Catalytic multicomponent reactions for the synthesis of N-aryl trisubstituted pyrroles

Article abstract of DOI:10.1021/jo0624086

Dirhodium(II) salts efficiently catalyze the three-component assembly reaction of an imine, diazoacetonitrile (DAN), and an activated alkynyl coupling partner to form substituted 1,2-diarylpyrroles in moderate to good yields. The transition-metal-catalyze

Full text of DOI:10.1021/jo0624086

reactivity or biological activity, thus underpinning the need to
access a wide variety of pyrrole scaffolds efficiently from
straightforward starting materials.5 In addition to restrictions
based on the substitution pattern of the target compound, various
methods to synthesize differentially substituted pyrroles can
require expensive reagents, prolonged reaction times, or numer-
ous synthetic steps.
Catalytic Multicomponent Reactions for the
Synthesis of N-Aryl Trisubstituted Pyrroles
Chris V. Galliford and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145
Sheridan Road, EVanston, Illinois 60208
We envisaged using our previously reported multicomponent
coupling reaction for the synthesis of nitrogen-containing
heterocycles for the synthesis of these pyrroles.6 This interest
was initiated by a desire to synthesize N-aryl-substituted pyrrole-
3,4-dicarboxylic acids for an application in materials/surface
attachment chemistry.7 We were surprised to discover relatively
few methods for the synthesis of the desired 3,4-substitution
pattern in the literature. For example, 4 has been reported on
four previous occasions, but none of the synthetic routes are
amenable to accommodate various substitutions efficiently in a
single-flask operation. Boyd and Wright have described the
preparation and chemistry of a range of unstable mesoionic
oxazolium-5-oxide perchlorates, including the dipolar cycload-
dition of these compounds with dimethyl acetylene dicarboxylate
(DMAD) to yield compound 4.8 Yamanaka has reported the
synthesis of the related 4-polyfluoroalkylated pyrrole-3-car-
boxylates through the 1,3-dipolar cycloaddition of a fluoro-
alkylated acetylenecarboxylate ester with the munchnones
described by Boyd.9 Additionally, phenylsydnonyl-substituted
pyrroles have been reported via a related cycloaddition.10 In
this approach, the pyrroles are prepared in five linear steps
starting from an N-aryl glycine derivative.
In 1984, Reutrakul reported the preparation of phenylsulfinyl
aziridines in modest to good yields from benzylidine anilines
and R-chloro R-lithio sulfoxides.11 Pyrolysis of these compounds
in the presence of DMAD promoted the thermal ring opening
of the aziridine at 90 °C to the corresponding azomethine ylide.
Cycloaddition followed by elimination of sulfinic acid afforded
the pyrroles in good yield. Similarly, Katritzky has reported
the synthesis of the compound 10 from the analogous thermal
reaction of 2-benzotriazolylaziridines in the presence of diethyl
acetylenedicarboxylate.12 Although the aziridine precursors are
readily accessed in this case, the cycloaddition step requires a
prolonged reaction time (48 h at 100 °C) to access the target
scheidt@northwestern.edu
ReceiVed NoVember 22, 2006
Dirhodium(II) salts efficiently catalyze the three-component
assembly reaction of an imine, diazoacetonitrile (DAN), and
an activated alkynyl coupling partner to form substituted 1,2-
diarylpyrroles in moderate to good yields. The transition-
metal-catalyzed decomposition of the diazo compound in the
presence of the imine presumably generates a transient
azomethine ylide that undergoes cycloaddition with dipo-
larophiles in a highly convergent manner.
Pyrroles are plentiful structural motifs in natural products,1
medicinal agents,2 and materials chemistry.3 There are many
efficient methods for the synthesis of this important class of
heterocycle, but all of the various approaches have certain
restrictions regarding the scope and placement of the substitution
pattern around the heterocycle core. For example, our recently
published N-heterocyclic carbene-catalyzed, one-pot approach
to the synthesis of pyrroles using an acylsilane, R,â-unsaturated
ketone, and primary amine4 does not access the 3,4-diester-
substituted pyrroles described here. In many instances, specific
pyrrole substitution patterns are more important than others for
(1) (a) Bullington, J. L.; Wolff, R. R.; Jackson, P. F. J. Org. Chem. 2002,
67, 9439-9442. (b) Groves, J. K.; Cundasaway, N. E.; Anderson, H. G.
