Iridium-catalyzed hydrogen transfer: Synthesis of substituted benzofurans, benzothiophenes, and indoles from benzyl alcohols

Article abstract of DOI:10.1021/ol401610e

An iridium-catalyzed hydrogen transfer has been developed in the presence of p-benzoquinone, allowing the synthesis of a diversity of substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.

Full text of DOI:10.1021/ol401610e

ORGANIC
LETTERS
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Vol. XX, No. XX
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Iridium-Catalyzed Hydrogen Transfer:
Synthesis of Substituted Benzofurans,
Benzothiophenes, and Indoles from
Benzyl Alcohols
Bruno Anxionnat,† Domingo Gomez Pardo,† Gino Ricci,‡ Kai Rossen,§ and
Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
ꢀ
75231 Paris Cedex 05, France, Sanofi, Process Development, 45 chemin de Meteline,
BP 15, 04201 Sisteron Cedex, France, Sanofi-Aventis Deutschland GmbH, Chemistry &
€
Biotechnology Development (C&BD) Frankfurt Chemistry Industriepark Hoechst,
Building G 838, 65926 Frankfurt am Main, Germany
janine.cossy@espci.fr
Received June 7, 2013
ABSTRACT
An iridium-catalyzed hydrogen transfer has been developed in the presence of p-benzoquinone, allowing the synthesis of a diversity of
substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.
Oxidation is one of the most important reactions, and
oxidation state adjustments are very frequent operations in
organic synthesis. In green chemistry processes, heavy
metal oxidants in stoichiometric quantities have to be
avoided, and methods using nontoxic and recyclable
reagents need to be developed. Transition metal catalysts
such as palladium, copper, and ruthenium catalysts have
been utilized to oxidize alcohols in the presence of H2O2
and O2,1 and oxidation/reduction sequences using hydro-
gen transfer induced by iridium, cobalt, and rhodium
catalysts have been developed in the past 20 years.2 Iridium
complexes are more stable than rhodium and cobalt com-
plexes under thermal conditions; therefore iridium cata-
lysts are the catalysts of choice for hydrogen transfer
processes.3 Recently, we have reported that acetonitrile
could be monoalkylated by primary alcohols through a
one-pot oxidation/reduction sequence in the presence of
iridium catalysts4 and that intramolecular alkylation of
nitriles by primary and secondary alcohols via a hydrogen
transfer using [Ir(cod)Cl]2 or [IrCp*Cl2]2 catalysts led to
tetrahydronaphthalenes, chromanes, and thiochromanes
† ESPCI ParisTech, CNRS.
‡ Sanofi.
§ Sanofi-Aventis Deutschland GmbH.
(1) (a) Sheldon, R. A.; Arends, I. W. C. E.; Brink, G.-J.; Dijksman, A.
€
Acc. Chem. Res. 2002, 35, 774–781. (b) Piera, J.; Backvall, J.-E. Angew.
Chem., Int. Ed. 2008, 47, 3506–3523 and references therein.
(2) Tejel, C.; Ciriano, M. A. In Topics in Organometallic Chemistry,
Vol. 22; Springer-Verlag: Berlin, Heidelberg, 2007; pp 97À124 and
references therein.
(3) (a) Suzuki, T. Chem. Rev. 2011, 111, 1825–1845 and references
therein. (b) Sawaguchi, T.; Obora, Y. Chem. Lett. 2011, 40, 1055–1057. (c)
Zhou, J.; Fang, J. J. Org. Chem. 2011, 76, 7730–7736. (d) Zhang, W.; Dong,
X.; Zhao, W. Org. Lett. 2011, 13, 5386–5389. (e) Xu, C.; Goh, L. Y.;
Sumod, A. Organometallics 2011, 30, 6499–6502. (f) Maenaka, Y.; Suenobu,
T.; Fukuzumi, S. J. Am. Chem. Soc. 2011, 134, 367–374. (g) Li, F.; Shan, H.;
Chen, L.; Kang, Q.; Zou, P. Chem. Commun. 2012, 48, 603–605. (h) Xu, C.;
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Song, M.-P. J. Organomet. Chem. 2012, 700, 214–218. (i) Kawahara, R.;
Fujita, K.-I.; Yamaguchi, R. J. Am. Chem. Soc. 2012, 134, 3646–3646. (j)
Fang, J.; Zhou, J. Org. Biomol. Chem. 2012, 10, 2389–2391. (k) Michlik, S.;
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Kang, Q.; Shan, H.; Chen, L.; Xie, J. Eur. J. Org. Chem. 2012, 5085–5092.
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Brinks, M. K.; Rominger, F.; Hofmann, P.; Limbach, M. Org. Lett. 2013,
15, 266–269. (o) Pan, S.; Shibata, T. ACS Catal. 2013, 3, 704–712.
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r
10.1021/ol401610e
XXXX American Chemical Society

