One-pot synthesis of symmetric and unsymmetric 1,1-bis-indolylmethanes via tandem iron-catalyzed C-H bond oxidation and C-O bond cleavage

Article abstract of DOI:10.1021/jo902093p

(Chemical Equation Presented) The reactions of indoles with ethers give a variety of symmetric and unsymmetric 1,1-bis-indolylmethane derivatives via iron-catalyzed C-H bond oxidation and C-O bond cleavage. 2009 American Chemical Society.

Full text of DOI:10.1021/jo902093p

pubs.acs.org/joc
Recently, we4 and others5 reported catalytic oxidative
One-Pot Synthesis of Symmetric and Unsymmetric
1,1-Bis-indolylmethanes via Tandem Iron-Catalyzed
C-H Bond Oxidation and C-O Bond Cleavage
coupling reactions of the sp3 C-H bond adjacent to an
oxygen atom with the sp3 C-H bond. However, the catalytic
oxidative coupling reaction of the sp3 C-H bond adjacent to
an oxygen atom with the sp2 C-H bond has virtually been
untouched.6 Herein, we report a novel, simple, and efficient
method to construct both symmetric and unsymmetric 1,1-
bis-indolylmethanes using simple iron catalyst,7 which is the
formal oxidative coupling reaction of the sp2 C-H bond and
the sp3 C-H bond.
Xingwei Guo, Shiguang Pan, Jinhua Liu, and Zhiping Li*
Department of Chemistry, Renmin University of China,
Beijing 100872, China
zhipingli@ruc.edu.cn
An extensive investigation of reaction conditions with a
range of catalysts and oxidants8 was carried out and some
representative results were shown in Table 1. The informa-
tion for 1,1-bis-indolylmethane product 3a was not observed
in the presence of Fe2(CO)9, Fe(OAc)2, Fe(acac)2, or Fe-
(acac)3 (Table 1, entries 1-4). Comparable yields were
obtained when FeCl2, FeBr2, and FeCl3 were used as cata-
lysts (Table 1, entries 5-7).9 However, FeI2 was a less
effective catalyst (Table 1, entry 8). tert-Butyl hydroperoxide
(TBHP) and tert-butyl peroxybenzoate were less effective
oxidants for the formation of 3a compared with di-tert-butyl
peroxide (Table 1, entries 9 and 10). The information for the
desired product 3a was not observed in the absence of an
oxidant or a catalyst (Table 1, entries 11 and 12). The
reaction was completely suppressed by adding 1.0 equiv of
TEMPO, a radical trapping reagent (Table 1, entry 13). This
result indicates that a radical intermediate is most likely
involved in the initial steps of the present transformation. It
should be noted that 3a was obtained exclusively even at
room temperature, albeit in a low yield.
Subsequently, the scope of the present transformation was
investigated with FeCl2 as a catalyst. The desired 1,1-bis-
indolylmethane derivatives 3 were obtained with good to
excellent yields (Table 2). The reaction appears general with
respect to the structural variation of 1 and 2. Both N-H and
N-Me indoles reacted smoothly with THF (Table 2, entries
1-5). Two regioisomers were obtained in a ratio of 1:1 when
2-methyl tetrahydrofuran 2b was used (Table 2, entry 6).10
1,3-Dihydroisobenzofuran 2c and isochroman 2d reacted
with various indoles selectively (Table 2, entries 7 and 8).
Received September 29, 2009
The reactions of indoles with ethers give a variety of
symmetric and unsymmetric 1,1-bis-indolylmethane de-
rivatives via iron-catalyzed C-H bond oxidation and
C-O bond cleavage.
1,1-Bis-indolylmethane derivatives are found in bioactive
metabolites of terrestrial and marine natural sources.1 The
condensation of carbonyl compounds with indoles is the
most practical method of synthesizing symmetric 1,1-bis-
indolylmethane compounds. However, a multistep synthesis
had to be used for the synthesis of unsymmetric 1,1-bis-
indolylmethanes.2 The conversion of aromatic C-H bonds
into C-C bonds classically has involved Friedel-Crafts
reactions, which generally require a stoichiometric amount
of the Lewis acids. Selective and efficient functionalization of
C-H bonds has attracted much attention in both academia
and industry in the past decades.3 The challenge of direct
functionalization of indoles stimulated us to investigate the
present oxidative coupling reactions.
(6) Oxidative coupling reactions of the indolyl sp2 C-H bond and the sp3
C-H bond, see: (a) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem.
Res. 2009, 42, 530. (b) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin,
D. W.; Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857.
(c) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45, 7083.
(d) Baran, P. S.; Ambhaikar, N. B.; Guerrero, C. A.; Hafensteiner, B. D.; Lin,
D. W.; Richter, J. M. Arkivoc 2006, 310. (e) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 6968.
(1) (a) Fahy, E.; Potts, B. C. M.; Faulkner, D. J.; Smith, K. J. Nat. Prod.
1991, 54, 564. (b) Garbe, T. R.; Kobayashi, M.; Shimizu, N.; Takesue, N.;
Ozawa, M.; Yukawa, H. J. Nat. Prod. 2000, 63, 596.
(2) (a) Yu, H.; Yu, Z. Angew. Chem., Int. Ed. 2009, 48, 2929. (b) Bandgar,
B. P.; Patil, A. V.; Kamble, V. T. Arkivoc 2007, 252. (c) Ma, S.; Yu, S. Org.
Lett. 2005, 7, 5063. (d) Zeng, X.-F.; Ji, S.-J.; Wang, S.-Y. Tetrahedron 2005,
61, 10235. (e) Kumar, S.; Kumar, V.; Chimni, S. S. Tetrahedron Lett. 2003,
44, 2101.
(3) For representative reviews, see: (a) Bergman, R. G. Nature 2007, 446,
391. (b) Godula, K.; Sames, D. Science 2006, 312, 67. (c) Ritleng, V.; Sirlin,
C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. (d) Dyker, G. Angew. Chem., Int.
Ed. 1999, 38, 1698. (e) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97,
2879. (f) Handbook of C-H Transformations; Dyker, D., Ed.; Wiley-VCH:
Weinheim, Germany, 2005.
(7) For representative reviews on iron catalyst, see: (a) Sherry, B. D.;
Furstner, A. Acc. Chem. Res. 2008, 41, 1500. (b) Correa, A.; Mancheno,
O. G.; Bolm, C. Chem. Soc. Rev. 2008, 37, 1108. (c) Enthaler, S.; Junge, K.;
Beller, M. Angew. Chem., Int. Ed. 2008, 47, 3317. (d) Furstner, A.; Martin, R.
Chem. Lett. 2005, 34, 624. (e) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
Rev. 2004, 104, 6217.
(8) The combination of an iron catalyst and peroxide is well-known in Gif
chemistry: (a) Stavropoulos, P.; Celenligil-Cetin, R.; Tapper, A. E. Acc.
Chem. Res. 2001, 34, 745. (b) Barton, D. H. R. Tetrahedron 1998, 54, 5805.
(c) Barton, D. H. R.; Doller, D. Acc. Chem. Res. 1992, 25, 504.
(9) A low yield of 3a was obtained by a condensation reaction of aldehyde
and indole, see: Giannini, G.; Marzi, M.; Moretti, G. P.; Penco, S.; Tinti,
M. O.; Pesci, S.; Lazzaro, F.; De Angelis, F. Eur. J. Org. Chem. 2004, 2411.
(10) Monoindolyl products were not observed, see: Bhuvaneswari, S.;
Jeganmohan, M.; Cheng, C. H. Chem.;Eur. J. 2007, 13, 8285.
(4) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497.
(5) (a) Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45, 1949.
(b) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242. (c) Li, C.-J.
Acc. Chem. Res. 2009, 42, 335.
8848 J. Org. Chem. 2009, 74, 8848–8851
Published on Web 10/26/2009
DOI: 10.1021/jo902093p
r
2009 American Chemical Society

