Direct use of methanol as an alternative to formaldehyde for the synthesis of 3, 3′-bisindolylmethanes (3, 3′-BIMs)

Article abstract of DOI:10.1002/chem.201301555

The article examines the direct use of methanol as an alternative to formaldehyde for the synthesis of 3,3'-Bisindolylmethanes (3,3'-BIM). The use of abundant and renewable feedstock reagents to construct C-C bonds, the essential link in all organic molecules, represents one of the most central subjects. Methanol, the simplest alcohol, can be made from fossil fuels, such as natural gas and coal, renewable resources, such as biomass and landfill gas, and carbon dioxide from the atmosphere. The catalytic dehydrogenation of methanol was regarded as the crucial step for such transformation. Very recently, Beller and co-workers demonstrated ruthenium-catalyzed dehydrogenation of methanol to hydrogen and C1 residuals.

Full text of DOI:10.1002/chem.201301555

DOI: 10.1002/chem.201301555
Direct Use of Methanol as an Alternative to Formaldehyde for the Synthesis
of 3,3’-Bisindolylmethanes (3,3’-BIMs)
Chunlou Sun, Xiaoyuan Zou, and Feng Li*[a]
Among the challenges facing the modern chemical indus-
try, the development of green and sustainable transforma-
tions for organic synthesis has become increasingly impor-
tant.[1] The use of abundant and renewable feedstock re-
À
agents to construct C C bonds, the essential link in all or-
ganic molecules, represents one of the most central subjects.
Methanol, the simplest alcohol, can be made from fossil
fuels, such as natural gas and coal, renewable resources,
such as biomass and landfil gas, and carbon dioxide from
the atmosphere. According to statistics, the annual global
production of methanol is about 75 million metric tons from
over 90 methanol plants. Each day more than 100000 tons
methanol is used as a chemical feedstock or as a transporta-
tion fuel.[2] Despite its significant importance, the catalytic
dehydrogenation of methanol remains less explored. It was
also speculated that a relatively high energy is required for
Scheme 1. The advances in transition metal-catalyzed activation of meth-
anol.
the dehydrogenation of methanol compared with higher al-
cohols, such as ethanol (DH= +84 vs. +68 kJmolÀ1, respec-
tively).[3] In 2011, Krische and co-workers reported iridium-
À
catalyzed direct C C bond coupling of 1,1-disubstituted al-
direct coupling of aldoximes with alcohols to N-alkylated
amides through tandem rearrangement/N-alylation reaction
using Ru/Ir dual catalyst system.[11] As part of our continu-
ing interest in exploring the activation of alcohols as electro-
lenes with methanol to homoallylic neopentyl alcohols. The
catalytic dehydrogenation of methanol was regarded as the
crucial step for such transformation (Scheme 1a).[4] Very re-
cently, Beller and co-workers demonstrated ruthenium-cata-
lyzed dehydrogenation of methanol to hydrogen and C1 re-
siduals (Scheme 1b).[5] Glorius and co-workers described
the synthesis of N-alkylated formamides by coupling of
amines with methanol catalyzed by a NHC–Ru complex
(Scheme 1c). It was speculated that the dehydrogenation of
methanol to formaldehyde in the presence of styrene
(3 equiv) as hydrogen acceptor is the key process for the
catalytic cycle.[6]
À
philes, we turned our attention to C C bond-forming reac-
tions. Herein, we report the first example of direct coupling
of indoles and methanol to 3,3’-bisindolylmethanes (3,3’-
BIMs) catalyzed by the commercially available [{Cp*IrCl2}2]
(Cp*=pentamethylcyclopentadienyl; Scheme 2, right). The
3,3’-BIMs are very important structural units of many natu-
ral products and pharmaceutically active compounds, and
they are also utilized as key synthetic intermediates for the
Recently, we reported transition-metal-catalyzed regiose-
lective N-alkylation with alcohols as environmentally benign
alkylating agents for the synthesis of 2-(N-alkylamino)-
ACHTUNGTRENNUNG
azoles,[7] 2-(N-alkylamino)quinazolines,[8] N,N’-alkylarylureas
and N,N’-dialkylureas[9] based on the hydrogen autotransfer
(or hydrogen-borrowing) process.[10] We also demonstrated
[a] C. Sun, X. Zou, Dr. F. Li
School of Chemical Engineering
Nanjing University of Science and Technology
Nanjing 210094 (P. R. China)
E-mail: fengli@njust.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301555.
