Regio- and stereoselective construction of highly functionalized 3-benzazepine skeletons through ring-opening cycloamination reactions catalyzed by Gold

Article abstract of DOI:10.1002/chem.201002502

Ring size under control: Highly functionalized 1-amino- or 1-hydroxy-1H-benzo[d]azepines have been prepared through a gold-catalyzed cyclization of (o-alkynyl)phenyl aziridines with heteronucleophiles. After removal of the phthalimido group, the products can be further transformed into 1H-benzo[d]azepin-1-ones (see scheme; IBX=2-iodoxybenzoic acid, Phth=pthalimido).

Full text of DOI:10.1002/chem.201002502

COMMUNICATION
DOI: 10.1002/chem.201002502
Regio- and Stereoselective Construction of Highly Functionalized 3-
Benzazepine Skeletons through Ring-Opening Cycloamination Reactions
Catalyzed by Gold
Xiangwei Du,[a] Shuang Yang,[a] Jingyu Yang,[b] and Yuanhong Liu*[a]
The intramolecular cyclizations of alkynes containing
proximate C, O, N nucleophiles catalyzed by transition
metals is a powerful strategy to provide a rapid and highly
efficient access to carbo- and heterocyclic structural
motifs.[1] Recent studies demonstrated that gold complexes
and their salts are emerging as unique catalysts for cycliza-
tion reactions owing to their superior chemoselectivities and
reactivities.[2] Aziridines are versatile synthetic building
blocks for the preparation of functional materials and nitro-
gen-containing biologically active molecules, as they can un-
dergo facile ring opening and expansion reactions because
of their extremely strained ring structures.[3] Despite the
growing interests in gold-catalyzed nucleophilic-addition re-
actions of structurally similar epoxides to alkynes,[4] few ap-
plications have been reported for the synthetic transforma-
tion of aziridine/alkynes.[5] For instance, Sarpong and co-
workers have reported a platinum(II)-catalyzed cycloiso-
idines. Herein, we describe a gold-catalyzed ring-opening
cyclization of (o-alkynyl)phenyl aziridines assisted by exter-
nal nitrogen and oxygen nucleophiles (Scheme 1). The reac-
Scheme 1. Proposed formation of 3-benzazepine derivatives. Nu=Nucle-
ophile.
tion provides a highly regio- and stereoselective route to 3-
benzazepine and its derivatives. It is noted that the attack of
the aziridine to the alkyne moiety results in a highly regiose-
À
merization of aziridinyl propargylic esters to 1,2-dihydropyr-
lective 6-endo-dig cyclization, and a selective benzylic C3 N
idines via a metallocarbenoid intermediate.[5a] Zhao et al.
have developed a gold-catalyzed rearrangement reaction of
propargylic aziridine ethers involving an tandem cyclization/
ring-opening/Wagner–Meerwein process.[5b] Recently, our re-
search group[5c] and others[4l,5d,e] have also succeeded in the
incorporation of aziridines as nucleophiles in annulations re-
actions with alkynes through gold-catalyzed cycloisomeriza-
tion of alkynylaziridines—an efficient synthesis of function-
alized pyrroles. These reactions likely proceed through the
formation of aziridinium ions that result from the nucleo-
philic attack of the aziridinyl nitrogen on the gold-com-
plexed alkyne. We envisioned that the resulted intermediate
might be further attacked by a nucleophile, thus leading to
1,2-difunctional ring-opened products. To test this hypothe-
sis, we then designed and synthesized (o-alkynyl)phenyl azir-
bond cleavage of the aziridine ring by nucleophiles is also
highlighted. Recently, a gold-catalyzed conversion of 2-alky-
nylaryl epoxides into 3-acylindenes has been reported by
Hashmi et al.[4g] The reaction proceeds through a different
pathway that involves an intramolecular oxygen transfer and
the cyclization of a pentadienyl cation as key steps.
