Iodide-Ion-Catalyzed carbon-carbon bond-forming cross-dehydrogenative coupling for the synthesis of indole derivatives

Article abstract of DOI:10.1002/ejoc.201201585

The nBu₄NI-catalyzed intramolecular cross-dehydrogenative coupling (CDC) reaction has been applied to the synthesis of 1H-indole derivatives. Intramolecular oxidative coupling of N-arylenamines proceeded in the presence of a catalytic amount of nBu₄NI and tert-butyl hydroperoxide (TBHP) to afford the corresponding 1H-indole derivatives in good-to-excellent yields. A preliminary study of the synthesis of 3H-indole is also reported. This is a rare example of the nBu₄NI-catalyzed C-C bond-forming CDC reaction. Copyright

Full text of DOI:10.1002/ejoc.201201585

Job/Unit: O21585
/KAP1
Date: 03-01-13 17:42:46
Pages: 5
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201585
Iodide-Ion-Catalyzed Carbon–Carbon Bond-Forming Cross-Dehydrogenative
Coupling for the Synthesis of Indole Derivatives
Zhenhua Jia,[a] Takashi Nagano,*[b] Xingshu Li,*[a] and Albert S. C. Chan[c]
Keywords: Synthetic methods / Homogeneous catalysis / Oxidation / Cross-coupling / Nitrogen heterocycles / Iodine
The nBu4NI-catalyzed intramolecular cross-dehydrogenative
coupling (CDC) reaction has been applied to the synthesis of
1H-indole derivatives. Intramolecular oxidative coupling of
N-arylenamines proceeded in the presence of a catalytic
amount of nBu4NI and tert-butyl hydroperoxide (TBHP) to
afford the corresponding 1H-indole derivatives in good-to-
excellent yields. A preliminary study of the synthesis of 3H-
indole is also reported. This is a rare example of the nBu4NI-
catalyzed C–C bond-forming CDC reaction.
Introduction
Recently, increasing attention has been paid to the devel-
opment of environmentally benign organic transforma-
tions.[1] Cross-dehydrogenative coupling (CDC) is one of
the most attractive synthetic tools for such transforma-
tions.[2] Recently, we reported on a new concept of catalysis
for CDC reactions by using the redox properties of halide
ions; we demonstrated that the use of catalytic amounts of
nBu4NBr and aq. TBHP was effective for the α-acetoxyl-
ation of ketones [Scheme 1, Eq. (1)].[3] Independently, Ishi-
hara and co-workers reported that quaternary ammonium
iodide/TBHP or H2O2 could be used for intramolecular
cycloetherification.[4] More recently, they extended the use
of their catalytic system to the intermolecular α-acyloxyl-
ation of carbonyl compounds.[5] Because non-metal-cata-
lyzed oxidative coupling reactions[6] are quite attractive,
other research groups have recently focused on the use of
the hydroperoxide/nBu4NI system for CDC reactions
(Scheme 2).[7,8] For example, Wan and co-workers reported
the oxidative coupling between carboxylic acids and 1,4-
dioxane under Ishihara’s conditions.[9] Nachtsheim and co-
workers reported the first iodide-catalyzed oxidative amin-
ation of heteroarenes,[10] and shortly afterwards Yu and
Scheme 1. Concept of our MX catalysis (S–H = substrate). In our
previous report,[3] S–H = ketone and Nu–H = AcOH.
