Synthesis of paullone and kenpaullone derivatives by photocyclization of 2-(2-chloro-1H-indol-3-yl)-N-arylacetamides

Article abstract of DOI:10.1002/ejoc.201101508

An efficient synthesis of paullone and kenpaullone derivatives in moderate to high yields has been achieved through photocyclizations of (2-chloro-1H-indole-3-yl)-N-arylacetamides in acetone at room temperature. Paullone and kenpaullone have been obtained

Full text of DOI:10.1002/ejoc.201101508

FULL PAPER
DOI: 10.1002/ejoc.201101508
Synthesis of Paullone and Kenpaullone Derivatives by Photocyclization of
2-(2-Chloro-1H-indol-3-yl)-N-arylacetamides
Zhanshan Li,[a] Nianhong Lu,[a] Lihong Wang,[a] and Wei Zhang*[a]
Keywords: Natural products / Alkaloids / Nitrogen heterocycles / Photochemistry / Cyclization
An efficient synthesis of paullone and kenpaullone deriva-
tives in moderate to high yields has been achieved through
photocyclizations of (2-chloro-1H-indole-3-yl)-N-arylacet-
amides in acetone at room temperature. Paullone and ken-
paullone have been obtained easily and in high yields by
deprotection of the photocyclization products.
Introduction
lar Heck reaction of N-(ethoxymethyl)-2-[1-(ethoxymethyl)-
indol-3-yl]-N-(2-iodophenyl)acetamide,[4a] a Bu3SnH-medi-
ated radical cyclization of N-[2-(indol-2-yl)phenyl]-N-meth-
ylchloroacetamide,[4b] and palladium-catalyzed borylation/
Suzuki coupling reactions between 2-bromindole-3-acetoni-
triles and 2-haloacetanilides with subsequent lactamiza-
tion.[4c]
Paullone (A), kenpaullone (B), and alsterpaullones (C,
D) are a series of fused tetracyclic compounds containing
the indolo[3,2-d][1]benzazepin-6(5H)-one structure. They
have been described as potent, ATP-competitive inhibitors
of the cell cycles regulating cyclin-dependent kinases
(CDKs), glycogen-synthase kinases (GSKs), and mito-
chondrial malate dehydrogenase (mMDH) and have be-
come a class of very useful agents for the treatment of neuro-
degenerative and proliferative disorders.[1a–1h] The synthe-
sis of paullone and analogues has thus attracted great inter-
est over the last decade.[2,3] Several synthetic strategies to
access the paullone system have been reported. The first
synthetic pathway involved the construction of the fused
1H-indole moiety through a Fischer indolization of benz-
azepinone.[2] Another pathway proceeded through the initial
construction of an indole precursor and subsequent exten-
sion to the paullone structure through intramolecular cou-
pling or condensation. Examples of this approach include
rhodium(III)-catalyzed cycloadditions between acetanilides
and methyl 4-(2-aminophenyl)but-3-ynoate and subsequent
lactamization,[3a] copper-catalyzed borylative cyclizations
of 2-alkenylaryl isocyanides and Suzuki–Miyaura couplings
with subsequent lactamization,[3b] a Strecker reaction be-
tween a protected 2-aminobenzaldehyde and a 2-aminocin-
namate and further cyclization of the deprotonated N-mon-
osubstituted amino nitrile,[3c] and a Bu3SnH-mediated radi-
cal cyclization of an o-alkenyl arylisonitrile followed by a
Stille coupling with N-Boc-2-iodoaniline to give the methyl
2-arylindoacetate with subsequent lactamization.[3d] Strate-
gies starting directly from an indole precursor have also
been widely used; they include a Pd-catalyzed intramolecu-
All of these syntheses, however, required the use of met-
allic catalysts and multi-step reactions, so a concise and
metal-free process was still required. We found that no syn-
theses of paullone or kenpaullone derivatives through pho-
tochemical reactions had been reported in the literature, al-
though photoinduced couplings between haloarenes and ar-
enes have been used extensively in the synthesis of alkaloids
and polycyclic compounds.[5] We have recently reported on
the synthesis of indolo[2,1-a]isoquinolines and indolo[2,1-
a][2]benzazepines through intramolecular photochemical
cross-coupling reactions between 3-acyl-2-haloindoles and
their tethered arene units.[6] Here we report a new synthesis
of paullone derivatives through photoinduced intramolecu-
lar cross-coupling reactions of 2-(2-chloro-1H-indol-3-yl)-
N-arylacetamides in acetone (Scheme 1).
