Novel synthesis of bicycles with fused pyrrole, indole, oxazole, and imidazole rings

Article abstract of DOI:10.1021/jo0485334

Reactions of benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 10 and benzotriazol-1-yl(1H-indol-2-yl)methanone 11 with diverse ketones, isocyanates, and isothiocyanates in the presence of base afforded pyrrolo[1,2-c]oxazol-1-ones 1, oxazolo[3,4-a]indol-1-ones 2, pyrrolo[1,2-c]imidazoles 3, and imidazo[1,5-a]indoles 4 by a simple one-step procedure.

Full text of DOI:10.1021/jo0485334

Novel Synthesis of Bicycles with Fused
Pyrrole, Indole, Oxazole, and Imidazole
Rings
Alan R. Katritzky,* Sanjay K. Singh, and Sergey Bobrov
Center for Heterocyclic Compounds, University of Florida,
Department of Chemistry, Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received August 20, 2004
FIGURE 1. Pyrrolo[1,2-c]oxazol-1-ones 1, oxazolo[3,4-a]indol-
1-ones 2, pyrrolo[1,2-c]imidazoles 3, imidazo[1,5-a]indoles 4,
and imidazo[1,5-a]indoles 5.
Abstract: Reactions of benzotriazol-1-yl(1H-pyrrol-2-yl)meth-
anone 10 and benzotriazol-1-yl(1H-indol-2-yl)methanone 11
with diverse ketones, isocyanates, and isothiocyanates in the
presence of base afforded pyrrolo[1,2-c]oxazol-1-ones 1, ox-
azolo[3,4-a]indol-1-ones 2, pyrrolo[1,2-c]imidazoles 3, and
imidazo[1,5-a]indoles 4 by a simple one-step procedure.
SCHEME 1
Pyrrolo[1,2-c]imidazole and imidazo[1,5-a]indole deriva-
tives exhibit a wide spectrum of biological activity. Thus,
pyrrolo[1,2-c]imidazole-1,3-diones 3 (X ) O) are of inter-
est due to their antidiabetic1 and aldose reductase inhibi-
tory activity.2 Applications of imidazo[1,5-a]indoles 5 (X
) O, S) derivatives include their use as central nervous
depressants, analgesics,3 and 5-NT3 receptor antago-
nists.4 Various 3-thioxo-2,3-dihydroimidazo[1,5-a]indol-
1-ones 4 (X ) S) have been evaluated as light-dependent
TNF-R antagonists5 and antifungals.6 Several examples
of oxazolo[3,4-a]indol-1-ones 2 (R ) R1 ) Ar) from indolyl-
2-carboxylic acid chloride and substituted 4,4′-bisalky-
laminobenzophenones have all been reported by Fukui.7
No pyrrolo[1,2-c]oxazol-1-ones 1 have been recorded.