Han and co-workers reported the oxidative coupling of
aminopyridines with β-keto esters.[11] Rodríguez and Moran
reported the first example of a C–C bond-forming reaction
by using the nBu4NI/H2O2 system, in which a δ-alkynyl β-
keto ester underwent oxidative cyclization.[12] In our pre-
vious report, we demonstrated that the oxidation of the
bromide ion in MBr to bromine in the presence of an or-
ganic substance with a sufficiently acidic hydrogen (Nu–H)
co-generated the corresponding conjugate base (NuM), as
shown in Scheme 1. In the case of the α-acetoxylation of
ketone, this NuM (AcONnBu4) reacts as a nucleophile with
intermediate S–X (α-bromo ketone) to give the product. In
the course of our study on this halide-ion catalysis, we con-
sidered the use of NuM as a base instead of a nucleophile
because various oxidative transformations using stoichio-
metric amounts of X2 and base might be catalytic.[13] To
[a] Institute of Drug Synthesis and Pharmaceutical Process, School
of Pharmaceutical Sciences, Sun Yat-sen University,
Guangzhou 510006, China
Fax: +86-20-3994-3050
E-mail: lixsh@mail.sysu.edu.cn
Homepage: http://sps.sysu.edu.cn/pharmacy/advisors/201001/
6176.html
[b] Department of Chemistry, Faculty of Science, Kochi University,
Kochi 780-8520, Japan
Fax: +81-88-844-8359
E-mail: tnagano@kochi-u.ac.jp
Homepage: http://www.sc.kochi-u.ac.jp/~apply/
[c] Institute of Creativity, Hong Kong Baptist University,
Hong Kong (China)
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201585.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O21585
/KAP1
Date: 03-01-13 17:42:46
Pages: 5
Z. Jia, T. Nagano, X. Li, A. S. C. Chan
SHORT COMMUNICATION
demonstrate our idea, we chose Li’s indole synthesis as a in decane instead of aq. TBHP gave a good yield of 83%
model reaction. Li and co-workers recently reported the use (entry 4). Needless to say, the reaction in the absence of
of stoichiometric amounts of iodine and K2CO3 as base for catalyst did not proceed at all (entry 5). A lower catalyst
the synthesis of 3H-indole derivatives (Scheme 3, a).[14] loading or decreased reaction temperature resulted in lower
More recently, they extended the use of their system to the yields (entries 6 and 7). However, increasing the amount of
synthesis of 1H-indoles by using a catalytic amount of I2 TBHP led to an excellent yield of the indole (entry 8). Fi-
and stoichiometric amounts of N-bromosuccinimide (NBS) nally, the counter cation in the MI catalyst was varied and
and base (Scheme 3, b).[15,16] Herein, we report on the C–C nBu4N+ was found to be the best (entries 8–13).
bond-forming CDC reaction using our catalyst system.
Table 1. Optimization of the reaction conditions for the CDC reac-
tion.[a]
Entry
Oxidant
(amount [equiv.])
MX cat.
(amount [mol-%]) [°C]
T
Yield[b]
[%]
1
2
3
4
5
6
7
8
aq. TBHP (1.5)
aq. TBHP (1.5)
aq. H2O2 (1.5)
TBHP (1.5)[c]
TBHP (1.5)[c]
TBHP (1.5)[c]
TBHP (1.5)[c]
TBHP (2.5)[c]
TBHP (2.5)[c]
TBHP (2.5)[c]
TBHP (2.5)[c]
TBHP (2.5)[c]
TBHP (2.5)[c]
nBu4NI (30)
nBu4NBr (30)
nBu4NI (30)
nBu4NI (30)
none
nBu4NI (20)
nBu4NI (30)
nBu4NI (30)
LiI (30)
NaI (30)
KI (30)
Me4NI (30)
NH4I (30)
100
100
100
100
100
100
80
67
trace
39
83
0
44
49
100 91 (99)[d]
9
100
100
100
100
100
41
36
57
70
11
10
11
12
13
Scheme 2. Examples of nBu4NI-catalyzed oxidative coupling reac-
tions recently reported by other groups.
[a] The reactions were carried out with 1a (0.5 mmol) in AcOH
(0.25 mL)/DMF (0.25 mL). [b] Isolated yield. [c] TBHP in decane.
[d] The reaction was carried out with 1.0 mmol of 1a.
With the optimized conditions in hand, we then investi-
gated the substrate scope of this catalytic system (Table 2).
