Iridium-catalyzed methylation of indoles and pyrroles using methanol as feedstock

Article abstract of DOI:10.1039/c5ra15822b

Iridium-catalyzed methylation of indoles and pyrroles using methanol as the methylating agent was achieved. This transformation takes place via a borrowing hydrogen methodology under an air atmosphere, which constitutes a direct route to 3-methyl-indoles and methyl-pyrroles.

Full text of DOI:10.1039/c5ra15822b

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DOI: 10.1039/C5RA15822B
A [Cp*IrCl2]2-catalyzed method for the direct methylation of indoles and pyrroles using the
abundant and bio-renewable methanol as C1 feedstock.

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Iridium-catalyzed methylation of indoles and
pyrroles using methanol as feedstock
Cite this: DOI: 10.1039/x0xx00000x
Shu-Jie Chen, Guo-Ping Lu and Chun Cai*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Iridium-catalyzed methylation of indoles and pyrroles using
Based
on
the
development
of
catalytic
methanol
methanol as the methylating agent was achieved. This dehydrogenation,10 we envisioned the possibility of a direct coupling
transformation takes place via borrowing hydrogen of indoles and methanol to achieve the methylation of indoles.
methodology under an air atmosphere, which constitutes a Although some pioneering works upon coupling of indoles with
direct route to 3-methyl-indoles and methyl-pyrroles.
benzylic alcohols or aliphatic alcohols have been developed, to the
best of our knowledge, the methylation of indoles with methanol has
not been achieved via hydrogen autotransfer.11 For examples, the
groups of Grigg,12 Shimizu,13 Piersanti14, and Ohta15 demonstrated the
C3-alkylation of indoles with alcohols in the presence of
homogeneous and heterogeneous transition-metal catalysts.16 In
addition, Beller and co-workers reported a N1-alkylation of indoles
Borrowing hydrogen methodology, which is also known as hydrogen
autotransfer, has emerged as an efficient synthetic strategy for the
construction of C-N and C-C bonds in organic synthesis, especially as
it represents an atom economic and green processes.1-2 Since
a
pioneering work conducted by Grigg, who reported a ruthenium-
catalyzed monoalkylation of arylacetonitriles using alcohols as
alkylating agents via so-called borrowing hydrogen methodology,3 the
transition-metal-catalyzed alkylation of C-nucleophiles with alcohols
has been investigated extensively by numerous research groups.2
However, most of these reactions were restricted to activated
(aromatic) alcohols and long-chain alkyl alcohols. The application of
methanol in alkylation reactions based on hydrogen borrowing
methodologies is less developed, although it is abundant and bio-
renewable. It’s believed that the relatively high energetic demand of
with alcohols through combination of Shvo’s catalyst and
p-
toluenesulfonic acid.17 In 2013, Li and co-workers described an iridium
catalytic system for the synthesis of 3,3’-bisindolylmethanes, which
utilized methanol as a surrogate of formaldehyde and proceeded via
an “interrupted-hydrogen-borrowing” process.18
In fact, there are two potential paths by which the intermediate
A
can be converted into different products. The first way is the Michael
addition with another indole to give the 3,3’-bisindolylmethane; the
latter route is a reduction by the metal hydride to afford the 3-
methylindole (Scheme 1). We speculated that the lack of metal
hydride suspended the “hydrogen-returning” process, so the Michael
addition became dominated. Our idea for producing 3-methylindole
was to interrupt the Michael addition by accelerating the consumption
methanol dehydrogenation (
∆
H
= +84 kJ mol-1) compared to higher
H
= +68 kJ mol-1), led to the situation.4
alcohols, e.g. ethanol (
∆
Nevertheless, some pioneering works using methanol as C1 feedstock
for C-C bond formation were realized in recent years. In 2011, Krische
and co-workers reported an iridium-catalysed direct C-C coupling of
methanol and allenes to furnish higher alcohols.5 Moreover,
contributions from the groups of Donohoe,6 Obora,7 Andersson,8 and
Beller9 have demonstrated methylation of ketones or alcohol in the
presence of rhodium- or iridium-complexes.
of indole and the reduction of the intermediate
A.
According to this train of thoughts, increasing the loading of the
catalyst, which promoted the formation of metal hydride with the
concomitant release of formaldehyde, was
to achieve this goal.
a
possible way
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O
+
+
MH2
M
CH3OH
H
H
NH
HN
NH
OH
O
addition
Established
Base
Michael
Reduction
MH2
H
Base
H
-H
2O
N
H
N
H
N
Proposed
N
A
H
Scheme 1. Chemoselectivity in the Coupling of Indole and Methanol.
To study the general applicability of the present system, the
methylation of a variety of indoles with methanol was investigated
under the optimized conditions (Table 1, entry 5), and the results are
summarized in Table 2. The cross coupling of C-2 substituted indoles
Table 1. Iridium-Catalyzed Methylation of Indole with Methanol under
Various Reaction Conditions.a
Cat.
+
+
CH3OH
N
17 h
Base,
N
H
1b
products 2b
electron-donating or electron-withdrawing groups on the phenyl ring
also proceeded smoothly. The 4-, 7-methyl-indoles 1d 1e and 5-
methoxyl-indole 1f participated in the reaction, and the
corresponding products 2d 2f were obtained in 84–85% yields. The
halide substituents such as fluoro- (1g 1h), chloro- (1i-1j) and bromo-
1k-1m), were tolerant under the conditions, affording the
corresponding products in good yields 2g 2m). In the case of
-
1c and methanol afforded the corresponding C-3 methylated
HN
NH
H
1a
2a
3a
-
2c with 82-91% yields. Reactions of indoles bearing
Entry Cat.
(mol %)
Atmos-
phere
N2
N2
N2
O2
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Conversion
(%)b
100
100
100
100
100
100
95
97
90
45
100
89
Yield (%)b
2a 3a
57 33
74 12
84
92
90
76 14
27 24
45 18
82
15 26
89
50 18
33 35
65
0
0
-
1
2
3
4
5
6
7
[Cp*IrCl2]2 (0.2)
[Cp*IrCl2]2 (0.5)
[Cp*IrCl2]2 (1)
[Cp*IrCl2]2 (1)
[Cp*IrCl2]2 (1)
IrCl3•3H2O (2)
[Ir(cod)Cl]2 (1)
-
2
0
2
-
(
(
-
substrate bearing an ester group, a slightly longer reaction time was
required to obtain good yield (2n). Notably, nitro group survived
under the conditions, although it is easily reduced in the presence of
8
9
[Ir(cod)Cl]2 (1)/PPh3 (2)
(PPh3)2(CO)IrCl (2)
[Ru(p-cymene)2Cl2]2 (1)
[Cp*RhCl2]2 (1)
[Cp*IrCl2]2 (1)
[Cp*IrCl2]2 (1)
[Cp*IrCl2]2 (1)
-
4
10
11
12c
13d
14e
15
16f
3
alcohols (hydrogen donor) and transition metal catalysts (2o-2p).
Similarly, the methylation of 5-cyanoindole (1n) gave the desired
product 2n in 87% yield. The coupling was also applied to indole
87
80
0
0
6
0
0
bearing an amino, except for C-3 methylation,
amino was also observed (2r). In addition, 7-azaindole successfully
yielded 62% of the desired product 2s Consistent with prior
N-methylation of
[Cp*IrCl2]2 (1)
a Indole 1a (0.3 mmol), methanol (1 mL), catalyst, KOtBu (1 equiv), 140 oC
for 17 h. b Determined by GC analysis. c 120 oC. d 100 oC, 24 h. e KOtBu
(0.5 equiv). f Base-free condition.
.
observations,
N-methyl indole 1t failed to undergo methylation,
which indicated an indole anion involved mechanism.13
Except for indoles, we also investigated the reaction of pyrroles with
methanol (Scheme 2). Unlike the indoles, pyrrole shown inferior
selectivity, which afforded methylated products consisting of the
mono-, di-, tri-, and tetra-methyl-pyrroles under the present
In an initial series of experiments, we surveyed the effect of the
catalyst loadings on the selectivity by using [Cp*IrCl2]2 as catalyst
(Table 1, entries 1-3). In the presence of [Cp*IrCl2]2 (0.2 mol%) and
KOtBu (1 equiv), a 57% yield of methylated product 2a was obtained,
conditions
(Eqn
1).
Although
this, it was observed that the
along with bisindolylmethane 3a as a side product in 33% yield (entry
1). Notably, with a higher catalyst loading (0.5 mol%), a better yield of
2a was achieved, and the yield was improved to 84% upon increasing
the catalyst loading to 1 mol% (entries 2-3). This is in line with our
assumption mentioned above. It is worth mentioning that an
atmosphere of oxygen was found to be beneficial to the methylation,6
and even under the air, the methylation could be accomplished in 90%
yield (entries 4-5). A quick screening of common hydrogen transfer
catalysts showed that [Cp*IrCl2]2 and it’s Rh analogs were the optimal
catalysts in both activity and selectivity among the testing catalysts
methylation occured preferentially at the α position (C2 or C5) of
pyrroles (Eqns 2-3).
An additional mechanistic experiment starting from the the
possible intermediate (1H-indol-3-yl)methanol gave 94% yield of the
desired product, which again verified the reaction process outlined in
[Cp*IrCl2]2 (1 mol%)
KOtBu
(1 equiv)
+
MeOH
(1 mL)
and
+
mono-,
(1)
di-, tri-,
tetra-methyl-pyrroles
140 o air
N
H
C,
17 h
100 % conversion
(0.3 mmol)
(entries 6-11). With regard to the base, LiO
were found to be equally effective for this transformation (see Table
S1, Supporting Information). decrease in temperature or the
t
Bu, KO
t
Bu, and Cs2CO3
As above
100 % conversion
+
MeOH
(2)
(3)
N
H
N
H
N
42
27
56
%
%
%
H
A
As above
37 % conversion
amount of base led to unreacted indole, with inferior yield of the
desired product (entries 12-14). Omission of the catalyst or base
resulted in no desired product formation (entries 15-16).
+
+
MeOH
N
H
N
H
N
H
9
%
Scheme 2. Methylation of pyrroles.
2 | J. Name., 2012, 00, 1-3
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Table 2. Coupling of a Variety of Indoles with Methanol.a,b
School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing 210094, P. R. China. Fax: (+86)-25-8431-5030;
phone: (+86)-25-8431-5514; e-mail: c.cai@mail.njust.edu.cn.
[Cp*IrCl2]2 (1 mol%)
tBu
KO
(100 mol%)
140 o air
R
+
CH3OH
R
Electronic Supplementary Information (ESI) available: Experimental
procedures and analytical data for products. See DOI: 10.1039/c000000x/
1 (a) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv. Synth.
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Chem. Rev., 2010, 110, 1611-1641. (c) S. Bähn, S. Imm, L. Neubert,
N
C,
N
H
H
1a-1t
2a-2t
Ph
M. Zhang, H. Neumann and M. Beller, ChemCatChem, 2011,
1853-1864. (d) Marr, A. C., Catal. Sci. Technol., 2012, , 279-287.
3,
N
N
H
82%
N
N
H
H
H
2
c
:
:
:
:
2d
84%
2a
2b
2c
80%
91%
2
3
(a) G. Guillena, D. J. Ramón and M. Yus, Angew. Chem., Int. Ed.,
2007, 46, 2358-2364. (b) S. Pan and T. Shibata, ACS Catal., 2013, 3,
F
O
704-712. (c) Y. Obora, ACS Catal., 2014, 4, 3972-3981.
N
H
85%
N
N
N
F
H
H
H
R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and N. Tongpenyai,
c
:
:
:
:
2h
82%
2e
2f
83%
74%
2g
Tetrahedron Lett., 1981, 22, 4107-4110.
Br
Br
Cl
4 (a) M. Qian, M. A. Liauw and G. Emig, Appl. Catal. A-Gen., 2003, 238
,
211-222. (b) W.-H. Lin and H.-F. Chang, Catal. Today, 2004, 97
,
N
H
88%
N
N
Cl
N
H
84%
H
H
181-188.
c
:
:
:
2l
2i
82%
83%
2j
:
2k
5
J. Moran, A. Preetz, R. A. Mesch and M. J. Krische, Nature Chem.,
2011, , 287-290.
O
3
N
O2
6 (a) L. K. Chan, D. L. Poole, D. Shen, M. P. Healy and T. J. Donohoe,
Angew. Chem., Int. Ed., 2014, 53, 761-765.(b) D. Shen, D. L. Poole,
C. C. Shotton, A. F. Kornahrens, M. P. Healy and T. J. Donohoe,
Angew. Chem., Int. Ed., 2015, 54, 1642-1645.
O
N
N
H
N
N
N
O2
N
H
H
H
Br
c
:
d
:
:
77%
2p
2m
2o
85%
82%
:
2n
80%
N
NC
7
S. Ogawa and Y. Obora, Chem. Commun., 2014, 50, 2491-2493.
8 X. Quan, S. Kerdphon and P. G. Andersson, Chem.-Eur. J., 2015, 21
,
,
N
H
N
H
N
N
3576-3579.
H
e
:
:
:
2s
2t
87%
62%
0%
2q
:
2r
34%
9
Y. Li, H. Li, H. Junge and M. Beller, Chem. Commun., 2014, 50
a Reaction conditions: 1 (0.3 mmol), 1 mL methanol, KOtBu (0.3 mmol), 140
oC for 17 h under air. b Isolated yield. c Reaction was carried out on1 mmol
scale. d 24 h. e 2r was separated by preparative HPLC.
14991-14994.
10 Other selected examples, see: (a) Tani, K.; Iseki, A.; Yamagata, T.,
Chem. Commun,. 1999, 1821-1833. (b) M. Nielsen, E. Alberico, W.
Baumann, H. J. Drexler, H. Junge, S. Gladiali and M. Beller, Nature,
2013, 495, 85-89. (c) S. Tanaka, T. Minato, E. Ito, M. Hara, Y. Kim,
Y. Yamamoto and N. Asao, Chem.-Eur. J., 2013, 19, 11832-11836.
(d) N. Ortega, C. Richter and F. Glorius, Org. Lett,. 2013, 15, 1776-
1779. (e) T. T. Dang, B. Ramalingam and A. M. Seayad, ACS Catal.,
OH
[Cp*IrCl2]2 (1 mol%)
tBu
KO
(1 equiv)
+
+
MeOH
(1 mL)
CD3OD
(1)
140 o air
C,
N
H
N
H
17 h
94
%
(0.3 mmol)
(GC)
2015, 5, 4082-4088.
CD3
11 C3-methylation of indole by supercritical methanol, see: (a) N.
Kishida, T. Kamitanaka, M. Fusayasu, T. Sunamura, T. Matsuda, T.
Osawa and T. Harada, Tetrahedron, 2010, 66, 5059-5064. (b) I. V.
Kozhevnikov, A. L. Nuzhdin, G. A. Bukhtiyarova, O. N. Martyanov
and A. M. Chibiryaev, J. of Supercritical Fluids, 2012, 69, 82-90.
As above
(2)
N
H
N
H
d -skatole
98
%
%,
(0.3 mmol)
(1 mL)
(84
D)
3
Scheme 3. Mechanistic Experiments.
12 S. Whitney, R. Grigg, A. Derrick and A. Keep, Org. Lett., 2007,
9
,
Scheme 1 (Scheme 3, Eqn 1). Furthermore, this methodology also
provides a simple and straightforward approach for the synthesis of
3299-3302.
13 S. M. Siddiki, K. Kon and K. Shimizu, Chem.-Eur. J., 2013, 19
,
d
3-skatole, which is widely used in the deuterium isotope techniques,
14416-14419.
such as the metabolism kinetics (Eqn 2).19
14 S. Bartolucci, M. Mari, A. Bedini, G. Piersanti and G. Spadoni, J.
Org. Chem., 2015, 80, 3217-3222.
In summary, we have developed a [Cp*IrCl2]2-catalyzed method for
the direct methylation of indoles and pyrroles using the abundant and
bio-renewable methanol as C1 feedstock. The methyaltion of indoles
was selectively occurred at the C3 position, while the methyaltion of
pyrroles was occurred at both the α position (C2 or C5) and the β
position (C3 or C4).
15 A. E. Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe and T. Ohta, Eur. J.
Org. Chem., 2013, 6344-6354.
16 For transition-metal-free protocol, see: R. Cano, M. Yus and D. J.
Ramón, Tetrahedron Lett., 2013, 54, 3394-3397.
17 S. Bahn, S. Imm, K. Mevius, L. Neubert, A. Tillack, J. M. Williams
and M. Beller, Chem.-Eur. J., 2010, 16, 3590-3593.
This work is supported by Chinese National Natural Science
Foundation (21402093, 21476116).
Notes and references
18 C. Sun, X. Zou and F. Li, Chem.-Eur. J., 2013, 19, 14030-14033.
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19 (a) J. Fischer, P. W. Elsinghorst and M. Wüst, J. Label Compd.
Radiopharm, 2011, 54, 591-596. (b) G. L. Skiles and G. S. Yost, Chem.
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