Me3SiCl-promoted intramolecular cyclization of aromatic compounds tethered with N,O-acetals leading to the facile preparation of 1,4-benzodiazepine skeletons

Article abstract of DOI:10.1016/j.tet.2010.09.077

The Me₃SiCl-promoted intramolecular aminomethylation of a novel type of N,O-acetals, which were prepared via a facile three-step synthesis from N-alkylaniline derivatives and N-alkyl-2-oxazolidinones that leads to the production of pharmaceutically useful 1,4-benzodiazepine skeletons with a variety of functional groups is described. This method was successfully applied to the facile preparation of both tricyclic benzodiazepine derivatives and a 1,4-benzoxazepine derivative via 7-exo-trig cyclization.

Full text of DOI:10.1016/j.tet.2010.09.077

Tetrahedron 66 (2010) 8837e8845
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Me3SiCl-promoted intramolecular cyclization of aromatic compounds
tethered with N,O-acetals leading to the facile preparation of
1,4-benzodiazepine skeletons
*
Norio Sakai , Akimasa Watanabe, Reiko Ikeda, Yumi Nakaike, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Yamazaki 2641, Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2010
Received in revised form 19 September 2010
Accepted 20 September 2010
Available online 24 September 2010
The Me3SiCl-promoted intramolecular aminomethylation of a novel type of N,O-acetals, which were
prepared via a facile three-step synthesis from N-alkylaniline derivatives and N-alkyl-2-oxazolidinones
that leads to the production of pharmaceutically useful 1,4-benzodiazepine skeletons with a variety of
functional groups is described. This method was successfully applied to the facile preparation of both
tricyclic benzodiazepine derivatives and a 1,4-benzoxazepine derivative via 7-exo-trig cyclization.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Benzodiazepine
N,O-Acetal
Intramolecular cyclization
Chlorosilane
1. Introduction
N
C
1,4-Benzodiazepine skeletons are one of the most important and
central building blocks in medicinal and pharmaceutical chemistry.
The 1,4-benzodiazepines are found in a wide variety of biologically
active substances, which show sedative, anxiolytic, anticonvulsant,
and hypnotic activity.1 A variety of approaches for the synthesis of
the 1,4-diazepine skeletons have been developed, which are orga-
nized in Scheme 1 based on the position of bond formation: (i)
1,7-bond-forming cyclization via an aromatic substitution with
a nitrogen atom (path a);2 (ii) 1,2-bond-forming cyclization that
proceeds via a SN2-type reaction with a nucleophilic nitrogen
atom3 and a Pd-catalyzed intramolecular N-arylation4 (path b); (iii)
3,4-bond-forming5 or 4,5-bond-forming cyclization6 (paths c and
d); (iv) a 5,6-bond-forming reaction via intramolecular cyclization
of a substrate with an N,O- or N,N-acetal moiety (path e);7 (v) 4,5-
and 5,6-bond-forming annulation via a PicteteSpengler reaction
with an aldehyde as a C1 unit8 and a Pd-catalyzed intramolecular
coupling reaction in the presence of CO gas9 (path f); (vi) 1,2- and
4,5-bond-forming annulation through a ring-expansion with an
aziridine (path g);10 and (vii) 1,7- and 5,6-bond-forming reaction by
direct annulation with an ethylenediamine derivative (path h).11
Of these synthetic pathways, we focused on the preparation of
a 1,4-benzodiazepine framework through intramolecular cyclization
N
N
N
C
N
C
N
(a)
C
(h)
(b)
(c)
1
N
2
N
N
C
C
N
(g)
(f)
7
6
3
C
N
N4
5
N
(d)
(e)
C
N
C
N
C
N
C
N
C
N
Scheme 1.
of a substrate with an N,O- or N,N-acetal moiety in the presence of an
acid catalyst (path e), because this facile synthesis of a fused seven-
memberedringstructuresuchasa1,4-benzodiazepinederivativehas
not been extensively studied. Previously, Katritzky et al. reported
intramolecular cyclization of a N-arylethylenediamine derivative
with a benzotriazole unit in the presence of AlCl3 that led to the
* Corresponding author. E-mail address: sakachem@rs.noda.tus.ac.jp (N. Sakai).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.077

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N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
production of a 1,4-benzodiazepine derivative.7d In addition, several
other groups found that a Lewis acid, such as SnCl4, and a strong acid,
such as TFA or hydrochloric acid, promoted intramolecular cycliza-
tion of a substrate with an N,O-acetal unit to produce 1,4-benzodi-
azepine skeletons.7aec,7e However, these methods have several
disadvantages, including the use of a strong acid and the use of more
than a stoichiometric amount of a Lewis catalyst, which limits the
reaction to substrates that are tolerant of these harsh conditions.
Therefore, a facile and efficient synthetic reaction that proceeds un-
der milder conditions is required.
In this context, we previously found that the relatively mild
Lewis acid trimethylchlorosilane (Me3SiCl) was a good catalyst to
activate N,O-acetals with a variety of functional group.12 Thus, to
overcome the limitation described above, we attempted to apply
intramolecular cyclization of aromatic compounds tethered with an
N,O-acetal moiety in the presence of a mild Lewis acid to the
preparation of the 1,4-benzodiazepine framework (Scheme 2). In
this paper, we report the results of a Me3SiCl-promoted intra-
molecular aminomethylation of novel N,O-acetals, which were
prepared via a three-step synthesis from N-alkylaniline derivatives
and N-alkyl-2-oxazolidinones, leading to the synthesis of 1,4-ben-
zodiazepine skeletons with a variety of functional groups. We also
describe the use of this method for the facile preparation of tricyclic
benzodiazepine derivatives and a 1,4-benzoxazepine derivative via
7-exo-trig cyclization.
2-oxazolidinone at 160 ꢀC for 10 h without a solvent, followed by
a standard work-up with an aqueous solution of KOH, which gave
the corresponding ethylenediamine derivative (R1, R2¼Me).13 The
formed 1,2-ethylenediamine derivative in the crude reaction mix-
ture, i.e., without isolation, was then treated with paraformaldehyde
and dehydrating agents in MeOH at room temperature for 8 h to
yield the starting material N,O-acetal 1a in 72% yield (path a).14 Also,
the ethylenediamine was treated with methyl 2-bromo-2-methox-
yacetate12d in the presence of diisopropylethylamine in THF at room
temperature for 1 h to produce the corresponding N,O-acetal 2a in
93% yield (path b).14
Moreover, use of indoline and tetrahydroquinoline instead of an
aniline derivative gave the N,O-acetals 3aed with a nitrogen-con-
taining heterocycle (Scheme 3).
1) neat
160°C, 10 h
O
n
+
N
O
NMe
2) KOH
H2O
N
H
NHMe
(n = 1 or 2)
(HCHO)n
n
(path a)
(path b)
MS3A / K2CO3
MeOH, rt, 8 h
Me
N
R
N
Br
OMe
R2(H)
OMe
Y
MeO
CO2Me
3a: 75% (n = 1, R = H)
3b: 50% (n = 2, R = H)
3c: 54% (n = 1, R = CO2Me)
3d: 95% (n = 2, R = CO2Me)
X
i
Acid catalyst
Y
Pr2NEt
THF, rt, 1 h
N
N
R2(H)
X
R1
R1
Scheme 2.
Scheme 3. Preparation of N,O-acetals 3.
2. Results and discussion
2.1. Preparation of N,O-acetals
2.2. Intramolecular cyclization of N,O-acetals leading to the
1,4-benzodiazepine derivatives
Initially, a series of N,O-acetals 1,2 were prepared via the three
steps shown in Table 1. For example, a representative reaction was
performed as follows: N-methylaniline was treated with N-methyl-
To identify the optimal cyclization conditions, the various cat-
alysts were tested using the intramolecular aminomethylation of
N,O-acetal 1a in CH2Cl2 as a model reaction (Table 2). In a previous
Table 1
Preparation of N,O-acetals 1 and 2
(HCHO)n
MS3A / K2CO3
R1
N
X
1) neat
160°C, 10 h
R1
N
O
MeOH, rt, 8 h (path a)
Ar NHR1
R2
+
Ar
N
OMe
O
NR2
Ar
N
H
Br
2) KOH
H2O
R2
MeO
CO2Me
1,2
i
Pr2NEt
THF, rt, 1 h
(path b)
Entry
Ar
Ph
R1
R2
X
Yielda (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Allyl
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
72
81
75
54
82
72
74
60
75
93
80
94
93
95
78
4-MeeC6H4
2-MeeC6H4
4-MeOeC6H4
4-CleC6H4
4-FeC6H4
3-CF3eC6H4
Ph
9
Ph
Ph
H
10
11
12
13
14
15
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
4-MeeC6H4
4-MeOeC6H4
3-CF3eC6H4
Ph
Ph
Bn
a
Isolated yield.

N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
8839
Table 2
the reactions that involved a substituted benzene ring, which had
either an electron-donating group such as an aliphatic group or an
electron-withdrawing group as a chloro group, were completed
within 0.5 h, yielding the corresponding benzodiazepine derivatives
4 in good to excellent yields. The use of N,O-acetal 1c, which has an
ortho-substituted methyl group, prolonged the reaction time and
reduced the reaction yield due to a steric repulsion between the
methyl group and a methyl substituent (R1¼Me) on a nitrogen atom,
which negatively affected the configuration of the benzene ring and
the N,O-acetal moiety. Intramolecular cyclization of N,O-acetal 1g
also required a long reaction time and resulted in a low product
yield. Obviously a strong electron-withdrawing group, such as a CF3
substituent markedly reduced the nucleophilicity of the substituted
position.
