Synthesis of pyrroles by consecutive multicomponent reaction/[4 + 1] Cycloaddition of α-iminonitriles with isocyanides

Article abstract of DOI:10.1021/ol9001619

[4 + 1] Cycloaddition of α,β-unsaturated imidoyl cyanide (2-cyano-1-azadienes) with isocyanides in the presence of a catalytic amount of AICI₃ afforded polysubstituted 2-amino-5-cyanopyrroles in good to excellent yields. In combination with the

Full text of DOI:10.1021/ol9001619

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1555-1558
Synthesis of Pyrroles by Consecutive
Multicomponent Reaction/[4 + 1]
Cycloaddition of r-Iminonitriles with
Isocyanides
Patrice Fontaine, Ge´raldine Masson,* and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr; masson@icsn.cnrs-gif.fr
Received January 26, 2009
ABSTRACT
[4 + 1] Cycloaddition of r,ꢀ-unsaturated imidoyl cyanide (2-cyano-1-azadienes) with isocyanides in the presence of a catalytic amount of
AlCl3 afforded polysubstituted 2-amino-5-cyanopyrroles in good to excellent yields. In combination with the IBX/TBAB-mediated oxidative
Strecker reaction, this important heterocycle is readily synthesized in two steps from simple starting materials.
Substituted 2-aminopyrrole is an important structural subunit
found in natural products,1 pharmacologically active mol-
ecules,2 and molecular sensors.3 Therefore, the development
of a mild, efficient, and modular synthesis of this heterocycle
is highly desirable.4 Although a large number of new pyrrole
syntheses have been reported in recent years that complement
the classical approaches,4 relatively few examples are known
for the preparation of 2-aminopyrroles.5-7 Recently, elegant
three-component syntheses of 2-aminopyrroles have been
developed by Nair8 and Shaabani.9,10 These reactions were
nevertheless restricted to the highly reactive dimethylacety-
lenedicarboxylate as reaction partner, leading to 3,4-sym-
metrically substituted pyrroles. To the best of our knowledge,
there is no convenient method for the preparation of
unsymmetrical polysubsituted 2-aminopyrroles, particularly
with regard to the availability of starting materials.
(1) (a) Kobayshi, J.; Cheng, J.; Kikuchi, Y.; Ishibashi, M.; Yamamura,
S.; Ohizumi, Y.; Ohta, T.; Nozoe, S. Tetrahedron Lett. 1990, 31, 4617–
4620.
(2) Selected examples: (a) Migawa, M. T.; Drach, J. C.; Townsend, L. B.
J. Med. Chem. 2005, 48, 3840–3851. (d) Lauria, A.; Bruno, M.; Diana, P.;
Barraja, P.; Montalbano, A.; Cirrincione, G.; Dattolo, G.; Almerico, A. M.
Bioorg. Med. Chem. 2005, 13, 1545–1553. (b) Krawezyk, S. H.; Nassiri,
M. R.; Kucera, L. S.; Kern, E. R.; Ptak, R. G.; Wotring, L. L.; Drach,
J. C.; Townsend, L. B. J. Med. Chem. 1995, 38, 4106–4114. (c) Bennet,
S. M.; Nguyen-Ba, N.; Ogilvie, K. K. J. Med. Chem. 1990, 33, 2162–2173.
(3) Sessler, J. L.; Pantos, G. D.; Gale, P. A.; Light, M. E. Org. Lett.
2006, 8, 1593–1596.
(6) 1,3-Dipolar cycloaddition: (a) Berre´e, F.; Morel, G. Tetrahedron
1995, 51, 7019–7034. (b) Burger, K.; Rottegger, S. Tetrahedron Lett. 1984,
25, 4091–4094. (c) Capuano, L.; Dahm, B.; Port, V.; Schnur, R.; Schramm,
V. Chem. Ber. 1988, 121, 271–274.
(4) (a) Patterson, J. M. Synthesis 1976, 281–304. (b) Jones, R. A.
Pyrroles, Part II: The Synthesis, ReactiVity and Physical Properties of
Substituted Pyrroles; Wiley and Sons: New York, NY, 1992. (c) Balme,
G. Angew. Chem., Int. Ed. 2004, 43, 6238–6241. (d) For a review of practical
syntheses of both indoles and pyrroles see: Gilchrist, T. L. J. Chem. Soc.,
Perkin Trans. 1 1999, 2849–2866.
