An efficient highly regioselective synthesis of 2,3,4-trisubstituted pyrroles by cycloaddition of polarized ketene S,S- and N,S-acetals with activated methylene isocyanides

Article abstract of DOI:10.1021/jo062139j

(Chemical Equation Presented) An efficient route for regioselective synthesis of 2,3,4- substituted pyrroles allowing precise control over the introduction of a number of substituents and functionalities (tosyl, carbalkoxy, aryl, cyano, nitro, acetyl, ben

Full text of DOI:10.1021/jo062139j

An Efficient Highly Regioselective Synthesis of 2,3,4-Trisubstituted
Pyrroles by Cycloaddition of Polarized Ketene S,S- and N,S-Acetals
†
with Activated Methylene Isocyanides
N. C. Misra, K. Panda, H. Ila,* and H. Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur-208016, India
hila@iitk.ac.in
ReceiVed October 16, 2006
An efficient route for regioselective synthesis of 2,3,4- substituted pyrroles allowing precise control over
the introduction of a number of substituents and functionalities (tosyl, carbalkoxy, aryl, cyano, nitro,
acetyl, benzoyl, cyclic amines, etc.) at the three positions of the pyrrole ring has been developed via
1,3-dipolar cycloaddition of readily accessible polarized ketene S,S- and N,S-acetals with carbanions
derived from activated methylene isocyanides.
2
a,4,5
nonlinear optics,5 and supramolecular
Introduction
material science,
6
7
chemistry as molecular sensors and devices. Therefore,
considerable attention has been paid to develop efficient general
methods for the synthesis of pyrroles. Previous approaches
such as Paal-Knorr cyclization and Hantzsch synthesis
involving classical condensation reactions between activated
Substituted pyrroles represent an important class of hetero-
cycles which are present in a wide range of natural products
such as porphyrins and bioactive molecules
blockbuster drug atorvastatin calcium as well as important
antiinflammatants, antitumor agents, and immunosuppres-
sants.3d Similarly, polypyrroles are of growing relevance in
1
1
,8
1c,f,2
including the
9
10
3
a
3
b
3c
(
4) (a) Baumgarlen, M.; Tyulyulkor, N. Chem.sEur. J. 1998, 4, 987-
†
989. (b) Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-S.; Tseng, J.-C.;
Luh, T.-Y. J. Am. Chem. Soc. 2000, 122, 4992-4993 and references therein.
(c) Groenendaal, L.; Meijere, E. W.; Vekemans, J. A. J. M. In Electronic
Materials: The Oligomer Approac; M u¨ llen, K., Wegner, G., Eds.; Wiley-
VCH: Weinheim, Germany, 1997. (d) Domingo, V. M.; Aleman, C.; Brillas,
F.; Julia, L. J. Org. Chem. 2001, 66, 4058-4061.
Dedicated to Professor S. V. Kessar on his 75th birthday.
*
To whom correspondence should be addressed. Fax: 91-0512-2597436 or
9
1-0512-2590260.
1) Reviews: (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1999, 1,
(
2
849-2866. (b) Jones, R. A., Ed. Pyrroles Chemistry of Heterocyclic
Compounds; Wiley: New York, 1990; Vol. 48. (c) Boger, D. L.; Boyce,
C. W.; Labroli, M. A.; Sehon, C. A. J. Am. Chem. Soc. 1999, 121, 54-62.
(5) (a) Skotheim, T. A., Elsenbaumer, R. L., Reynolds, J. R., Eds.
Handbook of Conducting Polymers, 2nd ed.; Marcell Dekker: NewYork,
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10.1021/jo062139j CCC: $37.00 © 2007 American Chemical Society
1
246
J. Org. Chem. 2007, 72, 1246-1251
Published on Web 01/25/2007

Synthesis of 2,3,4-Trisubstituted Pyrroles
methylene compounds and amino ketones can have limitations
in terms of efficiency, functional group compatibility, re-
giospecificity, and substituent diversity. More recent pyrrole
SCHEME 1
11
syntheses include transition-metal-based strategies such as the
addition of chromium carbene to dipolarophiles,12 the Cu(0)-
2
a,13
or palladium-catalyzed cycloisomerization of alkynylimines,
14
Rh-catalyzed N-H insertion or a combination of isonitrile and
,3-diketone insertion,15 palladium- and ruthenium-catalyzed
1
16
17,18
multicomponent reactions, and other methods.
