1,3- and 1,4-Benzdiyne equivalents for regioselective synthesis of polycyclic heterocycles

We developed a novel 1,3-benzdiyne equivalent sequentially generating two triple bonds in a single benzene ring and controlling the regiochemistry.


Introduction
The reactions of benzynes with arynophiles are widely utilized for introducing substituents to adjacent carbons of benzene rings. 1 The direct installation of fused rings onto benzenes is an advantage specic to the benzyne reaction and is not possible through other methods. Furthermore, a variety of new arynophiles have been recently reported, enriching the diversity of the method. 2 The reactions of benzdiynes, possessing two triple bonds in a single benzene ring, and two arynophiles, would provide a few-step synthesis for the convergent preparation of multifused benzenes. However, benzdiynes are observed only under gas-phase conditions due to their extreme instability, 3 and it would be impossible to react one with two different arynophiles for the synthesis of unsymmetrically fused benzene rings.
An alternative approach is to use benzdiyne equivalents, where two benzynes are generated sequentially in one pot to provide substituted acenes and polycyclic aromatic compounds. If we could control the regiochemistry of consecutive benzyne reactions, starting from benzdiyne equivalents, each with different arynophiles, we could produce a wide range of multiring fused unsymmetrical aromatic compounds. 4 However, only a limited number of such reactions have been reported, and most of them require several steps for functional group transformations to generate the second benzyne. 5,6 Therefore, the development of more sophisticated benzdiyne equivalents is needed to facilitate two-step sequential benzyne reactions. Crucial factors in the design of these benzdiyne equivalents include suitable functional groups which enable the generation of the second benzyne without further transformations, and a way to control the regiochemistry of each benzyne reaction. The work of Suzuki et al. involving their original 1,4-benzdiyne equivalent meets these requirements, which uses n-butyllithum to generate the benzynes. 6b Very recently, Peña et al. have demonstrated that triple bonds were sequentially generated twice under uoride-mediated mild conditions from 1,4-benzdiyne equivalents and reacted with two different arynophiles in both stepwise and one-pot manners. 7 In contrast, there have been no reports of a suitable 1,3-benzdiyne equivalent. 5,8,9 We have attempted sequential benzyne reactions starting from 1,3-benzdiyne equivalents 1, with various arynophiles (Scheme 1). This method was designed to afford unsymmetrically substituted polycyclic aromatic compounds 3, possessing consecutive fused-rings, as are oen seen in material and pharmaceutical science. 10 While compounds like 3 have been Scheme 1 Design of benzdiyne equivalent 1 that can sequentially generate two triple bonds in a single benzene ring and control the regiochemistry of two benzyne reactions by the substituents next to each triple bond. mainly synthesized via linear, multi-step routes, our approach is convergent and rapid, proceeding by the combination of 1 and two different arynophiles (I and II), and allows a rational design for the production of a library of compounds. We were particularly interested in its application to the synthesis of benzofused heterocycles for medicinal chemistry. Therefore, we planned reactions using heteroatomic 1,3-dipoles, such as azides, nitrones, diazo compounds, and nitrile oxides, as the arynophiles.
We aimed to develop a synthetic methodology in which (1) two benzynes (4 and 5) are chemoselectively generated in a stepwise manner without any additional functionalization steps, (2) each benzyne is generated under mild conditions using a uoride, and (3) the two cycloaddition reactions of 4 and 5 with I and II proceed in a highly regioselective manner (Scheme 1). In this article, we report the preparation of a new 1,3-benzdiyne equivalent 1b [SiR 3 ¼ Si(t-Bu)Me 2 ], and a method for the preparation of unsymmetrical, angular, and multi-ring fused heterocyclic compounds 3, which satises the above criteria. One signicant advantage of this method is the high regioselectivity of both benzyne reactions, in which the rst step is controlled by the traceless directing group, R 3 Si (ref. 11) of 4, and the second step by the cyclic systems 12 of 5.

