Facile synthesis of 2,3-benzodiazepines using one-pot two-step phosphate-assisted acylation-hydrazine cyclization reactions

Article abstract of DOI:10.1039/c8ob00708j

Here, we report new methodology for synthesizing 2,3-benzodiazepines and their analogues by means of phosphate-assisted acylation reaction of 1-arylpropan-2-ones with a carboxylic acid followed by hydrazine cyclization in a one-pot two-step manner. An unp

Full text of DOI:10.1039/c8ob00708j

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Facile Synthesis of 2,3-Benzodiazepines Using One-pot Two-step Phosphate-
Assisted Acylation-Hydrazine Cyclization Reactions
Akinari Sumita,1 Jinhee Lee, 1, 2 Yuko Otani, 1 Tomohiko Ohwada1,*
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo, 113-0033, Japan
2Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic University, 901 S.
Flagler Drive, West Palm Beach, FL 33401, U. S. A.
E-mail: ohwada@mol.f.u-tokyo.ac.jp
Abstract
Here, we report new methodology for synthesizing 2,3-benzodiazepines and
their analogues by means of phosphate-assisted acylation reaction of 1-arylpropan-2-
ones with a carboxylic acid followed by hydrazine cyclization in a one-pot two-step
manner. An unprotected amino group is tolerated in this reaction. This method
provides a direct access to 2,3-benzodiazepines containing aromatic 7,8-dimethoxy
and 1-p-aminophenyl groups, which are generally considered important for
bioactivity. The presence of 3,4-dimethoxy or 3-methoxy substitution on the benzene
ring of the 1-arylpropan-2-one is important for high regioselectivity in the acylation
reaction.
1

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Introduction
The 2,3-benzodiazepine skeleton is of interest to synthetic chemists and
medicinal chemists as a core structure of compounds with various bioactivities, such
as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor
antagonists, and consequently several new synthetic routes have recently been
developed (Figure 1). Chang and co-workers reported a four-step synthesis of the
2,3-benzodiazepine skeleton 3, employing Wacker oxidation reaction of 1 to generate
diketone intermediate (2) (Figure 1 [a])[7]. Zhu and co-workers also reported a 2,3-
benzodiazepine (6) synthesis via Rh(III)-catalyzed C-H functionalization of
hydrazone 4 with diazoketoester 5 (Figure 1 [b]).[8] Okuma and co-workers
synthesized the 2,3-benzodiazepine skeleton (10) from reactive benzyne generated
from 7 and ketoester 8 (Figure 1 [c]).[9] Generation of benzo[c]pyrilium salt 13 from
β-keto aromatic compound 11 and carboxylic acid chloride 12 through Friedel-Crafts
acylation reaction was also reported (Figure 2 [d]).[10] The pyrilium salt 13 reacted
smoothly with hydrazine to give the 2,3-benzodiazepine skeleton 14.[11] A similar
Friedel-Crafts acylation reaction of ketone 15 with p-nitrobenzonic acid 16 was also
reported to give the diketone 17, which was transformed into 2,3-benzodiazepine 18
(Figure 1 [e]).
2

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DOI: 10.1039/C8OB00708J
[a] Employment of Wacker oxidation [7]
OMe
OMe
OMe
6
Me
Me
MeO
5 steps
Claisen
MeO
MeO
7
PdCl2,
CuCl2,
N2H4
r.t., 10 min
N
N
O
O
OH
O
8
MeO
O2
r.t., 6 h
87%
(yield from 1)
CHO
rearrangement
91%
90%
OMe
MeO
MeO
1
3
2
[b] Employment of Rh(III)-catalyzed C-H activation [8]
O
EtO
Me
Me
Me
N
[Cp*RhCl2]2 (2 mol %)
HOAc (50 mol %)
N2
NHBoc
+
O
N
TFE, 80°C, 12 h
72%
N
EtO
O
1
Me
6
5
4
[c] Employment of reactivity of benzyne [9]
Me
O
Me
N
MeO
MeO
MeO
MeO
N2H4, EtOh
r.t., 16 h
CsF, MeCN,
r.t., 15 h
O
O
N
MeO
MeO
TMS
OTf
O
1
+
Me
60%
61%
NO2
7
(1.7 equiv.)
10
8
9
O2N
NO2
[d] Employment of reactivity of pyrilium ion generated from Friedel-Crafts acylation reaction [10, 11]
CN
NC
MeO
MeO
Me
Me
NH
CN
HClO4 aq.
r.t., overnight
N2H4, EtOH
r.t., overnight
O
MeO
MeO
MeO
MeO
Me
+
O
Cl
Me
ClO4
N
O
60%
Me
73%
12
(10 equiv.)
