Nickel and Nucleophilic Cobalt-Catalyzed Trideuteriomethylation of Aryl Halides Using Trideuteriomethyl p-Toluenesulfonate

Article abstract of DOI:10.1021/acs.orglett.8b01863

Herein, a novel approach for the trideuteriomethylation of aryl halides using nickel and nucleophilic cobalt catalysts and the readily available trideuteriomethyl p-toluenesulfonate (CD₃OTs) is described. This method provides access to a wide r

Full text of DOI:10.1021/acs.orglett.8b01863

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel and Nucleophilic Cobalt-Catalyzed Trideuteriomethylation of
Aryl Halides Using Trideuteriomethyl p‑Toluenesulfonate
Kimihiro Komeyama,* Yuta Yamahata, and Itaru Osaka
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Higashi-Hiroshima City 739-8527, Japan
S
* Supporting Information
ABSTRACT: Herein, a novel approach for the trideuteriomethylation of aryl halides using nickel and nucleophilic cobalt
catalysts and the readily available trideuteriomethyl p-toluenesulfonate (CD3OTs) is described. This method provides access to
a wide range of CD3-containing arenes. Moreover, a transmethylation step is revealed as crucial in the nickel/cobalt catalytic
mechanism.
ethylation is one of the most widely recognized
strategies for the structural modification of bioactive
hydrogen atom by a deuterium atom at metabolically labile
positions can significantly improve the metabolic stability of
the compounds. Indeed, some trideuteriomethyl (CD3)-
containing medicines have proved to be of vital importance
owing to their enhanced biological potency, thereby reducing
the formation of toxic metabolites.7
While significant advances have been made in the develop-
ment of protocols for the installation of a methyl group into
aromatic rings, analogous methods for the introduction of a
CD3 group remain scarce (Scheme 1). Hydrogen−deuterium
M
compounds. The introduction of a methyl group, which is the
smallest organic substituent, into organic skeletons can induce
their metabolic stabilization.1 Thus, for example, in the
selective cyclooxygenase-2 (COX-2) inhibitors celecoxib 1
and meloxicam 2,2 the methyl group protects the aromatic ring
against metabolic oxidation,3 which would otherwise lead to
the corresponding alcohol and carboxylic acid through
oxidation of the benzylic C−H bonds. This oxidation is
known to cause a decrease in the metabolic stability.4 In
contrast, fluorinated substituents such as F and CF3, which are
considered to be bioisosteric to the methyl group, are also used
in medicinal chemistry to improve the stability of compounds.
In the context of metabolic stability, while a rapid metabolism
has the obvious disadvantage of providing a short duration of
bioactivity, a long half-life may lead to drug accumulation in
tissues, with concomitant side effects.1a Therefore, the
development of alternative protocols that ensure an adequate
metabolic stability has been desired in the field of drug
discovery.
Scheme 1. Synthetic Routes for Trideuteriomethylated
Arenes
exchange in methylated arenes is one of the ideal approaches
(Scheme 1, route 1).8 However, owing to the difficult site-
selective labeling at the methyl group connected to multi-
functionalized arenes, this method is restricted to acidic methyl
C−H bonds coupled with heteroarenes.8j,l,m Also limited to
heteroarenes is the Minisci-type radical addition depicted in
Deuterium-labeled compounds have attracted much atten-
tion for the preparation of new chemical entities and the
development of improved drugs.5 Thus, as the carbon−
deuterium (C−D) bonds are stronger than the more common
carbon−hydrogen (C−H) bonds,6 the replacement of a
Received: June 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01863
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Scheme 1 (route 2).9 Conversely, methylated arenes are
conventionally prepared via transition metal-catalyzed cross-
coupling between aryl halides and methyl metal reagents
(Scheme 1, route 3), such as Me-[Mg],10a−c -[Li],10d -[B],10e
-[Zn],10f,g or -[Al];10h however, their applications to
trideuteriomethylation are restricted to a few examples10d,11
due to the low availability and high cost of CD3 metal sources.
