An improved process for the synthesis of 4H-imidazo[1,5-a][1,4] benzodiazepines

Article abstract of DOI:10.1055/s-0028-1083358

The construction of CNS active imidazo[1,5-a][1,4]benzodiazepines has been improved in a one-pot annulation process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083358

1036
PRACTICAL SYNTHETIC PROCEDURES
An Improved Process for the Synthesis of 4H-Imidazo[1,5-a][1,4]benzo-
diazepines
An
Improv
i
ed
S
yn
e
thesis of
4
H
-Imi
Y
a
][1,4]be
a
nzodiazepines g, Yun Teng, Shamim Ara, Sundari Rallapalli, James M. Cook*
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA
Fax +1(414)2295530; E-mail: capncook@uwm.edu
PSP
Received 5 September 2008; revised 4 November 2008
No151
Abstract: The construction of CNS active imidazo[1,5-a][1,4]benzodiazepines has been improved in a one-pot annulation process.
Key words: GABAA/Bz receptors, imidazo[1,5-a][1,4]benzodiazepines, ethyl isocyanoacetate, annulation
O
N
OPO(OEt)2
H
N
COOEt
N
N
N
N
X
X
N
X
1a–f
2a–f
or
3a–f
KOt-Bu
THF
CNCH2COOEt
KOt-Bu
or
or
ClPO(OEt)2
O
N
OPO(OEt)2
H
COOEt
N
N
N
N
N
X
X
Me
N
Me
X
O
O
Me
O
1g–j
2g–j
3g–k
Scheme 1 General scheme for the formation of various substituted imidazo[1,5-a][1,4]benzodiazepines (cf. Table 1)
achieved in low yield through an iminophosphate/
chloride intermediate.
Introduction
Imidazo[1,5-a][1,4]benzodiazepines are well documented
to exhibit potent activity at GABAA/Bz receptors. This se-
ries belongs to one of the very few chemical families,
which have been extensively investigated for GABAA/Bz
receptor mediated activity.1,2 Flumazenil (Ro 15-1788),
an imidazo[1,5-a][1,4]benzodiazepine, was earlier shown
to bind to central GABAA receptors with little or no intrin-
sic agonist activity, but with the ability to block the activ-
ity of an agonist or inverse agonist at GABAA/Bz
receptors.2 It is employed principally as an antidote to re-
verse the effect of exogenous benzodiazepines.3 More re-
cently ligands such as flumazenil have been shown to
behave as weak inverse agonists or weak agonists depend-
ing on the biological paradigm employed. Many proce-
dures have been reported to date to synthesize this
imidazo-type of structure.4,5 Most of them have been
As part of a program directed toward the development of
clinically relevant imidazo[1,5-a][1,4]benzodiazepines,1,6
the construction of the imidazo ring was considered a cru-
cial step for the synthesis of gram quantities of imida-
zobenzodiazepine analogues. The previous process of
using ethyl isocyanoacetate and iminophosphates/
chlorides7,8 was employed coupled with different solvents
and bases, but the yields of these reactions were very low
(15–30%). Since this step was highly convergent and at
the very end of the synthetic route, it affected the overall
economy of the route in a deleterious manner. It was,
therefore, of interest to improve the annulation sequence
for this series of CNS-active ligands.
Certainly a one-pot annulation process for the construc-
tion of imidazobenzodiazepines had been developed.7,8
This procedure permitted the condensation of the less
stable iminophosphates with ethyl isocyanoacetate under
basic conditions without isolation of the less stable imino-
phosphates and the preformation of the carbanion of ethyl
isocyanoacetate. For instance, Watjen et al.7a had reported
SYNTHESIS 2009, No. 6, pp 1036–1040
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083358; Art ID: M05108SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Improved Synthesis of 4H-Imidazo[1,5-a][1,4]benzodiazepines
1037
the formation of iminophosphates by using NaH or LDA ture lower than –35 °C (such as –78 °C) was also
in DMF, and then directly reacting this mixture with ethyl acceptable in this procedure and the second addition of
isocyanoacetate and potassium tert-butoxide to offer the potassium tert-butoxide was kept at 1.1 equivalents. This
imidazo molecules in 47% yield. Fryer and co-workers7b,c procedure made the separation of the product much easier,
had reported the use of potassium tert-butoxide as the which was critical for gram scale reactions. Most of the
base in both steps, and DMF as well as THF were chosen desired imidazobenzodiazepines were precipitated from
as solvents in these cases; however, this process gave the diethyl ether after workup for no chromatography was
ligands in only 44% yield. The latest report from Fryer’s needed.