Among the
cycloaddition approaches,19 the reaction between an activated
alkene and an activated methylene isocyanide under basic
conditions also represents an efficient method for the synthesis
of substituted and annulated pyrroles. The reaction of nitroal-
under either a copper1f or a phosphine23 catalysis. As part of
our ongoing studies on synthetic applications of polarized ketene
dithioacetals for heterocycle synthesis,
kenes (or arenes) with isocyanoacetate is known as Barton-
2
4,25
Zard synthesis,20 whereas the reaction of various Michael
we herein report a
facile base-induced [3 + 2] cycloaddition of these intermediates
with various activated methylene isocyanides, furnishing 2,3,4-
substituted pyrroles in high yields.
acceptors and TosMIC (p-toluenesulfonylmethyl isocyanide) is
called Van Leusen synthesis.21 Both of these cycloadditions
proceed with elimination of either nitrous acid or toluenesul-
finate, respectively, in the final pyrrole ring formation step.
Several variations of the Barton-Zard reaction with various
Results and Discussion
activated olefins and nitroarenes yielding substituted and
annulated pyrroles have been reported.22 Recently, these cy-
We first examined the cycloaddition of nitroketene S,S-acetal
126
with ethyl isocyanoacetate (2) under varying reaction
cloadditions have also been extended to activated acetylenes
conditions in the presence of different bases (NaH, BuLi,
t-BuOK, DBU). Under optimized conditions, when 1 was
reacted with 2 in the presence of DBU as the base in DMF at
120 °C, analysis of the reaction mixture revealed formation of
only one product, which was characterized as ethyl 4-nitro-3-
(
9) (a) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635-1637. (b) Paul,
C. Ber. Dtsch. Chem. Ges. 1885, 18, 367-370. For recent examples of
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T. J. J. Org. Lett. 2001, 3, 3297-3300.
(methylthio)pyrrole-2-carboxylate (3) (82%) on the basis of its
spectral and analytical data (Scheme 1). It should be noted that
unlike previous reactions of nitroalkene/arene with ethyl iso-
(
10) For recent examples of Hantzsch synthesis, see: (a) Palacios, F.;
Aparico, D.; de los Santos, J. M.; Vicario, J. Tetrahedron 2001, 57, 1961-
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(
6
(
(
7
(
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(
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Chem. 2003, 68, 3966-3975 and references therein.
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(
cycloannulation: (a) Tejedor, D.; Gonz a´ lez-Cruz, D.; Garc ´ı a-Tellado, F.;
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2
003, 5, 5099-5101. (b) Nakano, H.; Ishibashi, T.; Sawada T. Tetrahedron
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1
999, 55, 12969-12976.
(
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J. Org. Chem, Vol. 72, No. 4, 2007 1247

Misra et al.
SCHEME 2
SCHEME 3
TABLE 1. Synthesis of 2,4-Substituted 3-(Methylthio)pyrroles
cyanoacetate, the nitro group is retained in the 4-position of
the product pyrrole 3 with elimination of the methylthio group
(Scheme 1). A similar trend was observed when nitroketene
S,S-acetal 1 was subjected to cycloaddition with tosylmethyl
isocyanide (4) under identical conditions, furnishing the pyrrole
5
(81%) with a tosyl group incorporated in the 2-position.
With the success of these two reactions, we next extended
this pyrrole-forming reaction to R-acetyl- and R-benzoylketene
2
7
dithioacetals 6a,b and 2 with a view to prepare 4-acetyl/
benzoylpyrroles 7a,b. However, the ketene dithioacetal 6a or
6
b failed to give the desired pyrroles under the influence of
2-carbethoxy-3-(methylthio)pyrrole (7a) in 78% yield (Scheme
2). The corresponding dibenzoylketene dithioacetal 8b29 also
underwent facile cycloaddition with ethyl isocyanoacetate under
these conditions to give only one product. However, a precise
analysis of spectroscopic data revealed the product structure to
be 4,5-dibenzoyl-2-carbethoxy-3-(methylthio)pyrrole (10) (in-
stead of 7b), which is probably formed by the rearrangement
of the benzoyl group to the 5-position in the 4,4-dibenzoyl-2H-
pyrrole intermediate 11 via 12 as shown in Scheme 2. The
reaction of ketene dithioacetal 8a with tosylmethyl isocyanide
also proceeded in a similar fashion under identical reaction
conditions, yielding the corresponding 2-tosyl-4-acetylpyrrole
13 in 79% yield (Scheme 3 and Table 1, entry 1).
various bases (NaH, t-BuOK, DBU, LiHMDS, etc.) under
different conditions, yielding either the unreacted ketene dithio-
acetals 6a,b or an intractable reaction mixture under more drastic
conditions. In one of the reactions, pyrrole 7b was obtained in
low yield (20%) when ketene dithioacetal 6b was reacted with
2
in the presence of NaH in THF (10 h). The lower reactivity
of acylketene dithioacetals 6a,b appears to be due to poor
activation of the double bond as a Michael acceptor. We
therefore examined the reaction of diacylketene dithioacetals
2
8
8
a,b with 2 assuming that the introduction of another electron-
withdrawing group at the R-position of 6a,b will enhance the
reactivity of the double bond in 8a,b as a Michael acceptor.
