Facile synthesis of 1-Methyl-1 H -benzo[ b ]azepines from 1-methylquinolinium iodides and diazo(trimethylsilyl)methylmagnesium bromide

Article abstract of DOI:10.1055/s-0030-1258306

The reaction of diazo(trimethylsilyl)methylmagnesium bromide, TMSC(MgBr)N₂, with 1-methylquinolinium iodides followed by sequential ring expansion using copper(I) chloride gives 1-methyl-3-(trimethylsilyl)-1H- benzo[b]azepines in moderate to go

Full text of DOI:10.1055/s-0030-1258306

PAPER
4221
Facile Synthesis of 1-Methyl-1H-benzo[b]azepines from 1-Methylquinolinium
Iodides and Diazo(trimethylsilyl)methylmagnesium Bromide
S
ynthesis of 1-Methyl-
i
1
H
-ben
k
zo[
b
]azepin
i
e
s
from
o
1-Methylquinolini
M
um
I
odides orita,a Yoshiyuki Hari,*b Toyohiko Aoyamaa
a
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho, Nagoya 467-8603, Japan
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax +81(6)68798201; E-mail: hari@phs.osaka-u.ac.jp
b
Received 9 August 2010; revised 8 September 2010
rivatives having a seven-membered ring system fused to a
five-membered ring via the ring expansion of a benzene
ring.11 These results encouraged us to attempt the ring ex-
pansion of the quinoline skeleton by the use of TMSCHN2
Abstract: The reaction of diazo(trimethylsilyl)methylmagnesium
bromide, TMSC(MgBr)N2, with 1-methylquinolinium iodides fol-
lowed by sequential ring expansion using copper(I) chloride gives
1-methyl-3-(trimethylsilyl)-1H-benzo[b]azepines in moderate to
good yields. Moreover, the trimethylsilyl group can be removed or to construct benzazepines with a 6,7 ring system. Herein,
converted into a hydroxy(phenyl)methyl group.
we report a novel synthetic approach to 1-methyl-1H-ben-
zo[b]azepines from 1-methylquinolinium iodides and
TMSCHN2 by a ring-expansion reaction.
Key words: 1H-benzo[b]azepines, diazo(trimethylsilyl)methyl-
magnesium bromide, quinolinium salts, ring expansion, (trimethyl-
silyl)diazomethane
First, the coupling reaction between TMSCHN2 and 1-
methylquinolinium iodide (1a) was examined (Table 1).
Reaction of TMSC(Li)N2 with salt 1a resulted in an insep-
arable mixture of two products which were determined to
be adduct 2a and its regioisomer 3a by NOE experiments
(entry 1). The use of TMSC(MgBr)N2,12 instead of
TMSC(Li)N2, gave a mixture of 2a and 3a in low yield,
but the selectivity was improved (entries 2 and 3). The
1,2-adduct 2a was exclusively produced in quantitative
yield by using 3 equivalents of TMSC(MgBr)N2 at room
temperature (entry 4). Because 2a with a diazo moiety is
unstable, particularly when neat or on silica gel, it was
used immediately without purification for the next step.
1H-Benzo[b]azepines are common skeletons in biologi-
cally active compounds such as voltage-gated sodium
channel (Nav1.x) antagonists,1 N-methyl-D-aspartate
(NMDA) antagonists,2 and acetylcholinesterase (AChE)
inhibitors.3 Many efforts have so far been made to develop
synthetic approaches toward this class of compounds.
These include (i) direct thermolysis of dihydrocy-
clobut[b]indoles prepared by photocycloaddition between
alkynes and indoles,4 (ii) acid-catalyzed cyclization of
2-alkyl-2-[N-(3-oxobut-1-enyl)-o-aminobenzyl]-1,3-diox-
anes5 or N-(3-oxobut-1-enyl)-o-aminophenylacetaldehyde
dimethyl acetals,6 (iii) tin(II) chloride mediated reduction
Table 1 Nucleophilic Addition Reaction of TMSC(M)N2 (M = Li
of 2-nitro-4-(2-nitrobenzylidene)alkanoates,7 and (iv) or MgBr) to Quinolinium Iodide 1aa
ring expansion of quinoline derivatives.8 Among them,
the synthesis of 1H-benzo[b]azepines from 1-substituted
quinolinium salts via a ring-expansion reaction would be
quite practical because of the ready availability of starting
materials. In 2004, Yadav and co-workers demonstrated
that the ring expansion of 1-(ethoxycarbonyl)quinolinium
chlorides with ethyl diazoacetate in the presence of cop-
N2
TMS
H
TMSC(M)N2
H
N2
+
N
+
THF
0.5–1 h
N
I–
N
H
Me
TMS
Me
H
Me
1a
2a
3a
per(II) trifluoromethanesulfonate efficiently afforded 1,2-
Entry TMSC(M)N2
Temp
Yield (2a/3a)
bis(ethoxycarbonyl)-1H-benzo[b]azepines.8a
1
2
3
4
TMSC(Li)N2 (1.2 equiv)
–50 to –30 °C 76% (2.5:1)
Diazomethane (CH2N2) is a very useful and versatile re-
agent, but its hazardous nature and difficulty in handling
restrict its application in organic synthesis. We have fo-
cused on (trimethylsilyl)diazomethane9 (TMSCHN2) as a
more user-friendly alternative to CH2N2 and have already
found that TMSCHN2 and its lithium salt, TMSC(Li)N2,
can act as a C1-unit-introducing reagent, a [C–N–N]azole
synthon, and/or an alkylidene carbene generator.10 For ex-
ample, by capitalizing well on the diverse reactivity of
TMSCHN2, we succeeded in the synthesis of azulene de-
TMSC(MgBr)N2 (1.2 equiv) r.t.
TMSC(MgBr)N2 (1.2 equiv) r.t. to 50 °C
TMSC(MgBr)N2 (3.0 equiv) r.t.
34% (15:1)
32% (4:1)
quant (>20:1)
a Arrows indicate NOE correlations that were observed.
