Workable synthetic routes to functionalized 1,6-benzodiazocines

Article abstract of DOI:10.3987/COM-08-S(F)10

Two strategies for fusing a medium-sized building block to a benzene ring in the form of a functionalized 1,6-diazocine unit via one-pot procedures are presented.

Full text of DOI:10.3987/COM-08-S(F)10

HETEROCYCLES, Vol. 77, No. 1, 2009
163
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 163 – 166. © The Japan Institute of Heterocyclic Chemsitry
Received, 9th April, 2008, Accepted, 15th May, 2008, Published online, 19th May, 2008.
DOI: 10.3987/COM-08-S(F)10
WORKABLE SYNTHETIC ROUTES TO FUNCTIONALIZED 1,6-
BENZODIAZOCINES‡
Nicolas Proust, Adam J. Preston, and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, OH
43210, USA; e-mail: paquette@chemistry.ohio-state.edu
Abstract - Two strategies for fusing a medium-sized building block to a
benzene ring in the form of a functionalized 1,6-diazocine unit via one-pot
procedures are presented.
Although interest in the pharmacological activity of benzodiazepines has persisted for many decades,1 a
comparable level of scrutiny has, only in select instances, been accorded to eight-membered homologs,
likely because of more limited synthetic accessibility.2 Notable in this connection are members of the
uncommon 1,6-benzodiazocine class, as exemplified by the alleged preparation of 3.3 Contrary to the
claims of the Bhusare group, the acid-catalyzed cyclization of 1 does not lead to 2 and is not a source of
3,4 but produces instead the known5 succinimide derivative 4 (Scheme 1). A comparable error in
structural assignment has been reported for the dibenzo derivative as 5  84 and not 5  6.6
Scheme 1
___________
‡Dedicated with best wishes to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th
birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Our quest of functionalized 1,6-benzodiazocines has led us to investigate the feasibility of eight-
membered ring annulation reactions involving the bis-sulfonamide 97 as the principal reagent. The proven
ability of cis-1,4-dichloro-2-butene to undergo efficient conversion to macrocyclic products8
foreshadowed its capability for delivering 102 smoothly in the presence of potassium carbonate (Scheme
2).
The importance of gaining viable access to 10 was heightened when the possibility for effectively
removing the p-toluenesulfonyl protecting groups with phenol and HBr/AcOH in CH2Cl2 at room
temperature10,11 was demonstrated. Incorporation of a sulfinyl group into 11 delivered the bridged diamide
12 as a single configurational isomer at sulfur.12 Presumably the double bond residing in 12 can be
exploited as an implementation site for further functionalization.
Scheme 2
With a view toward the development of an eventual route to conjugated diene intermediates, other
investigations into the chemistry of 10 were carried out. To illustrate, this entity lent itself to cis-
dihydroxylation, and subsequently to formation of the cyclic sulfite 14.13
At this point, the possibility of a complementary annulation process was explored. Bromomethyl vinyl
ketone (15)14 was selected as the test case. Although this reagent is an electrophilic species capable of
reaction at three sites, mechanistic studies have suggested, but not proven, that primary amines are
thought to enter into the initial SN2 displacement of bromide ion.15 To the contrary, enamines are prone to
attack XCH2COCH=CH2 (X=Cl, I) via Michael addition.16

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165
Scheme 3
We have removed this ambiguity in the present circumstances by first adding 15 to the somewhat less
functionalized sulfonamide 16 (Scheme 3). Under conventional conditions, only 17 proved to be
generated. As a direct consequence of symmetry, the projected variation involving 9 would lead to 18 by
either mechanistic pathway. In practice, the experiment furnished 18 in 74 % yield (Scheme 4). Reduction
of 18 with diisobutylaluminum hydride at -78 ºC proceeded uneventfully with the formation of carbinol
19, which was expectedly identical with the product of hydroboration of 10. Treatment of 19 with p-
toluenesulfonyl chloride in the presence of sodium hydride gave rise to tosylate 20, which was subjected
to elimination in the presence of potassium tert-butoxide to afford 21 as a single regioisomer.17
Independent high-pressure hydrogenation of 10 and 21 converged as anticipated to the same saturated
diazocine.18
Scheme 4
In summary, the two routes described above are serviceable in that the one-step construction of a pair of
1,6-benzodiazocines is achieved. No unwanted transannular side reactions proved to be competitive with
eight-membered ring formation. Further deployment of these observations awaits advances made in the
context of more complex settings.
ACKNOWLEDGMENT
We thank The Ohio State University for partial financial support.

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