Photoinduced chlorine atom-transfer cyclization/photohydrolysis of 3-acyl-2-chloro-N-(ω-phenylalkynyl)pyrroles: A one-pot synthesis of benzoyl-substituted fused pyrroles

Article abstract of DOI:10.1039/c1ob05954h

A one-pot synthesis of benzoyl-substituted fused pyrroles or indoles in moderate to high yields has been achieved by the photocyclization/ photohydrolysis reactions of N-(ω-phenylalkynyl)-2-chloropyrrole-3- carbaldehydes or 3-acyl-N-(ω-phenylbutynyl)-2-haloindoles in wet acetone. The formation of all these products could be inferred by a two-step reactions, namely, photoinduced chlorine atom-transfer cyclization and subsequent photohydrolysis.

Full text of DOI:10.1039/c1ob05954h

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Photoinduced chlorine atom-transfer cyclization/photohydrolysis of
3-acyl-2-chloro-N-(x-phenylalkynyl)pyrroles: a one-pot synthesis
of benzoyl-substituted fused pyrroles†‡
Shen-Ci Lu, Wei-Xia Wang, Pan-Liang Gao, Wei Zhang* and Zhi-Feng Tu
Received 13th June 2011, Accepted 26th September 2011
DOI: 10.1039/c1ob05954h
A one-pot synthesis of benzoyl-substituted fused pyrroles
or indoles in moderate to high yields has been achieved
by the photocyclization/photohydrolysis reactions of N-(x-
phenylalkynyl)-2-chloropyrrole-3-carbaldehydes or 3-acyl-
N-(x-phenylbutynyl)-2-haloindoles in wet acetone. The for-
mation of all these products could be inferred by a two-
step reactions, namely, photoinduced chlorine atom-transfer
cyclization and subsequent photohydrolysis.
The transformation of alkynes to ketones is of prime interest
considering the wide availability of alkynyl substrates and the
fundamental importance of the carbonyl motif in modern organic
synthesis.1 The metal-catalyzed hydration reaction of alkynes is the
generally used method and has been studied extensively in recent
years (Scheme 1, eq 1).2 Besides the metal-catalyzed hydration of
alkynes, the addition of electrophilic agents such as alkyl cations
Scheme 1 Conventional synthesis of the ketones.
tion reactions of 2-chloro-1-(w-alkenyl)indole-3-carbaldehyde.6
to alkynes and subsequent capture of the vinyl cation by water has
also supplied another useful method for the synthesis of a-alkyl-
substituted ketones (Scheme 1, eq 2).3 The photochemical reaction
of aryl halides with pinacolone potassium enolate in liquid NH3 via
an SRN1 mechanism (Scheme 1, eq 3)4 or with enamines or silyl enol
ethers by an SN1 mechanism (Scheme 1, eq 4)5 has also afforded
two methods for the synthesis of aryl ketones. In our previous
paper, we reported photoinduced halogen atom-transfer cycliza-
Herein, we present a cascade process involving photoinduced
chlorine atom-transfer cyclization of N-(w-phenylalkynyl)-2-
chloropyrrole-3-carbaldehydes and 3-acyl-N-(w-phenylbutynyl)-
2-chloroindoles and subsequent photohydrolysis of intermediate
products, a-chlorostilbenoids, in acetone–water to give an access
to various benzoyl substituted cyclic compounds (Scheme 2). Pho-
tohydrolysis of a-chlorostilbenoids has not been reported before
in the literature, but the photoalcoholysis of a-chlorostilbene has
been extensively studied.7
State Key Laboratory of Applied Organic Chemistry, Lanzhou Univer-
sity, Lanzhou, China. E-mail: zhangwei6275@lzu.edu.cn; Fax:
+86(931)8625657; Tel: +86+ 15101212168
† Electronic supplementary information (ESI) available. CCDC reference
number 807627. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob05954h
‡ Photochemical reaction; general procedure: 1a (0.160 g, 0.5 mmol) was
dissolved in 25 mL acetone containing 0.1 mL H2O. The solution was
deaerated by bubbling Ar for 30 min and irradiated at l > 300 nm with
a medium-pressure mercury lamp (500 W) at ambient temperature. The
progress of the reaction was monitored by TLC at regular intervals. After
the solvent was removed under reduced pressure, the residue was separated
by column chromatography on silica gel eluted by hexane–ethyl acetate 6 : 1
(v/v) to afford product 2a.