in good yields.5 These tandem reactions proceed with a
concomitant liberation of hydrogen in the presence of Ir or
Ru catalysts.6 Some studies havealsobeen developedusing
a co-oxidant to regenerate the Ir catalyst.7
Here, we would like to report that substituted benzo-
furans, benzothiophenes, and indoles of type B can be pre-
pared from benzylic alcohols A using an iridium catalyst in
the presence of p-benzoquinone as the co-oxidant (Scheme 1).8
To avoid the reduction of 2 to 3 by the formal inter-
mediate [Ir]ÀH complex, resulting from the oxidation of
the alcohol, the addition of p-benzoquinone in the reaction
media was envisaged. If p-benzoquinone is reduced faster
by [Ir]ÀH to hydroquinone than benzofuran 2 to dihydro-
benzofuran 3, the iridium catalyst would be regenerated
(Scheme 3).
Scheme 3. Hypothesis for the Synthesis of Benzofurans in Pre-
sence of [Ir] Complex and p-Benzoquinone
Scheme 1. Cyclization of Benzylic Alcohols A to B
As substituted benzofurans are encountered in several
bioactive molecules such as cicerfuran (antifungal),9 and
machicendiol (asthma and rheumatism),10 it is of interest
to develop new methods to access benzofurans, and an
attractive approach will start from the easily accessible
compounds of type A (X = O). Compound 1 was prepared
and treated under Conditions I {[IrCp*Cl2]2 (2.5 mol %),
Cs2CO3 (20 mol %), 1,4-dioxane, 110 °C, 20 h, MW},4
Conditions II {[Ir(cod)Cl]2 (2.5 mol %), PPh3 (10 mol %),
Cs2CO3 (20 mol %), 1,4-dioxane, 110 °C, 20 h, MW},5
and Conditions III {([IrLCp*Cl]11 (5 mol %), Cs2CO3
(10 mol %), toluene, 110 °C, 20 h, MW)}. Under Con-
ditions I and II, a 50% conversion of1 and the formation of
2 and 3 in a ratio of 50/50 was observed. Under Conditions
III, the conversion of 1 was low (13%) but benzofuran 2
was the only observed product (Scheme 2).12
A screening ofthe conditions(base, solvent) was realized
to transform 1 to 2 in good yields. Using 0.2 equiv of
Cs2CO3 in toluene led, after 60 h, to aldehyde 4 as the
major product (85%) and to 5% of the desired benzofuran
2(Table 1, entry 1). Increasing the quantity of base (1.5 equiv)
produced, after 40 h, aldehyde 4 (45%) and benzofuran 2
(39%) (Table 1, entry 2). The best conditions were the use
of [IrCp*Cl2]2 (2.5 mol %), p-benzoquinone (1.1 equiv),
and Cs2CO3 (1.5 equiv) in 1,4-dioxane instead of toluene
at 110 °C for 20 h (Conditions IV), as 1 was fully converted
to 2 and isolated in 92% yield (Table 1, entry 3). We have
to point out that when t-BuOK was used instead of
Cs2CO3, whatever the solvent (toluene or 1,4-dioxane),
Scheme 2. Preliminary Results
Table 1. Screening of the Reaction Conditions
base
2a
5%
4a
a
entry
1
(equiv)
solvent
toluene
toluene
time
τc
Cs2CO3
(0.2 equiv)
Cs2CO3
60 h 90%
40 h 84%
85%
(5) Anxionnat, B.; Gomez Pardo, D.; Ricci, G.; Cossy, J. Eur. J. Org.
Chem. 2012, 4453–4456.
2
3
4
5
39%
45%
/
(1.5 equiv)
Cs2CO3
(6) See for examples: (a) Whitney, S.; Grigg, R.; Derrick, A.; Keep,
A. Org. Lett. 2007, 9, 3299–3302. (b) Aramoto, A.; Obora, Y.; Ishii, Y.
J. Org. Chem. 2009, 74, 628–633. (c) Srimani, D.; Ben-David, Y.;
Milstein, D. Angew. Chem. 2013, 125, 4104–4107. (d) Michlik, S.;
Kempe, R. Nat. Chem. 2013, 5, 140–144. (e) Zhang, M.; Neumann,
H.; Beller, M. Angew. Chem. 2013, 125, 625–629.
(7) See for examples: (a) Suzuki, T.; Matsuo, T.; Watanabe, K.;
Katoh, T. Synlett 2005, 1453–1455. (b) Izumi, A.; Obora, Y.; Sakaguchi,
S.; Ishii, Y. Tetrahedron Lett. 2006, 47, 9199–9201.
1,4-dioxane 20 h 100%
toluene 20 h 100%
1,4-dioxane 20 h 100%
100%
(92%)b
87%
(1.5 equiv)
t-BuOK
13%
30%
(1.5 equiv)
t-BuOK
70%
(1.5 equiv)
a Determined by GC/MS. b Isolated yield.
(8) Liu, Z.; Deeth, R. J.; Butler, J. S.; Habtemariam, A.; Newton,
M. E.; Sadler, P. J. Angew. Chem., Int. Ed. 2013, 52, 4194–4197.
B
Org. Lett., Vol. XX, No. XX, XXXX