Can. J. Chem. 1973, 51, 1089-1098. (c) Andersen, R. J.; Faulkner, D. J.;
Cun-heng, H.; van Duyne, G.; Clardy, J. J. Am. Chem. Soc. 1985, 107,
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Brasco, R.; Seldes, A. M. Tetrahedron 1996, 52, 2727-2732. (f) Rudi, A.;
Goldberg, I.; Stein, Z.; Frolow, F.; Benayahu, Y.; Schleyer, M.; Kashman,
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Ingram, M. D.; Ryder, C.; Ryder, K. S. Phys. Chem. Chem. Phys. 2004, 6,
2403-2408. (c) Li, X.; Run-Feng, C.; Huang, M. R.; Zhu, M.-Z.; Chen,
K. J. Polym. Sci., Part A Polym. Chem. 2004, 42 (9), 2073-2092. (d)
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2005, 96 (5), 1830-1836.
(4) (a) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465-2468.
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Chem. 2006, 71, 5715-5724.
(5) 1,2-Diaryl pyrroles (with adjacent aryl substituents) are common
structural motifs in biologically active natural products and medicinal agents,
whereas the analogous 1,3-diaryl motif is less common. For an excellent
review and discussion of pyrroles containing adjacent aryl groups, see:
Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213-7256.
(6) (a) Galliford, C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A.
Org. Lett. 2003, 5 (19), 3487-3490. (b) Galliford, C. V.; Martenson, J. S.;
Stern, C.; Scheidt, K. A. Chem. Commun. 2006, in press, available online
as an advance article: DOI: 10.1039/b609155e.
(7) Carboxylates provide anchoring points for TiO2 surfaces with strong
binding affinities: Gallopini, E. Coord. Chem. ReV. 2004, 248, 1283-1297.
(8) (a) Boyd, G. V. Chem. Commun. 1968, 22, 1410. (b) Boyd, G. V.;
Wright, P. H. J. Chem. Soc., Perkin Trans. 1 1972, 909-913. (c) Boyd, G.
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513-514.
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10.1021/jo0624086 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/27/2007
J. Org. Chem. 2007, 72, 1811-1813
1811

TABLE 1. Scope of the Multicomponent Reactiona
SCHEME 1. Multicomponent Assembly Reaction for the
Synthesis of Pyrroles
SCHEME 2. Proposed Reaction Pathway
pyrroles. Here we report a concise approach to 1,2-diarylpyrroles
using a multicomponent assembly reaction of an imine, diaz-
oacetonitrile, and an activated alkyne dipolarophile (Scheme 1).
The combination of rhodium(II) salt and a diazo compound
produces the corresponding metallocarbenoid.13 The presence
of an imine during this process generates an azomethine ylide
intermediate, which is trapped via a Huisgen [3 + 2] cycload-
dition onto an alkynyl dipolarophile.14 The resultant adduct then
undergoes elimination in situ to form the aromatic pyrrole
(Scheme 2).15
After examining a number of possible transition metal salts
for this reaction, we determined that rhodium acetate is the
catalyst of choice for this transformation, proving to be superior
to 10 mol % of copper triflate (as in our previous work),6 which
surprisingly yielded no product in this case. Other rhodium salts
also promoted the transformation (dirhodium tetraoctanoate and
dirhodium tetrahexafluorobutyrate), albeit in lower yields (27%
and 12%, respectively). We were pleased to discover that as
little as 1 mol % of catalyst smoothly effected the transforma-
tion.
a
Reaction conditions: a solution of DAN (2, 4.5 equiv) in CH2Cl2 (4
mL) was added via syringe pump over 3 h to a solution of imine (1a-h,
3 equiv), acetylene dicarboxylate (3a or 3b, 1 equiv), and Rh2(OAc)4 (1
mol %) in CH2Cl2 (3 mL), heating at gentle reflux.
