Doubly activated cyclopropanes as synthetic precursors for the preparation of 4-nitro- and 4-cyano-dihydropyrroles and pyrroles

Article abstract of DOI:10.1021/ol050442l

(Chemical Equation Presented) 1-Nitro- and 1-cyano-cyclopropyl ketones have been prepared in an expedient manner from cyclopropanation reactions of alkenes by diazo compounds or in situ-generated phenyliodonium ylides catalyzed by Rh(II) carboxylates. The doubly activated cyclopropanes were used as synthetic precursors for the regiospecific synthesis of 4-nitro- and 4-cyano- dihydropyrroles upon treatment with primary amines. Oxidation of the dihydropyrroles with DDQ allows rapid access to densely functionalized pyrroles.

Full text of DOI:10.1021/ol050442l

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2313-2316
Doubly Activated Cyclopropanes as
Synthetic Precursors for the Preparation
of 4-Nitro- and 4-Cyano-dihydropyrroles
and Pyrroles
Ryan P. Wurz and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P. O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received February 28, 2005
ABSTRACT
1-Nitro- and 1-cyano-cyclopropyl ketones have been prepared in an expedient manner from cyclopropanation reactions of alkenes by diazo
compounds or in situ-generated phenyliodonium ylides catalyzed by Rh(II) carboxylates. The doubly activated cyclopropanes were used as
synthetic precursors for the regiospecific synthesis of 4-nitro- and 4-cyano-dihydropyrroles upon treatment with primary amines. Oxidation of
the dihydropyrroles with DDQ allows rapid access to densely functionalized pyrroles.
Pyrrole and its derivatives are ubiquitous in nature. As such,
the pyrrole subunit has found widespread applications in
therapeutically active compounds, including fungicides,
antibiotics (1),1 nonsteroidal antiinflammatory drugs (NSAIDS)
(2),2 cholesterol-reducing drugs (3),3 and antitumor agents4
(Figure 1). The pyrrole subunit also plays an important role
in material science5 as it is found in organic conducting
polymers,6 indigoid dyes, and porphyrins.7
The abundance of the pyrrole motif in biologically active
compounds and potential drug candidates has resulted in the
development of many methods for their synthesis. Classical
methods for pyrrole synthesis include the Paal-Knorr
synthesis8 and the Hantzsch synthesis.9 These methods are
(1) For examples of biologically active 4-nitropyrroles, see: (a) Ono,
N.; Muratani, E.; Ogawa, T. J. Heterocycl. Chem. 1991, 28, 2053-2055.
(b) Nishiwaki, N.; Nakanishi, M.; Hida, T.; Miwa, Y.; Tamura, M.; Hori,
K.; Tohda, Y.; Ariga, M. J. Org. Chem. 2001, 66, 7535-7538. (c) Kaneda,
M.; Nakamura, S.; Ezaki, N.; Iitaka, Y. J. Antibiotics 1981, 34, 1366-
1368. (d) Koyama, M.; Kodama, Y.; Tsuruoka, T.; Ezaki, N.; Niwa, T.;
Inouye, S. J. Antibiotics 1981, 34, 1569-1576. (e) Koyama, M.; Ezaki,
N.; Tsuruoka, T.; Inouye, S. J. Antibiotics 1983, 36, 1483-1489. (f)
Koyama, M.; Ohtani, N.; Kai, F.; Moriguchi, I.; Inouye, S. J. Med. Chem.
1987, 30, 552-562.
(2) See for example: (a) Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins,
P. W.; Miyashiro, J. M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie, J. L.;
Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1619-1633. (b)
Wilkerson, W. W.; Copeland, R. A.; Covington, M.; Trzaskos, J. M. J.
Med. Chem. 1995, 38, 3895-3901. (c) Wilkerson, W. W.; Galbraith, W.;
Gans-Brangs, K.; Grubb, M.; Hewes, W. E.; Jaffee, B.; Kenney, J. P.; Kerr,
J.; Wong, N. J. Med. Chem. 1994, 37, 988-998.
