Facile Synthesis of 3-Alkylpyrroles

Full text of DOI:10.1021/jo9823339

J . Org. Chem. 1999, 64, 3379-3380
3379
first report of the use of inorganic base in the sulfonyl-
ation of pyrrole nitrogen in an anhydrous organic solvent
without a phase-transfer catalyst. Passing a concentrated
solution of 1 in dichloromethane through an alumina
column enabled rapid purification of the product.
F a cile Syn th esis of 3-Alk ylp yr r oles
Alexander Zelikin,† Venkatram R. Shastri,*,† and
Robert Langer*
Department of Chemical Engineering, Massachusetts
Institute of Technology, Cambridge, Massachusetts 01239
Friedel-Crafts acylation of 1 using 3-carbomethoxy-
propionyl chloride has been reported by Kakushima et
al.3 Their conditions call for a 3-fold excess of acyl chloride
in the presence of AlCl3 added over 1.5 h to give methyl
4-[1-(phenylsulfonyl)-3-pyrrolyl)-4-butanoate (2) in 100%
yield before purification. We found that such a high
excess of the acyl chloride is not necessary. Using a 1.5-
fold excess of the acyl chloride a 100% conversion was
achieved after 2.5 h with a 90% yield of 2 after recrys-
tallization.
Ketone intermediates are widely used to obtain sp3
carbon centers. Sodium cyanoborohydride has been shown
to be a mild, acid stable reducing agent of tosylhydra-
zones of ketones and aldehydes, including hindered
systems, and thus to be an excellent alternative to the
Clemmensen and Wolff-Kishner reductions.6-8 Although
reductive deoxygenation of aryl tosylhydrazones has been
achieved in some cases using sodium borohydride, the
reaction conditions are harsh and the yields are not
optimum.10 We report herein the reduction of a pyrrolyl
alkyl ketone using the tosylhydrazone intermediate and
sodium cyanoborohydride as the reducing agent under
mild conditions to produce the corresponding alkyl
derivative in high yield.
Received November 25, 1998
In tr od u ction
Polypyrrole films are currently being explored in
applications such as biosensors, addressable gene-chips,
and interactive conduits for neuronal tissue engineering.1
3-Substituted alkylpyrroles have utility as functionaliz-
able monomers for derivatization and modification of
polypyrrole surfaces. 3-Alkyl pyrroles bearing reactive
end groups on the alkyl moiety can be utilized to impart
certain biospecificity, for example, by attachment of
peptide ligands. Furthermore, 3-alkyl pyrroles are im-
portant synthetic intermediates. As the chemistry of
3-acyl pyrroles is well established,2 3-alkyl pyrroles are
usually synthesized from corresponding acyl derivatives
using the Clemmensen reduction.3,4 However, the reduc-
tion conditions are too harsh for acid labile functionalities
such as alkyl esters and the t-Boc protecting group.
We now report a facile five-step pathway to the
synthesis of 4-(3-pyrrolyl)butanoic acid with every step
being carried out under very mild reaction conditions
with good to excellent yields. The reaction conditions can
be easily modified to accommodate various pyrrole de-
rivatives and might have broad application in synthetic
organic chemistry.
1-(Phenylsulfonyl)-3-pyrrolyl-2-carbomethoxyethyl ke-
tone tosylhydrazone (3) was prepared by reaction of 2
with 1.2 equiv of p-toluenesulfonyl hydrazine in absolute
ethanol in 90% yield after purification. Reduction of 3
was carried out in glacial acetic acid using 1:5 mole ratio
of tosylhydrazone to sodium cyanoborohydride to yield
methyl 4-[1-(phenylsulfonyl)-3-pyrrolyl]butanoate (4) in
75% yield after column chromatography.11 Hydrolysis of
4 to 4-(3-pyrrolyl)butanoic acid (5) was then accomplished
in 90% yield. The mp and IR spectra of 5 matched with
the values reported in the literature.12 The overall
conversion of pyrrole to 5 was 40.5%. We have coupled 5
to hydroxy-terminated polymers under DCC/DMAP con-
ditions to yield polymer-modified pyrroles. This is a
subject of an ongoing investigation.
Resu lts a n d Discu ssion
The most effective pathway to 3-substituted pyrroles
requires introducing an electron-withdrawing group on
the pyrrole nitrogen which drives subsequent Friedel-
Crafts electrophilic substitution predominantly or exclu-
sively on the â-carbon.2,3 The most commonly used
directing group is the phenylsulfonyl group. This is
because phenylsulfonyl pyrrole (1) is easily synthesized
either via the pyrrole-potassium salt or by using NaOH
(solid or aqueous) in the presence of a phase-transfer
catalyst. Furthermore, this directing group is easily
removed under simple basic hydrolysis.2,5
The reduction of aryl alkyl ketone tosylhydrazone in
acetic acid is broad in its applicability as it is carried out
at moderate temperature in almost neutral pH. TLC, IR,
and 1H NMR analyses of the crude reaction product
revealed that the reduction of ketone tosylhydrazones by
NaBH3CN in acetic acid at room-temperature proceeds
Compound 1 was synthesized in 74% yield by overnight
treatment of 1 equiv of pyrrole with 1.2 equiv of phenyl-
sulfonyl chloride in dry dichloromethane in the presence
of solid NaOH (3-5 equiv). To our knowledge this is the
* Corresponding authors: 45 Carleton St., Bldg. E25, Rm. 342,
Cambridge, MA 02139; email: prasha@mit.edu; rlanger@mit.edu.
