CuI-catalyzed photochemical or thermal reactions of 3-(2-azidobenzylidene) lactams. Application to the synthesis of fused indoles

Article abstract of DOI:10.1039/c001715a

Photochemical or thermal reactions of 3-(2-azidobenzylidene)-lactams afforded fused indoles such as indolo[3,2-c]quinolin-6-ones, pyrido[4,3-b]indol-1-ones and other similar compounds in moderate to high yields via cyclization-ring expansion reactions. Th

Full text of DOI:10.1039/c001715a

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CuI-catalyzed photochemical or thermal reactions of 3-(2-azidobenzylidene)-
lactams. Application to the synthesis of fused indolesw
Zongjun Shi, Yuwei Ren, Bing Li, Shenci Lu and Wei Zhang*
Received 27th January 2010, Accepted 8th April 2010
First published as an Advance Article on the web 6th May 2010
DOI: 10.1039/c001715a
Photochemical or thermal reactions of 3-(2-azidobenzylidene)-
lactams afforded fused indoles such as indolo[3,2-c]quinolin-6-
ones, pyrido[4,3-b]indol-1-ones and other similar compounds in
moderate to high yields via cyclization-ring expansion reactions.
The photolytic process was much more facile than the thermal
process and could be further improved by addition of CuI.
Scheme 1
The chemistry of azides and nitrenes has long attracted the
Table 1 Optimization of photoreaction of 1a.
attention of chemists since the discovery of phenyl azide by
Peter Grieb.1 The photochemical and thermal reactions of aryl
azides are well known and are widely used in synthetic organic
chemistry,1,2 photolithography3 and photoaffinity labeling of
biopolymers.4 Very reactive singlet nitrenes with open-shell
electronic configurations are the key intermediates of photo-
chemical and thermal decomposition of aryl azides.2 The
cyclization of o-azidostyrene derivatives by photolysis or
thermolysis has been developed into a powerful synthetic
method for the construction of indole derivatives.1,2,5 In these
reactions, zwitterion intermediates5f were generally formed by
direct attack of a nitrene at the b-carbon atom of an adjacent
double bond and subsequently a proton shift led to the indole
derivatives. Despite these advantages, metal-catalyzed
reactions of azides also received increasing attention;6a–e for
example, copper-catalyzed decomposition of 1-azido-2-dienyl-
quinones for the synthesis of pyrroloindoloquinones6e and
CuI-catalyzed photochemical cyclization of 2-(allenyl)phenyl
azides in the synthesis of annulated indoles in good yields
and high regioselectivity.6b,c We are also interested in the
construction of heterocycles by the photoreaction of aryl
azides, especially the photolysis of b,b-doubly substituted
o-azidostyrenes because few such substrates have been
considered in synthetic strategies5f,g. We report in this paper
a novel synthesis of fused indoles by simple or CuI-catalyzed
photochemical or thermal cyclization and ring-expansion of
3-(2-azidobenzylidene)lactams, such as 3-(2-azidobenzylidene)-
indol-2-ones (1a–i) as shown in Scheme 1.
Entry
Solvents
t/h
Convn (%)
Yielda (%)
1
2
3
4
5
6
7
8
MeCN
CH2Cl2
CH3COCH3
C6H6
MeCN + 10% CuI
MeCN + 50% CuI
MeCN + 100% CuI
CH2Cl2 + 100% CuI
6
2
5
6
6
5
3
2
87
95
92
87
90
95
>98
93
65
82
46
62
70
84
90
80
a
Isolated yields.
We first investigated the photoreaction of 3-(2-azidobenzyl-
idene)indol-2-one (1a) in different solvents. The photolyses
were performed in a Pyrex flask under irradiation at l >
300 nm because the lmax for 1a was 322 nm (e322
=
11 400 molꢀ1cmꢀ1). It could be found from Table 1 that 6a
was obtained as the main product in these solvents. Compara-
tively, the yield was a little higher in dichloromethane than
that in other solvents. After addition of CuI in acetonitrile, the
efficiency of the photoreaction was enhanced gradually. This
may be ascribed to the catalysis of CuI to the photochemical
decomposition of azides, as described by Feldman.6c However,
no great change was found after addition of CuI in methylene
dichloride, probably because CuI could not be dissolved in
methylene dichloride. Thus, investigation of the photo-
reactions of other substrates were carried out under two
different conditions: simple photolysis in dichloromethane
and CuI-catalyed photoreaction in acetonitrile.