(3) Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.
(4) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603. (b)
Kral, V.; Davis, J.; Andrievsky, A.; Kralova, J.; Synytsya, A.; Pouckova,
P.; Sessler, J. L. J. Med. Chem. 2002, 45, 1075-1078.
Figure 1. Examples of biologically active pyrroles.
10.1021/ol050442l CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/13/2005

very useful when the appropriate starting materials are
available. However, there exist limitations that make certain
classes of pyrroles difficult to prepare or inaccessible using
these methods.
Table 1. Preparation of 1-Nitro-1-cyclopropyl Ketones
Cyclopropanes have been shown to be useful synthetic
precursors in organic synthesis.10 Depending on the func-
tionalities present on the cyclopropane ring, fragmentation
of these three-membered carbocycles represents a useful
method for the construction of a wide variety of carbon
skeletons. We recently reported a cyclopropanation reaction
involving in situ generation of phenyliodonium ylides for
the preparation of nitro cyclopropanecarboxylates using
hypervalent iodine(III) reagents.11 Reduction of the nitro
group using Zn-HCl affords a structurally diverse series of
cyclopropane R-amino acids.12
To extend the synthetic utility of 1-nitro-cyclopropylcar-
bonyls further,13 a strategy to access dihydropyrroles14 and
pyrroles was envisaged. Herein, we describe the preparation
of these compounds from nitro- and cyano-containing doubly
activated cyclopropyl ketones.
Preparation of 1-nitro-cyclopropyl ketones began by cy-
clopropanation of alkene substrates either with R-nitro-R-
diazoketones15 or with phenyliodonium ylides derived from
R-nitroketones. Ylide intermediates are presumably generated
in situ upon treatment of R-nitroketones with PhI(OAc)2
(Table 1).
The chemical yields of the desired cyclopropanes were
similar in most cases using the two different cyclopropanation
protocols. However, when the alkene substrate is expensive
or lacks R-stabilization (i.e., 4-Ph-1-butene), cyclopropana-
tion with the diazo substrate gives higher chemical yields
of the desired cyclopropane.
yield of
E:Z
ratio
product
R
R1
methoda
6 (%)b
6a
6a
6b
6b
6c
6c
6d
6d
6e
6f
Me
Me
Ph
Ph
A
B
A
B
A
B
A
B
A
A
A
77
78:22
78:22
81:19
88:12
16:84
10:90
76:24
74:26
73:27
79:21
53:47
59c
74
n-propyl Ph
n-propyl Ph
62c
74
Ph
Ph
Ph
Ph
Ph
Ph
75
69
c-C3H5
c-C3H5
Me
73
4-F-Ph
1-naphthyl
phenethyl
63d
52d
36
Me
Me
6g
a Method A: 4 (1.0 M in CH2Cl2) was added dropwise to the alkene
(2-3 equiv) and [Rh(Oct)2]2 (0.5 mol %). Method B: 5, PhI(OAc)2 (1.1
equiv), alkene (5.0 equiv), and [Rh(Oct)2]2 (0.5 mol %) stirred at 40 °C for
3 h. b Isolated yields after column chromatography. c Stirred at room
temperature for 20 h. d Performed with 1.0 equiv of alkene.
R-cyanoketones are also viable substrates. Accordingly, a
variety of additives, including 4 Å MS, Al2O3, Na2CO3, and
MgO, were screened in the cyclopropanation reaction involv-
ing benzoylacetonitrile (8a) and PhI(OAc)2 as the iodine-
(III) source.18 The reaction was also performed in organic
solvents, solventless, and under aqueous reaction conditions
(Table 2). The optimal reaction conditions for the benzoyl-
acetonitrile (8a) involved use of Na2CO3 (2.3 equiv) and 4
Mu¨ller and Ghanem have recently extended the in situ
protocol to include Meldrum’s acid16 and dimethyl mal-
onate17 as substrates, and we now wish to report that
Table 2. Cyclopropanation of Alkenes with R-Cyanoketones
and R-Cyano-R-diazoketones
(5) For reviews, see: (a) Baumgarten, M.; Tyutyulkov, N. Chem. Eur.