[a] State Key Laboratory of Applied Organic Chemistry and
College of Chemistry and Chemical Engineering, Lanzhou
University,
Lanzhou 730000, P. R. China
Fax: +86-931-8625657
E-mail: zhangwei6275@yahoo.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101508.
Scheme 1. Photocyclizations of 2-(2-chloro-1H-indol-3-yl)-N-aryl-
acetamides in acetone.
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Z. Li, N. Lu, L. Wang, W. Zhang
FULL PAPER
Table 2. Photocyclizations of 2-(2-chloro-1H-indol-3-yl)-N-aryl-
acetamides 1a–k in acetone.[a]
Results and Discussion
We first optimized the photoreaction conditions by using
the 2-(indol-3-yl)acetamide derivative 1a (see Table 1) as a
model substrate. The reaction was examined in different
solvents in a Pyrex flask (λ Ͼ 280 nm) because the ultravio-
let absorption of 1a was below 300 nm (λmax = 292 nm,
280 nm, 223 nm). The photoreaction efficiency of 1a in ace-
tone was clearly higher than those in other solvents such
as dichloromethane, acetonitrile, or benzene, as shown in
Table 1. This result may be attributed to the photosensitiza-
tion effect of acetone, because the triplet energy of acetone
(ET = 326 kJmol–1)[7a] was higher than that of 1-acylindole
(ET = 288 kJmol–1).[7b] In addition, it could be seen that
polar solvents favored the photocyclization reaction, be-
cause higher levels of conversion of 1a could be reached in
shorter time in more polar solvents. For these two reasons,
acetone was selected as the solvent in the photoreactions of
all substrates.
Table 1. Optimization of photoreaction conditions for the synthesis
of 2a.[a]
Entry
Solvent
Time
[h]
Conv. of 1a[b] Yield of 2a[c]
[%]
[%]
1
2
3
4
Me2CO
CH3CN
CH2Cl2
C6H6
5
95
62
57
53
90
71
68
62
16
22
30
[a] Compound 1a (0.5 mmol) and pyridine (79 mg, 1.0 mmol) were
dissolved in acetone (25 mL). The solution was irradiated at λ Ն
280 nm with a medium-pressure mercury lamp (500 W) under ar-
gon at ambient temperature. [b] Conversions calculated on the basis
of substrate. [c] Yields of isolated product based on consumed sub-
strate.
[a] Compounds 1a–1k (0.5 mmol) and pyridine (79 mg, 1.0 mmol)
were dissolved in acetone (25 mL). The solutions were irradiated
at λ Ն 280 nm with a medium-pressure mercury lamp (500 W) un-
der argon at ambient temperature. [b] Levels of conversion were
calculated on the basis of substrate. [c] Yields of isolated products
based on consumed substrate.
Figure 1. X-ray crystal structure of 2a.
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Paullone and Kenpaullone Derivatives by Photocyclization
We then examined the photoreactions of a group of 2- sults for 1l and 1m were compared with that for 1h and all
(2-chloro-1H-indol-3-yl)-N-arylacetamides with different are listed in Table 3. It was found by comparison of levels
substituents on both indolyl and aryl groups under the opti- of conversion and reaction times that the photoreaction
mized conditions. Photoreactions of all these substrates af- efficiency decreased gradually from 1h to 1m. In particular,
forded the corresponding cyclization products – paullone it could be seen that the photoreaction products of 1m were
derivatives – in moderate to high yields after 5–30 h irradia- different from those of 1h and 1l, the main product being
tion at room temperature. All products were fully identified not the cyclization product but the deiodination product 3,
1
by H NMR, 13C NMR, and HRMS, and the structure of which was obviously derived from a hydrogen-abstraction
2a was further confirmed by X-ray analysis as depicted in reaction of the 2-indoyl radical. It was therefore clear that
Figure 1.[8] It was found that the photocyclization of 1d the photoreactions of 2-chloro-substituted N-arylindole-3-
(Table 2), in which there were no substituents on the nitro- acetamides gave the best results for the synthesis of paul-
gen atoms, was difficult; substituents on both nitrogen lone derivatives.
atoms were therefore necessary to improve both the levels
of conversion of substrates and the yields of products. The
Table 3. Photoreactions of different halogen-substituted 2-(1H-
1-Boc-substituted substrates (1a and 1e) were more reactive
than 1-alkyl-substituted substrates (1c, 1f, and 1g) and the
photoreaction efficiencies were higher. The differences in re-
activity for 1a, 1c, and 1d originated from the different
properties of their triplet excited states: the triplet form of
the 1-acylindole system, for example, was diradical and re-
acted easily with olefins at the 2-position to form triplet 1,4-
biradicals,[7b] but the triplet form of 1-methylindole showed
some triplet charge transfer as well as the diradical,[7c] so
the indole could react with acetone through H-abstraction
from the N–H bond.[7c] It was also found that the presence
of a BOC group at the amide nitrogen atom retarded the
photocyclization in 1h and 1k relative to the presence of the
alkyl groups at the amide nitrogen atoms in 1a, 1e, and 1j.