Also, it was anticipated that the initial cycloadduct such as 4,4-
diacyl-4H-pyrrole 9 from diacylketene dithioacetal 8a and 2
should undergo facile aromatization to the product 4-acylpyrrole
Inspired by the success of these reactions, we further extended
2
7a
27a
our studies to other doubly activated ketene dithioacetals 8c
2
7a
and 8d (derived from ethyl acetoacetate and ethyl cyano-
acetate) with a view to demonstrate the versatility of the reaction
for incorporation of various electron-withdrawing groups (CO2-
Et, CN) in the 4-position (or 3-position) of the pyrrole ring.
Thus, the reaction of 8c and 8d with 2 also proceeded smoothly
according to our earlier prediction, yielding the desired 2,4-
dicarbethoxy-3-(methylthio)pyrrole (7c) and 2-carbethoxy-4-
cyano-3-(methylthio)pyrrole (7d) in 72% and 80% yields by
cleavage of acetyl or carbethoxy groups, respectively (Scheme
3 and Table 1, entries 3 and 4). Similarly, the ketene dithioacetal
7
a via cleavage of one of the acyl groups (Scheme 2). Indeed
we were pleased to find that 8a reacted cleanly with ethyl
isocyanoacetate according to our prediction under earlier
described reaction conditions, furnishing the expected 4-acetyl-
(
27) (a) Huang, Z.; Shi, X. Chem. Ber. 1990, 123, 541-547. (b) Potts,
K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Org. Chem. 1982, 47,
027-3038.
28) Attempted cycloaddition of monomethyl sulfoxide 6c27b with ethyl
3
(
isocyanoacetate in the presence of DBU as the base yielded only deoxy-
genated ketene dithioacetal 6b, and no trace of pyrrole 7b could be isolated
from the reaction mixture.
8
d reacted smoothly with tosylmethyl isocyanide under these
conditions with the loss of the carbethoxy group to give 2-tosyl-
4
-cyanopyrrole 14 in 86% yield (entry 4, Table 1).
As a further test for substrate and functional group compat-
ibility in this efficient pyrrole synthesis, cycloadditions of a few
(29) Sommen, G.; Comel, A.; Kirsch, G. Synthesis 2003, 5, 735-741.
1248 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of 2,3,4-Trisubstituted Pyrroles
SCHEME 4
SCHEME 5
TABLE 2. Synthesis of 4-Substituted 2-Aryl-3-(methylthio)pyrroles
SCHEME 6
SCHEME 7
polarized ketene dithioacetals with arylmethyl isocyanides were
examined. However, the reaction of nitroketene S,S-acetal 1 with
benzyl isocyanide (15a) using DBU as the base afforded the
expected 2-phenyl-3-(methylthio)-4-nitropyrrole (16) in poor
yield (9%). The lower yield of the pyrrole 16 appears to be due
to insufficient basicity of DBU for deprotonation of benzyl
isocyanide. This was evident by performing the reaction in the
presence of a stronger base such as potassium tert-butoxide,
when the pyrrole 16 was obtained in an improved yield of 65%
Interestingly, when 18 was reacted with 15b in the presence
of t-BuOK at -78 °C, workup of the reaction mixture did not
afford the expected 2-aryl-4-(benzoylamino)-3-(methylthio)-
pyrrole 22. The product isolated (72%) was found to be
unexpected bisoxazole derivative 23 on the basis of its spectral,
analytical, and X-ray crystallographic data (Scheme 6). Reaction
of 18 with 15a under identical conditions similarly afforded
the bisoxazole 24 in 86% yield (Scheme 6). Desulfurization of
(
Scheme 4 and Table 2, entry 1). Similarly, a few of the doubly
27a
activated ketene dithioacetals 8b, 8d, and 8e were also reacted
with either 15a or 4-chlorobenzyl isocyanide (15b), furnishing
various substituted 2-arylpyrroles 17b, 17d, and 17e in high
yields (Table 2, entries 2-4).