J. 1998, 4, 987-989. (b) Deronzier, A.; Moutet, J.-C. Curr. Top.
Electrochem. 1994, 3, 159-200.
(6) Review: Pagani, G. A. Heterocycles 1994, 37, 2069-2086.
(7) See, for example: (a) Ono, N.; Muratani, E.; Fumoto, Y.; Ogawa,
T.; Tazima, K. J. Chem. Soc., Perkin Trans. 1 1998, 3819-3824. (b)
Crossley, M. J.; King, L. G.; Newsom, I. A.; Sheehan, C. S. J. Chem. Soc.,
Perkin Trans. 1 1996, 2675-2684.
(8) (a) Paal, C. Ber. 1885, 18, 367-371. (b) Knorr, L. Ber. 1885, 18,
299-311.
yield of 9 E:Z
(9) Hantzsch, A. Ber. 1890, 23, 1474-1483.
product (R)
methoda
additive
(%)b
ratio
(10) For reviews, see: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12,
66-72. (b) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151-1196.
(c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. ReV. 1989,
89, 165-198.
(11) Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327-2329.
(12) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262-
1269.
(13) Nitrocyclopropane carboxylates as amino acid equivalents: (a)
O’Bannon, P. E.; Dailey, W. P. J. Org. Chem. 1990, 55, 353-355. (b)
Vettiger, T.; Seebach, D. Liebigs Ann. Chem. 1990, 195-201. (c) Seebach,
D.; Ha¨ner, R.; Vettiger, T. HelV. Chim. Acta 1987, 70, 1507-1515.
(14) For an example of a related dihydropyrrole synthesis, see: (a)
Jacoby, D.; Celerier, J. P.; Haviari, G.; Petit, H.; Lhommet, G. Synthesis
1992, 884-887. (b) Celerier, J. P.; Haddad, M.; Jacoby, D.; Lhommet, G.
Tetrahedron Lett. 1987, 28, 6597-6600.
9a (Ph)
9a (Ph)
9a (Ph)
9a (Ph)
9b (Bn)
9b (Bn)
9c (4-MeO-Ph)
9c (4-MeO-Ph)
9d (styryl)
9d (styryl)
A
B
B
B
A
B
A
B
A
B
95
63c
88
52
83
64
97
72
96
67c
88:12
86:14
86:14
87:13
77:23
78:22
94:6
89:11
57:43
56:44
none
Na2CO3 + 4 Å MS
H2O
Na2CO3 + 4 Å MS
Na2CO3 + 4 Å MS
none
a Method A: 7 (1.0 M in CH2Cl2) was added dropwise to styrene (2.0
equiv) and [Rh(Oct)2]2 (0.5 mol %). Method B: 8, PhI(OAc)2 (1.1 equiv),
[Rh(Oct)2]2 (1.0 mol %), and styrene (5.0 equiv), and the additive was stirred
(15) (a) Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000,
65, 9252-9254. (b) Charette, A. B.; Wurz, R. P.; Ollevier, T. HelV. Chim.
Acta 2002, 85, 4468-4484.
(16) Mu¨ller, P.; Ghanem, A. Synlett 2003, 1830-1833.
(17) Mu¨ller, P.; Ghanem, A. Org. Lett. 2004, 6, 4347-4350.
b
in CH2Cl2 (1.0 M) for 18 h at room temperature. Isolated yields after
column chromatography. c Reaction performed without solvent.