There has been considerable interest in the synthesis of
functionalized 3-benzazepines as they present as key struc-
tural subunits in alkaloids such as Cephalotaxus[6a] and Ben-
zindenoazepine alkaloids (Figure 1).[6b] Derivatives with a 3-
benzazepine framework have also displayed important bio-
logical activities for pharmaceutical use.[7] For example, they
are well known to act as dopamine receptor agonists and an-
tagonists (e.g., SCH-23390)[8] They are also active in animal
models of various neurological disorders, like Parkinsonꢀs
disease[9] and Alzheimerꢀs disease.[10]
[a] X. Du, S. Yang, Prof. Dr. Y. Liu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P.R. China)
Fax : (+86)021-64166128
E-mail: yhliu@mail.sioc.ac.cn
[b] J. Yang
Department of Chemistry, East China Normal University
3663 North Zhongshan road, Shanghai, 200062, (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002502.
Figure 1. Representative alkaloids and pharmacologically interesting sub-
stances containing 3-benzazepine derivatives.
Chem. Eur. J. 2011, 17, 4981 – 4985
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4981

The required (o-alkynyl)phenyl aziridines 2 were synthe-
sized easily through aziridination of the readily available
enynes 1 using the N-aminophthalimide/phenyliodineACHTUNTRGNEUNG(III)
place preferentially rather than the expected 5-exo-dig
mode. It is also clear that the amine-mediated ring opening
occurs selectively at C3 of the aziridine moiety, and only
trans-diastereomer of 3a was detected, as revealed by the
value of the coupling constant of the methine protons
diacetate (PIDA) system.[5c,11] This method was reported to
be versatile with regard to the electronic nature of the
olefin unit, and also to lead to high diastereoselectivities. A
series of trans-aziridine 2 with -CO2R, -COR, and -Ph func-
tionalities was conveniently prepared in good yields and
with high stereoselectivities from trans-enynes using this
method (Scheme 2). The isomer trans-2a, in which the
phthalimido residue and the ester group have the cis confi-
guration, was also characterized by X-ray crystallographic
analysis[12]. In the case of 2m, the aziridine exists as a mix-
1
(5.6 Hz determined by H NMR spectroscopy). The configu-
ration was further confirmed by X-ray crystallographic anal-
ysis of 3a.[12] Cationic gold complexes [(PPh3)AuSbF6] or
[(PPh3)AuNTf2] also showed significant reactivity (Table 1,
entries 2 and 3). The reaction could also be carried out in
toluene, CH2Cl2, DCE or 1,4-dioxane (Table 1, entries 4–7).
Acetonitrile afforded a moderate yield of 3a at 508C
(Table 1, entry 8). The use of AgOTf alone afforded low
yield (Table 1, entry 9). PtCl2 was not effective for this reac-
tion (Table 1, entry 10).
1
ture of invertomers as determined by H NMR analysis.
We chose the reaction conditions shown in Table 1,
entry 4 to examine the scope of this reaction. As illustrated
in Table 2, this gold-catalyzed ring-opening cycloamination
accommodates a wide range of substrates. The functional
groups Me, MeO, and Cl on the alkynyl aromatic ring (R4)
were well-tolerated during the reaction, and led to the cor-
responding 3-benzazepines 3b–3e in 43–83% yields
(Table 2, entries 2–5). However, the use of the stronger elec-
tron-withdrawing group CF3 resulted in a low yield (32%)
of 3 f, along with several undefined by-products (Table 2,
entry 6). The electronic nature of the aryl substituents influ-
ences the reaction rates, usually electron-rich alkynes made
the reaction faster than the electron-poor ones (Table 2,
compare entry 3 and 5). The thienyl-substituted alkyne 2g
was well-suited in this cyclization, and a high yield of 3g
could be achieved (Table 2, entry 7). Alkyl-substituted
alkyne 2h was also compatible, and led to 3h in 50% yield
(Table 2, entry 8). However, the use of a terminal alkyne
only resulted in a complicated mixture (Table 2, entry 9).
With a ketone present in the aziridine 2j, the regioselective
ring-opening product 3j was also generated smoothly in
90% yield (Table 2, entry 10). The substituents F or Me on
the parent aromatic ring were well-tolerated (Table 2, en-
tries 11 and 12). When aziridine 2m with a phenyl substitu-
ent as R1 group was employed, the reaction resulted compli-
cated and the desired benzazepines could not be isolated
(Table 2, entry 13). This result indicates that the electron-
withdrawing group on the aziridine ring plays an important
role for controlling the regioselectivity and the reaction
pathway. Other nitrogen nucleophiles such as p-methoxyani-
line, p-chloroaniline, and benzamide are not compatible for
this reaction.
Scheme 2. Aziridination of the enynes.
The reaction of 3-[2-(phenylethynyl)phenyl]aziridine-2-
carboxylate 2a with 4-nitroaniline was selected as the proto-
typical case to screen the experimental conditions (Table 1).