Considering such economical and synthetic aspects, Liao
recently developed a Barbier-type Negishi cross-coupling of
aryl halides with CD3−[Zn] reagents generated in situ from
CD3I and zinc powder.12 Recently, a nickel and vitamin B12-
catalyzed Csp2−Csp3 reductive cross-coupling between aryl
halides and alkyl sulfonates has been disclosed by Weix13 and
our group.14 In the transformation, alkyl sulfonates are
converted to alkyl radicals via the homolytic reductive cleavage
of the corresponding alkyl−[Co(III)] intermediate, which
stems from the substitution of the alkyl sulfonates with a
nucleophilic cobalt complex. Herein, we wish to describe an
efficient and mild trideuteriomethylation of aryl halides using
nickel and nucleophilic cobalt catalysts (Scheme 1, route 4),
wherein the choice of the nucleophilic cobalt species was key
to the success of the reaction. This method demonstrated high
catalytic performance and broad substrate scope, offering a
new synthetic approach for a diverse set of CD3-arenes
obtained from CD3OTs to act as an abundant CD3 source.
As the origin of our investigation, we explored suitable
reaction conditions, especially cobalt catalysts, for the
trideuteriomethylation of 4-phenyl-1-iodobenzene (1a) with
CD3OTs (2a) as a model substrate combination (Scheme 2).
nucleophilicity of square-planar [Co(I)] complexes. Thus, the
axial coordination raises the energy of the filling dz2 orbital of
[Co(I)], and the cobalt center becomes a strong nucleophile.15
Furthermore, the stability of the generated alkyl−[Co(III)]
species toward the homolytic reductive cleavage could also be
influenced by the ligand.15b In this regard, we speculated that
the low productivity might be attributed to the rapid formation
and cleavage of the D3C−[Co(III)] bond. Therefore, we set
out to explore other square-planar cobalt catalysts without axial
ligands. Consequently, we found to our delight that simple and
commercially available [Co(II)] complexes improved the
product yield. Among them, Co(salen) (R = H) was the
most effective, affording 3a in 77% yield. A slight improvement
of the yield up to 82% was further achieved by adding 1 equiv
of KI. None or a negligible amount of the desired product 3a
was detected in control experiments in the absence of the
nickel and cobalt catalysts. Additionally, we have confirmed
that no hydrogen−deuterium exchange reaction of C−H
bonds, which substrates have in advance, did not occur at all.
With the optimized reaction conditions in hand, we next
explored the scope of aryl halides in the Ni/Co-catalyzed
trideuteriomethylation, as summarized in Scheme 3. We
observed that aryl halides possessing electron-donating and
-withdrawing substituents at the para or ortho positions were
well tolerated, affording the CD3-containing products in good
yields. Furthermore, we found that the trideuteriomethylation
of 1e successfully proceeded on a gram scale (1.01 g, 3e).
However, when the strongly electron-deficient aryl iodides
corresponding to 1g and 1j were used, their homocoupling
products were exclusively formed, presumably due to their high
reactivity toward the oxidative addition. In contrast, the
trideuteriomethylated products 3g and 3j, which are key
precursors for the synthesis of deuterium-labeled drugs such as
celecoxib16 and orphenadrine,17 respectively, were obtained by
replacing the aryl iodides with the corresponding bromides or
chlorides. Furthermore, the transformation was also applicable
to heteroaryl halides. Thus, CD3-containing indole 3n and
quinoline 3o were obtained in good yields. Moreover, the
method was active not only for CD3-installation but also for
methylation, affording the corresponding methylated products
4−7 in satisfactory yields.
Scheme 2. Effect of Cobalts in the Ni/Co-Catalyzed
Trideuteriomethylation of 4-Phenyl Iodobenzene (1a) with
CD3OTs 2a
The relevance of the slow generation of MeI from MeOTs
upon addition of iodide in the nickel-catalyzed reductive cross-
coupling was previously discussed by Gong.18 We decided to
investigate the reaction of CD3OTs with metal salts such as the
KI additive or the generated MnI2 in our reaction. Although
the accurate role of the KI additive is not clear at present,19 2H
NMR monitoring of the reaction of CD3OTs with KI (or
MnI2) indicated that CD3I was quickly generated, and the
halogen−pseudohalogen exchange concluded within only 30
min (see the Supporting Information). Therefore, the
formation of CD3I would occur in the presence of KI as the
initial step. However, the results shown in Scheme 1 imply that
the reaction strongly depended on the presence and nature of
the cobalt catalysts rather than on the addition of KI.