(7) Synthesis of 2-amino-5-cyanopyrroles: (a) Verhe´, R.; De Kimpe,
N.; De Buyck, L.; Tilley, M.; Schamp, N. Tetrahedron 1980, 36, 131–142.
(b) Kusumoto, T.; Hiyama, T.; Ogata, K. Tetrahedron Lett. 1986, 27, 4197–
4200. (c) Chatani, N.; Hanafusa, T. Tetrahedron Lett. 1986, 27, 4201–
4204. (d) Chatani, N.; Hanafusa, T. J. Org. Chem. 1991, 56, 2166–2170.
(e) Abdelrazek, F. M.; Metwally, N. H. Synth. Commun. 2006, 36, 83–89.
(8) (a) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427–
4429. (b) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899–907.
(9) Shaabani, A.; Teimouri, M. B.; Arab-Ameri, S. Tetrahedron Lett.
2004, 45, 8409–8413.
(5) (a) Wamhoff, H.; Wehling, B. Synthesis 1976, 51. (b) Attanasi, O. A.;
Liao, Z.; McKillop, A.; Santeusanio, S.; Serra-Zanetti, F. J. Chem. Soc.,
Perkin Trans. 1 1993, 315–320. (c) Pichler, H.; Folker, G.; Roth, H. J.;
Eger, K. Liebigs Ann. Chem. 1986, 1485–1505. (d) Chien, T.-C.; Meade,
E. A.; Hinkley, J. M.; Townsend, L. B. Org. Lett. 2004, 6, 2857–2859. (e)
Demir, A. S.; Emrullahoglu, M. Tetrahedron 2006, 62, 1452–1458.
10.1021/ol9001619 CCC: $40.75
Published on Web 03/03/2009
2009 American Chemical Society

We have been working on heterocycle syntheses by
developing novel multicomponent reactions (MCRs)11 and
by using MCRs/post-functionalization strategy.12,13 In this
context, we have recently initiated a research program aimed
at developing oxidative MCRs14 and have reported a three-
component synthesis of R-iminonitriles.15 Encouraged by the
straightforward access to this otherwise difficultly accessible
chemical entity, we were interested in the synthetic potentials
offered by this unique functionality. We report herein the
development of a novel synthesis of 5-amino-2-cyanopyrroles
1 by way of a AlCl3-catalyzed [4 + 1] cycloaddition between
R,ꢀ-unsaturated imidoyl cyanides (2-cyano-1-azadienes) 2
with isocyanides 3.16 In combination with the oxidative
Strecker reaction, polysubstituted pyrroles 1 are readily
synthesized in two steps from simple starting materials
(Scheme 1).
lished.17,18 Morel and co-workers developed an alternative
pyrrole synthesis by a [4 + 1] cycloaddition between simple
1-azadienes and isocyanides.19-21 Although yields of this
reaction remained moderate as a result of the presence of a
number of side products, it provided incentive for our present
studies. We reasoned that the presence of a nitrile group in
2 could (a) stabilize the enamine resulting from the initial
1,4-addition, thus avoiding the rearrangement reaction, and
(b) deactivate the pyrrole ring, consequently inhibiting the
subsequent Friedel-Crafts type reaction.
The reaction between 2a and 2,6-dimethylphenyl isocya-
nide (3a) was selected for the survey of reaction conditions.
The representative results are summarized in Table 1.
Table 1. Optimization of Reaction Parameters for the Synthesis
of Pyrroles
Scheme 1. Sequential MCR/Cycloaddition Strategy
concn
temp time yield
entry
LA (equiv)
3 (equiv) (mol/L) (°C)
(h)
(%)b
1
2
3
4
5
none
1.1
1.1
2.0
1.1
1.1
0.3
0.3
0.3
0.7
0.7
60
60
90
90
90
15
15
24
15
15
AlCl3 (0.05)a
AlCl3 (0.05)a
GaCl3 (0.1)
AlCl3 (0.1)a
25
50
Under our previously developed conditions (IBX, TBAB,
MeCN, rt),15 the R-iminonitriles 2a-2e were prepared in
multigram scale from the respective R,ꢀ-unsaturated alde-
hydes 4, amines 5, and TMSCN (Scheme 2). The combined
88
a Used AlCl3 from Acros (98.5% purity). b Yields refer to chromato-
graphically pure product.
Scheme 2
.
