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Synthesis of Six-Membered Carbo-/Heterocycles via Cascade Reaction of Alkynes and Diazo Compounds Junxiang Min, Guangyang Xu, and Jiangtao Sun J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017 Downloaded from http://pubs.acs.org on April 25, 2017
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The Journal of Organic Chemistry
Synthesis of Six-Membered Carbo-/Heterocycles via Cascade Reaction of Alkynes and Diazo Compounds Junxiang Min, Guangyang Xu and Jiangtao Sun* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China Supporting Information Placeholder 2
3
R
CO2Me X
+ N2
R
CuI-L
R1
base
CO2Me
R2
R2
R1 MeO2C MeO2C
R1 or MeO2C MeO2C
X = C, N, O N MeO
N L
OMe
R2 or N Bn
R3
1
R MeO2C MeO2C
O
R3
double C-C bonds formation one pot-two steps reaction diverse 6-membered carbo/heterocyles
ABSTRACT: A novel approach towards diverse 6-membered carbo-/heterocycles has been developed using diazo compounds and alkyne-substituted malonates as the suitable substrates. The polyfunctionalized cyclohexenes, tetrahydropyridines and dihydropyrans have been prepared in moderate to high yield under mild reaction conditions. Importantly, the ligand plays a significant role in this copper-catalyzed protocol.
Transition-metal-catalyzed carbene transformations from diazo precursors are powerful tools for constructing structurally diverse compounds in organic synthesis,1,2 specially the preparation of 4 to 6-membered carbo-/heterocycles. Importantly, the ring formation via metal-catalyzed intermolecular reactions of diazo compounds with readily available substrates, have attracted much attention due to their ability to generate multiple bonds without the requirement of pre-installation of diazo moiety. Such methods for the construction of 5-membered carbo-/heterocycles are many, including the preparation of tetrahydrofurans,3 2,3-dihydrofurans,4 2,5-dihydrofurans,5 pyrrolidines,6 2,3-dihydropyrroles7 and cyclopentanes/cyclopentenes.8 By contrast, the construction of 6-membered carbo/heterocycles is short of such methods. Several elegant approaches have been developed recently. In 2012, Saá and co-workers described a ruthenium-catalyzed alkyne/carbene metathesis/carbene insertion reaction to produce 6-membered carbocycles (Scheme 1a).9a Later, this methodology was further utilized to synthesize vinyl dihydropyrans and dihydrooxazines.9b Hu and co-workers reported a rhodium/zirconium-catalyzed multicomponent reaction followed by intramolecular cyclization to prepare morpholines (Scheme 1b).10 Just recently, Katukojvala and co-workers developed a Rh/Au-relay catalysis for synthesizing functionalized 1,4oxazines (Scheme 1c).11 Despite those advances, general approaches for the rapid assembly of 6-membered cyclic compounds still remain scarce, especially for polysubstituted tetrahydropyridines and dihydropyrans. Based on the former reports and in continuation with our ongoing interests in carbene chemistry,12 we describe here a novel and general approach which can rapidly assemble a wide range of polyfunctionalized 6-membered carbo/heterocycles from readily available starting materials under mild reaction conditions (Scheme 1d). Scheme 1. Synthesis of 6-Membered Carbo-/Heterocycles: Previous Reports and Our Design
Recently, we developed a cascade reaction for the synthesis of 5-membered poly-functionalized 2,5-dihydroppyrroles and 2-/3methylenepyrrolidines (Scheme 2a).12 We conceived that 6membered carbocycles 3a could also be obtained through the same methodology. Unfortunately, using the same reaction conditions described before followed by addition of a base provided 3a in low yield (Scheme 2b). We speculated that there were two
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main reasons resulted in the low efficiency. First, in the earlier report, the allenoate formation was deemed as the key step. Since the existence of one strong nucleophilic amino group, even in the absence of a base, this intermediate would rapidly undergo azaMichael addition to give the cyclization products (Scheme 2a). Second, literature reports disclosed that this type of alkynylbiscarbonyl compounds readily underwent Conia-ene reaction to generate 5-membered carbocycles in the presence of Lewis acids such as copper catalysts (Scheme 2c).13 We envisioned that the key points to improve the reaction depending on developing a good catalytic system to enhance the formation of allenoate 2a′ and finding a suitable base to promote the intramolecular Michael addition, as well as minimizing the undesired Conia-ene reaction. It should be noted that although there are many elegant approaches to prepare allenes by copper-catalyzed cross-coupling of diazo surrogates with alkynes, most of them are substrate depending (either for alkynes or diazo compounds)14. Namely, no general approaches are suitable for various types of alkynes as well as diazo substrates. Thus, we determined to develop an effective catalytic system to circumvent this challenge. Scheme 2. Initial Attempts
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(L7 and L8) and L9, L10 were less active. Next, the phosphine ligands were also examined and no better results were observed (entries 13 to 17). It should be noted that the use of KOtBu as the base provided 3a in 77% yield in 1 h (entry 18), while LiOtBu and K2CO3 led to low yields (entries 19 and 20). Solvent screening revealed that acetonitrile still was the best one. It should be noted that the use of KOtBu (entry 18) led to shorter reaction time than Cs2CO3 (entry 6).
Table 1. Optimization of the Reaction Conditionsa
entry 1 2 3 4 5 6c 7 8 9 10 11 12 13 14 15 16 17 18d 19 20 21 22 23
[Cu]
ligand
base
solvent
3a/3a′ (%)b
CuCl CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L12 L13 L14 L15 L4 L4 L4 L4 L4 L4
Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 KOtBu K2CO3 LiOtBu KOtBu KOtBu KOtBu
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH2Cl2 1,2-dichloroethane toluene
32/16 46/12 34/9
