Palladium-catalysed direct C-2 methylation of indoles

Article abstract of DOI:10.1039/c6ob01281g

A direct C-2 methylation reaction of indoles bearing a readily removable N-2-pyrimidyl moiety as a site-specific directing group has been developed with a palladium catalyst. This reaction relied on the use of KF to promote efficient methylation. A moderate to good yield was achieved in a range of indole substrates.

Full text of DOI:10.1039/c6ob01281g

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Palladium-Catalysed Direct C-2 Methylation of Indoles
Daoquan Tu,a Xiuzhi Cheng,a Yadong Gao,a Panpan Yang,a Yousong Dingb* and Chao Jianga*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A direct C-2 methylation reaction of indoles bearing a readily re-
movable N-2-pyrimidyl moiety as a site-specific directing group
has been developed with a palladium catalyst. This reaction relied
on the use of KF to promote the efficient methylation. A moderate
to good yield was achieved on a range of indole substrates.
Methyl group (Me) as the smallest alkyl group is one of the most
common carbon fragments in organic compounds. In drug discovery
and development, the conversion of C-H to C-Me can significantly
improve the biological activity of a drug candidate, which is known
as the “magic methyl” effect.1 Capable catalytic and biocatalytic
approaches such as transition-metal catalysed C-H methylation2,
new methylating reagents3 and biocatalytic C-H methylation4 have
been developed to promote this industrially critical chemical trans-
formation. Recently, transition-metal-catalysed directed C-H meth-
ylation has become a versatile strategy in selectively methylating
C(sp2)-H and C(sp3)-H bonds.5,6 Aryl systems have commonly been
used in the studies of C(sp2)-H methylation, whose site-specificity
can be guided by different directing groups.5 However, the C-H
methylation of therapeutically important heterocycles, especially
indoles, has been studied to a significantly less extent.7
Figure 1 Select biologically active molecules and drug candidates
containing 2-methyindoles.
can be used to treat allergic inflammatory diseases.8d Despite their
validated importance in drug research, selective methylation proto-
cols for the synthesis of 2-methylindoles remain poorly developed.
Recently, Shi and co-workers reported one example of Rh(I)-
catalysed decarbonylative C-2 methylation of indole with acetic acid
(Scheme 1a).7a In 2015, Li and co-workers developed Rh(III)-
catalysed oxidative C−H alkylation of diverse arenes bearing differ-
ent ortho-directing groups using potassium alkyltrifluoroborates
(Scheme 1b).7b These studies achieved C-2 methylation of a few N-
(2-pyridine)indoles and N-(2-pyrimidyl)indoles with 42−94% yields.
Since both protocols required expensive rhodium catalysts, it is
strongly desired to develop new methods with cheaper transition
metals. Herein, we report our work of Pd-catalysed direct C-2
methylation of indoles (Scheme 1c). The site-selectivity in this
method was controlled by a removable N-pyrimidyl directing group.
Our study was inspired by a report of the methylation of 2-
phenylpyridine.5b After extensive screening of a range of Pd cata-
lysts, oxidants, ligands, additives and solvents (for detailed optimi-
zation studies, see the Supporting Information), we found that the
desired C-2methylation of N-(2-pyrimidyl)indole (1a) was achieved
using Pd(OAc)2 as catalyst, MeB(OH)2 as methyl source, Ag2CO3 and
benzoquinone (BQ) as co-oxidant, KF as base or boronic acid activa-
tor, and t-AmylOH as solvent. The only product in the reaction was
the methylated product 2a (55% yield; Table 1, entry 1), and the
rest was the unreacted starting material. A series of control experi-
2-Methylindoles are essential building blocks of a number of bio-
logically active molecules.8 Select medicinal molecules containing 2-
methylindoles are shown in Figure 1. Panobinostat, Brivanib, and
Cediranib are three FDA-approved drugs to treat various cancers by
targeting different cellular targets8a
, while bioactive molecules con-
taining 2-methylindoles are also being evaluated as drug candidates
toward various diseases. MOMIPP is a promising drug candidate
that effectively reduces the growth and viability of temozolomide-
resistant glioblastoma and doxorubicin-resistant breast cancer
cells.8b TG8-21 is a prostanoid receptor EP2 antagonist that could
mitigate the inflammatory consequences of EP2 activation,8c while
CRA-680 as a potent prostaglandin D2 receptor CRTH2 antagonist
a.Department of Pharmaceutical Engineering, School of Chemical Engineering,
Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China
E-mail: chaojiang@njust.edu.cn
b.Department of Medicinal Chemistry, College of Pharmacy, University of Florida,
Gainesville, FL 32610, USA. E-mail: YDing@cop.ufl.edu
Electronic Supplementary Information (ESI) available: [details of any supplemen-
tary information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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was observed (entry 2). BQ proved to be crucial forVtiehweArrteicdleuOcntilivnee
