Palladium-Catalyzed Regioselective Synthesis of 1-Benzoazepine Carbonitriles from o-Alkynylanilines via 7-endo-dig Annulation and Cyanation

Article abstract of DOI:10.1002/adsc.201800865

We herein report a three-component, one-pot cascade reaction involving an imination/annulation/cyanation sequence for the synthesis of 1-benzoazepine carbonitrile derivatives using readily available o-alkynylanilines, cyclic ketones and trimethylsilyl cyanide. This regio- and stereoselective reaction was achieved by combining palladium(II) trifluoroacetate and copper(II) acetate in dimethyl sulfoxide. The important features of this method include a broad substrate scope, the use of trimethylsilyl cyanide as a cyanating agent, the formation of two C?C bonds and one C?N bond, mild reaction conditions and good product yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201800865

Title: Palladium-Catalyzed Regioselective Synthesis of 1-
Benzoazepine Carbonitriles from <i>o</i>-Alkynylanilines via 7-
<i>endo</i>-dig Annulation and Cyanation
Authors: Ganesh Kumar Dhandabani, Mohana Reddy Mutra, and Jeh-
Jeng Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800865
Link to VoR: http://dx.doi.org/10.1002/adsc.201800865

10.1002/adsc.201800865
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Regioselective Synthesis of 1-
Benzoazepine Carbonitriles from o-Alkynylanilines via 7-endo-
dig Annulation and Cyanation
Ganesh Kumar Dhandabani,[a] Mohana Reddy Mutra,[a] and Jeh-Jeng Wang*[a,b]
[a]
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Rd,
Sanmin District, Kaohsiung City, 807 (Taiwan). Tel: (+886)-7-3121101, Fax: (+886)-7-3125339, Email:
jjwang@kmu.edu.tw
Department of Medical Research, Kaohsiung Medical University Hospital, No. 100 Tzyou 1st Rd, Sanmin District,
[b]
Kaohsiung City 807, Taiwan
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201#####. ((Please
delete if not appropriate))
Abstract. We herein report a three-component, one-pot copper(II) acetate in dimethyl sulfoxide. The important
cascade
reaction
involving
an features of this method include a broad substrate scope, the
imination/annulation/cyanation sequence for the synthesis of use of trimethylsilyl cyanide as a cyanating agent, the
1-benzoazepine carbonitrile derivatives using readily formation of two C-C bonds and one C-N bond, mild
available o-alkynylanilines, cyclic ketones and trimethylsilyl reaction conditions and good product yields.
cyanide. This regio- and stereoselective reaction was
achieved by combining palladium(II) trifluoroacetate and
Keywords: Regio- and stereoselective, hydroenamination,
cascade, 7-endo dig, cyanation, palladium
Introduction
reactions,[7] and others have been reported.[8] Despite
the potential advantages of these methods, some of
the reported methods require harsh reaction
conditions and starting materials that are difficult to
synthesize and have poor substrate scope. Thus, the
development of new synthetic strategies to construct
the benzoazepine core with a broad range of
functional groups in a simple and straightforward
Medium-sized carbocyclic and heterocyclic
structures are a pivotal class of compounds because
of their presence in many bioactive molecules,
pharmaceuticals and natural products.[1] Among these
structures, seven membered aza-heterocycles, such as
benzoazepines, possess excellent biological activities,
such
as
anti-depressant,[2a,b]
(MetAP)
methionine
and
aminopeptidase
inhibition[2c]
sphingosine kinase I enzyme inhibition (SphK1)[2d]
activities (Figure 1). On the other hand, α-
aminonitriles are vital bioactive motifs that are used
to treat various diseases and are one of the main
precursors for synthesizing α-amino acids.[3] In this
regard, we envisaged that the incorporation of α-
aminonitriles into a benzoazepine core will open a
new pathway for identifying potential compounds in
medicinal chemistry.
The 1-benzoazepine scaffold has attracted less
attention from the synthetic community than those of
2- and 3-benzoazepines, even though compounds
with this scaffold possess potential bioactivities.[4g]
Very few elegant methods have been reported in the
literature for synthesizing the 1-benzoazepine core;
however,
transition-metal-catalyzed
annulation
reactions,[4] ring openings of alkylidenecyclopropanes
and isoxazolidines,[5] cycloadditions,[6] rearrangement
Figure 1. Representative examples of benzoazopines
1
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10.1002/adsc.201800865
Advanced Synthesis & Catalysis
Table 1 Optimization of the reaction conditions[a]
manner, which is an interesting and undeveloped area
of research.[9]
Scheme 1. Previous work and this work on cyclization of
N-aryl enamine
Entry Pd catalyst
“Cu” Source Solvent
Yield%
[b]
3aa/4aa
55/ --
45/ --
47/--
65/--
72/--
84/--
30/--
25/18
--/--
33/41
Trace/--
--/--
--/28
63/--
--/25
--/59
44/--
62/--
1
Pd(OAc)2
Pd(OAc)2
PdCl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
2[c]
3
4
5
6
7
8
9
10
11
12
PdI2
PdCl2(PPh3)2 Cu(OAc)2
Pd(TFA)2
Pd(PPh3)4
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Cu(OAc)2
Cu(OAc)2
Cu(TFA)2
CuBr2
CuCl2
CuSO4
CuBr
CuBr
CuCN
CuCN
Activated N-aryl enamines generated from o-
alkynylanilines have been used to construct aza-
heterocycles such as indoles[10a] and quinolines.[10b,c]
For example, Chiba et al. discovered a copper-
catalyzed intramolecular aerobic oxidative method
to generate multisubstituted quinolines from N-aryl
enamines (Scheme 1a).[10a] In 2008, Fujioka et al.
reported a tandem imination/annulation strategy for
the synthesis of N-alkylated indoles (Scheme 1b).[10b]
To date, the in situ generation of N-aryl enamines
from o-alkynylanilines followed by 7-endo-dig
multicomponent cascade methodologies has not
been documented in the literature. Generally, the
synthesis of 7-membered rings demands expensive
metal catalysts, such as Pt,[11a] Ir,[11b] Rh,[11c] and
Au/Ag.[11d] To overcome the above issues and to
develop new reaction conditions for the construction
of heterocycles and heteroatom-containing acyclic
13[c,d] Pd(TFA)2
14[e]
15[e,f] Pd(TFA)2
Pd(TFA)2
16
17
18
19
20
21
Pd(TFA)2
--
--
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Dioxane 25/--
THF --/--
CH3NO2 --/--
Toluene --/--
22
[a]
All reactions were carried out using 1a (0.5 mmol), 2a
(0.75 mmol), TMSCN (1.0 mmol), Pd catalyst (5 mol %),
Cu salt (0.5 mmol) and DMSO solvent (1 mL) at 110 °C,
and the mixtures were stirred for 3-6h unless otherwise
noted.[b] Isolated yield. [c] Reaction was performed under O2
atmosphere. [d] Reaction was performed in the presence of
0.2 equiv CuBr. [e] Reaction was performed with 1.5 equiv
CuCN. [f] Reaction was performed without TMSCN.
structures,[12] we
herein
present
a
new
multicomponent reaction (MCR) strategy. The
synthesis of benzoazepine-tethered α-aminonitriles
was achieved through the in situ generation of
unactivated cyclic N-aryl enamines from o-
alkynylanilines and cyclohexanone followed by a 7-
endo-dig cascade reaction sequence involving
TMSCN as the cyanating agent (Scheme 1c). To the
best of our knowledge, there was only one previous
report on 7-endo-dig cyclizations of activated β-
enamino esters, and that reaction requires a multistep
protocol.[13]
improve the yield of 3aa (Table 1, entry 2). To
determine the optimal palladium source, we
performed the reaction using different Pd catalysts,
such as PdCl2, PdI2, PdCl2(PPh3)2, and Pd(TFA)2
(Table 1, entries 3-6). Among them, Pd(TFA)2
afforded the maximum yield (84%, Table 1, entry 6).