Additionally, the methylation of aryl triflate 1p with
CD3OTs afforded the corresponding trideuteriomethylated
product 3p (67% yield), even in the presence of 20 mol % of
Et4NI (Scheme 4, eq 1), wherein only a catalytic amount of
CD3I should have been formed. Furthermore, we observed that
the single nickel catalyst produced a negligible amount of
product 4 (4%) in the reaction of aryl iodide 1e with 2b
(Scheme 4, eq 2), whereas the nickel/cobalt combination
When 1a was treated with 2a (1.5 equiv) in the presence of
NiBr2bpy (10 mol %), vitamin B12 (10 mol %), and Mn
powder (2.0 equiv) at 30 °C for 24 h, surprisingly, no
formation of the desired product 3a was observed. Notably,
although 2a was wholly consumed, most of the iodide 1a
remained unchanged after the reaction. In addition, the use of
cobaloxim CoCl(dmgH)2(py) instead of vitamin B12 provided
similar results. Generally, the axial ligand is known to affect the
B
DOI: 10.1021/acs.orglett.8b01863
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Scheme 3. Ni/Co(salen)-Catalyzed Trifluoromethylation
and Methylation of Aryl Halides
Scheme 4. Methylation of the Aryl Iodide 1e with MeI Both
in the Presence and Absence of Co(salen)
a
Scheme 5. Plausible Reaction Mechanism
a
(a) 7.0 mmol of 1e was used; reaction time 30 h. (b)Et4NI (20 mol
%) was used instead of KI (1.0 equiv). (c) NiCl2(6,6′-Me2bpy) was
used instead of NiBr2bpy.
which would then be reduced by Mn to regenerate the [Ni(0)]
species.
afforded 54% of 4. These results add support to the important
role of the nucleophilic cobalt in the present cross-coupling
reaction.
A related transmethylation of Me−[Co(III)] with [Ni(I)]
had been previously demonstrated,20 wherein the nickel acts as
one electron reductant for Me−[Co(III)] to form Me−
[Co(II)], and a homolytic cleavage follows, providing Me−
[Ni(II)] species via a radical mechanism. Inspired by this
study, we conducted the stoichiometric reaction of aryl iodide
1e with Me−Co(III)(salen)(H2O) in the presence of
NiBr2bpy and Mn reductant, which afforded the methylated
product 4 in 22% yield (Scheme 4, eq 3). However, no product
was obtained when using a catalytic amount of nickel (10 mol
%). On the basis of these results, the controllable trans-
metalation between the Me-Co(salen) and nickel species
seems to be key to the present efficient methylation, most
likely due to the weakening of the Co−C bond prompted by
the axial ligand.15b
On the basis of these experimental results, we envisaged the
catalytic cycle illustrated in Scheme 5 for the Ni/Co(salen)-
catalyzed trideuteriomethylation and methylation of aryl
halides. First, two active catalysts, [Ni(0)] and [Co(I)] D,
would be initially generated from the reaction of [Ni(II)] and
[Co(II)] with the Mn reductant. The oxidative addition of aryl
halides 1 to [Ni(0)] and its subsequent reduction would
provide Ar−[Ni(I)] intermediate B. On the other hand, the
substitution of methyl electrophiles R−X 2 with the in situ
generated nucleophilic [Co(I)] D would afford R−[Co(III)]
E. Transmethylation between B and E through a single
electron transfer (SET) process would produce the high-valent
Ar−[Ni(III)X]−R nickel(III) species C and regenerate the
nucleophilic [Co(I)] D. The reductive elimination of C would
result in the formation of methylated arenes 3 and [Ni(I)]−X,
In conclusion, we have developed a nickel and nucleophilic
cobalt-catalyzed reductive cross-coupling between aryl halides
and CD3OTs, affording a diverse set of CD3-arenes. The
C
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(g) Erdogan, G. L.; Grotjahn, D. B. J. J. Am. Chem. Soc. 2009, 131,
10354. (h) Fujiwara, Y.; Iwata, H.; Sawama, Y.; Monguchi, Y.; Sajiki,
H. Chem. Commun. 2010, 46, 4977. (i) Sawama, Y.; Monguchi, Y.;
choice of the cobalt catalyst was found to be crucial to the
reaction efficiency, with Co(salen) exhibiting the highest
performance. Although the accurate role of the cobalt is still to
be clarified, some mechanistic investigations revealed that the
present reaction involved a transmethylation between organo-
nickel and methyl cobalt intermediates. Further studies on the
mechanism and synthetic applications of the Ni/Co catalytic
system are currently ongoing in our group.