Me
11
13
14
[e] Employment of Friedel-Crafts acylation reaction [12]
Me
O
O
Me
O
N
N
N2H4, EtOh
r.t., 1 h
P2O5, CH2Cl2
rt, 8h
O
O
Me
+
O
O
O
1
CO2H
O2N
O
50%
60%
15
16
18
17
O2N
O2N
Figure 1. Representative synthetic routes leading to the 2,3-benzodiazepine
skeleton.
However, these new methodologies (Figure 1) are not necessarily well suited
for the synthesis of bioactive 2,3-benzodiazepine derivatives in which aromatic 7, 8-
dimethoxy and substituted 1-phenyl groups are considered to be important, as
exemplified by the compounds shown in Figure 2. Among these compounds,
tofisopam 19a is a highly active nonsedative, anxiolytic agent in humans.[5] Other 2,3-
benzodiazepines such as girisopam 19b, nerisopam 19c and GYKI52466 19d also
possess similar biological activities.[6] In the cases of nerisopam 19c and GYKI52466
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19d, the amine functionality is considered to be particularly important for AMPA
receptor binding. [4c]
Et
Me
Me
7
7
8
MeO
MeO
MeO
MeO
N
N
N
N
8
1
1
R’
4
5
6
9
7
8
OMe
Cl
3
N
MeO
N 2
1
Girisopam 19b
Tofisopam 19a
R
Me
Me
7
2,3-benzodiazepine
O
7
MeO
MeO
N
N
N
N
8
8
O
1
1
H2N
H2N
Nerisopam 19c
GYKI 52466 19d
Figure 2. Representative bioactive 2,3-benzodiazepine derivatives.
But, such structures are not readily accessible via the methodologies shown in Figure
1. For example, in method [a], the Claisen rearrangement cannot afford 7,8-
dimethoxy substitution instead of the 6,7-dimethoxy substitution seen in 3. Method
[b] gives poor regiocontrol if another aromatic substituent is present, since the
regiochemistry of the hydroazone is crucial for ortho-directed insertion of the
ketoester. In method [c], several aromatic substituents at the C1 position are
compatible with the reaction, but the aromatic amino functionality found in 19c and
19d has to be obtained by hydrogenation of the corresponding nitro compound 10,
probably because the amino functionality can react with the putative benzyne
intermediate. Method [d] is restricted to the formation of tautomeric 2,3-
benzodiazepine 14. Method [e] is the most straightforward route to 2,3-
benzodiazepines, but the p-nitrobenzoic acid 16, instead of p-aminobenzoic acid, is
employed in this reaction. Thus, access to bioactive 2,3-benzodiazepine compounds is
still inconvenient; for example, the synthesis of bioactive 2,3-benzodiazepines such as
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nerisopam (19c) requires multi-step reactions according to the relevant patDeOnIt:s10.a10n3d9/C8OB00708J
methods (c) and (e) in Figure 1. Therefore, more direct and efficient methodology for
synthesizing bioactive 2,3-benzodiazepines is still required.
Recently, we reported a phosphate-assisted acylation reaction of carboxylic
acids (Figure 3).[13] The tailored phosphate ester 22 is activated under acidic
conditions, and reacts with carboxylic acid 21 to form acyl phosphate 21a. The acyl
phosphate 21a smoothly reacts with an aromatic compound to give the corresponding
ketone 23 in high yield at room temperature after a short time. The phosphate-assisted
acylation reaction can afford aromatic ketones containing a free amino functional
group (Figure 3). Thus, this reaction should provide direct access to 2,3-
benzodiazepines containing a free amino functional group, such as nerisopam (19c).
O
COOMe
MeOOC
P
O
O
O
MeOOC
O
HOOC
PO(osalMe)3 (22)
+
NH2
23: yield 98%
NH2
Triflic acid
20
21
20°C, 20 min
O
O
MeOOC
P
O
O
O
NH3
MeOOC
21a
Figure 3. Phosphate-assisted acylation reaction.
We report herein a one-pot two-step synthesis of bioactive 2,3-
benzodiazepines by means of phosphate-assisted acylation reaction followed by basic
hydrazine cyclization, staring from 1-(3,4-dimethoxyphenyl)propan-2-one 24. In this
synthesis, an appropriate choice of commercially available carboxylic acids allows
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various substituent groups to be introduced at the C1 position of 7,8-dimethDoOxI:y1-02.1,0339-/C8OB00708J
benzodiazepine. 3,4-Dimethoxy substitution, or at minimum a 3-methoxy group, on
the aromatic ring of the 1-arylpropan-2-one (24) is critical for high regioselectivity in
the acylation reaction.