Similarly, when intramolecular aminomethylation of N,O-ace-
tals 2 with an ester group was performed with 1.2 equiv of Me3SiCl
in CH2Cl2 at room temperature, the corresponding benzodiazepine
derivatives 5 were obtained in moderate to good yields (Table 4). In
general, although use of a strong acid/base or an excess amount of
a Lewis acid as the catalyst resulted in hydrolysis of the ester group
and a reduction in the product yield, the relatively mild Lewis acid
Me3SiCl showed no loss in product yield. In the case of a benzene
ring without a substituent, the type of R1 substituent did not affect
the reactivity, and the corresponding benzodiazepine derivatives
5e and 5f were produced in good yields. On the other hand, the N,O-
acetal 2d with a CF3 substituted at the para position gave the
benzodiazepine derivative 5d in only 23% yield along with 7% of the
6-trifluoromethylated benzodiazepine derivative 5d0. Although
there are no clear reasons for decrease of the yield, it seems to be
a steric repulsion between the carbomethoxy group and the ben-
zene ring.
Examinations of reaction conditions for intramolecular cyclization
Me
N
Me
N
catalyst
solvent
N
Me
OMe
N
4a
Me
1a
Run
Catalyst
Solv
Temp
(ꢀC)
(1.2) Hf(OTf)4 (0.1) CH2Cl2 rt
Time Yielda
(h)
(%)
1
2
3
4
5
6
7
Me3SiCl
Me3SiCl
Me3SiI
0.5
0.5
0.5
0.5
6
94
91
83
37
21
84
85
(1.2)
(1.2)
Me3SiOTf (1.2)
d
d
d
d
d
d
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
Me3SiCl
Me3SiCl
HCl
(0.2)
(0.1)
(0.1)
CH3CN Reflux
CH3CN Reflux
1
1
a
NMR yield.
study, we found that when N,O-acetal 1a was reacted with 10 mol %
of Hf(OTf)4 and 1.2 equiv of Me3SiCl in CH2Cl2 at room temperature,
the desired cyclization was completed within 0.5 h to produce
1,4-dimethyl-2,3,4,5-1H-1,4-benzodiazepine (4a) in 94% yield (run
1). When Me3SiCl was used in the absence of Hf(OTf)4, the reaction
also proceeded to give the product in 91% yield (run 2). But, use of
Me3SiOTf led to lower reaction yield, because use of the relatively
strong Lewis acid resulted in formation of complex mixtures (run
4). In addition, when the amount of Me3SiCl was decreased to
0.2 equiv of the N,O-acetal, the product yield was drastically re-
duced (run 5). On the other hand, it was noted that the reaction was
performed under reflux in CH3CN, a catalytic amount (0.1 equiv) of
Me3SiCl-promoted the intramolecular cyclization to give the cor-
responding benzodiazepine derivative in good yield (run 6).15 Be-
cause a catalytic amount of HCl was also highly effective for the
cyclization, it appears that in situ generation of HCl plays a key role
in catalysis of the reaction (run 7).
Table 4
Intramolecular cyclization of N,O-acetals 2 leading to benzodiazepine derivatives 5a
R1
N
R1
N
Me3SiCl
Preparation of a variety of benzodiazepine derivatives starting
with a variety of N,O-acetals was then examined (Table 3). Most of
(1.2 equiv)
X
X
CH2Cl2, rt
N
N
MeO2C
Me
Me
Me
Table 3
MeO2C
OMe
Intramolecular cyclization of N,O-acetals 1 leading to benzodiazepine derivatives 4a
5
2
R1
N
R1
N
Me
N
Me
N
Me
Me3SiCl
(1.2 equiv)
N
X
X
CH2Cl2, rt
N
N
NMe
NMe
R2
NMe
R2
MeO
4
MeO
MeO2C
5a: 66% (4 h)
MeO2C
5b: 72% (1 h)
MeO2C
5c: 63% (4 h)
1
Me
N
Me
Me
Me
N
Me
N
Et
N
Bn
N
F3C
N
N
N
NMe
Me
MeO
NMe
NMe
N
Me
Me
Me
CO2Me
b
5d: 23% (7 h)
MeO2C
5e: 89% (0.5 h)
MeO2C
4b: 83% (0.5 h)
4c: 44% (4 h)
4d: 88% (0.5 h)
5f: 89% (0.5 h)
Me
N
Me
N
Me
N
b6-Trifluoromethylated benzodiazepine derivative 5d0 was obtained in 7% yield.
CF3
a
Isolated yield.
N
N
N
Cl
F
Me
Me
Me
Moreover, to prepare a fused benzodiazepine skeleton, intra-
molecular cyclization of N,O-acetals 3aed, which are bound to
a nitrogen-containing heterocycle such as indoline and tetrahy-
droquinoline, was performed in the presence of Me3SiCl (Table 5).
With the exception of the N,O-acetal 3c, all intramolecular cycli-
zations proceeded smoothly to give the corresponding tricyclic
benzodiazepine derivatives 6 in good yields. For 3c, it seemed that
both steric hindrance between the benzene ring and the ester
group and an unfavorable alignment of the linear N,O-acetal moiety
4e: 85% (0.5 h)
4f: 85% (1 h)
4g: 37% (12 h)
Et
N
Me
N
N
N
Me
4i: 94% (0.5 h)
4h: 89% (0.5 h)
a
Isolated yield.

8840
N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
Table 5
underwent the expected intramolecular cyclization to give 5-car-
bomethoxy-8-N,N-dimethylamino-4-propyl-2,3,4,5-tetrahydro-1,4-
benzoxazepine (8b) in 57% yield. Evidently, the electron-donating
effect of the dimethylamino group markedly increased nucleophi-
licity at the substituted position of the benzene ring.
Intramolecular cyclization of N,O-acetals 3 leading to fused benzodiazepine de-
rivatives 6a
n
Me3SiCl
n
(1.2 equiv)
Me
N
N
R
N
CH2Cl2, rt
R
N
OMe
2.3. Aspect for reaction pathway
Me
6
3 (R = H or CO2Me)
(n = 1 or 2)
To better understand the mechanism of the cyclization reaction,
a control experiment was conducted. When the reaction with N,O-
acetal 1a was carried out with 0.1 equiv of Me3SiCl in the presence
of 1 equiv of Et3N as an acid scavenger, the benzodiazepine 4a was
obtained in only 12% yield (Scheme 5).16 Because the product yield
was nearly consistent with the addition equivalent of Me3SiCl, it
shows that in situ generated HCl functions as a catalyst to promote
the intramolecular cyclization. In addition, a catalytic amount
(10 mol %) of HCl promoted the cyclization (run 7 in Table 2), which
strongly supports the catalytic function of HCl. A plausible mech-
anism for the cyclization, that is, based on these results is shown in
Scheme 6.
N
N
N
N
MeO2C
Me
6d: 70% (0.5 h)
MeO2C
N
Me
N
N
Me
N
Me
6a: 76% (0.5 h) 6b: 72% (0.5 h) 6c: 37% (4 h)
a
Isolated yield.
tethered to the indoline skeleton precluded the approach of the
side chain needed for the intramolecular cyclization to occur.
Finally, to illustrate the utility of this method, we examined the
preparation of the benzoxazepine derivative 8 by Me3SiCl-pro-
moted intramolecular cyclization of a new type of N,O-acetal 7,
which was prepared from a phenol derivative using the three steps
described above for the preparation of N,O-acetals (Scheme 4).
When the reaction with the 4-methoxy-substituted N,O-acetal 7a
was conducted with Me3SiCl, the desired cyclization gave the
hydrolytic product rather than the benzoxazepine derivative 8a. On
the other hand, 3-N,N-dimethylaminomethylated N,O-acetal 7b
Me
Me
N
Me3SiCl (0.1 equiv)
Et3N (1 equiv)
N
NMe CH3CN, reflux, 6 h
NMe
4a: 12%
MeO
1a
Scheme 5. Intramolecular cyclization of N,O-acetal 1a in the presence of a base.
3. Conclusion
O
O
Me3SiCl
(1.2 equiv)
In summary, we demonstrated that the Me3SiCl-promoted
intramolecular cyclization of the N,O-acetals, which were prepared
via a facile three-step synthesis from N-alkylaniline derivatives and
N-alkyl-2-oxazolidinones, leads to the production of pharmaceu-
tically useful 1,4-benzodiazepine derivatives with a variety of
functional groups in good yield. Use of Me3SiCl enabled us to in-
troduce an ester group, which was sensitive to acid conditions, onto
the 1,4-benzezodiazepine framework. In addition, this method
could be extended to the facile preparation of both tricyclic ben-
zodiazepine derivatives and a benzoxazepine derivative via 7-exo-
trig cyclization. Moreover, we found that when the reaction was
conducted in CH3CN under reflux, Me3SiCl successfully catalyzed
the intramolecular cyclization.
N
N
MeO
MeO
CH2Cl2, rt
MeO2C
n-Bu
n-Bu
MeO2C
OMe
7a
8a: ND
O
O
Me2N
Me2N
Me3SiCl
(1.2 equiv)
N
N
CH2Cl2, rt
MeO2C
n-Pr
n-Pr
MeO2C
OMe
8b: 57%
7b
Scheme 4. Preparation of 1,4-benzoxazepine derivative 8.
