An oxidative cross-dehydrogenative-coupling reaction in water using molecular oxygen as the oxidant: Vanadium catalyzed indolation of tetrahydroisoquinolines

Article abstract of DOI:10.1039/c1cc15050b

An aerobic oxidative cross-dehydrogenative coupling reaction between sp³ C-H and sp² C-H bonds is developed by employing a vanadium catalyst (10 mol%) in an aqueous medium using molecular oxygen as the oxidant. This environmentally benign strategy exhibits larger substrate scope and shows high regioselectivity.

Full text of DOI:10.1039/c1cc15050b

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COMMUNICATION
An oxidative cross-dehydrogenative-coupling reaction in water using
molecular oxygen as the oxidant: vanadium catalyzed indolation of
tetrahydroisoquinolinesw
Kaliyamoorthy Alagiri, Guralamatta Siddappa Ravi Kumara and Kandikere Ramaiah Prabhu*
Received 14th August 2011, Accepted 12th September 2011
DOI: 10.1039/c1cc15050b
An aerobic oxidative cross-dehydrogenative coupling reaction
between sp3 C–H and sp2 C–H bonds is developed by employing a
vanadium catalyst (10 mol%) in an aqueous medium using molecular
oxygen as the oxidant. This environmentally benign strategy exhibits
larger substrate scope and shows high regioselectivity.
peroxide derivative as the sole product.11a In this context, to take
the complete advantage of the CDC reaction, it is important to
design reactions under green chemistry conditions, particularly in
water, under aerobic conditions. It is worth noting that organic
reactions in water under aerobic conditions are attractive as they
are cost-effective, less toxic, safer, and environmentally benign.12
Apart from this, better selectivity of the reactions is the
additional benefit of using water as the solvent.13 Moreover,
C–H bond activation via the CDC method in aqueous media is
less known,8 while indolation of N-aryl tetrahydroisoquinoline
by the CDC method under green chemistry conditions is scarce.
In continuation of our studies on the utility of transition metal
catalysts in organic synthesis under green conditions,14 herein we
report a vanadium catalyzed efficient CDC reaction by activating
C–H bonds in water using molecular oxygen as the oxidant.
The compatibility of vanadium catalysts for a variety of
aerobic oxidations15 and the synergy between the reactions
catalyzed by vanadium and copper catalyzed reactions15 have
led us to explore the reactivity of vanadium catalysts for CDC
reactions. Therefore, optimization experiments were carried out
with vanadium reagents such as vanadyl acetylacetonate
(VO(acac)2) and vanadium pentoxide (V2O5). Hence, preliminary
studies were initiated with N-phenyl tetrahydroisoquinoline (1a)
and indole (2a) as model substrates. As seen in Table 1, the
reaction of 1a and 2a in the presence of 10 mol% of VO(acac)2
with TBHP in the absence of solvent resulted in lower yield of the
product 3a either at room temperature or at 50 1C (17% and
30% respectively; Table 1, entries 1 and 2). However, the same
reaction in solvent MeOH either at room temperature or at
50 1C has resulted in enhanced yield of 3a (50% and 55%
respectively; Table 1, entries 3 and 4). Although a trace
amount of 3a was obtained in the indolation of 2a with
VO(acac)2 under aerobic conditions at room temperature
(entry 5), the same reaction at 60 1C produced the expected
product 3a in 65% yield (entry 6). Encouraged by these results,
we continued further investigation by reacting 1a and 2a in the
presence of TBHP with V2O5 (10 mol%) at ambient temperature
under neat reaction conditions as well as in solvent MeOH. But,
these reactions yielded either a complex mixture or poor yield of
the product 3a (entries 7 and 8). Varying the oxidant to H2O2 did
not improve the results (entries 9 and 10). Quite impressively,
the reaction of 1a and 2a with V2O5 using molecular oxygen as
the oxidant produced a dramatic change in the outcome of the
The key transformation in organic synthesis is C–C bond
formation, which is central to organic synthesis.1 Cross-
dehydrogenative-coupling (CDC) reactions have emerged as
an important tool as they provide an excellent alternative to
conventional methods of C–C bond forming reactions.2 One of
the major intents of the CDC reactions is the construction of
C–C bonds by catalytic activation of the C–H bond.2 In this
perspective, activation of two C–H bonds to form a new C–C
bond by the oxidative CDC method is an attractive synthetic
protocol.3–7 The additional advantage of CDC reactions is that
there is no necessity for pre-functionalization of precursors.