procedure gave the target imidazo framework in 30%
A variety of different amidobenzodiazepines 1a–h were
chosen as substrates for this study (Table 1). Both the 5-
yield.8
phenylbenzodiazepines 1a–f and N-methyl-6-oxobenzo-
diazepines 1g,h readily condensed with ethyl isocyano-
acetate to give the desired imidazobenzodiazepines 3a–k
Scope and Limitations
in 70–89% yields in this improved process. The substitu-
ents in ring A such as F, Cl, Br of 1a–h did not affect the
yield of the process. The a-substituted amidobenzodiaz-
epines 1c–e, and 1i, which are more hindered than their
To improve the one-pot annulation reaction, the procedure
was modified and after many attempts it was found that
the ratio of the reagent combination and reaction temper-
ature were critical for good yields on a consistent basis.
unsubstituted parents 1a,b and 1f–j, also gave the imidazo
As shown in Scheme 1, the initial amount of potassium
analogues in 70–81% yields. In the case of optically active
tert-butoxide used to form the iminophosphates should be
substrates 1c–e, and 1i, this procedure provided the de-
kept at 1.1 equivalents as compared to the amides 1a–k.
The yield of the reaction was much lower if more potassi-
um tert-butoxide (>1.1 equiv) was employed. The amount
of diethyl chlorophosphate (used as received) employed
was only slightly higher (1.3 equiv) than the potassium
tert-butoxide to convert all the starting amide into the de-
sired iminophosphates 2a–k. Importantly, the addition of
ethyl isocyanoacetate, followed by the second addition of
sired imidazo products without loss in optical activity.
The R- and S-isomers produced have much different BzR/
GABAergic receptor binding profiles. All of these reac-
tions can be scaled up with no difficulty. The lesser
amounts of 3d–g simply reflect the lesser need for this
material. When this process was employed for reactions
of tert-butyl isocyanoacetate, the corresponding imida-
zobenzodiazepine 3k was obtained in 70% yield.
potassium tert-butoxide should be carried out at low tem-
perature (–35 °C is recommended). However, a tempera-
Table 1 Imidazo[1,5-a][1,4]benzodiazepines Prepared
Starting material
Product
Yield (%)
Scale (g)
O
O
O
N
O
O
O
H
N
OEt
OEt
OEt
N
N
N
Cl
1a
3a
87
11
N
N
N
Cl
Br
Br
N
N
H
N
Br
1b
3b
77
15
N
N
H
N
Br
1c
3c
74
10
N
F
F
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1038
J. Yang et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Imidazo[1,5-a][1,4]benzodiazepines Prepared (continued)
Starting material
Product
Yield (%)
Scale (g)
O
O
O
N
O
H
N
OEt
OEt
OEt
N
N
N
Br
1d
3d
73
3.6
N
N
N
Br
N
F
F
N
O
H
N
Br
1e
3e
72
1
Br
N
F
F
N
O
H
N
Br
Br
1f
3f
75
5
S
S
N
O
N
O
H
N
OEt
N
1g
3g
3h
3i
75
89
81
72
2
15
15
15
F
N
F
N
Me
O
O
Me
O
O
N
H
N
OEt
N
1h
Cl
N
Cl
N
Me
O
Me
O
O
N
O
H
N
OEt
H
N
H
1i
Br
N
Br
N
O
O
O
N
O
H
N
OEt
N
1j
3j
Br
N
Br
N
Me
O
O
Me
O
O
N
H
N
Ot-Bu
N
1k
3k
70
20
Br
N
Br
N
Me
O
Me
O
Synthesis 2009, No. 6, 1036–1040 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Improved Synthesis of 4H-Imidazo[1,5-a][1,4]benzodiazepines
1039
J = 12.3 Hz, 1 H), 4.49–4.38 (m, 2 H), 4.09 (d, J = 12.1 Hz, 1 H),
1.44 (t, J = 7.1 Hz, 3 H).