In situ generated Pd(II) failed to produce better
results (Table 1, entry 7). Further screening of
various copper salts (Table 1, entries 8-14) revealed
that Cu(OAc)2 provided the best results. When
Cu(OAc)2/CuCN was used, the reaction produced
either a mixture of 3aa and 4aa or only 4aa as the
major product. These results suggested competition
between intramolecular nucleophilic attack of the
amine (5-exo dig) and the enamine (7-endo dig) by
the o-alkyne. The reaction failed to give the desired
product 3aa when TMSCN was replaced with CuCN
(Table 1, entry 15). These results suggested that
TMSCN is a key reagent in this reaction process.
Interestingly, when the reaction was performed
without Pd(TFA)2, we obtained 3aa, albeit in a low
yield (Table 1, entries 17). In contrast, no product
Results and Discussion
Our investigation began with 2-(phenylethynyl)
aniline 1a, cyclohexanone 2a and TMSCN as model
substrates using 5 mol% Pd(OAc)2 and 1 equiv of
Cu(OAc)2 with DMSO as the solvent at 110 °C. To
our surprise, the desired compound, 4aH-dibenzo[b,f]
azepine-4a-carbonitrile 3aa, was obtained as a single
stereoisomer in a 55% yield (Table 1, entry 1).
Conducting the reaction under an O2 balloon failed to
2
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10.1002/adsc.201800865
Advanced Synthesis & Catalysis
was observed when using Pd(TFA)2 alone (Table 1,
entry 16). Changing the solvent from DMSO to other
solvents resulted in trace or no product formation,
which confirmed that the solvent plays a crucial role
in this reaction (Table 1, entries 18-22).
3fa-3ha were still obtained. Next, we explored
substrates with R groups bearing electron-donating
and electron-withdrawing groups, such as m-Me-Ph
(1i), p-OMe-Ph (1j), m-OMe-Ph (1k), m-Cl-Ph (1l),
m-F-Ph (1m), m-CF3-Ph (1n), m-CN-Ph (1o) and m-
NO2-Ph (1p). These compounds readily provided the
expected products 3ia-3pa in 55-81% yields.
However, the o-methoxy-containing substituent (1q)
failed to give the desired product (3qa), which was
likely due to steric hindrance. When we tested our
reaction with a thiophene substituent (1r), we
obtained spiro compound 4ra along with the desired
product 3ra. A plausible mechanism for the
formation of 4ra is shown in the supporting
Table 2. Scope and limitations of different o-alkyne
anilines with cyclohexanone[a,b]
Table 3. Scope and limitations of o-alkyne aniline with
different cyclohexanones[a,b]
[a]
Reaction conditions: compounds 1a (0.5 mmol), 2b-d
(0.75 mmol), TMSCN (1.0 mmol), Pd catalyst (5 mol %),
Cu(OAc)2 (0.5 mmol) and DMSO solvent (1 mL) at
[b]
110 °C for the indicated times unless otherwise noted.
Single regioisomer confirmed by NMR analysis.
Scheme 2. Oxidation of 11-phenyl-1,2,3,4,5,11a-
hexahydro-4aH-dibenzo[b,f]azepine-4a-carbonitrile
[a]
Reaction conditions: compounds 1a-s (0.5 mmol), 2a
(0.75 mmol), TMSCN (1.0 mmol), Pd catalyst (5 mol %),
Cu(OAc)2 (0.5 mmol) and DMSO solvent (1 mL) at
[b]
110 °C for the indicated times unless otherwise noted.
Reaction was performed with 2.5 mol % Pd catalyst.
information.[14] This catalytic system did not tolerate
alkyl substituents, and these substrates provided only
the indole product (4sa). The structures of
compounds 3aa, 3la, 4ra and 4sa were confirmed by
X-ray crystallography analysis.[15]
To illustrate the generality and efficiency of our
optimized reaction conditions (Table 1, entry 6), we
synthesized an array of 4aH-dibenzo[b,f]azepine-4a-
carbonitrile derivatives (3aa-3fd). Initially, a series of
R1-substituted o-alkynylanilines (1a-1h) was reacted
with cyclohexanone (2a) under standard conditions,
and all tested substrates provided their respective
products in moderate to good yields (Table 2, 3aa-
3ha, 47-88%). The yields were slightly suppressed
when R1 contained an electron-withdrawing group,
such as m-CF3, p-CF3 and p-NO2, but the products
Next, we investigated the applicability of this
reaction to cyclohexanone derivatives with different
R2 substituents such as 4-Me (2b), 3-Me (2c) and 4-t-
Bu (2d). The reaction worked well and afforded
compounds 3ab-3fd in 50-84% yields (Table 3).
Surprisingly,
the
reaction
with
3-methyl
cyclohexanone regioselectively afforded product 3ac
(determined by 2D-NMR analysis), and the
cyclopentanone (2e), cycloheptanone (2f) and
3
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10.1002/adsc.201800865
Advanced Synthesis & Catalysis
acetophenone (2g) derivatives were not compatible
with these reaction conditions (Table 3). To show the
significance of this synthetic method, we synthesized
serves as a cyanating agent (Scheme 3 b and c).[16]
Furthermore, to confirm the in situ generation of
Cu(CN)2, we carried out the reaction with
combinations of Cu(OAc)2 and CuCN, which failed
to give product 3aa (Scheme 3, d). In addition, we
attempted to in situ generate Cu(CN)2 by combining
TMSCN and Cu(OAc)2 and reacting that solution
with the starting materials 1a and 2a in a sequential,
one-pot reaction, and this method afforded product
3aa in an 80% yield (Scheme 3, e).
biologically
valuable
10-phenyl-5H-dibenzo
[b,f]azepine (5aa) by oxidation of 11-phenyl-
1,2,3,4,5,11a-hexahydro-4aH-dibenzo[b,f] azepine-
4a-carbonitrile (3aa, Scheme 2).[12a]
Scheme 3. Control studies
Next, simple aniline was introduced instead of o-
alkynylaniline under the optimized reaction
conditions to successfully obtain the Strecker product
in the presence of Cu(OAc)2. This result confirmed
the role of copper salt in the cyanation step (Scheme
3, f).[17] When 1a and 2a were treated under the
optimized reaction conditions with 1 equiv of D2O,
we did not observe any H/D exchanged product 3aa,
and in the presence of 5 equiv D2O, the same reaction
failed to give the desired product (Scheme 3, g).