Scheme 2 Photoinduced chlorine atom-transfer cyclization/photohy-
drolysis of N-(w-phenylalkynyl)-2-chloropyrrole-5-carbaldehydes.
We first investigated the effect of solvents on the photoreaction
of 3,5-dichloro-1-(4-phenylbut-3-ynyl)pyrrole-2,4-dicarbaldehyde
(1a) (Table 1). It was found that the photoreaction of 1a could
afford cyclization product 2a in all selected wet solvents. The
conversion of 1a and the yield of the product 2a depended on
the solvent. In wet acetone, the conversion of 1a and the yield
Compound 2d (CCDC 807627), C16H11Cl2NO3 Mr = 336.16, monoclinic,
˚
˚
˚
space group P21/n, a = 6.393(13) A, b = 9.37(2) A, c = 26.44(6) A,
◦
3
b = 92.38(2) , V = 1582(6) A . colorless block, Dc = 1.411 g cm-3,
˚
T = 296(2) K, Z = 4, m(MoKa) = 0.71073 mm-1, 2qmax = 25.10◦,
7140 reflections measured, 2793 unique, (Rint = 0.1683) which were used
in all calculations. The final wR(F2) was 0.2454 (for all data), R1
=
0.3128.
232 | Org. Biomol. Chem., 2012, 10, 232–235
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Table 1 Photoreaction of 1a in different solventsa
Entry
Solvent
Time [h]
Convn [%]b
Yield [%]c
1
2
3
wet CH2Cl2
wet MeCN
wet Me2CO
8
8
8
83
83
98
78
80
94
Fig. 1 X-Ray crystal structure of 2d.
a 0.5 mmol 1a was dissolved in different solvents (25 mL). The solution
was irradiated at l > 300 nm with a medium-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.
on the phenyl ring (e.g., R1 = CH3, OCH3) in 1b–c (Table 2,
entries 2–3) had no great influence on the reactions. On the
other hand, the reactions turned slow when the substrates (1h–
j) contained only one formyl group (R2 = CHO) and two chlorine
atom (R4 = R5 = Cl, R4 = H). The substrates with a short tether
(1c, and 1d, n = 1) reacted more easily to form five-numbered
rings (2c, and 2d) than those with a longer tether (1e, and 1f,
n = 2) to form six-numbered rings (2e, and 2f). It was no-
ticed that both 3,5-dichloro-2,4-dihydroxymethyl-1-(4-phenylbut-
3-ynyl)pyrrole (1k) and dimethyl 3,5-dichloro-1-(4-phenylbut-3-
ynyl)pyrrole-2,4-dicarboxylate (1l), in which the formyl groups
were replaced by hydroxymethyl groups or ethoxycarbonyl groups,
could not react under the same conditions. Meanwhile, we also
examined the photoreaction of a substrate without a 5-chlorine
atom, 1-(4-phenylpent-3-ynyl)pyrrole-2-carbaldehyde (1m), and
also found that no reaction took place after prolonged irradiation
(24 h). Thus, it could be deduced that the formyl group and 2- or
5-chlorine atom were necessary for the photocyclization reaction
of 5-chloro-1-(w-phenylalkynyl)pyrrole-2-carbaldehydes.
of the product 2a were relatively higher than those obtained in
wet methylene dichloride or wet acetonitrile. This result may be
derived from the sensitization effect of acetone to 1a. Therefore,
acetone was selected as the solvent in all the photoreactions.
In order to investigate the effects of the substrate structures on
the photoreaction efficiency, other similar substrates 5-chloro-
1-(w-phenylalkynyl)pyrrole-2-carbaldehydes 1b–j with different
substituents on the phenyl group or pyrrole and different tethers
were synthesized and examined under the same photoreaction
conditions. All of the substrates except 1k and 1l could give
products 2 in high yields as shown in Table 2. The products were
fully identified by 1H, 13C NMR and HRMS, and the structure of
2d was further confirmed by X-ray crystallography (Fig. 1).