Next, the ring-expansion reaction of adduct 2a with vari-
ous catalysts was tested (Table 2). In the case of PdCl2,
CuCl2, or Rh2(OAc)4, no ring-expanded product was ob-
tained (entries 1–3); however, the reaction using copper(I)
chloride as a catalyst proceeded smoothly to give the 3-tri-
methylsilyl derivative 4a, not the 2-trimethylsilyl isomer
SYNTHESIS 2010, No. 24, pp 4221–4227
x
x.
x
x
.
2
0
1
0
Advanced online publication: 18.10.2010
DOI: 10.1055/s-0030-1258306; Art ID: F13910SS
© Georg Thieme Verlag Stuttgart · New York

4222
M. Morita et al.
PAPER
5a, as a single ring-expanded product (entries 4 and 5), the
structure of which was determined by NOE experiments.
CuCl
R
N2
N
Me
N
Table 2 Ring-Expansion Reaction of Adduct 2aa
R
Me
2a: R = TMS
6a: R = COOEt
4a: R = TMS
7a: R = COOEt
H
catalyst
(10 mol%)
TMS
2a
solvent
0.5–1 h
N
N
H
TMS
Me
Me
R
4a
5a
N
N
Me
R
Me
Entry
Catalyst
Solvent
toluene
toluene
CHCl3
toluene
CHCl3
Temp
80 °C
80 °C
50 °C
80 °C
60 °C
Yieldb of 4a
Scheme 2 Plausible reaction mechanism
c
1
2
3
4
5
PdCl2
–
c
CuCl2
Rh2(OAc)4
CuCl
–
As shown in Scheme 3, the obtained 1,3-disubstituted 1H-
benzo[b]azepine 4a was readily desilylated with tetrabu-
tylammonium fluoride (TBAF) to give 8a in 85% yield.
c,d
–
82%
80%
CuCl
TBAF (3 equiv)
4a
a Arrows indicate NOE correlations that were observed.
b Yield from 1a.
THF, reflux
N
12 h
85%
Me
8a
c Not obtained.
d 2a was recovered in 20% yield.
Scheme 3 Desilylation of benzazepine 4a
Surprisingly, the result that the 1,3-disubstituted 1H-ben-
zo[b]azepine was exclusively produced differed from that
in the reaction between 1-(ethoxycarbonyl)quinolinium
chlorides and ethyl diazoacetate, reported by Yadav and
co-workers, which produced 1,2-disubstituted 1H-ben-
zo[b]azepines.8a Thus, the reaction of ethyl diazoacetate
with iodide 1a followed by ring expansion was examined
(Scheme 1). The addition of the lithium reagent prepared
from ethyl diazoacetate and lithium diisopropylamide to
1a was quite slow, likely due to the poor reactivity com-
pared with that of TMSC(MgBr)N2. Consequently, analo-
gously to 2a, sequential ring expansion of 6a gave the
corresponding 3-substituted derivative 7a, not the 2-sub-
stituted isomer, albeit in low yield (12%) from iodide 1a.
Although the difference in the reaction modes is not clear,
the reaction mechanism of the ring expansion in the reac-
tion system using a 1-methylquinolinium salt would be as
follows (Scheme 2): the carbenoid regioselectively cy-
clizes by the effect of the electron-donating nitrogen at-
om, and the tricyclic intermediate is transformed into
benzazepine 4a or 7a.
This synthetic procedure was applied to substituted quin-
olinium salts 1b–h, easily prepared from commercially
available quinolines (Table 3). The 5-chloro derivative 1b
was smoothly converted into the corresponding 1H-ben-
zo[b]azepine 4b in 82% yield, and 8b was afforded in
moderate yield upon treatment of 4b with TBAF (entry 1).
The spectroscopic data of 8b were identical with the re-
ported data.4d Compounds 1c–e substituted at C-6 were
also converted into the benzazepines (entries 2–4). The 7-
methyl and 8-methoxy derivatives also underwent the ring
expansion to afford the corresponding benzazepines 4f
and 4g, desilylation of which gave 8f and 8g, respectively
(entries 5 and 6). Unfortunately, in the case of the 4-meth-
yl derivative 1h, the desired 4h was not obtained, though
the diazo(trimethylsilyl)methyl adduct 2h disappeared on
TLC in the ring-expansion reaction (entry 7).
Finally, derivatization of trimethylsilylated benzazepine
4a was examined. Under anhydrous conditions,13 activa-
tion of the trimethylsilyl group by TBAF resulted in cou-
pling with benzaldehyde to give the desired 9a in 79%
yield (Scheme 4). The use of 4 Å molecular sieves (4 Å
MS) was crucial for the reaction.14 Unfortunately, other
electrophiles including acetophenone, iodomethane, and
COOEt
(1.2 equiv)
N2
LDA (1.2 equiv)
1a
N2
THF
N
–78 °C to r.t., 1.5 h
Me
COOEt
6a
PhCHO (2 equiv)
TBAF
4 Å MS
3
CuCl (10 mol%)
COOEt
4a
DMF
r.t., 5 h
79%
toluene
80 °C, 1 h
OH
N
2
N
Me
Me
7a (12% from 1a)
9a
Scheme 1 Synthesis of a 1H-benzo[b]azepine using ethyl diazoace-
tate
Scheme 4 Conversion of the trimethylsilyl group in benzazepine 4a
Synthesis 2010, No. 24, 4221–4227 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Methyl-1H-benzo[b]azepines from 1-Methylquinolinium Iodides
4223
Table 3 Synthesis of 1-Methyl-1H-benzo[b]azepines by a Ring-Expansion Reaction
R1
R2
R1
R2
R2
R1
R3
R4
R3
R4
1) TMSC(MgBr)N2 (3 equiv)
THF, r.t., 30 min
R3
R4
TBAF (3 equiv)
TMS
THF, reflux
12 h
2) CuCl (10 mol%)
toluene, 80 °C
1–3 h
+
N
Me
4
N
I–
N
R5
R5
R5
Me
Me
8
1
Entry
Starting Material
Yielda of 4
82% (4b)
50% (4c)
52% (4d)
<40% (4e)b
63% (4f)
56% (4g)
– (4h)
Yield of 8
57% (8b)
56% (8c)
83% (8d)
25%a (8e)
52% (8f)
52% (8g)
– (8h)
1
2
3
4
5
6
7
1b (R1 = R3 = R4 = R5 = H, R2 = Cl)
1c (R1 = R2 = R4 = R5 = H, R3 = Me)
1d (R1 = R2 = R4 = R5 = H, R3 = OMe)
1e (R1 = R2 = R4 = R5 = H, R3 = Cl)
1f (R1 = R2 = R3 = R5 = H, R4 = Me)
1g (R1 = R2 = R3 = R4 = H, R5 = OMe)
1h (R1 = Me, R2 = R3 = R4 = R5 = H)
a Yield from 1.
b Contained an inseparable impurity.