Results and Discussion
Development of one-pot two-step acylation and hydrazine cyclization reactions
To build the desired 2,3-benzodiazepines (Figure 2) by means of phosphate-
assisted acylation reaction, we considered stepwise and one-pot two-step approaches
(Figure 4). We attempted to isolate the di-ketone intermediate 25-1 or 25-2, a
precursor for hydrazine cyclization, through basic aqueous work-up, extraction and
column-chromatography (see Experimental Sections) after phosphate-assisted
acylation reaction of 24 with 21, but the diketone 25 cannot be isolated. Instead, only
the isomeric diketone (26) was obtained in a low yield (17% yield) (Figure 4, [a]).
Because the related non-aminodiketone compounds such as 2, 9 and 13 and 17 were
inert and isolable in high yields (see Figure 1), the aniline-diketone compound 25-1 or
the resultant pyrilium ion (25-2) were unstable upon neutralization due to the
presence of two incompatible reactive functionalities, ketone and amino groups,
resulting in the formation of polar polymeric substances in the work-up process. A
similar situation was also encountered in the cases of reactions of various methoxy-
substituted 1-phenylpropan-2-ones (see Figure 6).
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Me
MeO
MeO
Me
O
O
MeO
6
O
O
1) NaOH,
[a] Isolation of Diketone
6
MeO
H2O
Triflic acid,
PO(osalMe)3 (22),
20°C, 20 min
(a basic
aqueous
work-up)
H2N
25
25-1
3
HOOC
Me
MeO
MeO
(not detected)
H3N
+
O
+
4
NH2
Me
2) Extraction
3) Column-
Chromatography MeO
MeO
24
21
O
MeO
MeO
Me
5
O
O
NH2
25-2
26: 17 %
Me
N
NH3
MeO
MeO
[b] Two Step Reactions
1) NaOH, H2O
(a basic aqueous work-up)
N
6
2) Extraction
3) N2H4·H2O, EtOH
20°C, 18 h
H2N
19c: 48%
[c] One-pot Two-step Reactions
Me
N
MeO
MeO
1) Triflic acid, PO(osalMe)3 (22),
3
HOOC
MeO
MeO
Me
N
0°C, 30 min
+
O
4
NH2
2) N2H4·H2O, 2M NaOH aq., EtOH,
20°C, 20 min
24
21
19c: 73%
H2N
Figure 4. Optimization of reaction procedures
Thus, we applied the above base work-up procedure after the phosphate-assisted
acylation reaction to neutralize the reaction mixture, and then added hydrazine to the
crude diketone mixture 25 without purification with column chromatography. The
desired 2,3-benzodiazepine, nerisopam 19c, was formed (Figure 4, [b]), while the
yield was still 48%, probably for the same reason as before (see Experimental
Sections).15] After treatment with hydrazine, it was difficult to identify the isomeric
diketone 26, probably hydrazine reacts with diketone 25 in multiple manners.
Therefore, we tried one-pot two-step reactions. The acid reaction mixture for
phosphate-assisted acylation of 24 was poured directly into an alkaline solution of
hydrazine monohydrate and sodium hydroxide in water and ethanol, which basified
the medium in situ (Figure 4, [c]). Ethanol was employed as a co-solvent to aid
dissolution of the substrates. This in situ quenching procedure worked well, and the
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yield of nerisopam 19c was increased to 73% (Figure 4, [c]). The regioselectivity of
acylation was approximately 81% (regioselectivity at the 6-position (19c)): 19%
(regioselectivity at the 5-position (26)) (see Figure 6 and discussion of
regioselectivities). Finally, we conducted detailed optimization of the reaction
conditions of the hydrazine cyclization reaction in the one-pot two-step reaction, as
follows.
