Enantioselective synthesis of 2,3-dihydro-1H-benzo [b]azepines: Iridium-catalyzed tandem allylic vinylation/amination reaction

Article abstract of DOI:10.1002/anie.200906638

"Chemical Equation Presented" Making azacycles: The [{lr(cod)Cl}₂]/L complex efficiently catalyzes the tandem allylic vinylation and asymmetric allylic amination of (E)-2 with ortho-amino styrene derivatives 1 to afford the title compounds 3 wi

Full text of DOI:10.1002/anie.200906638

Communications
DOI: 10.1002/anie.200906638
Homogeneous Catalysis
Enantioselective Synthesis of 2,3-Dihydro-1H-benzo[b]azepines:
Iridium-Catalyzed Tandem Allylic Vinylation/Amination Reaction**
Hu He, Wen-Bo Liu, Li-Xin Dai, and Shu-Li You*
Significant efforts have been made to develop new methods
for the preparation of benzannulated nitrogen heterocycles.[1]
Among them, seven-membered ring benzazepines represent a
particularly interesting class of heterocycles.[2] The 1-benz-
azepine moiety constitutes the core structure of numerous
pharmacologically important compounds. Several members
of this class have exhibited biological activity toward various
Scheme 1. Proposed tandem reaction for the synthesis of 1-benzaze-
targets such as enzymes, ion channels, and G-protein-coupled
receptors (GPCRs).[3,4] Despite their interesting biolog-
ical activities, 1-benzazepine derivatives have received
little synthetic attention.[5] The asymmetric synthesis of
1-benzazepine derivatives is even more underexplored
despite the importance of their related chiral com-
pounds.[6] Therefore, the development of an efficient
catalytic asymmetric synthesis of 1-benzazepine deriva-
tives is a highly desirable yet challenging subject.
pine derivatives.
Pioneered by Helmchen and Hartwig, asymmetric
iridium-catalyzed allylic substitution reactions have
developed significantly in the past decade.[7–9] Particu-
larly, Hartwig and co-workers have identified the cyclo-
metalated iridium complex as the active catalyst.[10] With Figure 1. Phosphoramidite ligands L1–L6.
this catalytic system, we recently discovered an iridium-
catalyzed allylic vinylation reaction of allylic carbonates
with ortho-amino styrene derivatives.[11] This reaction
provided a skipped Z,E diene instead of the amination
product. On the basis of this result, we envisioned that 1-
benzazepine motifs could be pursued by using an iridium-
catalyzed tandem allylic vinylation/intramolecular allylic
amination reaction (Scheme 1). Notably, Trost et al.[12] and
Helmchen and co-workers[13] reported on the intramolecular
asymmetric allylic amination reactions using palladium and
iridium catalysts, respectively. Herein we report an efficient
enantioselective synthesis of 1-benzazepine derivatives
through an iridium-catalyzed tandem allylic vinylation/intra-
molecular allylic amination reaction.
In the presence of 4 mol% of [{Ir(cod)Cl}2], 8 mol% of L1,
and 2.2 equivalents of K3PO4, 2-vinylaniline (1a) reacted with
(E)-but-2-ene-1,4-diyl dimethyl dicarbonate [(E)-2] in THFat
508C for 12 hours to give 3a in 33% yield with 34% ee
(Table 1, entry 1). The formation of 3a indicates that the
intramolecular allylic amination reaction proceeds faster than
the allylic vinylation reaction. Examination of various bases
such as Cs2CO3, DBU, KOAc, Et3N, DIEA, and DABCO
disclosed that DABCO was the optimal base, affording
product 3a in 73% yield with 92% ee (Table 1, entries 1–7).
Increasing the substrate ratio of (E)-2/1a to 1.3:1 with
2.6 equivalents of DABCO led to an excellent yield
(Table 1, entry 8). Varying the solvent (dioxane, toluene,
CH2Cl2, DME, CH3CN) and reaction temperature showed
that the reaction in THF at 508C afforded the best result
(Table 1, entries 9–15).
