to the [5,5] system (path A) is faster than formation of the
[7,5] system. Prolonged reaction times and/or heat would
allow Pd(0) complexation with 4, which would reintroduce
the intermediate π-allyl complex 6. Intramolecular proton
transfer to complex 7 followed by irreversible nucleophilic
attack (path B) of the sulfonamide nitrogen provides the
thermodynamically preferred benzodiazepine 5. Further
evidence that this pathway could be operative was found
when the dinitrobenzenesulfonamide group was replaced with
a 2-thiophenesulfonamide.
Scheme 5
Treatment of cycloadduct 3b with Pd(OAc)2 and PPh3 at
40 °C for 10 min resulted in formation of nitrone 8 in 83%
yield (Scheme 4). Prolonged heating of 3b in the pre-
Scheme 4
sence of various palladium reagents (Pd(OAc)2, Pd(dba)2,
Pd2(dba)3·CHCl3, PS-PPh3Pd), phosphine ligands, solvents,
and bases resulted in either no reaction or decomposition of
the reaction mixture. Isolation and purification of nitrone 8
followed by reexposure to Pd(0) was also unsuccessful. Since
the pKa of the sulfonamide NH is significantly higher in
cycloadduct 3b (compared to 3a), the essential proton transfer
was expected to be less facile and the benzodiazepine would
be unable to form. Still, formation of 9 was of particular
interest considering its structural similarity to the known
anticancer compound BMS-214662.4a
treated with several different sulfonyl chlorides. Reaction
with 2-thiophenesulfonyl chloride was first explored in an
effort to prepare compound 9. Unfortunately, compound 11
was completely unreactive with several sulfonyl chlorides,
including 2-thiophenesulfonyl chloride, dinitrobenzene sul-
fonyl chloride, and tosyl chloride.15 To derivatize 11, we
focused on reductive aminations, as aldehydes are unhindered
and strongly electrophilic.
Unable to convert cycloadduct 3b directly to the benzo-
diazepine core, we turned our attention to an alternative
multistep route toward functionalized benzodiazepines. Thus,
benzodiazepine 5 was treated with TBSCl in pyridine to give
protected hydroxamate 10 in good yield (Scheme 5). Upon
protection of the hydroxamate, attention was turned to
functionalization of the 4-amino position. Treatment of
benzodiazepine 10 with excess n-propylamine at rt allowed
for the mild deprotection of the dinitrobenzenesulfonamide
to afford core 11.13 The resulting deep yellow dinitro-N-
propylaniline byproduct was easily separated from 11 by
column chromatography. Alternatively, mercaptoacetic acid
was evaluated for the deprotection of the dinitrobenzene-
sulfonamide, but gave inconsistent results.14
Benzodiazepine 11 was treated with various aldehydes in
the presence of acetic acid and molecular sieves to form the
corresponding iminium species, which were subsequently
reduced with sodium triacetoxyborohydride to give protected
benzodiazepines 12a-e. Removal of the TBS group with
CsF in MeOH and purification with iron-free silica gel16
provided hydroxamate-containing benzodiazepines 13a-e in
32-48% yield over two steps (Scheme 5).
An important functionality present in benzodiazepines
13a-e is the hydroxamic acid. This group was anticipated
to play a role in the biological activity of these compounds.
Therefore, it was important to synthesize several analogues
that do not contain the hydroxamate. Benzodiazepine 5 was
deprotected with n-propylamine in 70% yield (Scheme 6).
Benzodiazepine 14 was then subjected to stoichiometric
titanocene chloride reduction conditions,17 which produced
To test the reactivity of the relatively hindered and electron
deficient 4-amino position, benzodiazepine 11 was first
(11) Unoptimized yield with Pd(OAc)2/PPh3/THF/∆ was 56%. See:
Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Org. Lett. 2002, 4, 139.
(12) Simply filtering the resin and concentrating the filtrate afforded a
yellow solid, which upon trituration with CH2Cl2 gave product 5 as a pure
white powder.
(13) Fukuyama, T.; Cheung, M.; Jow, C.; Hidai, U.; Kant, T. Tetrahe-
dron Lett. 1997, 38, 5831.
(14) Decomposition of mercaptoacetic acid due to oxidation and
occasional deprotection of TBS group proved problematic.
(15) Several bases, solvents, and temperatures were exhaustively
explored.
(16) The procedure for the preparation of iron free silica gel may be
found in the Supporting Information.
Org. Lett., Vol. 11, No. 7, 2009
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