Dearomative [4 + 3] cycloaddition of furans with vinyl-N-triftosylhydrazones by silver catalysis: stereoselective access to oxa-bridged seven-membered bicycles

The rst example of dearomative [4 + 3] cycloaddition between furans and vinyl-N-sulfonylhydrazones as vinylcarbene precursors is reported. The merger of silver catalysis and easily decomposable vinyl-N-triftosylhydrazones enabled the ecient synthesis of a variety of skeletally and functionally diverse oxa-bridged seven-membered bicyclic compounds with complete and predictable stereoselectivity. The combination of experimental studies and DFT calculations disclosed that the silver-catalyzed reaction proceeds via a concerted [4 + 3] cycloaddition mechanism, rather than the generally accepted cyclopropanation / Cope rearrangement pathway by rhodium catalysis.

As part of our continued efforts in the design and application of functionalized N-triftosylhydrazones, [43][44][45][46] we were intrigued by the possibility of applying this approach to solve the aforementioned issues in the [4 + 3] cycloaddition methodology. Here we report a silver-catalyzed dearomative [4 + 3] cycloaddition of furans using the easily decomposable vinyl-N-triftosylhydrazones as donor and donor-acceptor vinylcarbene precursors (Fig.1c). The use of vinyl-N-sulfonylhydrazones as vinylcarbene precursors is known to be challenging because they easily tend to form pyrazoles by self-cyclization. 47,48 We speculated that this could be addressed by the combined use of silver catalysis and vinyl-Ntriftosylhydrazones. Moreover, mechanistic investigations reveal that the silver-catalyzed reaction proceeds through a concerted [4 + 3] cycloaddition, rather than the cyclopropanation / Cope rearrangement sequence by rhodium catalysis, thus mechanically avoiding the formation of triene byproducts.

