Synthesis of Chiral 3-Substituted 1,3,4,5-Tetrahydro-1,4-benzo- diazepin-2-ones via a Domino Copper-Catalyzed SN2/Coupling Reaction

Article abstract of DOI:10.1002/adsc.201500477

A novel protocol for the facile synthesis of chiral 3-substituted 1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-ones via a domino reaction has been developed, which involves a cascade of S_N2 nucleophilic substitution and copper-catalyzed C- N coupling reactions of α-amino acid amides and ortho-halobenzyl halides. This protocol has some merits, such as one-pot process, easy operation, a wide scope of substrates. Furthermore, no heavy racemization occurs during the reaction.

Full text of DOI:10.1002/adsc.201500477

COMMUNICATIONS
DOI: 10.1002/adsc.201500477
Synthesis of Chiral 3-Substituted 1,3,4,5-Tetrahydro-1,4-benzo-
diazepin-2-ones via a Domino Copper-Catalyzed S 2/Coupling
N
Reaction
a
a
a
a
a,
Dongming Lu, Chang Ma, Shuai Yuan, Lihong Zhou, and Qingle Zeng *
a
Institute of Green Catalysis and Synthesis, College of Materials and Chemistry & Chemical Engineering, Chengdu
University of Technology, Chengdu 610059, Peopleꢀs Republic of China
E-mail: qinglezeng@hotmail.com
Received: May 18, 2015; Revised: August 21, 2015; Published online: November 17, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500477.
[7]
Abstract: A novel protocol for the facile synthesis
of chiral 3-substituted 1,3,4,5-tetrahydrobenzo[e]
orphan receptor-gamma. Therefore it is imperative
to explore novel and facile synthetic methods for di-
verse 1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-ones
based on a variety of available substrates.
[
1,4]diazepin-2-ones via a domino reaction has been
developed, which involves a cascade of S 2 nucleo-
N
philic substitution and copper-catalyzed CÀN cou-
pling reactions of a-amino acid amides and ortho-
halobenzyl halides. This protocol has some merits,
such as one-pot process, easy operation, a wide
scope of substrates. Furthermore, no heavy racemi-
zation occurs during the reaction.
Four synthetic routes of 1,3,4,5-tetrahydrobenzo[e]-
[1,4]diazepin-2-one derivatives have been reported
upto now (Scheme 1, routes A to D). These routes
consist of (i) diastereoselective [2+2]cycloaddition of
3,5-dimethoxyphenoxyketene
benzo[e][1,4]diazepin-2-ones (Scheme 1, route A);
ii) condensation, reductive alkylation, catalytic hy-
and
1,3-dihydro-
[2]
(
Keywords: a-amino acid amides; cross-coupling;
domino reactions; nucleophilic substitution; 1,3,4,5-
tetrahydrobenzo[e][1,4]diazepin-2-ones
drogenation and subsequent intramolecular cycliza-
tion with 2-nitrobenzaldehyde and amino acid esters
[5,7]
as starting materials (Scheme 1, route B);
(iii) SN2
substitution of ortho-nitrobenzyl bromide or methane-
sulfonate and amino acid esters with or without BOC-
protection and reduction and cyclization (Scheme 1,
[3,4,8]
route C);
(iv) nucleophilic substitution, hydroge-
Compounds with [1,4]benzodiazepine skeletons com- nation, condensation with ortho-nitrobenzylamines
prise valuable pharmaceuticals against anxiety, insom- and a-bromoacetate as starting materials (Scheme 1,
[3]
nia, agitation, seizures, muscle spasms, alcohol with- route D). Thus, the reported methods commonly
[
1]
drawal and so on. To date, thousands of different need two to five transformations for the synthesis of
benzodiazepines have been synthesized and about 1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-ones. This
thirty of them are in clinical use in various parts of leaves room for research into synthetic methodologies
[
1]
the world.
Most common benzodiazepine drugs are character- synthesis.
ized by a 3H-1,4-benzodiazepin-2-one skeletal unit, In this context, domino reactions, in which multiple
of higher efficiency, which is a salient goal of organic
[9]
such as diazepam, bromazepam, camazepam, cinol- reactions are combined into one synthetic operation
azepam, clonazepam, and clorazepate. These com- are ideal since they do not involve work-up and isola-
[10]
pounds have been proven invaluable in contemporary tion of numerous intermediates.
