Synthesis of the azepinoindole framework via oxidative heck (Fujiwara-Moritani) cyclization

Article abstract of DOI:10.1055/s-0030-1260057

A catalytic oxidative Heck (Fujiwara-Moritani) cyclization has been evaluated for construction of the azepinoindole framework starting from readily available 3-indoleacetic acid amides. The supporting role of the amide group in the substrate has been demonstrated necessary for the success of the cyclization. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260057

PAPER
2147
Synthesis of the Azepinoindole Framework via Oxidative Heck (Fujiwara–
Moritani) Cyclization
Synthesis of
A
a
zepinoindo
v
les via
O
xida
e
tive Heck
l
C
yclization A. Donets, Erik V. Van der Eycken*
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: erik.vandereycken@chem.kuleuven.be
Received 15 March 2011; revised 15 April 2011
Table 1 Primary Set of Conditions
Abstract: A catalytic oxidative Heck (Fujiwara–Moritani) cycliza-
tion has been evaluated for construction of the azepinoindole frame-
work starting from readily available 3-indoleacetic acid amides.
The supporting role of the amide group in the substrate has been
demonstrated necessary for the success of the cyclization.
O
O
PdCl2(MeCN)2
Me
(10 mol%)
N
N
Me
oxidant (1.5 equiv)
110 °C, 16 h
N
H
N
H
Key words: C–H activation, Heck reaction, palladium, indoles,
heterocycles
1a
2a
Entry
Solvent
1,4-dioxane
1,4-dioxane
THF
Oxidant
Yield (%)a
20
The palladium(II)-catalyzed oxidative Heck reaction in-
volving C–H bond activation (Fujiwara–Moritani reac-
tion) has been extensively studied1 as an expedient
alternative for the conventional Heck coupling in the di-
rect alkenylation of arenes. This transformation is partic-
ularly synthetically interesting for rapid and selective
functionalization of compounds containing the indole nu-
cleus.2 Considerable success has been achieved in the de-
velopment of intermolecular alkenylation of indoles.3
Remarkably efficient examples of the intramolecular cat-
alytic oxidative Heck reaction have also been reported for
annulation of indoles.4 However, in all of these cases ei-
ther a five- or a six-membered cycle is joined to the aro-
matic core via carbocyclization. On the other hand,
methods using mostly stoichiometric amount of palladi-
um have been elaborated for the synthesis of indoles fused
with medium-sized N-containing rings, namely
azepinoindoles5 or azocinoindoles,6 which are present in
certain alkaloids. To the best of our knowledge, the cata-
lytic oxidative Heck cyclization delivering the azepinoin-
dole framework has been described only once for the
synthesis of paullone derivatives.7
1
2
3
4
5
6
BQ
DTBQ
DTBQ
DMBQ
NQ
49
53
THF
31
THF
traces
n.r.b
THF
duroquinone
a Isolated yield.
b No reaction.
Various combinations of palladium catalyst, oxidant, and
solvent described in the literature1 have been applied to
the substrate 1a. The first successful hit leading to the for-
mation of the azepinoindolone 2a was found using the
combination of PdCl2(MeCN)2, BQ (p-benzoquinone),
and 1,4-dioxane (Table 1, entry 1). No product formation
was observed at a temperature lower than 110 °C. When
t-BuO2H or Bz2O2 were used as oxidants, the major isolat-
ed product was the amidoketone resulting from oxidation
of the benzylic position in 1a. Pd(OAc)2 and PdCl2
showed no catalytic activity, which in the case of PdCl2
may be due its low solubility in 1,4-dioxane. The reaction
turned very sluggish when MeCN, EtOAc, or toluene was
used as a solvent leading to precipitation of palladium-
black before any appreciable conversion of the starting
material had been attained. Addition of the strongly coor-
dinating polar solvents DMF, DMSO, or HMPA com-
pletely inhibited the reaction. LiCl or KOAc as additives
produced the same effect.