Iodides 1a,15 1c–e,16 1f,17 1g,18 and 1h15 were prepared in a similar
manner.
ethyl chloroformate gave complex mixtures and no de-
sired product was obtained.
In conclusion, we have developed a new synthetic route to
1-methyl-1H-benzo[b]azepines from 1-methylquinolini-
um iodides and diazo(trimethylsilyl)methylmagnesium
bromide via a copper-mediated ring-expansion reaction.
This synthetic method could be valuable in 1H-ben-
zo[b]azepine synthesis because various quinoline deriva-
tives are readily available as starting materials.
Adducts 2a and 3a by the Reaction of Quinolinium Salt 1a with
TMSC(Li)N2 (Table 1, Entry 1)
Under an argon atmosphere, n-BuLi (1.57 M in hexane, 0.42 mL,
0.66 mmol) was added to a soln of TMSCHN2 (1.73 M in hexane,
0.38 mL, 0.66 mmol) in anhyd THF (5 mL) at –78 °C and the mix-
ture was stirred at –78 °C for 20 min. To the mixture was added salt
1a (150 mg, 0.55 mmol), and the mixture was stirred at –50 to
–30 °C for 1 h. After the reaction was quenched with H2O (1 mL),
the mixture was poured into H2O (20 mL). The aqueous layer was
extracted with toluene (2 × 20 mL). The combined organic layer
was dried (MgSO4) and concentrated under reduced pressure to give
an inseparable mixture of adducts 2a and 3a as a brown oil; yield:
109 mg (76%).
Melting points were measured on a Yanagimoto micro melting
points apparatus and are uncorrected. IR spectra were recorded on a
Shimadzu FTIR-8400S spectrophotometer. 1H and 13C NMR spec-
tra were recorded on a JEOL JNM-EX-270 (1H, 270 MHz; 13C, 67.8
MHz) or a JEOL Lambda 500 (1H, 500 MHz; 13C, 125 MHz) spec-
trometer. Mass spectra were recorded on a JEOL JMS-SX-102A
spectrometer. The solution of MgBr2 in Et2O–toluene (1:1) was pre-
pared from MgBr2·OEt2 (Aldrich), dried well under reduced pres-
sure at 100 °C, and commercially available anhyd Et2O and toluene.
2-[Diazo(trimethylsilyl)methyl]-1-methyl-1,2-dihydroquino-
line (2a)
IR (neat): 2031 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.08 (s, 9 H), 2.91 (s, 3 H), 4.64
(d, J = 5.1 Hz, 1 H), 5.64 (dd, J = 5.1, 9.5 Hz, 1 H), 6.48 (d, J = 9.5
Hz, 1 H), 6.50 (d, J = 8.1 Hz, 1 H), 6.62 (t, J = 8.1 Hz, 1 H), 6.87 (d,
J = 8.1 Hz, 1 H), 7.07 (t, J = 8.1 Hz, 1 H). NOEs were observed at
0.08, 4.64, and 6.50 ppm upon irradiation of the signal at 2.91 ppm.
5-Chloro-1-methylquinolinium Iodide (1b); Typical Procedure
To a soln of 5-chloroquinoline (1.00 g, 6.11 mmol) in dioxane (20
mL) was added MeI (1.22 mL, 19.6 mmol), and the mixture was
stirred at r.t. for 1 h. The formed precipitate was collected by filtra-
tion to give the desired compound 1b as a yellow solid; yield: 752
mg (40%); mp 200–202 °C.
4-[Diazo(trimethylsilyl)methyl]-1-methyl-1,4-dihydroquino-
line (3a)
1H NMR (500 MHz, CDCl3): d = 0.18 (s, 9 H), 3.10 (s, 3 H), 4.20
(d, J = 4.5 Hz, 1 H), 4.59 (dd, J = 4.5, 8.0 Hz, 1 H), 6.16 (d, J = 8.0
Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 6.92–6.98 (m, 1 H), 7.10–7.20
(m, 2 H). NOEs were observed at 6.16 and 6.71 ppm upon irradia-
tion of the signal at 3.10 ppm.
IR (KBr): 3071, 1618, 1585, 1522 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 4.67 (s, 3 H), 8.22–8.32 (m, 3
H), 8.49–8.56 (m, 1 H), 9.43 (d, J = 8.6 Hz, 1 H), 9.61 (d, J = 5.9
Hz, 1 H).
13C NMR (67.8 MHz, DMSO-d6): d = 46.27, 119.15, 123.46,
127.18, 130.49, 132.84, 135.49, 139.71, 143.31, 151.43.
2-[Diazo(trimethylsilyl)methyl]-1-methyl-1,2-dihydroquino-
line (2a); Typical Procedure (Table 3)
Under an argon atmosphere, n-BuLi (1.58 M in hexane, 0.70 mL,
1.1 mmol) was added to a soln of TMSCHN2 (1.7 M in hexane, 0.65
mL, 1.1 mmol) in anhyd THF (5 mL) at –78 °C and the mixture was
stirred at –78 °C for 20 min. After MgBr2 [1.0 M in toluene–Et2O
MS (EI): m/z = 178 and 180 [M+ – I].
Anal. Calcd for C10H9ClIN·H2O: C, 37.12; H, 3.43; N, 4.33. Found:
C, 37.47; H, 3.26; N, 4.29.