Optimization of reaction conditions of hydrazine cyclization reaction
Using the optimal conditions of the acid-catalyzed acylation described above, we next
focused on the hydrazine cyclization reaction in the one-pot two-step method (Figure
4, [c]). We examined several factors including (a) the amount of hydrazine (b) solvent
(c) base (d) reaction time, and (e) reaction temperature (Table 1). When the amount
of hydrazine monohydrate was increased to 20 equivalents, the yield of 19c increased
from 53% to 73% (Table 1, entries 1, 2), probably because the hydrazine
monohydrate also worked as a base to neutralize triflic acid. On the other hand, when
the amount of hydrazine monohydrate was further increased to 30 equivalents, the
yield of the reaction did not change (74%, entry 3), so we considered that 20
equivalents of hydrazine monohydrate was sufficient. Moreover, cooling and a longer
reaction time during the hydrazine cyclization reaction had no effect on the yield
(71~77%, entries 3, 4 and 5). Also, cooling during the phosphate-assisted acylation
reaction was ineffective (78%, entry 6). A heterogeneous condition using ethanol
instead of water gave a comparable yield (79%, entry 7). Therefore, the conditions in
entries 6 and 7 were concluded to be optimal for the hydrazine cyclization reaction.
We applied these reaction conditions to another p-bromobenzonic acid 27a and
several aliphatic carboxylic acids (27b, 27c and 27d). Under either of the reaction
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conditions (entries 6 and 7), we obtained the corresponding 2,3-benzodiazepines in
good yields: (28a: 71%, (entry 8); 28b: 80% (entry 9); 28c: 74% (entry 10); 28d: 72%
(entry 11).
Table 1. Optimization of the one-pot two-step reaction.
Me
1) Triflic acid, PO(osalMe)3 (22),
MeO
MeO
MeO
Me
20°Cb), 20 minb)
N
HOOC R
+
O
N
2) N2H4·H2O, solvent,
MeO
base (40 eq.),temp., time
24
21, 27a-d
19c, 28a-d
X
Yield (%)a)
19c: 53%
19c: 73%
Entry
1b)
N2H4·H2O
5 eq.
R
Solvent
H2O-EtOH
H2O-EtOH
Base Temp. Time
p-NH2Ph (21)
p-NH2Ph (21)
NaOH
NaOH
NaOH
NaOH
0°C
0°C
20 min
20 min
20 min
20 min
2b)
20 eq.
3b)
30 eq.
20 eq.
20 eq.
20 eq.
20 eq.
p-NH2Ph (21)
p-NH2Ph (21)
p-NH2Ph (21)
p-NH2Ph (21)
p-NH2Ph (21)
H2O-EtOH
H2O-EtOH
H2O-EtOH
H2O-EtOH
19c: 74%
19c: 77%
19c: 71%
19c: 78%
0°C
4b)
20°C
5b)
6
NaOH
NaOH
20°C 1440 min
20°C
20°C
20 min
Na2CO3
7
EtOH
10 min 19c: 79%
p-BrPh (27a)
Me (27b)
20 eq.
20 eq.
8
9
10 min 28a: 71%
10 min 28b: 80%
EtOH
Na2CO3 20°C
H2O-EtOH
NaOH
20°C
20 eq.
20 eq.
Et (27c)
10
11
H2O-EtOH
EtOH
10 min 28c: 74%
10 min 28d: 72%
NaOH
20°C
20°C
C18H37 (27d)
Na2CO3
a) Isolation yields, calculated on the basis of the amount of carboxylic acids.
b) For the phosphate-assisted acylation reaction, the reaction temperature was 0°C,
and the reaction time was 30 minutes.
Scope of the present acylation reaction
Using the optimized one-pot two-step reaction, m-chlorobenzonic acid 27e and 1-
(3,4-dimethoxyphenyl)propan-2-one 24 successfully afforded girisopam 19b in 73%
yield (Figure 5). We also attempted the synthesis of GYKI52466 19d starting from
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24-acetal and p-aminobenzoic acid 21, but the reaction became complex, probably
because the acetal unit of 24-acetal decomposed under the acid conditions (Figure 5).
