[2,3]-Meisenheimer rearrangement of N-allyl phenylglycinol derivatives. N-C versus C-C chirality transfer

Article abstract of DOI:10.1016/S0040-4039(00)01460-X

The [2,3]-Meisenheimer rearrangement has been investigated on various allylic amines bearing phenylglycinol as a chiral appendage. The relative importance of N-C and C-C chirality transfer is discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01460-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8279–8283
[2,3]-Meisenheimer rearrangement of N-allyl phenylglycinol
derivatives. NꢀC versus CꢀC chirality transfer
Je´roˆme Blanchet, Martine Bonin*, Laurent Micouin* and Henri-Philippe Husson
Laboratoire de Chimie The´rapeutique associe´ au CNRS et a` l’Universite´ Rene´ Descartes (UMR 8638),
Faculte´ des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
Received 25 July 2000; accepted 30 August 2000
Abstract
The [2,3]-Meisenheimer rearrangement has been investigated on various allylic amines bearing phenyl-
glycinol as a chiral appendage. The relative importance of NꢀC and CꢀC chirality transfer is discussed.
© 2000 Elsevier Science Ltd. All rights reserved.
The Meisenheimer rearrangement, first reported in 1919, is one of the less studied [2,3]-sigma-
tropic rearrangements.1 In particular, only a few examples illustrate its potential for asymmetric
synthesis. Three kinds of chirality transfer can be considered in the course of this rearrangement
(Fig. 1).
Figure 1.
The first one consists in a 1,3-‘self-immolative’ asymmetric transformation, which was
reported to proceed efficiently by Reetz2 for 1 and more recently by Davies for compound 2.3
Enders and Kempen reported a second approach for 3, based on the use of a C2-symmetric
auxiliary, which avoids the problem of the selective oxidation of the nitrogen; however only a
moderate asymmetric induction was observed.4 Since tertiary amine N-oxides are configura-
tionally stable species, it is also possible to have chirality transfer from the nitrogen to the
* Corresponding authors. E-mail: micouin@pharmacie.univ-paris5.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01460-X

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carbon center. Although this chirality transfer has been suggested to proceed in an efficient
manner by the pioneering work of Inouye and co-workers, asymmetric oxidation of tertiary
amines usually gives amine oxides with low enantioselectivity.5
The stereospecific obtention of chiral N-oxides can be achieved using a chiral auxiliary on the
substrate. This strategy was mainly used by Coldham’s group, who extensively investigated the
[2,3]-Meisenheimer rearrangement starting from chiral non-racemic tertiary allylic amines 4.6
Despite recent successful results, the separate contribution of each chiral element in the final d.e.
observed remained unclear, since N-oxide could not be isolated prior to rearrangement.
We recently reported an easy access towards enantiopure a-substituted propargylamines using
(R)-phenylglycinol as a chiral auxiliary.7 Since this methodology allows the preparation of
analogous allylic amines, we decided to study the relative efficiency of the three possible chirality
transfers occurring in the Meisenheimer rearrangement starting from such derivatives.
a-Unsubstituted allylic amines 6a–f were prepared according to two classical ways, starting
from N-protected phenylglycinol (Scheme 1).
Scheme 1. Reagents and conditions : Method A : BrCH2CHꢁCHR2, MeCN, Na2CO3, D. Method B : (a) R2ꢀCꢂCH,
aq. HCHO, CuCl cat., ZnBr2, H2O/dioxane, 70°C. (b) DIBAH, toluene or H2, Pd/BaSO4, quinolein, MeOH
The Cu-mediated Mannich alkynylation was performed in water, and required one equivalent
of ZnBr2 for activation of the transient oxazolidine. Z configuration of the double bond was
controlled by the reduction step.
N-oxidation was then performed using a standard procedure (Scheme 2). The N-oxides 7a–f
were stable enough after being isolated, and the d.e. of the oxidation step could be determined
1
by H NMR analysis. Best results were obtained when performing the oxidation at low
temperature (−78°C). The absolute configuration of the newly created asymmetric center was
not determined at this step.
Scheme 2. Reagents and conditions: (a) mCPBA, Na2CO3, CH2Cl2, −78°C, 1 h. (b) Acetone, rt, 5 h