Synthesis 2010, No. 24, 4221–4227 © Thieme Stuttgart · New York

4224
M. Morita et al.
PAPER
(1:1), 1.1 mL, 1.1 mmol] was added, the mixture was stirred at
–78 °C for 20 min. To the mixture was added salt 1a (100 mg, 0.37
mmol), and the mixture was stirred at r.t. for 30 min. The mixture
was poured into H2O (30 mL), and the aqueous layer was extracted
with EtOAc (30 mL). The separated organic layer was dried
(MgSO4) and concentrated under reduced pressure to give crude 2a
as a yellow oil; yield: 99 mg (quant).
1-Methyl-3-(trimethylsilyl)-1H-benzo[b]azepine (4a); Typical
Procedure
A mixture of adduct 2a (120 mg, prepared from 100 mg of salt 1a)
and CuCl (3 mg, 0.03 mmol) in toluene (3 mL) was stirred at 80 °C
for 1 h. After the mixture was cooled to r.t., the solvent was re-
moved under reduced pressure. The residue was purified by column
chromatography (Fuji Silysia Chromatorex NH, hexane–EtOAc,
100:1) to give the desired compound 4a as an orange oil; yield: 69.5
mg (82% from 1a).
5-Chloro-2-[diazo(trimethylsilyl)methyl]-1-methyl-1,2-dihy-
droquinoline (2b)
IR (neat): 2953, 1626, 1585, 1489, 1470, 1448, 1248 cm–1.
IR (neat): 2035 cm–1.
1H NMR (270 MHz, CDCl3): d = 0.07 (s, 9 H), 2.94 (s, 3 H), 5.53
(s, 1 H), 6.08 (d, J = 10.8 Hz, 1 H), 6.50 (d, J = 11.0 Hz, 1 H), 6.68
(d, J = 8.1 Hz, 1 H), 6.83–6.92 (m, 2 H), 7.12–7.20 (m, 1 H). NOEs
were observed at 5.53 and 6.08 ppm upon irradiation of the signal
at 0.07 ppm.
1H NMR (270 MHz, CDCl3): d = 0.09 (s, 9 H), 2.92 (s, 3 H), 4.63
(d, J = 5.4 Hz, 1 H), 5.74 (dd, J = 5.4, 10.0 Hz, 1 H), 6.41 (d, J = 8.1
Hz, 1 H), 6.66 (d, J = 8.1 Hz, 1 H), 6.95 (d, J = 10.0 Hz, 1 H), 6.98
(t, J = 8.1 Hz, 1 H).
13C NMR (67.8 MHz, CDCl3): d = –1.34, 39.70, 116.35, 122.68,
2-[Diazo(trimethylsilyl)methyl]-1,6-dimethyl-1,2-dihydroquin-
123.55, 128.96, 129.02, 132.78, 133.10, 133.24, 148.52, 152.65.
oline (2c)
IR (neat): 2033 cm–1.
MS (EI): m/z = 229 [M+].
1H NMR (270 MHz, CDCl3): d = 0.08 (s, 9 H), 2.20 (s, 3 H), 2.88
(s, 3 H), 4.59 (d, J = 6.0 Hz, 1 H), 5.64 (dd, J = 6.0, 10.5 Hz, 1 H),
6.42 (d, J = 9.0 Hz, 1 H), 6.46 (d, J = 10.5 Hz, 1 H), 6.70 (d, J = 2.1
Hz, 1 H), 6.88 (dd, J = 2.1, 9.0 Hz, 1 H).
HRMS (EI): m/z calcd for C14H19NSi: 229.1287; found: 229.1288.
6-Chloro-1-methyl-3-(trimethylsilyl)-1H-benzo[b]azepine (4b)
Yield: 70.7 mg (82% from 1b).
IR (neat): 2955, 1626, 1580, 1454, 1445, 1248 cm–1.
2-[Diazo(trimethylsilyl)methyl]-6-methoxy-1-methyl-1,2-dihy-
droquinoline (2d)
1H NMR (270 MHz, CDCl3): d = 0.08 (s, 9 H), 2.93 (s, 3 H), 5.57
(s, 1 H), 6.28 (d, J = 11.1 Hz, 1 H), 6.54 (d, J = 8.1 Hz, 1 H), 6.85
(d, J = 11.1 Hz, 1 H), 6.97 (d, J = 8.1 Hz, 1 H), 7.11 (t, J = 8.1 Hz,
1 H).
13C NMR (67.8 MHz, CDCl3): d = –1.36, 40.03, 115.03, 124.04,
125.18, 129.29, 129.80, 130.66, 133.06, 134.50, 148.79, 155.38.
IR (neat): 2031 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.08 (s, 9 H), 2.88 (s, 3 H), 3.74
(s, 3 H), 4.54 (d, J = 5.5 Hz, 1 H), 5.73 (dd, J = 5.5, 9.5 Hz, 1 H),
6.45 (d, J = 9.0 Hz, 1 H), 6.48 (d, J = 9.5 Hz, 1 H), 6.53 (d, J = 3.0
Hz, 1 H), 6.69 (dd, J = 3.0, 9.0 Hz, 1 H).
MS (EI): m/z = 263 and 265 [M+].
HRMS (EI): m/z calcd for C14H1835ClNSi: 263.0897; found:
6-Chloro-2-[diazo(trimethylsilyl)methyl]-1-methyl-1,2-dihy-
droquinoline (2e)
IR (neat): 2035 cm–1.
263.0897.
1H NMR (270 MHz, CDCl3): d = 0.09 (s, 9 H), 2.88 (s, 3 H), 4.60
(d, J = 5.4 Hz, 1 H), 5.67 (dd, J = 5.4, 9.7 Hz, 1 H), 6.41 (d, J = 8.4
Hz, 1 H), 6.42 (d, J = 9.7 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 7.00
(dd, J = 2.4, 8.4 Hz, 1 H).
1,7-Dimethyl-3-(trimethylsilyl)-1H-benzo[b]azepine (4c)
Yield: 85.7 mg (50% from 1c).
