Cp*Rh(III)-Catalyzed Regioselective C(sp3)-H Methylation of 8-Methylquinolines with Organoborons

Article abstract of DOI:10.1021/acs.orglett.9b04331

Rh(III)-catalyzed highly regioselective methylation of the unactivated C(sp³)-H bond of 8-methylquinolines with bench stable organoboron reagents is described. A variety of substituted 8-methylquinolines provided the highly regioselective monom

Full text of DOI:10.1021/acs.orglett.9b04331

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cp*Rh(III)-Catalyzed Regioselective C(sp3)−H Methylation of
8‑Methylquinolines with Organoborons
Rakesh Kumar, Ritika Sharma, Rohit Kumar, and Upendra Sharma*
Natural Product Chemistry and Process Development Division and AcSIR, CSIR-IHBT, Palampur 176061, India
S
* Supporting Information
ABSTRACT: Rh(III)-catalyzed highly regioselective methylation
of the unactivated C(sp3)−H bond of 8-methylquinolines with
bench stable organoboron reagents is described. A variety of
substituted 8-methylquinolines provided the highly regioselective
monomethylated products with potassium methyltrifluorobo-
rates/methylboronic acid through primary C(sp3)−H bond
activation. Complete chemoselectivity and regioselectivity were
observed in all cases as methylation at the C2 position or dimethylation of the C(sp3)−H bond of 8-methylquinoline was not
detected. The mechanistic study uncovered the fact that the reaction may proceed through the five-membered rhodacycle
intermediate.
ransition metal-catalyzed C−H bond activation has been
T
broadly utilized for the building of numerous organic
molecules.1 Among various transition metal catalysts, a
rhodium(III) catalyst has been well explored for C(sp2)−H
bond functionalization reactions due to its high efficiency and
selectivity,2 whereas the functionalization of more challenging
C(sp3)−H bonds has not been explored much.3 Recently,
Rh(III)-catalyzed transformation has been reported for the
functionalization of 8-methylquinoline through C(sp3)−H
bond activation;4 however, the methylation/alkylation of 8-
methylquinolines using a Rh(III) catalyst has not yet been
explored.
Figure 1. Important methyl-substituted molecules.
Scheme 1. C(sp3)−H Methylation of 8-Methylquinolines
Methylation is greatly important in pharmaceuticals as the
substitution of the methyl group modifies the lipophilicity,
solubility, and conformation of the molecules, which leads to
the exceptional improvement in the biological activity of the
molecules.5 Among various bioactive molecules, the methyl-
substituted molecules such as renexa and NIBR-0213 have
shown much better activity as compared to their precursor.
Similarly, simvastatin6 has shown better results as compared to
lovastatin; i.e., the methylation leads to a remarkable increase
in the potency of these drug molecules (Figure 1). Therefore,
various groups reported the transition metal-catalyzed
methylation of organic molecules mainly through C(sp2)−H
bond activation.7
Significantly, there have been very few reports about the
more challenging C(sp3)−H methylation.8 Although the Yu
group reported the Pd-catalyzed methylation and alkylation of
8-methylquinolines with boroxine and boronic acid reagents
(Scheme 1),9 bench stable potassium methyltrifluoroborates
have not yet been explored in this reaction. The organoborane
reagents have been used for the C(sp2)−H bond functionaliza-
tion of various heterocyclic compounds,10 and reports of the
use of the organoboron reagents in Rh(III)-catalyzed
construction of the C(sp3)−C(sp3) or C(sp3)−C(sp2) bonds
are very limited.11
In continuation of our interest in the C(sp3)−H bond
activation/functionalization,12 herein we disclosed the first
Rh(III)-catalyzed highly regioselective methylation of the
primary C(sp3)−H bonds of 8-methylquinolines with bench
stable potassium methyltrifluoroborate.
We initiated our study with the reaction between 8-
methylquinoline (1a) and potassium methyltrifluoroborate
(2a) in the presence of [RhCp*Cl2]2/AgSbF6 as a catalyst,
AgF as an additive, and DME as a solvent at 100 °C for 24 h.
Pleasingly, under these conditions, we obtained a 45% yield of
Received: December 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04331
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
the expected methylated product (Table 1, entry 13). The
methylated product was confirmed on the basis of one-
Scheme 2. Methylation/Alkylation of 8-Methylquinolines
a
Table 1. Optimization Study
b
variation from standard conditions
yield (%)
c
1
2
−
66 (61)
38
without Ag2CO3
3
4
5
6
without [RhCp*Cl2]2/AgSbF6
24 h
36 h
72 h
nd
56
60
−
7
8
9
10
11
12
13
14
EtOH, 24 h
H2O, 24 h
DCE, 24 h
80 °C
under an Ar atmosphere
4 equiv of 2a
AgF instead Ag2CO3, 24 h
under an O2 atmosphere without Ag2CO3
53
40
30
50
64
61
45
<5
a
Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), [RhCp*Cl2]2
(5 mol %), AgSbF6 (20 mol %), Ag2CO3 (2 equiv), DME (0.5 mL),
100 °C, 48 h. Yield based on NMR analysis of the crude reaction
mixture using tetrachloroethane as an internal standard. Isolated
b
c
yield in parentheses.
dimensional and two-dimensional NMR and mass spectrom-