R
N
R
N
NR
H
Cl
NR
R
N
R
N
HCl
NR
Cl
Me3SiOMe
N
R
MeO
R
N
R
N
Me3SiCl
MeOH
NR
NR
MeO
MeO
HCl
Scheme 6. Plausible mechanism for the intramolecular cyclization of N,O-acetals.

N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
8841
4. Experimental
4.1. General
4.06 (s, 2H), 6.52 (br, 3H), 7.11 (dd, J¼7.2, 7.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3)
d 21.9, 38.5, 39.7, 50.7, 51.1, 55.8, 90.1, 109.2, 112.7,
117.0, 129.0, 138.7, 149.2; MS (FAB): m/z 223 (MþþH); HRMS (FAB):
calcd for C13H23N2O (MþþH): 223.1810, found: 223.1829.
All solvents were purified using conventional method prior to
use. Column chromatography was performed using silica gel. Ani-
lines, phenols, and 2-oxazolidinone derivatives were commercially
available, and anilines were distilled prior to use. Methyl 2-bromo-2-
methoxyacetate was prepared as described in our previous study.12d
All reactions were carried out under a N2 atmosphere, unless oth-
erwise noted. 1H NMR spectra were measured at 500 (or 300) MHz
using tetramethylsilane as the internal standard. 13C NMR spectra
were measured at 125 (or 75) MHz using TMS or a center peak of
chloroform (77.0 ppm) as an internal standard. High-resolution mass
spectra were measured using NBA (3-nitrobenzylalcohol) as the
matrix.
4.2.4. N,N0-Dimethyl-N-methoxymethyl-N0-(4-methoxyphenyl)eth-
ane-1,2-diamine (1d). Yield 82%; yellow oil; IR (neat) 3041, 2942,
1513 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 2.48 (s, 3H), 2.78 (t, 2H,
J¼7.5 Hz), 2.88 (s, 3H), 3.28 (s, 3H), 3.36 (t, 2H, J¼7.5 Hz), 3.74 (s,
3H), 4.06 (s, 2H), 6.59 (d, 2H, J¼9.0 Hz), 7.13 (d, 2H, J¼9.0 Hz); 13C
NMR (125 MHz, CDCl3) d 39.2, 39.6, 50.7, 52.3, 55.7, 55.8, 90.1, 114.2,
114.7, 144.2, 151.5; MS (FAB): m/z 239 (MþþH); HRMS (FAB): calcd
for C13H23N2O2 (MþþH): 239.1760, found: 239.1751.
4.2.5. N,N0-Dimethyl-N-methoxymethyl-N0-(4-chlorophenyl)ethane-
1,2-diamine (1e). Yield 82%; yellow oil; IR (neat) 3046, 2942, 2819,
1504 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 2.48 (s, 3H), 2.78 (t, 2H,
4.2. General procedure for the synthesis of N,O-acetals
J¼7.2 Hz), 2.91 (s, 3H), 3.27 (s, 3H), 3.42 (t, 2H, J¼7.2 Hz), 4.05 (s,
2H), 6.59 (d, 2H, J¼9.0 Hz), 7.13 (d, 2H, J¼9.0 Hz); 13C NMR (75 MHz,
To a reaction flask, an N-substituted aniline derivative (50 mmol)
and an N-substituted 2-oxazolidinone derivative (50 mmol) were
successively added and then were heated neat at 160 ꢀC for 10 h
with stirring. After completion of the reaction, the resulting solution
was cooled to rt. To quench the reaction, an aqueous solution of KOH
(10 mL) was added to the mixture. The organic layer was extracted
with AcOEt (30 mLꢁ3), dried over Na2CO3, and evaporated under
reduced pressure to produce the corresponding diamine derivative
as a pale brown liquid [path a]. The crude diamine (20 mmol),
NaOMe (2.2 g, 40 mmol), and paraformaldehyde (30 mmol) were
successively added in dried MeOH (10 mL) with MS3A, and the
resulting solution was stirred at rt for 6 h. After completion of the
reaction, NaBH4 (1.5 g, 40 mmol) was added to the solution at 0 ꢀC
and the solution was stirred for an additional 2 h. After removal of
volatile compounds, CHCl3 (15 mL) was added to the crude product.
The organic layer was washed with H2O, dried over Na2CO3, and
evaporated under reduced pressure. The crude products were dis-
tilled (Kugelrohr) to give the corresponding N,O-acetal 1 and 3a,b
[path b]. The crude diamine (10 mmol), methyl 2-bromo-2-
methoxyacetate (10 mmol), and iPr2NEt (12 mmol) were succes-
sively added in dried THF (20 mL), and the resulting solution was
stirred at rt for 1 h. After removal of volatile compounds, the crude
products were distilled (Kugelrohr) to give the corresponding N,O-
acetal 2 and 7.
CDCl3) d 38.6, 39.6, 50.5, 51.2, 55.7, 90.0, 113.0, 120.7, 128.8, 147.7;
MS (FAB): m/z 242 (MþþH), 240; HRMS (FAB): calcd for
C12H18ClN2O (MþꢂH): 241.1108, found: 241.1107.
4.2.6. N,N0-Dimethyl-N-methoxymethyl-N0-(4-fluorophenyl)ethane-
1,2-diamine (1f). Yield 72%; yellow oil; IR (neat) 3054, 2942,
1517 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 2.48 (s, 3H), 2.78 (t, 2H,
J¼7.5 Hz), 2.90 (s, 3H), 3.28 (s, 3H), 3.40 (t, 2H, J¼7.5 Hz), 4.05 (s,
3H), 6.64 (dd, 2H, J¼8.5, 2.5 Hz), 6.92 (dd, 2H, J¼8.5, 2.5 Hz); 13C
NMR (125 MHz, CDCl3)
d 38.9, 39.7, 50.6, 51.9, 55.8, 90.1, 113.3 (d,
JCeF¼7 Hz), 115.4 (d, JCeF¼22 Hz), 146.0, 155.1 (d, JCeF¼250 Hz). MS
(FAB): m/z 227 (MþþH); HRMS (FAB): calcd for C12H18FN2O
(MþꢂH): 225.1403, found: 225.1403.
4.2.7. N,N0-Dimethyl-N-methoxymethyl-N0-(3-trifluoromehylphenyl)
ethane-1,2-diamine (1g). Yield 74%; yellow oil: IR (neat) 3043,
2893, 1121 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 2.50 (s, 3H), 2.80 (t,
2H, J¼7.2 Hz), 2.98 (s, 3H), 3.28 (s, 3H), 3.48 (t, 2H, J¼7.2 Hz), 4.06 (s,
2H), 6.83e6.89 (m, 3H), 7.25e7.28 (m, 1H); 13C NMR (125 MHz,
CDCl3)
d
38.5, 39.7, 50.6, 51.0, 55.7, 90.1, 108.0 (q, JCeF¼4 Hz), 112.2
(q, JCeF¼5 Hz), 114.7, 124.9 (q, JCeF¼241 Hz) 129.5, 131.4 (q,
JCeF¼31 Hz), 149.1; MS (FAB): m/z 277 (MþþH); HRMS (FAB): calcd
for C13H20F3N2O (MþþH): 277.1528, found: 277.1555.
4.2.8. N0-Ethyl-N-methoxymethyl-N-methyl-N0-phenylethane-1,2-di-
4.2.1. N,N0-Dimethyl-N-methoxymethyl-N0-phenylethane-1,2-di-
amine (1h). Yield 60%; yellow oil; IR (neat) 3023, 2970, 1506 cmꢂ1
;
amine (1a). Yield 72%; yellow oil; IR (neat) 3025, 2941, 1506 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
1.15 (t, 3H, J¼7.0 Hz), 2.51 (s, 3H), 2.81
1H NMR (500 MHz, CDCl3)
d
2.49 (s, 3H), 2.80 (t, 2H, J¼7.3 Hz), 2.94
(t, 2H, J¼7.5 Hz), 3.30 (s, 3H), 3.37 (t, 2H, J¼7.5 Hz), 3.41 (q, 2H,
J¼7.5 Hz), 4.08 (s, 2H), 6.64 (dd, 1H, J¼8.5, 8.5 Hz), 6.68 (d, 2H,
J¼8.5 Hz), 7.20 (dd, 2H, J¼8.5, 8.5 Hz); 13C NMR (125 MHz, CDCl3)
(s, 3H), 3.28 (s, 3H), 3.45 (t, 2H, J¼7.3 Hz), 4.06 (s, 2H), 6.68 (dd, 1H,
J¼7.5, 7.5 Hz), 6.70 (d, 2H, J¼7.5 Hz), 7.21 (dd, 2H, J¼7.5, 7.5 Hz); 13C
NMR (125 MHz, CDCl3)
d
38.5, 39.7, 50.7, 51.2, 55.8, 90.1, 111.9, 116.0,
d 12.3, 39.8, 45.1, 49.0, 51.3, 55.8, 90.1, 111.7, 115.5, 129.3, 147.8; MS
129.1, 149.1; MS (FAB): m/z 209 (MþþH); HRMS (FAB): calcd for
(FAB): m/z 223 (MþþH); HRMS (FAB): calcd for C13H23N2O (MþþH):
C12H21N2O (MþþH): 209.1654, found: 209.1676.
223.1810, found: 223.1814.
