c  c bond activation / functionalization recently merged a useful method for synthesizing complex scaffolds from relatively simpler starting materials .
c bonds was first reported by liebeskind using a stoichiometric co - complex ( fig .
seminal work by murakami / ito described intramolecular insertions of styrene - type olefins into cyclobutanones catalyzed by either cationic rh or ni , albeit limited to benzo - fused skeletons ( fig .
1c ) . one key challenge for developing cyclobutanone - olefin couplings via metal - mediated oxidative addition into c 
1c ) , which leads to either ring contraction or fragmentation ( for cyclobutanone activations via -carbon elimination , see refs 3239 ) .
therefore , in order to develop a general cyclobutanone - olefin coupling that is broadly applicable for synthesizing bridged type ii - imda - like products , the decarbonylation challenge has to be overcome and the scope of the olefin substrates ( e.g. both aryl and alkyl substituted alkenes ) as well as the variety of the bridged - scaffolds must be extended .
our strategy is inspired by a  cofactor-assisted c  c activation mode initially developed by jun , which utilizes 2-amino-3-methylpyridine as a co - catalyst to generate an imine intermediate that serves as a directing group for cleaving the imine  c  c bond .
this strategy has been effectively utilized to cleave medium to large cyclic ketimines in the presence of alkenes to afford ring - opened products ( fig .
however , to the best of our knowledge , utilization of this mode in small - ring activation has not been reported previously .
we hypothesized that employment of 2-amino-3-methylpyridine as a co - catalyst would benefit the desired intramolecular cyclobutanone - olefin coupling , depicted in fig .
2 . the amine would first form an imine with the cyclobutanone , which would then direct c  c cleavage through forming a chelation complex with the metal ( e.g. rh ) .
subsequent olefin migratory insertion followed by reductive elimination is expected to provide the bridged scaffold and regenerate the metal catalyst . finally , the resulting imine can be hydrolyzed to give the bridged - ketone product and 2-amino-3-methylpyridine , which can be recycled . hence
, this strategy , distinct from the previous cyclobutanone activations , can ease the c  c cleavage but more importantly prevent the aforementioned decarbonylation problem , because the carbonyl group would be in situ protected by the imine formation .
moreover , in principle , both the transition metal and the aminopyridine can be catalytic . to test our hypothesis ,
cyclobutanone 1a was used as the model substrate , which was readily prepared in three steps from inexpensive commercially available materials . in the presence of 3-methyl-2-aminopyridine
( 3 ) , a variety of rh precatalysts , ligands and solvents were examined ( for details , see supplementary information ) .
the conditions ( cationic rh with dppp ) that gave the best results in the previous example ( fig .
1c , murakami / ito ) did not provide any of the desired bicycle ( entry 1 , table 1 ) .
however , [ rh(cod)cl]2 was found to be a promising precatalyst and the desired bridged bicycle ( 3-azabicyclononanone ) 2a was obtained albeit in low yields ( entry 2 ) .
the solvent effect was next evaluated and 1,4-dioxane proved to be the best solvent ( entries 35 ) . while the yield of bicycle 2a can be improved by adding more cod ligand ( entry 6 ) , employment of a monodentate electron - deficient phosphine ligand was found more effective likely due to that the migratory insertion and reductive elimination steps can be accelerated with more -acidic ligands ( entries 79 ) .
use of bidentate ligands , such as dppp and dppb , showed no catalytic activity .
[ rh(cod)cl]2 ( 10 mol % ) with p(3,5-c6h3(cf3)2)3 ( 22 mol % ) was found to give full conversion with an 82% isolated yield of product 2a ( entry 9 ) .
use of a catalytic amount of cofactor 3 ( 20 mol % ) is also feasible albeit giving a slightly lower yield ( 76% ) with extended reaction time ( entry 10 ) . ultimately , use of 5 mol% [ rh(c2h4)2cl]2 ( 10 mol% total on rh ) and 24 mol% p(3,5-c6h3(cf3)2)3 provided azanonanone 2a in 87% isolated yield ( entry 11 ) .
the use of cofactor 3 was critical . in the absence of 3 , no [ 4 + 2 ]
product was observed ; decarbonylation products and the rh - carbonyl complex ( a dead catalyst , see supplementary information ) can be detected by lcms , hrms and h - nmr ( entry 12 ) .
this control experiment strongly supports our hypothesis that decarbonylation can be inhibited by using 2-amino-3-methylpyridine ( vide supra ) .
the structure of bridged - bicycle 2a was unambiguously confirmed by h , c nmr , ir , hrms and x - ray crystallography .
given that the nitrogen - containing scaffold was obtained when the nitrogen - tether was employed , we expect this method can potentially be useful for alkaloid synthesis ( fig .