Copper-catalyzed
neuropsychiatry. However, compounds with a 1,3,4,5- coupling is a feasible approach for heterocycle synthe-
[
11]
[12]
tetrahydrobenzo[e][1,4]diazepin-2-one scaffold have sis. As part of our ongoing research on coupling
[13]
demonstrated promising diverse pharmacological ac- and domino reactions,
a domino copper-catalyzed
tivities in recent researches, such as endothelin recep- S 2/CÀN coupling reaction of a-amino acid amides
N
[
2]
[3]
tor antagonists,
anti-HIV agents,
anti-ischemic and ortho-halobenzyl halides is described herein, as
[
4]
agents, peptidomimetics for G-protein coupled re- shown in Scheme 1, route E.
The model substrates initially used to evaluate the
acids (M-BAR or TGR5) receptor agonists, and domino reaction were 2-iodobenzyl bromide and l-
[
5]
ceptors (GPCRs), membrane-type receptor for bile
[6]
modulators of retinoic acid receptor (RAR)-related phenylalaninamide (Table 1). It was observed that
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Dongming Lu et al.
COMMUNICATIONS
Table 1. Optimization of the conditions for the domino Cu-
[
a]
catalyzed S 2/coupling reaction.
N
[b]
Entry
Catalyst
Solvent
Base
Yield [%]
1
2
3
4
5
6
7
8
9
CuCl
CuBr
CuI
DMF
DMF
DMF
DMF
DMF
toluene
dioxane
DMA
DMF
DMF
DMF
DMF
DMF
K CO
46
54
92
79
76
trace
44
87
90
2
3
3
3
3
3
3
3
3
K CO
2
K CO
2
Cu O
K CO
2
2
CuO
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
K CO
2
K CO
2
K CO
2
K CO
2
Cs CO
2
3
10
11
12
13
t-BuONa
41
82
[
c]
K CO
2
3
3
3
[
d]
K CO
47 (42)
[e]
2
K CO
2
0 (84)
[
a]
Reaction conditions: 2-iodobenzyl bromide (0.5 mmol), l-
phenylalaninamide (0.75 mmol), CuI (0.05 mmol), K CO3
2
(1 mmol), DMF (5 mL), 1108C, 24 h, unless otherwise
stated.
Isolated yield.
[
[
[
b]
c]
9
1
08C.
2 h;
d]
(S)-2-(2-iodobenzylamino)-3-phenylpropanamide
(
4) (44% yield).
[
e]
No CuI, 1 h; (S)-2-(2-iodobenzylamino)-3-phenylpropan-
amide (4) (84% yield).
(
entries 9 and 10). Furthermore, a decrease of the
temperature or shortening of the reaction time was
not conducive to this reaction (entries 11 and 12).
It was noted that besides the target product, (S)-2-
(
2-iodobenzylamino)-3-phenylpropanamide (4), the
product of S 2 nucleophilic substitution was also iso-
N
lated from the reaction mixture when only half of the
reaction time was used (Entry 12). It is the only prod-
uct when the reaction was performed without CuI for
only one hour (entry 13). This information signifies
that the domino reaction under examination includes
a K CO -promoted S 2 nucleophilic substitution at
Scheme 1. The reported (A to D) and our new (E) synthetic
routes of 1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-ones.
2
3
N
first and then a CuI-catalyzed intramolecular CÀN
coupling reaction.
CuCl, CuBr and CuI could all promote this reaction
With the optimized conditions at hand, various
(
(
(
entries 1-3), with the latter being the best catalyst amino acid amides were examined to react with 2-io-
entry 3). Cu O and CuO also promoted the reaction dobenzyl bromide (Table 2). Most l-form amino acid
2
entries 4 and 5), but to a lesser degree than CuI.
amides are commercially available, but the dl- and d-
For the aforementioned domino reaction, the polar- forms are not. As such, dl-phenylalaninamide was
[14]
ity of the solvent is an important parameter. Low po- synthesized according to the literature, and it gave
larity solvents such as toluene gave nearly no product nearly the same yield as the l-form (entries 2 vs. 1).
(
entry 6). As a general observation, higher yields Chiral HPLC analysis demonstrated that the ee value
were obtained with increasing polarity of the solvent of the product of l-phenylalaninamide was 96% ee,
(
(
entries 3, 6–8) with DMF being the best one which means that about 2% to 3% of l-phenylalanin-
entry 3). Stronger bases did not afford higher yields amide was racemized during the domino reaction.
3
492
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COMMUNICATIONS Synthesis of Chiral 3-Substituted Tetrahydro-1,4-benzodiazepin-2-ones
[
a]
Table 2. Examination of various amino acid amides to react with 2-iodobenzyl bromide.