Gratifyingly, several imines can be employed in this reaction
manifold (Table 1). Substitution on the starting imine is
tolerated, especially on the benzylidene aryl ring (compounds
6-11, entries 4-8). Compound 8 required a longer reaction
time after the syringe pump addition was complete (12 h). Most
likely, this is due to a destabilizing effect on the putative
azomethine ylide. Diethyl acetylenedicarboxylate (3b) is readily
used in place of DMAD to yield the 3,4-diethyl ester in good
yield (compound 10, entry 7). Alternative activated acetylenes,
such as methyl propiolate, yielded no product. In addition to
our proposed mechanism, we could not discount the possibility
of a pathway involving initial formation of an aziridine that
undergoes ring opening (similar to that of Katritzky). Doyle
has shown that the analogous Rh(II)-catalyzed aziridination of
imines by carbene transfer of ethyl diazoacetate shows a strong
structure dependency on the imine substituents, with respect to
the reaction’s product distribution (the azomethine ylide can
undergo ring closure to yield aziridines or cycloaddition to afford
alternative products).16 In our case, this may suggest competing
pathways leading to the same product, with a strong dependency
(13) (a) Doyle, M. P.; Wee, A. G. H. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides;
Wiley, John & Sons: New York, 1998. (b) Curr. Org. Synth. 2006, 3 (4),
499-555. (c) Organic Synthesis Highlights II; Waldmann, H., Ed.; Wiley-
VCH: New York, 1995; pp 65-74. (d) Padwa, A.; Hornbuckle, S. F. Chem.
ReV. 1991, 91 (3), 263-309. (e) Padwa, A. HelV. Chim. Acta 2005, 88 (6),
1357-1374. (f) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56 (28),
4871-4880. (g) Davies, H. M. L.; Antoulinakis, E. G. J. Organomet. Chem.
2001, 617-618, 47-55. (h) Davies, H. M. L.; Beckwith, R. E. J. Chem.
ReV. 2003, 103, 2861. (i) Davies, H. M. L.; Loe, O. Synthesis 2004, 2595.
(j) Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J.
Am. Chem. Soc. 2003, 125, 15902-15911. (k) Davies, H. M. L.; Jin, Q.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5472-5475.
(14) (a) Huisgen, R.; Grashey, J. S. In Chemistry of Alkenes; Inter-
science: New York, 1964; pp 806-877. (b) Srihari, S. R.; Yaragorla, D.;
Basu, S.; Chandrasekhar Synthesis 2006, 2646-2648. (c) Gao, W.; Zhang,
X.; Raghunath, M. Org. Lett. 2005, 7, 4241-4244.
(15) (a) La Porta, P.; Capuzzi, L.; Bettarini, F. Synthesis 1994, 5, 287-
290. (b) Chan, H.; Chan, P.; Liu, J.; Mong, H. N. C. Chem. Commun. 1997,
1515-1516. (c) Linn, W. J.; Webster, O. W.; Benson, R. E. J. Am. Chem.
Soc. 1965, 87, 3651-3656.
(16) Doyle, M. P.; Yan, M.; Hu, W.; Gronenburg, L. S. J. Am. Chem.
Soc. 2003, 125, 4692-4693.
1812 J. Org. Chem., Vol. 72, No. 5, 2007

containing a magnetic stirring bar was added 1 mol % of Rh2(OAc)4
catalyst, imine, and acetylene diester in CH2Cl2 (3 mL). The mixture
was heated to a gentle reflux, and the diazoacetonitrile solution
was added via syringe pump (1.5 mL per hour). After complete
addition, the mixture was heated for a further 1-2 h (12 h in the
case of compounds 5 and 8) and then allowed to cool to 25 °C.
The unpurified reaction mixture was filtered through a silica
plug with CH2Cl2 (50 mL). The solvent was evaporated, and
purification by flash chromatography on silica gel provided the title
compounds.
on the imine structure being a prerequisite for this second
pathway to be substantial.
