Nickel-catalyzed methylation of aryl halides/tosylates with methyl tosylate

Article abstract of DOI:10.1039/c7cc06106d

This work describes the cross-electrophile methylation of aryl bromides and aryl tosylates with methyl tosylate. The mild reaction conditions allow effective methylation of a wide set of heteroaryl electrophiles and dimethylation of dibromoarenes.

Full text of DOI:10.1039/c7cc06106d

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Nickel-Catalyzed Methylation of Aryl Halides/Tosylates with
Methyl Tosylate
Jiawang Wang,† Jianhong Zhao‡,* and Hegui Gong†,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
not provide the methylation products under the equivalent
conditions, possibly due to rapid dimerization or formation of Me–
ZnI.7 Given the importance of methylarene scaffolds, development
of an efficient coupling strategy enabling methylation of aryl
electrophiles with methyl tosylate is appealing, although an in situ
Negishi protocol has been developed recently using MeI as the
methylation reagent.10 In particular, phenolic analogs are
ubiquitous in natural and medicinal products. They can be readily
converted into aryl tosylates.11 Effective methylation of tosylated
phenolic compounds via cross-electrophile protocols may facilitate
structural proliferation of natural products, which is advantageous
over the aryl halide counterparts. The latter often requires extra
steps converting from the phenolic precursors. To our surprise,
utilization of Ni-catalyzed protocols for alkylation of aryl tosylates
and mesylates are exceptionally rare even with the conventional
electrophile/nucleophile coupling strategies.12,13
This work describes cross-electrophile methylation of aryl
bromides and tosylates with methyl tosylate. The mild reaction
conditions allows effective methylation of a wide set of heteroaryl
electrophiles, and dimethylation of dibromoarenes.
Molecules bearing methyl groups widely exist in medicine and
materials.1 For instance, the commercial drugs Nexium and Gleevec
both contain methyl groups on the aromatic rings (Figure 1). In
many cases, introduction of a methyl group to aryl moieties can
significantly alter the biological activities of the parent compounds.2
Among the known methylation protocols,3-5 C–H and C–O bond
activation/methylation is of particularly notice due to atom
economy and synthetic challegnes.4–5 The asymmetric introduction
of a methyl group to alkyl groups should also be noted.6
Herein, we report the assembly of aryl halides and tosylates with
readily accessible methyl tosylate to give methylarenes under Ni-
catalyzed reductive conditions. The reaction accommodates a wide
arrange of functional groups, and broad substrate scope including
heteroaromatics. More importantly, di-methylation effectively
operates even for neighboring aryl dihalides.
nexium
Gleevec
N
Me
HN
N
N
N
O
S
H
N
Me
OMe
Me
N
O
N
MeO
previous work:
R1
N
R1
R2
Ni (cat)/ligand
Me
Br
+
+
MeOTs
1.5 equiv
(Bpin)2, MeOLi, NMP
Figure 1. Structures of Nexium and Gleevec
Recently, we disclosed Ni-catalyzed reductive methylation
strategy that allowed effective installation of methyl groups to
sterically more congested alkyl halides as well as acid chlorides to
afford methylated alkanes and ketones, respectively (Scheme 1).7,8
The use of methyl tosylate proved to be critical probably due to
slow generation of methyl halides.7,9 In contrast, methyl iodide did
R2
X = Br, I
a
this work:
Me
X
Ni (cat)/ligand
Zn, TBAI, DMA
MeOTs
2 equiv
R
Het
R
Het
X = OTs, Br
Scheme 1. Ni-catalyzed cross-electrophile coupling of methyl
tosylate.
We commenced our studies with the reaction of 1-(benzyloxy)-4-
bromobenzene and 2 equiv of MeOTs. The optimal reaction
conditions comprising a combination of NiI2/L1a/MgCl2/TBAI/Zn in
DMA delivered the methylation product 2 in 93% yield (method A,
Table 1, entry 1). Use of 1.5 equiv of MeOTs resulted in a decrease
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of the yield (entry 2). Alternation of the nickel sources and ligands in 12 and 13. Aryl bromides decorated with para-vinyl and Bpin
did not result in appreciable improvement (entries 3–10). Without
TBAI or MgCl2, the reaction yield diminished drastically (entries 11–
13). Both Zn and DMA were necessary (entries 14–17). Poor result
was obtained when the conditions used in Figure 4 were tested
(entry 18).
furnished the product 15 and 16 in good yields. Methylation of
naphthyl bromides effectively delivered 8 and 17. The methylation
protocol is also applicable to dimehylation of aryl dibromides. By
doubling the catalyst loading, the dimethyl arenes 17–19 were
obtained in moderate to excellent yields. Finally cross-electrophile
methylation of heteroaromatic halides were examined. By using of
10 mol% of nickel catalyst loading, quinone, thiophene, indole and
pyrimidine were suited for methylation, as evident in 20–25.