Three-Component Synthesis of R,ꢀ-Unsaturated
Although no reaction took place in toluene under thermal
conditions, the reaction performed in the presence of 5 mol%
of AlCl3 did provide the desired product 1a in 25% yield
together with the recovered 2a (75%). Increasing the amount
of isocyanide had only a marginal effect on the reaction
Imidoyl Cyanides
(10) Selected examples for multicomponent synthesis of pyrroles: (a)
Shiraishi, H.; Nishitani, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998,
63, 6234–6238. (b) Bossio, R.; Marcacini, S.; Pepino, R.; Torroba, T.
Heterocycles 1999, 50, 463–467. (c) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J.
Org. Lett. 2001, 3, 3297–3300. (d) Nishibayashi, Y.; Yoshikawa, M.; Inada,
Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003,
42, 2681–2684. (e) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004,
126, 468–469. (f) Galliford, C. V.; Scheidt, K. A. J. Org. Chem. 2007, 72,
1811–1813. (g) Cadierno, V.; Gimeno, J.; Nebra, N. Chem. Eur. J. 2007,
13, 9973–9981. (h) St. Cyr, D. K.; Martin, N.; Arndtsen, B. A. Org. Lett.
2007, 9, 449–452. (i) St. Cyr, D. K.; Arndtsen, B. A. J. Am. Chem. Soc.
2007, 129, 12366–12367, and ref 4b.
(11) Selected examples: (a) Ga´mez-Montano, R.; Gonza´lez-Zamora, E.;
Potier, P.; Zhu, J. Tetrahedron 2002, 58, 6351–6358. (b) Fayol, A.; Zhu, J.
Angew. Chem., Int. Ed. 2002, 41, 3633–3635. (c) Janvier, P.; Bienayme,
H.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41, 4291–4294. (d) Fayol, A.;
Zhu, J. Org. Lett. 2005, 7, 239–242. (e) Pirali, T.; Tron, G. C.; Zhu, J.
Org. Lett. 2006, 8, 4145–4148. (f) Pinto, A.; Neuville, L.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 3291–3295. (g) For an account: Zhu, J. Eur. J.
Org. Chem. 2003, 1133–1144.
use of 2-iodoxybenzoic acid (IBX) and tetrabutylammonium
bromide (TBAB) was crucial for the success of this oxidative
Strecker reaction.
Synthesis of pyrroles by a formal [3 + 2] cycloaddition
between R-isocyanoacetate and dipolarophiles is well estab-
(12) (a) Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron 2003, 59, 7859–
7870. (b) Cunny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed.
2003, 4774–4777. (c) Bughin, C.; Zhao, G.; Bienayme`, H.; Zhu, J. Chem.
Eur. J. 2006, 12, 1174–1184. (d) Bughin, C.; Masson, G.; Zhu, J. J. Org.
Chem. 2007, 72, 1826–1829. (e) Pirali, T.; Tron, G.; Masson, G.; Zhu, J.
Org. Lett. 2007, 9, 5275–5278.
1556
Org. Lett., Vol. 11, No. 7, 2009

efficiency (entry 3). GaCl3, the catalyst of choice for [4 +
1] cycloaddition between R,ꢀ-unsaturated carbonyl com-
pounds and isocyanides,20b was found to be inefficient with
iminonitrile 2a (entry 4). Finally, heating a toluene solution
of 3a and 2a (c 0.7 M) in the presence of 10 mol% of AlCl3
at 90 °C was found to be optimum, providing pyrrole 1a in
88% yield (Table 1, entry 5).
Table 2. AlCl3-Catalyzed [4 + 1] Cycloaddition of
R,ꢀ-Unsaturated Imidoyl Cyanides with Isocyanidesa
The scope of this novel synthesis of 2-amino-5-cyanopy-
rroles was next examined with different R,ꢀ-unsaturated
imidoyl cyanides (2a-e) and isocyanides (3a-d). The results
are depicted in Table 2. The reaction proceeded effectively
with aromatic (3a) and aliphatic isocyanides (3b-3d) to give
the corresponding 5-amino-2-cyanopyrroles (1b-j) in good
to excellent yields. R,ꢀ-Unsaturated imidoyl cyanides bearing
aromatic or aliphatic substituents at the R or ꢀ position react
smoothly to give highly substituted pyrroles. The 2-cyano-
1-azadiene 2c, having substituents at both the R and ꢀ
positions, was converted to the corresponding pentasubsti-
tuted 5-amino-2-cyanopyrrole 1d in 74% yield (entry 3).