Results
The study began by determining the optimal conditions for the cycloaddition of vinyl-N-triftosylhydrazone 1a with furan using NaH as the base in the presence of varied catalyst and solvent ( Table 1). The use of AgOTf as a catalyst in CHCl 3 at 60 °C ensued the desired product 2 in 24% yield, with a carbene dimer as the major product (Entry 1). The product yield could be substantially improved when using weakly coordinating trispyrazolylborate silver(I), [49][50][51] especially Tp (CF3)2 Ag affording 2 in 91% yield, with only a trace amount of undesired triene byproduct (entries 2 and 3). In contrast, Rh 2 (OAc) 4 14 and Cu(hfacac) 2 , 18 the most commonly used catalysts in the [4 + 3] cycloaddition of 1,3-dienes with vinyldiazoacetates, led to low yield, whereas Pd(OAc) 2 only enabled the carbene dimerization and the self-cyclization to pyrazole (entries 4-6). Further, the screening on solvents disclosed that CH 2 Cl 2 and PhCF 3 were less effective than CHCl 3 , whereas 1,4-dioxane was completely ineffective (entries 7-9). Vinyl-N-tosylhydrazone 1b as vinylcarbene source, instead of the easily decomposable vinyl-N-triftosylhydrazone 1a, afforded 2 in a far low yield (40%), owing to the self-cyclization to pyrazole (entry 10). The structural con guration of 2 was unambiguously established by the X-ray crystallographic analysis. 52 With the optimized conditions in hand (Table 1, entry 3), the substrate scope of this reaction with a series of furans was then investigated. As shown in Fig. 2, furans with various substituents at 2-position, including alkyl, alkenyl, alkynyl, and (hetero)aryl as well as bromo, tributylstannyl, siloxy, allyl, and benzyl ether, ester, and ketone functional groups reacted smoothly with phenyl vinyl-N-triftosylhydrazone 3 to afford the corresponding products (4-18) in 44-90% yield. We were pleased to nd that the substrates bearing a carbon-carbon double/triple bond and an activated C(sp 3 )−H bond (15-18) did not undergo competitive [2 + 1] cycloaddition [53][54][55] and C−H insertion, 10 thus achieving high chemoselectivity. The relatively low yields observed in some cases were ascribed to the ring-opening of furans to trienes and the carbene dimerization to ole ns. In comparison, 2-substituted furans resulted in trienes as the major product in rhodium-catalyzed [4 + 3] cycloaddition with alkenyl diazoacetates. [12a-c] In addition, the steric hindrance of furans had no apparent effect on the reaction, for instance, di-and tri-substituted furans reacted e ciently with 3, providing multi-substituted oxa-bridged bicycles 19-23 in 55-87% yield.
Encouraged by the above achievements, we then turned our attention towards the synthesis of fused [5.n.0] bicyclic systems, a challenging target that has attracted the interest of synthetic and medicinal chemists due to their structural diversity and biological relevance (Fig. 3). 1,58 First, we explored the [4 + 3] cycloaddition of furan with cyclic vinyl-N-triftosylhydrazones derived from cyclic enals, which were easily prepared by the one-carbon homologation reaction from commercially available cyclic ketones. 59  yield. Finally, the intramolecular [4 + 3] cycloaddition of diverse vinyl-N-triftosylhydrazones bearing a tethered furan was rationally designed and applied to prepare benzannulated bicyclic compounds, which are the common structural core of several biologically active natural products. 60 We were pleased to nd that these intramolecular [4 + 3] cycloaddition reactions proceeded smoothly under the silver-catalyzed conditions, affording the desired benzannulated bicyclic compounds (71-74) in 60-76% yield. To the best of our knowledge, this is the rst example of an intramolecular type I [4 + 3] cycloaddition between vinylcarbenes and furans. 61 To demonstrate the practicality of the protocol, a gram-scale reaction between hydrazone 75 and furan was performed under standard conditions, affording the product 50 in 80% yield (1.05 g) that is comparable to that obtained on small scale (Fig. 4) Fig. S1). Fortunately, the use of vinyl-N-triftosylhydrazone 79 in the reaction with furan produced a mixture of vinylcyclopropane 80 (which would correspond to the putative intermediates of the stepwise process) 13,32 and triene 81, along with a trace amount of 1,4-cycloheptadiene 82. When the isolated compound 80 was heated at 160 °C for 12 hours, only a triene 81 was isolated in 90% yield by the ring-opening of furanocyclopropane intermediate, whereas no rearrangement product 82 was observed (Fig. 5a). This result is different from the Rh-catalyzed [4 + 3] cycloaddition of 1,3-dienes with vinylcarbenoids. 13,30,32 Finally, we got a circumstantial evidence from the analysis of regioselectivity in the reaction of 3-phenylfuran with vinyl-N-triftosylhydrazone 3, which afforded a 1:1 mixture of 83 to 83'.
However, this is not consistent with the stereospeci city resulting from a tandem cyclopropanation / Cope rearrangement, where the initial cyclopropanation should selectively occur at the double bond with less sterical hindrance. 13,30,32 Hence, the involvement of a concerted [4 + 3] cycloaddition is more possible than a step-wise tandem cyclopropanation / Cope rearrangement.
To support our hypothesis concerning the involvement of a concerted [4 + 3] cycloaddition, in which silver vinylcarbenes act as a delocalized 2π system, 62 density functional theory (DFT) calculations were carried out for a model reaction, namely the silver-catalyzed reaction of 2-methylfuran with vinyl-Ntriftosylhydrazone 3 (for computational details see Fig. S2-S5 in supporting information). First, the diazo compound Int1, generated in situ from the decomposition of 3, coordinates to Tp (CF3)2 Ag and then releases a N 2 molecule to generate a silver carbene Int2 with an energy barrier of 11.3 kcal/mol (Fig. S3).
Subsequently, a concerted [4 + 3] cycloaddition of Int2 with 2-methylfuran occurs affording 1,4cycloheptadiene products 4, 4', and 4'', respectively, due to the approach of carbene intermediate Int2 to 2methylfuran from different orientations ( Fig. 5b and Fig. S4). The energy barrier for the generation of the desired product 4 from Int3-B1 via TS2-4 is only 1.8 kcal/mol, which is 12.0 and 23.4 kcal/mol lower than those for the formation of regioisomer 4' via TS2-4' from Int3-B2 and stereoisomer 4'' via TS2-4'' from Int3-C. To investigate the origin of the regio-and stereoselectivity, NCI and frontier molecular orbital analyses of transition states were performed ( Fig. 5c and Fig. S2). 63,64 A secondary orbital interaction exists in the boat form of transition states TS2-4 and TS2-4', and remarkably lowers the energy barriers for the generation of endo products and determines the stereoselectivity of this silver-catalyzed [4 + 3] cycloaddition. Furthermore, due to the C-H···π interactions between methyl and phenyl groups in TS2-4 and the steric exclusion between the methyl group and the bulky Tp (CF3)2 ligand of carbene moiety in TS2-4' (Figure 2c, for details see Figure S2), the secondary orbital interaction in TS2-4' is weaker than that in TS2-4. This result provides a suitable rationale for high regioselectivity observed in the experiment. By comparison, the DFT calculations for the tandem cyclopropanation / Cope rearrangement pathway have been carried out, but this process entails an energy barrier (14.1 kal/mol) that is higher than that for concerted [4 + 3] cycloaddition pathway (1.8 kal/mol) (see Fig. S5). At this moment, we cannot rule out completely that a tandem cyclopropanation / Cope rearrangement pathway is involved, but the experimental results and theoretical calculations indicate that a concerted [4 + 3] cycloaddition pathway is more favorable.