Despite this limited precedent success in the construction
of medium-sized rings via oxidative Heck cyclization
suitable conditions are sought for exploiting the reactivity
of a supporting functionality.3b,8 Hence the initial screen-
ing of reaction conditions was carried out on the example
of the amide 1a (Table 1) obtained by coupling of 3-in-
doleacetic acid and the corresponding allylamine in the
presence of EDCI. The ortho-directing effect of the amide
groups in oxidative Heck reaction has been unambiguous-
ly established for acylanilides.8
The low yield of 2a with BQ as oxidant was ascribed to
the unwanted reactivity of BQ as an electrophile, particu-
larly, as a strong Michael acceptor. Therefore, we tested a
number of substituted benzoquinones: NQ (1,4-naphtho-
quinone), DMBQ (2,4-dimethyl-1,4-benzoquinone),
DTBQ (2,4-di-tert-butyl-1,4-benzoquinone), and duro-
SYNTHESIS 2011, No. 13, pp 2147–2153
Advanced online publication: 19.05.2011
DOI: 10.1055/s-0030-1260057; Art ID: Z29311SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

2148
P. A. Donets, E. V. Van der Eycken
PAPER
quinone. These should be more stable against nucleophilic mation,12,8a and most importantly, of the C–H activation
attack owing to steric hindrance introduced by the substit- step.13 The change of the catalyst for the cationic complex
uents. Indeed, switching to DTBQ resulted in more than Pd(MeCN)4(BF4)2 allowed to conduct the reaction at a
two-fold increase of the yield (Table 1, entry 2). THF was lower temperature (entry 3). This result is consistent with
found to be a slightly superior solvent than 1,4-dioxane in the fact, that cationic palladium intermediates are often
terms of yield (Table 1, entry 3). However, at the current more reactive than the analogous neutral species in Heck
stage of work this difference was negligible.
reaction.14 However, no improvement of the yield was ob-
served even upon increasing the loading of DTBQ to
100%. Therefore, the previously established conditions
(Table 1, entry 3) were utilized as primary for further
elaboration.
Formation of 2a was also observed in a totally different
catalytic system employing DMSO as the solvent at
110 °C, Pd(OAc)2 as catalyst, and O2 as oxidant (Table 2,
entry 1). This combination for direct O2-coupled catalytic
turnover was independently discovered in 1990s by the A number of compounds 3a–f (Figure 1) with structural
groups of Hiemstra and Larock and was applied widely resemblance to 1a was tested as substrates for the cycliza-
for oxidative heterocyclization reactions.9
tion. No reaction was observed in any of these cases,
which allows drawing certain conclusions. Thus, the sub-
strate has to contain a free NH-indole core (e.g., com-
pounds 3a,b have no free NH-indole). The amide group of
1a, clearly induces palladation via an ortho-directing ef-
fect, since compounds 3c and 3e with a shifted amide
group position fail to cyclize. The 2-picolyl group in 3d,
reported to induce palladation in oxidative Heck reaction
of indole,3b is not functional under our conditions. The
case of compound 3f, bearing no amide group, but poten-
tially capable15 of forming a six-membered palladacycle,
also proves the exclusive effect of the amide function.
Table 2 Secondary Set of Conditions
O
O
Me
[Pd] (10 mol%)
N
N
Me
O2 (1 atm)
DMSO, 16 h
N
H
N
H
1a
2a
Entry
Catalyst
Temp (°C) Additive
Yield (%)a
1
2
3
Pd(OAc)2
Pd(OAc)2
110
110
80
none
22
37
37
O
N
DTBQb
DTBQb
O
CF3
N
Me
Pd(MeCN)4(BF4)2
a Isolated yield.
N
R
N
R
b DTBQ (40 mol%).
3a R = Ac
3b R = Me
3c R = H
3d R = 2-picolyl
The presence of 40 mol% DTBQ improved the reaction
outcome (Table 2, entry 2). No reaction occurred in the
absence of O2, thus, DTBQ clearly is not responsible for
the oxidation of palladium(0) in this case. However, BQ
has been reported to play several major roles in C–C
bond-forming palladium -catalyzed reactions involving
C–H activation10 apart from being an oxidant. It may act
as a ligand, stabilizing active palladium species during the
catalytic cycle,11 as well as a promoter of C–C bond for-
O
N
N
Me
Me
N
H
N
H
3e
3f
Figure 1
Me
N
O
O
Me
N
PdCl2(MeCN)2
– HCl
N
Me
O
S
N
H
Pd
Pd
Cl
S
S
Cl
1a
4
5
S = solvent
HQ = hydroquinone
O
O
Me
S
N
syn-insertion,
Me
BQ
N
Pd(II)
Pd(0)
HPdCl
+
β-hydride
– HCl
– HQ
elimination
N
Pd
H
Cl
6
2a
Scheme 1
Synthesis 2011, No. 13, 2147–2153 © Thieme Stuttgart · New York

PAPER
Synthesis of Azepinoindoles via Oxidative Heck Cyclization
2149
The described experimental facts enabled us to sketch a tained from indoles bearing a strong coordinating N-
possible mechanism (Scheme 1) for the cyclization of 1a group do not engage in coupling, as described by Ricci et
under the primary conditions with p-benzoquinone as an al.,3b also favors this hypothesis. Finally, the p-complex 6
oxidant. The key intermediate forming after coordination is formed with the relative alignment of the olefin double
of palladium(II) to the amide group should be the pallada- bond and the C–Pd bond being crucial14 for the cyclization
cycle 4. Strongly coordinating solvents (MeCN, DMF, regioselectivity. The given mechanistic rationalization
DMSO, HMPA) would be dominating in the ligand limits the role of p-benzoquinone to reoxidation16 of pal-
sphere of palladium(II) and, thus, would prevent pallada- ladium(0) to palladium(II) and is hardly applicable to the
tion via 4 suppressing the overall reaction, which indeed combination Pd(OAc)2/DMSO/O2/DTBQ.