Guo et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
TABLE 2. Synthesis of Symmetric Bis-indolylmethanesa
entry
catalyst
oxidant
(t-BuO)2
isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
Fe2(CO)9
Fe(OAc)2
Fe(acac)2
Fe(acac)3
FeCl2
FeBr2
FeCl3
FeI2
FeCl2
N.D.b
N.D.
N.D.
N.D.
86
85
85
37
50
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
(t-BuO)2
t-BuOOH
PhCOOO-t-Bu
FeCl2
FeCl2
<5
N.D.
N.D.
N.D.
(t-BuO)2
(t-BuO)2
FeCl2
a1a (1.0 mmol), 2a (1 mL), catalyst (0.1 mmol), and oxidant
(0.6 mmol). bNot detected by TLC. cTEMPO (0.5 mmol) was added.
Linear ethers reacted with 5-nitroindole 1f and 1a to give the
dealkoxyl products with moderate to excellent yields
(Table 2, entries 9-11). Importantly, two natural products,
Vibrindole A 3k11 and Streptindole 3l,12 were obtained in
37% and 17% yield, respectively, in one reaction under the
present reaction conditions (eq 1).
When the reaction of indole 1a with 2c was performed in
the presence of 1.2 equiv of peroxide at 60 °C, the mono-
indolation product 4a was formed in 13% together with a
83% yield of 3g (Scheme 1). Interestingly, the monoindola-
tion products, 4b and 4c, were obtained as major products
when electron-withdrawing substituted indoles, 1c and 1f,
were applied (Scheme 1). These results clearly demonstrated
that (1) the second indolation step is a Friedel-Craft alkyla-
tion reaction and (2) the second indolation step is the rate-
limiting step due to the energy being increased in the hetero-
lysis of the benzylic C-O bond.
With highly selective product 4c in hand, we envisioned
that the synthesis of unsymmetric bis-indolylmethane
derivatives might be achieved using our methodology.
Indeed, unsymmetric bis-indolylmethanes 5 were selec-
tively obtained by simply adding the second indole into
the reaction mixture in one pot (Scheme 2). The second
indolation step proceeds smoothly without the extra iso-
lation step and the additional catalyst. It is noteworthy
that iron catalyst is indispensable for the formation of 5.
The information for 5 was not observed in the reactions of
a1 (1.0 mmol), 2 (1 mL), FeCl2 (0.1 mmol), and (t-BuO)2 (0.6 mmol);
80 °C, 1 h. b5 h. cThe ratio of two isomers is given in parentheses. d50 °C,
12 h.
4 with other indoles without a catalyst. Not only 1,3-
dihydroisobenzofuran 2c but also isochroman 2d could
be used under the present reaction conditions. In all cases,
the information for symmetric 1,1-bis-indolylmethane
products generated from the second indoles was not ob-
served. Given the importance of nitro groups in organic
synthesis,13 the current procedure presents an alternative
method to construct various unsymmetric bis-indolyl-
methane derivatives, which are difficult to obtain by other
methods.
To investigate the possible mechanism of the present
double indolation, 1,3-deuterated indole 1a-D was synthe-
sized and subjected to the reaction under the standard
conditions. 3a was exclusively obtained in 61% yield
(11) Bell, R.; Carmeli, S.; Sar, N. J. Nat. Prod. 1994, 57, 1587.
(12) Osawa, T.; Namiki, M. Tetrahedron Lett. 1983, 24, 4719.
(13) The Nitro Group in Organic Synthesis; Ono, N., Ed.; Wiley-VCH:
New York, 2001.
J. Org. Chem. Vol. 74, No. 22, 2009 8849