1a ) . with the optimized conditions in hand , we next investigated the substrate scope ( table 2 ) .
in general , cyclobutanones tethered with 1,1-disubstituted olefins were converted into the corresponding 3-azabicyclononanones smoothly . not surprisingly , increasing the steric bulk on the olefin substituent from methyl to isopropyl to cyclopentyl slowed the reaction ( entries 15 ) , but the desired bridged bicycles were all nevertheless obtained in good to modest yields .
monosubstituted olefins can also insert into the c  c bond of cyclobutanones efficiently ( entries 6 and 7 ) . changing
the protecting group on the nitrogen from ts to carbamate ( co2me ) did not significantly affect the reactivity ( entry 7 vs 6 ) .
aryl - substituted olefins were found to be more challenging substrates likely due to their stability issue under the reaction conditions ; nevertheless , it is encouraging to note that they can still participate in this transformation , albeit with relatively lower efficiency .
the more electron - rich aryl olefins provided much higher yields than the corresponding electron - poor substrates ( entries 810 ) . changing the quaternary carbon substitution ( from me to et ) on cyclobutanones
both cis and trans - disubstituted olefins are suitable substrates , and higher reactivity was observed with the cis substrate ( entries 12 and 13 ) . both substrates 1l and 1
m provided the products with the same diastereomeric ratio ( dr ) , probably due to an enamine equilibration . besides forming
66 bridged [ 3.3.1 ] systems , the 56 bridged [ 3.2.1 ] scaffolds can also be obtained using this strategy .
the vinyl sulfonamide 1n can participate to give the desired bridged ring ( 2n ) ( entry 14 ) .
in addition , substrates with all - carbon linkages were also found suitable ( entries 15 and 16 ) .
it is interesting to note that with 1o as the substrate , a stable enamine derivative of 2o ( with 2-amino-3-methylpyridine 3 ) can be isolated as the major product , which was confirmed by x - ray crystallography ( see supplementary information ) .
subsequent hydrolysis with diluted acetic acid provided the ketone 2o in 54% ( 81% brsm ) yield ( entry 15 ) .
the substrate with an arene linkage ( 1p ) provided the desired benzo - bicycle ( 2p ) in nearly a quantitative yield under the standard conditions , suggesting a potentially broad substrate scope ( entry 16 ) .
two diastereomers of the desired product were obtained due to the diastereotopic difference between the two -c 
the products 2q - i and 2q - ii contain interesting tricyclic bridged and fused scaffolds , which have been found in a number of aconitum / delphinium alkaloids ( fig .
structures of both products were unambiguously confirmed by x - ray crystallography of their 2,4-dinitrophenylhydrazone derivatives ( see supplementary information ) .
furthermore , preliminary studies have revealed that chiral phosphoramidite ligands , such as 4 , effect the desymmetrization of cyclobutanone 1b with promising levels of enantioselectivity ( fig .
this result suggests that the  cofactor-assisted c  c activation mode is amenable to asymmetric catalysis , and work on this topic is ongoing .
finally , we demonstrated the carbonyl group in the formed bridged bicycles can serve as a convenient handle to access other ring systems through either ring contraction or expansion ( fig .
subsequent favorskii rearrangement afforded the ring - contraction product ( 6 ) in 78% yield .
oxime formation followed by beckmann rearrangement provided the ring - expansion product ( 76 bridged amide , 8) uneventfully .
saturated analogue  of type ii - imda reaction between cyclobutanones and simple alkenes via a rh - catalyzed  cofactor-assisted c  c activation approach .
substrates with different tethers and olefin substitutions ( both aryl and alkyl alkenes ) underwent this transformation .
while sharing a common feature to form 6-membered rings , this approach can provide scaffolds that are difficult to prepare using conventional imda reactions .
another advantage is that unactivated alkyl or aryl - substituted alkenes , instead of michael acceptors ( typically used in type - ii imda ) , can be used as coupling partners .
we expect the strategy developed here may provide inspirations for designing new tactics to synthesize complex natural products and other bioactive molecules .
in a nitrogen filled glove box , a 1-dram vial was charged with [ rh(c2h4)2cl]2 ( 1.9 mg , 5 mol% ) , tris[3,5-bis(trifluoromethyl)phenyl]phosphine ( 16 mg , 24 mol% ) and 2-amino-3-picoline ( 10 l , 0.1 mmol ) .
a solution of starting material 1a ( 32 mg , 0.1 mmol ) in dioxane ( 1 ml , 0.1 m ) was added and the 1-dram vial was capped and the solution was maintained at 152 c for 48 h. the reaction was removed from the glove box and purified by flash chromatography .
the product 2a was obtained as a bright orange solid ( 28 mg , 87% ) . the procedure to prepare compound 2a is generally representative for all the products shown in table 2 .
 bridged - ring systems are widely found in natural products and successful syntheses of them frequently feature intramolecular diels - alder ( imda ) reactions . 
 these reactions are subclassified as either type i or type ii imdas depending on how the diene motif is tethered to the rest of the substrate - type i are tethered at the 1-position of the diene and type ii at the 2-position . 
 while the type i imda has been used to great success , the molecular scaffolds accessible by type ii imdas are limited by the strain inherent in the formation of a sp2-carbon at a bridgehead position . here , we describe a complementary approach that provides access to these structures through the cc activation of cyclobutanones and their coupling with olefins . 
 various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons . 
 the ketone group of the products serves as a convenient handle for downstream functionalization . 
Results and discussion
Conclusion
Methods