1
2
[b]
Entry
R
R
Amino acid amide
Product
Yield [%]
[
c]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
Bn
Bn
H
H
H
H
H
H
H
H
H
l-phenylalaninamide
dl-phenylalaninamide
l-alaninamide
l-3a
dl-3a
l-3b
d-3b
dl-3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
92
93
78
75
80
56
85
91
58
68
75
90
0
[
[
d]
e]
Me
Me
Me
Et
i-Pr
i-Bu
Ph
d-alaninamide
dl-alaninamide
l-butyrinamide
l-valinamide
l-leucinamide
l-phenylglycinamide
l-prolinamide
l-tryptophanamide
l-tyrosinamide
l-threoninamide
l-serinamide
0
1
2
3
4
-(CH ) -
2
3
(1H-indol-3-yl)CH2
p-HOC H CH
CH CH(OH)
H
H
H
H
6
4
2
3
HOCH2
0
[a]
Reaction conditions: 2-iodobenzyl bromide (0.5 mmol), amino acid amide (0.75 mmol), CuI (0.05 mmol), K CO3
2
(
1 mmol), DMF (5 mL), 1108C, 24 h.
Isolated yield.
7% ee (S form).
7% ee (S form).
6% ee (R form).
[
[
[
[
b]
c]
d]
e]
9
9
9
Slight racemization (2% to 3%) also occurred for l- amide (entries 5–8), and, moreover, they demonstrat-
and d-alaninamides during the reaction (entries 3 and ed nearly the same reactivities as the 2-bromobenzyl
4
).
halides (entries 5–9 vs. 2–4). In general, unactivated
All of the amino acid amides examined afforded chloroarenes are poor substrates for Ullmann CÀN
moderate to excellent yields (Table 2, entries 1–12).
In brief, alaninamide, l-butyrinamide, l-valinamide,
l-leucinamide and l-phenylglycinamide all afforded
the target products with moderate to high yields (en-
tries 3–12), while the cyclic amino acid amide l-
prolinamide also gave a good yield (entry 10).
Table 3. Domino reaction of various ortho-halobenzyl hal-
[a]
ides and l-phenylalainamide.
l-Tryptophanamide with an indolyl group which
may participate in CÀN coupling reaction produced
the target material with 75% yield (entry 11). On the
other hand l-tyrosinamide which should have formed Entry
a phenolate under the basic conditions, gave a surpris-
[b]
R
X
Y
Product
Yield [%]
1
H
H
I
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Cl
3a
3a
3l
3m
3n
3o
3p
3p
3q
3r
92
87
82
47
89
82
83
80
42
0
ingly high yield of 90%, as shown by the absence or
trace of by-product formed during the domino reac-
2
3
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
F
4-CH O
3,4-OCH O
4-F
4-CF3
3-Cl
3-Cl
4-Cl
H
3
tion (entry 12).
4
2
In contrast to the above, both l-threoninamide and
l-serinamide gave no target product due to the strong
coordination between copper and this kind of sub-
strate (entries 13 and 14).
5
6
7
8
9
1
Subsequently, ortho-halobenzyl halides were exam-
ined to react with l-phenylalaninamide under the op-
timized conditions (Table 3). 2-Iodobenzyl bromide
was the best substrate among these ortho-halobenzyl
halides (entry 1). Surprisingly, unactivated 2-chloro-
benzyl halides could also react with l-phenylalanin-
0
[a]
Reaction conditions: ortho-halobenzyl halide (0.5 mmol),
l-phenylalaninamide (0.75 mmol), CuI (0.05 mmol),
K CO (1 mmol), DMF (5 mL), 1108C, 24 h.
b]
2
3
[
Isolated yield.
Adv. Synth. Catal. 2015, 357, 3491 – 3494
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Dongming Lu et al.
COMMUNICATIONS
[
15]
coupling reactions. The reason for the higher reac- du University of Technology (No. HY0084) for financial sup-
port.
tivity of unactivated 2-chlorobenzyl halides is proba-
bly due to the intramolecular coupling reaction.
The reactivity of 2-fluorobenzyl chloride was too
low to carry out this domino reaction (entry 10). Two
strong electron-donating groups apparently decreased
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2-ones
To an oven-dry test tube with a ground joint neck with
a magnetic stir bar were added a-amino acid amide
(
(
0.75 mmol), 2-halobenzylic halide (0.5 mmol), CuI
0.05 mmol), K CO (1 mmol) and DMF (5 mL). The test
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3
tube was sealed with a rubber sleeve stopper, and then evac-
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4
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1
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3
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ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3491 – 3494