In addition, the reactions of 1e and 1f, in which the N-
phenyl group was replaced by tetrahydroquinoline, were
slow and the yields of products 2e and 2f were lower than
in the cases of 1a–c.
indol-3-yl)-N-arylacetamides.[a]
Entry
Substrate
X
Time
[h]
Conv.[b] Product
[%]
Yield[c] [%]
2h
3
1
2
3
1h
1l
1m
Cl
Br
I
8
30
30
95
60
35
2h
2h
2h + 3
65
50
8
51
[a] Compound 1l or 1m (0.5 mmol) and pyridine (79 mg, 1.0 mmol)
were dissolved in acetone (25 mL). The solution was irradiated at
λ Ն 280 nm with a medium-pressure mercury lamp (500 W) under
argon at ambient temperature. [b] Levels of conversion calculated
on the basis of substrate. [c] Yields of isolated products based on
consumed substrate.
Because the synthesis of paullone by direct photocycliza-
tion of 1d in acetone was much more difficult than those of
its derivatives 2h and 2k from 1h and 1k, the syntheses of
paullone and kenpaullone were achieved in high yields by
No further reaction was detectable in the acetone solu-
the removal of the tert-butoxycarbonyl groups from the tion of 3 after prolonged irradiation (48 h), so it was clear
photocyclization products 2h and 2k through two-step mild that the presence of the 2-chlorine atom on the indole ring
hydrolysis reactions[9] (Scheme 2).
was essential for the photocyclizations of 1a–k. However, it
Although the photocyclizations of 2-(2-chloro-1H-indol- was also impossible that the photocyclizations of 1a–k were
3-yl)-N-arylacetamides had proceeded successfully, we initiated by the photoinduced homolysis of the C–Cl bonds
wanted to know whether or not photocyclizations of other to produce the free 2-indolyl radicals because of three facts:
2-(2-halo-1H-indol-3-yl)-N-arylacetamide derivatives would 1) no solvent-incorporated product – 2-(2-phenylindol-3-
be more efficient, because the bond dissociation energies of yl)-N-phenylacetamide – was detected from the photoreac-
C–Br and C–I bonds were lower than that of the C–Cl tion of 1a in benzene, 2) the triplet energy of the 1-acylind-
bond. Two other substrates – 1l and 1m (Table 3) – were ole system (ET = 288 kJmol–1)[7b] was not sufficient for the
therefore prepared and the photoreactions of the two sub- cleavage of the C–Cl and C–Br bonds [the bond dissoci-
strates were examined under the same conditions. The re- ation energies (DC–X) for C–Cl and C–Br are 339 and
Scheme 2. Synthesis of paullone and kenpaullone by hydrolysis of 2h and 2k.
Eur. J. Org. Chem. 2012, 1019–1024
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1021

Z. Li, N. Lu, L. Wang, W. Zhang
FULL PAPER
289 kJmol–1, respectively[10]], and 3) although the free 2-
indolyl radical could be produced from photolysis of 2-
iodo-indol-3-yl-N-phenylacetamide (1m; the bond dissoci-
ation energy for C–I was 222 kJmol–1[10]), the main product
was not the cyclization product 1h as shown in Table 3.
There might therefore be another, lower-energy path to in-
duce the cyclization. Grimshaw[11a] and Park[11b] proposed
a novel mechanism to explain the photocyclizations of 2-
chlorobenzanilide and 2-halo-N-pyridinylbenzamides. Cy-
clic transition states could be formed from the complexing
of the π-clouds of the N-phenyl or N-pyridinyl rings with
the developing aryl radical centers and chlorine atoms,
stretching the C–Cl bonds and thus lowering the transition
energies for the reactions. Such a low-energy pathway
would also be reasonable to explain the photocyclizations
of 1a–k, because the photoreactions were more efficient in
the triplet states of 1a–k (Table 2) and the triplet states of
the indole rings in 1a–k each have the diradical structure,[7b]
which should be favorable for coupling of the C-2 moiety
in the 2-chloroindole system with tethered N-aryl groups.
