Radical synthesis of guanidines from N-acyl cyanamides.

Guanidines—especially those embedded into polyclic frameworks—are an important structural unit of valuable synthetic intermediates and/or natural products. Therefore guanidines are appealing targets for total synthesis, bio-inspired molecular recognition, organocatalysis, and coordination chemistry. The development of innovative, efficient, and flexible methods to access these compounds thus remains an important goal. Radical cascade cyclization reactions have become an important tool used to construct polycyclic structures, in particular nitrogen-containing heterocycles. Our research group has introduced N-acyl cyanamides as novel radical partners for the preparation of quinazolinone systems such as luotonin A, through a radical domino sequence. Our approach to luotonin A included a retrosynthetic disconnection featuring the cyclization of a 2-quinolyl radical to an acylcyanamide A (Scheme 1). We reasoned that switching the initial carbon radical to a nitrogen-centered one (as in B) would provide an entry to cyclic guanidines after aromatic substitution of iminyl radical C, via tricyclic radical D (path a). To the best of our knowledge, a radical synthesis of guanidines is unprecedented in the literature. Iminyl radical C could also lead to a competing and unproductive b-elimination of an amidyl radical and deliver E, where the cyano group of the starting cyanamide has translocated to form a nitrogen-centered radical (path b). Nonetheless, our previous results with carbon-centered radicals made us confident that this would, at worst, be a minor path. Spagnolo and co-workers have shown that the stannylaminyl radicals obtained from reactions of tin radicals with alkyl azides add efficiently to the electrophilic cyano group. We thus decided to follow the same strategy, even though the reactivity of cyanamides may differ from that of nitriles because of the added nitrogen substituent. Substrate 1a was selected to validate our approach and was assembled in a very modular fashion from the corresponding amine, cyanogen bromide, and benzoyl chloride. We initially used the reaction conditions developed in our previous work; Bu3SnH (2 equiv) and AIBN (1.5 equiv) were slowly added (0.2 molh ) to 1a in benzene at reflux. Gratifyingly, the desired tricyclic guanidine 2a was isolated, but in a modest 41% yield (Table 1, entry 1). Replacement of benzene by toluene or tBuOH reduced the yields (Table 1, entries 2 and 3). Slow addition of Bu3SnH from a syringe pump was required and resulted in the yields increasing from 20 % (addition of Bu3SnH in one batch; Table 1, entry 4), to 41% (0.2 mmolh ; Table 1, entry 1), and then to 76 % (0.06 mmolh ; Table 1, entry 5). Lowering the amount of tin was not helpful (43 % yield with 1.2 equiv of Bu3SnH; Table 1, entry 6). Switching to [(CH3)3Si]3SiH or running the reaction at room temperature with initiation by light led to a near complete shutdown of the reaction (Table 1, entries 7 and 8). Therefore, the best yield was obtained by slowly adding Bu3SnH (0.06 molh , 2 equiv) and AIBN (1.5 equiv) to a solution of w-azido N-acyl cyanamide in benzene at reflux (Table 1, entry 5). With these optimized reaction conditions in hand, we next examined the scope for the radical synthesis of guanidine Scheme 1. Access to luotonin A and proposed route to guanidine derivatives.