Indolo[3,2-c]quinolin-6-ones and pyrido[4,3-b]indol-1-ones
are well known for their potential biological and pharmaco-
logical activities, such as antihypertensive, anti-inflammatory,
antitumor, antiviral, antimalarial and antipyretic activities.7
So several other methods have also been established for the
synthesis of these compounds.8
Five series of 3-(2-azidobenzylidene)lactams were studied,
but most of the work was done on the 3-(2-azidobenzylidene)-
indol-2-ones (1a–i) series. Both simple photolysis of 1a–i in
dichloromethane and CuI-catalyzed photoreactions gave
indolo[3,2-c]quinolin-6-ones as the main products (Table 2).
The results showed that the acyl group migrated more readily
State Key laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou, China. E-mail: zhangwei6275@lzu.edu.cn;
Fax: +86 (0931) 8625657; Tel: +86 (0931) 8912545
w Electronic supplementary information (ESI) available: Experimental
details, analytical data and NMR spectra. CCDC 750269. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c001715a
ꢁc
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Table 2 Photolysis and CuI-catalyzed photoreactions of substituted
3-(2-azidobenzylidene)indol-2-ones (1a–i)
Table 3 CuI-catalyzed photolysis of substituted 3-(2-azidobenzyl-
idene) lactams (2a–c, 3a–b, 4, 5)a
Yieldb
(%)
Entry
1
Reactant
Time/h Product
2a
2b
2
2
7a
7b
88
Reactant
2
3
83
65
R1
R2
R3
Entry
Prod. Time/h Yieldb (%)
R
1
2
3
4
5
6
7
8
9
1a
1b Me
1c Ph
1d Me MeO
1e Ph MeO
1f
1g Me CO2Et
1h Ph CO2Me
1i Ph
H
H
H
H
H
H
H
MeO
MeO
H
H
H
Cl
H
H
H
H
H
6a
6b
6c
6d
6e
2 (1)a
3 (2)a
5 (3)a
1 (1)a
2 (1)a
82 (90)a
78 (87)a
75 (83)a
85 (92)a
81 (88)a
2c
6
7c
H
H
Cl 6f
3.5 (2)a 75 (85)a
H
H
H
6g
6h
6i
5 (3)a
6 (3)a
65 (81)a
60 (73)a
4
5
3a
3b
3
3
8a
8b
82
75
H
10 (6)a 45 (72)a
a
b
CuI (100 mol%) employed in acetonitrile. Isolated yield.
than the phenyl group in an intermediate formed in the
photolytic decomposition of 1a–i. The substituents on the
azidophenyl group had a little effect on the photoreaction.
Electron-donating groups, such as the methoxy group, accel-
erated the decomposition of the azides and the electrophilic
addition of the nitrene to the double bond of styrenes, thus
higher yields of products were attained in shorter times in the
cases of 1d and 1e; in contrast, electron-attracting groups, such
as carboxylate and chloro groups, restrained the electrophilic
addition of the nitrene to the double bond of styrenes, so yields
of products were decreased in the cases of 1g–i. The yields of
products were all increased after addition of one equivalent of
CuI in acetonitrile as compared with those in dichloromethane.
We then examined the CuI-catalyzed photoreactions of four
other substrates: 3-(2-azidobenzylidene)pyrrole-2-ones (2a–c),
4-(2-azidobenzylidene)pyrazole-3-ones (3a–b), 4-(2-azidobenzyl-
idene)isoquinoline-1,3-dione (4) and 5-(2-azidobenzylidene)-
pyrine-2,4,6-trione (5). All these substrates afforded the fused
indoles as the main products under CuI-catalyzed condition
as shown in Table 3. Obviously the products were all
derived from the addition of nitrenes to a double bond with
subsequent shift of the acyl group.
6
4
5
5
3
9
68
55
7
10
a
b
CuI (100 mol%) employed in acetonitrile. Isolated yield.