In summary, an efficient, practical, improved, and one-pot
annulation reaction for the construction of potent BzR ac-
tive imidazobenzodiazepines is described. A variety of EIMS: m/z (%) = 411 (M + 1, 34), 410 (M+, 8), 409 (34), 365 (61),
337 (100), 335 (100), 285 (21), 232 (17).
substrates were successfully employed in this procedure.
This one-pot process required neither the isolation of the
unstable intermediates nor does it require the preforma-
tion of the carbanion of the isocyanocetate. Moreover,
potassium tert-butoxide is a safer and easier-to-handle
base for scale-up, as compared to other bases such as
NaH, LHMDS, and LDA. In addition, no chromatography
was required for this process.
Anal. Calcd for C20H16BrN3O2: C, 58.55; H, 3.93; N, 10.24. Found:
C, 58.30; H, 3.91; N, 9.94.
(R)-Ethyl 8-Bromo-4-methyl-6-(2¢-fluorophenyl)-4H-imida-
zo[1,5-a][1,4]benzodiazepine-3-carboxylate (3c)
White solid; mp 261–262 °C; [a]D25 –10.9 (c 0.54, EtOAc).
1H NMR (300 MHz, CDCl3): d = 7.92 (s, 1 H), 7.72 (dd, J = 1.5, 8.2
Hz, 1 H), 7.60 (t, J = 6.9 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.49–
7.42 (m, 2 H), 7.29–7.23 (m, 1 H), 7.05 (t, J = 9.3 Hz, 1 H), 6.71 (q,
J = 7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J = 7.1 Hz, 3 H), 1.29 (d,
J = 7.2 Hz, 3 H).
Imidazo[1,5-a][1,4]benzodiazepines; General Procedure
t-BuOK (1.1 mmol) was added to a solution of the amidobenzodi-
azepine 1 (1.0 mmol) in anhyd THF (20 mL) at 0 °C under argon.
After stirring the mixture at 0 °C for 20 min, the reaction mixture
was cooled to –35 °C and diethyl chlorophosphate (1.3 mmol) was
added slowly. After stirring this mixture at 0 °C for 30 min, the re-
action flask was cooled to –35 °C and ethyl isocyanoacetate (1.1
mmol) was added, followed by the addition of t-BuOK (1.1 mmol).
After stirring this mixture at r.t. for 4 h, the reaction solution was
quenched with sat. aq NaHCO3 (30 mL) and extracted with EtOAc
(3 × 50 mL ). The combined organic layers were dried (Na2SO4),
concentrated, and the product was precipitated from Et2O to give
most of the imidazobenzodiazepine. The mother liquor was purified
by flash chromatography on silica gel (40–60% EtOAc in hexanes)
to afford additional imidazobenzodiazepine (yields 70–89%)
(Table 1).
EIMS: m/z (%) = 442 (M+, 5), 428 (7), 381 (58), 355 (100).
Anal. Calcd for C21H17BrFN3O2: C, 57.03; H, 3.87; N, 9.50. Found:
C, 57.13; H, 3.89; N, 9.51.
(R)-Ethyl 8-Bromo-4-ethyl-6-(2¢-fluorophenyl)-4H-imida-
zo[1,5-a][1,4]benzodiazepine-3-carboxylate (3d)
White solid; mp 253–254 °C.
1H NMR (300 MHz, CDCl3): d = 7.93 (s, 1 H), 7.72 (dd, J = 8.1 Hz,
1 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.48–7.42 (m, 2 H), 7.28–7.23 (m, 1
H), 7.06 (t, J = 9.3 Hz, 1 H), 6.51 (q, J = 7.8 Hz, 1 H), 4.43 (m, 2
H), 1.76–1.52 (m, 3 H), 1.43 (t, J = 7.2 Hz, 3 H), 0.96 (t, J = 7.2 Hz,
3 H).
HRMS: m/z calcd for C22H19BrFN3O2: 456.0723; found: 456.0709.