A substituent on the phenyl group at the R2 position did
not affect the efficiency of this reaction, giving the corre-
sponding 1H-indoles 2b and 2c in yields of 97 and 93%,
respectively (entries 2 and 3). A variety of electron-donating
and -withdrawing groups at the R1 position gave good-to-
excellent yields (entries 4–18), although meta-substituted
substrates such as 1f, 1j, and 1o gave mixtures of regioiso-
mers with low selectivities (entries 6, 10, and 15). Not only
an ester but also a ketone functionality can be used at the
R3 position in this system (entry 19). However, a substrate
Scheme 3. (a) 3H-Indole synthesis and (b) indole synthesis per-
formed with stoichiometric “X+” and base, as reported by Li and
co-workers.
Results and Discussion
Initially we optimized the reaction conditions for the with an amide moiety at the R3 position gave a low yield,
synthesis of 1H-indoles by using ethyl (Z)-3-phenyl-3- as has already been reported by Li and co-workers (en-
(phenylamino)acrylate (1a) as a model substrate. Intramo- try 20).[14] The presence of alkyl groups instead of aryl
lecular oxidative coupling of 1a with aq. TBHP as oxidant groups at the R2 position did not give reproducible results
in the presence of 30 mol-% nBu4NI proceeded well to af- in our case because of the decomposition of the products.[17]
ford the corresponding 1H-indole 2a in 67% yield even A preliminary study of the synthesis of 3H-indoles was also
though our previous catalytic system using nBu4NBr was performed (Scheme 4); the reaction of ethyl (Z)-2-methyl-
not effective for this transformation (Table 1, entries 1 and 3-phenyl-3-(phenylamino)acrylate (3) under the optimized
2). The use of more environmentally benign aq. H2O2 re- conditions gave the corresponding 3H-indole 4 in 73%
sulted in a yield of only 39% (entry 3). The use of TBHP yield.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21585
/KAP1
Date: 03-01-13 17:42:46
Pages: 5
Synthesis of Indole Derivatives
Table 2. Substrate scope of iodide-ion-catalyzed CDC reaction.
AcOH (entry 8), we cannot completely exclude the possibil-
ity of a pathway via a hypoiodite and/or iodite formed by
the direct oxidation of I– with tBuOOH in the absence of a
proton source.[18] The addition of TEMPO did not suppress
the reaction completely, which suggests that a radical path-
way does not predominate (entry 9).[19] The mechanism
does not seem to be simple and further study will be needed
to elucidate the detailed mechanism of this transformation.
Entry R1
R2
Ph
R3
Product Yield [%][a]
Table 3. Control experiments.
1
2
H
H
COOEt
2a
2b
99
97
93
pBrC6H4 COOEt
pCF3C6H4 COOEt
3
4
5
6
7
8
H
2c
pOMe
oOMe
mOMe
pOEt
pCl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COPh
2d
2e
2f/2fЈ
2g
2h
2i
2j/2jЈ
2k
2l
2m
2n
2o/2oЈ
2p
2q
2r
84
82
84[b]
94
Entry Conditions
Yield
[%][a]
81
9
oCl
mCl
pBr
81
10
11
12
13
14
15
16
17
18
19
20
79[c]
95
1
2
3
4
5
6
7
8
9
I2 (1 equiv.)
I2 (1 equiv.)/nBu4NOAc (2 equiv.)
0
85
77
50
55
44
0
pI
71
80
TBHP[b]/I2 (15 mol-%)/nBu4NOAc (30 mol-%)
TBHP[b]/I2 (15 mol-%)/NaOAc (30 mol-%)
TBHP[b]/I2 (15 mol-%)/KOAc (30 mol-%)
TBHP[b]/I2 (15 mol-%)/K2CO3 (30 mol-%)
TBHP[b]/nBu4NOAc (30 mol-%)
pMe
oMe
mMe
pNO2
pCF3
75
77[d]
78
96
83
no AcOH was added under the optimized conditions
30
41
1-naphthyl[e] Ph
TBHP[b]/nBu4NI (30 mol-%)/TEMPO (1 equiv.)
H
H
Ph
Ph
2s
88
[a] Isolated yield. [b] 2.5 equiv.
