SmI2-mediated nitrile aldol reaction

Article abstract of DOI:10.1016/S0040-4039(00)00348-8

The SmI₂-mediated coupling of α-bromoacetonitrile and α- bromopropionitrile with aliphatic ketones and aldehydes produces β- hydroxynitriles in good yields. Reactions typically proceed with little diastereoselectivity, but selectivity enhanceme

Full text of DOI:10.1016/S0040-4039(00)00348-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3039–3041
SmI2-mediated nitrile aldol reaction
Andrei Caracoti and Robert A. Flowers II ∗
Department of Chemistry, University of Toledo, Toledo, OH 43606, USA
Received 21 February 2000; accepted 29 February 2000
Abstract
The SmI2-mediated coupling of α-bromoacetonitrile and α-bromopropionitrile with aliphatic ketones and
aldehydes produces β-hydroxynitriles in good yields. Reactions typically proceed with little diastereoselectivity,
but selectivity enhancement occurs with the addition of tetra-n-hexylammonium bromide. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: samarium; nitriles; aldol reactions; coupling reactions.
In the last two decades, lanthanides have been increasingly used in organic synthesis to successfully
replace traditional organometallic reagents.1 Among them, samarium(II) reagents have proven to be
the most useful due to their high reduction potential and to the fact that samarium iodide (SmI2), the
samarium reagent of choice, is fairly soluble in common organic solvents such as THF and acetonitrile.
Reactions of SmI2 include the selective reduction of aldehydes in the presence of ketones,2 the reduction
of α,β-unsaturated carbonyl compounds to the saturated derivatives,3 the reduction of alkyl halides,4
Barbier-type reactions,5 Reformatsky reactions5 and pinacol couplings.6
The nitrile aldol reaction is an important synthetic tool in organic chemistry, allowing the introduction
of a latent amino, carboxyl or other derived functionality into an organic molecule. Traditionally, the
reaction is carried out through the deprotonation of a nitrile followed by addition to an aldehyde or ketone
through a nucleophilic attack. The procedure has the disadvantage of being harsh on sensitive acidic
functional groups present in the substrate. Although the coupling of an α-halonitrile with a carbonyl
by SmI2 would appear to provide a mild pathway to a nitrile aldol product, very few examples of this
reaction have appeared in the literature. In 1993, Corey and Wu reported the SmI2-induced intramolecular
coupling of an α-chloronitrile with a ketone as a key step in the synthesis of paeoniflorin.7 The cyclization
produced a four-membered ring, proceeded in excellent yield, and provided the core substructure of
paeoniflorin.
To our knowledge, no general study of the SmI2-mediated bimolecular coupling of an α-halonitrile
and carbonyls has been carried out. We initiated the reaction in Scheme 1. All reactions were carried
out using the samarium Barbier procedure.8,9 All attempts to carry out the reaction using the samarium
∗
Corresponding author. Tel: (419) 530-1507; fax: (419) 530 4033; e-mail: rflower@uoft02.utoledo.edu (R. A. Flowers II)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00348-8
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Grignard procedure8 failed. The SmI2-mediated reaction of bromoacetonitrile and 2-bromopropionitrile
with a series of ketones and aldehydes is contained in Table 1. The reaction provides good yields in
reactions utilizing aliphatic ketones or aldehydes. The reaction is fast in all cases with substrates reacting
completely in less than 30 min at room temperature. Aromatic aldehydes and ketones do not react with
the α-halonitriles in the presence of SmI2. In these cases, reduction of the carbonyl to an alcohol occurs
instead because aryl ketones and aldehydes are readily reduced with SmI2. The yield of the reactions
are dependent on the way SmI2 is prepared. Preparation of SmI2 from a slight excess of Sm metal and
molecular iodine provides approximately 5–10% higher yields in the coupling reactions compared to
commercially available SmI2.
Scheme 1.
Table 1
Yields of coupling products
The diastereoselectivity of the nitrile aldol reaction has been studied extensively. Previous studies have
described very good diastereoselectivity for the reaction of lithiated acetonitrile and propionitrile with
substituted cyclohexanones and cyclohexenones.10 In the present case, the diastereoselectivity was not
very good. Reactions at low temperatures (−78°C) provided no increase in selectivity. Molander reported
that the addition of HMPA to the SmI2-mediated cyclization of olefinic ketones significantly enhanced the
diastereoselectivity of the reaction.11 We employed both HMPA and 1,1,3,3-tetramethylurea (TMU) as
additives to the SmI2 promoted coupling of α-bromoacetonitrile and (−)-menthone in order to enhance
the diastereoselectivity of the reaction. Unfortunately, only acetonitrile and unreacted menthone were
recovered from the reaction. An alternative additive, tetra-n-hexylammonium bromide (THAB) was used
in the coupling reaction. Surprisingly, THAB provided a 6:1 ratio of diastereomers.12
The nitrile aldol reaction mediated by SmI2 provides an alternative method for introducing a nitrile into
an organic molecule. The only limitation resides in the fact that SmI2, a powerful reductant, will readily
reduce activated carbonyls such as aromatic aldehydes and ketones, therefore the method is limited to
aliphatic substrates, which are not as easily reduced.

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Acknowledgements
R.A.F. is grateful to the donors of the Petroleum Research Fund, administered by the ACS (29492-G1),
for support of this research.
References
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9. Experimental details: the α-halonitrile (0.6 mmol) and the carbonyl compound (0.5 mmol) were dissolved in THF (3 mL) in
an oven-dried, 25 mL round-bottomed flask fitted with a septum, a magnetic stir bar, and connected to an N2 line. A solution
of SmI2 in THF (0.1 M, 12 mL, 1.2 mmol) was added. The solution was stirred for 30 min. The mixture was diluted with
ether and washed with a saturated solution of sodium thiosulfate (3×5 mL), then brine (3×5 mL) and dried over MgSO4.
The crude product was analyzed by GC/MS. Column chromatography on silica gel (hexane:ethyl acetate, 5:1 as eluant)
yielded the pure product.
10. (a) Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am. Chem. Soc. 1987, 109, 613; (b) Trost, B. M.; Florez, J.; Haller, K. J. J.
Org. Chem. 1988, 53, 2396.
11. Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132.
12. The ratio of diastereomers was determined by GC. The stereochemistry of the major isomer remains to be determined.