We began our studies with a well-developed iridium
catalytic system derived from [{Ir(cod)Cl}2] (cod = 1,5-cyclo-
octadiene) and the phosphoramidite ligand L1 (Figure 1).[10]
[*] H. He, W.-B. Liu, Prof. L.-X. Dai, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-5492-5087
Under the conditions listed in entry 8, Table 1, different
phosphoramidite ligands were evaluated, and the results are
summarized in Table 2. Phosphoramidite ligands L2 and L3,
which have different substituents on the amine moiety,
afforded the products in relatively low yields, albeit in with
an excellent ee value in the case of ligand L3 (Table 2,
entries 1–3). Ligand L4, bearing aromatic substituents on the
3,3’-positions of the binaphthyl scaffold, was not effective for
the reaction (Table 2, entry 4). The catalyst derived from L5,
the diastereoisomer of L1, could catalyze the reaction but
E-mail: slyou@mail.sioc.ac.cn
[**] We thank the NSFC (20872159, 20821002, 20932008) and the
National Basic Research Program of China (973 Program
2009CB825300) for generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906638.
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Table 1: Optimization of the reaction conditions.
Table 3: The substrate scope.
Entry
2
T
[8C]
Solvent
Base[a]
Yield
[%][b]
ee
Entry
1, R1, R2
3, Yield [%][a]
ee [%]
(equiv)
[%][c]
1
2
3
4
5
6
1a, H, H
3a, 95
3b, 89
3c, 86
3d, 87
3e, 89
3 f, 75
3g, 49
3h, 10
3i, 92
3j, 74
3k, 75
3l, 81
3m, 14
91
91
91
91
91
90
87
87
94
91
90
90
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
50
50
50
50
50
50
50
50
50
50
reflux
50
50
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
toluene
CH2Cl2
DME
CH3CN
THF
K3PO4
Cs2CO3
DBU
KOAc
Et3N
33
63
34
48
1b, H, 5-MeO
1c, H, 4-Me
1d, H, 5-Me
1e, H, 4-Cl
trace
trace
trace
trace
73
n.d.
n.d.
n.d.
n.d.
92
1 f, H, 5-Br
7[b]
8
9
10
11
12
13
1g, H, 5-CF3
1h, H, 4,5-Br,Br
1i, Me, H
1j, Me, 4-Br
1k, Me, 5-Cl
1l, Ph, 4-MeO
1m, Ph, 4-Br
DIEA
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
95
40
91
88
9
10
11
12
13
14
15
trace
n.r.
trace
trace
48
n.d.
n.d.
n.d.
n.d.
91
91 (R)
[a] Yield of isolated product. [b] 8 mol% of [{Ir(cod)Cl}2] and 16 mol% of
(S,S,Sa)-L1 were used.
22
reflux
THF
82
87
[a] Used 2.2 equiv for entries 1–7 and 2.6 equiv for entries 8–15. [b] Yield
of isolated product. [c] Determined by chiral HPLC analysis (Chiralcel
OD-H column). DABCO=1,4-diazabicyclo[2.2.2]octane, DME=dime-
thoxyehtane, DIEA=diisopropylethylamine, THF=tetrahydrofuran,
n.d.=not determined, n.r.=no reaction.
enantioselectivities (Table 3, entries 5–6). Substrate 1g
having a strong electron-withdrawing group (5-CF3) led to
product 3g in 49% yield and 87% ee, even with an increased
catalyst loading (Table 3, entry 7). The unfavorable effect of
the electron-withdrawing group was also observed for 4,5-
dibromo-2-vinylaniline (1h; Table 3, entry 8). To our delight,
the reaction of substrates 1i–1l (R1 = Me, or Ph) with (E)-2
reacted smoothly to afford the desired products in good yields
with excellent ee values (Table 3, entries 9–12).
To determine the absolute configuration of the product,
the enantiopure bromine-containing compound 3m was
obtained. An X-ray crystallographic analysis of enantiopure
3m disclosed the absolute configuration as R.[14]
Table 2: Screening of chiral ligands.[a]
Entry
Ligand
Yield [%][b]
ee [%]
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
95
90
78
n.r.