‡ Both authors contributed equally to this work.
(1) Shastri, V. R.; Pishko, M. V. Biomedical Applications of Elec-
troactive Polymers. In Electrical and Optical Polymer Systems, Wise,
D. L., Wnek, G. E., Trantolo, D. J ., Cooper, T. M., Gresser, J . D., Eds.;
Marcel Dekker: NY, 1998; p 1031.
(2) Anderson, H. J .; Loader, C. E. Synthesis 1985, 4, 353.
(3) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J . J . Org.
Chem. 1983, 48, 3214.
(4) Ryder, K. S.; Morris, D. G.; Cooper, J . M. Langmuir 1996, 12
(23), 5681.
(6) Hutchins, R. O.; Milewski C. A.; Maryanoff, B. E. J . Am. Chem.
Soc. 1973, 95, 3662.
(7) Miller, V. P.; Yang, D.; Weigel, T. M.; Han, O.; Liy, H. J . Org.
Chem. 1989, 54, 4175.
(8) Iida, T., Tamura, T., Matsumoto, T. Synthesis 1984, 957.
(9) Miller et al.7 reported that aryl ketones tosylhydrazones are
readily converted to tosylhydrazine derivatives, but no attempts were
made to obtain fully reduced hydrocarbon.
(10) Hutchins, R. O.; Natale N. R. J . Org. Chem. 1978, 43, 2299.
(11) We found that while scaling up the reaction the relative amount
of solvent may be reduced by a factor of 2 and the ratio of tosylhydra-
zone: NaBH3CN to 1: 3.
(5) Xu, R. X.; Anderson, H. J .; Gogan, N. J .; Loader, C. E.; McDonald,
R. Tetrahedron Lett. 1981, 22, 49, 4899.
(12) Kamogawa, H.; Nakata, T.; Ohori, S.; Komatsu, S.; Bull. Chem.
Soc. J pn. 1991, 64, 4 (3), 1066.
10.1021/jo9823339 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/16/1999

3380 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
Sch em e 1
needles: mp 74-76 °C; IR (KBr): 3150, 1740, 1680, 1375, 1175,
1100, 730 cm-1 1H NMR (CDCl3) δ 2.70 (2H, t); 3.09 (2H, t);
3.68 (3H, s); 6.8-7.6 (8H, m). Anal. Calcd for C15H15NO5S: C,
56.06; H, 4.70; N, 4.36; S, 9.98. Found: C, 56.02; H, 4.55; N,
4.22; S, 10.18.
free of side reactions and is compatible with labile
protecting groups such as alkyl esters.
;
Exp er im en ta l Section
1-(P h en ylsu lfon yl)-3-p yr r olyl-2-Ca r bom eth oxyeth yl Ke-
ton e tosylh yd r a zon e (3). p-Toluenesulfonylhydrazine (5.2 g,
28 mmol) and 2 (7.5 g, 23.4 mmol) were added to 9 mL of
absolute ethanol. The mixture was refluxed for 30 min during
which time a dense precipitate formed. The precipitate was
separated, thoroughly washed with cold ether and dried under
vacuum to give 3 as a white solid (10.3 g, 90%): mp: 161-163
All chemicals were purchased and used as received except
pyrrole, which was purified prior to use by passing through an
activated alumina (EM Science, 80-235 mesh) column until
colorless. Melting points were determined on a Fisher-J ohns
melting point apparatus. IR spectra were obtained on a Fourier
transform infrared spectrometer, and 1H NMR were recorded
at 360 MHz in CDCl3 solvent (Spectral Data Services, Inc.;
Champaign, IL). Elemental analyses were carried out by Quan-
titative Technologies Inc. (Whitehouse, NJ ). Chromatography
was performed using Aldrich silica gel, and TLC was performed
on Baker Flex silica gel 1B plates.
°C; IR (KBr): 3220, 1745, 1600, 1375, 1335, 1170, 810, 730 cm-1
;
1H NMR (CDCl3) δ: 2.40 (3H, s); 2.62 (2H, t); 2.72 (2H, t); 3.60
(3H, s); 6.5-8.0 (12H, m); 9.65 (1H, s). Anal. Calcd for
C22H23N3O6S2: C, 54.09; H, 4.54; N, 8.60; S, 13.13. Found: C,
54.07; H, 4.61; N, 8.51; S, 13.10.