4.2.2. N,N0-Dimethyl-N-methoxymethyl-N0-(4-methylphenyl)ethane-
4.2.9. N-Allyl-N0-ethyl-N-methoxymethyl-N0-phenylethane-1,2-di-
1,2-diamine (1b). Yield 81%; yellow oil; IR (neat) 3032, 2962,
amine (1i). Yield 75%; yellow oil; IR (neat) 3043, 2934 cmꢂ1 1H
;
1510 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
2.24 (s, 3H), 2.48 (s, 3H),
NMR (500 MHz, CDCl3)
d
2.87 (t, 2H, J¼7.5 Hz), 2.93 (s, 3H), 3.26 (s,
2.79 (t, 2H, J¼7.5 Hz), 2.91 (s, 3H), 3.28 (s, 3H), 3.41 (t, 2H, J¼7.5 Hz),
3H), 3.35 (d, 2H, J¼6.5 Hz), 3.43 (t, 2H, J¼7.5 Hz), 4.12 (s, 2H), 5.13 (d,
1H, J¼10 Hz), 5.20 (d, 1H, J¼16 Hz), 5.84 (ddt, J¼16, 10, 6.5 Hz, 1H),
6.68 (m, 3H), 7.21 (dd, 2H, J¼7.5, 7.5 Hz); 13C NMR (125 MHz, CDCl3)
4.06 (s, 2H), 6.64 (d, 2H, J¼8.5 Hz), 7.03 (d, 2H, J¼8.5 Hz); 13C NMR
(125 MHz, CDCl3) d 20.1, 38.6, 39.7, 50.6, 51.5, 55.8, 90.1, 112.4, 125.3,
129.6, 147.2; MS (FAB): m/z 223 (MþþH); HRMS (FAB): calcd for
d 38.4, 48.2, 51.5, 55.3, 55.4, 87.4, 111.9, 115.9, 117.1, 129.1, 136.2,
C13H21N2O (MþꢂH): 221.1654, found: 221.1656.
149.1; MS (FAB): m/z 235 (MþþH); HRMS (FAB): calcd for
C14H23N2O (MþþH): 235.1810, found: 235.1824.
4.2.3. N,N0-Dimethyl-N-methoxymethyl-N0-(2-methylphenyl)ethane-
1,2-diamine (1c). Yield 75%; yellow oil; IR (neat) 3020, 2908,
4.2.10. N-[Carbomethoxy(methoxy)methyl]-N,N0-dimethyl-N0-phen-
1532 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
2.30 (s, 3H), 2.49 (s, 3H),
ylethylamine (2a). Yield 93%; yellow oil; IR (neat) 2950, 1745,
2.80 (t, 2H, J¼7.5 Hz), 2.93 (s, 3H), 3.28 (s, 3H), 3.43 (t, 2H, J¼7.5 Hz),
1599 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 2.47 (s, 3H), 2.82 (t, 2H,

8842
N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
J¼7.2 Hz), 2.95 (s, 3H), 3.36 (s, 3H), 3.45 (td, 2H, J¼7.2, 3.3 Hz),
3.72 (s, 3H), 4.30 (s, 1H), 6.66e6.70 (m, 3H), 7.21 (dd, 2H,
(FAB): m/z 221 (MþþH); HRMS (FAB): calcd for C13H20N2O (Mþ):
220.1576, found: 221.1582.
J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d 37.1, 38.5, 49.2, 51.1, 51.8,
55.7, 93.7, 111.8, 116.0, 129.1, 149.0, 168.9; MS (FAB): m/z 267
(MþþH); HRMS (FAB): calcd for C14H22N2O3 (MþþH): 267.1709,
found: 267.1733.
4.2.17. N-Methoxymethyl-N-methyl-2-(1,2,3,4-tetrahydroquinolin-1-
yl)ethylamine (3b). Yield 50%; yellow oil; IR (neat) 2951, 1510 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
1.92 (q, 2H, J¼6.3 Hz), 2.50 (s, 3H), 2.72
(t, 2H, J¼6.3 Hz), 2.82 (t, 2H, J¼7.5 Hz), 3.32e3.30 (m, 5H), 3.39 (t,
2H, J¼7.5 Hz), 4.08 (s, 2H), 6.58e6.53 (m, 2H), 6.92 (d, 1H, J¼7.8 Hz),
4.2.11. N-[Carbomethoxy(methoxy)methyl]-N,N0-dimethyl-N0-(4-
methylphenyl)ethylamine (2b). Yield 80%; yellow oil; IR (neat) 2960,
7.03 (dd, 1H, J¼7.8, 7.8 Hz); 13C NMR (75 MHz, CDCl3)
d 22.2, 28.1,
1732 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
2.15 (s, 3H), 2.37 (s, 3H),
39.7, 49.8, 49.9, 50.2, 55.8, 90.1, 110.2, 115.4, 122.1, 127.1, 129.1, 145.1;
MS (FAB): m/z 235 (MþþH); HRMS (FAB): calcd for C14H21N2O
(MþꢂH): 233.1654, found: 233.1653.
2.71e2.73 (m, 2H), 2.83 (s, 3H), 3.28 (s, 3H), 3.32e3.33 (m, 2H), 3.64
(s, 3H), 4.21 (s, 1H), 6.54 (d, 2H, J¼8.5 Hz), 6.94 (d, 2H, J¼8.5 Hz); 13C
NMR (125 MHz, CDCl3) d 20.0, 36.9, 38.6, 49.1, 51.3, 51.6, 55.6, 93.5,
112.1, 125.1, 129.5, 129.6, 146.9, 168.8; MS (FAB): m/z 281 (MþþH);
HRMS (FAB): calcd for C15H25N2O3 (MþþH): 281.1865, found:
281.1858.
4.2.18. N-[Carbomethoxy(methoxy)methyl]-2-(indolin-1-yl)-N-
methylethylamine (3c). Yield 54%; yellow oil; IR (neat) 2952,
1734 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 2.48 (s, 3H), 2.83e2.92 (m,
2H), 2.95 (t, 2H, J¼8.5 Hz), 3.16e3.22 (m, 2H), 3.36e3.41 (m, 5H,
overlap), 3.75 (s, 3H), 4.36 (s, 1H), 6.46 (d, 1H, J¼7.5 Hz), 6.62 (dd,
1H, J¼7.5, 7.5 Hz), 7.04 (d, 1H, J¼7.5 Hz) 7.05 (dd, 2H, J¼7.5, 7.5 Hz);
4.2.12. N-[Carbomethoxy(methoxy)methyl]-N,N0-dimethyl-N0-(4-
methoxyphenyl)ethylamine (2c). Yield 94%; yellow oil; IR (neat)
2946, 1746 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
2.45 (s, 3H), 2.79 (t,
13C NMR (125 MHz, CDCl3)
d 28.5, 36.9, 47.8, 49.9, 51.7, 53.3, 55.6,
2H, J¼7.5 Hz), 2.88 (s, 3H), 3.35 (s, 3H), 3.36e3.39 (m, 2H), 3.72 (s,
93.4, 106.5, 117.2, 124.3, 127.2, 129.6, 152.3, 168.9; MS (FAB): m/z 278
(Mþ), 146 (Mþꢂ[indolinyleCH2CH2e]); HRMS (FAB): calcd for
C15H23N2O3 (MþþH): 279.1709, found: 279.1734.
3H), 3.74 (s, 3H), 4.30 (s, 1H), 6.68 (d, 2H, J¼9 Hz), 6.81 (d, 2H,
J¼9 Hz); 13C NMR (125 MHz, CDCl3)
d 36.9, 38.9, 49.1, 51.5, 52.0,
55.5, 93.4, 113.8, 114.5, 143.9, 151.2, 168.8; MS (FAB): m/z 297
(MþþH); HRMS (FAB): calcd for C15H24N2O4 (Mþ): 296.1736, found:
297.1736.
4.2.19. N-[Carbomethoxy(methoxy)methyl]-N-methyl-2-(1,2,3,4-tet-
rahydroquinolin-1-yl)ethylamine (3d). Yield 95%; yellow oil; IR
(neat) 2913, 1744 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 1.92 (t, 2H,
4.2.13. N-[Carbomethoxy(methoxy)methyl]-N,N0-dimethyl-N0-(3-tri-
J¼6 Hz), 2.48 (s, 3H), 2.73 (t, 2H, J¼6 Hz), 2.83 (t, 2H, J¼7.5 Hz),
3.30e3.32 (m, 2H), 3.36e3.39 (m, 5H, overlap), 3.73 (s, 3H), 4.32 (s,
1H), 6.54 (d, 2H, J¼7.5 Hz), 6.56 (dd, 2H, J¼7.5, 7.5 Hz), 6.92 (d, 1H,
J¼7.5 Hz), 7.03 (d, 1H, J¼7.5, 7.5 Hz); 13C NMR (125 MHz, CDCl3)
fluoromethylphenyl)ethylamine (2d). Yield 93%; yellow oil; IR (neat)
2964, 1733, 1132 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 2.48 (s, 3H),
2.82 (t, 2H, J¼7 Hz), 2.99 (s, 3H), 3.36 (s, 3H), 3.45e3.50 (m, 2H),
3.71 (s, 3H), 4.29 (s, 1H), 6.82 (d, 1H, J¼8 Hz), 6.87 (s, 1H), 6.90 (d,
1H, J¼8 Hz), 7.29 (dd, 1H, J¼8, 8 Hz); 13C NMR (125 MHz, CDCl3)
d
22.1, 28.1, 37.1, 48.8, 49.8, 49.9, 51.8, 55.7, 93.7, 110.1, 115.4, 122.1,
127.0, 129.1, 144.9, 168.9; MS (FAB): m/z 293 (MþþH), 160
d
37.4, 38.5, 49.0, 51.0, 51.8, 55.8, 93.7, 108.0 (q, JCeF¼4 Hz), 112.3 (q,
(quinolinyleCH2CH2e); HRMS (FAB): calcd for C11H14
N
JCeF¼4 Hz), 114.6, 124.8 (q, JCeF¼252 Hz), 129.5, 131.0 (q,
JCeF¼25 Hz), 149.1, 168.9; MS (FAB): m/z 335 (MþþH, 40%), 334
(Mþ); HRMS (FAB): calcd for C15H22F3N2O2 (MþþH): 335.1583,
found: 335.1566.