IR (neat): 2953, 1585, 1497, 1248 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.08 (s, 9 H), 2.23 (s, 3 H), 2.93
(s, 3 H), 5.57 (s, 1 H), 6.09 (d, J = 12.0 Hz, 1 H), 6.49 (d, J = 12.0
Hz, 1 H), 6.59 (d, J = 9.0 Hz, 1 H), 6.70 (s, 1 H), 6.99 (d, J = 9.0 Hz,
1 H).
2-[Diazo(trimethylsilyl)methyl]-1,7-dimethyl-1,2-dihydroquin-
oline (2f)
IR (neat): 2029 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.09 (s, 9 H), 2.27 (s, 3 H), 2.90
(s, 3 H), 4.62 (d, J = 5.0 Hz, 1 H), 5.58 (dd, J = 5.0, 9.5 Hz, 1 H),
6.33 (s, 1 H), 6.45 (d, J = 7.5 Hz, 1 H), 6.47 (d, J = 9.5 Hz, 1 H),
6.77 (d, J = 7.5 Hz, 1 H).
13C NMR (67.8 MHz, CDCl3): d = –1.31, 20.41, 39.76, 116.17,
123.19, 129.44, 129.70, 131.98, 132.77, 132.98, 133.02, 148.79,
150.12.
MS (EI): m/z = 243 [M+].
HRMS (EI): m/z calcd for C15H21NSi: 243.1443; found: 243.1436.
2-[Diazo(trimethylsilyl)methyl]-8-methoxy-1-methyl-1,2-dihy-
droquinoline (2g)
IR (neat): 2035 cm–1.
7-Methoxy-1-methyl-3-(trimethylsilyl)-1H-benzo[b]azepine
(4d)
Yield: 90.2 mg (52% from 1d).
IR (neat): 2953, 1574, 1489, 1470, 1248 cm–1.
1H NMR (270 MHz, CDCl3): d = 0.07 (s, 9 H), 2.92 (s, 3 H), 3.74
(s, 3 H), 5.60 (s, 1 H), 6.11 (d, J = 10.8 Hz, 1 H), 6.44 (d, J = 3.0 Hz,
1 H), 6.48 (d, J = 10.8 Hz, 1 H), 6.61 (d, J = 8.9 Hz, 1 H), 6.72 (dd,
J = 3.0, 8.9 Hz, 1 H).
13C NMR (67.8 MHz, CDCl3): d = –1.29, 39.95, 55.49, 113.74,
114.33, 116.96, 122.89, 132.44, 133.43, 134.39, 145.71, 149.32,
155.29.
1H NMR (500 MHz, CDCl3): d = 0.12 (s, 9 H), 2.96 (s, 3 H), 3.81
(s, 3 H), 4.33 (d, J = 5.5 Hz, 1 H), 5.73 (dd, J = 5.5, 9.5 Hz, 1 H),
6.60 (d, J = 9.5 Hz, 1 H), 6.68 (dd, J = 1.5, 8.0 Hz, 1 H), 6.75 (dd,
J = 1.5, 8.0 Hz, 1 H), 6.82 (t, J = 8.0 Hz, 1 H).
2-[Diazo(trimethylsilyl)methyl]-1,4-dimethyl-1,2-dihydroquin-
oline (2h)
IR (neat): 2027 cm–1.
1H NMR (270 MHz, CDCl3): d = 0.02 (s, 9 H), 2.06 (s, 3 H), 2.90
(s, 3 H), 4.65 (d, J = 5.7 Hz, 1 H), 5.52 (d, J = 5.7 Hz, 1 H), 6.52 (d,
J = 7.8 Hz, 1 H), 6.68 (t, J = 7.8 Hz, 1 H), 7.05–7.13 (m, 2 H).
MS (EI): m/z = 259 [M+].
HRMS (EI): m/z calcd for C15H21NOSi: 259.1393; found: 259.1384.
Synthesis 2010, No. 24, 4221–4227 © Thieme Stuttgart · New York

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Synthesis of 1-Methyl-1H-benzo[b]azepines from 1-Methylquinolinium Iodides
4225
1,8-Dimethyl-3-(trimethylsilyl)-1H-benzo[b]azepine (4f)
Yield: 54.1 mg (63% from 1f).
IR (neat): 2953, 1587, 1503, 1248 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.07 (s, 9 H), 2.27 (s, 3 H), 2.93
(s, 3 H), 5.52 (s, 1 H), 6.04 (d, J = 11.0 Hz, 1 H), 6.45–6.51 (m, 2
H), 6.71 (d, J = 7.5 Hz, 1 H), 6.76 (d, J = 7.5 Hz, 1 H).
13C NMR (67.8 MHz, CDCl3): d = 14.36, 41.33, 60.16, 112.39,
118.02, 124.74, 129.33, 129.44, 129.98, 130.83, 133.61, 150.55,
158.12, 166.49.
MS (EI): m/z = 229 [M+].
HRMS (EI): m/z calcd for C14H15NO2: 229.1103; found: 229.1106.
1-Methyl-1H-benzo[b]azepine (8a); Typical Procedure
To a soln of 4a (40 mg, 0.17 mmol) in THF (5 mL) was added a soln
of TBAF (1.0 M in THF, 0.52 mL, 0.52 mmol), and the mixture was
stirred at reflux for 12 h. After the mixture was cooled to r.t., it was
poured into H2O (30 mL), and the aqueous layer was extracted with
EtOAc (30 mL). The separated organic layer was dried (MgSO4)
and concentrated under reduced pressure. The residue was purified
by column chromatography (Fuji Silysia Chromatorex NH, hex-
ane–EtOAc, 100:1) to give the desired product 8a as an orange oil;
yield: 23.2 mg (85%).
13C NMR (125 MHz, CDCl3): d = –1.48, 21.25, 39.65, 117.31,
123.43, 123.78, 129.04, 130.42, 131.97, 133.10, 139.19, 148.17,
152.72.
MS (EI): m/z = 243 [M+].
HRMS (EI): m/z calcd for C15H21NSi: 243.1443; found: 243.1444.
9-Methoxy-1-methyl-3-(trimethylsilyl)-1H-benzo[b]azepine
(4g)
Yield: 48.1 mg (56% from 1g).