8281
The N-oxides 7a–f proved to be highly stable in dichloromethane or chloroform, probably
due to the presence of an intramolecular hydrogen bonding with the pendant hydroxyl group.8
Lowering the polarity of the solvent led to an increase of the rearrangement rate. In acetone,
compounds 8a–f were obtained in quantitative yield after less than 5 hours at room temperature.
However, in each case, no diastereoselectivity was observed after the rearrangement. Lowering
the reaction temperature (−20°C) led to a large decrease of chemical yield, without any
selectivity improvement. Z allylic N-oxide 7e rearranged about five times slower than its E
isomer 7f.
Such a poor chirality transfer has already been described by Coldham on allylic amines
derived from prolinol.9 This loss of selectivity was explained by the reversibility of the
Meisenheimer rearrangement, which could lead to some racemization of the final
hydroxylamine.
Another explanation can be proposed for this phenomenon (Fig. 2). Two reactive conformers
leading to opposite diastereoselectivities can exist in the reaction mixture. They are in equi-
librium by a simple NꢀC1 and C1ꢀC2 rotation.10 Obtention of a good chirality transfer requires
therefore that this equilibrium be strongly shifted towards one conformer, regardless of the
N-oxide stereochemistry.
Figure 2.
This shift can be obtained by tuning interactions between the chiral auxiliary and the allylic
moiety, or by introducing a substituent a to the nitrogen. We therefore investigated the
rearrangement of a-substituted allylic amines 10 a–b (Scheme 3).
Scheme 3. Reagents and conditions: R2ꢀCꢁCH, DIBAL, toluene, 4 h, then 9, 0°C, 1 h
These compounds were obtained in a straightforward manner by addition of mixed alkenyl-
aluminum compounds on oxazolidines 9a–b. This reaction proved to be as diastereoselective as
already reported for the addition of alkynylaluminum reagents.7 Absolute configuration of the
newly created asymmetric center was established by chemical correlation with the corresponding
propargylic compounds.7

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Under standard oxidation conditions, these compounds led very rapidly to hydroxylamines
11a–b, in a quantitative yield and with complete chirality transfer (Scheme 4). Absolute
configuration of compounds 11 was determined by chemical correlation of 11b with 12b11, and
the good agreement of the specific rotation with the value reported in the literature indicates
that reductive cleavage occurred without racemization, as already described by Davies and
co-workers.3 The introduction of a substituent a to the nitrogen led to a dramatic increase of
rearrangement rate.
Scheme 4. Reagents and conditions: (a) i. mCPBA, Na2CO3, CH2Cl2, 0°C, 1 h. ii. Acetone, rt, 1 h, quantitative. (b)
Na, NH3, 84% from 10b
Although N-oxides could not be isolated for such derivatives, it is highly probable that, as in
the case of compounds 7a–f, their formation was not fully stereoselective at 0°C. N-oxide
configuration is in this case unimportant, and the excellent CꢀC chirality transfer observed is
only due to the new asymmetric center, which controls the conformation of the reactive species,
as already reported by Reetz and co-workers.2
In conclusion, this study shows that the N-oxide configuration does not play an important
role in the [2,3]-Meisenheimer rearrangement if the conformation of allylic amine is not carefully
controlled. This can be done by using cyclic rigid chiral auxiliary,4,6 or by the introduction of a
substituent a to the nitrogen. In this case, diastereoselective N-oxide formation is unimportant,
since the CꢀC chirality transfer is highly efficient. In addition, we have shown that the use of
mixed organoaluminum reagents chemistry enables the straightforward preparation of
diastereomerically pure a-substituted allylic amines from readily available oxazolidines. This
methodology, followed by a very efficient [2,3-] Meisenheimer rearrangement, provides a simple
and scalable access towards various enantiopure allylic alcohols.
Acknowledgements
One of us (J. B.) thanks the MENRT for a grant.
References
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6. Burston, J. E. H.; Coldham, I.; Mulholland, K. R. J. Chem. Soc., Perkin Trans 1 1999, 2327.
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