is observed. On the other hand, formation of the interme-
diate 5 requires solvent to be capable of displacing the
amide group in 4. This assumption is consistent with the
A number of substrates 1b–j were prepared for evaluation
of the cyclization scope (Table 3). In all cases the primary
set of conditions (Table 1, entry 3) was applied first,
fact that weakly coordinating solvents (EtOAc, toluene)
changing the oxidant if necessary.
slow down the reaction. The fact that palladacycles ob-
Table 3 Investigation of the Cyclization Scope
Entry
Substrate
Oxidant
DTBQ
Solvent
THF
Product
Yield (%)a
O
O
Me
N
N
1
1a
2a
53
Me
Me
N
H
N
H
O
O
2b
3
none
DMBQ
MeCN
THF
40
35
Me
Me
1b
1c
2b
2c
N
N
N
H
N
H
O
O
25c
55d
N
4
5
DTBQ
DMBQ
Me
N
THF
THF
N
H
N
H
E/Z ~ 9:1
O
O
N
6
7
DTBQ
DMBQ
n.r.
13
N
1d
1e
1f
2d
2e
2f
N
H
N
H
E/Z ~ 9:1
O
O
Me
N
N
Me
8
DTBQ
DTBQ
THF
40e
1
N
H
N
H
2
3
O
O
Me
9
10
1,4-dioxane
THF
14
56
N
N
Me
N
H
N
H
Synthesis 2011, No. 13, 2147–2153 © Thieme Stuttgart · New York

2150
P. A. Donets, E. V. Van der Eycken
PAPER
Table 3 Investigation of the Cyclization Scope (continued)
Entry
Substrate
Oxidant
Solvent
Product
Yield (%)a
O
O
Bn
N
Bn
N
11
p-benzoquinonef THF
n.r.
36
1g
2g
12g
O2/DTBQ
DMSO
N
H
N
H
O
O
13
p-benzoquinonef THF
n.r.
20
N
1h
1i
2h
2i
14g
O2/DTBQ
DMSO
N
N
H
N
H
CO2Me
Ac
CO2Me
Ac
N
N
15
16
DMBQ
THF
THF
17 (28)h
N
H
N
H
O
O
N
N
1j
DMBQ
2j
20
N
H
N
H
a Isolated yields reproduced on three consecutive runs.
b PdCl2(MeCN)2/AgBF4 (1.5 equiv), 80 °C, 15 min.
c endo 17%/exo 8%.
d endo 38%/exo 17%.
e Ratio of D1,2/D2,3 = ~1:19.
f BQ or DMBQ, or DTBQ.
g DMSO, Pd(MeCN)4(BF4)2 (10 mol%), O2 (1 atm, balloon), DTBQ (40 mol%), 80–90 °C.
h Based on the recovered starting material.