Satisfyingly, the reaction proceeded smoothly, and the de-
sired 3-benzazepines 3a was obtained in 84% yield at room
temperature in THF with the use of [(PPh3)AuCl] (5 mol%)
and AgOTf (5 mol%) as catalysts (Table 1, entry 1). The re-
sults indicated that a 6-endo-dig heterocyclization took
Table 1. Optimization studies for the formation of 3-benzazepine deriva-
tives.
Catalyst [5 mol%]
[(PPh3)AuOTf]
[(PPh3)AuSbF6]
[(PPh3)AuNTf2]
[(PPh3)AuOTf]
[(PPh3)AuOTf]
[(PPh3)AuOTf]
[(PPh3)AuOTf]
[(PPh3)AuOTf]
Solvent
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
9
U
THF
THF
THF
toluene
CH2Cl2
DCE
1,4-dioxane
CH3CN
toluene
toluene
5
3
3
3
3
4
4
4.5
11.5
21
84
86
76
88
72
Next, we proceeded to examine the reactions with oxygen
nucleophile of water instead of amine. After much effort,
we found that the cationic gold complex [(PPh3)AuOTf]
showed high catalytic activity in THF in the presence of
H2O (5 equiv; Scheme 5). However, the desired hydroxy
product 4 was hard to be purified by column chromatogra-
phy. Therefore, 4 was oxidized by IBX (2-iodoxybenzoic
acid) to allow for product purification. To our surprise, the
oxidation followed by the treatment with base resulted in
the clean formation of 1-oxo-1H-benzo[d]azepin-1-one 5[12]
75
89
56[b]
16[c]
little
AgOTf
[d]
10
PtCl2
[a] Yield of isolated product. [b] The reaction was carried out at 508C.
[c] Yield determined upon NMR analysis. [d] 10 mol%.
4982
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4981 – 4985

Synthesis of 3-Benzazepine Derivatives
COMMUNICATION
Table 2. Gold-catalyzed regio- and stereoselective synthesis of 3-benza-
zepine derivatives.
tion followed by proton transfer/protondeauration to give
the trans-products.[14] According to our results, the presence
of the electron-withdrawing R1 group is crucial for regiose-
lective ring opening. The results can be explained by consid-
ering the electronic effect.[15] In the intermediate 7, the
newly formed positive charge on the nitrogen is dispersed
À
through the aziridine ring, while weakening the C N bonds.
The bond between N1 and benzylic carbon C3 accommo-
Aziridine R1
R2 R3 R4
t
Product Yield
[%][a]
À
[h]
dates the positive charge better than the N1 C2 bond which
has an ester substituent, thus it get easier to be broken
toward the attack of the nucleophile. On the other hand, the
addition of water to the aziridine 2a promoted by p-
TsOH·H2O occurred also regioselectively at the benzylic po-
sition to give acyclic (2S*,3R*)-b-hydroxy-a-amino acid de-
rivative 9 in 56% yield as a single diastereomer (Scheme 4).
1
2
3
4
2a
2b
2c
2d
CO2Et
H
H
H
H
H
H
H
H
Ph
3
1
1
1
3a
3b
3c
3d
88
79
83
43
CO2Et
CO2Et
CO2Et
p-MeC6H4
p-MeOC6H4
3,4,5-tri-
MeOC6H2
p-ClC6H4
p-CF3C6H4
2-thienyl
nBu
5
6
7
8
9
2e
2 f
2g
2h
2i
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COPh
CO2Et
CO2Et
Ph
H
H
H
H
H
H
F
H
H
H
H
H
H
H
6
3e
73[b]
32[c]
96
50
–
4.5 3 f
1
2
2
2
4
3g
3h
[d]
H
Ph
Ph
–
10 2j
11 2k
12 2l
13 2m
3j
3k
3l
90
91
74
–
H
H
Me Ph
Ph
4
[b,c,d]
H
24
–
[a] Yield of isolated product. [b] The reaction was carried out in THF.
[c] The reaction was carried out at 808C. [d] Product not determined.
