Article pubs.acs.org/Organometallics
Enantioselective Alkynylation of Aldehydes by Mixed Aggregates of 3‑Aminopyrrolidine Lithium Amides and Lithium Acetylides Gabriella Barozzino-Consiglio, Yi Yuan, Catherine Fressigné, Anne Harrison-Marchand,* Hassan Oulyadi, and Jacques Maddaluno* Normandie Université, Laboratoire COBRA, UMR 6014 & FR 3038 CNRS, Université de Rouen, INSA de Rouen, 76821 Mont-Saint-Aignan Cedex, France
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ABSTRACT: Lithium acetylides form, with 3-aminopyrrolidine lithium amides, noncovalent 1/1 mixed aggregates that have been characterized by 1D and 2D multinuclear NMR spectroscopy and DFT computations. The results show that the complex adopts a structure organized around a N−Li−C− Li core and that the acetylide appendage lies within the plane of this quadrilateral, midway between the two lithium cations. These complexes have been employed for the enantioselective alkynylation of a series of aromatic aldehydes and provided the expected propargylic alcohols in ee values up to 85% in THF at −78 °C.
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INTRODUCTION Propargylic alcohols are important building blocks for the synthesis of pharmaceuticals and agrochemicals as well as natural products, because they are direct precursors of useful derivatives going from the allylic or benzylic alcohols to allenes and many others. Accessing such compounds enantioselectively is therefore a persistent subject of interest.1 Two major methods are known to give enantioenriched propargylic alcohols: reduction of propargylic ketones or alkynylation of carbonyl compounds. The latter is more general, since the reduction requires the preliminary synthesis of sensitive ynones and does not give access to tertiary alcohols. The enantioselective alkynylation route demands a nucleophilic acetylide RCCM, generally obtained by deprotonation of the corresponding terminal alkyne. In combination with the appropriate chiral catalysts, diverse metals have been used. Zinc acetylides, such as those developed by Pu,2 Chan,3 Carreira,4 and others 5 have led to extremely efficient systems. Mukaiyama,6 Grabowski,7 Schäfer,8 Jiang,9 and more recently Nakajima10 have shown that lithium acetylides can also add enantioselectively. The work by Grabowski and Collum is worth underlining, since their results have been applied to the industrial synthesis of Efavirenz, an HIV-1 reverse transcriptase inhibitor, and have been the object of a remarkable structure− reactivity study.7,11 The conclusion of that study was that wellorganized [Li,Li] mixed aggregates between the lithium acetylides and the chiral lithium alkoxides employed as chiral inductors in this process are forming at low temperature in THF. Our own interest in the chemistry of these bimetallic entities led us previously to describe the enantioselective addition of alkyl (sp3),12 alkenyl,13 and aryl (sp2)13b,14 organolithium derivatives to aldehydes. The system we use consists of 1/1 mixed aggregates of 3-aminopyrrolidine lithium amides © XXXX American Chemical Society
(3APLi) as chiral inductors. With the aim of extending our procedure to the sp nucleophiles, we present in this paper results describing the enantioselective alkynylation of several aromatic aldehydes by 3APLi/RCCLi mixed aggregates. Additionally, a detailed multinuclear NMR analysis and a DFT theoretical study are presented that shine more light on the structure of the aggregates that could be at the origin of the asymmetric induction.
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RESULTS AND DISCUSSION Enantioselective Alkynylation of Aromatic Aldehydes. The alkynylations have been carried out with lithium acetylides 1-Li−4-Li (Scheme 1). The aggregation states of the lithium acetylides 1-Li−3-Li have been well described in THF at low temperature (−90 to −115 °C) and correspond to a dimer for 1-Li,15,16 a tetramer for 2-Li,15,17 and a dimer + tetramer mixture depending on the concentration for 3-Li.7b,15 The structure of lithium acetylide 4-Li has been elucidated in a 1/3 THF/Me2O mixture at −123 °C and corresponds to a dimer.18 On the other hand, three 3APLi compounds (5a-Li−5c-Li, Scheme 1) have been selected among those that have given the best results in previous cases.12−14 Each 3APLi/Li-acetylide aggregate was prepared in situ at −20 °C by simultaneous deprotonation of the terminal acetylenic substrate and the amine. They were then reacted at −78 °C with o-tolualdehyde (2-methylbenzaldehyde) 6 in a 1.5/1.5/1 3APLi/Li-acetylide/ aldehyde ratio in classical solvents (THF, diethyl ether, and toluene, Table 1).12−14 Note that the amide, acetylide, and aldehyde ratio was based on previous results optimized for alkylation and arylation reactions. Received: February 26, 2015
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DOI: 10.1021/acs.organomet.5b00647 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics
Scheme 1. Alkynylation of o-Tolualdehyde 6 by Lithium Acetylides 1-Li−4-Li in the Presence of 3APLi Compounds 5a-Li−5c-Li
Downloaded by UNIV OF PRINCE EDWARD ISLAND on September 6, 2015 | http://pubs.acs.org Publication Date (Web): September 4, 2015 | doi: 10.1021/acs.organomet.5b00647
Table 1. Enantioselective Alkynylation of o-Tolualdehyde 6 by 1-4-Li in the Presence of 3APLi Compounds 5a-Li−5c-Li entry RCCLi 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
1-Li
2-Li
3-Li
4-Li
3APLi
solvent
yield, %a (alcohol)
ee, %b (confign)d
5a-Li 5a-Li 5a-Li 5b-Li 5b-Li 5b-Li 5c-Li 5c-Li 5c-Li 5a-Li 5b-Li 5c-Li 5a-Li 5b-Li 5c-Li 5a-Li 5b-Li 5c-Li
THF Et2O toluene THF Et2O toluene THF Et2O toluene THF THF THF THF THF THF THF THF THF
51 (7) 71 (7)c 10 (7)c 71 (7) 60 (7)c 45 (7)c 81 (7) 45 (7)c 42 (7)c 59 (8) 69 (8) 67 (8) 42 (9) 58 (9) 46 (9) 56 (10) 67 (10) 80 (10)
31 (R) 21 (R)