Me
MeO
1) Triflic acid, PO(osalMe)3 (22)
N
HOOC
Cl
MeO
MeO
Me
20°C, 20 min
N
MeO
+
O
2) N2H4·H2O, 2M NaOH aq., EtOH,
20°C, 10 min
24
27e
21
19b: 73%
Cl
Me
O
1) Triflic acid, PO(osalMe)3 (22)
NH2
Me
N
O
20°C, 20 min
+
O
N
O
O
HO2C
2) N2H4·H2O, 2M NaOH aq., EtOH,
20°C, 10 min
24-acetal
19d: Complex Mixture
H2N
Figure 5. Synthesis of 19b and attempted synthesis of 19d
We found that the position of electron-donating methoxy groups on the
benzene ring of 29 was crucial for high regio-selective in situ acylation of 29 (Figure
6). Under the optimal reaction conditions, aromatic acylation of unsubstituted 1-
phenyl-3-methyl-butan-2-one 29a with p-aminobenzoic acid 21 in the presence of
triflic acid and phosphate 22 did not proceed, and instead only two esters were formed
(30a: 68% yield; 31: 28% yield) (Figure 6 (a)). Furthermore, when 1-(4-
methoxyphenyl)propan-2-one 29b and p-aminobenzoic acid 21 were used, the
acylation occurred at the 3-position of the benzene ring with high regioselectivity and
the di-ketone 30b was isolated in 75% yield (Figure 6 (b)). This di-ketone 30b was
sufficiently stable because it cannot cyclize to afford the pyrilium ion (such as 25, see
Figure 4). When the one-pot two-step reaction was applied to 1-(3-
methoxyphenyl)propan-2-one 29c and p-aminobenzoic acid 21, the corresponding
2,3-benzodiazepine 30c was obtained in 66% yield (Figure 6(c)). Therefore, the
acylation reaction of p-aminobenzoic acid 21 was significantly influenced by the
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electron-donating substituent at the 3-position of the aromatic ring of 29c.
Furthermore, when 1-(2-methoxyphenyl)propan-2-one 29d and p-aminobenzoic acid
Me
OH
Me
O
Triflic acid,
PO(osalMe)3 (22)
NH2
Me
Me
(a)
CO2Me
O
NH2
O
+
+
HO2C
20°C, 20 min
O
O
29a
21
21
21
31: 28%
NH 30a: 68%
2
Me
(b)
Triflic acid,
PO(osalMe)3 (22)
4
O
NH2
Me
MeO
3
+
4
O
O
HO2C
20°C, 20 min
MeO
30b: 75%
29b
NH2
Me
7
MeO
(c)
N
N
1) Triflic acid, PO(osalMe)3 (2)
3
NH2
MeO
Me
20°C, 20 min
+
O
2) N2H4·H2O, Na2CO3., EtOH,
20°C, 10 min
HO2C
30c: 66%
29c
OMe
H2N
(d)
2
Me
Triflic acid,
PO(osalMe)3 (22)
OMe
NH2
2
O
Me
+
5
20°C, 20 min
HO2C
O
O
30d: 71%
21
29d
NH2
(e)
OMe
Me
6
MeO
OMe
1) Triflic acid, PO(osalMe)3 (22)
7
N
N
2
MeO
Me
NH2
20°C, 20 min
3
+
O
6
HO2C
4
2) N2H4·H2O, Na2CO3., EtOH,
20°C, 10 min
5
30e: 51%
29e
21
H2N
OMe
OMe
2
MeO
Me
2
3
Triflic acid,
PO(osalMe)3 (22)
MeO
Me
O
O
3
4
polar compound(s)
+
O
+
(intermediate for 30e)
5
20°C, 20 min
O
32-1: 32%
32-2: 7%
NH2
NH2
Figure 6. Predominat regioselectivities of methoxy-substituted 1-phenylpropan-
2-ones
21 were used, the acylation occurred at the 5-position of the benzene ring with high
selectivity and the di-ketone 30d was isolated in 71% yield (Figure 6(d)). Finally, 1-
(2,3-methoxyphenyl)propan-2-one 29e and p-aminobenzoic acid 21 afforded the
corresponding 2,3-benzodiazepine 30e in 51% yield under the one-pot two-step
reaction conditions. When the same reagents were subject to acylation reaction
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without hydrazine cyclization, the acylation occurred at the 4- and 5-positionDsOaI:s10w.10e3l9l/C8OB00708J
as the 6-position of the benzene ring, affording a mixture of the di-ketones 32-1 and
32-2 in 32%, and 7% yields, respectively, while the 6-substituted compound
decomposed to polar products during the isolation. Therefore, the aromatic 3,4-
dimethoxy groups, or at a minimum the 3-methoxy group, on the benzene ring are
crucial for highly regioselective acylation leading to the generation of 2,3-
benzodiazepines (the regioselectivity of acylation was approximately 81%
(regioselectivity at the 6-position (19c)): 19% (regioselectivity at the 5-position (26)),
see Figure 4). The 4-methoxy group favored ortho-directed acylation (Figure 6 (b))
while the 3-methoxy group favored para-directed acylation (Figure 6 (c)). In the case
of 2,3-dimethoxy substitution (Figure 6 (e)), acylation at the para position with
respect to the 3-methoxy group was favored (57% regioselectivity), but acylation at
the 4 and 5-positions also occurred (43% regioselectivity). On the other hand, in the
case of 3,4-dimethoxy substitution (Figure 4 (c)), acylation at the para-position with
respect to the 3-methoxy group was predominant (at least more than 80%
regioselectivity). This difference of regioselectivity between the 2,3-dimethoxy (29e)
and 3,4-dimethoxy (24) substrates may be due to steric interactions of the methoxy
group(s).