These results indicate that H2O was not directly
involved in the metal protonation process, and we
speculate that acetic acid plays a major role in the
protolysis of the palladium complex.[18]
Scheme 4. Plausible reaction mechanism
Based on the literature reports and control studies,
a plausible mechanism was proposed, as shown in
Scheme 4.[16,19] Initially, the acid-catalyzed imination
and consecutive isomerization generated the enamine
intermediate B. The reaction of enamine B with a
To elucidate the mechanism of this reaction, we
conducted various control studies. Recently, Prof Liu
et al.[16a-b] proposed a radical mechanism for the in
situ generation of Cu(CN)2 for various cyanation
reactions. Herein, we performed this reaction in the
presence of two radical scavengers, TEMPO and 1,4-
cyclohexadiene. However, the reaction gave the
desired products in yields similar to those achieved in
the absence of radical scavengers. These results
suggested that the reaction does not occur via a
radical pathway (Scheme 3, a). To determine the role
of copper in the reaction mechanism, we carried out
reactions with CuCN in the presence and absence of
TMSCN. The reaction gave the desired product 3aa
in 63% only in the presence of both TMSCN and
CuCN. These results support a mechanism involving
in situ generation of an active Cu(CN)2 species that
Pd(II)/Cu(II)
catalyst
generated
active
Pd(II)/Cu(II) species C.[18,19] Further intramolecular
7-endo-dig cyclization gave metal complex D. Then,
the acid-promoted protolysis of intermediate D
regenerated the active Pd(II)/Cu(II) catalysts[18] and
produced the highly reactive intermediate E. Finally,
the active cyanating species Cu(CN)2 will cyanate E
at the electrophilic imine carbon to afford the final
Strecker reaction product.
Conclusion
In summary, we exploited the versatility of N-aryl
enamine in a regio- and stereoselective annulation
reaction to robustly synthesize 2-benzoazepine
carbonitrile derivatives. This reaction strategy
4
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10.1002/adsc.201800865
Advanced Synthesis & Catalysis
142.64, 140.14, 134.22, 129.43, 129.34, 128.27, 122.24,
120.90, 120.47, 119.33, 117.86, 113.00, 112.27, 55.30,
52.81, 52.50, 39.22, 28.24, 26.04, 20.05; HRMS (ESI)
calcd for C22H23N2O [M+H]+: 331.1801; found: 331.1805.
involved a tandem imination/annulation/cyanation
reaction that was catalyzed/mediated by
a
Pd(II)/Cu(II) bimetallic system. The mechanistic
studies revealed that the reaction occurred via a
Pd/Cu-catalyzed/mediated oxidative annulation and
Cu(OAc)2/TMSCN-mediated imine cyanation. To the
best of our knowledge, this is the first report of a 7-
endo-dig cyclization/cyanation with an in situ-formed
N-aryl enamine to prepare this valuable motif with a
carbonitrile substituent. Further synthetic applications
for the developed reactions are currently being
developed in our laboratory.
8-Chloro-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3da). Following the
general procedure on a 1.0 mmol scale for 4.50h giving the
compound as an off-white solid (227 mg, yield 68%); Mp
1
186-187 °C; H NMR (400 MHz, CDCl3) δ 7.41–7.33 (m,
4H), 7.33–7.27 (m, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.03 (dd,
J = 8.5, 2.4 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.43 (s, 1H),
4.03 (s, 1H), 3.19 (ddd, J = 11.4, 3.0, 1.7 Hz, 1H), 2.37 (d,
J = 12.8 Hz, 1H), 2.24 (ddd, J = 14.1, 11.9, 6.0 Hz, 1H),
1.84–1.61 (m, 5H), 1.47–1.33 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 144.00, 142.00, 141.17, 133.12, 128.47,
128.17, 127.87, 127.46, 126.78, 125.14, 123.74, 120.65,
119.20, 52.80, 52.49, 39.03, 28.22, 25.97, 19.98; HRMS
(ESI) calcd for C21H19N2Cl [M+H]+: 337.1130; found:
357.1129.
Experimental Section
General procedure for preparation of 11-Phenyl-
1,2,3,4,5,11a-hexaHydro-4aH-dibenzo[b,f]azepine-4a-
carbonitrile (3aa):In an oven dried 15 mL sealed tube 2-
(phenylethynyl) aniline 1a (193 mg, 1.0 mmol) was added
in 1 mL of DMSO followed by the sequential addition of
Pd(TFA)2 (16 mg, 5.0 mol %), Cu(OAc)2 (181 mg, 1.0
mmol), TMSCN (251 µL, 2.0 mmol) and cyclohexanone
2a (156 µL, 1.5 mmol). The reaction mixture was allowed
to stir at 110 °C for 3h. After the completion, the reaction
mixture was cooled to room temperature and diluted with
25.0 mL of cold water. The water layer was extracted with
(3X25 mL) of ethyl acetate and the combined ethyl acetate
layer was given brine wash (1X10 mL). The final ethyl
acetate layer was dried over sodium sulfate and
concentrated under reduced pressure to get the crude
compound. The obtained crude was purified using column
chromatography by eluting from hexane to 6-10% ethyl
acetate/hexane to afford pure 11-phenyl-1,2,3,4,5,11a-
hexaHydro-4aH-dibenzo[b,f]azepine-4a-carbonitrile (3aa)
as an off white solid (252 mg, yield 84%); Mp. 185-186
oC; 1H NMR (400 MHz, CDCl3) δ 7.42–7.38 (m, 2H), 7.37
–7.31 (m, 2H), 7.3–7.25 (m, 1H), 7.17 (dd, J = 7.8, 1.3 Hz,
1H), 7.09 (td, J = 8, 1.2 Hz, 1H), 6.85 (td, J = 7.5, 1.2 Hz,
1H), 6.67 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 4.00 (s, 1H),
3.23–3.12 (m, 1H), 2.37 (d, J = 14.9 Hz, 1H), 2.30–2.15
(m, 1H), 1.83–1.63 (m, 5H), 1.46–1.32 (m, 1H); 13C NMR
(101 MHz, CDCl3) δ 144.45, 142.60, 140.29, 134.20,
129.49, 128.39, 128.22, 127.15, 126.83, 122.29, 120.95,
120.45, 117.86, 52.82, 52.51, 39.22, 28.19, 26.05, 20.05;
HRMS (ESI) calcd for C21H21N2 [M+H]+: 301.1695;
found: 301.1699.