24 with Raney Ni in refluxing ethanol gave the dethiomethylated
bisoxazole 25 in 78% yield (Scheme 6). The probable mecha-
nism for the formation of bisoxazoles 23-24 from 18 and 15
is shown in Scheme 7. The carbanion from benzyl isocyanide
appears to undergo nucleophilic addition to the carbonyl group
of 18, resulting in the cleavage of the lactone ring and formation
of imidate anion 26. Subsequent cascade intramolecular con-
jugate addition of the anion 26 to the activated bis(methylthio)-
methylene double bond and intramolecular addition of a
nucleophilic carbonyl oxygen to the isonitrile group followed
by aromatization of the newly formed oxazole ring via elimina-
tion of the methylmercapto anion affords the bisoxazoles 23
and 24 in good yields. However, we are unable to explain at
this stage the different behaviors of carbethoxymethyl isocyanide
and phenylmethyl isocyanide anions toward 18 (1,4-addition
vs 1,2-addition), leading to formation of different products.
A few of the newly synthesized pyrroles (7a, 17e, 19) were
dethiomethylated with Raney Ni in refluxing ethanol, furnishing
the corresponding 3-unsubstituted pyrroles 28-30 in good yields
To further probe the efficiency of the reaction for the synthesis
of a pyrrole ring with diverse functionalities, the cycloaddition
30
of ketene dithioacetal 18 (derived from 2-phenyloxazolone)
with 2 was examined as shown in Scheme 5. Thus, when 18
was reacted with 2 under earlier described reaction conditions,
product analysis revealed formation of only one product (80%),
which after spectroscopic characterization was found to be ethyl
4-(benzoylamino)-3-(methylthio)pyrrole-2-carboxylate (19). Al-
though the initial cycloadduct, i.e., spiropyrroleisoxazolone 20
could not be isolated, the probable mechanism for the formation
of observed product 19 appears to be the ring opening of the
isoxazolone ring in the intermediate 20 by some nucleophilic
species such as water during workup followed by aromatization
of the resulting intermediate 21 by elimination of carbon dioxide
(Scheme 5).
(Scheme 8).
Finally, to further add a point of diversity at the 3-position
(30) Tripathy, P. K.; Roy, J.; Mukerjee, A. K. Indian J. Chem., Sect.B:
Org. Chem. Incl. Med. Chem. 1986, 25B, 1275-1276.
of the newly synthesized pyrroles, reaction of a few polarized
J. Org. Chem, Vol. 72, No. 4, 2007 1249

Misra et al.
SCHEME 8
N-piperazino N,S-acetals 33a-c underwent smooth cycloaddi-
tion with various activated methylene isocyanides (2, 4, 15b)
under similar conditions, affording the respective 2-substituted
3
-(N-cycloamino)-4-cyanopyrroles 34a-c, 35, and 36 in overall
high yields (Scheme 9), thus demonstrating further the substrate
and functional group compatibility of this versatile pyrrole
synthesis.
Conclusion
In summary, we have developed a concise and efficient
protocol for regioselective synthesis of 2,3,4-substituted pyrroles
from readily available polarized ketene S,S- and N,S-acetals and
activated methylene isocyanides. The methodology allows
precise control over the introduction of a number of substituents
and functionalities (tosyl, carbalkoxy, aryl, cyano, nitro, acetyl,
benzoyl, cyclic amines, etc.) at the three positions of the pyrrole
ring. The reaction is particularly promising for the introduction
of electron-withdrawing groups at the 3-position (or 4-position)
of the pyrrole ring. The reaction of nitroketene S,S-acetal with
ethyl isocyanoacetate is to our knowledge the first example of
the Barton-Zard reaction in which a nitro group is retained in
the 4-position of the pyrrole ring. Some of the prepared pyrroles
are useful intermediates for the synthesis of biologically
important compounds (distamycin, netropsin, etc.).32 Further
application of this methodology is under way in our laboratory.
SCHEME 9
Experimental Section
General Procedure for the Synthesis of Substituted Pyrroles
from Various Polarized Ketene S,S- and N,S-Acetals via Ethyl
Isocyanoacetate/TosMIC (3, 5, 7a, 7c, 7d, 10, 13, 14, 19, 32, 34a,
34b, 34c, 35). DBU (6.0 mmol) was added dropwise to a stirring
solution of the corresponding ketene S,S-acetal (or N,S-acetal) (3.0
mmol) and ethyl isocyanoacetate (0.58 g, 6.0 mmol) (or TosMIC,
1.2 g, 6.0 mmol) in DMF (40 mL) under a nitrogen atmosphere.