Scheme 4. Ring-opening reaction mediated by TsOH·H2O. Tf =trifluoro-
methanesulfonyl.
with the elimination of the phthalimido (Phth) group. This
further transformation by facile removal of the phthalimido
protection group also makes this method attractive for as-
sembling multisubstituted 1-oxo-benzo[d]azepines. As
shown in Scheme 5, the substrates containing aryl, heteroar-
yl, and 1-naphthyl groups afforded moderate to good yields
of the desired 5a–5j with multiple functionalities, which
should be very useful for further elaborations. The hydroxy-
lated products 4c and 4i could be obtained in a pure form
in 90% and 44% yield, respectively. In both cases, only the
trans-diastereomers were observed. The structural assign-
ment of the trans-isomers was verified by X-ray crystallo-
graphic analysis of 4a purified by recrystallization.[12]
These cycloamination reactions can be rationalized by the
regioselective 6-endo-dig cyclization of the aziridine nitro-
gen with gold(I)-alkyne complex, which leads to the aziridi-
nium ion intermediate 7 (Scheme 3).[13] Instead of deproto-
nation, 7 undergoes rapid nucleophilic ring opening by
amine or H2O at the benzylic carbon through an SN2 reac-
The syn-stereochemistry of 9 was confirmed by X-ray crys-
tallographic analysis.[12] To our surprise, the results indicated
that the configuration of C3 is retained by unusual syn-
attack during the reaction, which is quite rare in ring-open-
ing reactions of aziridines.[16] Compound 9 did not lead to
the benzazepine derivative under the catalysis of
[(PPh3)AuOTf]; instead, a mixture of 10 and one unknown
by-product[17] were obtained in a combined yield of 90%
(Scheme 4). The structural assignment of 10 was deduced
from a series of 2D NMR spectra of a pure sample. We also
prepared a mixture of syn- and anti-isomers of 9 through a
BF3·Et2O mediated reaction.[18] The gold-catalyzed reaction
of these isomers also did not afford the benzazepine deriva-
tive.[19] Based on these results, we suggest that the gold-cata-
lyzed cyclization of 2 with nucleophiles to form 3-benzaze-
pine derivatives probably does not involve the ring-opening
intermediate 9 or its diastereomer, that means, the starting
aziridine 2 might not be first opened by nucleophile.
In conclusion, we have developed a gold-catalyzed cycli-
zation of (o-alkynyl)phenyl aziridines[20] with heteronucleo-
philes to highly functionalized 1-amino or -hydroxy-1H-ben-
zo[d]azepines with trans-stereoselectivity. The latter could
be further transformed to 1H-benzo[d]azepin-1-ones by oxi-
dation/elimination sequence using IBX and base. The cycli-
zation reaction likely proceeds through the formation of an
aziridinium ion intermediate through a regioselective 6-
endo-dig cycloaddition. The existence of the electron-with-
drawing group on the aziridine ring is also important to
induce the regioselective ring opening at the benzylic posi-
tion. Further studies to expand the scope of these reactions
are in progress.
Scheme 3. Proposed mechanism for the gold-catalyzed heterocyclization.
Chem. Eur. J. 2011, 17, 4981 – 4985
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4983

Y. Liu et al.
(DIPEA;
diisopropylethylamine
0.5 mL) was added to a solution of the
above crude product in THF (3.0 mL).
The resulting solution was stirred at
room temperature until the reaction
was complete as monitored by thin-
layer chromatography. Then
a 5%
NaOH solution was added and the
mixture was extracted with ether. The
aqueous phase was extracted twice
with ether. The combined organic
layers were dried over anhydrous
Na2SO4, and concentrated under re-
duced pressure. The crude product
was purified by flash chromatography
on silica gel (petroleum ether/ethyl
acetate=7:1) to give (2E,4Z)-ethyl 1-
oxo-4-phenyl-1H-benzo[d]azepine-2-
carboxylate (5a) in 74% yield as a
pale yellow solid. m.p. 1038C.
1H NMR (CDCl3, Me4Si, 400 MHz):
d=1.40 (t, J=7.6 Hz, 3H), 4.43 (q, J=
7.2 Hz, 2H), 7.37–7.48 (m, 4H), 7.67–
7.71 (m, 1H), 7.74–7.76 (m, 2H), 7.93–
7.96 (m, 2H), 8.07 ppm (d, J=8.0 Hz,
1H); 13C NMR (CDCl3, Me4Si,
100.6 MHz): d=14.07, 62.39, 122.02,
127.03, 128.02, 128.75, 129.17, 130.52,
131.65, 133.23, 135.20, 136.71, 138.50,
Scheme 5. Gold-catalyzed synthesis of 1-oxo-4-phenyl-1H-benzo[d]azepines. Overall yield of the isolated prod-
ucts 5 for the three reaction steps. DMSO=dimethyl sulfoxide.