Moreover, the steric effect at the α-position of the β-keto aromatic compound
greatly affected the efficiency of the hydrazine cyclization reaction (Figure 7). When
a methyl group was introduced at the α-position of the β-keto aromatic compound 33,
the one-pot two-step reaction became complex, although the formation of 34 was
detected. Moreover, when two methyl groups were introduced at the α-position of the
β-keto aromatic compound 35, the desired 2,3-benzodiazepine skeleton 36 was not
12

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Organic & Biomolecular Chemistry
formed. These results are consistent with the idea that the initial addition of hDyOdIr: a10z.1i0n3Ve9ie/Cw8AOrtiBcl0e0O7n0li8nJe
occurs at the aliphatic ketone rather than the aromatic ketone; that is, steric hindrance
at the β-keto moiety hampers the addition of hydrazine, inhibiting hydrazine
cyclization. This in turn suggests that benzoic acid derivatives bearing an o-
substituent would be challenging substrates in this Friedel-Crafts acylation process.
Indeed, less sterically demanding o-substituents such as halogen atoms were found to
be compatible (see Table 2). These data suggested that the present method would not
provide access to tofisopam 19a from a ketone starting material similar to 33.
Me
Me
MeO
Me
N
N
1) Triflic acid, PO(osalMe)3 (22),
20°C, 20 min
HOOC
MeO
MeO
Me
MeO
+
O
2) N2H4·H2O, EtOH, Na2CO3,
20°C, 10 min
NH2
33
21
H2N
34: Complex Mixture
Me
Me
Me
MeO
MeO
Me Me
N
N
1) Triflic acid, PO(osalMe)3 (22),
20°C, 20 min
HOOC
MeO
MeO
Me
+
O
2) N2H4·H2O, EtOH, Na2CO3,
20°C, 10 min
NH2
21
35
H2N 35: <1%
Figure 7. Effect of steric hindrance on the acylation reaction.
Scope of the synthesis for 7,8-dimethoxy-2,3-benzodiazepine derivatives
With the optimized conditions in hand, we examined the substrate generality of this
sequential reaction (Table 2). Among aromatic carboxylic acids, benzoic acid 27d,
toluic acid (27g, 27h, 27i), halogen-substituted benzoic acid (27a, 27e, 27j, 27k, 27l,
27m),[19] and aminobenzoic acid (21, 27n) could be used in the one-pot two-step
phosphate-assisted acylation and ring formation. Interestingly, o-substituted benzoic
acids (27i, 27k, 27l, 27m) afforded high yields. The presence of an aromatic ring
substituted at the C1 position on the 2,3-benzodiazepine ring is suggested to be
crucial for interaction with the AMPA receptor.[4c,20] However, the one-pot two-step
13

Organic & Biomolecular Chemistry
Page 14 of 22
reaction from o-substituted aminobenzoic acid failed (27n) (recovery 24: 52%). ThiVsiew Article Online
DOI: 10.1039/C8OB00708J
inertness of 24 may be due to charge-charge repulsion between protonated 24 and the
o-substituted ammonium-acylium dication. As for heteroaromatic carboxylic acids,
thiophene 2-carboxylic acid 27p and quinoline 6-carboxylic acid 27q gave the desired
2,3-benzodiazepines in high or moderate yields. This one-pot two-step reaction also
afforded 2,3-benzodiazepines from conjugated carboxylic acid or aliphatic carboxylic
acid. As for the conjugated carboxylic acids (27r, 27t, 27u), β-keto aromatic
compound 24 reacted with these conjugated carboxylic acids only in the Friedel-
Crafts acylation mode, and side products derived from 1,4-addition reaction (i.e.
Michel addition reaction) were not observed.[21] When an electron-rich functional
group was introduced into the conjugated carboxylic acid (27s), the desired 2,3-
benzodiazepine skeleton was not formed. Probably the electron-rich conjugated
system would be activated under the acidic condition to promote polymerization.[22]
Among aliphatic carboxylic acids, both small molecules such as acetic acid (27b) and
large molecules such as nonadecanoic acid (27d) were suitable for the one-pot two-
step reaction. Also, secondary carboxylic acid (27v), carboxylic acid containing ethyl
ester (27w),[23] and benzylacetic acid (27x) were tolerated in the one-pot two-step
reaction. A protection-free aliphatic secondary amino group (27y) was also tolerated,
and the desired 2,3-benzodiazepine skeleton was obtained in good yield.