Chlorine and bromine atoms are electron-deficient species
with high electron affinities,[12] their complexation by aro-
matic molecules is well known, and anchimeric assistance to
C–X bond cleavage by radical complexation has also been
confirmed by dynamic methods[13] and flash photolysis
studies.[11b,14] A plausible mechanism based on the above
suggestions is shown in Scheme 3. This mechanism also af-
fords an explanation of why the chlorine-substituted sub-
strate 1h reacts more rapidly than the bromine-substituted
substrate 1l even though DC–Cl Ͼ DC–Br, because the transi-
tion state 1h–1 is reached earlier along the reaction coordi-
nate for X = C1 than for X = Br, due to the higher electron
affinity of the chlorine atom. Photocyclization of 1m might
proceed by homolysis of the C–I bond to give a free 2-
indolyl radical and an iodine atom and subsequent coupling
of the 2-indolyl radical with the N-aryl group.
Conclusions
In conclusion, an efficient synthesis of paullone deriva-
tives through photocyclizations of 2-(2-chloro-1H-indol-3-
yl)-N-arylacetamides in acetone has been developed. The
photocyclizations of 2-(1-acyl-2-chloro-1H-indol-3-yl)-N-
arylacetamides are more efficient than those of 2-(1-alkyl-
2-chloro-1H-indol-3-yl)-N-arylacetamides and the photocy-
clizations of 2-chlorine-substituted (1H-indol-3-yl)-N-aryl-
acetamides are more efficient than those of 2-bromine- or
2-iodine-substituted
Paullone and kenpaullone can be obtained in high yields by
deprotection of the photocyclization products.
(1H-indol-3-yl)-N-arylacetamides.
Experimental Section
General: Melting points were measured with a micro melting point
apparatus. 1H NMR and 13C NMR (400 MHz and 100 MHz,
respectively) spectra were recorded with a Bruker AM 400 NMR
spectrometer in CDCl3 or [D6]DMSO. Chemical shifts (δ) are re-
ported in ppm with use of TMS as internal standard and spin–spin
coupling contants (J) are given in Hz. IR spectra were recorded
with a BOMEM MB-100 FTIR instrument. The high-resolution
mass spectra (HRMS) were measured by ESI with a Bruker Dal-
tonics APEX II 47e spectrometer. The X-ray crystallographic
analysis was performed with a Bruker APEX II CCD instrument.
Analytical TLC was performed with silica gel GF254 plates and
the products were visualized by UV detection. Flash chromatog-
raphy was carried out on silica gel (200–300 mesh) eluted with hex-
ane/acetone 8:1 to 14:1 (v/v).
General Procedure for the Photocyclizations of 2-(2-chloro-1H-indol-
3-yl)-N-arylacetamides: Compound 1a (156 mg, 0.5 mmol) and
pyridine (79 mg, 1.0 mmol) were dissolved in anhydrous acetone
(25 mL) in a reaction flask. The solution was deaerated by bubbling
with Ar for half an hour and irradiated at λ Ն 280 nm with a
medium-pressure mercury lamp (500 W) at ambient temperature.
The progress of the reaction was monitored by TLC at regular in-
tervals. After the solvent had been removed under reduced pressure,
the residue was separated by silica gel column chromatography to
give the product 2a.
tert-Butyl 5-Methyl-6-oxo-6,7-dihydroindolo[3,2-d][1]benzazepine-
12(5H)-carboxylate (2a): Colorless solid, m.p. 169–171 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.46 (s, 9 H, tBu), 2.96 and
3.87 (AB system, J = 14.4 Hz, 2 H, CH2), 3.38 (s, 3 H, NCH3),
7.23–7.33 (m. 2 H, ArH), 7.36–7.46 (m, 3 H, ArH), 7.45 (d, J =
7.6 Hz, 1 H, ArH), 7.65 (d, J = 7.6 Hz, 1 H, ArH), 8.19 (d, J =
8.0 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
27.7, 32.0, 37.2, 83.9, 115.5, 118.6, 120.5, 123.2, 123.4, 124.0, 125.4,
127.2, 127.7, 127.8, 129.9, 132.5, 138.1, 140.2, 149.9 (C=O), 172.1
(C=O) ppm. IR (KBr): ν = 3057, 2930, 1731, 1666, 1423, 1363,
˜
1154, 698 cm–1. ESI-HRMS: calcd. for C22H22N2O3
363.1709; found 363.1703.