(S)-Ethyl 8-Bromo-4-ethyl-6-(2¢-fluorophenyl)-4H-imidazo[1,5-
a][1,4]benzodiazepine-3-carboxylate (3e)
White solid; mp 254–255 °C.
1H NMR (300 MHz, CDCl3): d = 7.92 (s, 1 H), 7.72 (dd, J = 7.2 Hz,
1 H), 7.59 (t, J = 6.9 Hz, 1 H), 7.48–7.41 (m, 2 H), 7.28–7.23 (m, 1
H), 7.06 (t, J = 9.3 Hz, 1 H), 6.51 (m, 1 H), 4.45–4.37 (m, 2 H),
1.75–1.54 (m, 3 H), 1.42 (t, J = 6.9 Hz, 3 H), 0.94 (t, J = 7.2 Hz, 3
H).
Imidazo[1,5-a][1,4]benzodiazepines; Ethyl 8-Bromo-5,6-dihy-
dro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-
carboxylate (3j); Large-Scale Procedure
t-BuOK (6.88 g, 61.33 mmol) was added to a solution of 1j (15 g,
55.76 mmol) in anhyd THF (1500 mL) at 0 °C and stirred for 20
min. The reaction mixture was cooled to –35 °C and diethyl chloro-
phosphate (10.42 mL, 72.49 mmol) was added slowly. After stirring
at 0 °C for 30 min, the mixture was cooled to –78 °C and ethyl iso-
cyanoacetate (6.70 mL, 61.33 mmol) was added followed by the ad-
dition of t-BuOK (6.88g, 61.33 mmol). After stirring at r.t. for 4 h,
the reaction was quenched with sat. aq NaHCO3 (500 mL) and ex-
tracted with EtOAc (3 × 1000 mL). The combined organic layers
were dried (Na2SO4) and concentrated to give a solid residue. This
solid residue was treated with Et2O (250 mL) and the product 3j was
precipitated as an off-white solid. The mother liquor was further pu-
rified by flash chromatography on silica gel (gradient elution 40–
60% EtOAc in hexane) to afford additional product 3j with an over-
all yield of 72% (14.61 g).
HRMS: m/z calcd for C22H19BrFN3O2: 456.0723; found: 456.0703.
Ethyl 7-Bromo-6-phenyl-4H-imidazo[1,5-a]thieno[2,3-f][1,4]di-
azepine-3-carboxylate(3f)
White solid; mp 180–182 °C.
1H NMR (300 MHz, CDCl3): d = 8.33 (s, 1 H), 8.02 (s, 1 H), 7.63–
7.35 (m, 5 H), 5.31 (s, 2 H), 4.34–4.27 (q, J = 7.1 Hz, 2 H), 1.32 (t,
J = 7.1 Hz, 3 H).
HRMS: m/z calcd for C18H14BrN3O2S: 416.0068; found: 416.0049.
Ethyl 8-Chloro-6-phenyl-4H-imidazo[1,5-a][1,4]benzo-
diazepine-3-carboxylate (3a)
Mp 180–182 °C.
Ethyl 8-Fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-
a][1,4]benzodiazepine-3-carboxylate (3g)
Off-white solid; mp 200–202 °C.
1H NMR (300 MHz, CDCl3): d = 7.93 (s, 1 H), 7.68 (dd, J = 2.3, 2.3
Hz, 1 H), 7.58 (s, 1 H), 7.55–7.37 (m, 6 H), 6.06 (d, J = 12.3 Hz, 1
H), 4.70 (m, 2 H), 4.15 (d, J = 14 Hz, 1 H), 1.46 (t, J = 7.12 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.88 (s, 1 H), 7.81–7.78 (m, 1 H),
7.74–7.36 (m, 2 H), 5.25 (br s, 1 H), 4.44 (q, J = 7.3 Hz, 2 H), 4.38
(br s, 1 H), 3.27 (s, 3 H), 1.47 (t, J = 7.3 Hz, 3 H).
HRMS: m/z calcd for C20H16ClN3O2 (M + 1): 366.1007; found:
HRMS: m/z calcd for C15H14FN3O3 (M + 1): 304.1097; found:
366.1000.