Pyrroles 1h and 1i, having a p-NO2-phenylethyl group at
the N-1 position, were obtained in yields of 78% and 75%,
respectively (entries 7 and 8). N-Cyclopropylated hetero-
cycles are important structural units in medicinal chemistry;
however, only limited synthetic methods are available.22 It
is thus interesting to note that the N-cyclopropyl iminonitrile
2e participated readily in the reaction to afford directly the
N-cyclopropyl pyrrole 1j in 81% yield (entry 9). In all cases,
pyrroles were obtained as a single product without concurrent
(13) For reviews, see: (a) Marcaccini, S.; Torroba, T. Post-condensation
Modifications of the Passerini and Ugi Reactions; Zhu, J., Bienayme´, H.,
Eds.; Wiley-VCH: Weinheim, 2005; pp 33-75. (b) Akritopoulou, I.; Djuric,
S. W. Heterocycles 2007, 73, 125–147.
(14) (a) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
5775–5778. (b) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2006,
45, 3495–3497. See also: (c) Leon, F.; Rivera, D. G.; Wessjohann, L. A. J.
Org. Chem. 2008, 73, 1762–1767.
(15) Fontaine, P.; Chiaroni, A.; Masson, G.; Zhu, J. Org. Lett. 2008,
10, 1509–1512.
(16) Synthesis of pyrrole from R,ꢀ-unsaturated aldehydes: Fuchibe, K.;
Ono, D.; Akiyama, T. Chem. Commun. 2006, 2271–2273.
(17) (a) Van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; Van
Leusen, D. Tetrahedron Lett. 1972, 13, 5337–5340. (b) Barton, D. H. R.;
Zard, S. Z. J. Chem. Soc., Chem. Commun. 1985, 1098–1099. (c) Takaya,
H.; Kojima, S.; Murahashi, S.-I. Org. Lett. 2001, 3, 421–424. (d) Kamijo,
S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260–
9266. (e) Misra, N. C.; Panda, K.; Ila, H.; Junjappa, H. J. Org. Chem. 2007,
72, 1246–1251. (f) Lygin, A. V.; Larionov, O. V.; Korotkov, V. S.; de
Meijere, A. Chem. Eur. J. 2009, 15, 227–236.
(18) For a review, see: Marcaccini, S.; Torroba, T. Org. Prep. Proc.
Int. 1993, 25, 143–208.
(19) Marchand, E.; Morel, G.; Sinbandhit, S. Eur. J. Org. Chem. 1999,
1729–1738.
a Reaction conditions: R,ꢀ-unsaturated imidoyl cyanides (1.0 mmol),
isocyanide (1.1 mmol), AlCl3 (0.1 mmol), toluene (1.4 mL), 90 °C. b Yield
refer to chromatographically pure product.
(20) Examples of [4 + 1] cycloaddition of R,ꢀ-unsaturated carbonyls
with isocyanides: (a) Ito, Y.; Kato, H.; Saegusa, T. J. Org. Chem. 1982,
47, 741–743. (b) Oshita, M.; Yamashita, K.; Tobisu, M.; Chatani, N. J. Am.
Chem. Soc. 2005, 127, 761–766, and references therein.
(21) Examples of [4 + 1] cycloaddition of nitroalkenes with isocyanides:
(a) Foucaud, A.; Razorilalana-Rabearivony, C.; Loukakou, E.; Person, H.
J. Org. Chem. 1983, 48, 3639–3644. (b) Person, H.; Del Aguila Pardo, M.;
Foucaud, A. Tetrahedron Lett. 1980, 21, 281–284. (c) Saegusa, T.;
Kobayashi, S.; Ito, Y.; Morino, I. Tetrahedron 1972, 28, 3389–3392. (d)
Fe´dou, N. M.; Parsons, P. J.; Viseux, E. M. E.; Whittle, A. J. Org. Lett.
2005, 7, 3179–3182.
formation of byproducts issued from the rearrangment of the
nitrilium intermediate or isocyanide insertion to the resulting
pyrrole.19,23
Removal of the N-p-NO2-phenylethyl group from 1h under
thermal basic conditions24 afforded a low yield of the desired
N-unsubstituted pyrrole 6. We found that under microwave
irradiation conditions (DBU, MeCN, MW, 300 W), 1h was
(22) (a) Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabe´, F.
J. Am. Chem. Soc. 2007, 129, 44–45. (b) Tsuritani, T.; Strotman, N. A.;
Yamamoto, Y.; Kawasaki, M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10,
1653–1655. (c) Be´nard, S.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73,
6441–6444, and references therein.