Guo et al.
JOCNote
SCHEME 1. Monoindolylation vs. Double Indolylation
SCHEME 4. The Reaction of 1a and 1c with 4c
SCHEME 2. Synthesis of Unsymmetric Bis-indolylmethanesa
SCHEME 5. The Reaction of 1a and 1c with 2a
SCHEME 6. A Tentative Mechanism for the Formation of 3
and 5
aReaction conditions: The first indole (0.5 mmol), 2 (0.5 mL), FeCl2
(0.05 mol), and (t-BuO)2 (0.6 mmol) and the second indole (0.5 mmol).
The overall yield was provided.
SCHEME 3. The Reactions of 1,3-Deuterated Indole 1a-D and
THF
properties of indoles in two indolation steps. The results
indicated that the second indolation step depended on the
electronic effect of indoles, which agrees with the Friedel-
Crafts aromatic alkylation (Schemes 4 and 1). However, the
first indolation step is less influenced by the electronic
properties of indoles (Scheme 5).15 In others words, the first
C-C bond formation is likely a radical process rather than
an ionic one.
On the basis of the above results, a tentative mechanism
was proposed (Scheme 6). H-abstraction gives an intermedi-
ate A. Radical addition offers an intermediate B, followed by
oxidation leading to the oxidative coupling product 4.16 The
(Scheme 3). The deuterated product 3a-D was not observed.
Therefore, the possible intermediate of 2,3-dihydrofuran 2a0
was excluded.14
Furthermore, a series of competition experiments were
investigated to address the influences of the electronic
(15) See the details in the Supporting Information.
(16) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, Germany, 2001. (b) Guerrero, M. A.; Miranda, L. D. Tetra-
hedron Lett. 2006, 47, 2517. (c) Miranda, L. D.; Cruz-Almanza, R.; Pavon, M.
Arkivoc 2002, 15.
(14) Yadav, J. S.; Reddy, B. V. S.; Satheesh, G.; Prabhakar, A.; Kunwar,
A. C. Tetrahedron Lett. 2003, 44, 2221.
8850 J. Org. Chem. Vol. 74, No. 22, 2009