Under our optimized reaction conditions, we did not isolate
any aziridine products. However, other side products are known
to form with diazoacetonitrile.17 The pyrrole-3,4-diester products
are known to undergo other side reactions with acetylene
dicarboxylates,18 and optimization efforts were therefore pri-
marily directed at the minimization of these side products.
Diazoacetonitrile was conveniently prepared by the diazotization
of the commercially available aminoacetonitrile bisulfate ac-
cording to the procedure of Witiak and Lu and handled only as
a solution in methylene chloride.19 It is important to note that
explosions caused by concentrating diazoacetonitrile solutions
have been reported,20 but solutions (approximately 0.4-0.5 M
in CH2Cl2) could be safely prepared in our laboratory and
handled without incident.
In summary, the combination of a diazoacetonitrile and an
imine in the presence of a rhodium(II) catalyst generates a
reactive, transient azomethine ylide. This 1,3-dipole undergoes
a [3 + 2] cycloaddition with activated alkynyl dipolarophiles
to afford 1,2-diaryl-substituted pyrroles in a convergent three-
component assembly reaction. Notably, this process works
efficiently at low catalyst loadings.
Dimethyl 1,2-Diphenyl-1H-pyrrole-3,4-dicarboxylate (4). Pre-
pared according to the general procedure using imine 1a (213 mg,
1.2 mmol), DMAD 3a (49 mL, 0.4 mmol), and a solution of DAN
2 in methylene chloride (4.0 mL, 0.45 M). Flash column chroma-
tography using gradient elution mixtures of EtOAc/toluene (6-
12%) afforded 94 mg (71%) of 4 as a viscous white foam.
Analytical data for 4: Rf 0.24 (3:1 EtOAc/hexanes); IR (film) cm-1
1
2947.9, 2860.2, 1722.7, 1560.1; H NMR (400 MHz, CDCl3) δ
7.50 (s, 1H), 7.36-7.08 (m, 10H), 3.84 (s, 3H), 3.77 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 165.5, 163.6, 138.7, 135.1, 130.4, 129.9,
129.0, 128.1, 127.9, 127.7, 125.9, 117.0, 115.7; LRMS (electro-
spray) exact mass calcd for C20H17NO4 [M]+, 335.12; found [M +
H], 336.5.
Experimental
Acknowledgment. Support for this research has been
provided by Northwestern University, the NSF (CAREER CHE-
0348979), and the Elizabeth Tuckerman Foundation (fellowship
to C.V.G.). K.A.S. thanks Abbott, Amgen, Boehringer-Ingel-
heim, and 3M for generous unrestricted research support.
Funding for the NU Analytical Services Laboratory has been
furnished in part by the NSF (CHE-9871268).
Sample Procedures for Pyrrole Synthesis. To a flame-dried,
two-necked, round-bottom flask fitted with a reflux condenser
(17) Diazoacetonitrile 2 slowly undergoes dipolar cycloaddition with
benzylidene anilines as the dipolarophile to yield triazolines as the major
product. Enamines and aziridines are also formed in this reaction: Roelants,
F.; Bruylants, A. Tetrahedron 1978, 34, 2229-2232.
(18) 3,4-Diester-substituted pyrroles have been shown to undergo Diels-
Alder cycloadditions: (a) Groves, J. K.; Cundawasawy, N. E.; Anderson,
H. J. Can. J. Chem. 1973, 51, 1089-1098. Pyrrole conjugate additions with
acetylene dicarboxylates to form 2-substituted pyrroles have also been
reported: (b) Noland, W. E.; Lee, C.-K. J. Org. Chem. 1980, 45, 4573-
4582.
(19) Witiak, D. T.; Lu, M. C. J. Org. Chem. 1970, 35, 4209-4217.
(20) (a) Phillips, D. D.; Champion, W. C. J. Am. Chem. Soc. 1956, 78,
5452. (b) Dewar, M. J. S.; Pettit, R. J. Chem. Soc. 1956, 2026.
Supporting Information Available: Characterization data and
details of experimental techniques and procedures used in this
manuscript. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0624086
J. Org. Chem, Vol. 72, No. 5, 2007 1813