2314
Org. Lett., Vol. 7, No. 12, 2005

Scheme 1
Table 3. Preparation of 4-Nitro-dihydropyrroles from
1-Nitro-1-cyclopropyl Ketones and Primary Amines
yield of 10
product
R
R1
R2
(%)
10a
Me
Ph
Ph
Ph
Ph
Ph
91
78
91
79
97
48a
35
84b
47a
95
96
99
84
18c
10b n-propyl Ph
10c Ph Ph
10d c-C3H5 Ph
10e
10f
10g
10h Me
10i
10j
10k Ph
10l Me
10m Me
10n Me
c-C3H5 Ph
Me
Me
4-MeO-Ph
allyl
benzyl
(R)-(+)-R-methylbenzyl
t-Bu
4-Cl-Ph
4-MeO-Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
the rearrangement proved to be most facile with aromatic
amines (Table 3). Less nucleophilic amines such as carbam-
ates did not result in dihydropyrrole formation under these
reaction conditions, and the starting materials were recovered.
The 2-substituent on the cyclopropane ring (R1) was also
examined and found to lead to efficient dihydropyrrole
formation when aromatic groups were directly attached to
the cyclopropane ring (10l,m). However, the cyclopropane
derived from 4-phenyl-1-butene 6g exhibited greatly reduced
rates of reaction.
Me
Me
4-F-Ph
1-naphthyl Ph
phenethyl Ph
a Reaction performed in a sealed tube. b 55:45 mixture of the two
diastereomers isolated. c Mass balance was unreacted cyclopropane 6g.
If desired, trisubstituted 4-nitro-dihydropyrroles can also
be accessed. Cyclopropylcarboxaldehyde 13 was prepared
by LiAlH4 reduction of cyclopropylester 11 followed by IBX
oxidation of the resulting cyclopropylmethanol 12. Treatment
of aldehyde 13 with 4-chloroaniline afforded the desired
4-nitro-1-(4-chlorophenyl)-2-phenyl-2,3-dihydro-1H-pyr-
role (14) in 79% yield (Scheme 1).
1-Cyano-cyclopropyl ketones 9 rearranged with various
primary amines in an analogous fashion to those observed
with 1-nitro-cyclopropyl ketones. The desired 4-cyano-
dihydropyrroles 15 could be isolated in excellent yields
(Table 4).
The regiospecific nature of the dihydropyrrole formation
was confirmed by X-ray crystallography of dihydropyrrole
10b, illustrating the expected connectivity.21
The mechanism of the dihydropyrrole formation is thought
to proceed by initial nucleophilic ring opening of the
Å MS, resulting in isolation of the desired cyclopropane 9a
in 88% yield (Table 2). Somewhat inferior yields were
possible when the reaction was performed under solventless
or biphasic aqueous conditions. For comparison, the cyclo-
propanation reaction was performed with the corresponding
diazo compound 7a19 (method A), affording cyclopropane
9a in 95% yield (Table 2).
Other R-cyanoketone substrates were also found to un-
dergo cyclopropanation reactions in modest yields ranging
from 64 to 72% (Table 2). The pKa values of these substrates
are somewhat higher than that of benzoylacetonitrile, which
likely accounts for the observed decline in reaction yields.
With the doubly activated cyclopropanes in hand, dihy-
dropyrroles could be prepared by treatment of the E:Z
mixtures with a variety of primary amines in refluxing
toluene.20 In this manner, the corresponding 4-nitro-dihy-
dropyrroles 10 could be isolated in modest to excellent yields
from 1-nitro-1-cyclopropyl ketones 6 (Table 3).
Table 4. Preparation of 4-Cyano-dihydropyrroles from
1-Cyano-cyclopropyl Ketones and Amines
Modification of the ketone (R) had little influence on the
reaction yields when aniline was used (10a-d, Table 3).
Interestingly, when R was a cyclopropyl group, dihydro-
pyrroles 10d-e were obtained exclusively, resulting from
reaction with only the doubly activated cyclopropane (Table
3). Variation of the primary amine (R2) demonstrated that
(18) For recent reviews on hypervalent iodine chemistry, see: (a) Wirth,
T. A. Angew. Chem., Int. Ed. 2005, 44, 2-11. (b) Moriarty, R. M. J. Org.
Chem. 2005, 70, 2893-2903. (c) Mu¨ller, P. Acc. Chem. Res. 2004, 37,
243-251.