Guo et al.
JOCNote
double indolation product 3 or 5 is formed by Friedel-Craft
alkylation reaction in the presence of iron catalyst.17
In summary, we demonstrated an efficient method to
synthesize symmetric and unsymmetric bis-indolylmethane
derivatives. These results demonstrate the dichotomous
catalytic behavior of the iron catalysts, which are transition
metal catalyst in C-C bond oxidative coupling and Lewis
acid in C-O bond cleavage. The knowledge should prompt a
broad range of applications of iron-catalyzed C-H bond
oxidation and C-O bond cleavage.
5 mmol), and FeCl2 (0.05 mmol) was dropped di-tert-butyl
peroxide (0.6 mmol) under nitrogen at room temperature. The
resulting mixture was stirred at 60 °C for 1 h. 5-Methylindole 1d
(0.5 mmol) was added into the reaction mixture. The resulting
mixture was stirred at 60 °C for 2 h. The reaction temperature
was cooled to room temperature; the resulting reaction solution
was mixed with some silica gel. Solvent was evaporated and the
residue was purified by flash column chromatography on silica
gel with ethyl acetate/petroleum ether (1:3) as eluent. The
fraction with a Rf 0.3 (ethyl acetate/petroleum ether = 1:1)
was collected to give the desired product 5a. IR (neat) νmax 3393,
3321, 3283, 3084, 3034, 2982, 2918, 1722, 1626, 1518, 1468, 1325,
1250, 1098, 1038, 1009, 797, 752, 606 cm-1; 1H NMR (ppm) δ
11.60 (s, 1H), 10.74 (s, 1H), 8.35 (s, 1H), 8.00 (d, J = 9.2 Hz, 1H),
7.57 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.29 (d, J =
8.0 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.18-7.09 (m, 3H), 6.95 (s,
1H), 6.91 (d, J = 8.4 Hz, 1H), 6.65 (s, 1H), 6.27 (s, 1H), 5.31 (t,
J = 5.2 Hz, 1H), 4.69 (dd, J = 13.2, 5.2 Hz, 1H), 4.62 (dd, J =
13.2, 5.2 Hz, 1H), 2.30 (s, 3H); 13C NMR (ppm) δ 141.8, 140.7,
140.4, 140.0, 135.5, 128.4, 128.1, 127.8, 127.3, 127.2, 127.1,
126.5, 124.5, 123.2, 121.3, 118.9, 117.0, 116.7, 112.5, 111.8,
61.3, 34.7, 21.8; MS (EI) m/z (%) 411, 393(100), 376, 361, 346,
331, 304, 280, 263, 232, 231, 204, 189, 165, 144, 131, 119, 91, 84,
66, 46; HRMS calcd for C25H20N3O3 [M - H] 410.1499, found
410.1493.
Experimental Section
General Procedure for Products 3. To a mixture of indole 1a
(1 mmol), THF 2a (1.0 mL, 12 mmol), and FeCl2 (0.1 mmol) was
dropped di-tert-butyl peroxide (0.6 mmol) under nitrogen at
room temperature. The resulting mixture was stirred at 80 °C for
1 h. The reaction temperature was cooled to room temperature;
the resulting reaction solution was mixed with some silica gel.
Solvent was evaporated and the residue was purified by flash
column chromatography on silica gel with ethyl acetate/petro-
leum ether (1:3) as eluent. The fraction with a Rf 0.4 (ethyl
acetate/petroleum ether = 1:1) was collected to give the desired
product 3a. 1H NMR (ppm) δ 7.75 (s, 2H), 7.53 (d, J = 8.0 Hz,
2H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 7.6 Hz, 2H), 6.99 (t,
J = 7.6 Hz, 2H), 6.74 (s, 2H), 4.40 (t, J = 7.2 Hz, 1H), 3.52 (t,
J = 6.4 Hz, 2H), 2.18 (q, J = 7.6 Hz, 2H), 1.56 (q, J = 7.2 Hz,
2H); 13C NMR (ppm) δ 136.5, 127.0, 121.6, 121.5, 119.8, 119.5,
118.9, 111.1, 62.9, 33.7, 31.9, 31.3.
Acknowledgment. We thank the NSFC (20602038 and
20832002) and the State Key Laboratory of Fine Chemi-
cals (No. KF0704) for financial support. We also thank
the program for New Century Excellent Talents in Uni-
versity. We are indebted to Prof. Zhenfeng Xi, Peking
University.
General Procedure for Products 5. To a mixture of 5-nitroin-
dole 1f (0.5 mmol), 1,3-dihydroisobenzofuran 2c (0.5 mL,
(17) Indolation by Lewis acid-catalyzed C-O bond cleavage: (a) Refer-
ences 11 and 15. (b) Barluenga, J.; Fernandez, A.; Rodriguez, F.; Fanans, F. J.
J. Organomet. Chem. 2009, 694, 546. (c) Yadav, J. S.; Reddy, B. V. S.; Aravind,
S.; Kumar, G. G. K. S. N.; Reddy, A. S. Tetrahedron Lett. 2007, 48, 6117.
(d) Zeng, X.-F.; Ji, S.-J.; Wang, S.-Y. Tetrahedron 2005, 61, 10235. Indolation by
protic acid-catalyzed C-O bond cleavage: (e) Reference 2b.
Supporting Information Available: Representative experi-
mental procedures, characterization of all new compounds, and
the copies of 1H NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8851