IR (neat): 2953, 1562, 1470, 1248 cm–1.
IR (neat): 3021, 2953, 1643, 1589, 1493, 1470, 1452, 1316 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.91 (s, 3 H), 5.12 (dd, J = 5.5, 7.5
Hz, 1 H), 5.51 (d, J = 7.5 Hz, 1 H), 5.95 (dd, J = 5.5, 11.0 Hz, 1 H),
6.46 (d, J = 11.0 Hz, 1 H), 6.65 (d, J = 7.5 Hz, 1 H), 6.82 (d, J = 7.5
Hz, 1 H), 6.88 (t, J = 7.5 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 0.07 (s, 9 H), 3.07 (s, 3 H), 3.79
(s, 3 H), 5.90 (s, 1 H), 6.10 (d, J = 11.0 Hz, 1 H), 6.50 (dd, J = 1.5,
8.0 Hz, 1 H), 6.52 (d, J = 11.0 Hz, 1 H), 6.82 (dd, J = 1.5, 8.0 Hz, 1
H), 6.92 (t, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 39.73, 113.00, 116.79, 123.00,
13C NMR (125 MHz, CDCl3): d = –1.31, 41.19, 55.59, 113.11,
120.95, 122.99, 124.45, 131.89, 134.00, 137.31, 138.52, 151.57,
152.69.
129.19, 129.42, 130.04, 133.61, 134.20, 143.52, 152.93.
MS (EI): m/z = 157 [M+].
MS (EI): m/z = 259 [M+].
HRMS (EI): m/z calcd for C11H11N: 157.0892; found: 157.0888.
HRMS (EI): m/z calcd for C15H21NOSi: 259.1393; found: 259.1376.
6-Chloro-1-methyl-1H-benzo[b]azepine (8b)4d
Yield: 26.7 mg (57% from 4b).
IR (neat): 2954, 1645, 1580, 1445, 1315 cm–1.
1H NMR (270 MHz, CDCl3): d = 2.92 (s, 3 H), 5.28 (dd, J = 5.1, 7.6
Hz, 1 H), 5.57 (d, J = 7.6 Hz, 1 H), 6.17 (dd, J = 5.1, 11.3 Hz, 1 H),
6.62 (d, J = 8.1 Hz, 1 H), 6.86 (d, J = 11.3 Hz, 1 H), 6.98 (d, J = 8.1
Hz, 1 H), 7.11 (t, J = 8.1 Hz, 1 H).
13C NMR (67.8 MHz, CDCl3): d = 40.11, 114.25, 115.37, 124.30,
129.57, 130.82, 130.85, 131.61, 133.07, 143.92, 155.82.
MS (EI): m/z = 191 and 193 [M+].
HRMS (EI): m/z calcd for C11H1035ClN: 191.0502; found:
Ethyl Diazo(1-methyl-1,2-dihydroquinolin-2-yl)acetate (6a)
Under an argon atmosphere, n-BuLi (1.57 M in hexane, 0.56 mL,
0.89 mmol) was added to a soln of diisopropylamine (90 mg, 0.89
mmol) in THF (8 mL) at –78 °C and the mixture was stirred at 0 °C
for 15 min. The mixture was recooled to –78 °C, and a soln of ethyl
diazoacetate (101 mg, 0.89 mmol) in THF (2 mL) was added. After
the mixture was stirred at –78 °C for 15 min, salt 1a (200 mg, 0.74
mmol) was added. The mixture was stirred at –78 °C for 1 h, then
warmed to r.t. The resulting mixture was poured into H2O (30 mL),
and the aqueous layer was extracted with EtOAc (2 × 30 mL). The
combined organic layer was dried (MgSO4) and concentrated under
reduced pressure to give adduct 6a (85 mg) as a brown oil. This was
used in the next step without purification.
191.0516.
IR (neat): 2087 cm–1.
1,7-Dimethyl-1H-benzo[b]azepine (8c)
Yield: 10.2 mg (56% from 4c).
IR (neat): 2953, 1626, 1585, 1499, 1248 cm–1.
1H NMR (270 MHz, CDCl3): d = 2.20 (s, 3 H), 2.90 (s, 3 H), 5.09
(dd, J = 5.7, 7.5 Hz, 1 H), 5.53 (d, J = 7.5 Hz, 1 H), 5.93 (dd,
J = 5.7, 11.1 Hz, 1 H), 6.43 (d, J = 11.1 Hz, 1 H), 6.56 (d, J = 8.1
Hz, 1 H), 6.64 (d, J = 1.9 Hz, 1 H), 6.99 (dd, J = 1.9, 8.1 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 1.26 (t, J = 7.0 Hz, 3 H), 2.95 (s,
3 H), 4.22 (q, J = 7.0 Hz, 2 H), 5.25 (d, J = 5.5 Hz, 1 H), 5.74 (dd,
J = 5.5, 10.0 Hz, 1 H), 6.57 (d, J = 7.5 Hz, 1 H), 6.67 (d, J = 10.0
Hz, 1 H), 6.68 (dd, J = 1.5, 7.5 Hz, 1 H), 6.91 (dd, J = 1.5, 7.5 Hz,
1 H), 7.12 (dt, J = 1.5, 7.5 Hz, 1 H). NOEs were observed at 2.95
and 5.74 ppm upon irradiation of the signal at 5.25 ppm.
13C NMR (67.8 MHz, CDCl3): d = 20.38, 39.87, 112.63, 116.53,
Ethyl 1-Methyl-1H-benzo[b]azepine-3-carboxylate (7a)
A mixture of adduct 6a (85 mg) and CuCl (3 mg, 0.03 mmol) in tol-
uene (3 mL) was stirred at 80 °C for 1 h. After the mixture was
cooled to r.t., the solvent was removed under reduced pressure. The
residue was purified by column chromatography (Fuji Silysia Chro-
matorex NH, hexane–EtOAc, 20:1) to give the desired compound
7a as a brown oil; yield: 20.3 mg (12% from 1a).
129.78, 129.81, 129.94, 132.25, 133.32, 133.96, 143.64, 150.24.