It can be seen in Table 2 that substituents on the phenyl ring or
pyrrole and tethers all had some influence on the photoreaction
efficiency of the substrates 1. Electron-withdrawing groups on
the phenyl ring (e.g., R1 = Cl, or R2 = CO2CH3) in 1d and 1g
(Table 2, entries 4 and 7) retarded the reactions and decreased the
yield of the products 2; comparatively, electron-donating groups
Since the photoreactions of aryl aldehydes were generally
derived from long-lived triplets, especially after the acetone sensi-
tization, it could be proposed that the reaction of triplet 3-formyl-
2-chloropyrroles or 5-formyl-2-chloropyrroles with alkynes was
Table 2 Photoreaction of 3,5-dichloro-1-(w-phenylalkynyl)pyrrole-2,4-dicarbaldehydes and 4,5-dichloro-1-(w-phenylalkynyl)pyrrole-2-carbaldehydesa
Entry
Substrate
n
R1
R2
R3
R4
R5
Time [h]
Convn [%]b
Product
Yield [%]c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1
1
1
1
2
2
2
1
1
1
1
1
H
H
H
H
H
H
H
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CH2OH
CO2CH3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
Cl
Cl
CHO
CHO
CHO
CHO
CHO
CHO
CHO
Cl
Cl
Cl
CH2OH
CO2CH3
8
8
8
8
8
8
8
10
10
10
16
16
98
98
99
95
90
84
86
96
98
99
0
2a
2b
2c
2d
2e
2f
2g
2h
2i
94
96
98
90
88
80
84
92
93
95
0
CH3
OCH3
Cl
OCH3
Cl
H
H
CH3
OCH3
H
CO2CH3
H
H
H
H
H
9
10
11
12
1j
1k
1l
2j
2k
2l
H
0
0
a 1a–l (0.5 mmol) was dissolved in acetone (25 mL) containing H2O (0.1 mL). The solution was irradiated at l > 300 nm with a medium-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.
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Table 3 Photoreaction of 3-acyl-2-halo-1-(4-phenylbut-3-ynyl)indolesa
much like that of the photoreaction of triplet a,b-unsaturated
enones (a diradical) with alkenes as proposed in Winkler’s8
and our previous papers.5 The Michael-like coupling of the b-
carbon of the diradical in excited 3-formylpyrroles with the
triple bonds of the alkyne gave new diradicals; subsequently,
the chlorine atom-transfer occurred from the diradicals to afford
the cyclization products like 3 before the coupling of diradicals
to form cyclobutanes (Scheme 3). Comparatively, it is difficult
for 2,4-dihydroxymethylpyrrole (1k) and dimethyl pyrrole-2,4-
dicarboxylate (1l) to become diradicals. Thus, no reaction took
place in the irradiation of these two substances under the same
conditions.
Entry Substrate R1
R6 X Time [h] Convn [%]b Product Yield [%]c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
H
CH3
H
H
Cl 10
Cl 10
96
96
98
92
92
94
82
86
5a
5b
5c
5d
5e
5f
82
83
86
78
80
83
76
77
OCH3 H Cl 10
CH3 Cl 12
CH3 CH3 Cl 12
H
Cl
H
CH3
CH3 Cl 12
H
H
4g
4h
Br 18
Br 18
5a
5b
a 4a–h (0.5 mmol) was dissolved in acetone (25 mL) containing H2O (0.1
mL). The solution was irradiated at l > 300 nm with a medium-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.
the formation of these chlorine-retained products 6 and 7 that
our proposal of chlorine atom-transfer photocyclization to form
the intermediate “chloro-stilbenoids” might be right (Scheme
3). Meanwhile, the photoinduced electron transfer mechanism
between 2-chloroindole-3-carbaldehyde and phenylacetylene
could be excluded from the formation of 6 in wet acetone
because no stilbenoid cation, which could also be generated in the
photoinduced electron transfer reaction, was trapped by water to
produce 5i (Scheme 4).
Scheme 3 Photoinduced chlorine atom-transfer cyclization reactions.