8-Fluoro-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ea). Following the
general procedure on a 1.0 mmol scale for 3h giving the
compound as an orange solid (206 mg, yield 65%); Mp
1
162-163°C; H NMR (400 MHz, CDCl3) δ 7.41–7.34 (m,
4H), 7.33–7.28 (m, 1H), 6.89 (dd, J = 9.8, 2.9 Hz, 1H),
6.84–6.79 (ddd, J = 8.7, 7.6, 2.9 Hz, 1H), 6.63 (dd, J = 8.7,
4.8 Hz, 1H), 6.42 (s, 1H), 3.92 (s, 1H), 3.18 (ddd, J = 11.2,
3.5, 1.7 Hz, 1H), 2.37 (d, J = 14.2 Hz, 1H), 2.26 (ddd, J =
14.2, 12.3, 5.6 Hz, 1H), 1.82–1.66 (m, 5H), 1.40 (dd, J =
10.8, 6.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 157.19
(d, JF = 237.7 Hz), 144.10, 142.17, 138.95, 128.46, 128.32
(d, JF = 1.7 Hz), 127.44, 127.25, 126.85, 123.75 (d, JF =
7.2 Hz),, 120.77, 119.23 (d, JF = 22.35 Hz),, 118.99 (d, JF
= 7.8 Hz), 115.24, 115.01, 52.83, 52.53, 39.05, 28.34,
25.98, 20.04; HRMS (ESI) calcd for C21H20N2F
[M+H]+:319.1598; found: 319.1605.
11-(3-(Trifluoromethyl)phenyl)-1,2,3,4,5,11a-
hexahydro-4aH-dibenzo[b,f]azepine-4a-carbonitrile
(3fa). Following the general procedure on a 1.0 mmol scale
for 12h giving the compound as an off-white solid (172 mg,
1
yield 47%); Mp 190-191 °C; H NMR (400 MHz, CDCl3)
δ 7.43 (s, 1H), 7.42–7.39 (m, 2H), 7.39–7.34 (m, 2H), 7.33
–7.26 (m, 2H), 6.74 (d, J = 12.0 Hz, 1H), 6.51 (s, 1H), 4.39
(s, 1H), 3.22 (dd, J = 9.2, 1.7 Hz, 1H), 2.38 (d, J =13.9 Hz,
1H), 2.28–2.13 (m, 1H), 1.86–1.59 (m, 5H), 1.50–1.32 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 145.05, 143.77,
142.03, 131.23 (q, JF = 3.9 Hz), 128.50, 128.37, 127.55,
126.68, 125.67, 124.70 (q, JF = 3.6 Hz), 122.98, 122.39,
122.06, 121.70, 120.52, 118.01, 52.80, 52.48, 38.91, 28.10,
25.93, 19.87; HRMS (ESI) calcd for C22H20N2F3 [M+H]+:
369.1570; found: 369.1573.
8-Methyl-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ba). Following the
general procedure on a 1.0 mmol scale for 5h giving the
compound as an yellow solid (276 mg, yield 88%); Mp
11-Phenyl-7-(trifluoromethyl)-1,2,3,4,5,11a-hexahydro-
1
174-175 °C; H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m,
4aH-dibenzo[b,f]azepine-4a-carbonitrile
(3ga).
2H), 7.38–7.32 (m, 2H), 7.30–7.26 (m, 1H), 6.99 (s, 1H),
6.91 (dd, J = 8.0, 1.6 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H),
6.49 (s, 1H), 3.90 (s, 1H), 3.18 (dd, J = 8.7, 4.4 Hz, 1H),
2.36 (d, J = 14.4 Hz, 1H), 2.28–2.18 (m, 4H), 1.85–1.66
(m, 5H), 1.41 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
144.54, 140.33, 140.24, 130.58, 129.59, 129.50, 129.08,
128.36, 127.09, 126.84, 122.21, 121.06, 117.91, 52.89,
52.47, 39.19, 28.18, 26.06, 20.25, 20.07; HRMS (ESI)
calcd for C22H23N2 [M+H]+: 315.1852; found: 315.1856.
Following the general procedure on a 1.0 mmol scale for
7h giving the compound as an white solid (198 mg, yield
1
54%); Mp 219-220 °C; H NMR (400 MHz, CDCl3) δ
7.40–7.25 (m, 6H), 7.07 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H),
6.54 (s, 1H), 4.21 (s,1H), 3.23 (d, J = 14.4 Hz, 1H), 2.42 (d,
J = 14.2 Hz, 1H), 2.30–2.22 (m, 1H), 1.82–1.65 (m, 5H),
1.47–1.37 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 143.57
(d, JF = 79.1 Hz), 142.67, 134.71, 129.92 (d, JF = 23.8 Hz),
128.47, 128.42, 127.74, 125.24 (q, JF = 5.7 Hz), 122.63,
120.55 (d, JF = 6.7 Hz), 116.93 (d, JF = 3.8 Hz), 114.83 (d,
JF = 3.8 Hz), 52.89, 52.86, 39.07, 28.51, 26.05, 20.14;
HRMS (ESI) calcd for C22H20N2F3N2 [M+H]+: 369.1572;
found: 369.1573.
8-Methoxy-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ca). Following the
general procedure on a 1.0 mmol scale for 3h giving the
compound as a brown solid (280 mg, yield 85%); Mp 142-
143 °C; 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 7.9 Hz,
1H), 7.18 (d, J = 7.7 Hz, 1H), 7.10 (td, J = 7.6, 1.2 Hz, 1H),
7.00 (ddd, J = 7.7, 1.6, 0.9 Hz, 1H), 6.94 (t, J = 2.4 Hz,
1H), 6.87 (dd, J = 7.5, 1.0 Hz, 1H), 6.84 (ddd, J = 8.1, 2.6,
0.8 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.55 (s, 1H), 4.00 (s,
1H), 3.84 (s, 3H), 3.23–3.14 (m, 1H), 2.38 (d, J = 14.9 Hz,
1H), 2.32–2.17 (m, 1H), 1.84–1.66 (m, 5H), 1.48–1.34 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 159.57, 146.00,
8-Nitro-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-dibenzo
[b,f]azepine-4a-carbonitrile (3ha). Following the general
procedure on a 1.0 mmol scale for 12h giving the
compound as an yellow solid (213 mg, yield 62%); Mp
237-238 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 2.5
Hz, 1H), 7.96 (dd, J = 8.9, 2.6 Hz, 1H), 7.45–7.39 (m, 3H),
7.38–7.29 (m, 2H), 6.74 (d, J = 8.9 Hz, 1H), 6.60 (s, 1H),
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800865
Advanced Synthesis & Catalysis
4.67 (s, 1H), 3.31–3.20 (m, 1H), 2.43 (d, J = 14.3 Hz, 1H),
2.33–2.19 (m, 1H), 1.88–1.63 (m, 5H), 1.50–1.39 (m, 1H);
13C NMR (101 MHz, CDCl3) δ 147.65, 143.31, 143.14,
140.84, 130.07, 128.64, 127.89, 127.67, 126.64, 123.53,
121.47, 120.00, 117.94, 110.00, 53.17, 52.43, 39.03, 27.97,
25.90, 19.89; HRMS (ESI) calcd for C21H20N3O2 [M+H]+:
346.1551; found: 346.1550.
