ 9.22 (s, br, 1H), 7.41 (dd, J )
8.5, 5.5 Hz, 2H), 7.34 (t, J ) 2.3 Hz, 1H), 7.00 (t, J ) 8.5 Hz,
2H), 6.59 (t, J ) 2.3 Hz, 1H), 4.22 (q, J ) 7.4 Hz, 2H), 1.26
(t, J ) 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.6,
161.9 (d, J ) 243 Hz), 131.0 (d, J ) 8.3 Hz), 125.8, 125.5,
118.7, 114.7 (d, J ) 21 Hz), 113.2, 59.9, 14.4.
(8) One reviewer reminded us of a reference which describes the general
concept of our approach as a “bottom-up” approach to the development
of direct-drop process. Please refer to Chen, C.-K.; Singh, A. K. Org.
Process Res. DeV. 2001, 5, 508.
(9) Sodium tert-butoxide and tert-amylate have 6 wt % and 41 wt %
solubility in toluene at 25 °C, respectively. For general information on
metal alkoxides, please visit http://www.alcoholates.com.
Ethyl 4-[4-(trifluoromethyl)phenyl]-1H-pyrrole-3-car-
292
•
Vol. 12, No. 2, 2008 / Organic Process Research & Development

boxylate (2c): 1H NMR (500 MHz, CDCl3) δ 8.65 (s, br, 1H),
7.59 (s, 4H), 7.50 (t, J ) 2.4 Hz, 1H), 6.81 (t, J ) 2.4 Hz, 1H),
4.22 (q, J ) 7.3 Hz, 2H), 1.25 (t, J ) 7.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 164.7, 138.5, 129.6, 128.7, 128.4, 125.7,
125.6, 125.5, 124.7, 124.6, 118.8, 113.9, 59.9, 14.4; HRMS
(ESI) for [M + H+] C14H13F3NO2: calcd, 284.0892; found,
284.0891.
Ethyl 4-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-car-
boxylate (2d): 1H NMR (500 MHz, CDCl3) δ 8.60 (s, br, 1H),
7.72 (s, 1H), 7.67 (d, J ) 7.3 Hz, 1H), 7.52 (m, 1H), 7.50 (t,
J ) 2.3 Hz, 1H), 7.44 (m, 1H), 6.79 (t, J ) 2.3 Hz, 1H), 4.20
(q, J ) 7.4 Hz, 2H), 1.23 (t, J ) 7.4 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 164.7, 135.6, 132.8, 130.1 (q, J ) 31 Hz),
128.1, 126.2, 125.8, 125.5, 123.3, 118.7, 114.1, 59.9, 14.2;
HRMS (ESI) for [M + H+] C14H13F3NO2: calcd, 284.0892;
found, 284.0891.
Ethyl 4-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate (2e):
1H NMR (500 MHz, CDCl3) δ 8.75 (s, br, 1H), 7.40 (t, J )
2.3 Hz, 1H), 7.27 (m, 2H), 6.95 (t, J ) 7.4 Hz, 1H), 6.90 (d,
J ) 8.0 Hz, 1H), 6.72 (t, J ) 2.3 Hz, 1H), 4.14 (q, J ) 7.4 Hz,
2H), 1.15 (t, J ) 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
165.4, 157.3, 131.2, 128.2, 124.4, 124.2, 121.9, 120.9, 118.7,
115.5, 110.4, 59.6, 55.5, 14.3; HRMS (ESI) for [M + H+]
C14H16NO3: calcd, 246.1124; found, 246.1125.
Ethyl 4-(4-phenoxyphenyl)-1H-pyrrole-3-carboxylate (2g):
1H NMR (500 MHz, CDCl3) δ 9.14 (s, br, 1H), 7.44 (d, J )
8.5 Hz, 2H), 7.36 (s, 1H), 7.28 (t, J ) 8.0 Hz, 2H), 7.06 (t, J
) 7.4 Hz, 1H), 6.98 (t, J ) 7.4 Hz, 2H), 6.62 (s, 1H), 4.22 (q,
J ) 7.4 Hz, 2H), 1.26 (t, J ) 7.4 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 165.6, 157.4, 156.0, 130.8, 130.2, 129.9, 125.9,
123.3, 118.9, 118.6, 118.4, 113.2, 59.9, 14.5; HRMS (ESI) for
[M + H+] C19H18NO3: calcd, 308.1281; found, 308.1280.
Ethyl 4-tert-butyl-1H-pyrrole-3-carboxylate (2h): 1H NMR
(500 MHz, CDCl3) δ 8.20 (s, br, 1H), 7.46 (d, J ) 2.5 Hz,
1H), 6.54 (d, J ) 2.5 Hz, 1H), 4.24 (q, J ) 7.4 Hz, 2H), 1.38
(s, 9H), 1.27 (t, J ) 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 165.0, 135.7, 126.8, 115.4, 113.9, 59.5, 31.4, 30.4, 14.5;
HRMS (ESI) for [M + H+] C11H18NO2: calcd, 196.1332; found,
196.1331.
Ethyl 4-iso-butyl-1H-pyrrole-3-carboxylate (2i): 1H NMR
(500 MHz, CDCl3) δ 8.81 (s, br, 1H), 7.37 (d, J ) 1.9 Hz,
1H), 6.50 (d, J ) 1.9 Hz, 1H), 4.24 (q, J ) 7.3 Hz, 2H), 2.56
(d, J ) 7.3 Hz, 2H), 1.86 (m, 1H), 1.33 (t, J ) 7.3 Hz, 3H),
0.90 (d, J ) 7.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 165.9,
125.0, 124.7, 117.8, 114.4, 59.5, 35.4, 29.1, 22.6, 14.5; HRMS
(ESI) for [M + H+] C11H18NO2: calcd, 196.1332; found,
196.1331.
Ethyl 4-(3,5-dimethoxyphenyl)-1H-pyrrole-3-carboxylate
(2f): 1H NMR (500 MHz, CDCl3) δ 8.57 (s, br, 1H), 7.47 (s,
1H), 6.79 (s, 1H), 6.66 (s, 2H), 6.40 (s, 1H), 4.22 (q, J ) 7.4
Hz, 2H), 1.25 (t, J ) 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 164.8, 160.1, 136.7, 126.5, 125.4, 118.5, 114.1, 107.7, 98.9,
59.8, 55.4, 14.4; HRMS (ESI) for [M + H+] C15H18NO4: calcd,
276.1230; found, 276.1231.
Supporting Information Available
1H and 13C NMR spectra of 2a-j. This material is available
free of charge via the Internet at http://pubs.acs.org.
Received for review December 12, 2007.
OP7002826
Vol. 12, No. 2, 2008 / Organic Process Research & Development
•
293