The resulting mixture was heated at 120 °C with constant stirring
for 5-6 h (monitored by TLC). It was then cooled and poured
into a saturated NH
extracted with chloroform (3 × 50 mL), washed with H
SO , and distilled
4
Cl solution (100 mL). The mixture was
2
O (2 ×
5
0 mL) and brine (1 × 50 mL), dried over Na
2
4
under reduced pressure to give crude products. The crude products
were purified by column chromatography over silica gel using
hexane-EtOAc (7:3) as the eluent.
Data for ethyl 3-(methylthio)-4-nitropyrrole-2-carboxylate
(
3): yield 82% (0.57 g); white solid; mp 134-135 °C (CHCl
3
-
hexane); R 0.2 (7:3 hexane-EtOAc); IR (KBr) 3247, 2990, 1673,
1
f
-
1 1
498, 1363, 1309 cm ; H NMR (400 MHz, CDCl
3
) δ 1.39 (t, J
7.1 Hz, 3H), 2.48 (s, 3H), 4.40 (q, J ) 7.2 Hz, 2H), 7.81 (d, J
3.9 Hz, 1H), 9.75 (br s, 1H); 13C NMR (100 MHz, CDCl
) δ
)
)
3
ketene N,S-acetals (derived from cyclic secondary amines) with
1
4.3, 19.4, 61.8, 120.3, 122.9, 123.7, 143.1, 159.4; MS m/z (rel
2
, 4, and 15b was examined (Scheme 9). It should be noted
intens) 231 (M + 1, 100); HRMS (EI) m/z calcd for C
30.0361, found 230.0357.
Data for ethyl 4-acetyl-3-(methylthio)pyrrole-2-carboxylate
7a): yield 78% (0.53 g); white crystalline solid; mp 132-133 °C
CHCl -hexane); R 0.3 (7:3 hexane-EtOAc); IR (KBr) 3138,
H NMR (400 MHz,
8 10 2 4
H N O S
that such push-pull enamines have not been studied earlier as
2
dipolarophiles in this isocyanide cycloaddition reaction. The
desired N,S-acetals 313 and 33a-c
1a
31b,c
were prepared by direct
(
(
displacement of one of the methylthio groups in the respective
ketene dithioacetals by the appropriate secondary amines. Thus,
when the nitroketene N,S-acetal 31 was reacted with 2 under
standard reaction conditions, the corresponding 4-nitro-3-(N-
piperidino)-2-carbethoxypyrrole (32) was obtained in 85% yield
3
f
2980, 1708, 1636, 1528, 1377, 1173 cm-1
1
;
CDCl ) δ 1.33 (t, J ) 7.1 Hz, 3H), 2.40 (s, 3H), 2.52 (s, 3H), 4.35
3
(q, J ) 7.1 Hz, 2H), 7.52 (d, J ) 3.4 Hz, 1H), 10.14 (br s, 1H);
1
3
3
C NMR (100 MHz, CDCl ) δ 14.3, 19.8, 29.0, 61.0, 123.9, 124.8,
1
27.4, 128.2, 160.0, 193.7; MS m/z (rel intens) 228 (M + 1, 100);
(
Scheme 9). Similarly, the corresponding N-morpholino and
HRMS (EI) m/z calcd for C10 S 227.0616, found 227.0608.
H13NO
3
(
31) (a) Manjunatha, S. G.; Reddy, K. V.; Rajappa, S. Tetrahedron Lett.
1
1
990, 31, 1327-1330. (b) Kuwayama, Y.; Kataoka, S. Yakugaku Zasshi
(32) (a) Lown, J. W.; Krowicki, K. J. Org. Chem. 1985, 50, 3774-
3779. (b) Wang, Y.; Wright, S. C.; Larrick, J. W. Bioorg. Med. Chem.
Lett. 2003, 13, 459-461.
965, 85, 387-390. (c) Kumar, A.; Aggarwal, V.; Ila, H.; Junjappa, H.
Synthesis 1980, 748-751.
