Photoinduced intramolecular addition of 3-acyl-2-haloindoles to alkenes

Article abstract of DOI:10.1021/ol901498f

1,2-Fused indoles and pyrroles were prepared via an efficient intmolecular photoaddition reaction of 1-(ωalkenyl)-2 haloindole-3-carbaldehydes and 1-(ωalkenyl)-2 chloropyrrole-3-carbaldehydes. The presence of an acyl group was necessary for the photocycizntion reactions. The halogen-atom retained exo and endo cyclization prodects were generally prodeced with result similar to those of atom transfer cyclization reaction. in contrast, unsaturated cyclization prodects were obtained in the photoreactions of substrates having monthyl groups on vinyl group.

Full text of DOI:10.1021/ol901498f

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3902-3905
Photoinduced Intramolecular Addition of
3-Acyl-2-haloindoles to Alkenes
Shen-Ci Lu, Xiao-Yong Duan, Zong-Jun Shi, Bing Li, Yu-Wei Ren, Wei Zhang,*
Yong-Hui Zhang, and Zhi-Feng Tu
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
zhang_wei6275@yahoo.com
Received July 1, 2009
ABSTRACT
1,2-Fused indoles and pyrroles were prepared via an efficient intramolecular photoaddition reaction of 1-(ω-alkenyl)-2-haloindole-3-carbaldehydes
and 1-(ω-alkenyl)-2-chloropyrrole-3-carbaldehydes. The presence of an acyl group was necessary for the photocyclization reactions. The halogen-
atom-retained exo- and endo-cyclization products were generally produced with results similar to those of an atom-transfer cyclization reaction.
In contrast, unsaturated cyclization products were obtained in the photoreaction of substrates having methyl groups on the vinyl group.
The photochemistry of R,ꢀ-unsaturated carbonyl compounds
has long been the subject of extensive investigation for both
mechanistic revelation and synthetic application.1 Among
them, the light-induced [2 + 2] reaction of an excited-state
R,ꢀ-unsaturated ketone to a ground-state alkene is a highly
useful reaction in organic synthesis since two new carbon-
carbon bonds are formed and a maximum of four new
stereogenic centers are introduced into the molecule in the
process.2 The de Mayo reaction has provided an efficient
approach to the synthesis of bicyclic ring systems by the
photocycloaddition/retro-aldol fragmentation reactions of
ꢀ-diketones with alkenes.3 Winkler and his collaborators have
established the utility of the intramolecular photocycload-
dition/retro-Mannich fragmentation of ꢀ-acylamino enones
with alkenes in the synthesis of azabicyclic ring systems.4
We have long been interested in the inter- and intramolecular
photoreactions of ꢀ-acyl-substituted heterocycles with alk-
enes in order to develop a new method for the synthesis of
polycyclic heterocycles.5 Recently, we found that irradiation
of 2-chloro-1-(ω-alkenyl)indole-3-carbaldehyde (1) could
afford high yields of cyclization products 2 and 3 with
retained chlorine atoms (Scheme 1), but no reaction could
Scheme 1. Photoinduced Intramolecular Addition Reactions
(1) (a) Ninomiya, I.; Naito, T. Photochemical Synthesis; Academic Press:
New York, 1989. (b) De Keukeleire, D.; He, S.-L. Chem. ReV. 1993, 93,
359. (c) Schutt, L.; Bunce, N. J. CRC Handbook of Organic Photochemistry
and Photobiology, 2nd ed.; CRC Press: Boca Raton, 2004.
(2) (a) Crimmins, M. T. Chem. ReV. 1988, 88, 1453. (b) Andrew, D.;
Hastings, D. J.; Oldroyd, D. L.; Rudolph, A.; Weedon, A. C.; Wong, D. F.;
Zhang, B. Pure. Appl. Chem. 1992, 64, 1327. (c) Schuster, D. I.; Lem, G.;
Kaprinidis, N. A. Chem. ReV. 1993, 93, 3. (d) Crimmins, M. T.; Reinhold,
T. L. Organic Reactions: John Wiley & Sons, Inc.: Hoboken, NJ, 1993;
Vol. 44, 624 pp.
be detected after a long irradiation of the reactant without a
chlorine atom, 1-(but-3-enyl)indole-3-carbaldehyde, in ac-
etone, although it was reported that [2 + 2] products could
be obtained in the photoreaction of 1-benzoylindole-3-
carbaldehyde with vinyl acetate6a and in the intramolecular
(3) (a) de Mayo, P. Pure. Appl. Chem. 1964, 9, 597. (b) de Mayo, P.
Acc. Chem. Res. 1971, 4, 41. (c) Oppolzer, W. Acc. Chem. Res. 1982, 15,
135.
10.1021/ol901498f CCC: $40.75
Published on Web 07/30/2009
 2009 American Chemical Society