In all the examples in Table 2, no significant amount of other regioisomers was
detected, confirming that the aromatic 3,4-dimethoxy groups are crucial for high
regioselectivity in the Friedel-Crafts acylation.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00708J
Table 2. Substrate generality in one-pot two-step build-up of the 2,3-
benzodiazepine skeleton.a)
15

Organic & Biomolecular Chemistry
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View Article Online
DOI: 10.1039/C8OB00708J
Me
N
1) Triflic acid, PO(osalMe)3 (22),
20°C, 20 min
MeO
MeO
MeO
MeO
Me
HOOC
21, 27a-y 2) N H ·H O, EtOH, Na CO ,
+
R
O
N
2
4
2
20°C, 10 min
2
3
24
R
19b, 19c, 28a-y
Me
N
Me
Me
N
Me
N
Me
N
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
MeO
N
N
MeO
Me
Me
Me
Br
28i: 90%
28f: 75%
28g: 82%
28h: 88%
28a: 71%
Me
N
Me
Me
N
Me
Me
N
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
N
N
N
Br
F
Cl
Br
Br
28k: 87%
28j: 86%
28l: 90%
28m: 90%
19b: 73%
Me
Me
N
Me
Me
N
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
N
N
NH2
S
NH2
H2N
19c: 79%
28n: 72%
28o: <1%
28p: 86%
Me
Me
N
Me
N
MeO
MeO
MeO
MeO
Me
MeO
N
N
MeO
MeO
N
N
N
N
MeO
N
NO2
Me
Cl
MeO
28s:
Complex Mixture
28t: 75%
28q: 44%
28r: 93%
Me
N
Me
N
Me
MeO
MeO
Me
N
MeO
MeO
MeO
MeO
MeO
N
N
N
N
MeO
N
C18H37
Me
28d: 72%
28c: 74%
28u: 70%
28b: 81%
Me
N
Me
Me
N
Me
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
N
N
N
H
EtOOC
Cl
28v: 72%
28w: 37%
28x: 65%
28y: 82%
a) Isolation yields, calculated on the basis of carboxylic acids are shown.
16

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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00708J
Conclusion
We have developed a straightforward synthesis of bioactive 2,3-
benzodiazepines by means of phosphate-assisted acylation and hydrazine cyclization
reactions using one-pot two-step methodology. This methodology was also applicable
to aromatic and aliphatic carboxylic acids and a β-keto aromatic compound 24. A
free amino functional group was tolerated under the reaction conditions. We found
that the 3,4-dimethoxy groups of 1-phenylpropan-2-one are crucial for high
regioselectivity in the Friedel-Crafts acylation. Thus, bioactive 2,3-benzodiazepines
such as girisopam 19b and nerisopam 19c can be directly synthesized in the present
reaction from commercially available compounds at room temperature within a short
reaction time. However, further work will be needed to achieve direct access to other
bioactive 2,3-benzodiazepines.
Acknowledgement
This research was partially supported by a Grant-in-Aid for Research Fellow for
Young Scientists (JSPS) to A.S. (16J08260) and by the University of Tokyo.
Experimental Section
General Procedures
Melting points were determined with a Yanaco micro melting point apparatus without
1
13
31
correction. H-NMR (400 MHz), C-NMR spectra (100 MHz) and P-NMR spectra
(162 MHz) were recorded on a Bruker Avance400. Chemical shifts are given in ppm
(δ) values, and coupling constants are shown in hertz (Hz). Chemical shifts were
1
calibrated with internal tetramethylsilane or with the solvent peak for the H NMR
13
and C NMR spectra, and with 85% H3PO4 in a sealed capillary used as an external
17

Organic & Biomolecular Chemistry
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31
View Article Online
standard for P NMR spectra. The following abbreviations are used: s = sinDgOleI:t1,0.d103=9/C8OB00708J
doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, dt
= double triplet, td = triple doublet, qd = quarto doublet, qt = quarto triplet m =
multiplet, and brs = broad singlet. Electron spray ionization time-of-flight mass
spectra (ESI-TOF MS) were recorded on a Bruker micrOTOF-05 to obtain high-
resolution mass spectra (HRMS). All of the reactions were performed in heat-gun-
dried or oven-dried glassware. Trifluoromethanesulfonic acid (triflic acid) was treated
with trifluoromethanesulfonic anhydride (Tf2O) before distillation, and purified prior
to use by distillation under reduced pressure. Other commercially available
compounds and solvents were used as received.