+
H+
12-Acetyl-5-methyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-
one (2b): Colorless solid, m.p. 223–226 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 2.33 (s, 3 H, CH3), 2.98 and 3.93 (AB system,
J = 14.0 Hz, 2 H, CH2), 3.43 (s, 3 H, NCH3), 7.31 (td, J = 8.4,
1.6 Hz, 1 H, ArH), 7.35 (td, J = 8.0, 0.8 Hz, 1 H, ArH), 7.40–7.49
(m, 4 H, ArH), 7.66 (d, J = 7.6 Hz, 1 H, ArH), 8.32 (d, J = 8.4 Hz,
1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 27.9,
32.2, 37.2, 115.8, 118.7, 122.6, 123.9, 124.1, 125.1, 126.3, 127.0,
127.6, 128.4, 129.4, 131.9, 138.3, 140.4, 170.7 (C=O), 172.1
Scheme 3. A plausible mechanism for the photoreactionsof 1h, 1l,
and 1m in acetone.
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Paullone and Kenpaullone Derivatives by Photocyclization
(C=O) ppm. IR (KBr): ν = 3059, 2925, 2854, 1708, 1663, 1453,
138.1, 149.7 (C=O), 151.4 (C=O), 171.7 (C=O) ppm. IR (KBr): ν
˜
˜
1368, 1297, 752 cm–1. ESI-HRMS: calcd. for C19H16N2O2 + H+
305.129; found 305.134.
= 3058, 2971, 2928, 1769, 1731, 1391, 1240, 1159, 753 cm–1. ESI-
HRMS: calcd. for C26H28N2O5 + H+ 449.2076; found 449.2077.
5,12-Dimethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one
(2c): Pale yellow solid, m.p. 134–138 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 3.05 (d, J = 14.0 Hz, 1 H, CHH), 3.34 (s, 3 H,
NCH3), 3.90 (s, 3 H, NCH3), 3.95 (dd, J = 14.0, 0.4 Hz, 1 H,
CHH), 7.19 (t, J = 8.0 Hz, 1 H, ArH), 7.28–7.35 (m, 2 H, ArH),
7.38–7.41 (m, 1 H, ArH), 7.45 (t, J = 8.0 Hz, 2 H, ArH), 7.54 (d,
J = 8.0 Hz, 1 H, ArH), 7.72 (d, J = 7.6 Hz, 1 H, ArH) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 31.7, 32.2, 37.6, 109.7, 112.3,
118.6, 119.9, 122.7, 124.2, 124.6, 124.9, 125.6, 127.9, 128.5, 133.6,
tert-Butyl 3-{2-[(tert-Butoxycarbonyl)(phenyl)amino]-2-oxoethyl}-
1H-indole-1-carboxylate (3): Pale yellow syrup. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.36 (s, 9 H, tBu), 1.64 (s, 9 H, tBu),
4.39 (s, 2 H, CH2), 6.98–7.00 (m, 2 H, ArH), 7.21–7.25 (m, 1 H,
ArH), 7.27–7.36 (m, 4 H, ArH), 7.57 (d, J = 8.0 Hz, 1 H, ArH),
7.60 (s, 1 H, ArH), 8.15 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 27.7, 28.1, 34.4 (azepine CH2), 83.2,
83.4, 113.6, 115.1, 119.2, 122.6, 124.4, 124.9, 127.7. 128.0, 128.8,
130.4, 135.3, 138.8, 149.6 (C=O), 152.7 (C=O), 173.2 (C=O) ppm.
IR (KBr): ν = 3059, 2970, 2931, 1759, 1730, 1391, 1160, 752 cm–1.
139.2, 141.7, 172.7 (C=O) ppm. IR (KBr): ν = 3057, 2931, 2850,
˜
˜
1670, 1493, 1385, 1321, 754 cm–1. ESI-HRMS: calcd. for
C19H16N2O + H+ 277.1341; found 277.1347.
ESI-HRMS: calcd. for C26H30N2O5 + H+ 451.2233; found
451.2236.
tert-Butyl 8-Oxo-5,6,8,9-tetrahydro-4H,14H-indolo[2Ј,3Ј:4,5]-
azepino[3,2,1-ij]quinoline-14-carboxylate (2e): Colorless solid, m.p.