photoreaction of 1-alkenoylindoles.6b Therefore, the presence
of a chlorine atom on the R-position of the indole ring is
important for both driving the photoreaction of 1a and
presenting new cyclization products which are different from
that obtained in the intermolecular photoreaction of 1-ben-
zoylindole-3-carbaldehyde with vinyl acetate.6a
secondary radical and chlorine atom. In comparison, the
reaction was more efficient in acetone than in other solvents
as shown in Table 1. Therefore, acetone was selected as the
solvent in all other photoreactions of 1-(ω-alkenyl)-2-
haloindoles 1a-o (Table 2). All products were fully identi-
1
fied by H, 13C NMR and MS, and the structures of 2b, 3b
Several methods have been reported for the synthesis of
1,2-fused indoles. For example, SmI2-promoted reductive
cyclization of indole dialdehydes,7a Fenton agent-mediated
oxidative cyclization of 1-(ω-iodoalkyl)indole,7b R2BH-
mediated reductive cyclization of 1-(ω-alkenyl)indoles,7c
sodium benzenesulfinate-copper acetate catalyzed radical
cyclization of 1-(ω-allylsulfonylalkyl)indole,7d and Bu3SnH-
AIBN-mediated radical cyclization of 1-(ω-iodoalkyl)-
indoles.7e However, these reactions required the use of
metallic catalysts, especially the tributyltin hydride, and the
yields were not satisfactory and always accompanied by
noncyclization reactions. Therefore, a more effective and
metal-free process is desirable.
We first investigated the effect of solvent on the photo-
reaction of 1-(but-3-enyl)-2-chloroindole-3-carbaldehyde (1a)
(Table 1). It was found that 1a could be reacted in all selected
solvents to afford two cyclization products. The conversions
of 1a and the yields and ratio of the products depended on
solvents. In methylene dichloride and acetone, two chlorine-
retained products 2a and 3a were obtained in excellent
overall yields; in acetonitrile or ethyl acetate, an unsaturated
compound 4a was formed in addition to 2a; in methanol, a
new product 5a was produced, which was obviously derived
from the coupling of carbocation with methanol, and only
minor chlorine-retained product 2a was separated. The results
indicated that secondary carbocation was formed in more
polar solvents probably from electron transfer between the
were further confirmed by X-ray crystallography (Figure 1).
Compound 2b (CCDC 695497) forms a monoclinic unit cell
that belongs to the P2(1)/c space group with the unit cell
parameters a ) 9.601(4) Å, b ) 10.575(5) Å, c ) 12.022(5)
Å, ꢀ ) 92.744(7)°, V ) 1219.3(10) Å3. Compound 3b
(CCDC 695496) forms a monoclinic unit cell that belongs
to the P2(1)/c space group with the unit cell parameters a )
9.2370(7) Å, b ) 15.9270(12) Å, c ) 7.9660(6) Å, ꢀ )
93.3640(10)°, V ) 1169.92(15) Å3.
It is noticeable from Table 2 that the photoreactions of
1-(ω-alkenyl)-2-halo-3-acylindoles (1a,b,d-l) exclusively
led to the cyclization products when these substrates were
irradiated in the deaerated acetone solution at ambient
temperature except 1c. Two halogen-retained products were
generally produced in each photoreaction, which was much
like the result of an atom-transfer cyclization reaction.8 The
advantages of this reaction over Bu3SnH-mediated cyclization
of 1-(ω-alkenyl)-2-haloindoles7e are not only the high yields
but also the halogen-atom retention in the products which
allows for further functionalization. However, it was found
that 1-(but-3-enyl)-2-chloro-3-methylindole (1n) and ethyl
1-(but-3-enyl)-2-chloroindole-3-carboxylate (1o), both of
which had no acyl groups on indoles, could not afford the
cyclization products under similar conditions. It could be
deduced that the formyl and acetyl groups were necessary
for the photocyclization reaction of 1-(ω-alkenyl)-2-haloin-
doles. Since both a halogen is needed on the R-position and
an acyl group on the ꢀ-position of the indole ring, it could
be proposed that the reaction mechanism of 3-acyl-2-
haloindoles with alkenes was much like that of the [2 + 2]
photoreaction of R,ꢀ-unsaturated enones with alkenes.2c,4b
The Michael-like coupling of the ꢀ-carbon of the diradical
in excited 3-acylindoles with double bonds of alkenes gave
new diradicals (Scheme 2). Subsequently, the halogen atom
transfer occurred from the diradical before the coupling of
diradical to form cyclobutane. Comparatively, it is difficult
for 3-methylindole and ethyl indole-3-carboxylate to become
Table 1. Photoreaction of 1a in Different Solventsa
(4) (a) Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. ReV. 1995, 95,
2003. (b) Winkler, J. D.; Ragains, J. R. Org. Lett. 2006, 8, 4031. (c) Ragains,
J. R.; Winkler, J. D. Org. Lett. 2006, 8, 4437.
yieldc (%)
(5) (a) Wang, C.-L.; Zhang, W.; Lu, S.-C.; Wu, J.-F.; Shi, Z.-J. Chem.
Commun. 2008, 5176. (b) Lu, S.-C.; Zhang, W.; Pan, J.-H.; Zhang, J.
Synthesis 2008, 10, 1517.
entry solvent time (h) convnb (%) 5-exo 6-endo 6-endo
(6) (a) Ikeda, M.; Ohno, K.; Mohri, S.; Takahashi, M.; Tamura, Y.
J. Chem. Soc., Perkin Trans. 1 1984, 405. (b) Oldroyd, D. L.; Weedon,
A. C. Chem. Commun. 1992, 1491.
1
2
3
4
5
CH2Cl2
Me2CO
AcOEt
MeCN
MeOH
4
4
8
8
8
81
99
78
76
81
2a 48 3a 39
2a 53 3a 43
2a 72
4a 14
4a 48
5a 88
(7) (a) Lin, S.-C.; Yang, F.-D.; Shiue, J. S.; Yang, S.-M.; Fang, J.-M.
J. Org. Chem. 1998, 63, 2909. (b) Artis, D. R.; Cho, I. S.; Figueroa, S. J.;
Muchowski, J. M. J. Org. Chem. 1994, 59, 2456. (c) Ishikura, M.; Idaa,
W.; Yanada, K. Tetrahedron 2006, 62, 1015. (d) Wang, S.-F.; Chuang,
C.-P.; Lee, W.-H. Tetrahedron 1999, 55, 6109. (e) Dobbs, A. P.; Jones,
K.; Veal, K. T. Tetrahedron Lett. 1995, 36, 4857.
2a 38
2a
6
a 0.3 mmol of 1a was dissolved in different solvents (20 mL). The
solution was irradiated at λ g 300 nm with a high-pressure mercury lamp
(500 W) under argon atmosphere at ambient temperature. b Conversion was
calculated on the basis of 1a. c Yield of isolated product based on consumed
1a.
(8) (a) Lin, H.-H.; Chang, W.-S.; Luo, S.-Y.; Sha, C.-K. Org. Lett. 2004,
19, 3289. (b) Rey, V.; Pierini, A. B.; Penenory, A. B. J. Org. Chem. 2009,
74, 1223. (c) Sanz, M.; Douhal, A. Chem. Phys. Lett. 2005, 435. (d) Cheung,
E.; Netherton, M. R.; Scheffer, J. R.; Trotter, J. Org. Lett. 2000, 1, 77.
Org. Lett., Vol. 11, No. 17, 2009
3903

