Rh-Catalyzed rearrangement of vinylcyclopropane to 1,3-diene units attached to N-heterocycles

Dienes embedded in quinolizidine and indolizidine structures can be prepared in four steps from cyclic nitrones and bicyclopropylidene. The key intermediates α-spirocyclopropanated N-heterocyclic ketones, generated via a domino 1,3-dipolar cycloaddition/thermal rearrangement sequence, were converted by Wittig methylenation to the corresponding vinylcyclopropanes (VCPs), which underwent rearrangement to 1,3-dienes in the presence of the Wilkinson Rh(I) complex under microwave heating. The previously unexplored Rh(I)-catalyzed opening of the VCP moiety embedded in an azapolycyclic system occurs at high temperature (110–130 °C) to afford the corresponding 1,3-dienes in moderate yield (34–53%).


Introduction
The cyclopropyl group endows many natural and synthetic compounds with a broad spectrum of interesting properties, mainly related to its unusual bonding and inherent ring strain [1][2][3]. This characteristic confers on molecules containing this moiety high reactivity, especially towards ring expansion and ring-opening transformations. The smallest carbocycle can therefore be considered as a peculiar functional group that can promote unique reactivities and synthetic possibilities [4]. The main obstacle to full exploitation of this chemistry is the difficulty of selectively introducing a cyclopropyl group into a given substrate so that the various specific cyclopropane transformations can be used as a synthetic tool. In recent years we have shown that 1,3-dipolar cycloadditions of nitrones 1 to the highly strained alkene bicyclopropylidene (BCP, 2) [5][6][7] afford spirocyclopropanated isoxazolidines 3 [8,9] which, on heating, rearrange [10] to yield a large variety of spirocyclopropanated heterocyclic ketones 4 depending on the nature of the starting nitrone (Scheme 1) [11][12][13][14][15][16][17]. Scheme 1: General approach to spirocyclopropanated tetrahydropyridones by 1,3-dipolar cycloaddition/thermal rearrangement.
This rather general and convenient access to spirocyclopropaneannelated heterocyclic ketones 4 makes it attractive for the construction of other heterocyclic compounds by selective elaboration of the α-oxocyclopropane functionality, for example, to vinylcyclopropane (VCP) by simple Wittig olefination. The rearrangement of VCPs to cyclopentenes and dienes are well known processes [18][19][20][21][22][23][24][25] that occur thermally or under catalysis by various transition metals including Rh, Ni, Pd, Cu, Cr, Mo, and Fe [26][27][28][29][30][31][32][33][34]. To date the metal-catalyzed rearrangement of azaheterocyclic VCP has not been reported. In the context of our interest in the VCP chemistry of spirocyclopropaneannelated heterocyclic compounds [35], we started to investigate some metal-catalyzed rearrangements. The first choice was the readily available so-called Wilkinson catalyst Rh(PPh 3 ) 3 Cl, because of its documented efficiency in catalyzing the rearrangement [26] and of the possibility to extend its use to other interesting transformations, such as the [5 + 2] cycloadditions of vinylcyclopropanes to alkynes developed by Wender and co-workers [36,37]. It is known, that rhodium-catalyzed rearrangements of unactivated VCPs, without any functional substituent, usually afford dienes. In order to evaluate the influence of the N-heterocyclic system on the rearrangement, some model VCPs were generated by Wittig olefination of the α-oxocyclopropane group of functionalized oligocyclic spirocyclopropane-tetrahydropyridones and converted into the corresponding 1,3-dienes by treatment with Rh(PPh 3 ) 3 Cl.
The open-chain isomer 9 is derived from a rarely observed 1,5hydrogen shift in the cyclopropanated 1,6-diradical intermediate, which in this case is probably facilitated by the enhanced mobility of the benzylic hydrogen and by the formation of the conjugationally stabilized imine 9 [11]. The 1,3-dipolar cycloaddition/thermal rearrangement domino reaction of BCP (2) with the enantiopure nitrone 10 [42] derived from L-tartaric acid was complete within only 1.5 h at 120-125 °C under microwave (MW) heating and afforded the oxospirocyclopropanes anti-12 and syn-12 in 55% overall yield along with the 1,5-hydrogen shift product 13 (13%) (Scheme 3, see Supporting Information File 1 for full experimental data). The two diastereomeric indolizidinones anti-12 and syn-12 are formed by the thermal rearrangement of the cycloadducts anti-(3-t-BuO)-11 and syn-(3-t-BuO)-11, respectively.