1H), 7.03–6.95 (m, 1H), 6.87 (td, J = 7.6, 1.1 Hz, 1H),
6.69 (d, J = 7.7 Hz, 1H), 6.57 (s, 1H), 4.05 (s, 1H), 3.21–
3.08 (m, 1H), 2.38 (d, J = 14.0 Hz, 1H), 2.24 (td, J = 12.8,
5.2 Hz, 1H), 1.87–1.63 (m, 5H), 1.48–1.35 (m, 1H); 13C
NMR (101 MHz, CDCl3) δ 162.78 (d, JF = 246.08 Hz),
146.65 (d, JF = 7.1 Hz), 142.70, 138.86, 138.84, 134.34,
130.16, 129.88, 129.80, 128.55, 122.42 (d, JF = 2.81 Hz),
121.33 (d, JF = 106.73Hz), 117.90, 113.93 (d, JF = 21.24
Hz), 113.77 (d, JF = 21.54 Hz), 52.70, 52.38, 39.10, 28.23,
25.99, 19.98; HRMS (ESI) calcd for C21H19N2FNa
[M+Na]+: 341.1422; found: 341.1424.
11-(m-Tolyl)-1,2,3,4,5,11a-hexahydro-4aH-dibenzo[b,f]
azepine-4a-carbonitrile (3ia). Following the general
procedure on a 1.0 mmol scale for 3h giving the compound
as an off white solid (188 mg, yield 60%); Mp 163-
164 °C ; 1H NMR (400 MHz, CDCl3) δ 7.26–7.23 (m, 2H),
7.21–7.14 (m, 2H), 7.13–7.05 (m, 2H), 6.86 (td, J = 7.6,
1.2 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H), 4.01 (s,
1H), 3.17 (ddd, J = 11.2, 3.3, 1.6 Hz, 1H), 2.38 (s, 3H),
2.36–2.35 (m, 1H), 2.24 (td, J = 12.8, 4.8 Hz, 1H), 1.79–
1.67 (m, 5H), 1.48–1.34 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ 144.49, 142.58, 140.47, 137.94, 134.14, 129.26,
128.25, 128.13, 127.91, 127.54, 123.97, 122.35, 120.99,
120.41, 117.84, 52.81, 52.53, 39.18, 28.18, 26.03, 21.49,
20.04; HRMS (ESI) calcd for C22H23N2 [M+H]+: 315.1851;
found: 315.1856.
11-(3-(Trifluoromethyl)phenyl)-1,2,3,4,5,11a-
hexahydro-4aH-dibenzo[b,f]azepine-4a-carbonitrile
(3na). Following the general procedure on a 1.0 mmol
scale for 7h giving the compound as an off white solid
(276 mg, yield 75%); Mp 182-183 °C; 1H NMR (400 MHz,
CDCl3) δ 7.64 (s, 1H), 7.57 (dd, J = 16.2, 7.7 Hz, 2H), 7.48
(t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.13 (td, J =
8.0, 1.6 Hz, 1H), 6.89 (td, J = 7.7, 1.0 Hz, 1H), 6.71 (d, J =
8.0 Hz, 1H), 6.56 (s, 1H), 4.06 (s, 1H), 3.17 (t, J = 6.4 Hz,
1H), 2.40 (d, J = 14.3 Hz, 1H), 2.27 (td, J = 12.8, 5.2 Hz,
1H), 1.91–1.67 (m, 5H), 1.47–1.39 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 145.23, 142.75, 138.72, 134.42, 131.01,
130.79, 130.69, 130.13, 128.92, 128.73, 125.44, 123.89 (q,
JF = 3.8 Hz), 123.58 (q, JF = 3.8 Hz), 121.28 (d, JF =
106.83 Hz), 119.27 (d, JF = 260.1 Hz), 52.72, 52.55, 39.06,
28.20, 25.96, 19.98; HRMS (ESI) calcd for C22H20N2F3
[M+H]+: 369.1572; found: 369.1573.
11-(4-Methoxyphenyl)-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ja). Following the
general procedure on a 1.0 mmol scale for 5h giving the
compound as an brown solid (224 mg, yield 68%); Mp
1
156-157 °C ; H NMR (400 MHz, CDCl3) δ 7.33 (m, 2H),
7.17 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H), 6.87 (m,
3H), 6.67 (d, J = 8.0 Hz, 1H), 6.49 (s, 1H), 3.96 (s, 1H),
3.83 (s, 3H), 3.16 (d, J = 8.8 Hz, 1H), 2.38 (d, J = 15.2 Hz,
1H), 2.25 (td, J = 13.6, 4.8 Hz, 1H), 1.81–1.69 (m, 5H),
143–1.38 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 159.00,
142.57,139.96, 136.91, 134.16, 128.66, 128.10, 127.98,
122.56, 120.55, 117.90, 113.86, 55.41, 52.97, 52.52, 39.39,
28.30, 26.19, 20.17; HRMS (ESI) calcd for C22H23N2O
[M+H]+: 331.1799; found: 331.1805.
11-(3-Cyanophenyl)-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f] azepine-4a-carbonitrile (3oa). Following the
general procedure on a 1.0 mmol scale for 3.50h giving the
compound as an brown solid (178 mg, yield 55%); Mp
194-195 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (t, J = 1.5
Hz, 1H), 7.68–7.62 (m, 1H), 7.57 (dt, J = 7.7, 1.3 Hz, 1H),
7.46 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.14 (td,
J = 8.4, 1.6 Hz,1H), 6.89 (td, J = 7.6, 1.1 Hz, 1H), 6.71 (d,
J = 8.0 Hz, 1H), 6.55 (s, 1H), 4.10 (s, 1H), 3.13 (dd, J =
8.8, 4.5 Hz, 1H), 2.41 (d, J = 13.5 Hz, 1H), 2.26 td, J =
12.0, 5.2 Hz, 1H), 1.89–1.64 (m, 5H), 1.51–1.36 (m, 1H);
13C NMR (101 MHz, CDCl3) δ 145.61, 142.76, 137.70,
134.49, 131.31, 131.17, 130.58, 130.42, 129.32, 128.96,
121.48, 120.64, 120.56, 118.75, 118.00, 112.65, 52.62,
52.43, 39.01, 28.19, 25.94, 19.92; HRMS (ESI) calcd for
C22H19N3Na [M+Na]+: 348.1471; found: 348.1471.