elimination step (entry 3), and 0.5 equivalent of BQ provided the
DOI: 10.1039/C6OB01281G
same conversion rate (entry 6). The removal of co-oxidant Ag2CO3
from the reaction led the yield reduction to 27% (entry 4). However,
the higher amount of Ag2CO3 promoted a less effective reaction
(entry 7). The absence of KF5b dropped the reaction yield by about
three times, indicating its critical role in promoting the methylation
(entry 5). CsF proved to be less efficient (entry 8), and the use of
Ag2O, which was effective in methylating 2-phenylpyridine5b, gave a
yield less than 10% (entry 11). The use of methylboroxine5b as the
methyl resource gave an undesired yield (entry 9), while MeBF3K5h
showed no conversion at all (entry 10). Moreover, we applied San-
ford’s5h and Carretero’s5d conditions to 1a, and no methylation oc-
curred (entry 12 and 13).
After establishing the optimized conditions, we extended the re-
Table 2 The scope of C-2 methylation of indoles.a,b
Scheme 1 Select approaches for site-specific C2-methylation of
indoles.
ments were subsequently conducted to understand the role of each
reactant (Table 1). In the absence of the Pd catalyst, no conversion
Table 1 Control Experiments for the C-2 methylation.
[a] Reaction conditions: 1a (0.2 mmol), catalyst, methyl source and addi-
1
tives as specified, solvent (1M), 6 h. [b] Determined by H NMR spectrosco-
py. nr = no reaction. [c] 1a (0.2 mmol), 10 mol % Pd(OAc)2, Ag2O (1 equiv.),
BQ (0.5 equiv.), MeB(OH)2 (3 equiv.), t-AmylOH (1mL), 100 oC, 6 h. [d] 1a
(0.2 mmol), 10 mol % Pd(OAc)2, MnF3 (4 equiv.), CH3BF3K (2 equiv.),
TFE/H2O/AcOH (8:1:1), 25-40 oC, 6 h. [e] 1a (0.2 mmol), 10 mol % Pd(OAc)2,
AgOAc (3 equiv.), BQ (0.5 equiv.), MeB(OH)2 (2 equiv.), t-AmylOH, 100 oC,
20 h.
a Reaction scale: 0.3 mmol. b Isolated yield. c 50 mol % Pd(OAc)2 was used.
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action to a range of indole substrates (Table 2). This reaction was indole derivative is an important building block of CRA-680 (Figure 1)
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DOI: 10.1039/C6OB01281G
compatible with different substitutions on the indole ring (C4-, C5-, and other useful medication as shown in Scheme 2.9
or C6- positons) and regioselectively afforded 2-methylindoles in
The indole C-2 methylation may follow the same pathway previ-
moderate to good yields. Both electron-donating groups (EDG) and ously proposed for the alkylation of thiophene.10 Its plausible
electron-withdrawing groups (EWG) on indoles afforded C-2 meth- mechanism was shown in Scheme 3. First, the coordination of the
ylated products. Electron-donating methyl (2b and 2f), benzyloxy pyrimidyl group of compound 1a to Pd(II) is followed by the selec-
(2c) and methoxy (2g) groups usually gave slightly higher yields than tive C-2 C-H bond activation, which gives the cyclopalladated inter-
electron-withdrawing ester (2h), cyano (2i) and halogen (2d-2e and mediate A. Transmetallation of A with boronic acid generates the
2j-2n) groups. Notably, C-3 substituted indole substrates can have precursor B for a reductive elimination step, which releases product
excellent yields (2o and 2p), but N-pyrimidyl tryptophan derivative 2a and produces the Pd(0). Reoxidation of Pd(0) by Ag2CO3 and BQ
reached a yield of 35% (2r). Furthermore, a few examples of N- regenerates the Pd(II) catalyst to fulfil the catalytic cycle.
pyridyl indole substrates (2s-2v) were tested. These substrates gave
comparable yields as the N-pyrimidyl indoles. However, the pyrim-
idyl group could be removed more easily than the pyridyl group.
Conclusions
Remarkably, all reactions in the Table 2 had excellent mass balances:
In conclusion, we have developed a Pd(II)-catalysed C-2 methylation
unreacted starting materials in these reactions including those with
of indoles directed by the removable 2-pyrimidyl group. It serves as
low yields were fully recovered.
a novel and alternative route for preparation of 2-methyl-1H-
Next, we demonstrated that this reaction was amenable to scale
indoles. Further understanding of the reaction mechanism and ap-
up. Under the optimal conditions, the C-2 methylation reaction of
plications of this approach to other synthetically useful substrates
indole 1j was carried out on a gram scale. Product 2j was successful-
are ongoing in our laboratory.
ly obtained with a slightly decreased yield, and the starting material
was fully recovered after the reaction (Scheme 2). Moreover, we
attempted to remove the pyrimidyl directing group. Upon treat-
ment of 2j with NaOEt in DMSO under nitrogen atmosphere, 5-
Acknowledgements
fluoro-2-methyl-1H-indole 3j was isolated with excellent yield. This
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (Grant No. 21402092), Natural Science Founda-
tion of Jiangsu Province – China (Grant No. BK20140775), Nanjing
University of Science and Technology – China (‘‘Zijin Star Program”),
the Priority Academic Program development of Jiangsu Higher Edu-
cation Institutions – China (PAPD) (CJ),the University of Florida and
Ralph E. Powe Junior Faculty Enhancement Award – United States
(YD).
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