Fleming et al.
(Figure 1).11 In solution metalated nitriles exhibit stereoselec-
tivities consistent with a similar range of geometries, implicating
a configurational lability of the nucleophilic carbon analogous
to that hinted at by the continuum of solid-state geometries.12
For example, deprotonating either diastereomer of the cyclic
nitrile 4 causes cyclization to the same ratio of cis- and trans-
decalins regardless of the starting nitrile configuration (Scheme
1).13 In these cyclizations the stereochemistry is consistent with
the solvent-determined formation of either the planar, sp2-type
N-metalated nitrile 5a/5a′ or the pyramidal, sp3-type nitrile anion
5b. Deprotonating 4 in toluene with KHMDS favors cyclization
to the cis-decalin 6 via the planar N-metalated nitrile conformer
5a′, which avoids the tortional strain imposed by twisting of
the electrophilic tether for cyclization via conformer 5a.
Alternatively, cyclizing 4 with KHMDS in refluxing THF
proceeds via the pyramidal ion pair 5b where the increased
attack angle (5b vs 5a′) ideally orients the nucleophilic orbital
for an SN2 displacement to the trans-decalin 7.
is to envisage a structural change of the metalated nitrile induced
by chelation of the electrophilic lithium cation with the π-system
of the nitrile15 (see inset 11, Scheme 2).
SCHEME 2. Metal-Dependent Cyclizations of a Cyclic
Nitrile
Complexation of metals, particularly lithium,16 with the
π-electrons of a nitrile17 provides a particularly effective method
of stereocontrol in a diverse range of reactions.18 In the case of
nitrile 8, deprotonating with a lithium base in benzene is
anticipated to favor tight association of the lithium cation with
the nitrile π-electrons and the proximal acetal oxygen leading
SCHEME 1. Solvent-Dependent Cyclizations of Metalated
Nitriles
(9) (a) Naota, T.; Tannna, A.; Kamuro, S.; Murahashi, S.-I. J. Am. Chem.
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18, 1177. (e) Ragaini, F.; Porta, F.; Fumagalli, A.; Demartin, F Organo-
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F. Organometallics 1990, 9, 929. (g) Ko, J. J.; Bockman, T. M.; Kochi, J.
K. Organometallics 1990, 9, 1833. (h) Cowan, R. L.; Trogler, W. C. J.
Am. Chem. Soc. 1989, 111, 4750. (i) Chopra, S. K.; Cunningham, D.;
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J. Chem. Soc., Dalton Trans. 1979, 1862. (k) Lenarda, M.; Pahor, N. B.;
Calligaris, M.; Graziani, M.; Randaccio, L. J. Chem. Soc., Chem. Commun.
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(10) Fluxional mixtures of N- and C-metalated nitriles are observed in
some instances: Sott, R.; Granander, J.; Hilmersson, G. J. Am. Chem. Soc.
2004, 126, 6798.
(11) Pyramidalization is conveniently monitored by comparing the
deformation angles, defined as the CN-C-X angle where X is the midpoint
between the two substituents at the anionic carbon: Wiberg, K. B.; Castejon,
H. J. Org. Chem. 1995, 60, 6327.
(12) For a discussion of the inversion barrier and mechanism see: Carlier,
P. R. Chirality 2003, 15, 340.
(13) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885.
(14) (a) Stork, G.; Gardner, J. O.; Boeckman, R. K., Jr.; Parker, K. A.
J. Am. Chem. Soc. 1973, 95, 2014. (b) Stork, G.; Boeckman, R. K., Jr. J.
Am. Chem. Soc. 1973, 95, 2016.
(15) Chelation of nitriles by lithium cations is directly analagous to the
chelation of organolithiums with proximal alkenes and aromatic π sys-
tems: (a) Harris, C. R.; Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434.
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The solVent-dependent cyclizations of the parent nitrile 4
contrast with the metal-dependent cyclizations of the analogous
ketal-containing nitrile 8 (Scheme 2). Unlike 4 where both
LiHMDS and KHMDS in toluene preferentially cyclize to the
cis-decalin 6 (Scheme 1), the cyclizations of 8 in benzene
depend intimately on the identity of the metal counterion:
KHMDS affords the cis-decalin 9, as anticipated for a planar
N-metalated nitrile (cf. 5a′ Scheme 1), whereas LiHMDS
unexpectedly affords the trans-decalin 10. Although arguments
were advanced to explain the stereoselectivity on the basis of
early and late contact distances,14 a more compelling rationale
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(18) (a) Kakiuchi, F.; Sonoda, M.; Tsujimoto, T.; Chatani, N.; Murai, S.
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1432 J. Org. Chem., Vol. 72, No. 4, 2007