Thus, the allylamine amide 1b failed to cyclize in the ble bond substitution in 1g renders the latter inert under
presence of DTBQ. Nevertheless, the corresponding primary reaction conditions (Table 3, entry 11). However,
product 2b was obtained using stoichiometric amount of the corresponding azepinoindolone 2g could be obtained
palladium(II) (Table 3, entry 2)5 revealing the principal applying the secondary set of conditions (Table 3, entry
possibility of cyclization. Switching to DMBQ (Table 3, 12). Interestingly, when conducted without DTBQ reac-
entry 3) allowed catalytic conversion of 1b to 2b with a tion of 1g led to a complete degradation of the starting ma-
comparable efficiency. The example of 1b gave us a terial. Application of the secondary condition set was also
sound proof for a complex role of p-benzoquinone in the fruitful in the case of amide 1h successfully leading to the
reaction. DTBQ was also less efficient than DMBQ in the teracycle 2h (Table 3, entry 14). We also decided to test
case of 1c (Table 3, entries 4, 5) containing a disubstituted tryptophan derivative 1i as a substrate for the cyclization
double bond. The corresponding product 2c was obtained under our conditions. The results previously reported for
as a separable mixture of endo- and exo-cyclic double the stoichiometric oxidative Heck cyclization of this com-
bond isomers. The presence of a bulky isopropyl substitu- pound in Pd(OAc)2/DMSO/O2 system strongly suggest
ent in 1d otherwise analogous to 1c led to a significant de- that the methoxycarbonyl group may induce palladation.6a
crease of the yield (Table 3, entry 7). Amide 1e was Indeed, we managed to obtain the azepinoindol 2i using
cyclized under the optimal primary conditions with a sat- DMBQ as an oxidant (Table 3, entry 15). However, the
isfactory yield (Table 3, entry 8). The product azepino- yield did not exceed 17% due to the incomplete conver-
indolone 2e was isolated as a chromatographically sion, which failed to improve even with an additional
inseparable mixture of double bond isomers. The example amount of catalyst. Low conversion was plaguing the sim-
of 1f containing a trisubsituted double bond reveals a pe- ilar reported transformation as well.6a Perhaps this is a
culiar solvent effect. Namely, THF (Table 3, entry 10) is consequence of the less efficient palladation step, which
far more superior to 1,4-dioxane (Table 3, entry 9), even has to proceed via a seven-membered intermediate instead
though in the case of 1a (Table 1, entries 2, 3) there was of a six-membered 4 (Scheme 1). In contrast to all afore-
almost no difference between these solvents. Heavier dou- mentioned substrates amide 1j afforded the azocino-
Synthesis 2011, No. 13, 2147–2153 © Thieme Stuttgart · New York

PAPER
Synthesis of Azepinoindoles via Oxidative Heck Cyclization
2151
1H NMR (400 MHz, CDCl3): d = 8.28 (s, 1 H), 7.64 (d, J = 7.7 Hz,
1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.10–7.21 (m, 2 H), 6.11 (s, 1 H),
3.56 (s, 2 H), 3.11 (s, 3 H), 2.57 (q, J = 7.4 Hz, 2 H), 1.15 (t, J = 7.4
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.09, 137.64, 132.86, 126.33,
126.30, 122.85, 122.13, 119.95, 118.48, 110.94, 109.14, 36.51,
33.10, 26.06, 14.45.
indolone 2j. This outcome should be the consequence of a
different pattern for coordination of the double bond on
palladium(II) in the intermediate 6 determined by the
structure of the substrate. Under the secondary set of con-
ditions 1j underwent complete decomposition.
In summary, we have developed an approach towards aze-
pino[4,5-b]indol-2-ones via oxidative Heck cyclization of
readily accessible 3-indoleacetic acid amides. The initial-
ly speculated crucial role of the amide function as a sup-
porting group has been confirmed. It has also been
demonstrated, that the nature of the solvent and the struc-
ture of the p-benzoquinone ensure the success of the cy-
clization. Despite the moderate efficiency of the
developed method, the discovered effects may be helpful
in the further development of novel applications of the
oxidative Heck reaction in general.
HRMS (EI): m/z calcd for C15H16N2O: 240.1263; found: 240.1267.
exo-2c
Prepared from 1c (48 mg) with DMBQ; yield: 8 mg (17%); eluent:
hexane–EtOAc (2:3); Rf = ~0.12. An analytically pure sample was
obtained after recrystallization from EtOAc.
1H NMR (400 MHz, CDCl3): d = 8.10 (s, 1 H), 7.52 (d, J = 7.9 Hz,
1 H), 7.27 (d, J = 7.9 Hz, 1 H), 7.14–7.19 (m, 1 H), 7.06–7.11 (m, 1
H), 5.95 (q, J = 7.0 Hz, 1 H), 4.31 (s, 2 H), 3.96 (s, 2 H), 3.04 (s, 3
H), 1.97 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 172.55, 136.16, 134.38,
128.21, 127.28, 122.51, 120.35, 119.27, 118.27, 111.17, 150.47,
47.17, 33.68, 33.06, 13.54.
1H and 13C NMR spectra were recorded on Bruker Avance 300 or
Bruker 400 instruments with TMS as an internal standard at 298 K
unless otherwise stated. High-resolution mass spectra (EI) were re-
corded on Kratos MS50TC and Kratos Mach III system.
HRMS (EI): m/z calcd for C15H16N2O: 240.1263; found: 240.1268.
2d
Prepared from 1d (54 mg) with DMBQ; yield: 7 mg (13%); eluent:
hexane–EtOAc (1:1); Rf = ~0.19.
Oxidative Heck Cyclization Under Primary Conditions; Gener-
al Procedure
1H NMR (400 MHz, CDCl3): d = 7.99 (s, 1 H), 7.71 (d, J = 8.0 Hz,
1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.21–7.26 (m, 1 H), 7.15–7.20 (m, 1
H), 6.25 (s, 1 H), 4.92 (sept, J = 6.7 Hz, 1 H), 3.53 (s, 2 H), 2.63 (q,
J = 7.6 Hz, 2 H), 1.20 (t, J = 7.6 Hz, 3 H), 1.18 (d, J = 6.7 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 167.69, 137.59, 132.94, 126.33,
123.91, 122.76, 120.79, 119.90, 118.54, 110.91, 109.59, 46.25,
33.71, 26.47, 20.71, 14.61.
Amide 1 (0.2 mmol), PdCl2(MeCN)2 (5 mg, 10 mol%), and the p-
benzoquinone [1.5 equiv; either DTBQ (66 mg) or DMBQ (40 mg)]
were loaded into a screw-cap vial equipped with a stir bar. The vial
was evacuated and flushed back with argon. Anhyd THF (4 mL)
was added, the vial was sealed under argon, and kept with stirring
at 110 °C (oil bath temperature). After 16 h, the reaction mixture
was filtered through a short pad of Celite. The filtrate was evaporat-
ed with silica gel under reduced pressure. The residue was subjected
to column chromatography on silica gel.
HRMS (EI): m/z calcd for C17H20N2O: 268.1576; found: 268.1573.
2e
2a
Prepared from 1e (56 mg) with DTBQ; yield: 22 mg (40%); eluent:
hexane–EtOAc (1:1); Rf = ~0.10. An analytically pure sample was
obtained after recrystallization from DMSO.
1H NMR (400 MHz, CDCl3): d = 8.23 (s, 1 H), 7.55 (d, J = 7.7 Hz,
1 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.09–7.19 (m, 2 H), 5.98–6.04 (m, 1
H), 5.90–5.96 (m, 1 H), 3.93 (d, J = 16.1 Hz, 1 H), 3.88 (d, J = 16.1
Hz, 1 H), 3.85 (d, J = 14.8 Hz, 1 H), 3.58 (d, J = 14.8 Hz, 1 H), 3.14
(s, 3 H), 2.38–2.46 (m, 1 H), 2.29–2.36 (m, 2 H), 2.19–2.27 (m, 1
H), 2.01–2.10 (m, 1 H), 1.77–1.85 (m, 1 H).
Prepared from 1a (51 mg) with DTBQ; yield: 27 mg (53%); eluent:
hexane–EtOAc (1:3); Rf = ~0.21.
1H NMR (400 MHz, DMSO-d6, 327 K): d = 10.55 (s, 1 H), 7.46 (d,
J = 7.7 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.01–7.07 (m, 1 H),
6.95–7.00 (m, 1 H), 6.02 (dd, J = 10.6, 17.4 Hz, 1 H), 5.16 (dd,
J = 1.2, 10.6 Hz, 1 H), 4.93 (dd, J = 1.2, 17.4 Hz, 1 H), 3.72–3.81
(m, 3 H), 3.67 (d, J = 15.0 Hz, 1 H), 2.95 (s, 3 H), 1.45 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.47, 141.94, 136.77, 135.27,
127.62, 122.06, 119.53, 118.17, 116.10, 110.47, 104.20, 59.28,
43.44, 37.42, 32.44, 23.84.
13C NMR (100 MHz, DMSO-d6, 363 K): d = 173.53, 141.45,
135.88, 127.68, 126.37, 125.14, 121.20, 118.87, 117.67, 111.18,
102.77, 53.48, 38.30, 36.97, 33.74, 32.46, 30.20, 22.58.
