M. Rogers-E6ans et al. / Tetrahedron Letters 44 (2003) 2425–2428
2427
amidine derived from 3 at −35°C gave rise to a mixture
of the open chain intermediate 8a and flumazenil 1
(ꢀ20:1, pH 7 quench). Although such intermediate
2-dehydroglycinates are believed not to be isolatable in
systems where subsequent intramolecular cyclisations
are possible,4a a non-aqueous work-up permitted the
isolation of 8a. Subsequent acidification with AcOH in
THF or dioxane to pH 5 with heating facilitated the
isomerisation of 8a to 8b followed by spontaneous
cyclisation and elimination of dimethylamine to pro-
duce flumazenil 1. This method was applied directly to
the original reaction mixtures containing 8a which gave
reproducible, isolated yields of 1 of 98% from imi-
nochloride 2 after recrystallisation. If this protocol was
not followed, a normal aqueous work-up led to hydrol-
ysis of any remaining uncyclised 8a, resulting in vari-
able yields. Reactions using non-isolated imino chloride
(i.e. as a crude solution in toluene) resulted in reduced
yields of ca. 70% of 1. Application of this process to the
synthesis of nitrile 9 using amidine 105b as the requisite
building block resulted in an overall yield of only 43%
from iminochloride 2. The reaction could be inter-
rupted at an intermediate stage to afford a ca. 1:1
mixture of cyano amidines 11a and 11b. Upon standing
or in solution, 11a was converted to its more stable
isomer 11b, which could then be heated in the presence
of acetic acid to quantitatively give 9. This reduced
yield was therefore caused en route to 11, most likely
by polar by products formed from the self-condensa-
tion of starting material 10.
1688; (d) Gu, Z.-Q.; Wong, G.; Dominguez, C.; de Costa,
B. R.; Rice, K. C.; Skolnick, P. J. Med. Chem. 1993, 36,
1001–1006; (e) Gerecke, M.; Kyburz, E.; Borer, R.;
Gassner, W. Heterocycles 1994, 39, 693–721; (f) Watjen,
F.; Baker, R.; Engelstoff, M.; Herbert, R.; MacLeod, A.;
Knight, A.; Merchant, K.; Moseley, J.; Saunders, J.;
Swain, C. J.; Wong, E.; Springer, J. P. J. Med. Chem.
1989, 32, 2282–2291; (g) F. Hoffmann-La Roche & Co.
Ltd., Neth. Pat. Appl. 7,803,585, 1978; Chem. Abstr. 1978,
90, 152254g.
4. Only the dimorpholinylphosphinyloxy imines have been
isolated as stable analogues of the corresponding imi-
doylphosphates but are cumbersome to prepare and
require careful handling. See: (a) Fryer, R. I.; Kudzma, L.
V.; Gu, Z.-Q.; Lin, K.-Y.; Rafalko, P. W. J. Org. Chem.
1991, 56, 3715–3719; (b) Ning, R. Y.; Fryer, R. I.; Madan,
P. B.; Sluboski, B. C. J. Org. Chem. 1976, 41, 2720–2724;
(c) Ning, R. Y.; Fryer, R. I.; Madan, P. B.; Sluboski, B. C.
J. Org. Chem. 1976, 41, 2724–2727.
5. (a) Fitt, J. J.; Gschwend, H. W. J. Org. Chem. 1977, 42,
2639–2641; (b) The corresponding amidine 10, was pre-
pared in 91% yield as a clear oil (41–65°C/6.0×10−3 mbar)
by the room temperature condensation of
a
dichloromethane solution of aminoacetonitrile hydrochlo-
ride with 1.3 equiv. of N,N-dimethylformamide dimethyl
acetal in the presence of 1.5 equiv. of Et3N followed by
concentration and distillation.
6. Rogers-Evans, M.; Spurr, P. Eur. Pat. Appl. EP 787,729,
1997; Chem. Abstr. 1997, 128, 75426.
7. (a)
2-Chloro-7-fluoro-4-methyl-3,4-dihydrobenzo[e][1,4]-
diazepin-5-one (2): A suspension of fluketazepam (5)
(20.80 g, 1.0 equiv., 100 mmol) and N,N-dimethyl-p-tolu-
idine (38.0 ml, 2.63 equiv., 263 mmol) in toluene (200 ml)
was heated to 100°C. Phosphorus oxychloride (10.20 ml,
1.1 equiv., 110 mmol) was then added dropwise over 20
min producing a slight exotherm. After 2 h at 100°C, the
reaction mixture was cooled to 5–10°C and slowly poured
onto ice-cold aqueous potassium carbonate (1.70 M, 200
ml). After 10 min, the mixture was filtered and the phases
separated. The organic phase was washed with water
(2×100 ml) and the combined aqueous phases were
extracted with two portions of toluene (2×40 ml). The
organic phases were combined, filtered and evaporated
then dried at 35°C/15 mbar for 2 h followed by 25°C/3.0×
10−3 mbar for 2 h. To the resultant oily solid was added
diisopropylether (50 ml) with stirring at 22°C. After 30
min, n-hexane (20 ml) was added dropwise over 15 min.
The resultant suspension was stored for a further 30 min
at 22°C, then at 0–5°C for 60 min. The crystalline product
was filtered under an argon atmosphere and washed por-
tionwise with a mixture of diisopropylether (30 ml) and
n-hexane (20 ml) and dried (3.0×10−3 mbar/12 h) at 22°C
Acknowledgements
Dr. John Daly and Mr. Peter Schoenholzer (X-ray),
Mr. Antoine Ritter and Mr. Gerd Schaffner (scale-up)
are thanked for their technical assistance.
References
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1
yielding 2 as orange crystals (19.32 g, 86%); H NMR (250
MHz, CDCl3+N,N-diisopropyl-3-pentylamine):
(3H, s), 4.05 (2H, s), 7.27 (2H, m), 7.69 (1H, dd, J6,F=9
Hz, 6,8=2.5 Hz); MS (EI): C10H8ClFN2O requires:
226.0309. Found: 226.0306.
X-Ray data for 2: A crystal in space group P1 with cell
l 3.32
J
(
,
3. (a) Gan, T.; Van Ornum, S. G.; Cook, J. M. Tetrahedron
Lett. 1997, 38, 8453–8456; (b) Liu, R.; Hu, R. J.; Zhang,
P.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1996, 39,
1928–1934; (c) Zhang, P.; Zhang, W.; Liu, R.; Harris, B.;
Skolnick, P.; Cook, J. M. J. Med. Chem. 1995, 38, 1679–
dimensions a=6.584(5), b=8.220(5), c=9.223(5) A; h=
97.760(5), i=94.290(5), k=92.750(5)° and Z=2 was
obtained from diisopropylether/hexane. All measurements
were made at 173(2) K on a Siemens P4 diffractometer
with graphite-monochromated Cu Ka radiation. The