(19) For the synthesis of R-cyano-R-diazocarbonyls, see: Wurz, R. P.;
Lin, W.; Charette, A. B. Tetrahedron Lett. 2003, 44, 8845-8848.
(20) For examples of Lewis acid-catalyzed ring opening of cyclopropanes,
see: (a) Young, I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139-141. (b) Ganton,
M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554-8557. (c) Pohlhaus, P.
D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057-1059.
yield of 15
product
R
R1
R2
(%)
15a
15b
15c
15d
15e
styryl
Bn
Ph
Ph
Ph
Ph
Ph
4-Cl-Ph
4-Cl-Ph
Ph
4-Cl-Ph
Ph
82
91
97
99
77
Ph
Ph
4-MeO-Ph
Org. Lett., Vol. 7, No. 12, 2005
2315

Scheme 2
Scheme 3
In summary, the in situ-generated phenyliodonium ylide
cyclopropanation protocol was extended to include R-cy-
anoketone substrates. The doubly activated cyclopropanes
were then applied to the preparation of a series of highly
functionalized dihydropyrroles and pyrroles. The synthesis
is modular, allowing the preparation of a variety of analogues
in an efficient and expedient manner.
activated cyclopropane 16 at the 2-position, followed by
intramolecular condensation of intermediate 17 to yield the
dihydropyrrole 19 (Scheme 2). This would suggest that
aromatic substituents serve to make the 2-position more
electrophilic.14b Following this logic, the phenethyl-derived
cyclopropane 6g activates the cyclopropane to a lesser extent,
and the rates of dihydropyrrole formation decrease, leading
to reduced yields along with unreacted 6g (Table 3).
Alternatively, the mechanism could involve imine forma-
tion between the ketone and amine followed by ring opening.
1H NMR experiments show that the rate of consumption of
the E- and Z-diastereomers is similar, suggesting the former
mechanism. Moreover, only starting materials and products
can be observed during the reaction.
Acknowledgment. This research was supported by
NSERC/Merck Frosst Canada/Boehringer Ingelheim Indus-
trial Chair and the Universite´ de Montre´al. R.W. thanks
NSERC for a postgraduate (PGS B) scholarship.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Oxidation of the 4-nitro- and 4-cyano-dihydropyrroles to
pyrroles 20 could be successfully accomplished using DDQ
in refluxing toluene (Scheme 3).22 These pyrroles can also
serve as precursors to 4-amino pyrroles23 via reduction of
the nitro group through known literature methods.24
OL050442L
(23) See for example: (a) Rochais, C.; Lisowski, V.; Dallemagne, P.;
Rault, S. Tetrahedron 2004, 60, 2267-2270. (b) Wang, C. C. C.; Dervan,
P. B. J. Am. Chem. Soc. 2001, 123, 8657-8661.
(24) (a) Baird, E. E.; Dervan, P. B. J. Am. Chem. Soc. 1996, 118, 6141-
6146. (b) Almerico, A. M.; Cirrincione, G.; Aiello, E.; Dattolo, G. J.
Heterocycl. Chem. 1989, 26, 1631-1633. (c) Lee, M.; Coulter, D. M.; Lown,
J. W. J. Org. Chem. 1988, 53, 1855-1859. (d) Lown, J. W.; Krowicki, K.
J. Org. Chem. 1985, 50, 3774-3779. (e) Grehn, L.; Ragnarsson, U. J. Org.
Chem. 1981, 46, 3492-3497.
(21) See Supporting Information.
(22) (a) Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg, L. S. J. Am. Chem.
Soc. 2003, 125, 4692-4693. (b) Dell’Erba, C.; Mugnoli, A.; Novi,
M.; Pani, M.; Petrillo, G.; Tavani, C. Eur. J. Org. Chem. 2000, 903-
912.
2316
Org. Lett., Vol. 7, No. 12, 2005