Reactions of Morita-Baylis-Hillman Acetates with Huisgen Zwitterions: A Novel Strategy for the Synthesis of β-Amino Acid Derivatives

Abstract

N o v e l S t r a t e g y f o r t h e S y n t h e s i s o f b -A m i n o A c i d D e r i v a t i v e sAbstract: The reaction of Huisgen Zwitterion with Morita-BaylisHillman acetates afforded b-amino acid derivatives.Although Huisgen zwitterion 1 was known for nearly four decades, its synthetic potential remained largely unexploited except in some notable reactions like Mitsunobu Reaction. 2 In view of our longstanding interest in zwitterion chemistry, 3 recently we have explored the reactivity of Huisgen zwitterion towards various substrates like aldehydes, ketones, chalcones, diaryl 1,2-diones, quinones, isatins, and allenes. 4-6 In this context it was of interest to examine the reactivity of Huisgen zwitterion towards Morita-Baylis-Hillman (MBH) adducts, 7,8 which are unique substrates of great synthetic potential incorporating three manipulatable groups, namely, a hydroxy group, a double bond, and an electron-withdrawing group. In this paper, we describe the results of our investigations on the reaction of Huisgen zwitterion with MBH acetates.The present studies were initiated by treating methyl 2-[(4-chlorophenyl)acetyloxymethyl]acrylate (1a) with diisopropyl azodicarboxylate and triphenylphosphine in THF at room temperature for 2 hours. The reaction afforded two products, namely, diisopropyl N-acetyl-N¢-[3-(4-chlorophenyl)-2-(methoxycarbonyl)allyl]hydrazine-1,2-dicarboxylate (3a) and diisopropyl N-[3-(4-chlorophenyl)-2-(methoxycarbonyl) allyl]hydrazine-1,2-dicarboxylate (4a) in 46% and 51% yield, respectively (Scheme 1).The structure elucidation of 3a and 4a was accomplished by usual spectroscopic analysis. The 1 H NMR spectrum of the compound 3a showed singlet resonance signals at d = 2.35 and 3.81 due to CH 3 CO group and CH 3 OCO groups. The NCH 2 group was discernable at d = 4.14-4.73 as a multiplet. In the 13 C NMR spectrum the three ester carbonyl groups were present at d = 169.4, 167.4 and 154.7 and that of the keto carbonyl group appeared at d = 152.7, supporting the IR absorption observed in the region 1750-1700 and 1631 cm -1 . All other signals were also in good agreement with the proposed structure. The structure and stereochemistry of the compound was unambiguously established by single crystal X-ray analysis (Figure 1) of a representative compound, 3g. Figure 1Single crystal X-ray structure of di-tert-butyl N-acetyl-N¢-[3-(3,4-dichlorophenyl)-2-(methoxycarbonyl)allyl]hydrazine-1,2-dicarboxylate (3g) Scheme 1 Reaction of Huisgen zwitterion with MBH acetate N N CO 2 i-Pr

Regioselective SN2' Mitsunobu reaction of Morita–Baylis–Hillman alcohols: A facile and stereoselective synthesis of α-alkylidene-β-hydrazino acid derivatives

“…An ortho substituent on the benzene ring of the MBH alcohol was also well tolerated (Table 2, entry 5 vs 6). Notably, in contrast with Nair’s report [24], it was revealed that aliphatic MBH alcohols were excellent candidates in the reaction. By switching the solvent to dichloromethane, several alkyl MBH alcohols containing ethyl, methyl, or hydrogen substituents ( 1h–l ) readily reacted with representative azodicarboxylates, producing the corresponding α-alkylidene-β-hydrazino esters 3 in high yields (80–90%) and good E / Z selectivity (Table 2, entries 9–18).…”

“…In 2009, Nair and co-workers [24] reported an interesting reaction of MBH acetates with azodicarboxylates in the presence of PPh 3 (Mitsunobu reaction conditions), which gives an efficient access to α-alkylidene-β-hydrazino acid derivatives, an important precursor for many bioactive compounds [25–30] including β-amino acids [25] (Scheme 1, top). However, the reaction exhibited poor chemoselectivity which gave comparable yields of tri- and tetrasubstituted hydrazines.…”