5,6,7-Trisubstituted pyrrolo[1,2-c]imidazole-1,3-diones
3 (X ) O) have previously been synthesized by cyclocon-
densation from the corresponding 2-pyrrolocarbonylami-
noacetates with carbonyl diimidazole.1,2 Papadopoulos8,9
employed isocyanates and alkali salts of pyrroles to first
generate the pyrrole-1-carboxamides 6, which were then
condensed with phosgene or thiophosgene in the presence
of a base to give pyrrolo[1,2-c]imidazoles 3 (X ) O; R )
Ph and X ) S; R ) H, Ph) (Scheme 1 (i)). He also treated
pyrrole-2-carboxamides 7 (R ) Ph, CO2Et) with phenyl
isocyanate in the presence of a base to give 3 (X ) O; R
) Ph) (Scheme 1 (ii)).10,11
SCHEME 2
condensed the appropriate indole-2-carboxylic acid 8 (R
) alk, allyl; R1 ) alk, alkoxy; R2 ) H; Z ) OH) or its
methyl ester (Z ) OMe) with isocyanate or isothiocyanate
in the presence of triethylamine at high temperatures
to give 4 (R1 ) alk, alkoxy; R2 ) H; X ) O, S) in moderate
to low yields (Scheme 2 (iii)). Unstable acid chloride 8 (R
) H; R1 ) 5-Cl; R2 ) 2-fluorophenyl; Z ) Cl) generated
in situ was condensed with urethane to give imidazo[1,5-
a]indole 4 (R ) Ph; R1 ) 5-Cl; R2 ) 2-fluorophenyl; X )
O) (Scheme 2 (iii)).12 Papadopoulos also reacted indole-
2-carbonyl compounds 8 (R1 ) R2 ) H; Z ) NHPh, OEt)
with phenyl isocyanate to form 4 (R1 ) R2 ) H; X ) O)
(Scheme 2 (iii)).14 Compound 4 (R1 ) R2 ) H; R ) H; X )
S) has also been prepared in moderate yield by reaction
of indole-2-carbonyl isothiocyanate 9 with sodium meth-
anethiolate (Scheme 2 (iv)).6,13
The synthetic strategies previously employed for com-
pounds of type 4 are depicted in Scheme 2. Carter5
The valuable and diverse biological properties of com-
pounds incorporating the pyrrolo[1,2-c]imidazole or imi-
dazo[1,5-a]indole ring system encouraged the develop-
ment of efficient methods for their preparation. The pyr-
rolo[1,2-c]oxazoles 1 (Figure 1) represent rare types of
fused heterocycles with a bridgehead nitrogen atom. This
work reports a novel synthetic method for the ring closure
to fused heterocyclic bicycles such as pyrrolo[1,2-c]oxazol-
1-ones 1, oxazolo[3,4-a]indol-1-ones 2, pyrrolo[1,2-c]imi-
(1) Ogawa, K.; Yamawaki, I.; Matsushita, Y. Jpn. Kokai. Patent JP
04297478; Chem. Abstr. 1992, 118, 234056.
(2) Yamawaki, I.; Matsushita, Y.; Asaka, N.; Ohmori, K.; Nomura,
N.; Ogawa, K. Eur. J. Med. Chem. 1993, 28, 481.
(3) Wright, W. B. US Patent 3,565, 902; Chem. Abstr. 1971, 75,
36033.
(4) Varasi, M.; Heidempergher, F.; Caccia, C.; Salvati, P. PCT Int.
Appl. WO 9532209; Chem Abstr. 1995, 124, 232456.
(5) Voss, M. E.; Carter, P. H.; Tebben, A. J.; Scherle, P. A.; Brown,
G. D.; Thompson, L. A.; Xu, M.; Lo, Y. C.; Yang, G.; Liu, R.-Q.;
Strzemienski, P.; Everlof, J. G.; Trzaskos, J. M.; Decicco, C. P. Bioorg.
Med. Chem. Lett. 2003, 13, 533.
(6) Kutschy, P.; Suchy, M.; Dzurilla, M.; Takasugi, M.; Kovacik, V.
Collect. Czech. Chem. Commun. 2000, 65, 1163.
(7) Fukui, T.; Kondo, Y. Jpn. Kokai. Patent JP 04223467, 1992.
(8) Papadopoulos, E. P. J. Org. Chem. 1966, 31, 3060.
(9) Papadopoulos, E. P. J. Org. Chem. 1973, 38, 667.
(10) Papadopoulos, E. P.; Habiby, H. S. J. Org. Chem. 1966, 31, 327.
(11) Papadopoulos, E. P. J. Org. Chem. 1972, 37, 351.
(12) Ishizumi, K.; Inaba, S.; Yamamoto, H.J. Org. Chem. 1973, 38,
2617.
(13) Kutschy, P.; Dzurilla, M.; Takasugi, M.; Sabova, A. Collect.
Czech. Chem. Commun. 1999, 64, 348.
(14) Papadopoulos, E. P.; Bedrosian, S. B. J. Org. Chem. 1968, 33,
4551.