1250 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of 2,3,4-Trisubstituted Pyrroles
Data for ethyl 4-cyano-3-(methylthio)pyrrole-2-carboxylate
MHz, CDCl
J ) 5.0, 1.8 Hz, 3H), 7.84 (d, J ) 8.6 Hz, 2H), 8.00 (s, 1H), 8.02-
8.05 (m, 2H); 13C NMR (100 MHz, CDCl
3
) δ 2.45 (s, 3H), 7.36 (d, J ) 8.5 Hz, 2H), 7.47 (dd,
(
7d): yield 80% (0.5 g); white solid; mp 92-93 °C (CHCl
3
-
hexane); R 0.2 (7:3 hexane-EtOAc); IR (KBr) 3237, 2984, 2227,
f
3
) δ 17.7, 126.46, 126.52,
-
1 1
1
692, 1436, 1238 cm ; H NMR (400 MHz, CDCl
3
) δ 1.38 (t, J
7.1 Hz, 3H), 2.58 (s, 3H), 4.37 (q, J ) 7.2 Hz, 2H), 7.10 (d, J
2.7 Hz, 1H), 10.07 (br s, 1H); 13C NMR (100 MHz, CDCl
): δ
128.5, 128.9, 129.2, 129.7, 131.1, 131.8, 134.1, 136.9, 137.9, 144.4,
+
)
150.5, 163.0; MS m/z (rel intens) 368 (M , 100), 370 (M + 2, 33);
)
3
13 2 2
HRMS (EI) m/z calcd for C19H N O SCl 368.0386, found 368.0334.
1
4.2, 18.7, 61.6, 99.2, 114.7, 118.9, 124.5, 136.8, 160.0; MS m/z
General Procedure for Raney Ni Dethiomethylation/Reduc-
+
(
rel intens) 210 (M , 70); HRMS (EI) m/z calcd for C
H N
9 10 2
O
2
S
tion. Raney Ni (W ) (ca. 1 g) was added to an ethanolic solution
2
2
10.0463, found 210.0447.
Data for ethyl 4,5-dibenzoyl-3-(methylthio)pyrrole-2-car-
boxylate (10): yield 76% (0.9 g); yellow solid; mp 114-116 °C
Cl ) 3261,
) δ 1.36 (t, J
(20 mL) of the appropriate substrate (7a, 17e, 19, or 24) (2 mmol),
and the suspension was heated at reflux with stirring for 2-3 h
(monitored by TLC). It was then filtered through a sintered glass
funnel and washed with hot ethanol. The filtrate was concentrated
to afford a viscous residue which was purified by column
chromatography over silica gel with hexane-EtOAc (7:3) as the
eluent to give the pure products.
(
2
EtOAc-hexane); R
f
0.2 (7:3 hexane-EtOAc); IR (CH
2
2
-
1 1
988, 1712, 1655, cm ; H NMR (400 MHz, CDCl
3
)
7.3 Hz, 3H), 2.29 (s, 3H), 4.39 (q, J ) 7.3 Hz, 2H), 7.08 (t, J
)
(
7.8 Hz, 2H), 7.15 (t, J ) 7.8 Hz, 2H), 7.28-7.38 (m, 6H), 10.28
br s, 1H); 13C NMR (100 MHz, CDCl
3
) δ 14.3, 20.0, 61.7, 124.2,
Data for ethyl 4-(benzoylamino)pyrrole-2-carboxylate (30):
126.6, 128.1, 128.2, 128.5, 128.9, 129.0, 130.8, 132.7, 133.0, 137.4,
yield 96% (0.5 g); white solid; mp 212-214 °C (CHCl -hexane);
3
1
38.6, 159.2, 186.2, 191.8; MS m/z (rel intens) 394 (M + 1, 70);
R 0.2 (3:2 hexane-EtOAc); IR (KBr) 3338, 2981, 1683, 1644,
f
-
1 1
HRMS (EI) m/z calcd for C22
H19NO
4
S 393.1035, found 393.1021.
1569, 1391, 1263, 1214, 1128 cm ; H NMR (400 MHz, CDCl
3
General Procedure for the Synthesis of Substituted Pyrroles
from Various Polarized Ketene S,S- and N,S-Acetals via Benzyl
Isocyanide/4-Chlorobenzyl Isocyanide (16, 17b, 17d, 17e, 36)
and Bisoxazoles 23 and 24. Potassium tert-butoxide (6.0 mmol)
+ DMSO-d ) δ 1.12 (t, J ) 7.1 Hz, 3H), 4.07 (q, J ) 7.2 Hz, 2H),
6
6.78 (d, J ) 1.7 Hz, 1H), 7.19-7.29 (m, 3H), 7.35 (d, J ) 1.7 Hz,
1H), 7.72 (dd, J ) 7.6, 1.4 Hz, 2H), 9.52 (s, 1H), 10.40 (br s, 1H);
13
C NMR (100 MHz, CDCl + DMSO-d ) δ 14.1, 59.6, 106.5,
3
6
(
dissolved in 20 mL of THF) was added dropwise to a stirring
114.5, 119.7, 124.2, 127.0, 127.8, 130.7, 134.3, 160.7, 164.5; MS
m/z (rel intens) 259 (M + 1, 100); HRMS (EI) m/z calcd for
C H N O 258.1004, found 258.1003.