169–174 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.43 (s, 9 H,
Di-tert-butyl 2-Methoxy-6-oxo-6,7-dihydroindolo[3,2-d][1]benz-
azepine-5,12-dicarboxylate (2i): Colorless solid, m.p. 166–170 °C.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.41 (s, 9 H, tBu), 1.46
(s, 9 H, tBu), 3.08 (d, J = 14.4 Hz, 1 H azepine CH), 3.87 (d, J =
13.6 Hz, 4 H, azepine CH, OCH3), 6.90–6.92 (m, 2 H, ArH), 7.26–
7.33 (m, 2 H, ArH), 7.40 (t, J = 8.0 Hz, 1 H, ArH), 7.62 (d, J =
8.0 Hz, 1 H, ArH), 8.29 (d, J = 8.4 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 27.7, 27.9, 34.1, 55.5, 83.4, 83.9,
113.7, 113.8, 115.6, 118.4, 118.6, 123.3, 125.7, 127.7, 128.5, 129.0,
130.3, 132.7, 138.1, 149.7, 151.5 (C=O), 157.1 (C=O), 172.2
1
tBu), 1.78–1.88 (m, 1 H), 2.17–2.28 (m, 1 H), 2.77–2.85 (m, 1 H),
2.89–3.00 (m, 2 H), 3.01 and 3.91 (AB system, J = 14.0 Hz, 2 H,
CH2), 4.57–4.63 (m, 1 H), 7.14–7.19 (m, 2 H, ArH), 7.29–7.33 (m,
2 H, ArH), 7.37 (td, J = 7.6, 1.2 Hz, 1 H, ArH), 7.67 (d, J =
7.2 Hz, 1 H, ArH), 8.17 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 23.9, 27.6, 27.7, 32.2, 43.0, 83.7,
115.3, 118.6, 119.9, 123.1, 123.2, 125.2, 126.1, 127.2, 127.7, 127.9,
132.8, 133.0, 135.9, 138.3, 150.0 (C=O), 171.4 (C=O) ppm. IR
(C=O) ppm. IR (KBr): ν = 3055, 2979, 2932, 1773, 1733, 1395,
˜
(KBr): ν = 3058, 2975, 2929, 1732, 1664, 1452, 1362, 1152,
˜
1315, 1150, 755 cm–1. ESI-HRMS: calcd. for C27H30N2O6 + H+
479.2182; found 479.2177.
754 cm–1. ESI-HRMS: calcd. for C24H24N2O + H+ 389.1865; found
389.1870.
9-Bromo-5,12-dimethyl-7,12-dihydroindolo[3,2-d][1]benzazepin-
6(5H)-one (2j): Pale yellow syrup. H NMR (400 MHz, CDCl3, 25
14-Methyl-5,6,9,14-tetrahydro-4H,8H-indolo[2Ј,3Ј:4,5]azepino-
[3,2,1-ij]quinolin-8-one (2f): Pale yellow solid, m.p. 188–192 °C. H
1
1
°C): δ = 3.04 and 3.88 (AB system, J = 14.0 Hz, 2 H azepine CH2),
3.34 (s, 3 H, NCH3), 3.88 (s, 3 H, NCH3), 7.25 (d, J = 8.4 Hz, 1
H, ArH), 7.33–7.38 (m, 2 H, ArH), 7.47 (d, J = 3.6 Hz, 2 H, ArH),
7.54 (d, J = 8.0 Hz, 1 H, ArH), 7.84 (d, J = 1.6 Hz, 1 H, ArH) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 31.8 (azepine CH2), 32.1,
37.6, 111.1, 111.6, 132.2, 121.2, 124.3, 124.5, 124.7, 125.5, 127.1,
NMR (400 MHz, CDCl3, 25 °C): δ = 1.82–1.91 (m, 1 H), 2.18–
2.25 (m, 1 H), 2.81–2.97 (m, 3 H), 3.09 and 4.00 (AB system, J =
14.0 Hz, 2 H), 3.87 (s, 3 H, NCH3), 4.60–4.67 (m,1 H), 7.17–7.25
(m, 3 H), 7.29 (td, J = 7.6, 1.2 Hz, 1 H, ArH), 7.37–7.42 (m, 2 H,
ArH), 7.30 (d, J = 8.0 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 23.9, 27.7, 31.7, 32.5, 42.8, 109.6, 111.8, 118.6,
119.9, 122.6, 123.8, 124.0, 125.5, 126.5, 127.7, 133.6, 133.9, 137.4,
128.4, 128.5, 134.7, 137.7, 141.8, 172.4 (C=O) ppm. IR (KBr): ν =
˜
3059, 2920, 2850, 1656, 1360, 1290, 759 cm–1. ESI-HRMS: calcd.
for C18H15BrN2O + H+ 355.0446; found 355.0449.
139.3, 171.9 (C=O) ppm. IR (KBr): ν = 3055, 2970, 2930, 1668,
˜
1452, 1365, 1152, 754 cm–1. ESI-HRMS: calcd. for C20H18N2O +
H+ 303.1497; found 303.1500.