Scheme 2. Direct coupling of indoles with alcohols.
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Chem. Eur. J. 2013, 19, 14030 – 14033

COMMUNICATION
Table 1. Coupling of 1a with methanol 2 under various conditions.[a]
construction of a large number of biologically active com-
pounds. Traditionally, 3,3’-BIMs are prepared by Friedel–
Crafts reaction of indoles with aldehydes in the presence of
protic acids or Lewis acids (Scheme 3).[12] However, it is
Entry Cat.
Base
x
A
T
t
Yield
[equiv] [oC] [h] [%]
1
2
3
4
5
6
7
8
U
–
1.0
1.0
150
150
150
150
150
150
150
150
150
130
150
150
12
12
12
12
12
12
12
12
12
12
12
12
0
8
K2CO3
Cs2CO3 1.0
31
19
83
48
86
6
45
42
30
0
Scheme 3. Traditional methods for the synthesis of 3,3’-BIMs.
K3PO4
NaOH
KOH
KOtBu
KOtBu
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
known that aldehydes are highly poisonous substances and
serious environmental pollutants. The experimental results
shown here are in sharp contrast with previous reports on
transition-metal-catalyzed coupling of indoles with alco-
hols.[13,14] In 2007, Grigg and co-workers reported
[{Cp*IrCl2}2]-catalyzed coupling of indoles with benzylic al-
cohols or aliphatic alcohols (exclude methanol) to C3-alky-
lated indoles (only minor bisindolylmethanes were formed
as byproducts, Scheme 2, left, top line).[13] Subsequently,
Williams, Beller and co-workers demonstrated the transfor-
mation of indoles with alcohols to N1-alkylated indoles
using Shovꢁs catalyst (ruthenium complex; Scheme 2, left,
bottom line).[14]
Our initial investigations focused on the coupling of
indole 1a with methanol 2. In the presence of [{Cp*IrCl2}2]
(0.2 mol%),[15] the reaction of 1a (2 mmol) with 2 (1 mL,
12.4 equiv) as the reagent and solvent was carried out at
1508C for 12 h, none of the products was observed (Table 1,
entry 1). When K2CO3, Cs2CO3 or K3PO4 was used as an ad-
ditive, reactions afforded 3,3’-bisindolylmethane 3a with 8–
31% yields (Table 1, entries 2–4). The product 3a could be
obtained with higher yields in the presence of stronger
bases, such as NaOH, KOH and KOtBu (Table 1, entries 5–
7). Among them, KOtBu was found to be the most effective
and the product 3a was obtained with 86% yield (Table 1,
9
G
10
11
12
KOtBu
KOtBu
KOtBu
[a] Reaction conditions: 2 mmol 1a, 1 mL methanol, 0.2 mol% catalyst,
x equiv base, 12 h. [b] Isolated yield.
pling of 7-ethylindole (1 f) gave the desired product 3 f with
80% yield (Table 2, entry 5). The 5-methoxylindole (1g)
and 6-methoxylindole (1h) were also converted to the de-
sired products 3g and 3h with 86 and 78% yields, respec-
tively (Table 2, entries 6–7). Further, reactions of indoles
bearing a halogen atom, such as fluoro- (1i,j), chloro- (1k,l)
and bromo- (1m,n), afforded the corresponding products
3i–3n with 85–91% yields (Table 2, entries 8–13). High cata-
lytic activities were also found in the coupling of indole
bearing strong electron-withdrawing nitro group 1o
(Table 2, entry 14). In the case of 7-azaindole (1p), the de-
sired product 3p was successfully obtained with 80% yield
(Table 2, entry 15). The coupling was also applied to indole
bearing a substituent on its five-member ring 1q, affording
the corresponding products 3q with 75% yield (Table 2,
entry 16).
entry 7). Using [{Cp*RhCl2}2] or [{Ru
(p-cymene)Cl2}2] as the
It should be pointed that apart from the desired products
3,3’-BIMs, only minor C3-methylindoles as byproducts were
observed in a few cases.
Based on experimental results, a possible mechanism is
proposed to account for this iridium-catalyzed direct cou-
alternative catalyst, the product 3a was obtained with 6 and
45% yields, respectively (Table 1, entries 8–9). Attempts to
decrease the reaction temperature and reduce the amount
of KOtBu resulted in low yields of product 3a (Table 1, en-
tries 10–11). It was also found
that no reaction occurred in
the presence of KOtBu alone
(Table 1, entry 12).
To expand the scope of the
reaction, the coupling of a va-
riety of indoles with methanol
was examined under the
optimal conditions (Table 1,
entry 7), and the results are
summarized in Table 2. Reac-
tions of 4-, 5-, 6- and 7-methyl-
indoles (1b–e) afforded the
corresponding products 3b–3e
with 80–85% yields (Table 2,
entries 1–4). Similarly, the cou-
Scheme 4. Possible mechanism for direct coupling of indoles with methanol.
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F. Li et al.
Table 2. Coupling of a variety of indoles 1 with methanol 2.[a,b]
Entry
1
Indole
Product
Yield [%][b]
81
Entry
9
Indole
Product
Yield [%][b]
91
2
3
4
5
85
10
11
12
13
87
85
88
86
80[c]
83
80
6
86
14
77[d]
7
8
78
88
15
16
80
75
[a] Reactions conditions: 2 mmol indoles, 1 mL methanol, 0.2 mol% [{Cp*IrCl2}2], 1 equiv KOtBu, 1508C, 12 h. [b] Isolated yield. [c] 0.5 mol%
[{Cp*IrCl2}2]. [d] 0.5 equiv KOtBu.
pling of indoles with methanol to 3,3’-BIMs (Scheme 4). In
the presence of base, the reaction of [{Cp*IrCl2}2] with
methanol afforded the methoxo iridium species A. Accom-
panied by the b-hydrogen elimination of methoxo iridium
species A, and iridium hydride species B and formaldehyde
C were generated. Further, the reaction of indoles D with
Scheme 5. Coupling of indole with paraformaldehyde.
the resulting formaldehyde C gave enamine intermediates
E, which could undergo Michael addition with second in-
doles to afford the corresponding 3,3’-BIMs F in the pres-
ence of iridium species as Lewis acids.[12] Finally, hydrogen
was released and the catalytic active methoxo iridium spe-
cies A was regenerated through the reaction of hydride spe-
cies B with methanol.
To support the proposed mechanism, the coupling of
indole with paraformaldehyde was undertaken.[16] In the
presence of [{Cp*IrCl2}2] as an additive, the reaction of 1a
with 4 was carried out at 1508C for 12 h to afford the prod-
uct 3a with 81% yield. When KOtBu used as the alternative
additive or in the absence of additive, none of the products
3a was found (Scheme 5). Thus, these results suggest that
iridium species act as Lewis acid catalyst for the coupling of
indoles with the resulting formaldehyde to 3,3’-BIMs during
reaction process.
In summary, we have demonstrated the direct coupling of
indoles with methanol to 3,3’-BIMs with good to excellent
yields using a commercially available iridium complex. Sig-
nificantly, the study exhibits the potential of direct use of
abundant and renewable methanol as an alternative for the
highly poisonous formaldehyde for synthetic transformation.
Efforts to explore new application of methanol as the elec-
trophile are underway in our laboratory.
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Methanol as an Alternative to Formaldehyde
COMMUNICATION
[9] F. Li, C. Sun, H. Shan, X. Zou, J. Xie, ChemCatChem 2013, 5, 1543–
1552.