Results and discussion
We synthesized two 1,3-benzdiyne equivalents, 1a and 1b, which were treated with CsF in the presence of 2,4-dimethylfuran 6a. The reaction of 1a with 6a produced the undesired cycloaddition product 8 via benzyne 7 (Scheme 2). However, the reaction of 1b afforded the desired cycloaddition product 10a (78% yield) through the Diels-Alder reaction of the expected benzyne 4a with 6a. An important observation is that the double cycloaddition product 3a was not detected by GC analysis of the crude reaction mixture aer 30 min (see ESI †). This may be due to the lower reactivity of the Me 2 (t-Bu)Si group, even in the presence of excess CsF and 6a. The generation of the second benzyne 5a was achieved aer long reaction time (19 h) under the same reaction conditions using CsF to give 3a in 90% isolated yield.
We applied these ndings to the convergent synthesis of the antipsychotic drug risperidone 14 (Scheme 4). The silylbenzyne 4a and a nitrile oxide 6i (ref. 2e) were simultaneously generated from a mixture of 1b and a chloro-oxime 11 and then reacted in situ to form distal-10f as a single regioisomer. The next reaction of 6,7-benzisoxazolyne 5f, generated by BnMe 3 NF (ref. 14 and 15) and a uoride 6j, provided 3h with excellent regioselectivity. Finally, the synthesis was completed by the N-deprotection of 3h to give 12 and the alkylation with 13. 16 This result suggests that 1b should be useful tool for the expeditious divergent synthesis of a wide variety of biologically active compounds and their derivatives by choosing different arynophiles 6 once 1b become easily available (for the rst synthesis of 1b, see ESI †).
We also report the synthesis of linearly fused, unsymmetrical polycyclic aromatics 19 using 15 (ref. [17][18][19] as a 1,4-benzdiyne equivalent ( Table 2). The rst benzyne generation proceeds using CsF at room temperature in MeCN for a short time, under which conditions, generation of the second benzyne does not occur (see ESI †). The mono-cycloaddition products 17, obtained as a mixture of two regioisomers, were subjected to the second reaction with arynophiles II, without separation of the regioisomers, 20 to afford the multicyclic compounds 19. Due to the dual effect of the TfO group 13a and Me 3 Si group 11e of 16, the all rst benzyne reactions proceeded in a regioselective manner Table 1 Reactions of 1b with two different arynophiles 6 for the synthesis of angular polycycles 3 a a Conditions: 1b or 10 (1.0 equiv.), arynophile (3.0 equiv.), CsF (3.0 equiv.) in MeCN at rt. b The ratio of major and minor products was determined by 1 H NMR. c Total isolated yield of distal-10 (or distal-3) and its regioisomer proximal-10 (or proximal-3). Mes ¼ C 6 H 2 -2,4,6-Me 3 .
beyond expectation ( Table 2, entries 1-1, 2-1 and 3-1), although these selectivities were only a little lower than those of the 1,3benzdiyne equivalent 1b (see , Table 1). Interestingly, the second benzyne reactions also regioselectively provided cycloaddition products 19 probably because of the inductive effect of heteroatoms such as nitrogen and oxygen constructing heterocycles (entries 2-2 and 3-2). These results provide useful information for regioselectivity control of benzyne cycloadditions from distant positions. Importantly, the one-pot synthesis of a linear tricyclic compound 19a from 15, 6b and 6l was also successfully achieved (see entry 1-2).

Conclusions
In conclusion, we have developed a novel synthetic route to multi-ring fused heterocycles by the combination of benzdiyne equivalents and arynophiles. In this study, the newly generated azole-fused benzynes were found to exhibit higher regioselectivities than those of sterically similar 4,5-indolyne. 12b This method has facilitated the convergent synthesis of the antipsychotic risperidone. Therefore, we believe that this synthetic methodology will be invaluable to drug discovery. Work is ongoing into easier, scalable synthetic methods for these benzdiyne equivalents, 19 analysis of the origin of the regioselectivity (see ESI †), and applications to medicinal chemistry.