sulfamidates to the synthesis of seven- and eight-ring
heterocyclic systems based on a departure from the chemistry
outlined in Scheme 1. There is currently significant interest
in targets based on 1,4-benzofused heterocycles of general
structure 3a-c; for example, the tetrahydro-1,4-benzothiaz-
epines S107 and JTV519 are being evaluated for treating
conditions linked to stabilization of cardiac ryanodine
receptors (RyR1), which leak Ca2+ when subjected to stress.6
(as in 6). It is, however, possible to exploit o-quinomethide
reactivity (see below) and extend the scope of the nitrogen
nucleophile used under Mitsunobu conditions.] alb/alb
Similar transformations were achieved using (i) thiophenol
5b to give 3-substituted 1,4-benzothiazepine 7b and (ii)
N-sulfonyl aniline 5c to give 3-substituted 1,4-benzodiazepine
7c.10 It is appropriate to point out that free anilines (ArNH2)
are not, in our hands, generally effective nucleophiles toward
cyclic sulfamidate electrophiles. These problems are, how-
ever, readily overcome using N-sulfonyl (e.g., 5c) or N-
carbamoyl variants.
Scheme 2. Synthesis of Substituted 1,4-Benzoxazepines,
Benzothiazepines, and Benzodiazepines
Utilizing an electrophilic 1,2-sulfamidate, our approach
to 1,4-benzoxazepines, thiazepines, and diazepines 3a-c is
outlined in Scheme 2 and is based on use of an aryl-based
nucleophile carrying an adjacent benzylic alcohol. Treatment
of the N-sulfonyl 1,2-cyclic sulfamidate 4a7 with (2-
hydroxymethyl)phenol 5a gave adduct 6 which underwent
smooth cyclization under Mitsunobu conditions8,9 to provide
3-benzyl-substituted tetrahydro-1,4-benzoxazepine 7a in 50%
overall yield. [Note that the synthesis of 7a (and 7c) has
recently been reported also using a Mitsunobu reaction to
construct the seven-membered ring.9 However, all of the
examples cited employ a highly acidic TsNH nucleophile
(5) Examples of these heterocycles abound in the literature and in the
patent literature. A recent example is BMS-214662, an enantiomerically
pure 1,4-benzodiazepine that is a highly apotopic farnesyltransferase
inhibitor displaying potent antitumor activity. Hunt, J. T.; Ding, C. Z.;
Batorsky, R.; Bednarz, M.; Bhide, R.; Cho, Y.; Chong, S.; Chao, S.; Gullo-
Brown, J.; Guo, P.; Kim, S. H.; Lee, F. Y. F.; Leftheris, K.; Miller, A.;
Mitt, T.; Patel, M.; Penhallow, B. A.; Ricca, C.; Rose, W. C.; Schmidt, R.;
Slusarchyk, W. A.; Vite, G.; Manne, V. J. Med. Chem. 2000, 43, 3587–
3595. Reid, T. S.; Beese, L. S. Biochemistry 2004, 43, 6877–6884.
(6) (a) Bellinger, A. M.; Mongillo, M.; Marks, A. R. J. Clin. InVest.
2008, 118, 445–453. Bellinger, A. M.; Reiken, S.; Dura, M.; Murphy, P. W.;
Deng, S. X.; Landry, D. W.; Nieman, D.; Lehnart, S. E.; Samaru, M.;
LaCampagne, A.; Marks, A. R. Proc. Natl. Acad. Sci. U.S.A. 2008, 105,
2198–2202. Bellinger, A. M.; Reiken, S.; Carlson, C.; Mongillo, M.; Liu,
X. P.; Rothman, L.; Matecki, S.; Lacampagne, A.; Marks, A. R. Nat.
Medicine 2009, 15, 325–330.
While the cyclization of, e.g., 6 to 7a is a conventional
Mitsunobu reaction (i.e., requiring an acidic NH), an
equivalent overall transformation was achieved using the
corresponding N-benzyl cyclic sulfamidate 4b with aniline
5c (Scheme 3). Using standard Mitsunobu conditions, the
N-benzyl amine 8b cyclized to give 3-substituted 1,4-
benzodiazepine 9b, the structure of which was confirmed
by X-ray crystallography.
Clearly adduct 8b does not incorporate a sufficiently acidic
NH for the usual Mitsunobu mechanism to operate, but
Nikam11 has demonstrated that in the presence of a suitable
activator (here PPh3, DEAD) benzylic alcohols react via an
o-quinomethide intermediate as a direct result of the presence
of an ortho-positioned ether or aniline. Interestingly, while
the corresponding phenolic adduct 8a (Scheme 3) was
prepared in excellent yield, this substrate did not cyclize
(7) Cyclic sulfamidates 4a/b and 10 provide a useful and validated test
bed for demonstrating chemistry in this area. Clearly 4a/b and 13 lack a
substituent at the reacting center, but our experience3 is that phenols, anilines,
and thiophenols are effective nucleophiles towards a range of other and
more substituted cyclic sulfamidates and that chemistry demonstrated with
4a/b and 10 is not limited in terms of its further application and scope. For
this reason, our focus was on the range of heterocyclic scaffolds available
rather than the substitution pattern associated with each individual substrate.
In addition, the enantiomeric purity of adducts such as 6 and 7a-c is based
on this earlier experience where loss of stereochemical integrity at a
nonreacting center was never observed. By analogy, we have assumed that
12b derived from 10 is also a single enantiomer.
(8) For recent examples of conventional (i.e., using acidic NH nucleo-
philes) Mitsunobu cyclizations to generate medium ring benzofused
heterocycles, see: Banfi, L.; Guanti, A. B. G.; Lecinska, P.; Riva, R. Org.
Biomol. Chem. 2006, 4, 4236–4240. Banfi, L.; Basso, A.; Guanti, G.;
Kielland, N.; Repetto, C.; Riva, R. J. Org. Chem. 2007, 72, 2151–2160.
For a very recent entry to benzoxazepines via an alternative (but related)
double displacement, see: Yar, M.; McGarrigle, E. M.; Aggarwal, V. K.
(10) Sulfonyl migration from the aniline nitrogen to the other nitrogen
center within the initial adduct (resulting from reaction of 4a with 5c) was
observed. Varying amounts of sulfonyl migration (from the aniline moiety
and depending on the workup conditions) also accompanied formation of
8b and 11b. See Supporting Information.
(11) Nikam, S. S.; Kornberg, B. E.; Rafferty, M. F. J. Org. Chem. 1997,
62, 3754–3757.
Org. Lett. 2009, 11, 257–260
.
(9) Mishra, J. K.; Panda, G. J. Comb. Chem. 2007, 9, 321–338. This
group employed (i) an intermolecular Mitsunobu alkylation (using a 2-amino
alcohol) and (ii) a Mitsunobu cyclization of an NHTs nucleophile to achieve
medium ring formation. An example of a 1,4-benzodiazocine (compare the
1,5-isomer 12b described here) was also reported.
Org. Lett., Vol. 11, No. 23, 2009
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Rujirawanich, Janjira