304.1091.
The spectral data for 3g were identical to the published values.2,4
Ethyl 8-Bromo-6-phenyl-4H-imidazo[1,5-a][1,4]benzo-
diazepine-3-carboxylate (3b)
Mp 180–182 °C.
1H NMR (300 MHz, CDCl3): d = 7.95 (s, 1 H), 7.82 (dd, J = 2.2, 8.6
Hz, 1 H), 7.60 (d, J = 2.2 Hz, 1 H), 7.53–7.40 (m, 6 H), 6.08 (d,
Ethyl 8-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-
a][1,4]benzodiazepine-3-carboxylate (3h)
Mp 200–202 °C.
1H NMR (300 MHz, CDCl3): d = 8.10 (s, 1 H), 7.90 (s, 1 H), 7.62
(dd, J = 8.6, 2.5 Hz, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 5.23 (br s, 1 H),
Synthesis 2009, No. 6, 1036–1040 © Thieme Stuttgart · New York

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J. Yang et al.
PRACTICAL SYNTHETIC PROCEDURES
References
4.46 (q, J = 7.1 Hz, 2 H), 4.13 (br s, 1 H), 3.27 (s, 3 H), 1.47 (t,
J = 7.1 Hz, 3 H).
EIMS: m/z = 319 (M+, 100%).
(1) Clayton, T.; Chen, J. L.; Ernst, M.; Richter, L.; Cromer, B.
A.; Morton, C. J.; Ng, H.; Kaczorowski, C. C.; Helmstetter,
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(S)-Ethyl 7-Bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imida-
zo[1,5-a]pyrrolo[2,1-d][1,4]benzodiazepine-1-carboxylate (3i)
White solid; mp 248.5–249 °C; [a]D25 +45 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.23 (s, 1 H), 7.82 (s, 1 H), 7.75
(d, J = 7.5 Hz, 1 H), 7.26 (d, J = 10.0 Hz, 1 H), 4.72 (d, J = 6.0 Hz,
1 H), 4.38 (q, J = 7.5 Hz, 2 H), 3.75 (m, 1 H), 3.56–3.48 (m, 2 H),
2.27–2.14 (m, 3 H), 1.41 (t, J = 7.5 Hz, 3 H).
EIMS: m/z (%) = 390 (M+, 10), 345 (60), 316 (100), 314 (98), 154
(24).
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Anal. Calcd for C17H16BrN3O3: C, 52.32; H, 4.13; N, 10.77. Found:
C, 52.70; H, 4.48; N, 10.64.
HRMS: m/z calcd for C17H16BrN3O3: 389.0375; found: 389.0373.
Ethyl 8-Bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-
a][1,4]benzodiazepine-3-carboxylate (3j)
Off-white solid; mp 192–193 °C.
1H NMR (300 MHz, CDCl3): d = 8.23 (s, 1 H), 7.79 (s, 1 H), 7.77
(d, J = 2.3 Hz, 1 H), 7.35 (d, J = 6.4 Hz, 1 H), 5.17 (br s, 1 H), 4.43
(m, 3 H), 3.28 (s, 3 H), 1.45 (t, J = 7.1 Hz, 3 H).
EIMS: m/z = 364 (M+, 100%).
tert-Butyl 8-Bromo-5,6-dihydro-5-methyl-6-oxo-4H-imida-
zo[1,5-a][1,4]benzodiazepine-3-carboxylate (3k)
Mp 180–183 °C.
1H NMR (300 MHz, DMSO-d6): d = 8.33 (s, 1 H), 7.92 (s, 1 H), 7.69
(d, J = 10.8 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H), 4.71 (br s, 1 H), 4.12
(br s, 1 H), 3.10 (s, 3 H), 1.56 (s, 9 H).
EIMS: m/z = 394 (M+, 100%).
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Marinelli, L.; Limongelli, V.; Novellino, E.; Betti, L.;
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Acknowledgment
We thank the National Institute of Mental Health (MH46851) and
the Lynde and Harry Bradley Foundation for generous financial
support.
Synthesis 2009, No. 6, 1036–1040 © Thieme Stuttgart · New York