(P h en ylsu lfon yl)p yr r ole (1). Pyrrole (9.7 g, 0.144 mol) was
added to a well-agitated suspension of NaOH (17.3 g, 0.433 mol)
in 100 mL of dichloroethane. This mixture was then cooled to 0
Meth yl 4-[1-(P h en ylsu lfon yl)-3-p yr r olyl)]bu ta n oic Acid
(4). Sodium cyanobohydride (0.6 g, 10 mmol) was added to a
solution of 3 (1 g, 2 mmol) in 15 mL of glacial acetic acid, and
the reaction mixture was allowed to stir at 40 °C for 2 h. Reaction
was quenched by pouring onto 60 mL of ice-cold water, and the
mixture was thoroughly extracted with ether. Combined organic
extracts were washed with sodium bicarbonate and water to
neutrality and dried over Na2SO4. Removal of the solvent
resulted in the crude product, which was then purified by
chromatography on a silica gel column (eluent 1:8 ethyl acetate-
hexanes) to yield 4 as a white crystalline solid (0.5 g, 75%): mp
44-46 °C; IR (KBr) 3150, 1740, 1370, 1175, 1100, 735 cm-1; 1H
NMR (CDCl3) δ: 1.85 (2H, q); 2.28 (2H, t); 2.43 (2H, t); 3.65
(3H, s); 6,1-7,9 (8H, m). Anal. Calcd for C15H17NO4S: C, 58.61;
H, 5.57; N, 4.56; S, 10.43. Found: C, 58.76; H, 5.59; N, 4.39; S,
10.65.
°C and stirred for 10 min, following which
a solution of
phenylsulfonyl chloride (30.5 g, 0.173 mol) in 20 mL of dichlo-
roethane was added dropwise over a period of 20 min. Thirty
minutes after the completion of addition, the reaction was
allowed to come to room temperature and left stirring overnight.
The reaction was quenched by pouring onto 300 mL of distilled
water. The organic layer was separated, and the aqueous layer
was extracted with dichloromethane (3 × 20 mL). The combined
organic extract was washed with distilled water to neutrality
and dried over Na2SO4. Removal of the solvent in vacuo gave 1
(22.0 g, 74%) as white crystalline solid. This solid was subse-
quently purified by passing a concentrated solution in dichlo-
romethane through an alumina column in greater than 70%
overall yield: mp 87-88 °C; IR (KBr): 3130, 1580, 1535, 1455,
1370, 1170, 1100, 730 cm-1; 1H NMR (CDCl3) δ 6.30 (2H, t), 7.17
(2H, t), 7.50 (2H, t), 7.60 (1H, t); 7.85 (2H, m). Anal. Calcd for
C10H9NO2S: C, 57.95; H, 4.38; N, 6.76; S, 15.47. Found: C, 58.13;
H, 4.23; N, 6.64; S, 15.56.
Meth yl 4-[1-(P h en ylsu lfon yl)-3-pyr r olyl]-4-bu tan oate (2).
To a suspension of AlCl3 (10.8 g, 81 mmol) in 50 mL of
1,2-dichloroethane was added in portions 3-carbomethoxypro-
pionyl chloride (6.1 g, 40.6 mmol), and mixture was stirred at 0
°C. After complete solubilization of aluminum chloride, a solution
of 1 (5.6 g, 27.1 mmol) in 20 mL of same solvent was added
dropwise with cooling. The mixture was allowed to stir for 2.5 h
at room temperature after which time the reaction was quenched
by pouring onto ice-cold water (300 mL). The organic layer was
separated, and the aqueous layer was extracted with dichlo-
romethane (3 × 20 mL). The combined organic extract was
washed with 10% sodium bicarbonate, then with water to
neutrality and dried over Na2SO4. Removal of the solvent under
reduced pressure resulted in a dark oil, from which 2 (7.8 g,
90%) was then recrystallized (ethyl acetate/hexanes) as colorless
4-(3-P yr r olyl)bu ta n oic Acid (5). 4 (0.6 g, 2 mmol) was
placed in 12 mL of 2:1 (v:v) mixture of MeOH and 5 N aqueous
NaOH and refluxed for 1.5 h, after which time the reaction
mixture was allowed to cool and methanol was removed in vacuo.
The aqueous solution was acidified with 5 N HCl to pH 3 and
thoroughly extracted with ethyl ether. Combined organic ex-
tracts were washed with water to neutrality and dried over Na2-
SO4. Removal of the solvent in vacuo yielded 5 (0.3 g, 90%) as a
beige solid: mp 91-93 °C (lit. mp 89-91 °C); IR (KBr): 3400-
2500, 3400, 2920, 1700, 1435, 1345, 1230, 1200, 1075 cm-1
.
Ack n ow led gm en t. A.Z. thanks the Russian Minis-
try of Education for funding via The President Yeltsin
Fellowship for Undergraduate Research. This work was
supported in part by a NSF grant to R.L. (grant no.
9202311). Authors thank Dr. D. Putnam for useful
discussions.
J O9823339