10.1021/jo0485334 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/12/2004
J. Org. Chem. 2004, 69, 9313-9315
9313

TABLE 1. Preparation of Pyrrolo[1,2-c]oxazol-1-ones 1a-h and Oxazolo[3,4-a]indol-1-ones 2a-d
compd
R
R1
time (h)
product
yield (%)
mp (°C)
1
10
10
10
10
10
10
10
10
11
11
11
11
Me
Me
H
2
2
2
2
2
2
2
2
4
4
4
4
1a
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
2d
80
98
80
76
81
80
64
47
50
83
16
30a
52-53
oil
99-100
143-144
oil
39-41
76-77
oil
2
i-Pr
3
-(CH2)5-
p-Tol
-(CH2)4-
Et
2-furyl
Ph
Me
i-Pr
-(CH2)5-
p-Tol
4
H
5
6
Et
H
Me
Me
H
7
8
9
81-82
117-118
oil
10
11
12
H
143-144
a Product 12 was also isolated in 23% yield (see Scheme 4).
TABLE 2. Preparation of Pyrrolo[1,2-c]imidazoles 3a-g and Imidazo[1,5-a]indoles 4a-g
compd
R
X
time (h)
product
yield (%)
mp (°C)
1
10
10
10
10
10
10
10
11
11
11
11
11
11
11
Bn
S
10
10
10
10
4
3a
41
26
77
30
71
75
95
62
21
34
27
79
81
87
75-76
2
Ph
S
3b8,17
3c
138-139
60-61
3
Et
S
S
4
i-Pr
p-Tol
Bn
3d
3e
70-71
5
O
O
O
S
194-195
75-76
6
4
3f18
3g
7
Ph(Me)CH-
4
63-64
8
Bn
10
10
10
10
4
4a
136-137
200-201
110-112
185-186
158-159
153-154
105-106
9
Ph
S
4b
10
11
12
13
14
Et
S
4c5
4d6
4e
Me
S
p-Tol
O
O
O
Bn
4
4
4f
4g
Ph(Me)CH-
SCHEME 3
SCHEME 4
(Scheme 3, Table 1). These reaction conditions were ap-
plied to the reactions of 10 with various ketones and alde-
hydes to give pyrrolo[1,2-c]oxazoles 1a-h in high yields
(Scheme 3, Table 1). The reactions were monitored by
TLC, which indicated completion of the reaction within
2-4 h with compounds 1a-h being the sole products. As
shown in Table 1, the reaction is of wide scope and works
well with both enolizable and nonenolizable carbonyl
compounds.
This result offered an opportunity to extend the syn-
thetic method to oxazolo[3,4-a]indol-1-ones 2, which was
achieved by reactions of benzotriazol-1-yl(1H-indol-2-yl)-
methanone 11 with carbonyl compounds to give 2a-d
(Scheme 3, Table 1). In contrast to 10, compound 11,
under the same reaction conditions, reacted sluggishly
with ketones and aldehydes to afford 2a-d in lower yields
sometimes together with side products. For example, re-
action of 11 with p-tolualdehyde (entry 12, Table 1) pro-
duced 2d in 30% yield and compound 12 in 23% yield
(Scheme 4).
dazoles 3, and imidazo[1,5-a]indoles 4, by a simple one-
step procedure starting from readily available and stable
benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 10 and ben-
zotriazol-1-yl(1H-indol-2-yl)methanone 11 (Scheme 3).15,16
We found that the novel bicycle 1a, a rare representa-
tive of the pyrrolo[1,2-c]oxazole ring system, was formed
in low yield when compound 10 was treated with a stoi-
chiometric amount of triethylamine or guanidine hydro-
chloride in refluxing acetone. Efficient conversion to the
product 1a in 80% yield, however, occurred when 10 was
refluxed with the ketone in THF for 2 h in the presence
of a strong, nonnucleophilic base (3 equiv), such as DBU
(15) Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org.
Chem. 2003, 68, 5720.
(16) Katritzky, A. R.; Shobana, N.; Pernak, J.; Afridi, A. S.; Fan,
W. Q. Tetrahedron. 1992, 48, 7817.
(17) Budhram, R. S.; Uff, B. C.; Jones, R. A.; Jones, R. O. Org. Magn.