Experimental Section
[10] For selected reviews about the hydrogen autotransfer (or hydrogen-
borrowing) process, see: a) G. Guillena, D. J. Ramon, M. Yus,
Angew. Chem. 2007, 119, 2410–2416; Angew. Chem. Int. Ed. 2007,
46, 2358–2364; b) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Wil-
liams, Adv. Synth. Catal. 2007, 349, 1555–1575; c) T. D. Nixon,
M. K. Whittlesey, J. M. J. Williams, Dalton Trans. 2009, 753–765;
d) G. E. Dobereiner, R. H. Grabtree, Chem. Rev. 2010, 110, 681–
703; e) G. Guillena, D. Ramon, M. Yus, Chem. Rev. 2010, 110,
1611–1641; f) T. Suzuki, Chem. Rev. 2011, 111, 1825–1845; g) S.
Bahn, S. Imm, L. Neubert, M. Zhang, H. Neumann, M. Beller,
ChemCatChem 2011, 3, 1853–1864; h) A. C. Marr, Catal. Sci. Tech-
nol. 2012, 2, 279–287; i) S. Pan, T. Shibata, ACS Catal. 2013, 3, 704–
712.
General procedure for iridium-catalyzed direct coupling of indoles with
methanol to 3,3’-BIMs: Indoles (1; 2 mmol), methanol (2; 1 mL),
[{Cp*IrCl2}2] (0.004 mmol, 0.2 mol%) and KOtBu (2 mmol, 1 equiv) were
added to an oven-dried, nitrogen purged 25 mL Schlenk tube. The mix-
ture was heated at 1508C for 12 h and was then allowed to cool to ambi-
ent temperature. The reaction mixture was concentrated in vacuo and pu-
rified by flash column chromatography with hexanes/ethyl acetate to
afford the corresponding products 3.
Safety and reproducibility: The 25 mL Schlenk tubes were purchased
from Beijing Synthware Glass, Inc. (P.R. China). Tube O.D.ꢂlength was
26 mmꢂ110 mm. During the reaction, the Schlenk tube was inserted into
an oil bath at 13 mm depth, with the liquid phase in the Schlenk tube
and oil bath at the same level (see the Supporting Information). All ex-
periments outlined in this study are safe under current reaction condi-
tions and were repeated at least two times.
[11] F. Li, P. Qu, J. Ma, X. Zou, C. Sun, ChemCatChem 2013, 5, 2178–
2182.
[12] For selected review about 3,3’-BIMs, see: M. Shiri, M. A. Zolfigol,
H. G. Kruger, Z. Tanbakouchian, Chem. Rev. 2010, 110, 2250–2293,
and references therein.
[13] S. Whitney, R. Grigg, A. Derrick, A. Keep, Org. Lett. 2007, 9, 3299–
3302.
[14] S. Bahn, S. Imm, K. Mevius, L. Neubert, A. Tillack, J. M. J. Williams,
M. Beller, Chem. Eur. J. 2010, 16, 3590–3593.
Acknowledgements
Financial support by the National Natural Science Foundation of China
(No. 20902046, 21272115) and Fundamental Research Funds for the Cen-
tral Universities (No. 30920130111005) is greatly appreciated.
[15] ACHTNUGTRENUNG[{Cp*IrCl2}2] was also used as an efficient catalyst for the hydrogen
autotransfer (or hydrogen-borrowing) process, see: a) K. Fujita, K.
Yamamoto, R. Yamaguchi, Org. Lett. 2002, 4, 2691–2694; b) K.
Fujita, Z. Li, N. Ozeki, R. Yamaguchi, Tetrahedron Lett. 2003, 44,
2687–2690; c) K. Fujita, T. Fujii, R. Yamaguchi, Org. Lett. 2004, 6,
3525–3528; d) C. Lofberg, R. Grigg, A. Keep, A. Derrick, V. Srid-
haran, C. Kilner, Chem. Commun. 2006, 5000–5002; e) C. Lofberg,
R. Grigg, M. A. Whittaker, A. Keep, A. Derrick, J. Org. Chem.
2006, 71, 8023–8027; f) L. U. Nordstrøm, R. Madsen, Chem.
Commun. 2007, 5034–5036; g) K. Fujita, Y. Enoki, R. Yamaguchi,
Tetrahedron 2008, 64, 1943–1954; h) R. Yamaguchi, S. Kawagoe, C.
Asai, K. Fujita, Org. Lett. 2008, 10, 181–184; i) K. Fujita, A. Komat-
subara, R. Yamaguchi, Tetrahedron 2009, 65, 3624–3628; j) M. Zhu,
K. Fujita, R. Yamaguchi, Org. Lett. 2010, 12, 1336–1339; k) W.
Zhang, X. Dong, W. Zhao, Org. Lett. 2011, 13, 5386–5389; l) I.
Cumpstey, S. Agrawal, K. E. Borbasa, B. Martin-Matute, Chem.
Commun. 2011, 47, 7827–7829; m) M. A. Berliner, S. P. A. Dubant,
T. Makowski, K. Ng, B. Sitter, C. Wager, Y. Zhang, Org. Process
Res. Dev. 2011, 15, 1052–1062; n) S. Bhat, V. Sridharan, Chem.
Commun. 2012, 48, 4701–4703; o) B. Anxionnat, D. G. Pardo, G.
Ricci, J. Cossy, Eur. J. Org. Chem. 2012, 4453–4456.
Keywords: bisindolylmethanes
homogeneous catalysis · iridium · methanol
·
dehydrogenation
·
[1] For selected examples, see: a) R. A. Sheldon, Green Chem. 2007, 9,
1273–1283; b) J. P. Lange, ChemSusChem 2009, 2, 587–592; c) I. T.
Horvath, P. T. Anastas, Chem. Rev. 2007, 107, 2169–2173; d) P.
Anastas, N. Eghbali, Chem. Soc. Rev. 2010, 39, 301–312.
[2] For a more detailed introduction about methanol, see: www.metha-
nol.org.
[3] a) M. Qian, M. A. Liauw, G. Emig, Appl. Catal. A 2003, 238, 211–
222; b) W. H. Lin, H. F. Chang, Catal. Today 2004, 97, 181–188;
c) K. Tani, A. Iseki, T. Yamagata, Chem. Commun. 1999, 1821–
1822.
[4] J. Moran, A. Preetz, R. A. Mesch, M. J. Krische, Nat. Chem. 2011, 3,
287–290.
[5] M. Nielsen, E. Alberico, W. Baumann, H. J. Drexler, H. Junge, S.
Gladiali, M. Beller, Nature 2013, 495, 85–89.
[6] N. Ortega, C. Richter, F. Glorius, Org. Lett. 2013, 15, 1776–1779.
[7] a) F. Li, H. Shan, Q. Kang, L. Chen, Chem. Commun. 2011, 47,
5058–5060; b) F. Li, H. Shan, L. Chen, Q. Kang, P. Zou, Chem.
Commun. 2012, 48, 603–605; c) F. Li, Q. Kang, H. Shan, L. Chen, J.
Xie, Eur. J. Org. Chem. 2012, 5085–5092; d) F. Li, J. Xie, H. Shan,
C. Sun, L. Chen, RSC Adv. 2012, 2, 8645–8652.
[16] Che and co-workers demonstrated that ruthenium porphyrins and
RuCl3 can act as Lewis acid catalysts for the coupling of indole with
paraformaldehyde, see: M. Z. Wang, C. Y. Zhou, M. K. Wong, C. M.
Che, Chem. Eur. J. 2010, 16, 5723–5735.
Received: April 23, 2013
Revised: July 15, 2013
Published online: September 17, 2013
[8] F. Li, L. Chen, Q. Kang, J. Cai, G. Zhu, New J. Chem. 2013, 37, 624–
631.
Chem. Eur. J. 2013, 19, 14030 – 14033
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