Experimental Section
146.43, 149.98, 163.99, 183.51 ppm; IR (neat): n˜ =1734, 1510, 1373, 1246,
886, 707 cmÀ1
305.1054.
;
HRMS (EI): calcd for C19H15NO3: 305.1052; found:
Typical procedure for gold(I)-catalyzed cyclization reactions of (o-alky-
nyl)phenyl aziridines 2 with 4-nitroaniline to 1-amino-1H-3-benzo[d]aze-
pines: All the reactions were carried out on 0.2 or 0.4 mmol scale. 4-ni-
troaniline (27.6 mg, 0.2 mmol) was added to a solution of aziridine 2a
(87.3 mg, 0.2 mmol) in toluene (2 mL). Once the 4-nitroaniline was
mostly dissolved, [(PPh3)AuCl] (5.0 mg, 0.01 mmol) was added followed
by AgOTf (0.01 mmol, 0.2 mL, used as a 0.05m solution in THF). The re-
sulting solution was stirred at room temperature until the reaction was
complete as monitored by thin-layer chromatography. The solvent was
removed under reduced pressure and the residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate/dichloro-
Acknowledgements
We thank the National Natural Science Foundation of China (Grant Nos.
20872163, 20732008, 20821002), the Chinese Academy of Science, Science
Technology Commission of Shanghai Municipality (Grant No.
08QH14030), and the Major State Basic Research Development Program
(Grant No. 2006CB806105) for financial support. We also thank Prof.
Guangyu Li for his helpful discussion about 2D NMR.
ACHTUNGTRENNUNGmethane=4:1:1) to afford (1S*, 2S*)-ethyl 3-(1,3-dioxo-isoindolin-2-yl)-
1-(4-nitrophenyl-amino)-4-phenyl-2,3-dihydro-1H-benzo[d]-azepine-2-car-
boxylate (3a) in 88% yield as a yellow solid. m.p. 1188C. 1H NMR
(CDCl3, Me4Si, 400 MHz): d=0.98 (t, J=7.6 Hz, 3H), 3.98–4.12 (m, 2H),
4.97 (d, J=5.6 Hz, 1H), 5.64 (dd, J=10.0, 6.0 Hz, 1H), 5.79 (s, 1H), 6.36
(d, J=10.0 Hz, 1H), 6.76 (d, J=9.2 Hz, 2H), 7.14–7.25 (m, 6H), 7.42 (d,
J=7.6 Hz, 1H), 7.57–7.68 (m, 5H), 7.68–7.70 (m, 1H), 7.94 ppm (d, J=
9.2 Hz, 2H); 13C NMR (CDCl3, Me4Si, 100.6 MHz): d=13.74, 58.28,
61.57, 68.10, 108.70, 111.79, 123.50, 123.59, 125.35, 126.10, 127.91, 127.98,
128.20, 128.35, 128.57, 130.72, 132.11, 133.63, 134.20, 134.75, 134.84,
137.90, 138.11, 142.55, 151.28, 165.32, 166.33, 166.35 ppm; IR (neat): n˜ =
Keywords: benzazepines · aziridine · cyclization · gold
catalysis · heterocycles
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Typical procedure for gold(I)-catalyzed cyclization reactions of (o-alky-
nyl)phenyl aziridines 2 with water followed by oxidation: H2O (18 uL,
1 mmol), [(PPh3)AuCl] (5.0 mg, 0.01 mmol), and AgOTf (0.2 mL,
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to a solution of the above crude product 4a in DMSO (1.5 mL). The re-
sulting solution was stirred at 508C until the reaction was complete as
monitored by thin-layer chromatography. Then H2O was added and the
mixture was extracted with ether. The aqueous phase was extracted with
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4984
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Chem. Eur. J. 2011, 17, 4981 – 4985

Synthesis of 3-Benzazepine Derivatives
COMMUNICATION
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[18] For details, see the Supporting Information.
[19] In this reaction, a mixture of four isomers was obtained, and two of
which are the same as that obtained from the syn-9 isomer.
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Received: August 30, 2010
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Revised: January 18, 2011
Published online: March 23, 2011
Chem. Eur. J. 2011, 17, 4981 – 4985
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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