solution of the corresponding ketene S,S-acetal (or N,S-acetal) (3.0
mmol) and benzyl isocyanide (0.53 g, 4.5 mmol) (or 4-chlorobenzyl
isocyanide, 0.68 g, 4.5 mmol) in THF (60 mL) at -78 °C under a
nitrogen atmosphere. The resulting mixture was further stirred at
room temperature for 2-3 h (monitored by TLC). It was then
14
14
2
3
Data for ethyl 4-nitro-3-piperidinopyrrole-2-carboxylate
(32): yield 85% (0.68 g); yellow crystalline solid; mp 110-112
°C (CHCl -hexane); R 0.2 (1:1 hexane-EtOAc); IR (KBr) 3248,
3
f
-
1 1
poured into a saturated NH
extracted with chloroform (3 × 50 mL), washed with H
SO , and distilled
4
Cl solution (100 mL). The mixture was
2936, 1663, 1559, 1361, 1294 cm ; H NMR (400 MHz, CDCl )
3
2
O (2 ×
δ 1.36 (t, J ) 7.1 Hz, 3H), 1.59 (d, J ) 4.4 Hz, 2H), 1.68 (br s,
5
0 mL) and brine (1 × 50 mL), dried over Na
2
4
4H), 3.16 (d, J ) 4.6 Hz, 4H), 4.33 (q, J ) 7.1 Hz, 2H), 7.65 (s,
1H), 9.37 (br s, 1H); 13C NMR (100 MHz, CDCl ) δ 14.5, 24.0,
under reduced pressure to give crude products. The crude products
were purified by column chromatography over silica gel using
hexane-EtOAc (7:3) as the eluent.
3
26.4, 53.0, 60.9, 113.2, 122.8, 122.9, 131.9, 159.5; MS m/z (rel
intens) 269 (M + 1, 100); HRMS (EI) m/z calcd for C H N O
1
2
17
3
4
Data for 3-(methylthio)-4-nitro-2-phenyl-1H-pyrrole (16):
267.1219, found 267.1211.
yield 65% (0.46 g); yellow solid; mp 92-94 °C (CHCl
3
-hexane);
Data for ethyl 4-(4-cyano-2-(ethoxycarbonyl)-1H-pyrrol-3-
yl)piperazine-1-carboxylate (34c): yield 76% (0.77 g); white solid;
mp 98-100 °C (CHCl -hexane); R 0.5 (1:1 hexane-EtOAc); IR
R
f
0.4 (4:1 hexane-EtOAc); IR (KBr) 3208, 2920, 1479, 1360
-
1 1
cm ; H NMR (400 MHz, CDCl
3
) δ 2.31 (s, 3H), 7.37-7.47 (m,
3
f
3
H), 7.62-7.64 (m, 2H), 7.82 (d, J ) 3.7 Hz, 1H), 9.56 (br s, 1H);
(DCM solution) 3246, 2982, 2222, 1682, 1688, 1552, 1413, 1256
13
-1 1
C NMR (100 MHz, CDCl
30.3, 135.8, 138.4, 193.2; MS m/z (rel intens) 235 (M + 1, 100);
S 234.0463, found 234.0457.
3
) δ 19.7, 108.2, 121.8, 128.2, 128.7,
cm ; H NMR (400 MHz, CDCl ) δ 1.21 (t, J ) 7.0 Hz, 3H),
3
1
1.29 (t, J ) 7.2 Hz, 3H), 3.26 (br s, 4H), 3.54 (d, J ) 4.8 Hz, 4H),
HRMS (EI) m/z calcd for C11
H
10
N
O
2 2
4.09 (q, J ) 7.1 Hz, 2H), 4.26 (q, J ) 7.1 Hz, 2H), 7.15 (d, J )
Data for ethyl 5-(4-chlorophenyl)-4-(methylthio)pyrrole-3-
carboxylate (17e): yield 96% (0.8 g); white crystalline solid; mp
4.0 Hz, 1H), 9.72 (br s, 1H); 13C NMR (100 MHz, CDCl ) δ 14.4,
3
14.6, 44.0, 51.5, 60.8, 61.5, 88.6, 112.3, 116.0, 128.0, 145.4, 155.5,
1
(
80-182 °C (CHCl
KBr) 3288, 2980, 1687, 1481, 1332, 1184 cm ; H NMR (400
MHz, CDCl ) δ 1.35 (t, J ) 7.1 Hz, 3H), 2.32 (s, 3H), 4.30 (q, J
7.1 Hz, 2H), 7.39 (d, J ) 7.8 Hz, 1H), 7.52 (d, J ) 3.4 Hz, 1H),
.57 (d, J ) 7.7 Hz, 2H), 8.99 (br s, 1H); 13C NMR (100 MHz,
CDCl ) δ 14.4, 20.1, 59.9, 113.2, 118.7, 125.4, 128.7, 129.3, 129.9,
3
-hexane); R
f
0.3 (4:1 hexane-EtOAc); IR
159.2; MS m/z (rel intens) 320 (M
(EI) m/z calcd for C H N O 320.1484, found 320.1482.