Table 2. Photoreaction of N-(ω-Alkenyl)-2-halo-3-acylindolesa
entry
substrate
R1
R2
R3
X
n
time (h)
convnb (%)
yieldc (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
CHO
CHO
CHO
COCH3
COCH3
CHO
CHO
CHO
CHO
COCH3
CHO
COCH3
CHO
CH3
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
CH3
CH3
CH3
H
H
H
Cl
Cl
Cl
Cl
Cl
Br
Br
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
1
2
3
1
2
1
2
1
1
1
1
1
0
1
1
4
6
6
6
5
6
6
6
6
6
6
6
9
9
9
99
98
87
96
95
89
92
97
85
92
95
90
0
2a
2b
2c
2d
2e
2f
2g
2h
2h
2j
53
58
32
56
80
51
71
54
58
34
33
37
3a
3b
2c
3d
3e
3f
3g
3h
3h
3j
43
36
27
39
16
40
21
37
33
61
24
32
6
20
9
10
11
12
13
14
15
2k
2l
3k
3l
4k
4l
31
23
H
H
H
H
0
0
CO2Et
a 0.3 mmol of 1a-o was dissolved in acetone (20 mL). The solution was irradiated at λ g 300 nm with a high-pressure mercury lamp (500 W) under
argon atmosphere at ambient temperature. b Conversion was calculated on the basis of substrate. c Yield of isolated product based on consumed substrate.
diradicals. Thus, no reaction took place in the irradiation of
the two substances under the same conditions.
The length of the chain between the indolyl and vinyl
groups and the substitutents on the vinyl group had great
obtained in high yields. However, a noncyclization reduction
product 6 was produced when the chain length further
extended in 1c in addition to the normal cyclization products.
Although the photoreaction of 1a-g afforded mainly the
halogen-atom-retained cyclization products, the photoreaction
of 1h-l gave only unsaturated cyclization products which
were derived from deprotonation of carbocation intermedi-
ates. It could be proposed that the methyl groups linked to
a double bond directed the coupling of ꢀ-carbon of the
diradical in excited 3-acylindole only with a small hindered
carbon of a double bond, leading to more stable tertiary
radicals; the subsequent dehalogenation and electron transfer
between the tertiary radicals and halogen atoms occurred to
give the tertiary carbocations (Scheme 2). Therefore, only
unsaturated cyclization products were produced from 1h-l.
Figure 1. (a) X-ray crystal structure of 2b. (b) X-ray crystal
structure of 3b.
In order to expand the scope of this photoinduced addition
reaction, we further investigated the photoreactions of N-(ω-
alkenyl)-2-chloropyrrole-3-carbaldehydes in acetone. As
shown in Table 3, the results of photoreactions were very
similar to those of N-(ω-alkenyl)-2-haloindole-3-carbalde-
hydes. The photoinduced intramolecular addition reactions
afforded chlorine-retained exo- and endo-cyclization products
effects on the photoaddition reactions of 1a-c,m as shown
in Table 2. No cyclization product was detected in the
photoreaction of 1-allyl-2-chloroindole-3-carbaldehyde (1m).
When the chain length was extended in 1a-c, the chlorine-
atom-retained exo- and endo-cyclization products were
3904
Org. Lett., Vol. 11, No. 17, 2009