MS (EI): m/z = 171 [M+].
HRMS (EI): m/z calcd for C12H13N: 171.1048; found: 171.1054.
7-Methoxy-1-methyl-1H-benzo[b]azepine (8d)
Yield: 38.3 mg (83% from 4d).
IR (neat): 2952, 1641, 1601, 1578, 1501, 1470, 1260 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.90 (s, 3 H), 3.73 (s, 3 H), 5.10
(dd, J = 5.5, 8.0 Hz, 1 H), 5.58 (d, J = 8.0 Hz, 1 H), 5.98 (dd,
J = 5.5, 11.5 Hz, 1 H), 6.41 (d, J = 3.0 Hz, 1 H), 6.43 (d, J = 11.5
Hz, 1 H), 6.59 (d, J = 9.0 Hz, 1 H), 6.72 (dd, J = 3.0, 9.0 Hz, 1 H).
IR (neat): 2924, 1692 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.26 (t, J = 7.0 Hz, 3 H), 3.05 (s,
3 H), 4.14 (q, J = 7.0 Hz, 2 H), 6.01 (d, J = 11.5 Hz, 1 H), 6.12 (d,
J = 11.5 Hz, 1 H), 6.53 (d, J = 7.5 Hz, 1 H), 6.61 (d, J = 7.5 Hz, 1
H), 6.83 (t, J = 7.5 Hz, 1 H), 6.87 (s, 1 H), 7.05 (t, J = 7.5 Hz, 1 H).
NOEs were observed at 6.53 and 6.87 ppm upon irradiation of the
signal at 3.05 ppm.
13C NMR (125 MHz, CDCl3): d = 39.93, 55.40, 112.32, 113.93,
114.53, 117.35, 130.63, 133.41, 134.77, 144.30, 145.83, 155.54.
Synthesis 2010, No. 24, 4221–4227 © Thieme Stuttgart · New York

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M. Morita et al.
PAPER
MS (EI): m/z = 187 [M+].
MS (EI): m/z = 263 [M+].
HRMS (EI): m/z calcd for C12H13NO: 187.0997; found: 187.0990.
HRMS (EI): m/z calcd for C18H17NO: 263.1310; found: 263.1319.
7-Chloro-1-methyl-1H-benzo[b]azepine (8e)
Yield: 15.7 mg (25% from 1e).
Acknowledgment
IR (neat): 2955, 1643, 1605, 1487, 1468, 1445, 1315 cm–1.
This work was supported in part by the Special Coordination Funds
for Promoting Science and Technology of the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan (MEXT) and
by a Grant-in-Aid for Scientific Research (KAKENHI) from the
Japan Society for the Promotion of Science (JSPS). M.M. was fi-
nancially supported by Pfizer Japan Inc.
1H NMR (270 MHz, CDCl3): d = 2.89 (s, 3 H), 5.11 (dd, J = 5.7, 7.8
Hz, 1 H), 5.49 (d, J = 7.8 Hz, 1 H), 5.97 (dd, J = 5.7, 11.1 Hz, 1 H),
6.34 (d, J = 11.1 Hz, 1 H), 6.54 (d, J = 8.6 Hz, 1 H), 6.77 (d, J = 2.4
Hz, 1 H), 7.10 (dd, J = 2.4, 8.6 Hz, 1 H).
13C NMR (67.8 MHz, CDCl3): d = 39.90, 112.91, 117.83, 128.15,
128.63, 128.77, 131.26, 132.72, 135.26, 143.70, 151.39.
MS (EI): m/z = 191 and 193 [M+].
References
HRMS (EI): m/z calcd for C11H1035ClN: 191.0502; found:
191.0505.
(1) Hoyt, S. B.; London, C.; Gorin, D.; Wyvratt, M. J.; Fisher,
M. H.; Abbadie, C.; Felix, J. P.; Garcia, M. L.; Li, X.; Lyons,
K. A.; McGowan, E.; MacIntyre, D. E.; Martin, W. J.; Priest,
B. T.; Ritter, A.; Smith, M. M.; Warren, V. A.; Williams, B.
S.; Kaczorowski, G. J.; Parsons, W. H. Bioorg. Med. Chem.
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(2) Fabio, R. D.; Micheli, F.; Baraldi, D.; Bertani, B.; Conti, N.;
Forno, G. D.; Feriani, A.; Donati, D.; Marchioro, C.;
Messeri, T.; Missio, A.; Pasquarello, A.; Pentassuglia, G.;
Pizzi, D. A.; Provera, S.; Quaglia, A. M.; Sabbatini, F. M.
Farmaco 2003, 58, 723.
1,8-Dimethyl-1H-benzo[b]azepine (8f)
Yield: 19.2 mg (52% from 4f).
IR (neat): 2952, 1644, 1601, 1503, 1450, 1310 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.26 (s, 3 H), 2.91 (s, 3 H), 5.11
(dd, J = 5.5, 8.0 Hz, 1 H), 5.49 (d, J = 8.0 Hz, 1 H), 5.90 (dd,
J = 5.5, 11.0 Hz, 1 H), 6.44 (d, J = 11.0 Hz, 1 H), 6.47 (s, 1 H), 6.69
(d, J = 7.5 Hz, 1 H), 6.72 (d, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 21.20, 39.75, 113.11, 117.67,
123.61, 129.13 (2), 130.67, 134.14, 139.57, 143.04, 152.87.
(3) Ishihara, Y.; Hirai, K.; Miyamoto, M.; Goto, G. J. Med.
Chem. 1994, 37, 2292.
(4) (a) Davis, P. D.; Neckers, D. C. Tetrahedron Lett. 1978,
2979. (b) Ikeda, M.; Ohno, K.; Uno, T.; Tamura, Y.
Tetrahedron Lett. 1980, 21, 3403. (c) Ikeda, M.; Ohno, K.;
Takahashi, M.; Uno, T.; Tamura, Y. J. Chem. Soc., Perkin
Trans. 1 1982, 741. (d) Motyka, L. A. Tetrahedron Lett.
1985, 26, 2827.
