Organic Letters
Letter
Scheme 3. Representative Derivatizations
convert the amide into corresponding ester 5 in 94% yield. A
two-step approach via protection followed by substitution
achieved the secondary amide transamidation to afford tertiary
amide 6. The cyano and amide groups could be reduced by
diisobutyl aluminum hydride into aldehyde and secondary
amine moieties, respectively, to give 7 in 85% yield. In
comparison, diamine compound 8 was obtained when
reduction of 4b with lithium aluminum hydride in refluxing
diethyl ether. Moreover, 4b could be hydrogenated into
cyanoamide 9 or undergo dihydroxylation to produce diol 10.
Several control experiments were conducted to gain insight
into the mechanism (Scheme 4). Addition of 3.0 equiv of
Figure 2. Proposed reaction mechanism.
nearby Cu(II) species. This formal migratory insertion process
afforded a putative directing-group-coordinated Cu(III)
intermediate M5.7,27,29 Eventually, Ha and Hb were distin-
guished during the concerted Ha−OBz (path a) or Hb−OBz
(path b) elimination of the conformationally strained metal-
lacyclic intermediate M5.8b,18 Major product 3a and minor one
3a′ were produced through the subsequent protodemetalation,
along with the regeneration of Cu(I) salt. The screening
conditions in Table 1 indicated that the solvent played a key
role in controlling the reaction selectivities, with 2-butanol
serving as the most effective one. Further DFT calculations
performed at the SMD(2-butanol)/(U)M06/[6-31G(d,p)/
LanL2DZ(Cu)] level (see Figure S1) showed that 2-butanol
was involved in the transition state of the concerted H−OBz
elimination process. The concerted Ha−OBz elimination is
much more difficult than concerted Hb−OBz elimination
(ΔΔG⧧ = 2.2 kcal/mol), and the barriers leading to the
formation of E- and Z-M7 were 19.0 and 20.5 kcal/mol,
respectively. It was found that the slight preference for E-M7
was attributed to the steric effect. In the transition state leading
to the formation of Z-M7, the distance between the hydrogen
of 2-butanol and the hydrogen of the substrate was only 2.2 Å.
These calculated results were consistent with the experimental
data of an excellent rr value and a good E:Z ratio.
In summary, a directed intermolecular Heck-type reaction of
cycloketone oxime esters and unactivated alkenes was achieved
for the first time, which represented a conceptually new type of
coupling between the unactivated alkene and alkyl electrophile
via nonstabilized alkyl radical species. All cyclobutanone-,
cyclopentanone-, and cyclohexanone-derived oxime esters and
a wide range of unactivated alkenes, including α-substituted,
1,1-disubstituted, and internal alkenes, were compatible.
Further derivatization of the resultant cyanoalkenes showed
the potential application prospect of this methodology in
organic synthesis. Detailed mechanistic studies and DFT
calculations disclosed that 2-butanol-assisted concerted H−
OBz elimination of the conformationally strained Cu(III)
cyclic transition state is the key to delivering the coupled
products in excellent regioselectivities and good E:Z ratios.
Scheme 4. Mechanistic Investigations
either BHT or TEMPO to the reaction mixture completely
suppressed the formation of desired product 3a, and the
cyanoalkyl−BHT and −TEMPO adducts 11 and 12 were
isolated in 57% and 68% yields, respectively, based on the
amount of oxime ester 2a.12f Moreover, a radical clock
experiment using oxime ester 13 as the substrate produced
ring-closed product 14 in 45% yield as a mixture of
diastereoisomers.12b,d These results indicate that the reaction
may involve a cyanoalkyl radical species.
According to the aforementioned experimental results and
previous reports,25−27 we propose a plausible reaction
mechanism. As shown in Figure 2, the disproportionation
reaction of the Cu(II) catalyst generated a Cu(I) species.28
Then species M1 was generated through the coordination of
Cu(I) salt with alkene 1a. A SET process between M1 and
oxime ester 2a would give the oxidized Cu(II)−OBz species
M2 and an iminyl radical M3, which underwent a fast selective
β-C−C bond scission to generate cyanoalkyl radical M4.
Subsequently, the nonstabilized radical species M4 might be
trapped in time by the environmental olefin moiety of M2, and
the resultant carbon radical would recombine rapidly with the
D
Org. Lett. XXXX, XXX, XXX−XXX