In order to expand the scope of this photoinduced chlorine
atom-transfer cyclization/photohydrolysis reaction, we further
investigated the photoreactions of 3-acyl-2-halo-1-(4-phenylbut-
3-ynyl)indoles (4a–h) in wet acetone. As shown in Table 3, the
results of these photoreactions were very similar to those of 3,5-
dichloro-1-(w-phenylalkynyl)pyrrole-2,4-dicarbaldehydes (1a–g)
and
4,5-dichloro-1-(w-phenylalkynyl)pyrrole-2-carbaldehydes
To verify that the ketone was formed from the photohydrolysis
of intermediate a-chlorostilbenoid (3), we carried the photore-
action of 1a in dry acetone and found that the intermediate
3 was readily separated as the main product and it could be
further converted to 2a after irradiation in wet acetone (Scheme 6).
Thus we are certain that all these benzoyl-substituted bicyclic or
tricyclic products (2a–j and 5a–f) were derived from the photolysis
of the intermediate a-chlorostilbenoids like 3 via photoinduced
heterolysis of C–Cl bond and the trapping of the stilbenoid cations
by water.
From the above discussion, a plausible mechanistic rationale
to account for the formation of 2a was proposed as shown
in Scheme 7. Firstly, the chlorine atom-transfer cyclization
occurred from triplet 3,5-dichloro-1-(4-phenylbut-3-ynyl)pyrrole-
2,4-dicarbaldehyde (1a) to give a-chlorostilbenoid 3; then a cation
(1h–j). Both 3-formyl- and 3-acetyl-2-chloro-1-(4-phenylbut-3-
ynyl)indoles afforded the corresponding products in moderate to
high yields. Comparatively, 2-chloroindole-3-carbaldehydes (4a,
and 4b) reacted more easily with the tethered phenylacetylene
to form photocyclization/photohydrolysis products (5a and 5b)
than 2-bromoindole-3-carbaldehydes (4g, and 4h). While another
substrate 4i with a longer tether (n = 2) behaved differently, no
desired product 5i was separated instead product 6 was formed
(Scheme 4). Obviously, this product was derived from a 6p
electrocyclization reaction of the intermediate a-chlorostilbenoid
via deacylation before photohydrolysis. We then examined the
photoreaction of 4b (n = 1) and 4i (n = 2) in dry acetone and found
both of them could give the deacetylative cyclization product 6
and 7 as main products (Scheme 5). It could be deduced from
Scheme 4 The photoreaction of 3-acetyl-2-chloro-1-(5-phenylpent-4-ynyl) indole (4i) in wet acetone.
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Scheme 5 Photoreaction of 3-acetyl-2-chloro-1-(5-phenylbut-4-ynyl) indole (4b).
tion of N-(w-phenylalkynyl)-5-chloropyrrole-2-carbaldehydes
or 3-acyl-N-(w-phenylbutynyl)-2-chloroindoles and subsequent
photohydrolysis.
We thank the National Natural Science Foundation of China
(Grant No. 20872056 and J0730425) and the award “Young
Scholar of Distinction of Lanzhou University” for financial
support.
Scheme 6 Photoinduced chlorine atom-transfer cyclization/photohy-
drolysis reactions.
Notes and references
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Scheme 7 A plausible photoreaction mechanism of 2-chloro-N-(2-
phenylbutynyl)indole-3-carbaldehydes in acetone.
was produced from this intermediate by photoinduced heterolysis
of C–Cl and the trapping of the stilbenoid cation by water to afford
product 2a.
In summary, a one-pot synthesis of benzoyl-substituted fused
pyrroles and indoles in moderate to high yields has been
achieved by the photocyclization/photohydrolysis reactions of
N-(w-phenylalkynyl)-5-chloropyrrole-2-carbaldehydes or 3-acyl-
2-chloro-N-(w-phenylbutynyl)indoles in wet acetone. The for-
mation of all these products could be inferred by a two-step
reaction, namely, photoinduced chlorine atom-transfer cycliza-
6 S.-C. Lu, X.-Y. Duan, Z.-J. Shi, B. Li, Y.-W. Ren, W. Zhang, Y.-H. Zhang
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