HETEROCYCLES

Communication | Special issue | Vol. 77, No. 1, 2009, pp. 163-166
Received, 9th April, 2008, Accepted, 15th May, 2008, Published online, 19th May, 2008.
DOI: 10.3987/COM-08-S(F)10

■ Workable Synthetic Route to Functionalized 1,6-Benzodiazocines

Nicolas Proust, Adam J. Preston, and Leo A. Paquette*

Evans Chemical Laboratories, The Ohio State University, 120 W. 18th Avenue, Columbus, Ohio 43210, U.S.A.

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

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.

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

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

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.

‡Dedicated with best wishes to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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