26
25
91
87
92
n.d.
20
19
[a] Reaction conditions: as listed in entry 8, Table 1. [b] Yield of isolated
product.
Notably, as evidence for the proposed reaction pathway
(Scheme 1), the intermediate 4 could be isolated. When 4 was
subjected to the same catalytic system, product 3a was formed
with an identical ee value [Eq. (1)]. This result suggests that 4
is the intermediate in the tandem process.
with decreased yield and enantioselectivity, indicating the
importance of match of chiralities in (S,S,Sa)-L1 (Table 2,
entry 5). The catalyst derived from ligand L6, bearing
the 8H-binol scaffold, catalyzed the reaction in 25%
yield with 19% ee (Table 2, entry 6).
In the presence of 4 mol% of [{Ir(cod)Cl}2],
8 mol% of L1, and 2.6 equivalents of DABCO in
THF at 508C, various 2-vinylanilines were examined
as substrates. As summarized in Table 3, the reactions
of 2-vinylaniline derivatives 1b–1d, having electron-
donating groups (5-MeO, 4-Me, and 5-Me) on the
phenyl ring, gave the desired products in excellent
yields with 91% ee (Table 3, entries 2–4). 2-Vinylaniline
derivatives 1e–1 f, having electron-withdrawing groups (4-
Cl, 5-Br), were well tolerated and furnished the 2,3-dihydro-
1H-benzazepine products in good yields and excellent
Interestingly, when (Z)-but-2-ene-1,4-diyl dimethyl dicar-
bonate [(Z)-2] was tested in the reaction with 1i, the double
vinylation product 5 was obtained instead of the cyclic
compound [Eq. (2)].
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Communications
bonate with ortho-amino styrene derivatives,
affording the 2,3-dihydro-1H-benzo[b]azepines
with high enantioselectivity. The ready avail-
ability of the starting materials and the great
importance of the enantiopure products make
the current methodology particularly interesting
in organic synthesis.
The synthetic versatility of 2-vinyl-2,3-dihydro-1H-ben-
Experimental Section
General procedure for the iridium-catalyzed tandem allylic vinyl-
ation/amination reaction: A flame dried Schlenk tube was cooled to
room temperature and filled with argon. [{Ir(cod)Cl}2] (5.4 mg,
0.008 mmol), phosphoramidite ligand L1 (8.6 mg, 0.016 mmol), THF
(0.5 mL), and propylamine (0.5 mL) were then added to this flask.
The reaction mixture was heated at 508C for 0.5 h, during which the
color of the solution changed from orange to light yellow. Then the
reaction mixture was cooled to room temperature, and the solvent
was removed in vacuo. Styrene derivative 1 (0.20 mmol), (E)-but-2-
ene-1,4-diyl dimethyl dicarbonate [(E)-2; 53.0 mg, 0.26 mmol],
DABCO (58.2 mg, 0.52 mmol), and degassed THF (2 mL) were
then added to the flask. The reaction mixture was stirred at 508C for
12 h. After the reaction was complete (monitored by TLC), the crude
reaction mixture was filtered through celite and washed with EtOAc.
The solvents were removed under reduced pressure, and the resulting
residue was purified by silica gel column chromatography to afford
the product 3.
zo[b]azepines has also been explored. Hydrogenation of 3a
afforded the secondary amine 3aa in excellent yield (90%)
without loss of optical purity [Eq. (3)].
Full experimental details and characterization data are given in
the Supporting Information.
Received: November 25, 2009
Published online: January 20, 2010
Keywords: allylic amination · heterocycles · iridium ·
synthetic methods · tandem reactions
The fused tricyclic compound 7[15] could also be readily
synthesized from 3a. Treatment of 3a with allyl bromide led
to 6 in 94% yield with 91% ee. The subsequent ring-closing
metathesis[16] and hydrogenation[8e] afforded the tricyclic
product 7 in 68% yield with 91% ee [Eq. (4)].
.
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=
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amination reaction of (E)-but-2-ene-1,4-diyl dimethyl dicar-
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