ACS Catalysis
Letter
aryl ethers (3d, 3e), terminal alkene (3g), chloride (3f), cyano-
(3h), and ketone (3i), have proven to be capable substrates for
this coupling reaction. Interestingly, compound 3j having silicon
atom beta to imine could also be synthesized via this protocol.
This is a particularly surprising finding, considering silyl methyl
radicals are more electrophilic compared with simple alkyl
radicals.18 Notably, β-D-ribofuranoside derivative 3k, as well as
dipeptide derivative 3l, could be accessed via this approach, thus
indicating the applicability of this method to functionalization
reactions in a more complex setting. Secondary alkyl halides
were found to be the most effective coupling partners. Thus,
oximes possessing acyclic substituents (3m, 3n), could be
obtained in good yields. Oximes having varied size carbocycles
(3o−3s) could also be efficiently synthesized. Oxime,
possessing secondary adamantyl derivative (3t), was obtained
in nearly quantitative yield. Saturated heterocyclic derivatives,
such as oxetane (3u), tetrahydropyran (3v), and piperidine
(3w), were also successfully obtained. Intriguingly, this reaction
exhibited a notable halide effect (3p, 3q). While efficiencies of
processes for alkyl bromides and iodides were comparable, the use of
iodides resulted in products with substantially higher Z isomer
content. This counterion effect was observed throughout the
entire scope of the reaction, where alkyl iodides in general
resulted in products with higher amount of Z oxime. Tertiary
alkyl halides 3x−3ab are also capable coupling partners. In the
reaction with tert-adamantyl iodide, however, a substantial
amount of nonseparable Friedel−Crafts arylation side product
was observed. Accordingly, the product in reduced form (3ac)
was isolated. A simple tert-butyl derivative 3x was obtained in
good yield from both respective iodide and bromide. As in the
cases of primary and secondary alkyl halides, the reaction gave a
mixture of E/Z isomers. In this case, however, it is particularly
surprising, as Z isomer containing bulky tertiary substituent is
thermodynamically much less favorable. On the other hand,
cyclobutene-containing product 3ab formed with almost
exclusive E selectivity.
Next, the scope of oxime in reaction with cyclohexyl bromide
was tested. First, benzylic formaldoximes possessing different
functional groups at the aryl group were examined. Overall, the
process demonstrated outstanding efficiencies for these
substrates (4a−4f). Notably, styrene derivative 4g could be
synthesized in an excellent yield, despite a potential side addition
of the alkyl radical at the double bond leading to a highly
stabilized benzylic radical.13,14 Linear molecules possessing
various distant functionalities, such as phenyl (4h), ester (4i),
cyano- (4j), and protected primary amine (4k), all worked well.
Synthesis of formaldoximes bearing secondary alkoxy groups
posed no problem either (4l, 4m). Gratifyingly, imines 4n and
4o having easily removable trimethylsilylethoxymethyl (SEM)
and benzyloxymethyl (BOM) groups were synthesized with
moderate to good yields, which opens access to O-unprotected
oximes. At this point, attempts to perform this imine-Heck
reaction on aldoximes resulted in reductive radical additions
only. Obviously, the presence of additional substituent hampers
the reoxidation of amine into imine.
Scheme 2. Synthetic Utility of Obtained Products
Scheme 3. Impact of Base and Halide on E/Z Selectivity
of substituted oximes 3 operating via a direct C−H Heck-type
alkylation protocol (Scheme 1c).
In recent years, the visible light-induced photoexcited
chemistry of palladium has become an emerging field of
study.12 Particularly, we13 and others14 have demonstrated the
feasibility of the visible light-induced palladium-catalyzed alkyl-
Heck reaction of a broad range of alkyl electrophiles proceeding
via hybrid palladium C(sp3)-centered radical species. Encour-
aged by this novel mild protocol for generation of alkyl
radicals13,14 and motivated by the need of new synthetic
methods toward substituted oximes,7 we aimed at the
development of alkyl imino-Heck reaction. The feasibility of
this transformation was supported by the effectiveness for
generation of nucleophilic alkyl radicals under light-induced Pd-
catalyzed conditions;12 the affinity of oximes toward nucleo-
philic alkyl radicals;15 and the propensity of palladium catalysis
for the oxidative end-game.16
Toward this end, we investigated the reaction between
formaldoxime (1) and iodocyclohexane (2) under our standard
palladium(II) acetate/Xantphos catalytic system13 in the
presence of indium(III) chloride additive. Gratifyingly, it was
found that under these conditions, the desired coupling product 3
was formed, albeit in moderate yield (Table 1, entry 1). The
combination of monodentate and bidentate phosphine ligands17
resulted in a significant improvement of the reaction efficiency
(entry 2). Further optimization revealed indium(III) acetate to
be a superior additive with high reproducibility (entry 3).
Control experiments demonstrated that thermal reaction (entry
4) is much less efficient and Pd catalyst is essential for this
transformation (entry 5). Notably, this reaction can proceed
without Lewis acid additive, however with lower reproducibility
(entry 6).
As discussed in the introduction, oximes enjoy vast synthetic
applications.7,8 There is a number of reported protocols
highlighting transformations of oximes 3 obtained via our alkyl
Heck-type alkylation protocol and its derivatives (Scheme 2).
Primarily, these feature the construction of different nitrogen
containing heterocycles 8−10.19 Diverse additions to electro-
philic carbon of oxime are also well-established (11, 12).20 We
have also found that 3 could undergo partial (6) or exhaustive
With the optimized conditions in hand, the scope of alkyl
halides was examined first (Scheme 4). It was found that all
linear alkyl halides tested, including those having distant
functional groups, such as phenyl (3b), ester (3c), alkyl and
3750
ACS Catal. 2021, 11, 3749−3754
Kvasovs, Nikita
