One-step synthesis of 3-aryl- and 3,4-diaryl-(1H)-pyrroles using tosylmethyl isocyanide (TOSMIC)

Article abstract of DOI:10.1021/ol0267073

(matrix presented) A one-step synthesis of 3-aryl and 3,4-diaryl-(1H)-pyrroles from TOSMIC and commercially available or readily synthesized arylalkenes is reported. Optimal conditions were found to be NaOtBu in DMSO. The methodology was particularly efficient (yields > 65%) when electron poor aryl groups were attached to the alkene.

Full text of DOI:10.1021/ol0267073

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3537-3539
One-Step Synthesis of 3-Aryl- and
3,4-Diaryl-(1H)-Pyrroles Using
Tosylmethyl Isocyanide (TOSMIC)
Nicholas D. Smith,* Dehua Huang, and Nicholas D. P. Cosford
Merck Research Laboratories, 3535 General Atomics Court,
San Diego, California 92121
Nicholas_Smith@merck.com
Received August 9, 2002
ABSTRACT
A one-step synthesis of 3-aryl and 3,4-diaryl-(1H)-pyrroles from TOSMIC and commercially available or readily synthesized arylalkenes is
reported. Optimal conditions were found to be NaOtBu in DMSO. The methodology was particularly efficient (yields > 65%) when electron poor
aryl groups were attached to the alkene.
The pyrrole ring is an important heterocycle in biological
systems being incorporated into the porphyrin ring systems
of chlorophyll, heme, Vitamin B12, and the bile pigments.
Additionally, there are a number of pyrrole-containing small
molecules that exhibit useful biological activities.1,2 As such,
a lot of effort has been spent developing practical methods
for the synthesis of pyrrole units that incorporate appropriate
functionality.3 One such method developed by van Leusen
is the reaction of tosylmethyl isocyanide (TOSMIC) with a
Michael acceptor 1 to generate a 3,4-disubstituted pyrrole 2
(Scheme 1).4 This procedure necessarily installs the activating
Z group of the Michael acceptor at the 3-position of the
pyrrole ring formed.2,4,5
Scheme 1
(1) Arima, K.; Imanaka, H.; Kousaka, M.; Fukuta, A.; Tamura, G. Agr.
Biol. Chem. 1964, 28, 575. Nakeno, H.; Umio, S.; Kariyone, K.; Tanaka,
K.; Kishimpto, T.; Noguchi, H.; Ueda, I.; Nakamura, H.; Morimoto, Y
Tetrahedron Lett. 1966, 7, 737. Unverferth, K.; Engel, J.; Hofgen, N.;
Rostock, A.; Gunther, R.; Lankau, H. J.; Menzer, M.; Rolfs, A.; Liebscher,
J.; Muller, B.; Hofmann, H. J. J. Med. Chem. 1998, 41, 63.
(2) Dannhardt, G.; Kiefer, W.; Kraemer, G.; Maehrlein, S.; Nowe, U.;
Fiebich, B. Eur. J. Med. Chem. 2000, 35, 499. Rango, R.; Marshall, G. R.;
Santo, R. D.; Costi, R.; Massa, S.; Rompei, R.; Artico, M. Bioorg. Med.
Chem. 2000, 8, 1423. Artico, M.; Santo, R. D.; Costi, R.; Massa, S.; Retico,
A. J. Med. Chem. 1995, 38, 4223. Magnus, P.; Gallagher, T.; Schultz, J.;
Or, Y. S.; Ananthanarayan, T. P. J. Am. Chem. Soc. 1987, 109, 2706.
(3) Sundberg, R. G. in ComprehensiVe Heterocyclic Chemistry; Katritsky,
A. R., Ed.; Pergamon Press: Oxford, 1984; Vol. IV, p 313. Gilchrist, T. L.
In Heterocyclic Chemistry; Pitman Publishing: London, 1985; Chapters 4
and 6.
(4) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen,
D. Tetrahedron Lett. 1972, 52, 5337. Possel, O.; van Leusen, A. M.
Heterocycles 1977, 7, 77. Barton, D. H. R.; Kervagoret, J.; Zard, S. Z.
Tetrahedron 1990, 46, 7587. ten Have, R.; Leusink, F. R.; van Leusen, A.
M. Synthesis 1996, 871. Dijkstra, H. P.; ten Have, R.; van Leusen, A. M.
J. Org. Chem. 1998, 63, 5332.
Recently, we required a facile and general synthesis of
3-aryl-substituted pyrroles 4 (R1 ) aryl). These 3-aryl
pyrroles have typically been accessed via multistep cross-
coupling methodology requiring the use of a protecting group
for the pyrrole NH6 or by using van Leusen’s TOSMIC
(5) Pavri, N. P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649.
(6) Alvarez, A.; Guzman, A.; Ruiz, A.; Velarde, E. J. Org. Chem. 1992,
57, 1653. Bumagin, N. A.; Nikitina, A. F.; Belatskaya, I. P. Russ. J. Org.
Chem. 1994, 30, 1619.
10.1021/ol0267073 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/13/2002