Di-tert-butyl 9-Bromo-6-oxo-6,7-dihydroindolo[3,2-d][1]benzazepine-
5,12-dicarboxylate (2k): Pale yellow solid, m.p. 184–185 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.41 (s, 9 H, tBu), 1.42 (s, 9
H, tBu), 3.01 and 3.81 (AB system, J = 14.0 Hz, 2 H, azepine CH2),
7.33–7.38 (m, 3 H, ArH), 7.44–7.48 (m, 2 H, ArH), 7.74 (d, J =
2.0 Hz, 1 H, ArH), 8.16 (d, J = 8.8 Hz, 1 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 27.6, 27.7, 33.7 (azepine CH2), 83.7,
84.4, 116.5, 117.1, 117.2, 121.2, 125.9, 127.5, 127.6, 128.3, 128.5,
129.2, 130.0, 133.6, 135.2, 136.7, 149.3 (C=O), 151.2 (C=O), 171.2
14-Benzyl-5,6,9,14-tetrahydro-4H,8H-indolo[2Ј,3Ј:4,5]azepino-
[3,2,1-ij]quinolin-8-one (2g): Yellow solid, m.p. 210–216 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.79–1.88 (m, 1 H), 2.17–
2.26 (m, 1 H), 2.76–2.95 (m, 3 H), 3.15 and 4.04 (AB system, J =
13.6 Hz, 2 H, azepine CH2), 4.61–4.67 (m, 1 H), 5.46 (q, J =
17.2 Hz, 2 H, benzyl CH2), 7.06–7.18 (m, 3 H, ArH), 7.19–7.23 (m,
5 H, ArH), 7.27–7.32 (m, 3 H, ArH), 7.78 (m, 1 H, ArH) ppm. 13
C
NMR (100 MHz, CDCl3, 25 °C): δ = 23.8, 27.6, 32.5, 42.7, 48.3,
110.6, 112.3, 118.7, 120.2, 122.8, 123.9, 124.0, 125.8, 125.9, 126.0,
127.2, 127.9, 128.8, 133.6, 134.2, 137.4, 137.9, 139.1, 171.9
(C=O) ppm. IR (KBr): ν = 3058, 2971, 2922, 1778, 1735, 1389,
˜
1325, 1156, 752 cm–1. ESI-HRMS: calcd. for C26H27BrN2O5 + H+
527.1182; found 527.1187.
(C=O) ppm. IR (KBr): ν = 3057, 2979, 2940, 1661, 1446, 1355,
˜
1149, 753 cm–1. ESI-HRMS: calcd. for C26H22N2O + H+ 379.181;
found 379.1795.
tert-Butyl 6-Oxo-6,7-dihydroindolo[3,2-d][1]benzazepine-12(5H)-
carboxylate (2h–1): White solid, m.p. Ͼ 300 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 1.42 (s, 9 H, tBu), 3.50 (m, 2 H,
Di-tert-butyl 6-Oxo-6,7-dihydroindolo[3,2-d][1]benzazepine-5,12-di-
1
carboxylate (2h): Pale yellow syrup. H NMR (400 MHz, CDCl3, azepine CH2), 7.18 (d, J = 8.0 Hz, 1 H, ArH), 7.23 (td, J = 7.6,
25 °C): δ = 1.41 (s, 9 H, tBu), 1.43 (s, 9 H, tBu), 3.04 and 3.89 (AB
system, J = 14.0 Hz, 2 H, azepine CH2), 7.29–7.42 (m, 5 H, ArH),
7.47–7.49 (m, 1 H, ArH), 7.63 (d, J = 7.6 Hz, 1 H, ArH), 8.29 (d,
J = 8.4 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 27.7, 27.8, 33.9 (azepine CH2), 83.6, 84.0, 115.7, 118.3, 118.5,
123.3, 125.6, 125.9, 127.1, 127.6, 127.7, 129.1, 130.0, 132.6, 135.1,
0.8 Hz, 1 H, ArH), 7.29–7.470 (m, 3 H, ArH), 7.47 (dd, J = 8.0,
1.2 Hz, 1 H, ArH), 7.64 (d, J = 7.6 Hz, 1 H, ArH), 8.19 (d, J =
8.4 Hz, 1 H, ArH), 8.36 (s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 27.7, 31.3 (azepine CH2), 84.0, 115.3, 118.4,
118.8, 122.3, 123.2, 123.6, 125.0, 125.4, 127.8, 128.1, 130.4, 132.8,
134.1, 138.4, 150.1 (C=O), 173.9 (C=O) ppm. IR (KBr): ν = 3150,
˜
Eur. J. Org. Chem. 2012, 1019–1024
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1023

Z. Li, N. Lu, L. Wang, W. Zhang
FULL PAPER
2975, 1730 (C=O), 1661 (C=O), 751 cm–1. ESI-HRMS: calcd. for
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C21H20N2O3 + H+ 349.1552; found 349.1557.