̈
Sajiki, H. Synlett 2012, 23, 959. (j) Neubert, L.; Michalik, D.; Bahn,
S.; Imm, S.; Neumann, H.; Atzrodt, J.; Derdau, V.; Holla, W.; Beller,
M. J. J. Am. Chem. Soc. 2012, 134, 12239. (k) Ma, S.; Villa, G.; Thuy-
Boun, P. S.; Homs, A.; Yu, J.-Q. Angew. Chem., Int. Ed. 2014, 53, 734.
̈
(l) Neranon, K.; Ramstrom, O. RSC Adv. 2015, 5, 2684. (m) Kerr, W.
J.; Reid, M.; Tuttle, T. ACS Catal. 2015, 5, 402. (n) Kim, S.; Han, S.;
Park, J.; Sharma, S.; Mishra, N. K.; Oh, H.; Kwak, J. H.; Kim, I. S.
Chem. Commun. 2017, 53, 3006. (o) Liu, M.; Chen, X.; Chen, T.; Yin,
S.-F. Org. Biomol. Chem. 2017, 15, 2507.
ASSOCIATED CONTENT
* Supporting Information
■
S
(9) (a) Gui, J.; Zhou, Q.; Pan, C.-M.; Yabe, Y.; Burns, A. C.; Collins,
M. R.; Ornelas, M. A.; Ishihara, Y.; Baran, P. S. J. J. Am. Chem. Soc.
2014, 136, 4853. (b) Jin, J.; MacMillan, D. W. C. Nature 2015, 525,
87.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01863.
(10) Methylation of aryl halides with Me-[Mg]: (a) Tamao, K.;
Kodama, S.; Nakajima, I.; Kumada, M.; Minato, A.; Suzuki, K.
Experimental procedure and spectroscopic data (PDF)
Tetrahedron 1982, 38, 3347. (b) Sun, C. L.; Furstner, A. Angew.
̈
AUTHOR INFORMATION
Chem., Int. Ed. 2013, 52, 13071. (c) Agrawal, T.; Cook, S. P. Org. Lett.
2014, 16, 5080 with Me-[Li]:. (d) Heijnen, D.; Tosi, F.; Vila, C.;
Stuart, M. C. A.; Elsinga, P. H.; Szymanski, W.; Feringa, B. L. Angew.
Chem., Int. Ed. 2017, 56, 3354 with Me-[B]:. (e) Gray, M.; Andrews,
I. P.; Hook, D. F.; Kitteringham, J.; Voyle, M. Tetrahedron Lett. 2000,
41, 6237 with Me-[Zn]:. (f) Herbert, J. M. Tetrahedron Lett. 2004, 45,
817. (g) Wang, T.; Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629
with Me-[Al]:. (h) Cooper, T.; Novak, A.; Humphreys, L. D.; Walker,
M. D.; Woodward, S. Adv. Synth. Catal. 2006, 348, 686.
■
Corresponding Author
*E-mail: kkome@hiroshima-u.ac.jp.
ORCID
Kimihiro Komeyama: 0000-0001-7111-2112
Itaru Osaka: 0000-0002-9879-2098
Notes
(11) (a) Qian, B.; Xie, P.; Xie, Y.; Huang, H. Org. Lett. 2011, 13,
2580. (b) Falb, E.; Ulanenko, K.; Tor, A.; Gottesfeld, R.; Weitman,
M.; Afri, M.; Gottlieb, H.; Hassner, A. Green Chem. 2017, 19, 5046.
(12) Hu, L.; Liu, X.; Liao, X. Angew. Chem., Int. Ed. 2016, 55, 9743.
(13) Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix,
D. J. Chem. Sci. 2015, 6, 1115.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI grant no.
JP18K05106.