methodology where saponification (2f3) and decarboxyl-
ation (3f4) are required to remove the ester Z group.5,7 As
a more efficient entry into 3-aryl-pyrroles 4, we reasoned
that electron-deficient vinyl arenes 1 (i.e., R1 ) aryl, Z )
H) could act as Michael acceptors, thus negating the need
for an electron-withdrawing Z group and so providing 3-aryl
pyrroles directly (1f4). Testing this hypothesis with 4-vinyl
pyridine (1: R1 ) 4-pyridyl, Z ) H), we indeed found that
using Et2O/DMSO as a solvent, we obtained a 37% yield of
the desired 3-aryl pyrrole 4 in a single step (Scheme 1).
Further investigation of the factors affecting this trans-
formation using the more challenging substrate styrene led
to the optimum conditions of NaOtBu in DMSO. Using these
conditions, we investigated the scope of this transformation
using a variety of 1-aryl alkenes (Table 1).
expected, compared to styrene (entry 1), an electron-
withdrawing group on the aryl ring (para-chloro, entry 5)
gave an improved yield of 58%.8 The retarding effect of
sterics on the reaction are illustrated in entries 6-8 where
ortho substituents on the aryl ring require higher reaction
temperatures or give slightly reduced yields. As an illustration
of the efficiency of this approach, a recent publication
reported the synthesis of 3-(4-chlorophenyl)-1H-pyrrole
(entry 5) in four steps and 48% overall yield.5 The present
approach proceeds in one step in 58% yield from com-
mercially available starting materials.9
The synthesis of 3,4-diaryl pyrroles has not yet been
reported using TOSMIC.10 Therefore, we decided to inves-
tigate whether 1,2-diarylalkenes would also react under our
conditions to give 3,4-diaryl pyrroles in a single step. The
results are shown in Table 2.
Table 1. Synthesis of 3-Aryl Pyrroles Using TOSMICa
Table 2. Synthesis of 3,4-Diaryl Pyrroles Using TOSMICa
a TOSMIC (1.3 equiv), NaOtBu (2 equiv), DMSO, T in °C. b Isolated
yield after chromatography.
a TOSMIC (1.3 equiv), NaOtBu (2 equiv), DMSO, T in °C. b Isolated
yield after chromatography.
Again, electron-withdrawing aryl groups attached to the
alkene led to higher yields of the desired pyrrole at lower
temperatures and with shorter reaction times. Thus a bis-
pyridyl-substituted alkene (entry 1) gave an excellent yield
(91%) of the desired 3,4-dipyridyl pyrrole after only 4 h at
In general, higher yields of the desired 3-aryl pyrrole were
obtained at lower temperatures and with shorter reaction
times when the aryl group of the styrene starting material
was more electron deficient. Thus, styrene (entry 1) gave
47% yield after 18 h at 50 °C, while 4-vinyl pyridine (entry
2), 2-vinyl pyridine (entry 3), and 2-vinyl pyrazine (entry
4) all gave good yields (>65%) after only 2 h at 25 °C. As
(8) Electron-rich arylalkenes such as 4-methoxystyrene gave low conver-
sion upon extended reaction times at 100 °C.
(9) Further, 3-(phenyl)-1H-pyrrole (entry 1) was prepared previously in
two steps and 32% overall yield: Boger, D. L.; Coleman, R. S.; Panek, J.
S.; Yohannes, D. J. Org. Chem. 1984, 49, 4405.
(10) van Leusen has reported the synthesis of 3,4-diphenyl pyrrole using
a deriVatiVe of TOSMIC: van Leusen, D.; van Echten, E.; van Leusen, A.
M. J. Org. Chem. 1992, 57, 2245.
(7) Balasubramanian, T.; Strachan, J. P.; Boyle, P. D.; Lindsey, J. S J.
Org. Chem. 2000, 65, 7919. For another example of saponification/
decarboxylation route to 3-aryl pyrroles, see: Sakai, K.; Suzuki, N.; Ken-
ichi, N.; Yoneda, N.; Onoda, Y.; Iwasawa, Y. Chem. Pharm. Bull. 1980,
28, 2384.
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Org. Lett., Vol. 4, No. 20, 2002

room temperature. When one of the pyridyl rings was
changed to a phenyl (entry 2) or a thiophene ring (entry 3),
good yields were still obtained but higher reaction temper-
atures were required. Entry 4 illustrates that alkyl-substituted
alkenes will also undergo the reaction to give 3-aryl- and
4-alkyl-substituted pyrroles in good yields. Finally, the
isoquinoline-substituted alkene (entry 5) further demonstrates
that nonsymmetrical 3,4-disubstituted pyrroles can be as-
sembled rapidly and in good yields. Again the utility of this
approach is underlined as present methodology for the
synthesis of nonsymmetrical 3,4-diaryl pyrroles is limited,
requiring multiple synthetic steps.11,12
significant improvement over existing multistep sequences
based on decarboxylation5,7 or cross-coupling6,12 sequences.
Acknowledgment. We thank Michael Gardner for help
with determining HPLC yields.
Supporting Information Available: Reaction procedures
and characterization of products (1H and 13C NMR, MS, and
melting point). This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0267073
In summary, we have demonstrated that the synthesis of
3-aryl- and 3,4-diaryl-substituted pyrroles may be achieved
in a single step from TOSMIC and commercially available
or readily accessible aryl-substituted alkenes.13,14 We believe
this facile synthesis of aryl-substituted pyrroles represents a
(13) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968-4971 and
references cited within.
(14) Typical procedure: To a suspension of NaOtBu (2 equiv) in dry
DMSO was added a solution of the arylalkene (1 equiv) and tosylmethyl-
isocyanate (1.3 equiv) in DMSO (0.1 M final concentration). The reaction
mixture was stirred at the appropriate temperature for the required time,
whereupon it was diluted with EtOAc and brine and shaken. The aqueous
layer was washed with EtOAc (three times), dried over Na2SO4, filtered,
concentrated, and purified by liquid chromatography on silica gel. For full
experimental details and product characterization, please see Supporting
Information.
(11) Ono, N.; Miyagawa, H.; Ueta, T.; Ogawa, T.; Tani, H. J. Chem.
Soc., Perkin Trans. 1 1998, 1595.
(12) Liu, J. H.; Chan, H. W.; Wong, H. N. C. J. Org. Chem. 2000, 65,
3274.
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