Reson. 1980, 13, 89.
The formation of 12 probably occurred as a result of
the opening of the lactam ring with the in situ generated
nucleophilic benzotriazole in the presence of the base.
(18) Noguchi, S.; Obayashi, M.; Imanishi, M.; Kawai, K. Jpn. Kokai.
Patent JP 47042790; Chem. Abstr. 1972, 78, 84249.
9314 J. Org. Chem., Vol. 69, No. 26, 2004

SCHEME 5
readily available benzotriazol-1-yl(1H-pyrrol-2-yl)metha-
none 10 and benzotriazol-1-yl(1H-indol-2-yl)methanone
11.
Experimental Section
General Procedure for the Reactions of Compound 10
or 11 with Ketones or Aldehydes. A solution of 10 or 11 (0.5
mmol) in freshly distilled dry THF (5 mL) was treated with 1.2
equiv of the appropriate ketone or aldehyde and 3 equiv of DBU
under an atmosphere of argon (except for the preparation of 1a
and 2a, where dry acetone was used as solvent). The reaction
mixture was refluxed for the periods shown in Table 1. The
cooled reaction mixture was concentrated under vacuum to give
a crude, usually brown resin that was refined by flash chroma-
tography on silica gel to give the products 1a-h and 2a-d.
General Procedure for the Reactions of Compound 10
or 11 with Isothiocyanates. Compound 10 or 11 (0.5 mmol)
was placed in a tube with triethylamine (5 equiv, 1 mL) and 3
equiv of the appropriate isothiocyanate were added. The tube
was sealed, and the reaction mixture was heated to 130 °C for
a period of 10 h. Triethylamine was removed under reduced
pressure, and the crude reaction mixture was subjected to flash
chromatography to give the compounds 3a-d and 4a-d.
General Procedure for the Reactions of Compound 10
or 11 with Isocyanates. A solution of 10 or 11 (0.5 mmol) in
freshly distilled dry THF (5 mL) was treated with 1.2 equiv of
the appropriate isocyanate and 3 equiv of DBU under an
atmosphere of argon. The mixture was heated under reflux for
5-7 h and monitored by TLC. The cooled solution was concen-
trated under vacuum, and the crude residue was refined by flash
chromatography over silica gel (hexanes/ethyl acetate 45:5) to
give compounds 3e-g and 4e-g.
However, no such ring opening was observed in the
reaction of 10 with p-tolualdehyde (entry 6, Table 1),
which resulted in the formation of 1d in 76% yield.
This methodology was extended to synthesize pyrrolo-
[1,2-c]imidazoles 3a-g and imidazo[1,5-a]indoles 4a-g
by treatment of 10 or 11, respectively, with isocyanates
or isothiocyanates (Scheme 5, Table 2). Reactions of 10
or 11 with isocyanates in THF under reflux for 4 h in
the presence of DBU gave high yields of pyrrolo[1,2-c]-
imidazoles 3e-g and imidazo[1,5-a]indoles 4e-g. The
same condition when applied to the reactions of 10 or 11
with isothiocyanates gave low yields of 3a-d and 4a-d
(Scheme 5, Table 2). Optimally, the preparation of 3a-d
and 4a-d was achieved in the presence of triethylamine
in a sealed tube at 130 °C over a period of 10 h (Scheme
5, Table 2). Employing the benzotriazole moiety as
leaving group for the synthesis of 3a-g and 4a-g from
10 and 11 provides an alternative to the routes already
available for their synthesis.1,2,8-11
Supporting Information Available: Characterization
data for compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, we have developed novel and convenient
methods for the syntheses of derivatives of pyrrolo[1,2-
c]imidazole, imidazo[1,5-a]indole, oxazolo[3,4-a]indole,
and pyrrolo[1,2-c]oxazole ring systems starting from
JO0485334
J. Org. Chem, Vol. 69, No. 26, 2004 9315