Journal of the American Chemical Society
Article
Table 1. Reaction Evaluation for Aryl Methylation
Table 2. Methylation of Aryl Bromides
a
Reactions performed on 0.25 mmol scale with 1,3,5-trimethox-
ybenzene added as an external standard (GC yield). TBACl =
tetrabutylammonium chloride.
a
Reactions performed on 0.1 mmol scale with 1,3,5-trimethoxyben-
zene added as an external standard (GC yield). 0.05 M trimethyl
b
c
orthoformate = 182 equiv. 24 h. n.d. = not determined.
presumably because the weak H−Br bond (BDE = 88 kcal/
mol) renders HAT from bromine radical less favorable.
However, reactivity could be restored by using aryl bromides
in conjunction with an exogenous chloride additive for halide
exchange (Table 2, entries 3 and 6), delivering 24 and 25 in
56% and 52% yield, respectively.
omission of the base, 3 was obtained in 9% yield, suggesting
that HCl formation without sequestration may be deleterious
to reactivity (Table 1, entry 5). All other components of the
reaction were required for productive methylation, as
individual omission of NiCl ·glyme, dtbbpy, photocatalyst,
2
and light source resulted in no product formation and
complete recovery of the aryl chloride (Table 1, entries 6−9).
Substrate Scope. With optimized conditions, we exam-
ined the reaction scope (Figure 3A). Generally, electron-
deficient aryl chlorides underwent methylation in higher yields
than electron-rich aryl substrates, consistent with their relative
reactivity to Ni(0) oxidative addition. Unlike methods that
employ reactive nucleophilic or electrophilic methylating
reagents, a variety of sensitive functionality was well tolerated,
including ketones 3 and 4, nitriles 5 and 6, aldehyde 7, and
ester 8. Ortho-substituted aryl chlorides (5, 11) also delivered
methylated product in moderate to high yield. Methylation of
substrates containing heteroaryl functionality distal to the site
of cross-coupling, including pyridines 13, 16, and 17, furan 14,
and pyrrole 15, could also be achieved. Biologically relevant
aryl chlorides loratadine 19, fenofibrate 20, and zomepirac 21
provided the corresponding methylated product in high yields,
indicating that this method is amenable to late-stage
Next, we sought to explore the scope of heteroaryl chloride
coupling partners (Figure 3B). A variety of nitrogen-, oxygen-,
and sulfur-containing heteroaryl chlorides underwent methyl-
ation in moderate to high yields, including pyridines 26−29,
quinolines 30−34 and 42, quinoxaline 35, quinazoline 41,
pyrimidines 36−37, thiophenes 38 and 39, and thiazole 40.
Importantly, this method for radical methylation enables
functionalization at sites that are not accessible via Minisci-
type reactivity; for example, the 3-, 6-, and 7-positions of
quinolines (32, 33, and 34, respectively) and positions meta to
nitrogen atoms in pyridines (27−29) underwent site-selective
methylation. Biologically relevant heteroaryl chlorides, such as
etoricoxib (43), also underwent methylation in good yield.
The primary byproduct in this methodology is derived from
alkoxymethylation of the aryl chloride. Since this byproduct is
a benzylic ether, a solution that we pursued was subjecting the
reaction to Pd/C hydrogenolysis to convert the byproduct into
methylated product. Select examples of the improvement in
yields afforded by this workup protocol, including for high-
value targets 19 and 20, are shown in Figure 3.
10
functionalization of bioactive compounds. In the methylation
of perphenazine (22), exclusive methylation of the aryl
chloride was observed, in contrast to methods employing
electrophilic methylating reagents that would be expected to
methylate the primary alcohol. Finally, procymidone, which
contains two chemically equivalent aryl chlorides, underwent
selective monomethylation to produce 23 in 55% yield, likely a
result of the sensitivity of the catalytic system to electronic
effects.
Furthermore, our group has previously demonstrated that
acid chlorides can be used as coupling partners in Ni/
3
photoredox-catalyzed C(sp )−H functionalization of alka-
11c
nes.
We recognized that application of the methylation
conditions to acid chloride coupling partners could potentially
deliver a mild synthesis of aliphatic and aromatic methyl
9b
ketones as compared to traditional protocols which rely on
17
Employment of electron-rich aryl chlorides in the nickel/
photoredox cross-coupling reaction delivered low yields of
methylated products, likely due to sluggish oxidative addition
harsh organometallic reagents or strong Lewis acids.
Gratifyingly, we found that application of the optimized
methylation conditions to this substrate class afforded access to
methyl ketones from primary (44), secondary (45), tertiary
(46), and aryl (47) acid chlorides (Figure 3C). The method
was also applicable to acid chlorides prepared from biologically
(
Table 2, entries 1 and 4). To overcome this challenge, we
turned to aryl bromides as substrates, but productive
methylation was not observed from these substrates either,
C
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX