Organic Letters
Letter
the indoles with halogen substituents (including F−, Cl−, Br−)
all showed high reactivity, achieving 92−95% yields for 6g−m
without dehalogenated byproducts being detected. 7-Azoindole
(5n) also displayed high reactivity, giving 6n in a yield of 91%.
To explore the possible reaction mechanism, some control
experiments and deuterium-labeling experiments were per-
formed. For the methylation of acetophenone, 2-methyl-1-
phenylprop-2-en-1-one (VI in Scheme 2) was reported to be a
possible intermediate.5c In this work, using VI as the substrate,
nearly quantitative yield of isobutyrophenone (2a) was
obtained in the presence of Co(BF4)2·6H2O/PP3 with or
without K2CO3 (Scheme S3a). Hence, it suggested that the
base was only needed for the formation of VI from
acetophenone and played no role in the subsequent hydro-
1a occurred in the presence of Co(BF4)2·6H2O/PP3/K2CO3 in
CD3OD (Scheme S3b), giving hexa- and heptadeuterium-
substituted products 2a, which indicated that the C−H bond at
the α-position of the substrate broke during the reaction
process and the methyl group was surely supplied by methanol.
In addition, the formation of the new C−H/D bond at the α-
position (1a) was through hydrogen transfer from cobalt-
hydride intermediate, which went through H/D exchange with
byproduct H2O during the reaction process. This was further
verified by the methylation reaction of 1a with CH3OD under
otherwise identical reaction conditions, in which unsubstituted
and mono-, di-, and trideuterium-substituted products 2a were
obtained (Scheme S3c). When propiophenone was utilized as
the substrate, monomethylated product was formed. Hence, tri-
and tetradeuterium substituted products 2a were formed with
CD3OD as the solvent (Scheme S3d), while unsubstituted and
mono- and dideuterium-substituted products 2a were detected
in the presence of CH3OD (Scheme S3e). This was consistent
with the proposed reaction process involving 2-methyl-1-
phenylprop-2-en-1-one (VI in Scheme 2) formation, mono-
hydride transfer, and H/D exchange between methanol and the
byproduct H2O.
Taking the methylation of propiophenone using methanol as
an example, a possible reaction pathway was proposed on the
basis of the above results, as illustrated in Scheme 2. First, in
the presence of the base, the Co salt coordinated with PP3 to
yield complex (I), and a Co−methoxy complex (II) was further
formed in methanol, which then transformed into the Co−
hydride (III) intermediate through β-hydride abstraction,
releasing formaldehyde. For the substrate propiophenone, a
nucleophilic carbon anion (IV) was formed in the presence of
the base (K2CO3), which then attacked formaldehyde to
generate alcohol intermediate (V). Intermediate VI was then
formed through a dehydration reaction, which further
coordinated with Co−hydride (III) to produce intermediate
VII. Finally, methylated product 2a was produced through
hydrogen transfer from methanol and recoordination of Co
complex with methoxide.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
Experimental details, Schemes S1−S3, Table S1, as well
as isolation and characterization of the products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
ORCID
Author Contributions
∥Z.L. and Z.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(Nos. 21673256, 21402208, 21403252, and 21503239).
■
REFERENCES
■
(1) (a) Yang, Y.; Lan, J.; You, J. Chem. Rev. 2017, 117, 8787−8863.
(b) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117, 9247−9301.
(c) Kim, D. S.; Park, W. J.; Jun, C. H. Chem. Rev. 2017, 117, 8977−
9015. (d) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; Dong, G. Chem.
Rev. 2017, 117, 9333. (e) Hummel, J. R.; Boerth, J. A.; Ellman, J. A.
Chem. Rev. 2017, 117, 9163−9227.
(2) Desnoyer, A. N.; Love, J. A. Chem. Soc. Rev. 2017, 46, 197−238.
(3) (a) Thrimurtulu, N.; Nallagonda, R.; Volla, C. M. R. Chem.
Commun. 2017, 53, 1872−1875. (b) Nakanowatari, S.; Mei, R.; Feldt,
M.; Ackermann, L. ACS Catal. 2017, 7, 2511−2515. (c) Wang, H.;
Lorion, M. M.; Ackermann, L. Angew. Chem., Int. Ed. 2016, 55,
10386−10390.
(4) (a) Beller, M.; Rajenahally, J.; Natte, K.; Neumann, H. Angew.
Chem., Int. Ed. 2017, 56, 6384−6394. (b) Obora, Y. ACS Catal. 2014,
4, 3972−3981. (c) Li, Y.; Cui, X.; Dong, K.; Junge, K.; Beller, M. ACS
Catal. 2017, 7, 1077−1086. (d) Zhu, N.; Zhao, J.; Bao, H. Chem. Sci.
2017, 8, 2081−2085.
(5) (a) Shen, D.; Poole, D. L.; Shotton, C. C.; Kornahrens, A. F.;
Healy, M. P.; Donohoe, T. J. Angew. Chem., Int. Ed. 2015, 54, 1642−
1645. (b) Ogawa, S.; Obora, Y. Chem. Commun. 2014, 50, 2491−2493.
(c) Chan, L. K. M.; Poole, D. L.; Shen, D.; Healy, M. P.; Donohoe, T.
J. Angew. Chem., Int. Ed. 2014, 53, 761−765. (d) Quan, X.; Kerdphon,
S.; Andersson, P. G. Chem. - Eur. J. 2015, 21, 3576−3579. (e) Dang, T.
T.; Seayad, A. M. Adv. Synth. Catal. 2016, 358, 3373−3380.
(6) (a) Kang, B.; Hong, S. H. Adv. Synth. Catal. 2015, 357, 834−840.
(b) Dang, T. T.; Ramalingam, B.; Seayad, A. M. ACS Catal. 2015, 5,
4082−4088. (c) Kim, S. H.; Hong, S. H. Org. Lett. 2016, 18, 212−215.
(d) Li, F.; Lu, L.; Liu, P. Org. Lett. 2016, 18, 2580−2583.
(e) Neumann, J.; Elangovan, S.; Spannenberg, A.; Junge, K.; Beller,
M. Chem. - Eur. J. 2017, 23, 5410−5413.
(7) Kim, S.; Hong, S. H. Adv. Synth. Catal. 2017, 359, 798−810.
(8) Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011,
̈
111, 5215−5246.
In summary, a readily available and highly efficient cobalt-
based catalytic system was developed for the methylation of the
C(sp3)−H bond in aryl alkyl ketones/aryl acetonitriles, as well
as C(sp2)−H bond in indoles using methanol, and various
kinds of methylated products were obtained in good to
excellent yields. This type of Co-based catalytic system may
find promising applications in methylation.
(9) Li, Y.; Yan, T.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2014,
53, 10476−10480.
D
Org. Lett. XXXX, XXX, XXX−XXX