Scheme 2
.
Plausible Photoreaction Mechanism of
Table 3. Photoreaction of N-(ω-Alkenyl)-2-chloropyrrole-3-
1-(Alkenyl)-2-haloindole-3-carbaldehydes in Acetone
carbaldehydesa
entry substrate time (h) convnb (%)
yieldc (%)
1
2
3
1p
1q
1r
4
4
4
98
98
96
2p 63 3p 32
2q 81 3q 16
2r
6
3r 83
a 0.3 mmol of 1p-r was dissolved in acetone (20 mL). The solution
was irradiated at λ g 300 nm with a high-pressure mercury lamp (500 W)
under argon atmosphere at ambient temperature. b Conversion was calculated
on the basis of substrate. c Yield of isolated product based on consumed
substrate.
afforded the halogen-atom-retained exo- and endo-cyclization
products in excellent yields, which were much like the results
of an atom-transfer cyclization reaction. In contrast, the
photoreactions of substrates having methyl groups on a vinyl
group gave only unsaturated cyclization products. Further
investigations into the detailed mechanism is currently
underway in our laboratory.
Acknowledgment. We are grateful to the National Nature
Science Foundation of China (Grant No. 20872056 and
J0730425) for financial support. We also thank two col-
leagues, Prof. Wei Yu and Dr. Jing Wang, in the Department
of Chemistry, Lanzhou University, for helpful discussions.
from 1p-q and two unsaturated cyclization products from
1r in high yields.
Supporting Information Available: Experimental pro-
cedures, solubility data, spectroscopic data, 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed an efficient method for
the annulation of indolecarbaldehydes and pyrrolecarbalde-
hydes by the photoinduced intramolecular additions of
N-alkenyl-2-haloindole-3-carbaldehydes and N-alkenyl-2-
chloropyrrole-3-carbaldehydes in acetone. The photoreactions
OL901498F
Org. Lett., Vol. 11, No. 17, 2009
3905