1
All products were identified fully by H NMR, 13C NMR,
MS and HRMS. The major differences between reactants and
1
products in their H NMR spectra were the disappearance of
Fig. 1 X-Ray crystal structure of 7b.
the peaks (d = 7.8–8.7 ppm (s, 1H)) of the olefin protons in the
reactants, indicating the shift of acyl group to the olefinic
position, and the appearance of the N–H peaks (d = 11–13 ppm
(s, 1H)) in the products, showing the formation of indole rings.
The structure of 7b was further confirmed by X-ray crystallo-
graphy, as shown in Fig. 1.z
time was needed and conversions of substrates and yields of
products decreased greatly, probably because of the low
solubility of these substrates in refluxing xylene. Little reaction
was detected in refluxing acetonitrile after addition of CuI and
also no great change was found after addition of CuI in
refluxing xylene. Both of these reactions indicated that CuI
had no catalytic effect on the thermal reactions. Thus, it could
be deduced that the catalysis of CuI to the photoreaction
of the azides was played by forming an easily photolyzed
complex with the azides.
The thermal reactions of several azides, such as 3-(2-azido-
benzylidene)indol-2-ones (1a–b), 3-(2-azidobenzylidene)pyrrol-
2-one (2a) and 4-(2-azidobenzylidene) pyrazol-5-one (3a), were
also investigated in refluxing xylene as shown in Table 4.
Thermolysis of these substrates afforded the same products
as those (6a–b, 7a, 8a) formed in photolysis. However, more
ꢁc
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Table 4 Thermal decompositions of 1a–b, 2a, 3a
Entry
Reactant
Solvent
t/h
Convn (%)
Prods
Yielda (%)
1
2
3
4
5
6
1a
1b
2a
3a
1a
1a
Xylene
Xylene
Xylene
Xylene
Acetonitrile + 100% CuI
Xylene + 100% CuI
12
12
12
12
12
12
86
80
76
70
6a
6b
7a
8a
6a
6a
65
72
64
54
—
63
o5
85
a
Isolated yield.
unique (Rinit = 0.0512) which was used in all calculations. Final
wR (F2) = 0.1213 (all data). CCDC 750269.
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Scheme 2
Two mechanisms are possible for the transformation of
3-(2-azidobenzylidene)lactams into fused indoles under two
different conditions (Scheme 2). Photolytic and thermal
reactions are believed to occur via nitrene I attacking onto
the b-position of the adjacent double bond to form a zwitter-
ion II5f and subsequently the shift of the acyl group to the
carbocation. The tautomerization of intermediate III
affords 6a. Similar to that proposed for metal-catalyzed
decomposition of azides,6 the Cu(I)-catalyzed photoreaction
can be assumed to proceed via initial coordination of Cu(I) to
the azide (in acetonitrile) to provide complex IV. Photolysis of
IV expels N2 to directly produce the electrophilic Cu-nitrene
intermediate V. Following a similar route as for I to 6a, V can
be also transformed to 6a in higher efficiency.
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In conclusion, we have developed an efficient method for the
synthesis of fused indoles such as indolo[3,2-c]quinolin-6-ones,
pyrido[4,3-b]indol-1-ones, pyridazino[4,5-b]indol-1-ones, dihydro-
indolo[3,2-d][2]benzazepin-5,7-dione and [1,3]diazepino[5,6-b]-
indole-1,3,5-trione by either direct photolysis or CuI-catalyzed
photoreaction or thermolysis in refluxing xylene of five series
of 3-(2-azidobenzylidene)lactams.
We thank the National Natural Science Foundation of
China (20472027) for financial support.
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Notes and references
z Crystal data: for compound 7b (recrystallized from acetone-hexane).
C21H16N2O3, M = 344.36, monoclinic, a = 10.1086(18) A, b =
12.6741(18) A, c = 14.238(2) A, b = 106.962(11), V = 1744.8(5) A3,
yellow plates, r = 1.311 g cmꢀ3, T = 296(2) K, space group P2 (1)/c,
Z = 4, m (MoK mmꢀ1, 2ymax = 51.72, 2866 reflection collected, 1957
ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 3973–3975 | 3975