Tetrahedron Letters 51 (2010) 6526–6530
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Reaction of 2-alkyl pyridine N-oxide derivatives with Mosher’s acyl chloride: ﬁrst example of stereoselective Boekelheide rearrangement Daniele Andreotti ⇑, Emanuele Miserazzi, Arnaldo Nalin, Alfonso Pozzan, Roberto Profeta, Simone Spada ⇑ Neurosciences CEDD Medicine Research Centre, GSK Spa, Via Fleming 4, 37135 Verona, Italy
a r t i c l e
i n f o
Received 29 July 2010
Revised 29 September 2010
Accepted 5 October 2010
Available online 27 October 2010
Dedicated to the memory of Alessandro
a b s t r a c t
Treatment of 2-alkyl pyridine N-oxides with acylating reagents represents an established procedure for the introduction of oxygen functionality into alkyl group at the ortho position of N heteroaromatic rings. We have reported the ﬁrst example of asymmetric Boekelheide rearrangement applied to a set of 2-alkylpyridine N-oxide derivatives using (R) Mosher’s acyl chloride as activator of the rearrangement to give, after hydrolysis, enantiomerically enriched 1-(2-pyridinyl)alkyl alcohol. Diastereoselectivity of the process was studied at low temperatures in different solvents, and was supported by a preliminary in silico modeling.
Ó 2010 Elsevier Ltd. All rights reserved.
Mosher’s acyl chloride
The development of new synthetic methods has reached a level that allows organic chemists to plan and perform almost any kind of functional group transformation. Nevertheless, despite this achievement, advances in the ﬁeld are still highly desirable particularly if they can solve problems that allow easy and rapid access to chiral pool of compounds.
An interesting and productive way to improve synthetic efﬁciency, which can give access to a multitude of Csp3 chiral compounds, is to take a new look at poorly exploited and old pioneer reactions using current knowledge of organic chemistry. In this manner, we re-investigated the so-called Boekelheide rearrangement1 with the aim of obtaining an asymmetric version of the reaction, and in this way expand the available tools for accessing at enantiomerically enriched 1-(2-pyridinyl)alkyl alcohol derivatives. Since its discovery in the late 1940s, the reactivity of pyridine N-oxide mediated by activators, such as Ac2O has attracted the interest of several research groups. The conversion of 1 to the corresponding 2-pyridone 2 with acetic anhydride performed by Katada, Scheme 1, was the ﬁrst example reported in this ﬁeld.2 Shortly thereafter, it was found that also activation of 2-alkyl pyridine N-oxides 3 either with Ac2O3 or with other promoters, ⇑ Corresponding authors. Tel.: +39 0458219953; fax: +39 0458218196 (D.A.). E-mail addresses: email@example.com (D. Andreotti), firstname.lastname@example.org (S. Spada). 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.10.020
such as TFAA4 and tosyl chloride5 give access to 1-(2-pyridinyl)-alkyl alcohol derivatives 5. Today this is a well established procedure known as the
Boekelheide rearrangement,6 Scheme 1. Under the classical
Boekelheide’s reaction conditions, the 2-alkyl pyridine N-oxide 3 heated with a large excess of acetic anhydride is converted to 4, generally in moderate-good yields, and after hydrolysis, the corresponding alcohol 5 is obtained. This can then be resolved using classical techniques7 to give enantiomers 5-S and 5-R.
Despite much research, the mechanism of the rearrangement
has not been fully understood, and remains controversial.6 The most common and accepted explanation is an ion-pair mechanism (see Scheme 2) proposed by Oae8 and Katritzky9c,d. However, we cannot exclude the possibility that other mechanisms, such as a hetero-Claisen...
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