a mixture of aldehyde 4 and benzofuran 2 was obtained
(Table 1, entries 4 and 5).
To introduce structural diversity into the benzofuran,
secondary benzylic alcohols 15 and 16 were subjected to
the reaction conditions and, after 20 h, a complete conver-
sion of the starting material was observed. To our delight,
we were able to isolate the corresponding benzofurans 17
and 18 in good to excellent yields (60% to 92%). A
diversity of functional groups was tolerated; however
no conversion was observed in the case of the dithianyl
derivative 15e as the steric hindrance prevents oxida-
tion of the alcohol to the intermediate ketone, and
treatment of 15f with [IrCp*Cl2]2 [p-benzoquinone,
Cs2CO3, 1,4-dioxane] led only to the degradation of
this alcohol (Scheme 6).
Having determined a useful set of reaction conditions,
the scope and limitation of the transformation of benzylic
alcohols of type A to benzofurans of type B was examined.
In this transformation, the presence of various electron-
withdrawing groups was not detrimental to the process, as
benzofurans 2, 8, 9, and 10 were obtained with good to
excellent yields (Scheme 4).
Scheme 4. Generalization of the Reaction
Scheme 6. Cyclization of Secondary Benzylic Alcohols, Scope,
and Limitations
The substitution of the aromatic ring was then studied,
and benzofurans 13 and 14 were obtained in good to
excellent yields from the corresponding benzylic alcohols
11 and 12 possessing electron-donating or electron-with-
drawing groups on the aromatic ring. However, when
the aromatic ring of benzylic alcohols 11 and 12 was
substituted by a methoxy group at C5, no cyclized product
(13c and 14c) was observed but only degradation of the
alcohols occurred (Scheme 5).
Scheme 5. Influence of the Substitution of the Aromatic Ring of
the Benzylic Alcohol on the Formation of Benzofurans
With an efficient synthesis of benzofurans established,
we turned our attention to the synthesis of benzothiophenes
Scheme 7. Synthesis of Benzothiophenes and Indoles
(9) Stevenson, P. C.; Veitch, N. C. Phytochemistry 1998, 48, 947–951.
(10) Schneiders, G. E.; Stevenson, R. J. Org. Chem. 1979, 44, 4710–
4711.
(11) Fujita, K.-I.; Yoshida, T.; Imori, Y.; Yamaguchi, Y. Org. Lett.
2011, 13, 2278–2281.
(12) Conversions were determined by GC/MS.
Org. Lett., Vol. XX, No. XX, XXXX
C

21 and indoles 22 (Scheme 7). For that purpose, we have
examined the reactivity of 19 and 20 toward the standard
reaction conditions (Conditions IV). We were able to
isolate benzothiophenes 21 and indoles 22 in yields ranging
from 40% to 86%. Surprisingly, N-tosylbenzyl alcohol 20d
(X = NTs, EWG = CO2t-Bu) was transformed to 22d in
80% yield (Scheme 7).
Scheme 8. Supposed Mechanism for the Formation of 22d
The transformation of 20d to22d can be explainedby the
oxidation of 20d to aldehyde 23 which cyclized to 24,
probably via an aldolization. After cleavage of the N-tosyl
group under basic conditions, the hydroxyimine 25 could
be formed, and this latter transformed to 22d through a
tautomeric equilibrium (Scheme 8).
In conclusion, we have developed an efficient che-
moselective hydrogen transfer method catalyzed by
[IrCp*Cl2]2 which, in the presence of p-benzoquinone,
allows the synthesis of diversely substituted benzofur-
ans, benzothiophenes, and indoles from substituted
benzylic alcohols.
Supporting Information Available. Experimental pro-
cedure and characterization data and NMR spectra of
benzylics alcohols and heterocyclic compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. B.A. thanks Sanofi for a grant. Sanofi
is gratefully acknowledged for financial support.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX