B(C6F5)3-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles

Article abstract of DOI:10.1021/acscatal.0c01141

The direct C3 alkylation of indoles and oxindoles is a challenging transformation, and only a few direct methods exist. Utilizing the underexplored ability of triaryl boranes to mediate the heterolytic cleavage of α-nitrogen C-H bonds in amines, we have developed a catalytic approach for the direct C3 alkylation of a wide range of indoles and oxindoles using amine-based alkylating agents. We also employed this borane-catalyzed strategy in an alkylation-ring opening cascade.

Full text of DOI:10.1021/acscatal.0c01141

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Letter
B(C6F5)3‑Catalyzed Direct C3 Alkylation of Indoles and Oxindoles
Shyam Basak, Ana Alvarez-Montoya, Laura Winfrey, Rebecca L. Melen,* Louis C. Morrill,*
and Alexander P. Pulis*
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ABSTRACT: The direct C3 alkylation of indoles and oxindoles is a
challenging transformation, and only a few direct methods exist.
Utilizing the underexplored ability of triaryl boranes to mediate the
heterolytic cleavage of α-nitrogen C−H bonds in amines, we have
developed a catalytic approach for the direct C3 alkylation of a wide
range of indoles and oxindoles using amine-based alkylating agents.
We also employed this borane-catalyzed strategy in an alkylation-
ring opening cascade.
KEYWORDS: catalysis, boranes, N-heterocycles, alkylation, indoles, oxindoles
ndoles and oxindoles are prevalent motifs in biologically
active molecules.1 Classic indole syntheses involve ring
unrecognized as a synthetic strategy for almost a decade
until Stephan and co-workers reported its use in the transfer
hydrogenation of imines.16 Subsequently, Grimme and
Paradies,17a Kanai,17b and Zhang17c disclosed methods for
the dehydrogenation of N-heterocycles. A major breakthrough
came when Erker reported the use of this unusual reactivity in
C−C bond-forming reactions where stoichiometric B(C6F5)3
was used to generate iminium ions for Mannich-type
processes.18 Wasa greatly advanced the strategy by reporting
the catalytic use of B(C6F5)3 in an asymmetric Mannich
process.19 The iminium ions generated have also been used in
electrocyclizations,20 and in the β-functionalization of
amines.21,22 However, the use of this reactivity in catalytic
C−C bond-forming reactions remains rare.19,20 Inspired by
these reports and borrowing hydrogen alkylation reactions,23
we have applied this underutilized reactivity in challenging
alkylation processes.
I
construction.2 Another approach involves the functionalization
of the readily accessible heterocycle core; yet, the direct and
selective C3 alkylation of indoles and oxindoles is a surprisingly
challenging transformation as the reaction with simple alkyl
halides is often not synthetically useful.2,3 For example, with
methyl iodide, 1,2-dimethylindole and 1-methylindole are
unreactive,4 2-methylindole results in mixtures of N- and C-
methylation,5 and oxindoles undergo dialkylation at C3.3 The
installation of a methyl group is a worthwhile endeavor,
considering the interest of medicinal chemists in the “magic
methyl effect”;6 yet only a few methods exist for the direct C3
methylation of indoles and oxindoles (Scheme 1a). Direct C3
methylation is possible with CO2/H2 and a ruthenium catalyst
(e.g., for 1,2-dimethylindole and 2-methylindole),7 and with
borrowing hydrogen methods with methanol (e.g., for 2-
methylindole8 and 1-phenyl oxindole).8a,9 The direct methyl-
ation of 1-methylindole is currently unknown.4
Here, we have developed a new strategy for the direct C3
methylation of indoles and oxindoles (Scheme 1c). The
process utilizes a B(C6F5)3-mediated α-N C(sp3)−H bond
cleavage events to activate readily available amine-based
alkylating agents. Using this borane-catalyzed method,
common undesired reactions, such as the N-methylation of
Because of their intrinsic Lewis acidity, borane catalysts have
found numerous applications in synthesis and are traditionally
used to activate polarized bonds.10 Triaryl boranes can also
activate unpolarized bonds, such as H−H11 and Si−H bonds.12
In a similar vein, we considered if boranes could also be used
to cleave C(sp3)−H bonds heterolytically13 and unveil new
approaches to challenging transformations. Related to this, we
were intrigued by a report by Santini that described the
heterolytic cleavage of an α-nitrogen C(sp3)−H bond during
the stoichiometric reaction of dimethyl aniline and B(C6F5)3 to
form an iminium borohydride ion pair (Scheme 1b).14
B(C6F5)3-mediated α-N C(sp3)−H bond cleavage15 was
Received: March 9, 2020
Revised: April 2, 2020
https://dx.doi.org/10.1021/acscatal.0c01141
© XXXX American Chemical Society
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Scheme 1. B(C6F5)3-Catalyzed α-N C(sp3)−H Bond
3). Notably, the direct methylation of 1-methylindole (1f),
which is a transformation that was previously absent from the
literature,4 was successfully accomplished in high isolated yield
(2f, 75%) using the B(C6F5)3-catalyzed approach with
methylating agent 6a.25 2-Substituted indoles (i.e., NH indoles,
cf. 2l−2s) were efficiently methylated when 2,2,6,6-tetrame-
thylpiperidine (TMP, 10 mol %) was used with alkylating
agent 6a and B(C6F5)3 (10 mol %).26 Importantly, N-
methylation was not observed with NH-bearing indoles. In
contrast, N-alkylation, or mixtures of N- and C-alkylation,
typically result when NH indoles are treated with methyl
iodide under basic conditions.5 The successful reaction of 1-
(cf. 2f−2k) and 2-substituted indoles (cf. 2l−2s) was
surprising, given that B(C6F5)3 has been reported to react
readily with these classes of heterocycle to produce
zwitterionic species.27 3,3′-Bisindolylmethanes, which are a
common product formed in the reaction of formaldehyde or
iminium electrophiles with indoles, were not observed.28
Oxindoles (8a−8q) were successfully employed in the
B(C6F5)3-catalyzed methylation to give products 9a−9q. In
this class of heterocycle, 1,2,2,6,6-pentamethylpiperidine
(PMP, 13) was used as the alkylating agent and higher
temperatures were required. Crucially, C3 dimethylation was
not observed. Therefore, the borane-catalyzed process comple-
ments traditional alkylating agents: C3 dialkylation typically
occurs when oxindoles are treated with methyl iodide under
basic conditions.3
The methylation of 6-methylindole (cf. 2n) and unsub-
stituted oxindole (cf. 9n) occurred in low yield, presumably
because of competitive coordination of N or O to the B(C6F5)3
catalyst. Otherwise, across the different classes of substrates,
the process tolerated a range of functional groups and
substituents, such as OCH3 (2c, 2s, 9i, 9k), F (2o, 9d), Cl
(2d, 2p, 9e), Br (2q, 9f), CF3 (9m), NO2 (2e, 9j), CO2Me
(9c), and other carbonyl derivatives (9o, 9p), which contrasts
the dogma sometimes associated with B(C6F5)3-mediated
processes.29 We also performed the B(C6F5)3-catalyzed
methylation of 1,2-dimethylindole (1a) on a preparative
scale, producing 1.3 g of 1,2,3-trimethylindole (2a) in 83%
yield.30
Cleavage Used in the Methylation of Indoles and Oxindoles
indoles, the formation of 3,3′-bisindolylmethanes, and the
dialkylation of oxindoles, are not observed. In addition, the
substrate scope is broad and encompasses 1-, 2-, and 1,2-
substituted indoles, as well as other challenging alkylations,
including a novel alkylation-ring opening cascade.
We began by investigating various aniline derivatives as
methylating agents in the borane-catalyzed methylation of 1,2-
dimethyl indole (1a) (Scheme 2). Generally, we discovered
Scheme 2. B(C6F5)3-Catalyzed Methylation of Indole 1a
a
with Various Alkylating Agents
In addition, we briefly explored other challenging alkylation
reactions using the B(C6F5)3-catalyzed method and discovered
that 1,2-dimethylindole (1a) was successfully ethylated (10a),
decylated (11a) and benzylated (12a), at C3 using the ethyl-
(6b), decyl- (6c), or benzyl- (4b)31 diaryl amines,
respectively.32
The borane catalyst, B(C6F5)3, is a commercially available
white powder that forms a water adduct, H2O·B(C6F5)3, when
exposed to moisture in air and is therefore routinely handled in
an inert atmosphere.33 Inspired by related methods,34 we
developed a procedure where B(C6F5)3 can be used as received
from the supplier and weighed in air on the open bench, and
the reaction performed using standard Schlenk line techniques
(Scheme 4). Thus, H2O·B(C6F5)3 (10 mol %) was dissolved in
the desired solvents (as received from the supplier) and treated
with triethyl silane (20 mol %). The resultant solution contains
active B(C6F5)3 and O(SiEt3)2 that can be used directly in the
alkylation of indoles and oxindoles to provide methylated
indoles (2a, 2f, and 2l), benzylated indole (12a), and
methylated oxindole (9a)35 in good yields. Therefore, this
shows that access to specialized equipment (such as a dry
glovebox), a separate purification of commercially available
a
Reactions were performed using 0.2 mmol of 1a. Yields were
1
determined after H NMR spectrum analysis of the crude reaction
mixture with an internal standard.
that a variety of aryl and diaryl amines were effective in
methylating 1a using B(C6F5)3 (10 mol %).24 Electron-rich
diaryl methyl amines, such as 4a and 6a, were determined to be
optimal and allowed the formation of 2a in quantitative yields
at ambient temperature.
We surveyed the scope of the B(C6F5)3-catalyzed methyl-
ation of various 1,2-, 1-, and 2-substituted indoles and
oxindoles and found that the reaction broadly tolerated a
range of functional groups and substitution patterns (Scheme
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Scheme 3. Substrate Scope in the B(C6F5)3-Catalyzed Alkylation of Indoles and Oxindoles*
*
Reactions were performed using 0.5 mmol of 1 or 8 except conditions g and h, where 0.2 mmol of 1a was used. Yields are isolated. Yields in
1
a
parentheses determined after H NMR spectrum analysis of the crude reaction mixture with an internal standard. B(C6F5) (10 mol %), 6a (R =
CH3, 1.2 equiv), 25 °C, DCE, 16 h. bB(C6F5)3 (10 mol %), 6a (R = CH3, 1.2 equiv), 95 °C, DCE, 16 h. cB(C6F5)3 (20 mol %), 6a (R = CH3, 1.2
d
e
equiv), 95 °C, DCE, 8 h. B(C6F5)3 (10 mol %), 6a (R = CH3, 1.2 equiv), TMP (10 mol %), 110 °C, toluene, 16 h. B(C6F5)3 (10 mol %), 13
(PMP, 2 equiv), 150 °C, xylenes, 16 h. fCombined yield of tautomers. gB(C6F5)3 (10 mol %), 6b (R = Et) or 6c (R = (CH2)9CH3) (1.2 equiv), 95
h
°C, DCE, 24 h. B(C6F5)3 (20 mol %), 4b (R = Bn, 2 equiv), 150 °C, xylenes, 24 h.
Scheme 4. Use of H2O·B(C6F5)3 in the Borane-Catalyzed
Alkylation of Indoles and Oxindoles
Scheme 5. B(C6F5)3-Catalyzed Alkylation-Ring Opening
Cascade*
a6a, 25 °C, DCE, 16 h. b6a, B(C6F5)3 (20 mol %), Et3SiH (40 mol %),
c
d
95 °C, DCE, 8 h. 6a, TMP (10 mol %), 110 °C, toluene, 16 h. 4b,
150 °C, p-xylene, 24 h. ePMP (13) (2 equiv), 150 °C, p-xylene, 16 h.
B(C6F5)3, and rigorously anhydrous solvent is not required in
the B(C6F5)3-catalyzed alkylation.
Beyond methylation and alkylation, we also explored the
B(C6F5)3-catalyzed alkylation strategy in a novel alkylation-
ring opening cascade process for the generation of function-
alized indoles 15 (Scheme 5). Product 15 contains a 4-(3-
indolyl)butylamine motif that is found in several serotonergic/
dopaminergic drug molecules, such as vilazodone, roxindole,
siramesine, and carmoxirole.36 Upon reaction of N-aryl
*
Standard conditions: H2O·B(C6F5)3 (10 mol %), Et3SiH (20
mol %), 14 (1 equiv), 1 (2.2 equiv), 1,2-Cl2C6H4, 110 °C, 20−24
h. DCE, 85 °C. Toluene.
a
b
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Letter
pyrrolidines 14,37 indoles 1 and B(C6F5)3 catalyst, a variety of
4-(3-indolyl)butylamines 15 were formed in good yields.38
In order to probe the mechanism and provide direct access
to deuterated methyl groups at C3 of indoles, we used
deuterated methylating agent 6a-d3 in the B(C6F5)3-catalyzed
methylation of indoles 1a and 1l under previously optimized
conditions (Scheme 6a). Deuterated C3 methylindoles 2a-d3
and 2l-d3 were formed in high yield in both cases.39
counterion, producing the alkylated indoles 2 (and oxindoles
9) and regenerating the borane-catalyst (step (iv)). In the
boron-catalyzed alkylation/ring opening cascade process (cf.
Scheme 5), the cyclic nature of the iminium 20 enables the
amino fragment to be retained in product 15 after elimination
(Scheme 6c).
In summary, we have developed a new approach to the
direct C3 alkylation of indoles and oxindoles. Using a B(C6F5)3
catalyst and amine-derived alkylating agents, we exploit the
underexplored ability of boranes to cleave heterolytically α-N
C(sp3)−H bonds in a catalytic C−C bond-forming reaction.
This method provides a metal-free and complementary
approach to the few existing methods for the direct C3
alkylation of indoles. Unlike other procedures, this B(C6F5)3-
catalyzed methodology encompasses several classes of indole,
including 1-, 2-, and 1,2-substituted indoles, and allows
previously unreported direct methylations. The reaction
displays broad scope and exceptional chemoselectivity,
avoiding N-methylation and formation of 3,3′-bisindolyl-
methanes in indole substrates, and dialkylation in oxindoles.
Other alkylations are also reported, including a novel
alkylation-ring opening cascade process to generate privileged
4-(3-indolyl)butylamines from N-aryl pyrrolidines.
Scheme 6. Mechanistic Studies and Proposed Catalytic
Cycle*
ASSOCIATED CONTENT
■
sı
* Supporting Information
Information about the data that underpins the results
presented in this article, including how to access them, can
be found in the Cardiff University data catalogue at http://doi.
org/10.17035/d.2020.0104936560 or from the lead authors
upon request. The Supporting Information is available free of
charge at https://pubs.acs.org/doi/10.1021/acscatal.0c01141.