(quinolinyleCH2CH2e): 160.1126, found: 160.1141.
4.2.20. N-Butyl-N-[Carbomethoxy(methoxy)methyl]-2-[(4-methoxy)
phenoxy]ethylamine (7a). Yield 98%; yellow oil; IR (neat) 2834,
1749 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
0.91 (t, 3H, J¼7.2 Hz), 1.31
4.2.14. N-[Carbomethoxy(methoxy)methyl]-N0-ethyl-N-methyl-N0-
(sext, 2H, J¼7.2 Hz), 1.46 (qt, 2H, J¼7.2 Hz), 2.73e2.79 (m, 2H),
3.04e3.15 (m, 2H), 3.38 (s, 3H), 3.75 (s, 3H), 3.76 (s, 3H), 3.95e3.98
phenylethylamine (2e). Yield 95%; yellow oil; IR (neat) 2971, 1742,
750 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
1.15 (t, 3H, J¼7.2 Hz), 2.49 (s,
(m, 2H), 4.47 (s, 1H), 6.82 (s, 4H); 13C NMR (125 MHz, CDCl3)
d 13.9,
3H), 2.82 (t, 2H, J¼7.5 Hz), 3.36e3.41 (m, 7H, overlap), 3.75 (s, 3H),
20.2, 31.0, 49.1, 50.6, 51.8, 55.3, 55.7, 68.0, 92.1, 114.6, 115.3, 152.9,
153.8, 169.7; MS (FAB): m/z 326 (MþþH); HRMS (FAB): calcd for
C17H28NO5: 326.1967, found: 326.1996.
4.32 (s, 1H), 6.64 (t, 3H, J¼8.0 Hz), 6.67 (m, 3H), 7.20 (dd, 2H, J¼8,
8 Hz); 13C NMR (75 MHz, CDCl3)
d 12.2, 37.2, 45.1, 48.9, 49.8, 51.8,
55.8, 93.7, 111.6, 115.6, 129.3, 147.6, 169.0; MS (FAB): m/z 281
(MþþH, 40%), 280 (Mþ); HRMS (FAB): calcd for C15H25N2O3:
281.1787, found: 281.1804.
4.2.21. N-[Carbomethoxy(methoxy)methyl]-N-propyl-2-[(3-N,N-di-
methyl)phenoxy]ethylamine (7b). Yield 99%; yellow oil; IR (neat)
2955, 1731 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 0.89 (t, 3H,
4.2.15. N0-Benzyl-N-[Carbomethoxy(methoxy)methyl]-N-methyl-N0-
J¼8.5 Hz), 1.52 (sext, 2H, J¼8.5 Hz), 2.72e2.74 (m, 2H), 2.93 (s,
6H), 3.06e3.17 (m, 2H), 3.39 (s, 3H), 3.76 (s, 3H), 4.01e4.02 (m,
2H), 4.48 (s, 1H), 6.26e6.27 (m, 2H), 6.35 (d, 1H, J¼8 Hz), 7.13 (dd,
phenylethylamine (2f). Yield 78%; yellow oil; IR (neat) 2944,
1730 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 2.45 (s, 3H), 2.89 (t, 2H,
J¼7.5 Hz), 3.37 (s, 3H), 3.54 (t, 2H, J¼7.5 Hz), 3.71 (s, 3H), 4.30 (s,1H),
1H, J¼8, 8 Hz); 13C NMR (125 MHz, CDCl3)
d 11.5, 22.0, 40.5, 49.2,
51.8, 52.7, 55.2, 67.2, 92.1, 99.5, 102.0, 105.7, 129.7, 151.9, 159.8,
4.57 (s, 2H), 6.66e6.68 (m, 3H), 7.18e7.29 (m, 7H); 13C NMR
(75 MHz, CDCl3)
d
37.2, 49.4, 51.8, 54.5, 55.8, 67.9, 93.7, 112.0, 116.3,
169.7; MS (FAB): m/z 325 (MþþH); HRMS (FAB): calcd for
126.5, 126.7, 128.5, 129.2, 138.8, 148.3, 168.9. MS (FAB): m/z 343
(MþþH); HRMS (FAB): calcd for C20H25N2O3(MþꢂH): 341.1865,
found: 341.1879.
C17H29N2O4 (MþþH): 325.2127, found: 325.2145. (
þ5.5 ppm,
D
D
þ1.8 mmu).
4.3. General procedure for synthesis of 1,4-benzodiazepine
derivatives
4.2.16. 2-(Indolin-1-yl)-N-methoxymethyl-N-methylethylamine
(3a). Yield 75%; yellow oil; IR (neat) 2943, 2813, 1494 cmꢂ1 1H
;
NMR (300 MHz, CDCl3)
d
2.51 (s, 3H), 2.87 (t, 2H, J¼7.5 Hz), 2.95 (t,
An N,O-acetal (0.5 mmol) and Me3SiCl (76 mL, 0.060 mmol) were
2H, J¼8.1 Hz), 3.20 (t, 2H, J¼7.5 Hz), 3.30 (3H, s), 3.38 (t, 2H,
J¼8.1 Hz), 4.10 (2H, s), 6.48 (d, 1H, J¼8.4 Hz), 6.62 (dd, 1H, J¼8.4,
successively mixed in dried CH2Cl2 (2 mL) at room temperature
under a N2 atmosphere with stirring. The mixture was stirred at
room temperature until the reaction was completed, as verified by
TLC (SiO2/hexane/AcOEt¼2:1). After completion of the reaction, the
8.4 Hz), 7.05e7.03 (2H, m); 13C NMR (75 MHz, CDCl3)
d 28.6, 39.7,
47.9, 51.5, 53.4, 55.8, 89.9, 106.8, 117.4, 124.3, 127.2, 129.8, 152.5; MS

N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
8843
organic layer was extracted with AcOEt, dried over anhydrous
Na2CO3, and evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography (hexaneeAcOEt)
to afford the corresponding 1,4-benzodiazepine derivative.
z 245 (MþþH); HRMS (FAB): calcd for C12H16F3N2 (MþþH):
245.1266, found: (MþþH): 245.1259.
4.3.8. 1-Ethyl-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
(4h). Yield 89%; yellow oil; IR (neat) 2932, 2843, 1492 cmꢂ1 1H
;
4.3.1. 1,4-Dimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine7d
NMR (500 MHz, CDCl3)
d
1.20 (t, 3H, J¼7 Hz), 2.36 (s, 3H), 2.78 (t,
(4a). Yield 91%; yellow oil; IR (neat) 2958, 1452 cmꢂ1
;
1H NMR
2H, J¼4.5 Hz), 3.00 (t, 2H, J¼4.5 Hz), 3.21 (q, 2H, J¼7 Hz), 3.68 (s,
2H), 6.84 (dd, 1H, J¼7.5, 7.5 Hz), 6.90 (d, 1H, J¼7.5 Hz), 7.13 (d, 1H,
(500 MHz, CDCl3)
d
2.36 (s, 3H), 2.84 (t, 2H, J¼5.0 Hz), 2.89 (s, 3H),
2.99 (t, 2H, J¼5.0 Hz), 3.69 (s, 2H), 6.87 (t, 1H, J¼7.5 Hz), 6.88 (d, 1H,
J¼7.5 Hz), 7.18 (dd, 1H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d 13.8,
J¼7.5 Hz), 7.13 (d, 1H, J¼5.5 Hz), 7.20 (t, 1H, J¼7.5 Hz); 13C NMR
43.9, 47.5, 51.1, 59.2, 61.6, 116.5, 120.4, 127.8, 130.8, 130.9, 152.4; MS
(FAB): m/z 191 (MþþH); HRMS (FAB): calcd for C12H19N2 (MþþH):
191.1548, found: 191.1557.
(125 MHz, CDCl3)
d 42.7, 43.8, 54.6, 58.7, 61.8, 115.4, 120.6, 127.9,
130.3, 130.8; MS (FAB): m/z 177 (MþþH).