11-(3-Methoxyphenyl)-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f] azepine-4a-carbonitrile (3ka). Following the
general procedure on a 1.0 mmol scale for 5h giving the
compound as an off white solid (217 mg, yield 66%); Mp
140-141 °C ; 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 7.9
Hz, 1H), 7.17 (dd, J = 7.8, 1.2 Hz, 1H), 7.12–7.05 (m, 1H),
7.00 (ddd, J = 7.7, 1.6, 0.9 Hz, 1H), 6.94 (t, J = 2.4 Hz,
1H), 6.86 (dd, J = 7.7, 1.2 Hz, 1H), 6.84–6.82 (m 1H),
6.68 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 4.05 (s, 1H), 3.83 (s,
11-(3-Nitrophenyl)-1,2,3,4,5,11a-hexahydro-4aH-
3H), 3.21–3.13 (m, 1H), 2.36 (d, J = 14.6 Hz, 1H), 2.21 (td, dibenzo[b,f]azepine-4a-carbonitrile (3pa). Following the
J = 13.6, 4.9 Hz, 1H), 1.79–1.65 (m, 5H), 1.44–1.34 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 159.52, 145.96,
142.66, 140.08, 134.16, 129.40, 129.32, 128.23, 122.15,
120.94, 120.37, 119.27, 117.84, 112.95, 112.21, 55.27,
52.76, 52.46, 39.07, 28.21, 25.99, 19.99; HRMS (ESI)
calcd for C22H23ON2 [M+H]+: 331.1796; found: 331.1805.
general procedure on a 1.0 mmol scale for 12h giving the
compound as an yellow solid (248 mg, yield 72%); Mp
225-226 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (t, J = 2.0
Hz, 1H), 8.15 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.75 (ddd, J
= 7.7, 1.8, 1.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.22 (d, J
= 7.7 Hz, 1H), 7.15(td, J = 8.0, 1.6 Hz, 1H), 6.90 (td, J =
7.6, 1.1 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.62 (s, 1H),
4.08 (s, 1H), 3.24–3.16 (m, 1H), 2.43 (d, J = 14.0 Hz, 1H),
2.35–2.21 (m, 1H), 1.91–1.68 (m, 5H), 1.50–1.37 (m, 1H);
13C NMR (101 MHz, CDCl3) δ 148.41, 146.04, 142.84,
137.55, 134.59, 132.81, 131.59, 129.43, 129.07, 122.01,
121.65, 121.50, 120.65, 120.60, 118.04, 52.66, 52.38,
39.04, 28.28, 25.94, 19.96; HRMS (ESI) calcd for
C21H19N3NaO2 [M+Na]+: 368.1369; found: 368.1369.
11-(3-Chlorophenyl)-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3la). Following the
general procedure on a 1.0 mmol scale for 4.50h giving the
compound as an off-white solid (270 mg, yield 81%); Mp
1
185-187 °C; H NMR (400 MHz, CDCl3) δ 7.39–7.38 (m,
1H), 7.32–7.23 (m, 3H), 7.19 (dd, J = 7.7, 1.2 Hz, 1H),
7.11 (td, J = 7.2, 1.6 Hz, 1H), 6.87 (td, J = 7.5, 1.1 Hz, 1H),
6.69 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 4.03 (s, 1H), 3.17–
3.08 (m, 1H), 2.38 (d, J = 14.0 Hz, 1H), 2.28 (td, J = 12.4,
11-(Thiophen-2-yl)-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f] azepine-4a-carbonitrile (3ra). Following the
5.2 Hz, 1H), 1.90–1.66 (m, 5H), 1.48–1.34 (m, 1H); 13
C
NMR (101 MHz, CDCl3) δ 146.31, 142.70, 138.80, 134.36, general procedure on a 1.0 mmol scale for 3h giving the
134.26, 130.33, 129.64, 128.59, 127.19, 127.00, 125.02,
121.88, 117.92, 52.70, 52.45, 39.10, 28.20, 25.97, 19.99;
HRMS (ESI) calcd for C21H20N2Cl [M+H]+: 335.1306;
found: 335.1310.
compound as a brown solid (156 mg, yield 51%); Mp 201-
202 °C; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.2 Hz,
1H), 7.18 (dd, J = 5.1, 1.0 Hz, 1H), 7.11–7.06 (m, 2H),
7.00 (dd, J = 5.1, 3.7 Hz, 1H), 6.91– 6.85 (m, 2H), 6.67 (d,
J = 7.9 Hz, 1H), 4.00 (s, 1H), 3.27 (d, J = 11.5 Hz, 1H),
2.39 (d, J = 14.1 Hz, 1H), 2.28 (td, J = 12.4, 5.6 Hz, 1H),
1.98 (d, J = 13.2 Hz, 1H), 1.88–1.74 (m, 4H), 1.54–1.43
(m, 1H); 13C NMR (101 MHz, CDCl3) δ 147.32, 142.61,
134.35, 132.84, 128.47, 127.70, 127.58, 123.94, 122.72,
121.81, 120.56, 117.82, 52.37, 51.72, 39.31, 28.77, 26.12,
20.08; HRMS (ESI) calcd for C19H19N2S [M+H]+:
307.1257; found: 307.1263.
11-(3-Fluorophenyl)-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ma). Following
the general procedure on a 1.0 mmol scale for 5h giving
the compound as an yellow solid (254 mg, yield 80%); Mp
1
162-163 °C; H NMR (400 MHz, CDCl3) δ 7.33–7.28 (m,
1H), 7.21–7.17 (m, 2H), 7.14–7.10 (m, 1H), 7.11–7.07 (m,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800865
Advanced Synthesis & Catalysis
3-Methyl-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ab). Following the
general procedure on a 1.0 mmol scale for 5h giving the
compound as an yellow solid (263 mg, yield 84%); Mp
1H), 2.28 (td, J = 13.9, 4.2 Hz, 1H), 1.77 (dd, J = 8.3, 5.3
Hz, 2H), 1.56–1.37 (m, 2H), 1.24 (tt, J = 12.2, 3.5 Hz, 1H),
0.80 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 150.18 (d, JF
= 238.6 Hz), 142.96 (d, JF = 189.2 Hz), 138.93, 128.48,
128.38, 127.44, 126.68, 123.67, 120.83, 119.24 (d, JF =
22.45 Hz), 119.00 (d, JF = 8.0 Hz), 115.13 (d, JF = 22.95
Hz), 52.68, 52.37, 48.01, 39.24, 32.43, 29.46, 27.30, 21.07;
HRMS (ESI) calcd for C25H28FN2 [M+H]+: 375.2233;
found: 375.2231.
1
165-166 °C; H NMR (400 MHz, CDCl3) δ 7.42–7.39 (m,
2H), 7.38–7.33 (m, 2H), 7.32–7.26 (m, 1H), 7.18 (dd, J =
7.8, 1.2 Hz, 1H), 7.09 (ddd, J = 8.0, 7.3, 1.6 Hz, 1H), 6.86
(td, J = 7.6, 1.2 Hz, 1H), 6.68 (dd, J = 7.8, 0.8 Hz, 1H),
6.54 (s, 1H), 4.04 (s, 1H), 3.24 (d, J = 10.8, 1H), 2.42–
2.27 (m, 1H), 2.07–1.97 (m, 1H), 1.97–1.88 (m, 1H), 1.82
–1.68 (m, 3H), 1.22–1.02 (m, 1H), 0.98 (d, J = 6.3 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 144.51, 142.69,
140.03, 134.19, 131.55, 129.44, 128.39, 128.21, 127.15,
126.84, 122.43, 120.78, 120.53, 117.86, 53.28, 52.35,
47.10, 34.89, 28.34, 26.44, 21.72; HRMS (ESI) calcd for
C22H23N2 [M+H]+: 315.1854; found: 315.1856.
