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Table 1: Counterion effects on Cu-catalyzed allylic cyanoalkylation.[a,b]
[a] Reaction conditions: 1a (0.20 mmol), CuXn (20 mol%) and DTBP
(0.80 mmol) in acetonitrile 2a (1.5 mL), 1108C, 6 h. The transformation
was performed in a 1 dram vial (diameter 1.4 cm/height 4.3 cm) which
was sealed using a screw cap with a Teflon septum. [b] Yields were
determined by NMR analysis of the unpurified reaction mixture using
1,3,5-trimethoxybenzene as an internal standard. Yield of isolated
product is shown within parentheses. [c] (CuOTf)2·PhMe (10 mol%).
[d] With veratronitrile (0.20 mmol). A 4:1 E/Z ratio was determined by
NMR analysis of the unpurified reaction mixture.
lysts used by Zhu and co-workers were not effective in our
proposed allylic cyanoalkylation.[14a,b,d,e,16] In contrast, (thio-
phene-2-carbonyloxy)copper(I) (CuTc, previously used as
a catalyst in allylic trifluoromethylation[4b]) provided cyanoal-
kene 3a as the major product in 30% yield. In comparison to
copper(I) acetate, we found that copper(II) acetate showed
higher efficiency and chemoselectivity, providing 3a in 47%
yield with > 20:1 regioselectivity. By replacing acetate with
the more basic pivalate, the desired alkene was obtained in
65% yield, > 20:1 regioselectivity. Other oxidants such as tert-
butyl hydroperoxide (TBHP) and dicumyl peroxide (DCP)
were ineffective. Using an electron-rich benzonitrile deriva-
tive as an additive further improved efficiency, presumably by
improving catalyst solubility. In the presence of one equiv-
alent of veratronitrile, 3a was obtained in 90% yield, greater
than 20:1 rr, and 4:1 E/Z. Only trace amounts of 4a were
observed (< 5% yield). These results support the notion that
a carboxylate counterion facilitates the elimination and
enables > 20:1 regioselectivity to provide the g,d-unsaturated
nitrile. A syn elimination affords the E isomer as the major
product.[19]
With this method, we elaborated a wide-range of terminal
olefins (Scheme 1). Unactivated linear terminal olefins gave
the corresponding g,d-unsaturated nitriles (3a–c) in 80–86%
yields with > 20:1 rr and 4:1 E/Z. For the substrates bearing
ester (3d, 3e), amide (3 f), cyano (3g), and ether (3h) groups,
regioselective CDC reactions with acetonitrile provided the
corresponding products in 75–82% yields. Increasing the
steric hindrance at the 4-position of the olefins slightly
decreased the yields but increased the E/Z ratios of the
products (3i 7:1 E/Z; 3j 11:1 E/Z; 3k > 20:1 E/Z). With a tert-
butyl group at the 3-position, we observed > 20:1 regioselec-
tivity and > 20:1 E/Z selectivity (3k). The regioselectivity was
unaffected by increased steric hindrance at the 4-position of
the olefins. 3-Aryl-substituted substrates gave the corre-
Scheme 1. Allylic cyanoalkylation of terminal olefins. Reaction condi-
tions: 1 (0.20 mmol), Cu(OPiv)2 (20 mol%), DTBP (0.80 mmol). and
veratronitrile (0.20 mmol) in alkylnitrile 2 (1.5 mL), 1108C, 6 h. E/Z
ratios determined by NMR analysis of the unpurified reaction mixture
are shown in parentheses. [a] 3t1 and 3t2 were isolated as a mixture.
[b] 24 h.
sponding nitriles (3l–n) in 40–46% yields with > 20:1 E/Z
selectivity. A substrate with an electron-withdrawing group
on the phenyl ring (3n) showed slightly higher reactivity than
one with an electron-donating group (3m). Trisubstituted
alkenyl nitriles were synthesized in 50–77% yields from 3,3-
and 1,1-disubstituted olefins (3o–r and 3t). A series of nitriles
were also tested as coupling partners and solvent. Propioni-
trile and butyronitrile showed decreased reactivity compared
to acetonitrile, most likely due to steric effects and the lower
solubility of the copper catalyst in these nitriles (3v, 3w).
À
Transformation with styrene, which has no allylic C H bond,
gave b,g-unsaturated nitrile 3x in 10% yield. Only trace
amounts of the hydrocyanoalkylation product
4 were
observed with the olefins shown in Scheme 1. Having
established facile access to various nitriles, we next focused
on applying them as building blocks.
Owing to the versatility of the cyano group, we were able
to use simple olefins to access a range of motifs, including an
industrial flavor agent, a natural product, and a polymer
precursor (Scheme 2). For example, treatment of 3b with
TMSCl in ethanol provided the pear flavoring ethyl 4-
2
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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