Wittig olefination of ketones 8, anti-12 and 16 [43] with MePPh 3 Br/t-BuOK in THF at room temperature gave the VCPs 14, 15, and 17 in good yields (53-96%) (Scheme 4, see Supporting Information File 1 for full experimental data). The configuration was retained under the reaction conditions in compounds 15 and 17, as ascertained by the unique set of 1 H NMR signals in the crude reaction mixture.
The tricyclic compound 14 was then treated with a catalytic amount of Rh(PPh 3 ) 3 Cl (Table 1). In toluene at room temperature no reaction occurred, but on heating under reflux (110 °C) or at 130 °C in a microwave (MW) oven a rearrangement occurred leading to a main product assigned as the diene 18 and a mixture of the two diastereomers (E)-and (Z)-19. No trace of the cyclopentene-annelation product was observed in the reaction mixture. In refluxing toluene, the reaction was quite slow and after 15 h in the presence of 5 mol % of catalyst, a considerable amount of starting material still remained. Even after the addition of a second portion of the catalyst and further heating at 110 °C for 18 h, the conversion was incomplete, and  1, entry 4). When the reaction was allowed to continue until all the starting material was completely consumed led to complete decomposition of the products (Table 1, entry 5). Higher temperatures (160 °C in xylenes) or the addition of AgOTf [44] did neither improve the conversion rate nor the yield of the rearrangement products (Table 1, entries 6 and 7). A slight improvement was achieved by addition of trifluoroethanol (TFE, 5% of the total volume) as a co-solvent [45]. Under these conditions, the conversion of the VCP was complete after 5.5 h at 130 °C, and the dienes 18 and 19 were obtained in a 1:1 ratio in 46% overall yield after chromatography (Table 1, entry 8, see Supporting Information File 1 for full experimental data).
The collected data show that longer reaction times significantly influence the product ratio in favour of the dienes 19 (Table 1). These results are in accord with an isomerization of 18 into 19 under the reaction conditions. However, in the absence of the catalyst, heating of diene 18 under otherwise identical conditions did not induce any isomerization of 18 to 19, which confirms that Rh also catalyzes the 1,5-hydrogen shift in 18.
The structure assignment was easily made on the basis of 1 H NMR data. In particular, the diene 18 showed the typical  11b-H (δ 5.02 ppm) in agreement with the assigned configuration ( Figure 1).
The VCPs 15 and 17 were completely consumed on heating in toluene in a MW oven at 130 °C for 3 h and 110 °C for 3.5 h, respectively, in the presence of Rh(PPh 3 ) 3 Cl (10%) and TFE (5%). In these cases, dienes 20 and 21 were obtained in 53 and 34% yield, respectively, as the sole reaction products (Scheme 5, see Supporting Information File 1 for full experimental data). Their structures were assigned analogously as before. Compounds 20 and 21 were found to be unstable upon standing for prolonged periods, even at low temperatures. This explains the low isolated yields in their syntheses.
Analogously to other Rh(I)-catalyzed VCP rearrangements [46,47], the mechanism of the rearrangement likely involves insertion of the Rh(I) species into the cyclopropane ring of the VCP system, with or without incorporation of the double bond to form the intermediates C which can undergo metal hydride elimination or 1,3-hydride migration to the rhodium to give, respectively, the allyl-and alkylrhodium(III) hydride complexes D and F. Metal extrusion by reductive elimination leads to the observed dienes and regeneration of the catalyst (Scheme 6).

Supporting Information
Supporting information features experimental procedures and spectroscopic data.

Supporting Information File 1
Experimental part.