MS (EI): m/z = 171 [M+].
HRMS (EI): m/z calcd for C12H13N: 171.1048; found: 171.1051.
9-Methoxy-1-methyl-1H-benzo[b]azepine (8g)
Yield: 16.6 mg (52% from 4g).
(5) Teuber, H. J.; Emmerich, G. Tetrahedron Lett. 1970, 4069.
(6) Gonzalez, E. Bull. Soc. Chim. Fr. 1993, 130, 143.
(7) Singh, V.; Batra, S. Eur. J. Org. Chem. 2007, 2970.
(8) (a) Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.; Prabhakar,
A.; Jagadeesh, B. Chem. Commun. 2004, 2124. (b) Gogte,
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1238. (c) Sato, Y.; Kojima, H.; Shirai, H. J. Org. Chem.
1976, 41, 195. (d) Sato, Y.; Kojima, H.; Shirai, H. J. Org.
Chem. 1976, 41, 3325.
(9) CAUTION! Two deaths were recently reported from the use
of TMSCHN2 without proper ventilation; see: Barnhart, R.
W.; Dale, D. J.; Ironside, M. D.; Vogt, P. F. Org. Process
Res. Dev. 2009, 13, 1388.
(10) For reviews, see: (a) Shioiri, T.; Aoyama, T. In Advances in
the Use of Synthons in Organic Chemistry, Vol. 1; Dondoni,
A., Ed.; JAI Press: London, 1993, 51. (b) Shioiri, T.;
Aoyama, T. In Science of Synthesis, Houben–Weyl Methods
of Molecular Transformations, Vol. 4; Fleming, I., Ed.;
Thieme: Stuttgart, 2002, 569.
(11) (a) Ogawa, H.; Aoyama, T.; Shioiri, T. Synlett 1994, 757.
(b) Hari, Y.; Tanaka, S.; Takuma, Y.; Aoyama, T. Synlett
2003, 2151. (c) Tsuchida, S.; Hari, Y.; Aoyama, T.
Heterocycles 2005, 65, 2667. (d) Morita, M.; Hari, Y.;
Iguchi, T.; Aoyama, T. Tetrahedron 2008, 64, 1753.
(12) Recently, we have established the usability of
TMSC(MgBr)N2 in some synthetic reactions; see: (a) Hari,
Y.; Tsuchida, S.; Aoyama, T. Tetrahedron Lett. 2006, 47,
1977. (b) Hari, Y.; Tsuchida, S.; Sone, R.; Aoyama, T.
Synthesis 2007, 3371. (c) Hari, Y.; Date, K.; Kondo, R.;
Aoyama, T. Tetrahedron Lett. 2008, 49, 4965.
IR (neat): 2932, 1572, 1470, 1258, 1242, 1076 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.06 (s, 3 H), 3.78 (s, 3 H), 5.18
(dd, J = 5.5, 7.0 Hz, 1 H), 5.87 (d, J = 7.0 Hz, 1 H), 5.99 (dd,
J = 5.5, 11.0 Hz, 1 H), 6.46–6.50 (m, 2 H), 6.83 (dd, J = 1.0, 8.0 Hz,
1 H), 6.93 (t, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 41.16, 55.66, 113.28, 113.55,
121.07, 124.81, 130.84, 132.64, 137.32, 139.04, 146.12, 153.05.
MS (EI): m/z = 187 [M+].
HRMS (EI): m/z calcd for C12H13NO: 187.0997; found: 187.0999.
(1-Methyl-1H-benzo[b]azepin-3-yl)(phenyl)methanol (9a)
To a mixture of 4a (30 mg, 0.13 mmol), PhCHO (28 mg, 0.26
mmol), and 4 Å MS (200 mg) in DMF (0.5 mL) was added anhyd
TBAF in DMF (2 mL) (prepared from 80 mg of TBAF·H2O and 4
Å MS using the reported procedure13), and the mixture was stirred
at r.t. for 5 h. Next, the mixture was poured onto H2O (30 mL), and
the aqueous layer was extracted with hexane–EtOAc (1:2, 2 × 30
mL). The combined organic layer was dried (MgSO4) and concen-
trated under reduced pressure. The residue was purified by column
chromatography (Fuji Silysia Chromatorex NH, hexane–EtOAc,
2:1) to give the desired compound 9a as an orange oil; yield: 27.2
mg (79%).
IR (neat): 3420, 1738, 1244, 1043 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.90 (d, J = 3.0 Hz, 1 H), 2.95 (s,
3 H), 5.21 (d, J = 3.0 Hz, 1 H), 5.71 (s, 1 H), 5.87 (d, J = 11.2 Hz, 1
H), 6.49 (d, J = 11.2 Hz, 1 H), 6.70 (d, J = 7.9 Hz, 1 H), 6.83 (d,
J = 7.9 Hz, 1 H), 6.92 (t, J = 7.9 Hz, 1 H), 7.12–7.41 (m, 6 H).
13C NMR (125 MHz, CDCl3): d = 39.96, 74.76, 116.75, 123.02,
126.25, 127.34, 127.85, 128.23, 129.04, 129.35, 129.45, 133.08,
134.79, 141.88, 142.02, 153.02.
(13) Majetich, G.; Casares, A.; Chapman, D.; Behnke, M. J. Org.
Chem. 1986, 51, 1745.
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Synthesis of 1-Methyl-1H-benzo[b]azepines from 1-Methylquinolinium Iodides
4227
(14) Production of only 8a was observed without the use of 4 Å
MS.
(15) Ruiz, A.; Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron Lett. 1997, 38, 6205.
(16) Zelichenok, A.; Burtman, V.; Zenou, N.; Yitzchaik, S.;
Bella, S. D.; Mushulam, G.; Kotler, Z. J. Phys. Chem. B
1999, 103, 8702.
(17) Hamada, Y.; Sugiura, M. Yakugaku Zasshi 1979, 99, 493.
(18) Gesto, C.; De la Cuesta, E.; Avendano, C. Synth. Commun.
1989, 19, 3523.
Synthesis 2010, No. 24, 4221–4227 © Thieme Stuttgart · New York