Pericyclic Reaction of Ketenes with Cascade Reaction Products of Pyridine N-Oxides and Dipolarophiles. X-Ray Structures of the Adducts and Formation Mechanism

Oiso, Shigeru; Eto, Masashi; Yoshitake, Yasuyuki; Harano, Kazunobu

doi:10.1248/cpb.51.1068

Cited by 8 publications

(1 citation statement)

References 16 publications

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“…This finding has caused a revolution in ketene chemistry. 14) In this connection, we previously reported another cycloaddition mechanism for the reaction of dihydropyridines with ketenes on the basis of MO calculations, 15) in which the lactam ring formation does not proceed via a sequential pericyclic reaction mechanism but takes place by a stepwise reaction mechanism (Chart 3, entry c). Based on the results for dihydropyridines, we considered that the reaction of a ketene with an a,b-unsaturated cyclic imine does not fall into the new category but involves initial nucleophilic attack of the imine nitrogen on the ketene sp-hybridized carbon, followed by 4p electrocyclic ring closure to give the [2ϩ2] cycloaddition product.…”

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Chemical Reactivity of Dihydropyrazine Derivatives. Cycloaddition Behavior toward Ketenes

Nakahara

Yamaguchi

Yoshitake

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Dihydropyrazines (DHPs), which are derived from aminosugars, exhibit various properties such as specific DNA strand-breakage activity, [1][2][3] facile dimerization, [4][5][6] unique ESR spectral behavior, [7][8][9] in vitro, induction of apoptosis 10) and mutagenesis 11,12) in vivo. It is thought that all these phenomena originate from the two natural characteristics of DHPs, i.e., their high chemical reactivity and radical generation ability. [4][5][6][7][8][9] As exemplified in Chart 1, less substituted DHPs such as 5,6-dimethyl-2,3-dihydropyrazine exhibit high chemical reactivity and readily transform to dimeric heterocyclic compounds via aldol condensation or pericyclic ene reaction (Chart 1). 5,6) In order to clarify the inherent chemical reactivity of DHPs, we studied the cycloaddition behavior of DHPs as diazadienes or imines towards ketenes. The results are discussed in detail on the basis of molecular orbital (MO) calculations on the cycloaddition pathways and the single crystal X-ray analyses of the cycloadducts. Results and DiscussionFirst, reactions of relatively stable 2,3-diphenyl DHP derivatives (1a-c) 13) with ketenes (2a-c) were performed (Chart 2).The reaction of 1a with 2a provided the 1 : 1 adduct (3aa) and two stereoisomeric 1:2 adducts (anti 4aa and syn 4aa). The yields and product ratios for the reactions with 1a-c and 2a-c are summarized in Table 1. ; 4-22-1 Ikeda, Kumamoto 860-0082, Japan. Received April 9, 2009; accepted May 7, 2009; published online May 12, 2009 The cycloaddition behavior of dihydropyrazines toward ketenes was investigated using single-crystal X-ray structures of the cycloadducts and density functional theory (DFT) calculation data. The reaction proceeds via a stepwise pathway involving an orientation complex prior to formation of the betaine intermediate. This is followed by electrocyclization to afford the 1 : 1 and 1 : 2 adducts bearing b b-lactam ring(s).

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