Experimental procedures and spectroscopic data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Rebecca L. Melen − Cardiff Catalysis Institute, School of
Chemistry, Cardiff University, Cardiff CF10 3AT, United
Kingdom; orcid.org/0000-0003-3142-2831;
Email: MelenR@cardiff.ac.uk
Louis C. Morrill − Cardiff Catalysis Institute, School of
Chemistry, Cardiff University, Cardiff CF10 3AT, United
Kingdom; orcid.org/0000-0002-6453-7531;
Email: MorrillLC@cardiff.ac.uk
Alexander P. Pulis − School of Chemistry, University of
Leicester, Leicester LE1 7RH, United Kingdom; orcid.org/
0000-0003-1754-527X; Email: a.pulis@leicester.ac.uk
*
1
Yields are isolated and %D incorporation was determined after H
NMR spectrum analysis of the purified compounds. aDCE, 25 °C, 16
h. TMP (10 mol %), toluene, 110 °C, 16 h.
b
Based on these results and literature precedent, we propose
the following catalytic cycle for the B(C6F5)3-catalyzed
alkylation of indoles and oxindoles (Scheme 6b). The
borane-catalyst mediates heterolytic cleavage, via hydride
abstraction, of the α-N C(sp3)−H bond in the amine-based
alkylating agents (3−7, 13, 14) forming iminium-borohydride
ion pairs 16 (Scheme 6b, step (i)). Analogous ion pairs have
been observed by Santini and co-workers using NMR
spectroscopy (cf. Scheme 1A).14 The electrophilic iminium
16 is trapped with an indole 1 (or oxindole 8), forging a new
C−C bond (step (ii)) in an analogous fashion to the Mannich
reaction. Proton transfers enable the ion pair 17 to eliminate
the amine 18 (which can be recovered from the reaction) via
an E1CB-type mechanism (step (iii)).40 The α,β-unsaturated
iminium-based ion pair 19 is reduced by the borohydride
Authors
Shyam Basak − Cardiff Catalysis Institute, School of Chemistry,
Cardiff University, Cardiff CF10 3AT, United Kingdom
Ana Alvarez-Montoya − School of Chemistry, University of
Leicester, Leicester LE1 7RH, United Kingdom
Laura Winfrey − School of Chemistry, University of Leicester,
Leicester LE1 7RH, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c01141
Notes
The authors declare no competing financial interest.
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Letter
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ACKNOWLEDGMENTS
■
S.B., R.L.M., and L.C.M. gratefully acknowledge the School of
Chemistry, Cardiff University for generous support and the
Leverhulme Trust for a Research Project Grant (No. RPG-
2015-361). R.L.M. would like to acknowledge the EPSRC for a
research fellowship (No. EP/R026912/1). A.A.-M., L.W., and
A.P.P. thank the School of Chemistry, University of Leicester,
for their generous support and the Royal Society for a Research
Grant (No. RGS\R1\191082).
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(24) See the Supporting Information for further details of
optimization. Electron-rich diaryl amines are expected to be better
hydride donors and, thus, undergo the B(C6F5)3 C−H cleavage more
readily. For studies of C−H hydride donor abilities, see: Ilic, S.;
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(37) Wasa has previously shown that N-aryl pyrrolidines undergo
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(38) Electron-rich aromatic rings can be removed from nitrogen
under oxidative conditions (cf. PMP protecting groups). For a
relevant example, see ref 19b.
(39) Partial deuterium incorporation at the N-CH3 site of 2a-d3 may
indicate that hydride abstraction may also occur at N-CH3, or that a
1,5-prototropic shift in intermediate 19 (R = CH3) occurs prior to
hydride transfer (cf. Scheme 6b, step iv).
(40) Attempts to prevent the elimination and isolate the
corresponding aminomethylation derivative of 17 were unsuccessful.
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(25) Amine 6a was found to be a more-general methylating agent
versus 4a.
(26) The addition of TMP significantly improved the yield when
NH indoles were used. See the Supporting Information.
(27) Guidotti, S.; Camurati, I.; Focante, F.; Angellini, L.; Moscardi,
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(28) For an example where 3,3′-bisindolylmethane products form,
see ref 7.
(29) For an example of the impressive functional group
compatibility of catalytic B(C6F5)3 processes, see: Bender, T. A.;
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(30) The amine byproduct (cf. amine 18, Scheme 6) was recovered
in 98% yield.
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