etry.13 When the reaction was carried out at 80 °C, a 50% yield
of the desired product was observed (Table 1, entry 10).
Control experiments without using a catalyst or an additive
explained the necessity of both for the formation of the desired
product (Table 1, entries 2 and 3). A variety of solvents were
screened, and DME was found to be the solvent of choice
(Table 1, entries 1 and 7−9). Increasing the reaction time to
48 h was found to be helpful, but beyond, 48 h diminution in
the yield of 3a was observed (Table 1, entries 1 and 4−6). An
increase in the loading of 2a (≤4 equiv) was not helpful (Table
1, entry 12). Using molecular O2 as an oxidant instead of
Ag2CO3 provided only traces of the desired alkylated product
(Table 1, entry 14). The comparative yield was observed under
an inert atmosphere (Table 1, entry 11). The reaction
conditions using 0.1 mmol of 1a and 0.3 mmol of 2a in the
presence of [RhCp*Cl2]2/AgSbF6 as a catalytic system and
Ag2CO3 as an oxidant in the presence of DME at 100 °C for
48 h were finalized (Table 1, entry 1). The detailed
optimization study has been included in the Supporting
Information (Table S1).13
Next, substituted 8-methylquinolines (1) were reacted with
potassium methyltrifluoroborate (2a) under the best devel-
oped reaction condition (Scheme 2). The methyl substituents
at positions C3−C7 of 8-methylquinolines were well tolerated
and afforded the methylated products in 39−67% yields with
complete monoselectivity (3b−g). 8-Methylquinolines sub-
stituted with -OMe, -F, -Cl, and -Br at C7 and -Cl and -Br at
C5 and C6 were also quite compatible under the developed
reaction conditions and gave the desired monomethylated
product in moderate to good yields (3h−n, 42−92%). 4-
Phenyl- and 8-methyl-4-(thiophen-3-yl)quinoline also reacted
a
Reaction conditions: 1 (0.30 mmol), 2 (0.90 mmol), [RhCp*Cl2]2
(5 mol %), AgSbF6 (20 mol %), Ag2CO3 (2 equiv), DME (1.5 mL),
b
c
100 °C, 48 h. Use of MeB(OH)2 instead of 2a. Reaction time of 60
d
h. In a 1.0 mmol scale reaction using [RhCp*Cl2]2 (2.5 mol %) and
AgSbF6 (10 mol %).
smoothly (3o and 3p). A sensitive functional group such as an
olefin at C6 of 8-methylquinoline remains intact and provided
the corresponding desired monomethylated products in
moderate yield (3q and 3r). The reaction of 1a with potassium
n-butyltrifluoroborate provided a very low yield of the desired
alkylated product (3s) along with the formation of an
uncharacterized side product. When 5-nitro-8-methylquinoline
and 2,8-dimethylquinoline were reacted with 2a under the
optimal reaction conditions, no product formation was
observed (Scheme 2, entries 3t and 3u, respectively).
Unfortunately, in the case of potassium cyclopentyltrifluor-
oborate and phenyltrifluoroborate, no product was observed
(3v and 3w, respectively). Significantly, the reaction also
proceeds with methylboronic acid affording the desired
product 3a in 42% yield.
Several control experiments were performed to gain insight
into the reaction pathway (Schemes S1−S6).13 A deuteration
experiment in DME/CD3OD revealed irreversible C−H bond
cleavage with or without potassium methyl trifluoroborate (2a)
(Scheme 3a). The kinetic isotope effect was analyzed by
competition and parallel experiments that revealed that the C−
B
DOI: 10.1021/acs.orglett.9b04331
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
quinolines with organoboron reagents. The developed method
has a broad substrate scope with excellent regioselectivity and
good to high yields. The preliminary mechanistic study
revealed a five-membered rhodacycle as the key intermediate.
Scheme 3. Deuterium Labeling Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04331.
General considerations, preparation of substituted 8-
methylquinolines, reaction of 8-methylquinolines with
potassium methyltrifluoroborate, mechanistic study,
references, and H and 13C spectral data (PDF)
1
H bond cleavage step might be the rate-determining step
(Scheme 3b). Subsequently, a five-membered rhodacycle (A)
of 8-methylquinoline was synthesized by an earlier known
method.4b Use of the rhodacycle (A) as a catalyst afforded 35%
methylated product, confirming its intermediacy in the
reaction (Scheme 4).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: upendra@ihbt.res.in or upendraihbt@gmail.com.
ORCID
Rakesh Kumar: 0000-0002-8588-5615
Rohit Kumar: 0000-0002-3722-2278
Upendra Sharma: 0000-0002-7693-8690
Notes
Scheme 4. Intermediate Study
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thanks the Director of CSIR-IHBT for continuous
encouragement and providing the necessary facilities. Rakesh
Kumar acknowledge UGC, New Delhi, for the Senior Research
Fellowship. Financial support from CSIR (MLP0203) is also
acknowledged. CSIR-IHBT communication 4507.
On the basis of the experiments described above and
literature reports,11 a possible mechanism is proposed (Scheme
5). Initially, active Rh(III) species is formed in the presence of
Scheme 5. Plausible Mechanistic Cycle
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E
DOI: 10.1021/acs.orglett.9b04331
Org. Lett. XXXX, XXX, XXX−XXX