■
(14) Komeyama, K.; Ohata, R.; Kiguchi, S.; Osaka, I. Chem.
Commun. 2017, 53, 6401.
REFERENCES
■
(15) (a) Schrauzer, G. N.; Deutsch, E. J. J. Am. Chem. Soc. 1969, 91,
3341. (b) Hirota, S.; Polson, S. M.; Puckett, J. M.; Moore, S. J.;
Mitchell, M. B.; Marzilli, L. G. Inorg. Chem. 1996, 35, 5646.
(16) Ellis-Sawyer, K.; Bragg, R. A.; Bushby, N.; Elmore, C. S.;
Hickey, M. J. J. J. Labelled Compd. Radiopharm. 2017, 60, 213.
(17) Ohkuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori,
R. Org. Lett. 2000, 2, 659 and references therein..
(18) Wang, J.; Zhao, J.; Gong, H. Chem. Commun. 2017, 53, 10180.
(19) The addition of KI might accelerate an electron transfer from
Mn reductant to catalysts. See: (a) Zembayashi, M.; Tamao, K.;
Yoshida, J.-I.; Kumada, M. Tetrahedron Lett. 1977, 18, 4089.
(b) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull.
Chem. Soc. Jpn. 1990, 63, 80.
(1) (a) Barreiro, E. J.; Ku mmerle, A. E.; Fraga, C. A. M. Chem. Rev.
2011, 111, 5215. (b) Schonherr, H.; Cernak, T. Angew. Chem., Int. Ed.
2013, 52, 12256.
̈
(2) (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. J. Med. Chem. 1997, 40, 1347. (b) Engelhardt, G.; Homma, D.;
Schlegel, K.; Utzmann, R.; Schnitzler, C. Inflammation Res. 1995, 44,
423.
(3) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R.
S.; O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15, 269.
(4) For celecoxib: (a) Tang, C.; Shou, M.; Mei, Q.; Rushmore, T.
H.; Rodrigues, A. D. J. J. Pharmacol. Exp. Ther. 2000, 293, 453.
(20) (a) Ram, M. S.; Riordan, C. G. J. J. Am. Chem. Soc. 1995, 117,
2365. (b) Ram, M. S.; Yap, G. P. A.; Liable-Sands, L.; Rheingold, A.
L.; Marchaj, A.; Norton, J. R. J. J. Am. Chem. Soc. 1997, 119, 1648.
̈
̈
̈
̈
(b) Sandberg, M.; Yasar, U.; Stromberg, P.; Hoog, J. O.; Eliasson, E.
Br. J. Clin. Pharmacol. 2002, 54, 423. (c) Schmid, J.; Busch, U.;
Trummlitz, G.; Prox, A.; Kaschke, S.; Wachsmuth, H. Xenobiotica
1995, 25, 1219.
(5) (a) Sanderson, K. Nature 2009, 458, 269. (b) Gant, T. G. J. J.
Med. Chem. 2014, 57, 3595. (d) Tung, R. D. Future Med. Chem. 2016,
8, 491.
(6) Wiberg, K. B. Chem. Rev. 1955, 55, 713.
(7) Harbeson, S. L.; Tung, R. D. Medchem News 2014, No. 2, 8.
(8) (a) Cioffi, E. A.; Prestegard, J. H. Tetrahedron Lett. 1986, 27,
415. (b) Klei, S. R.; Golden, J. T.; Tilley, T. D.; Bergman, R. G. J. J.
Am. Chem. Soc. 2002, 124, 2092. (c) Ito, N.; Esaki, H.; Maesawa, T.;
Imamiya, E.; Maegawa, T.; Sajiki, H. Bull. Chem. Soc. Jpn. 2008, 81,
278. (d) Kurita, T.; Hattori, K.; Seki, S.; Mizumoto, T.; Aoki, F.;
Yamada, Y.; Ikawa, K.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Chem. -
Eur. J. 2008, 14, 664. (e) Maegawa, T.; Fujiwara, Y.; Inagaki, Y.; Esaki,
H.; Monguchi, Y.; Sajiki, H. Angew. Chem., Int. Ed. 2008, 47, 5394.
(f) Zhou, J.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 5783.
D
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