HRMS (EI): m/z calcd for C16H18N2O: 254.1419; found: 254.1428.
HRMS (EI): m/z calcd for C18H20N2O: 280.1576; found: 280.1589.
2b
Prepared from 1b (46 mg) with DMBQ; yield: 16 mg (35%); eluent:
hexane–EtOAc (1:1); Rf = ~0.21.
1H NMR (400 MHz, DMSO-d6): d = 11.15 (s, 1 H), 7.61 (d, J = 7.8
Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.11–7.16 (m, 1 H), 7.02–7.07
(m, 1 H), 6.32 (d, J = 1.2 Hz, 1 H), 3.45 (s, 2 H), 3.01 (s, 3 H), 2.21
(d, J = 1.2 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 167.25, 138.11, 134.65,
127.46, 126.14, 122.39, 119.46, 118.23, 115.76, 111.74, 106.97,
36.36, 33.08, 18.44.
2f
Prepared from 1f (51 mg) with DTBQ; yield: 29 mg (57%); eluent:
hexane–EtOAc (2:1); Rf = ~0.16.
1H NMR (400 MHz, CDCl3): d = 8.05 (s, 1 H), 7.70 (d, J = 7.8 Hz,
1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.21–7.26 (m, 1 H), 7.15–7.9 (m, 1
H), 6.11 (d, J = 0.8 Hz, 1 H), 3.55 (s, 2 H), 3.13 (s, 3 H), 2.93 (sept,
J = 6.7 Hz, 1 H), 1.27 (d, J = 6.7 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 168.39, 137.67, 132.87, 127.06,
126.16, 125.44, 122.80, 119.89, 118.43, 110.97, 109.57, 36.46,
33.02, 31.08, 22.53.
HRMS (EI): m/z calcd for C14H14N2O: 226.1106; found: 226.1110.
HRMS (EI): m/z calcd for C16H18N2O: 254.1419; found: 254.1418.
endo-2c
Prepared from 1c (48 mg) with DMBQ; yield: 18 mg (38%); eluent:
hexane–EtOAc (2:3); Rf = ~0.33.
Synthesis 2011, No. 13, 2147–2153 © Thieme Stuttgart · New York

2152
2i
P. A. Donets, E. V. Van der Eycken
PAPER
Hz, 1 H), 4.43 (d, J = 14.2 Hz, 1 H), 4.10 (d, J = 15.0 Hz, 1 H), 3.62
(dd, J = 3.4, 14.2 Hz, 1 H), 3.44–3.55 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 175.48, 136.97, 135.17,
128.89, 128.03, 127.97, 121.15, 119.04, 117.82, 111.18, 101.81,
47.06, 44.30, 33.56, 32.13.
Prepared from 1i (66 mg) with DMBQ; yield: 11 mg (17%); eluent:
hexane–EtOAc (2:3); Rf = ~0.35. During chromatography 26 mg of
the starting amide 1i was recovered (eluent: hexane–EtOAc, 2:3;
Rf = ~0.14); recalculated yield of 2i: 28% (brsm).
1H NMR (400 MHz, CDCl3): d = 7.98 (s, 1 H), 7.56 (d, J = 7.8 Hz,
1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.17–7.22 (m, 1 H), 7.10–7.15 (m, 1
H), 6.52 (s, 1 H), 5.66 (t, J = 5.0 Hz, 1 H), 3.71 (dd, J = 5.7, 16.7
Hz, 1 H), 3.56 (s, 3 H), 3.22 (dd, J = 4.6, 16.7 Hz, 1 H), 2.91 (sept,
J = 6.7 Hz, 1 H), 2.22 (s, 3 H), 1.32 (d, J = 6.7 Hz, 1 H), 1.25 (d,
J = 6.7 Hz, 1 H).
HRMS (EI): m/z calcd for C15H14N2O: 238.1106; found: 238.1106.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
13C NMR (100 MHz, CDCl3): d = 170.13, 169.72, 135.36, 130.54,
128.59, 127.39, 123.48, 122.91, 119.80, 118.60, 113.03, 110.68,
56.10, 52.11, 30.11, 26.73, 23.24, 22.66, 22.10.
References
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reaction, see: (a) Karimi, B.; Behzadnia, H.; Elhamifar, D.;
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Fujiwara, Y. Org. Lett. 1999, 1, 2097.