Besides this, CDC reactions provide ample opportunity to
device coupling reactions under green chemistry conditions.8
Indoles and tetrahydroisoquinolines are naturally occurring
heterocycles, which are important biologically active pharma-
ceuticals.9 Although there are myriad methods known to
accomplish the synthesis of these privileged molecules and their
derivatives,9c,d,f,g there are sustained efforts to develop efficient
synthetic methods under user-friendly conditions.3–7 The tradi-
tional methods of forming C–C bonds employ prefunctionalized
precursors.10 In this context, the CDC methodology has been
adopted for coupling of tetrahydroisoquinoline with indole.11 In
their pioneering work Li and Li11a have synthesized indolyl
tetrahydroisoquinoline by using the CuBr/TBHP system. Further
Schnurch and co-workers11b demonstrated iron catalyzed
indolation of N-protected tetrahydroisoquinolines, while Che
and co-workers11c presented a silica supported iron system for
the oxidative cross-coupling reaction of tertiary amines with
indoles. However, indolation of tetrahydroisoquinoline in an
aqueous medium resulted in the formation of an unwanted
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, Karnataka, India.
E-mail: prabhu@orgchem.iisc.ernet.in; Fax: +91-80-23600529
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and NMR spectra for all products.
See DOI: 10.1039/c1cc15050b
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11787–11789 11787

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Table 1 Optimization of reaction conditions
Entry
Catalyst (mol%)
Indole (equiv.)
Oxidant (equiv.)
Solvent
t/h
T/1C
Yielda (%)
1
2
3
4
5
6
7
8
VO(acac)2(10)
VO(acac)2(10)
VO(acac)2(10)
VO(acac)2(10)
VO(acac)2(10)
VO(acac)2(10)
V2O5(10)
V2O5(10)
V2O5(10)
V2O5(10)
V2O6(10)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
TBHP(1.5)
TBHP(1.5)
TBHP(1.5)
TBHP(1.5)
O2
Neat
Neat
16
16
16
16
36
36
16
16
18
18
36
72
24
24
24
rt
50
rt
50
rt
65
rt
rt
rt
rt
65
72
100
100
100
17
30
50
55
MeOH
MeOH
MeOH
MeOH
Neat
MeOH
H2O
MeOH
MeOH
CF3CH2OH
H2O
Trace
O2
65b
Complex mixture
30
TBHP(1.5)
TBHP(1.5)
H2O2(2)
H2O2(2)
O2
O2
O2
Air
O2
9
32b
Complex mixture
10
11
12
13
14
15
65
V2O5(10)
V2O5(10)
V2O5(10)
V2O5(5)
89b
83
H2O
H2O
30b
42b
a
b
Isolated yield. NMR conversion based on starting material.TBHP (5–6 M in decane).H2O2 (50% aqueous solution).
experiments (entries 11–14). As seen in Table 1, the indolation of 1a
with V2O5 (10 mol%) proceeded well in MeOH in a molecular
oxygen atmosphere at 65 1C to furnish 3a in 65% yield (entry 11;
36 h). Interestingly, the same reaction in CF3CH2OH proceeded
better under reflux conditions to furnish 89% of 3a during a
prolonged reaction time (72 h; entry 12). The outcome of the
reaction of 1a and 2a with V2O5 (10 mol%) in water in the presence
of oxygen was most satisfying, as the reaction was found to be
successful in furnishing 3a in very good yield (83%, entry 13) in
24 h. However, further alteration of the reaction conditions such as
using air instead of oxygen or reducing the catalyst loading resulted
in lowering of the yield of 3a (entries 14 and 15). Therefore, further
reactions of N-phenyl tetrahydroisoquinolines (1 equiv.) and indole
derivatives (1.2 equiv.) were carried out with catalytic amounts of
V2O5 (10 mol%) in water under aerobic conditions using molecular
oxygen as the oxidant under reflux conditions. In contrast to
the reaction catalyzed by Cu/TBHP in water, there was no
peroxidation observed at the benzylic position of N-phenyl tetra-
hydroisoquinolines.11a To the best of our knowledge, this is the first
report of successful indolation of tetrahydroisoquinolines under
green conditions using molecular oxygen as the oxidant.
coupling with indoles 2a, 2b, 2c, 2d, or 2e to furnish the coupled
products 3e, 3f, 3g, 3h, or 3i in good yields (entries 5–9, Table 2).
From these results, it appears that the electron-donating group or
the electron-withdrawing group at the 2- and 5-position of indole
has no effect on the outcome of the reaction. Similarly, N-phenyl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1c) also reacted well
with indoles 2a, 2b, 2c, 2d or 2e to furnish the products 3j, 3k, 3l,
3m, or 3n in good yields (Table 2, entries 10–14). p-Methoxyphenyl
(PMP) protected N-phenyl tetrahydroisoquinoline (1d) reacted
well with indoles 2a, 2b, 2d, or 2e under optimized conditions to
afford the coupled products 3o, 3p, 3q, or 3r in good yields (entries
15–18, Table 2).
Unlike the CDC reaction of indoles with N-aryl tetrahydro-
isoquinoline catalyzed by copper11a or iron11b,c systems, the
present aerobic oxidative CDC reaction proceeds well in the
presence of a radical scavenger BHT (2,6-bis(1,1-dimethylethyl)-
4-methylphenol), eliminating the radical pathway. We believe that
the reaction goes through an iminium ion intermediate,17 which
further reacts with indole to afford the coupled product.
In conclusion, we have developed a mild, efficient and
environmentally benign strategy for the synthesis of indolyl
tetrahydroisoquinoline derivatives catalyzed by vanadium in
aqueous media using molecular oxygen as the oxidant. Most
importantly, to the best of our knowledge, this is the first
report of indolation of N-aryl tetrahydroisoquinoline under
green chemistry conditions. The advantages of this methodol-
ogy are larger substrate scope, high regioselectivity, synthetic
simplicity and greener reaction conditions. We believe that this
strategy provides an elegant method for the construction of
biologically active natural products and alkaloids. Further
study is underway in our laboratory.
The scope of this vanadium catalyzed CDC reaction under
green conditions was evaluated by employing a variety of
N-aryl tetrahydroisoquinoline derivatives and substituted indole
derivatives. As presented in Table 2, N-phenyl tetrahydroiso-
quinoline (1a) reacted with indole (2a) with V2O5 (10 mol%)
in H2O under an oxygen atmosphere to furnish the coupled
product 3a in 83% yield (10 h; Table 2, entry 1). As expected,
the CDC reactions in water proceeded smoothly without protec-
tion of NH of indole. More interestingly, the CDC reaction
proceeded well with a variety of indole derivatives with a range
of substitutions at positions 2 and 5 of indole.16 Thus, 2-methyl-
indole (2b), 5-methoxyindole (2c), and 5-bromoindole (2e) reacted
well with 1a to afford the coupled products 3b, 3c, or 3d in good to
excellent yields (entries 2–4, Table 2). Further, heliotropin derived
N-phenyl tetrahydroisoquinoline (1b) underwent a successful
We are grateful to Indian Institute of Science, CSIR, New
Delhi (no. 01(2415)/10/EMR-II) for financial assistance and
Dr A. R. Ramesha and Prof. Sosale Chandrasekhar for
encouragement and useful discussions. One of the authors
(KA) thanks CSIR, New Delhi, for a research fellowship.
c
11788 Chem. Commun., 2011, 47, 11787–11789
This journal is The Royal Society of Chemistry 2011

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Table 2 Vanadium-catalyzed CDC reaction of tetrahydroisoquino-
lines with indolesa
Notes and references
1 E. J. Corey and X. M. Cheng, The Logic of Chemical Synthesis,
John Wiley & Sons, New York, 1989.
2 CDC reviews (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011,
111, 1215; (b) C.-J. Li, Acc. Chem. Res., 2009, 42, 335;
(c) C. J. Scheuermann, Chem.–Asian J., 2010, 5, 436;
(d) S.-I. Murahashi and D. Zhang, Chem. Soc. Rev., 2008,
37, 1490; (e) Z. Li, D. S. Bohle and C.-J. Li, Proc. Natl. Acad.
Sci. U. S. A., 2006, 103, 8928.
3 Cyanation by CDC: (a) S.-I. Murahashi, T. Nakae, H. Terai and
N. Komiya, J. Am. Chem. Soc., 2008, 130, 11005; (b) S. Singhal,
S. L. Jain and B. Sain, Adv. Synth. Catal., 2010, 352, 1338;
(c) S.-I. Murahashi, N. Komiya and H. Terai, Angew. Chem.,
Int. Ed., 2005, 44, 6931; (d) W. Han and A. R. Ofial, Chem.
Commun., 2009, 5024; (e) Z. Li and C.-J. Li, Eur. J. Org. Chem.,
2005, 3173; (f) S.-I. Murahashi, N. Komiya, H. Terai and
T. Nakae, J. Am. Chem. Soc., 2003, 125, 15312; (g) X.-Z. Shu,
X.-F. Xia, Y.-F. Yang, K.-G. Ji, X.-Y. Liu and Y.-M. Liang,
J. Org. Chem., 2009, 74, 7464.
4 (a) O. Basle and C.-J. Li, Chem. Commun., 2009, 4124; (b) W. Han
and A. R. Ofial, Chem. Commun., 2009, 6023; (c) W. Han,
P. Mayer and A. R. Ofial, Adv. Synth. Catal., 2010, 352, 1667.
5 (a) A. Sud, D. Sureshkumar and M. Klussmann, Chem. Commun.,
2009, 3169; (b) Y. Shen, M. Li, S. Wang, T. Zhan, Z. Tan and
C.-C. Guo, Chem. Commun., 2009, 953; (c) F. Yang, J. Li, J. Xie
and Z.-Z. Huang, Org. Lett., 2010, 12, 5214.
6 (a) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2005, 127, 3672;
(b) A. G. Condie, J. C. Gonzalez-Gomez and C. R. J.
Stephenson, J. Am. Chem. Soc., 2010, 132, 1464; (c) A. S.-K.
Tsang and M. H. Todd, Tetrahedron Lett., 2009, 50, 1199.
7 (a) L. Zhao and C.-J. Li, Angew. Chem., Int. Ed., 2008, 47, 7075;
(b) J. Xie and Z.-Z. Huang, Angew. Chem., Int. Ed., 2010, 49, 10181.
8 O. Basle and C.-J. Li, Green Chem., 2007, 9, 1047.
Yield
(%) Entry Product
Yieldb,c
(%)
Entry Product
1
83(71) 10
71(50) 11
59(50) 12
88(70)
96(87)
82(69)
2
3
9 (a) R. J. Sundberg, The Chemistry of Indoles, Academic Press,
New York, 1970; (b) R. K. Brown, in Indoles, ed. W. J. Houlihan,
Wiley-Interscience, New York, 1972; (c) M. Bandini and
A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608;
(d) L. Joucla and L. Djakovitch, Adv. Synth. Catal., 2009,
351, 673; (e) R. J. Sundberg, Pyrroles and their Benzoderivatives:
Synthesis and Applications in Comprehensive Heterocyclic Chemistry,
ed. A. R. Katritzky and C. W. Rees, Pergamon, Oxford, 1984, vol.
4, p. 313; (f) J. D. Scott and R. M. Williams, Chem. Rev., 2002,
102, 1669; (g) P. Siengalewicz, U. Rinner and J. Mulzer, Chem.
Soc. Rev., 2008, 37, 2676.
10 (a) R. B. Bedford, C. S. J. Cazin and D. Holder, Coord. Chem.
Rev., 2004, 248, 2283; (b) E.-I. Negishi, Acc. Chem. Res., 1982,
15, 340.
11 (a) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2005, 127, 6968;
(b) M. Ghobrial, K. Harhammer, M. D. Mihovilovic and
M. Schnurch, Chem. Commun., 2010, 46, 8836; (c) P. Liu,
C.-Y. Zhou, S. Xiang and C.-M. Che, Chem. Commun., 2010,
46, 2739; (d) F. Yang, J. Li, J. Xie and Z.-Z. Huang, Org. Lett.,
2010, 12, 5214; (e) M.-Z. Wang, C.-Y. Zhou, M.-K. Wong and
C.-M. Che, Chem.–Eur. J., 2010, 16, 5723.
4
5
6
7
8
55(44) 13
79(65) 14
89(77) 15
92(76) 16
85(65)
74(61)
65(64)
55(50)
12 (a) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb
and K. B. Sharpless, Angew. Chem., Int. Ed., 2005, 44, 3275;
(b) D. C. Rideout and R. Breslow, J. Am. Chem. Soc., 1980,
102, 7816.
13 (a) C.-J. Li and T.-H. Chan, Organic Reactions in Aqueous Media,
John Wiley & Sons, New York, 1997; (b) Organic Synthesis in
Water, ed. P. A. Grieco, Blackie Academic and Professional,
London, 1998; (c) I. T. Horvath and P. T. Anastas, Chem. Rev.,
2007, 107, 2167; (d) D. Dallinger and C. O. Kappe, Chem. Rev.,
2007, 107, 2563; (e) R. A. Sheldon, Green Chem., 2005, 7, 267.
14 (a) M. Lamani and K. R. Prabhu, Angew. Chem., Int. Ed., 2010,
49, 6622; (b) M. Maddani and K. R. Prabhu, J. Org. Chem., 2010,
75, 2327; (c) M. Maddani and K. R. Prabhu, Tetrahedron Lett.,
2008, 49, 4526; (d) M. Maddani and K. R. Prabhu, Tetrahedron
Lett., 2007, 48, 7151.
70(51) 17
66(48) 18
67(58)
95(83)
9
15 B. Sedai, C. Diaz-Urrutia, R. T. Baker, R. Wu, L. A. P. Silks and
S. K. Hanson, ACS Catal., 2011, 1, 794.
16 It was observed that in all the reactions, no by-products are
detected other than the unreacted starting materials.
17 S. Singhal, S. L. Jain and B. Sain, Chem. Commun., 2009, 2371.
a
Standard reaction conditions: 1a (1 mmol), 2a (1.2 mmol), V2O5
(10 mol%), H2O (2 mL), O2 (1 atm), 24 h, 100 1C. b NMR yields based
on tetrahydroisoquinoline. c Isolated yields are presented in the parentheses.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11787–11789 11789