Preparation of tris(methylsalicylate) phosphate ester 22
To
a
mixture of methyl salicylate (11976.5 mg, 78.7 mmol), N,N-
diisopropylethylamine (15.0 mL) in CH2Cl2 (10.0 mL), phosphoryl trichloride (2.5
mL, 26.7 mmol) was added slowly at 0°C. The whole was stirred at 20°C for 22 hours
and then evaporated to give a residue, which was column-chromatographed on silica
gel (eluent: EtOAc : n-hexane = 1 : 1) to afford tris(methylsalicylate) phosphate ester
22 (11781.3 mg, 23.5 mmol, 90%) as a colorless solid.
1
Mp. 74.2-75.1°C (colorless plates, recrystallized from Et2O/n-hexane).ꢀ H-NMR
(CDCl3, 400 MHz) : δ (ppm): 7.901 (3H, d, J = 7.6 Hz), 7.557-5.479 (6H, m), 7.273
(3H, dd, J = 7.2, 7.2 Hz), 3.696 (9H, s). 13C-NMR (CDCl3, 100 MHz) δ (ppm):
165.85, 149.68 (d, JCP = 7 Hz), 134.13, 132.50, 126.02, 123.82 (d, JCP = 7 Hz),
122.38 (d, JCP = 3 Hz), 52.74. 31P-NMR (CDCl3, 162 MHz) δ (ppm): -19.95. HRMS
(ESI-TOF, [M+Na]+): Calcd. for C24H21NaO10P+: 523.0765. Found: 523.0765. Anal.
Calcd. for C24H21O10P: C, 57.61; H, 4.23. Found: C, 57.47; H, 4.30.
18

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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB00708J
Typical procedure for the phosphate-assisted acylation reaction and hydrazine
cyclization reaction under one-pot two-step conditions. – Synthesis of Nerizopam
19c
Triflic acid (2.0 mL) was added to a mixture of 1-(3,4-dimethoxyphenyl)propan-2-
one (24) (197.6 mg, 1.02 mmol), 4-aminobenzoic acid 21 (137.6 mg, 1.00 mmol), and
tris(methylsalicylate) phosphate ester 22 (501.8 mg, 1.00 mmol) at 20°C. The reaction
mixture was stirred for 20 minutes at 20°C. The crude mixture was added to a mixture
of hydrazine monohydrate (1.0 mL, 20.6 mmol), EtOH (20.0 mL), and sodium
carbonate (4221.9 mg, 39.83 mmol) at 0°C. The whole was stirred for 10 minutes at
20°C, and then CHCl3 (50 mL) and water (50 mL) were added. The reaction mixture
was extracted with CHCl3 (50 mL x 3). The organic phase was washed with brine (40
mL), dried over Na2SO4, and evaporated under reduced pressure to give a residue,
which was column-chromatographed on silica gel (eluent : EtOAc : MeOH = 10 : 1)
to afford 4-(7,8-dimethoxy-4-methyl-5H-benzo[d][1,2]diazepin-1-yl)aniline 19c
(243.3 mg, 0.79 mmol, 79%) as a yellow solid.
1
Mp. 120.1-122.2°C (colorless plates, recrystallized from EtOH). H-NMR (CDCl3,
400 MHz) δ (ppm): 7.504 (2H, d, J = 8.8 Hz), 6.837 (1H, s), 6.715 (1H, s), 6.680 (2H,
d, J = 8.4 Hz), 3.960 (3H, s), 3.746 (3H, s), 3.220 (1H, d, J = 12.0 Hz), 3.031 (1H, d,
13
J = 12.0 Hz), 2.126 (3H, s). C-NMR (CDCl3, 100 MHz) δ (ppm): 158.72, 155.62,
152.30, 148.79, 148.32, 133.45, 131.51, 129.54, 123.11, 114.93, 113.38, 108.93,
56.67, 56.61, 38.85, 23.56. HRMS (ESI-TOF, [M+H]+): Calcd. for C13H12NO+:
310.1550. Found: 310.1545. Anal.: Calcd. for C13H11NO + 0.46 EtOH: C, 67.06; H,
6.75; N, 12.40. Found: C, 66.68; H, 6.82; N, 12.21.
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DOI: 10.1039/C8OB00708J
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