HRMS (EI): m/z calcd for C19H22N2O3: 326.1630; found: 326.1637.
2j
Prepared from 1j (50 mg) with DMBQ; yield: 10 mg (20%); eluent:
hexane–EtOAc (1:4); Rf = ~0.11.
1H NMR (400 MHz, CDCl3): d = 7.96 (s, 1 H), 7.65 (d, J = 7.9 Hz,
1 H), 7.25 (d, J = 7.9 Hz, 1 H), 7.15–7.19 (m, 1 H), 7.09–7.14 (m, 1
H), 6.39 (dd, J = 2.1, 11.9 Hz, 1 H), 5.59 (dd, J = 4.9, 11.9 Hz, 1 H),
5.00–5.05 (m, 1 H), 4.29 (d, J = 14.5 Hz, 1 H), 3.77 (d, J = 14.5 Hz,
1 H), 3.48–3.62 (m, 2 H), 2.08–2.18 (m, 1 H), 1.89–2.00 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 169.22, 135.57, 133.46,
131.42, 129.14, 123.99, 122.62, 119.48, 118.74, 111.39, 109.21,
56.69, 45.55, 33.96, 32.78, 23.12.
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HRMS (EI): m/z calcd for C16H16N2O: 252.1263; found: 252.1276.
Oxidative Heck Cyclization Under Secondary Conditions; Gen-
eral Procedure
Amide 1 (0.2 mmol), Pd(MeCN)4(BF4)2 (9 mg, 10 mol%), and
DTBQ (18 mg, 40 mol%) were loaded into a round-bottom single-
necked flask equipped with a stir bar. Anhyd DMSO (2 mL) was
added and an O2 balloon was attached to the neck via a three-port
valve. The flask was evacuated and flushed back with O2. After stir-
ring for 16 h at elevated temperature (oil bath) under O2 atmosphere,
the reaction mixture was poured into H2O (20 mL) and extracted
with EtOAc (2 × 10 mL). The combined organic layers were washed
with H2O (20 mL), brine (10 mL), dried (MgSO4), and concentrated
under reduced pressure with silica gel. The residue was subjected to
column chromatography on silica gel.
(6) Azocinoindole in Deoxyisoaustamide and Okaramine N:
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7904. (b) Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am.
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2g
Prepared from 1g (69 mg) at 90 °C; yield: 25 mg (36%); eluent:
hexane–EtOAc (3:1); Rf = ~0.16.
(7) Joucla, L.; Montagne, C.; Fournet, G.; Joseph, B. Lett. Org.
1H NMR (400 MHz, DMSO-d6, 363 K): d = 10.43 (s, 1 H), 7.49 (d,
J = 7.6 Hz, 1 H), 7.25–7.39 (m, 6 H), 6.97–7.08 (m, 2 H), 5.01 (m,
1 H), 4.65–4.71 (m, 2 H), 4.47 (d, J = 15.3 Hz, 1 H), 3.93 (d,
J = 15.7 Hz, 1 H), 3.87 (d, J = 15.7 Hz, 1 H), 3.82 (d, J = 15.2 Hz,
1 H), 3.57 (d, J = 15.2 Hz, 1 H), 1.72 (d, J = 0.8 Hz, 3 H), 1.48 (s, 3
H).
13C NMR (75 MHz, CDCl3): d = 173.43, 147.00, 137.92, 137.49,
135.24, 128.75, 128.04, 127.52, 127.48, 121.98, 119.44, 118.09,
115.25, 110.60, 103.92, 54.22, 51.13, 45.68, 32.59, 24.00, 19.99.
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HRMS (EI): m/z calcd for C23H24N2O: 344.1889; found: 344.1889.
2h
Prepared from 1h (48 mg) at 80 °C; yield: 10 mg (20%); eluent:
CH2Cl2–MeCN (2:1); Rf = ~0.26.
1H NMR (400 MHz, DMSO-d6): d = 11.08 (s, 1 H), 7.48 (d, J = 7.8
Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.04 (m, 1 H), 6.98–7.04 (m, 1
H), 6.02–6.10 (m, 1 H), 5.72–5.78 (m, 1 H), 4.50 (dd, J = 4.0, 17.3
Synthesis 2011, No. 13, 2147–2153 © Thieme Stuttgart · New York

PAPER
Synthesis of Azepinoindoles via Oxidative Heck Cyclization
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Synthesis 2011, No. 13, 2147–2153 © Thieme Stuttgart · New York