α,β-Unsaturated nitriles: Preparative MgO elimination

Article abstract of DOI:10.1016/S0040-4039(00)01583-5

Double deprotonation of β-hydroxynitriles with MeMgCl (2.1 equiv.) generates a dianion that ejects MgO to provide the corresponding α,β-unsaturated nitriles. Structurally diverse β-hydroxynitriles readily eliminate MgO providing an expedient route to highly substituted α,β-unsaturated nitriles. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01583-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8847–8851
a,b-Unsaturated nitriles: preparative MgO elimination
Fraser F. Fleming* and Brian C. Shook
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282-1530, USA
Received 15 September 2000
Abstract
Double deprotonation of b-hydroxynitriles with MeMgCl (2.1 equiv.) generates a dianion that ejects
MgO to provide the corresponding a,b-unsaturated nitriles. Structurally diverse b-hydroxynitriles readily
eliminate MgO providing an expedient route to highly substituted a,b-unsaturated nitriles. © 2000
Published by Elsevier Science Ltd.
a,b-Unsaturated nitriles are versatile synthetic intermediates1 being readily transformed into
an array of carbocycles2 and heterocycles.3 Conjugate additions4 to a,b-unsaturated nitriles
provide substituted nitriles that are equally valuable synthetic intermediates. The use of nitriles
in synthesis,5 combined with the increasing isolation of nitrile-containing natural products,6
provides a strong impetus for new, efficient syntheses of a,b-unsaturated nitriles.
The versatility of a,b-unsaturated nitriles has stimulated numerous syntheses of this function-
ality.7 Typically, a,b-unsaturated nitriles are synthesized by condensing nitrile anions (1) with
aldehydes and ketones to generate b-hydroxynitriles8 (2) that are subsequently dehydrated
(Scheme 1). This strategy is particularly effective for condensing aromatic acetonitriles with aryl
aldehydes and ketones since the dehydration is facilitated by the aromatic substituents.9
Aliphatic b-hydroxy nitriles dehydrate less readily10 requiring conversion to the corresponding
mesylate (4) for elimination to the a,b-unsaturated nitrile (3).11
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01583-5

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Conceptually the elimination of hydroxide, or a metal oxide, represents the most direct
conversion of b-hydroxy nitriles to a,b-unsaturated nitriles. Metal oxide eliminations generally
require elevated temperatures and strong bases.12 The elimination of MgO is anomalous in
occurring at significantly lower temperatures,13 reflecting the highly covalent character of the
MgO bond.14 In fact, the elimination of MgO from dianions, such as 6, occurs readily under
mild conditions providing a facile methylenation of ketones (Scheme 2).15
Scheme 2.
The facile MgO eliminations with Grignard reagents provide a strong precedent for the
elimination of MgO from b-hydroxy nitriles—providing the potential addition to the nitrile
group is avoided. Encouraged by the low proclivity of several Grignard reagents to add to
nitriles,16 the reaction of b-hydroxynitriles with Grignard reagents was investigated and found to
provide a very efficient route to a,b-unsaturated nitriles.
The elimination of MgO was first established with the b-hydroxynitrile 8f (Scheme 3).
Addition of MeMgCl (2.1 equiv.) initially generates a magnesium alkoxide that is further
deprotonated adjacent to the nitrile to form the dianion 9.2 Formation of the dianion 9, at
−78°C, followed by warming to room temperature, initiates the elimination of MgO to provide
10f in 92% yield.
Scheme 3.
The elimination of MgO from b-hydroxynitriles17 is remarkably facile (Table 1). Elimination
of MgO is equally efficient with secondary (a–b), tertiary (c–e), and allylic alcohols (b, d) and
tolerates acyclic (a–b), exocyclic (c–d), and endocyclic hydroxylation (f–h). A diverse range of di-
and tri-substituted unsaturated nitriles are obtained as virtually exclusive products (71–92%
yield), even in the presence of pendant alkyl chlorides (Table 1, entries 6–8).18–20
Formation of the unsaturated nitrile 10c illustrates the inherent advantage of this MgO
elimination method (Table 1, entry 3). The two-step addition of lithiated acetonitrile to hindered
ketones (84–93% for 8a–8e) and subsequent MgO elimination provides an efficient synthesis of
highly substituted a,b-unsaturated nitriles that are otherwise difficult to access. Furthermore, the
reaction displays an intriguing stereoselectivity with highly substituted b-hydroxynitriles (Table
1, entries 2, 3, and 5), while the sterically unbiased b-hydroxynitrile 8a exhibits a stereoselectivity
comparable to that obtained in Wittig olefinations.21

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Table 1
MgO eliminations from b-hydroxynitriles
MgO elimination from the stereoisomeric b-hydroxynitriles 8g and 8h provide insight into the
reaction mechanism (Scheme 4). Nitriles 8g and 8h react under identical conditions in virtually
the same yield, implying the intermediacy of a common dianion intermediate. Formation of the
dianion is an integral requirement since the addition of less than 2 equiv. of MeMgCl does not
provide the unsaturated nitrile 10g,22 indicating that MgO, and not hydroxide, is the leaving
group.

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Scheme 4.
a,b-Unsaturated nitriles are readily synthesized from b-hydroxynitriles by deprotonation with
an excess of MeMgCl. Deprotonation generates a dianion intermediate that ejects MgO
providing an efficient synthesis of a diverse array of a,b-unsaturated nitriles.
Acknowledgements
Financial support from NIH is gratefully acknowledged.
References
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14. Simanek, E.; Huang, N. L. Phys. Rev. Lett. 1966, 17, 699.
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17. The b-hydroxynitriles a–e were prepared by the addition of lithioacetonitrile to the corresponding aldehyde or
ketone. The b-hydroxynitriles a and e have been prepared previously by this method. For a see: Barhdadi, R.;
Gal, J.; Heintz, M.; Troupel, M.; Pe´richon, J. Tetrahedron 1993, 49, 5091. For e see: Trost, B. M.; Florez, J.;
Jebaratnam, D. J. J. Am. Chem. Soc. 1987, 109, 613.
18. The procedure for 8e is representative: A THF solution of MeMgCl (2.00 mmol) was added to a rt, THF solution
(5 mL) of 8e (134 mg, 0.95 mmol). The solution was stirred at rt for 10 h and then saturated, aqueous NH4Cl
was added. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts dried
(Na2SO4), and concentrated. The crude material was purified by radial chromatography (1 mm plate, 1:9
EtOAc:hexanes) to afford 95 mg (81%) of 10e: IR (film): 2219, 1613 cm−1 1H NMR l 1.09 (s, 9H), 2.06 (d,
;
J=0.7 Hz, 3H), 5.17 (br s, 1H); 13C NMR l 17.8, 28.3, 37.4, 93.4, 117.8, 172.8; MS m/e 124 (M+H). All new
1
compounds exhibited satisfactory H NMR, 13C NMR, MS, and IR spectra.
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22. Nitrile 8h is completely recovered precluding the formation of any ‘retro nitrile-aldol’ product.
.