2-(Tert-butyl)-11-phenyl-8-(trifluoromethyl)-1,2,3,4,5,
11a-hexahydro-4aH-dibenzo[b,f]azepine-4a-carbonitrile
(3fd). Following the general procedure on a 1.0 mmol
scale for 3h giving the compound as an off white solid
(301 mg, yield 50%); Mp 219-220 °C; 1H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 1.6 Hz, 1H), 7.43–7.39 (m, 2H),
7.40–7.35 (m, 2H), 7.34– 7.28 (m, 2H), 6.75 (d, J = 8.4 Hz,
1H), 6.58 (s, 1H), 4.31 (s, 1H), 3.31–3.20 (dt, J = 9.2, 1.6
Hz, 1H) 2.45 (dt, J = 6.7, 3.6 Hz, 1H), 2.25 (td, J = 13.9,
4.2 Hz, 1H), 1.80 (ddd, J = 12.5, 5.7, 2.0 Hz, 2H), 1.56–
1.38 (m, 2H), 1.32–1.24 (m, 1H), 0.81 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ 145.00, 143.63, 141.93, 131.30 (q, JF
= 3.9 Hz) 128.54, 128.46, 127.56, 126.57, 125.67, 124.79
(q, JF = 3.9 Hz), 122.97, 122.35, 121.73, 120.53, 118.03,
52.64, 52.37, 48.04, 39.20, 32.43, 29.25, 27.28, 20.98;
HRMS (ESI) calcd for C26H27F3N2 [M+Na]+: 447.2017;
found: 447.2018.
3-Methyl-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ac). Following the
general procedure on a 1.0 mmol scale for 6h giving the
compound as an yellow solid (229 mg, yield 73%); Mp
1
150-151 °C; H NMR (400 MHz, CDCl3) δ 7.42–7.39 (m,
2H), 7.38–7.33 (m, 2H), 7.32–7.26 (m, 1H), 7.18 (dd, J =
7.8, 1.2 Hz, 1H), 7.09 (ddd, J = 8.0, 7.3, 1.6 Hz, 1H), 6.86
(td, J = 7.6, 1.2 Hz, 1H), 6.68 (dd, J = 7.8, 0.8 Hz, 1H),
6.54 (s, 1H), 4.04 (s, 1H), 3.20–3.09 (m, 1H), 2.42–2.27
(m, 1H), 2.07–1.97 (m, 1H), 1.97–1.88 (m, 1H), 1.82–1.68
(m, 3H), 1.22–1.02 (m, 1H), 0.98 (d, J = 6.3 Hz, 3H); 13
C
NMR (101 MHz, CDCl3) δ 144.51, 142.69, 140.03, 134.19,
129.44, 128.39, 128.21, 127.15, 126.84, 122.43, 120.78,
120.53, 117.86, 53.28, 52.35, 47.10, 34.89, 28.34, 26.44,
21.72; HRMS (ESI) calcd for C22H23N2 [M+H]+: 315.1850;
found: 315.1856.
1-(Cyclohex-1-en-1-yl)-2-phenyl-1H-indole
(4aa).
Following the general procedure on a 1.0 mmol scale for
3h giving the compound as a brown solid; Mp 109-110 °C;
1H NMR (400 MHz, CDCl3) δ 7.69–7.57 (m, 3H), 7.43–
7.34 (m, 3H), 7.34–7.27 (m, 1H), 7.17 (ddd, J = 8.2, 7.1,
1.3 Hz, 1H), 7.10 (td, J = 8.0, 1.2 Hz, 1H), 6.66 (s, 1H),
6.08–5.99 (m, 1H), 2.29 (s, 2H), 1.94 (s, 2H), 1.66 (t, J =
2.8 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 139.70,
138.26, 135.80, 133.43, 128.27, 128.06, 127.92, 127.68,
127.44, 121.74, 120.29, 120.08, 110.58, 102.45, 29.24,
24.90, 22.79, 21.76. HRMS (ESI) calcd for C20H20N
[M+H]+: 274.1587; found: 274.1590.
3-(Tert-butyl)-11-phenyl-1,2,3,4,5,11a-hexahydro-4aH-
dibenzo[b,f]azepine-4a-carbonitrile (3ad). Following the
general procedure on a 1.0 mmol scale for 6h giving the
compound as an brown solid (267 mg, yield 75%); Mp
1
196-197 °C; H NMR (400 MHz, CDCl3) δ 7.43–7.41 (m,
2H), 7.39–7.33 (m, 2H), 7.29 (ddd, J = 7.1, 3.7, 1.3 Hz,
1H), 7.19 (d, J = 7.7 Hz, 1H), 7.10(td, J = 8.0, 1.2 Hz, 1H),
6.87 (td, J = 7.6, 1.0 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H),
6.58 (s, 1H), 4.01 (s, 1H), 3.23 (d, J = 11.1 Hz, 1H), 2.44
(dt, J = 14.3, 3.4 Hz, 1H), 2.26 (td, J = 13.8, 4.2 Hz, 1H),
1.84–1.71 (m, 2H), 1.63–1.44 (m, 2H), 1.26 (tt, J = 12.2,
3.4 Hz, 1H), 0.80 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
144.27, 142.60, 140.13, 134.20, 129.54, 128.40, 128.22,
127.12, 126.65, 122.26, 121.02, 120.42, 117.88, 52.67,
52.36, 48.10, 39.37, 32.41, 29.31, 27.31, 21.08 ; HRMS
(ESI) calcd for C21H21N2 [M+H]+: 301.1695; found:
301.1699; HRMS (ESI) calcd for C25H29N2 [M+H]+:
357.2322; found: 357.2325.
((E)-2-(spiro[Cyclohexane-1,2'-indolin]-3'-ylidene)-2-
(thiophen-2-yl)acetonitrile (4ra). Following the general
procedure on a 1.0 mmol scale for 3h giving the compound
as a yellow solid (113 mg, yield 37%); Mp 194-195 °C; 1H
NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 5.2, 1.3 Hz, 1H),
7.16 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.11 (dd, J = 5.1, 3.5
Hz, 1H), 7.07 (dd, J = 3.5, 1.3 Hz, 1H), 6.67 (d, J = 8.1 Hz,
1H), 6.42 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 6.33 (dd, J = 8.0,
0.8 Hz, 1H), 4.90 (s, 1H), 2.57 (td, J = 12.6, 4.4 Hz, 2H),
1.92 (d, J = 7.7 Hz, 2H), 1.80 (s, 1H), 1.71 (d, J = 11.9 Hz,
2H), 1.51 (t, J = 9.2 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 153.72, 136.06, 133.83, 128.28, 127.89, 127.69, 126.92,
122.87, 119.21, 118.36, 110.75, 68.02, 33.99, 24.26, 23.08;
HRMS (ESI) calcd for C19H19N2S [M+H]+: 307.1264;
found: 307.1263
2-(Tert-butyl)-8-chloro-11-phenyl-1,2,3,4,5,11a-
hexahydro-4aH-dibenzo[b,f]azepine-4a-carbonitrile
(3dd). Following the general procedure on a 1.0 mmol
scale for 5h giving the compound as an brown solid (261
1
mg, yield 67%); Mp 216-217 °C; H NMR (400 MHz,
1-(2-Cyclopropyl-5-methyl-1H-indol-1-yl)cyclohexane-
1-carbonitrile (4sa). Following the general procedure on a
1.0 mmol scale for 8h giving the compound as an light
pink solid (200 mg, yield 72%); Mp 123-124 °C; 1H NMR
(400 MHz, CDCl3) δ 7.61 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H),
7.00 (dd, J = 8.6, 1.5 Hz, 1H), 6.19 (t, J = 1.0 Hz, 1H),
2.84 (dd, J = 13.1, 1.5 Hz, 2H), 2.49–2.38 (m, 5H), 2.11–
2.03 (m, 1H), 2.01–1.95 (m, 3H), 1.95–1.83 (m, 2H), 1.39
–1.25 (m, 1H), 1.05–0.99 (m, 2H), 0.89–0.82 (m, 2H); 13C
NMR (101 MHz, CDCl3) δ 142.73, 134.84, 129.41, 128.58,
123.02, 120.15, 119.09, 112.37, 103.49, 60.73, 36.48,
24.62, 23.69, 21.04, 12.19, 9.53; HRMS (ESI) calcd for
C19H22N2Na [M+Na]+: 301.1677; found: 301.1675.
