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Chemical Science
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DOI: 10.1039/C7SC00953D
Journal Name
ARTICLE
under visible light followed by C
-
C bond formation (43). In
Table 1. Optimization for allylic alkylation
batch reactors, the reaction was slow, most likely due to the
increased steric hindrance. Disubstituted olefins, including
cyclic (44 to 46) and acyclic alkenes (47), can also participate in
the photoredox alkylation. Notably, despite the high oxidation
potential of cyclopentene (+2.32 V vs SCE in MeCN),17 it
afforded product 44 in a good yield. Overall, the observed
regioselectivity was attributed to both electronic and steric
effects. The most stable allylic radical would be preferentially
formed through deprotonation of the selectively generated
radical cation intermediate, which subsequently underwent
alkylation with its least hindered resonance. To the best of our
knowledge, this study represents the first example of effective
alkylation of allylic sp3
alkenes.4
C-H bonds with electron-deficient
Scope of benzylic compounds
This alkylation protocol was further extended to benzylic
substrates (Scheme 2c). Toluene moieties with electron-
donating substituents were good candidates for the alkylation
(
48 to 52). Electron-neutral and electron-poor arenes reacted
Scope of Michael acceptors for allylic alkylation
much slower than electron-rich arenes because of their
increased oxidative potential (e.g. E1/2tolueneox = +2.36 V vs SCE
in MeCN).17 However, the use of the SFMT reactor could
accelerate the reaction and give satisfactory conversions (53 to
55). Notably, 2-(p-tolyl)pyridine uneventfully afforded its
alkylation product in good yield (56). In addition to toluenes,
ethylbenzene, tetralin, and indane were all suitable candidates
and the reactions proceeded smoothly to give alkylation
products in good to excellent yields (57 to 59). Methyl-
substituted heterocycles such as thiophenes and furans were
alkylated in good yields with the assistance of the SFMT
reactor (60, 61). Incorporation of an alkyl substituent instead
of the aryl substituent in methylene-malononitriles, or
changing of the Michael acceptor to maleic anhydride and
dimethyl maleate, was also feasible (62 to 64). This
photoredox induced allylic/benzylic alkylation therefore
Adopting the optimized batch conditions described in entry 8
(Table 1), we sought to determine the generality of the allylic
alkylation by evaluating various methylene-malononitriles
(Scheme 2ꢀ•X ^{š}‰-(o}Á_ ꢁ}vꢂ]š]}v• ~Çꢀꢃoꢄ íU ꢄvšŒÇ õ• ÁꢄŒꢄ
applied in cases where conversions were low in batch reactors.
Experiments probing the scope of methylene-malononitriles
revealed that a variety of electron-rich (8 to 11) and electron-
deficient arenes (12 to 20) on the Michael acceptor were well
tolerated, even with functional groups such as phenols (11),
aryl halides (12 to 16), and acids (18). Sterically demanding
arenes (21) and heterocycles such as furan (22), thiophene (23),
and benzothiadiazol
(24) were readily accommodated.
Substrates with alkyl instead of aryl substituents on the
methylene-malononitrile participated in this coupling reaction
smoothly (25 and 26). The change of one nitrile group in
malononitrile moiety to ester was feasible (27). However,
other Michael acceptors such as an unsaturated diketone
represents a metal-free, atom-, and redox-economical C
functionalization protocol.
-H
Synthetic utilities of alkylation products
afforded only sluggish reactivity
(28). Interestingly, the
alkylation using the Michael acceptor with a terminal alkene
moiety went smoothly (29). Notably, diene Michael acceptors
can be successfully applied to this transformation to give 1,6-
addition type products (30 and 31).
To further demonstrate the synthetic utility of this
methodology, the alkylations were amenable to scale-up to
gram quantities in both batch reactors and continuous-flow
reactors (Scheme 3a).The resulted alkylation products can be
Scope of allylic compounds
directly transformed to
g
,
d
-unsaturated or
a,b-diaryl acids (66,
67),18 esters (68 69),19 amides (70
,
,
71),20 and lactones (72) in a
convenient manner (Scheme 3b). These building blocks are
We next examined the scope of allylic substrates for this
convenient alkylation reaction. As shown in Scheme 2b, a wide
range of tri-substituted alkenes could be used in this
photoredox process because they were sufficiently electron-
core structures for a variety of drug molecules, such as
23
nafronyl
( ( (78)
76),21 racecadotril 77),22 and DX-9065a
(Scheme 3c), enabling a convenient way to synthesize these
pharmaceutical compounds and their derivatives. The
opportunities to effect synthetic streamline with this general
rich to be oxidized by
4 (32 to 42). Both acyclic and cyclic
olefins were readily accommodated. A series of 2-methyl
arylpropenes provided high alkylation efficiency while
exhibiting good regioselectivity (32 to 37). The use of 2-
methyl-2-pentene led predominantly to the formation of the
branched alkylation product (38) with moderate selectivity.
The regioselectivity with 2-methyl-2-butene (39) was low
compared to that achieved with 2-methyl-2-pentene (38).
C-H reactivity are further illustrated in a facile synthesis of 75
(Scheme 3b), a representative compound of a group of M1
antagonists.24 In addition, the malononitrile moieties can be
directly converted to diaminopyrazoles (73), that are
important intermediates for preparing therapeutically
Remarkably, cyclic substrates bearing alkyl substituents served interesting pyrazolo[1,5-
as excellent allylic coupling partners with excellent
regioselectivity favoring the less hindered cyclic methylene (40
a
]pyrimidines,25 and aminoisoxazoles
26
(
74) with potential hypoglycemic activity.
to 42).16 Tetra-substituted alkenes with unhindered allylic C
-H
bonds could be oxidized effectively using the SFMT reactors
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Zhou, Rong