Org. Lett., Vol. 11, No. 7, 2009
1557

deproteced efficiently to afford 6a in 84% yield (eq 1,
Scheme 3). On the other hand, deprotection of 2-benzylamine
the resulting 5-aminooxazole indicated that the reaction was
initiated by attack of the R-carbon of 9, rather than the
divalent carbon of isonitrile as was often observed.25 We
reasoned that in this case AlCl3, being oxophilic, would
coordinate preferentially to the amide oxygen of 9, conse-
quently increasing the acidity of its R-CH. The Michael
addition of the resulting enolate onto the azadiene 2 followed
by oxazole ring formation and enamine-imine tautomer-
ization would then furnish the compound 10a.26 This
reactivity profile seemed to be general since compound 10b
was similarly obtained from 2e in 63% yield.
Scheme 3. Synthesis of 2-Amino-5-cyano-1H-pyrrole
In summary, we have described an efficient synthesis of
2-amino-5-cyanopyrroles by an AlCl3-catalyzed [4 + 1]
cycloaddition between R,ꢀ-unsaturated imidoyl cyanides 2
and isocyanides 3. Substituents at the C-3 and C-4 can be
introduced as well by starting from the appropriately
substituted iminonitrile 2. Furthermore, the presence of a
cyano group in the pyrroles makes them useful synthetic
intermediates for the preparation of other nitrogen-containing
heterocycles.27 By combining this cycloaddition with the
oxidative three-component synthesis of 2, diversely substi-
tuted pyrroles are readily prepared in two steps from simple
starting materials.
in 1f can also be realized by performing MnO2-mediated
oxidation followed by hydrolysis to afford 6b in 79% yield
(eq 2, Scheme 3).
A mechanistic rationale for the formal [4 + 1] cycload-
dition is given in Scheme 4. Coordination of AlCl3 to the
Scheme 4. Mechanistic Rational for the [4 + 1] Cycloaddition
Scheme 5. Unusual Reactivity of R-Isocyanoacetamide
Acknowledgment. Financial support from CNRS and
ANR are gratefully acknowledged. P.F. thanks ICSN for a
doctoral fellowship.
nitrogen atom of the iminonitrile 2 followed by 1,4-addition
of isocyanide 3 could lead to the formation of two geometric
isomers 7a and 7b. The nitrogen of isomer 7a was properly
positioned to attack the nitrilium to provide the primary
cycloadduct 8, which would then isomerize to the pyrrole 1
by a [1,3] H shift. We hypothesized that 7b, if formed, could
isomerize to 7a via an imine intermediate.
Supporting Information Available: Experimental pro-
1
cedures, product characterization, and copies of the H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL9001619
Interestingly, when R-isocyanoacetamide 9 was allowed
to react with 2a, a completely different reaction occurred to
afford oxazole 10a in 65% yield. The ring connectivity of
(25) (a) Janvier, P.; Sun, X.; Binaymé, H.; Zhu, J. J. Am. Chem. Soc.
2002, 124, 2560–2567. (b) Tron, G. C.; Zhu, J. Synlett 2005, 532–534. (c)
Janvier, P.; Bois-Choussy, M.; Bienaymé, H.; Zhu, J. Angew. Chem., Int.
Ed. 2003, 42, 811–814. (d) Elders, N.; Ruijter, R.; de Kanter, F. J. J.; Groen,
M. B.; Orru, R. V. A. Chem. Eur. J. 2008, 14, 4961–4973.
(23) Examples of insertion of isocyanide into C-H bonds of hetero-
cycles: (a) Tobisu, M.; Yamaguchi, S.; Chatani, N. Org. Lett. 2007, 9, 3351–
3353. (b) Treibs, A.; Diettl, A. Chem. Ber. 1961, 94, 298–299.
(24) (a) Edstrom, E. D.; Wei, Y. J. Org. Chem. 1995, 60, 5069–5076.
(b) Jolicoeur, B.; Chapman, E. E.; Thompson, A.; Lubell, W. D. Tetrahedron
2006, 62, 11531–11563.
(26) Note that reaction with 9 and aldehyde in the presence of AlCl3
underwent Passerini-type reaction; see: Wang, S.-X.; Wang, M.-X.; Wang,
D.-X.; Zhu, J. Eur. J. Org. Chem. 2007, 4076–4080.
(27) Dohi, T.; Morimoto, K.; Takenaga, N.; Goto, A.; Maruyama, A.;
Kiyono, Y.; Tohma, H.; Kita, Y. J. Org. Chem. 2007, 72, 109–116.
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