CDCl3) δ 7.39–7.25 (m, 5H), 7.16 (d, J = 2.0 Hz 1H), 7.03
(dd, J = 8.8, 2.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.45 (s,
1H), 3.97 (s, 1H), 3.20 (d, J = 11.2 Hz, 1H), 2.42 (d, J =
14.4 Hz, 1H), 2.25 (td, J = 14.0, 4.0 Hz 1H), 1.77 (d, J =
13.6 Hz, 2H), 1.51–1.43 (m, 1H), 1.27–1.21 (m, 1H), 0.87
(t, J = 6.8 Hz, 1H), 0.83 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 143.93, 141.98, 141.24, 133.25, 128.61, 128.34,
128.01, 127.57, 126.74, 125.28, 123.84, 120.81, 119.32,
52.73, 52.46, 48.14, 39.36, 32.54, 29.45, 27.40, 21.14;
HRMS (ESI) calcd for C25H28ClN2 [M+H]+: 391.1933;
found: 391.1935.
2-(Tert-butyl)-8-fluoro-11-phenyl-1,2,3,4,5,11a-
hexahydro-4aH-dibenzo[b,f]azepine-4a-carbonitrile
(3ed). Following the general procedure on a 1.0 mmol
scale for 6h giving the compound as an off white solid
(291 mg, yield 78%); Mp 240-241 °C; 1H NMR (400 MHz,
CDCl3) δ 7.42–7.34 (m, 4H), 7.32–7.28 (m, , 1H), 6.90 (dd,
J = 9.8, 2.9 Hz, 1H), 6.83 (ddd, J = 8.7, 7.6, 2.9 Hz, 1H),
6.63 (dd, J = 8.7, 4.8 Hz, 1H), 6.45 (s, 1H), 3.89 (s, 1H),
3.21 (dd, J = 9.2, 2.0 Hz, 1H), 2.43 (dt, J = 14.0, 3.5 Hz,
10-Phenyl-5H-dibenzo[b,f]azepine (5aa). In an oven
dried 15 ml seal tube 11-phenyl-1,2,3,4,5,11a-hexahydro-
4aH-dibenzo[b,f]azepine-4a-carbonitrile 4aa (269 mg, 1.0
mmol) was added in 1 ml of DMSO followed by addition
of 2 equiv TFA and 2 equiv 70% aq TBHP. The reaction
mixture was allowed to stir at 110 °C for 8h under O2
atmosphere. After the reaction completion, the reaction
7
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10.1002/adsc.201800865
Advanced Synthesis & Catalysis
mixture was cooled to room temperature and diluted with
25.0 mL of 10% aqueous NaHCO3 solution. The water
layer was extracted with (3X25 mL) of ethyl acetate and
the combined ethyl acetate layer was given brine wash
(1X10 mL). The final ethyl acetate layer was dried over
sodium sulfate and concentrated under reduced pressure to
get the crude compound. The obtained crude was purified
using column chromatography by eluting from hexane to
3-6% ethyl acetate/hexane to afford pure 10-phenyl-5H-
dibenzo[b,f]azepine (5aa) as a pale yellow solid (174 mg,
N. Hareyama, M. Terada, M. Yamazaki, T. Suzuki,
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1
yield 65%); Mp 123-124 °C; H NMR (400 MHz, CDCl3)
δ 8.28 (d, J = 8.4 Hz, 2H), 7.80–7.75 (m, 2H), 7.71 (d, J =
8.4 Hz, 2H), 7.62–7.58 (m, 3H), 7.46–7.43 (m, 5H); 13C
NMR (101 MHz, CDCl3) δ 148.90, 147.28, 136.06, 135.64,
130.52, 130.01, 129.69, 128.73,128.52, 128.42, 127.99,
126.93, 125.66, 125.23; HRMS (ESI) calcd for C20H16N
[M +H]+: 270.1279; found: 270.1277.
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1-(phenylamino)cyclohexane-1-carbonitrile. In an oven
dried 15 ml seal tube aniline (93 mg, 1.0 mmol) was added
in 1 ml of DMSO followed by the addition of Cu(OAc)2
(181 mg, 1.0 mmol), TMSCN (251 µL, 2.0 mmol) and
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reaction completion, the reaction mixture was cooled to
room temperature and diluted with 25.0 mL of cooled
water. The water layer was extracted with (3X25 mL) of
ethyl acetate and the combined ethyl acetate layer was
given brine wash (1X10 mL). The final ethyl acetate layer
was dried over sodium sulfate and concentrated under
reduced pressure to get the crude compound. The obtained
crude was purified using column chromatography by
eluting from hexane to 8-10% ethyl acetate/hexane to
afford pure 1-(phenylamino)cyclohexane-1-carbonitrile as
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1
pale yellow solid (166 mg, yield 83%); Mp 71-73 °C; H
NMR (400 MHz, CDCl3) δ 7.27–7.21 (m, 2H), 6.94–6.87
(m, 3H), 2.35–2.31 (m, 2H), 1.84–1.76 (m, 2H), 1.73–1.62
(m, 5H), 1.39–1.25 (m, 1H); 13C NMR (101 MHz, CDCl3)
δ 143.48, 129.19, 121.10, 120.56, 117.56, 54.36, 36.62,
24.86, 22.17.[17]
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Acknowledgements
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for Re-
search and Development of Kaohsiung Medical University for
400 MHz NMR, LC-MS and GC-MS analyses. The authors also
thank to Dr. Gopal Chandru Senadi for technical discussions and
for preparation of manuscript.
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9
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FULL PAPER
Palladium-Catalyzed Regioselective Synthesis of
1-Benzoazepine Carbonitriles from o-
Alkynylanilines via 7-endo-dig Annulation and
Cyanation
Adv. Synth. Catal. Year, Volume, Page – Page
G. K. Dhandabani, M. R. Mutra, J.-J. Wang*
10
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