4.3.2. 1,4,7-Trimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
4.3.9. 4-Allyl-1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine7d
(4b). Yield 83%; yellow oil; IR (neat) 29,402, 1508 cmꢂ1
;
1H NMR
(4i). Yield 94%; yellow oil; IR (neat) 2952, 1512 cmꢂ1 1H NMR
;
(500 MHz, CDCl3)
d
2.26 (s, 3H), 2.34 (s, 3H), 2.83e2.86 (m, 5H,
(500MHz, CDCl3)
d
2.89(s,3H), 2.92(t, 2H, J¼4Hz), 2.99(t, 2H, J¼4Hz),
overlap), 2.94 (t, 2H, J¼4.5 Hz), 3.68 (s, 2H), 6.78 (d, 1H, J¼8 Hz),
3.10 (d, 2H, J¼6.5Hz), 5.15e5.19 (m, 2H), 5.88e5.91(m,1H), 6.87(d,1H,
J¼7 Hz), 6.88 (dd,1H, J¼8, 8 Hz), 7.11 (d,1H, J¼7 Hz), 7.21 (dd,1H, J¼8,
6.95 (s, 1H), 7.00 (d, 1H, J¼8 Hz); 13C NMR (125 MHz, CDCl3)
d 20.3,
42.9, 43.5, 54.5, 58.7, 61.6, 115.3, 128.3, 129.9, 130.1, 131.7, 150.2; MS
(FAB): m/z 191 (MþþH); HRMS (FAB): calcd for C12H19N2 (MþþH):
191.1548, found: 191.1550.
8 Hz); 13C NMR (125 MHz, CDCl3)
d 42.8, 54.5, 56.4, 58.1, 59.0, 115.4,
117.6, 120.6, 127.9, 130.3, 130.9, 135.9, 152.5; (FAB): m/z 203 (MþþH).
4.3.10. 5-Carbomethoxy-1,4-dimethyl-2,3,4,5-tetrahydro-1H-1,4-
4.3.3. 1,4,9-Trimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
benzodiazepine (5a). Yield 66%; yellow oil; IR (neat) 2947,
(4c). Yield 44%; yellow oil; IR (neat) 2926, 1469 cmꢂ1
;
1H NMR
1747 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 2.41 (s, 3H), 2.52 (br, 1H, H-
(500 MHz, CDCl3)
d
2.29 (s, 3H), 2.37 (s, 3H), 2.84 (br s, 5H,
3a), 2.77 (s, 3H), 2.89 (ddd, 1H, J¼12, 6, 3 Hz, H-3b), 3.00 (ddd, 1H,
J¼12, 6, 3 Hz, H-2a), 3.17 (dd,1H, J¼12, 3 Hz, H-2b), 3.67 (s, 3H), 4.39
(s, 1H), 6.92 (d, 1H, J¼7 Hz), 6.96 (dd, 1H, J¼7 Hz), 7.06 (d, 1H,
overlap), 3.23 (br, 2H), 3.71 (br, 2H), 6.90e6.95 (m, 2H), 7.08 (d,
1H, J¼7 Hz); 13C NMR (125 MHz, CDCl3)
d 18.3, 39.3, 43.9, 51.9,
54.6, 61.2, 123.9, 128.3, 128.8, 123.0, 135.5, 149.5; MS (FAB): m/z
191 (MþþH); HRMS (FAB): calcd for C12H19N2 (MþþH): 191.1548,
found: 191.1557.
J¼7 Hz), 7.30 (dd, 1H, J¼7 Hz); 13C NMR (125 MHz, CDCl3)
d 40.8,
42.5, 51.8, 52.5, 52.6, 69.7, 116.9, 121.1, 127.7, 128.9, 129.6, 149.1,
173.3; MS (FAB): m/z 235 (MþþH); HRMS (FAB): calcd for
C13H19N2O2 (MþþH): 235.1447, found: 235.1447.
4.3.4. 1,4-Dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-1,4-benzodi-
azepine (4d). Yield 88%; yellow oil; IR (neat) 2956, 2854 cmꢂ1
;
1H
4.3.11. 5-Carbomethoxy-1,4,7-trimethyl-2,3,4,5-tetrahydro-1H-
NMR (500 MHz, CDCl3)
d
2.35 (s, 3H), 2.85 (br s, 5H, overlap), 2.91 (t,
1,4-benzodiazepine (5b). Yield 72%; yellow oil; IR (neat) 2946, 2854,
2H, J¼5 Hz), 3.69 (s, 2H), 3.77 (s, 3H), 6.75 (s, 1H), 6.76 (d, 2H,
1740 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 2.30 (s, 3H), 2.39 (s, 3H),
J¼8 Hz), 6.83 (d, 1H, J¼8 Hz); 13C NMR (125 MHz, CDCl3)
d
43.2,
2.47 (br, 1H, H-3a), 2.74 (s, 3H), 2.81 (ddd, 1H, J¼12, 6, 3 Hz, H-3b),
2.98 (ddd, 1H, J¼12, 6, 3 Hz, H-2a), 3.12 (dd, 1H, J¼12, 3 Hz, H-2b),
3.68 (s, 3H), 4.36 (s,1H), 6.82 (d, 1H, J¼8 Hz), 6.88 (s,1H), 7.10 (d,1H,
43.5, 54.6, 55.5, 58.9, 61.7, 112.4, 116.3, 116.9, 132.0, 146.3, 153.9; MS
(FAB): m/z 207 (MþþH); HRMS (FAB): calcd for C12H19N2O (MþþH):
207.1497, found: 207.1499.
J¼8 Hz); 13C NMR (125 MHz, CDCl3)
d 20.5, 40.8, 42.5 (br), 51.8, 52.6,
69.6, 116.8, 127.8, 129.4, 130.3, 130.5, 146.7, 173.4; MS (FAB): m/z 249
4.3.5. 7-Chloro-1,4-dimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiaze-
(MþþH); calcd for C14H21N2O2 (MþþH): 249.1603, found: 249.1605.
pine (4e). Yield 85%; yellow oil; IR (neat) 2960, 2811 cmꢂ1; 1H NMR
(500 MHz, CDCl3)
d
2.34 (s, 3H), 2.83 (t, 2H, J¼5 Hz), 2.86 (s, 3H),
4.3.12. 5-Carbomethoxy-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahy-
2.97 (t, 2H, J¼5 Hz), 3.65 (s, 2H), 6.79 (d, 2H, J¼8.5 Hz), 7.10 (d, 1H,
dro-1H-1,4-benzodiazepine (5c). Yield 63%; yellow oil; IR (neat)
J¼2.5 Hz), 7.14 (dd, 1H, J¼8.5, 2.5 Hz); 13C NMR (125 MHz, CDCl3)
2944, 1746 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 2.39 (s, 3H), 2.47 (br,
d
42.8, 43.5, 54.4, 58.4, 61.3, 116.7, 125.3, 127.5, 130.4, 132.0, 151.1;
1H, H-3a), 2.73 (s, 3H), 2.78 (ddd,1H, J¼12, 6, 3 Hz, H-3b), 3.00 (ddd,
1H, J¼12, 6, 3 Hz, H-2a), 3.10 (dd, 1H, J¼12, 3 Hz, H-2b), 3.69 (s, 3H),
3.78 (s, 3H), 4.36 (s, 1H), 6.68 (d, 1H, J¼2.6 Hz), 6.83 (dd, 1H, J¼8.7,
MS (FAB): m/z 211 (MþþH); HRMS (FAB): calcd for C11H16ClN2
(MþþH): 211.1002, found: 211.0979.
2.6 Hz), 6.87 (d, 1H, J¼8.7 Hz); 13C NMR (125 MHz, CDCl3)
d 41.1,
4.3.6. 7-Fluoro-1,4-dimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiaze-
42.5 (br), 51.9, 52.6, 52.7, 55.4, 69.4, 112.9, 117.7, 129.6, 142.7, 154.4,
173.1; MS (FAB): m/z 265 (MþþH); HRMS (FAB): calcd for
C12H16N2O2 (MþþH): 265.1552, found: 265.1547.
pine (4f). Yield 85%; yellow oil; IR (neat) 2942, 2796, 1501 cmꢂ1; 1H
NMR (500 MHz, CDCl3)
3H), 2.93 (t, 2H, J¼5 Hz), 3.66 (s, 2H), 6.81 (dd, 1H, J¼8.5, 5.0 Hz),
6.87e6.89 (m, 2H); 13C NMR (125 MHz, CDCl3)
43.1, 43.6, 54.5,
58.7, 61.3, 113.6 (d, JCeF¼22 Hz), 116.2 (d, JCeF¼8 Hz), 117.3 (d,
JCeF¼23 Hz), 132.4, 148.8, 157.3 (d, JCeF¼240 Hz); MS (FAB): m/z 195
(MþþH); HRMS (FAB): calcd for C11H16FN2 (MþþH): 195.1298,
found: 195.1292.
d
2.34 (s, 3H), 2.83 (t, 2H, J¼5 Hz), 2.85 (s,
d
4.3.13. 5-Carbomethoxy-1,4-dimethyl-8-trifluoromethyl-2,3,4,5-tet-
rahydro-1H-1,4-benzodiazepine (5d). Yield 23%; yellow oil; IR (neat)
2932, 1739, 1161 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 2.43 (s, 3H), 2.56
(m, 1H, H-3a), 2.95 (m, 1H, H-3b), 3.05 (m, 1H, H-2a), 3.25 (m, 1H, H-
2b), 3.68 (s, 3H), 4.40 (s, 1H), 7.11 (s, 1H), 7.18e7.19 (m, 2H); 13C NMR
(125 MHz, CDCl3) (a mixture of 5d and 5d0)
d 40.2, 40.8, 42.9, 45.8,
4.3.7. 1,4-Dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-1,4-
benzodiazepine (4g). Yield 37%; yellow oil; IR (neat) 2972,
50.9, 51.9, 52.0, 52.4, 52.5, 54.1, 64.9, 69.7, 113.6, 113.6, 117.6, 117.6,
119.2, 119.3, 121.8, 123.0, 125.2, 127.4, 128.7, 130.3, 131.0, 131.7, 149.4,
149.6, 172.6, 173.2; MS (FAB): m/z 303 (MþþH); HRMS (FAB): calcd
for C14H18F3N2O2 (MþþH): 303.1320, found: 303.1292.