tert-Butyl 9-Bromo-6-oxo-6,7-dihydroindolo[3,2-d][1]benzazepin-
12(5H)-carboxylate (2k–1): Colorless solid, m.p. Ͼ 300 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 1.40 (s, 9 H, tBu), 3.43 (m,
2 H, azepine CH2), 7.21–7.25 (m, 2 H, ArH), 7.37 (td, J = 8.0,
1.2 Hz, 1 H, ArH), 7.44–7.46 (m, 2 H, ArH), 7.76 (d, J = 1.2 Hz,
1 H, ArH), 8.06 (d, J = 8.8 Hz, 1 H, ArH), 9.03 (s, 1 H, NH) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 27.6, 31.2 (azepine CH2),
84.5, 116.4, 116.8, 117.6, 121.1, 122.4, 123.5, 124.4, 128.1, 128.5,
129.4, 130.3, 134.0, 134.5, 137.1, 149.7 (C=O), 173.8 (C=O) ppm.
IR (KBr): ν = 3151 (NH), 2972, 1732 (C=O), 1660 (C=O),
˜
753 cm–1. ESI-HRMS: calcd. for C21H19BrN2O3 + H+ 427.0657;
found 427.0652.
Paullone (2d): Colorless solid, m.p. Ͼ 300 °C. 1H NMR (400 MHz,
[D6]DMSO, 25 °C): δ = 3.50 (s, 2 H, azepine CH2), 7.07 (td, J =
7.6, 0.8 Hz, 1 H, ArH), 7.17 (td, J = 8.0, 1.2 Hz, 1 H, ArH), 7.24–
7.29 (m, 2 H, ArH), 7.37 (td, J = 8.0, 1.2 Hz, 1 H, ArH), 7.43 (d,
J = 8.4 Hz, 1 H, ArH), 7.65 (d, J = 7.6 Hz, 1 H, ArH), 7.74 (dd,
J = 7.6, 1.2 Hz, 1 H, ArH), 10.08 (s, 1 H, NH), 11.57 (s, 1 H,
indole NH) ppm. 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ =
31.6 (CH2), 107.5, 111.4, 117.9, 119.0, 122.0, 122.2, 122.8, 123.6,
126.5, 126.8, 127.9, 132.4, 135.4, 137.4, 171.5 (C=O) ppm. IR
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(KBr): ν = 3410 (br., NH), 1666 (C=O), 1025, 999, 764 cm–1. ESI-
˜
HRMS: calcd. for C16H12N2O + H+ 249.1022; found 249.1019.
Kenpaullone (6): Pale yellow solid, m.p. Ͼ 300 °C. 1H NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 3.52 (s, 2 H, azepine CH2),
7.25–7.30 (m, 3 H, ArH), 7.37–7.41 (m, 2 H, ArH), 7.74 (dd, J =
8.0, 1.6 Hz, 1 H, ArH), 7.91 (d, J = 1.6 Hz, 1 H, ArH), 10.11 (s, 1 [6] S. Lu, X. Zhang, Z. Shi, Y. Ren, B. Li, W. Zhang, Adv. Synth.
H, NH), 11.80 (s, 1 H, indole NH) ppm. 13C NMR (100 MHz, [D6]
DMSO, 25 °C): δ = 31.3 (CH2), 107.1, 111.6, 113.3, 120.3, 122.2,
122.3, 123.6, 124.4, 126.9, 128.3, 128.4, 134.0, 135.6, 136.0, 171.4
Catal. 2009, 351, 2839.
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(C=O) ppm. IR (KBr): ν = 3415 (br., NH), 1655 (C=O), 1025,
˜
1000, 764 cm–1. ESI-HRMS: calcd. for C16H11BrN2O
H+:327.0133; found 327.0140.
+
hexane). C22H22N2O3, Mr
= 362.42. Monoclinic, a =
11.171(4) Å, b = 11.202(4) Å, c = 14.889(5) Å, β = 92.732(3),
Supporting Information (see footnote on the first page of this arti-
cle): procedures for the preparation of the photoreaction substrates
and copies of the 1H and 13C NMR spectra for all new compounds.
V = 1861.1(11) Å3, colorless plates, ρ = 1.293 gcm–3, T =
296(2) K, space group P21/n,
Z = 4, μ (Mo-Kα) =
0.71073 mm–1, 2θmax = 51.0°, 3443 reflections measured, 2203
unique (Rint = 0.0914) which were used in all calculation. the
final wR(F2) was 0.1112 (for all data), R1 = 0.0516. CCDC-
842943 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We are grateful to the National Nature Science Foundation of
China (NSFC) (grant number 20872056) for financial support.
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Received: October 16, 2011
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Published Online: December 21, 2011
1024
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Eur. J. Org. Chem. 2012, 1019–1024