Table 1. Optimization for the coupling between methyl 4-
bromobenzoate with methyl tosylate.
entrya
variation from the "standard
conditions"
yieldb
1
none
93%c
82%
NDd
72%
80%
85
NDd
56%
NDd
NDd
59%
44%
NDd
69%
NDd
NDd
83%
37%
2
1.5 equiv of TsOMe
without NiI2
3
4
Ni(COD)2 instead of NiI2
L1b instead of L1a
L1c instead of L1a
L2 instead of L1a
L3 instead of L1a
L4 instead of L1a
Without L1a
5
6
7
8
9
10
11
12
13
14
15
16
17
18
NaI instead of TBAI
Without TBAI
without MgCl2
Mn instead of Zn
Without Zn
THF instead of DMA
NMP instead of DMA
NiCl2·glyme(10 mol%) instead of NiI2,
dppf (20 mol%) instead of L1a
a Reaction conditions: 1 (0.30 mmol), methyl tosylate (2 equiv), Ni (5
mol %), ligand (7 mol %), TBAI (100 mol %), Zn (2 equiv), DMA ( 1 mL).
b NMR yield using 2,5-dimethylfuran as the internal reference. c
Isolated yields. d Not detected by 1H NMR.
Figure 3. a Standard reaction conditions as in Table 1, entry 1. b NiI2
(20 mol%) , L1a (30 mol%), 5 equiv of MeOTs and 1.5 mL of DMA
c
were used. NiI2 (10 mol%), L1a (15 mol%) and 2 equiv of MeOTs
were used.
Figure 2. Structures of ligands
Due to the abundance of phenolic compounds in nature, and the
challenges of using aryl tosylates as the coupling partners,
extension of the standard methylation method A (Table 1, entry 1)
to 4-(benzyloxy)phenyl 4-methylbenzenesulfonate was carried out
(Table S2, entry 19).14 Only 40% yield was obtained for 2. However,
use of NiCl2·glyme and dppf with LiCl as an additive could promote
the yield to 75% (Figure 4). The reaction was suited for aryl
tosylates bearing electron-withdrawing groups, thus affording 3 in
The optimized reaction conditions were suited for a wide array of
substrates (Figure 3). Both electron-withdrawing and –donating
groups were compatible, as evident in the products 3–16. Good and
excellent yields were obtained for meta-methyl acetophenone and
ortho-methyl benzoates
4 and 5, respectively. The reactions
tolerated sensitive functional groups such as amides as manifested
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(tosyloxy)benzoate with method B gave such a ratio in 4:5 (eq 3). It
is reasonably to conclude that an in situ Negishi process is
disfavoured for the methylation of aryl halides with method A.
However, it is not clear whether a Negishi mechanism predominate
the methylation of aryl tosylate using method B.
73% yield. The generality of this method was also testified by the
examples in Figure 4. Of note is the efficient methylation of
sterically congested 2,6-dimethylphenyl tosylate affording 27 in
good yield. The methylation method B was also applicable to aryl
mesylate (Table S2, entries 20),14 whereas a low yield was delivered
for nathyl pivalate (Table S3, entries 17).14
+ MeOTs
X
R
(2.0 equiv)
standard method
(3)
+ CD3ZnI
(2.0 equiv)
MeO2C
X= Br, OTs
MeO2C
R = CH3 or CD3
X = Br: CH3/CD3 = 46:1, yield 47%
X = OTs: CH3/CD3 = 4:5, yield 90%
The coupling of complex (A) with methyl iodide in the presence of
MgCl2 furnished the methyl product 2 in 26% yield (eq 4). Although
lack of direct evidence, this result is seemingly consistent with a
radical chain mechanism proposal, wherein addition of methyl
radical to complex (A) leads to Ar-NiIII(Ln)-Me.15
In summary, we have developed
a mild cross-electrophile
Figure 4. a the reaction mixture was allowed to stir at 25 oC for 12 h,
PPh3 (20 mol%) instead of dppf, and MgCl2 (150 mol%) instead of
LiCl.
coupling method that allows effective methylation of aryl halides
and tosylates by using methyl tosylate as the methylation reagent.
A wide set of aryl and heteroaryl electrophiles are compatible. In
particular, the use of naturally abundant phenolic derivatives
render this method more practical, which avoids use of halides as
the substrates.
We also examined the methylation method in the presence of acid
group, and obtained the product 33 in 60% yield, indicating that the
methylation method A tolerates acidic conditions (eq 1)
Acknowledgement
Financial support was provided by the Chinese NSF (Nos.
21372151 and 21572127), Shanghai Municipal Education
Commission for the Peak Discipline Construction (N.13-A302-15-
L02). We thank Dr. Hongmei Deng (Shanghai Univ.) for use of the
NMR facility.
To gain insight into the reaction details, we performed the coupling
reaction using MeI in lieu of MeOTs under both conditions A and B,
and delivered the methyl product 2 in 40% and 36% yield,
respectively (eq 2). These outcomes indicated that in situ
conversion of methyl tosylate to methyl halides may be crucial for
effective methylation, wherein low concentrations of methyl
halides may disfavor the competitive formation of ethane and/or
MeZnX. The coupling of equimolar CD3ZnI and MeOTs with methyl
4-bromobenzoate using method A delivered the methyl and CD3
products in a ratio of 46:1, whereas the use of methyl 4-
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