1137 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 2.37 (s, 3H), 2.85 (t, 2H,
J¼5 Hz), 2.93 (s, 3H), 3.04 (t, 2H, J¼5 Hz), 3.71 (s, 2H), 7.07 (s, 1H),
7.11 (d, 1H, J¼8 Hz), 7.21 (d, 1H, J¼8 Hz); 13C NMR (125 MHz, CDCl3)
d
42.6, 43.8, 54.5, 58.2, 61.5, 112.1 (q, JCeF¼4 Hz), 117.1, 124.3 (q,
4.3.14. 5-Carbomethoxy-1,4-dimethyl-6-trifluoromethyl-2,3,4,5-tet-
rahydro-1H-1,4-benzodiazepine (5d0). Yield 7%; yellow oil; IR (neat)
JCeF¼272 Hz),130.1 (q, JCeF¼32 Hz),131.0,133.8,152.8; MS (FAB): m/

8844
N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
2932, 1739, 1161 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
2.27 (m, 1H, H-
1H), 3.08 (br s, 3H), 3.20 (m, 1H), 3.68 (s, 3H), 4.42 (s, 1H), 6.83 (dd,
3a), 2.50 (s, 3H), 2.70 (br s, 3H, overlapping NeMe and H-3b), 2.95
(m, 1H, overlap, H-2a), 3.49 (m, 1H, H-2b), 3.58 (s, 3H), 4.66 (s, 1H),
7.11 (m, 1H), 7.37e7.39 (m, 2H); 13C NMR (125 MHz, CDCl3) (a
1H, J¼7 Hz), 6.88 (d, 1H, J¼7 Hz), 7.01 (d, 1H, J¼7 Hz); 13C NMR
(125 MHz, CDCl3)
d 19.1, 27.7, 41.9 (br), 51.6, 51.7, 52.1, 53.0, 69.4,
120.1, 126.8, 127.5, 127.8, 129.2, 145.1, 173.3; MS (FAB): m/z 261
(MþþH), 201 (MþꢂCO2Me); HRMS (FAB): calcd for C15H21N2O2
(MþþH): 261.1603, found: 261.1604.
mixture of 5d and 5d0)
d 40.2, 40.8, 42.9, 45.8, 50.9, 51.9, 52.0, 52.4,
52.5, 54.1, 64.9, 69.7, 113.6, 113.6, 117.6, 117.6, 119.2, 119.3, 121.8,
123.0, 125.2, 127.4, 128.7, 130.3, 131.0, 131.7, 149.4, 149.6, 172.6,
173.2; MS (FAB): m/z 303 (MþþH); HRMS (FAB): calcd for
C14H18F3N2O2 (MþþH): 303.1320, found: 303.1292.
4.3.21. 5-Carbomethoxy-8-N,N-dimethylamino-4-propyl-2,3,4,5-tet-
rahydro-1,4-benzoxazepine (8b). Yield 57%; pale yellow oil; IR
(neat) 2955, 1735 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 0.88 (t,
4.3.15. 5-Carbomethoxy-1-ethyl-4-methyl-2,3,4,5-tetrahydro-1H-
1,4-benzodiazepine (5e). Yield 76%; yellow oil; IR (neat) 2945,
J¼7.3 Hz, 3H), 1.54 (q, J¼7.3 Hz, 2H), 2.55e2.57 (m, 2H), 2.93 (s, 6H),
2.97 (s, 1H), 3.50 (dd, J¼15.1, 9.6 Hz, 1H), 3.70 (s, 3H), 3.99 (t,
J¼9.6 Hz, 1H), 4.09 (d, J¼15.1 Hz, 1H), 4.53 (s, 1H), 6.37e6.39 (m,
1743 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
1.11 (t, 3H, J¼7 Hz), 2.41 (s,
3H), 2.45 (br, 1H, H-3a), 2.82 (ddd, 1H, J¼12, 6, 3 Hz, H-3b), 3.00
(ddd, 1H, J¼12, 6, 3 Hz, H-2a), 3.20 (q, 2H, J¼7 Hz), 3.21 (m, 1H, H-
2b), 3.67 (s, 3H), 4.33 (s, 1H), 6.93 (d, 1H, J¼7.5 Hz), 6.96 (dd, 1H,
J¼7.5 Hz), 7.09 (d, 1H, J¼7.5 Hz), 7.28 (dd, 1H, J¼7.5 Hz); 13C NMR
2H), 6.95 (d, J¼8.2 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 11.6, 21.1,
40.3 (br), 51.9, 52.5, 54.7, 67.8, 68.9, 104.9, 107.0, 116.7, 131.5, 151.4,
159.4, 172.2; MS (FAB): m/z 293 (MþþH); HRMS (FAB): calcd for
C16H25N2O3 (MþþH): 293.1865, found: 293.1847.
(125 MHz, CDCl3) d 13.2, 43.1, 46.8, 50.4, 51.8, 52.5, 69.9, 118.0, 121.2,
128.6, 128.8, 129.9, 148.4, 173.3; MS (FAB): m/z 249 (MþþH); HRMS
Acknowledgements
(FAB): calcd for C14H21N2O2 (MþþH): 249.1603, found: 249.1626.
This work was partially supported by a grant from the Japan
Private School Promotion Foundation supported by MEXT. The
authors deeply thank Dow Corning Toray Co., Ltd. for the Me3SiCl.
The authors are grateful to Mr. Kosuke Tamura and Mr. Hitoshi
Nakatsuka for their experimental assistance with the spectral
measurements.
4.3.16. 1-Benzyl-5-carbomethoxy-4-methyl-2,3,4,5-tetrahydro-1H-
1,4-benzodiazepine (5f). Yield 53%; yellow oil; IR (neat) 2940,
1739 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 2.41 (s, 3H), 2.63 (br, 1H, H-
2a), 2.91 (t, 2H, J¼5 Hz, H-3), 3.07 (br,1H, H-2b), 3.76 (s, 3H), 4.24 (d,
2H, J¼13.7 Hz), 4.30 (d, 2H, J¼13.7 Hz), 4.61 (s, 1H), 6.98 (dd, 1H,
J¼7.6, 7.6 Hz), 7.03 (d, 1H, J¼7.6 Hz), 7.10 (d, 1H, J¼7.6 Hz), 7.29e7.24
(2H, m), 7.35e7.32 (4H, m); 13C NMR (125 MHz, CDCl3)
d 41.7 (br),
Supplementary data
48.9, 51.9, 53.1 (br), 57.9, 69.9 (br), 117.9, 121.6, 127.1, 128.3, 128.4,
128.8, 128.9, 130.1, 138.6, 150.3, 172.7; MS (FAB): m/z 311 (MþþH),
251 (MþꢂCO2Me); HRMS (FAB): calcd for C19H23N2O2 (MþþH):
311.1760, found: 311.1758.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2010.09.077.
References and notes
4.3.17. 4-Methyl-pyrrolo[3.2.1-jk]2,3,4,5-tetrahydro-1H-1,4-benzodi-
azepine (6a). Yield 76%; pale yellow oil; IR (neat) 2941, 1492 cmꢂ1
;
1. (a) Sternbach, L. H. J. Med. Chem. 1979, 22, 1 and references cited therein; (b)
Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (c) Had-
jipavlou-Litina, D.; Garg, R.; Hansch, C. Chem. Rev. 2004, 104, 3751.
1H NMR (500 MHz, CDCl3)
d 2.44 (s, 3H), 2.94 (m, 2H), 2.98 (m, 4H),
3.33 (dd, 2H, J¼8.5 Hz), 3.68 (s, 2H), 6.69 (dd, 1H, J¼7.5, 7.5 Hz), 6.84
(d, 1H, J¼7.5 Hz), 7.00 (d, 1H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
2. For selected papers, see: (a) Clement, E. C.; Carlier, P. R. Tetrahedron Lett. 2005,
46, 3633; (b) Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W.
Tetrahedron Lett. 2006, 47, 3423; (c) Deschrijver, T.; Verwilst, P.; Broos, K.;
Deckmyn, H.; Dehaen, W.; De Borggraeve, W. M. Tetrahedron 2009, 65, 4521.
3. For selected papers, see: (a) Uskokovic, M.; Iacobelli, J.; Wenner, W. J. Org. Chem.
1962, 27, 3606; (b) Santilli, A. A.; Osdene, T. S. J. Org. Chem. 1964, 29, 1998; (c)
Hardtmann, G. E.; Ott, H. J. Org. Chem. 1969, 34, 2244; (d) Weidner-Wells, M. A.;
DeCamp, A.; Mazzocchi, P. H. J. Org. Chem. 1989, 54, 5746; (e) Boojamra, C. G.;
Burow, K. M.; Ellman, J. A. J. Org. Chem. 1995, 60, 5742; (f) Boojamra, C. G.;
Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem. 1997, 62, 1240; (g)
Pei, Y.; Lilly, M. J.; Owen, D. J.; D’Souza, L. J.; Tang, X.-Q.; Yu, J.; Nazarbaghi, R.;
Hunter, A.; Anderson, C. M.; Glasco, S.; Ede, N. J.; James, I. W.; Maitra, U.;
Chandrasekaran, S.; Moos, W. H.; Ghosh, S. S. J. Org. Chem. 2002, 68, 92; (h)
Kamal, A.; Ramana, A. V.; Reddy, K. S.; Ramana, K. V.; Hari Babu, A.; Prasad, B. R.
Tetrahedron Lett. 2004, 45, 8187; (i) Al-awar, R. S.; Ray, J. E.; Hecker, K. A.;
Joseph, S.; Huang, J.; Shih, C.; Brooks, H. B.; Spencer, C. D.; Watkins, S. A.;
Schultz, R. M.; Considine, E. L.; Faul, M. M.; Sullivan, K. A.; Kolis, S. P.; Carr, M. A.;
Zhang, F. Bioorg. Med. Chem. Lett. 2004, 14, 3925; (j) Marcaccini, S.; Miliciani, M.;
Pepino, R. Tetrahedron Lett. 2005, 46, 711; (k) Hemming, K.; Loukou, C. Tetra-
hedron 2004, 60, 3349.
d
29.2, 44.1, 52.9, 56.4, 58.5, 62.7, 119.4, 123.0, 123.2, 127.9, 131.1,
152.3; MS (FAB): m/z 189 (MþþH); HRMS (FAB): calcd for C12H17N2
(MþþH): 189.1392, found: 189.1418.
4.3.18. 4-Methyl-piperidino[3.2.1-jk]2,3,4,5-tetrahydro-1H-1,4-ben-
zodiazepine (6b). Yield 72%; yellow oil; IR (neat) 2934, 1475 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d 1.79e1.87 (m, 2H), 2.35 (s, 3H), 2.75 (t,
2H, J¼6.3 Hz), 2.83 (t, 2H, J¼4.8 Hz), 3.06 (t, 2H, J¼4.8 Hz), 3.21 (t,
2H, J¼4.8 Hz), 3.65 (s, 2H), 6.73 (dd, 1H, J¼7.5 Hz), 6.92 (d, 2H,
J¼7.5 Hz), 6.94 (d, 2H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 20.6,
28.3, 43.7, 54.8, 55.0, 58.7, 61.6, 119.7, 126.8, 128.5, 128.8, 129.6,
148.2; MS(FAB): m/z 203 (MþþH); HRMS (FAB): calcd for C13H19N2
(MþþH): 203.1548, found: 203.1546.
4.3.19. 5-Carbomethoxy-4-methyl-pyrrolo[3.2.1-jk]2,3,4,5-tetrahy-
4. For a selected paper, see: Beccalli, E. M.; Broggini, G.; Paladino, G.; Zoni, C.
Tetrahedron 2005, 61, 61.
dro-1H-1,4-benzodiazepine (6c). Yield 37%; yellow oil; IR (neat)
5. For selected papers, see: (a) Sternbach, L. H.; Reeder, E. J. Org. Chem. 1961, 26,
1111; (b) Sternbach, L. H.; Reeder, E. J. Org. Chem. 1961, 26, 4936; (c) Hamann, L.
G.; Ding, C. Z.; Miller, A. V.; Madsen, C. S.; Wang, P.; Stein, P. D.; Pudzianowski, A. T.;
Green, D. W.; Monshizadegan, H.; Atwal, K. S. Bioorg. Med. Chem. Lett. 2004, 14,
1031.
2928, 1739 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 2.62 (s, 3H),
2.96e3.05 (m, 5H), 3.27 (dd, 1H, J¼9 Hz), 3.37e3.39 (2H, m), 3.71 (s,
3H), 4.53 (s, 1H), 6.72 (dd, 1H, J¼7.5 Hz), 6.86 (d, 1H, J¼7.5 Hz), 7.04
(d, 1H, J¼7.5 Hz); 13C NMR (125 MHz, CDCl3)
d 29.3, 42.8, 50.9, 51.9,
6. For selected papers, see: (a) Gates, M. J. Org. Chem. 1980, 45, 1675; (b) Sherrill,
R. G.; Sugg, E. E. J. Org. Chem. 1995, 60, 730; (c) Herrero, S.; Garcia-Lopez, M. T.;
Cenarruzabeitia, E.; Del Rio, J.; Herranz, R. Tetrahedron 2003, 59, 4491; (d)
Herrero, S.; Garcia-Lopez, M. T.; Herranz, R. J. Org. Chem. 2003, 68, 4582; (e)
Wiklund, P.; Rogers-Evans, M.; Bergman, J. J. Org. Chem. 2004, 69, 6371; (f)
52.6, 56.4, 70.6, 119.2, 120.1, 123.7, 129.0, 131.9, 152.0, 171.9; MS
(FAB): m/z 247 (MþþH), 187 (MþꢂCO2Me); HRMS (FAB): calcd for
C14H19N2O2 (MþþH): 247.1447, found: 247.1446.
€
€
Hussenether, T.; Hubner, H.; Gmeiner, P.; Troschutz, R. Bioorg. Med. Chem. 2004,
12, 2625; (g) Ferrini, S.; Ponticelli, F.; Taddei, M. J. Org. Chem. 2006, 71, 9217.
7. For selected papers, see: (a) Archer, S.; Lewis, T. R.; Unser, M. J.; Hoppe, J. O.;
Lape, H. J. Am. Chem. Soc. 1957, 79, 5783; (b) Kraus, G. A.; Yue, S. J. Org. Chem.
1983, 48, 2936; (c) Massa, S.; Mai, A.; Artico, M.; Corelli, F.; Botta, M. Tetrahedron
1989, 45, 2763; (d) Katritzky, A. R.; Xu, Y.-J.; He, H.-Y. J. Chem. Soc., Perkin Trans. 1
4.3.20. 5-Carbomethoxy-4-methyl-piperidino[3.2.1-jk]2,3,4,5-tetra-
hydro-1H-1,4-benzodiazepine (6d). Yield 70%; yellow oil; IR (neat)
2966, 1731 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
1.75e1.82 (br, 2H),
2.41 (s, 3H), 2.56e2.66 (br, 1H), 2.76 (t, 2H, J¼6.3 Hz), 2.99e3.00 (br,

N. Sakai et al. / Tetrahedron 66 (2010) 8837e8845
8845
2002, 592; (e) Cul, A.; Daich, A.; Decroix, B.; Sanz, G.; Van Hijfte, L. Tetrahedron
2004, 60, 11029.
68, 483; (c) Sakai, N.; Asano, J.; Shimano, Y.; Konakahara, T. Synlett 2007,
2675; (d) Sakai, N.; Asano, J.; Shimano, Y.; Konakahara, T. Tetrahedron 2008,
64, 9208; (e) Sakai, N.; Sato, A.; Konakahara, T. Synlett 2009, 1449; (f) Sakai,
N.; Asano, J.; Kawada, Y.; Konakahara, T. Eur. J. Org. Chem. 2009, 917.
13. Poindexter, G. S.; Owens, D. A.; Dolan, P. L.; Woo, E. J. Org. Chem. 1992, 57, 6257.
14. Aqueous isolation and silica gel purification of the acetals having an ester
resulted in decomposition of the N,O-acetals.
15. When the intramolecular reaction of 1a was performed with 1.2 equiv of HCl or
0.6 equiv of TMSCl, the benzodiazepine 4a was obtained in 49 or 48% yields,
respectively. The results show that a stoichiometric amount of a relatively weak
Lewis acid TMSCl functions as the best promoter. In this context, one reviewer
suggests NMR monitoring of interaction between N,O-acetal 1a and TMSCl.
However, we could not observe such results.
8. For selected papers, see: (a) Welmaker, G. S.; Sabalski, J. E. Tetrahedron Lett.
2004, 45, 4851; (b) Duncton, M. A. J.; Smith, L. M.; Burdzovic-Wizeman, S.;
Burns, A.; Liu, H.; Mao, Y.; Wong, W. C.; Kiselyov, A. S. J. Org. Chem. 2005, 70,
9629; (c) Che, X.; Zheng, L.; Dang, Q.; Bai, X. Tetrahedron 2006, 62, 2563.
9. For a selected paper, see: Ishikura, M.; Mori, M.; Ikeda, T.; Terashima, M.; Ban, Y.
J. Org. Chem. 1982, 47, 2456.
10. For selected papers, see: (a) Hancock, M. T.; Minto, R. E.; Pinhas, A. R. Tetra-
hedron Lett. 2003, 44, 8357; (b) Wang, J.-Y.; Guo, X.-F.; Wang, D.-X.; Huang, Z.-T.;
Wang, M.-X. J. Org. Chem. 2008, 73, 1979.
11. For selected papers, see: (a) Kraus, G. A.; Maeda, H. Tetrahedron Lett. 1994, 35,
9189; (b) Breslin, H. J.; Kukla, M. J.; Ludovici, D. W.; Mohrbacher, R.; Ho, W.;
Miranda, M.; Rodgers, J. D.; Hitchens, T. K.; Leo, G. J. Med. Chem. 1995, 38, 771;
(c) Wang, X. L.; Zheng, X. F.; Liu, R. H.; Reiner, J.; Chang, J. B. Tetrahedron 2007,
63, 3389.
16. Theoretically, the yield of product 4a must be identical to the equivalent of
Me3SiCl. Although there are no clear explanations, it seems that the product
yield involves an error in experimental handling. However, the important point
in the results is that HCl functions as a catalyst to promote the intramolecular
cyclization.
12. (a) Sakai, N.; Hamajima, T.; Konakahara, T. Tetrahedron Lett. 2002, 43, 4821;
(b) Sakai, N.; Hirasawa, M.; Hamajima, T.; Konakahara, T. J. Org. Chem. 2003,