+
, 89), 321 (M + 1, 100); HRMS
-
1 1
15
20
4
4
3
Data for 4-(4-N-benzyl-N-piperazino)-5-(4-chlorophenyl)-3-
cyanopyrrole (36): yield 74% (0.84 g); white solid; mp 163-165
)
7
°
2
C (CHCl
3
-hexane); R 0.6 (3:2 hexane-EtOAc); IR (KBr) 3294,
f
-1
1
3
3
929, 2220, 1490, 1456, 1132 cm ; H NMR (400 MHz, CDCl )
+
1
3
2
33.8, 134.6, 164.0; MS m/z, (rel intens) 295 (M , 100), (M + 2,
δ 2.52 (br s, 4H), 3.08 (br s, 4H), 3.53 (s, 2H), 7.06 (d, J ) 2.9
2
3); HRMS (EI) m/z calcd for C14H14ClNO S 295.0434, found
95.0421.
Hz, 1H), 7.17-7.27 (m, 7H), 7.56 (d, J ) 8.3 Hz, 2H), 9.30 (br s,
13
1
1
1
H); C NMR (100 MHz, CDCl
3
) δ 51.9, 53.6, 63.1, 90.0, 116.9,
Data for ethyl 4-(benzoylamino)-3-(methylthio)pyrrole-2-
carboxylate (19): yield 80% (0.73 g); white solid; mp 142-144
C (EtOAc-hexane); R 0.2 (7:3 hexane-EtOAc); IR (KBr) 3268,
984, 1681, 1645, 1574, 1230 cm ; H NMR (400 MHz, CDCl
δ 1.29 (t, J ) 7.1 Hz, 3H), 2.26 (s, 3H), 4.31 (q, J ) 7.2 Hz, 2H),
22.2, 125.2, 127.0, 127.1, 128.2, 128.9, 129.2, 129.6, 132.7, 136.2,
38.0; MS m/z (rel intens) 376 (M , 100), 378 (M + 2, 30); HRMS
EI) m/z calcd for C15
+
°
2
f
(
H
20
N O
4 4
376.1454, found 376.1451.
-
1 1
3
)
Acknowledgment. N.C.M. thanks CSIR, New Delhi, for a
senior research fellowship. Financial assistance under the DST
project is also acknowledged.
7
2
1
1
.40-7.49 (m, 3H), 7.56 (d, J ) 2.7 Hz, 1H), 7.83 (d, J ) 7.1 Hz,
H), 8.11 (s, 1H), 9.79 (br s, 1H); 13C NMR (100 MHz, CDCl
) δ
3
4.3, 20.2, 60.8, 107.9, 114.9, 122.9, 127.0, 128.0, 128.7, 131.8,
+
34.3, 161.1, 164.4; MS m/z (rel intens) 304 (M , 100); HRMS
Supporting Information Available: 1H and 13C NMR spectral
data of all new compounds and CIF files containing the X-ray
crystallographic data of compounds 7a, 23, and 32. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
EI) m/z calcd for C15
Data for 4′-(4-chlorophenyl)-5-(methylthio)-2-phenyl-4,5′-
bioxazolyl (23): yield 72% (0.51 g); white crystalline solid; mp
28-130 °C (CHCl -hexane); R 0.6 (3:1 hexane-EtOAc); IR
KBr) 3126, 2929, 1476, 1094, 1020, 939 cm ; H NMR (400
16 2 3
H N O S 304.0881, found 304.0851.
1
(
3
f
-
1
1
JO062139J
J. Org. Chem, Vol. 72, No. 4, 2007 1251