CONHPh 2t
27
[a] Isolated yield. [b] A mixture of regioisomers was formed (2f/2fЈ
= 1.1:1). [c] Combined yield of 2j (38%) and 2jЈ (41%). [d] A mix-
ture of regioisomers was formed (2o/2oЈ = 1:2.2). [e] 1-Naphthyl
was used instead of R1-C6H4-.
Conclusions
We have developed an iodide-ion-catalyzed intramolecu-
lar oxidative coupling of N-arylenamines to yield indole de-
rivatives. This is a rare example of the nBu4NI-catalyzed C–
C bond-forming CDC reaction. We have demonstrated that
our catalyst system, in which X2 and MOAc are generated
from the reaction of MX and hydroperoxide in the presence
of AcOH, can be applied to the oxidative transformations
that have been traditionally performed by using stoichio-
metric amounts of X2 and base. Further applications of this
halide-ion catalysis are in progress in our laboratory.
Scheme 4. Preliminary study of the synthesis of 3H-indole.
To confirm our hypothesis that the catalytic formation
of I2 and nBu4NOAc from nBu4NI and TBHP in the pres-
ence of acetic acid promoted the reaction, we carried out Experimental Section
control experiments as shown in Table 3. Although the re-
General Procedure for Iodide-Ion-Catalyzed CDC Reaction: An
action of 1a with 1 equiv. of I2 in AcOH/DMF did not give
the product 2a, the addition of both 1 equiv. of I2 and
2 equiv. of nBu4NOAc promoted the reaction to afford 2a
in 85% yield (entry 2). Catalytic amounts of I2 and
oven-dried Schlenk flask was charged with ethyl (Z)-3-phenyl-3-
(phenylamino)acrylate (134 mg, 0.50 mmol) and nBu4NI (55 mg,
30 mol-%). The flask was sealed, evacuated, and backfilled with
argon (repeated three times). AcOH (0.25 mL) and DMF
nBu4NOAc also promoted the reaction by using TBHP as (0.25 mL) were added through a syringe, and then TBHP in decane
(227 mL, ca. 2.5 mmol) was added. The mixture was stirred at
100 °C for 24 h, cooled to 0 °C, and diluted with water. The mix-
ture was poured into a saturated aqueous solution of NaHCO3 and
extracted with CH2Cl2 (3ϫ 10 mL). The extracts were dried with
MgSO4 and concentrated in vacuo. The residue was added to a
short column of silica gel and eluted by using hexane/AcOEt (3:2)
as eluent. After evaporation, the residue was purified by
chromatography on silica gel using petroleum ether/EtOAc (50:1)
as eluent to give ethyl 2-phenyl-1H-indole-3-carboxylate (121 mg,
91%). 1H NMR (400 MHz, CDCl3): δ = 8.72 (s, 1 H), 8.20 (d, J =
re-oxidant (entry 3). These experiments suggest the impor-
tance of both iodine and base to the reaction. Other bases
such as NaOAc, KOAc, and K2CO3 also promoted the re-
action, but the efficiency was low, in accord with the experi-
ments reported in Table 1 (entries 4–6). It was also con-
firmed that nBu4NOAc does not catalyze the reaction (en-
try 7). Judging from these observations, we can tentatively
conclude that this oxidative transformation mainly proceeds
by the catalytic formation of I2 and nBu4NOAc. Because
the product 2a was obtained in 30% yield in the absence of 7.3 Hz, 1 H), 7.61–7.60 (m, 2 H), 7.40–7.38 (m, 3 H), 7.34–7.23 (m,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O21585
/KAP1
Date: 03-01-13 17:42:46
Pages: 5
Z. Jia, T. Nagano, X. Li, A. S. C. Chan
SHORT COMMUNICATION
3 H), 4.26 (q, J = 7.1 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 165.4, 144.5, 135.2, 132.0, 129.6,
129.1, 128.0, 127.6, 123.1, 122.1, 122.0, 111.0, 104.6, 59.7,
14.2 ppm. HRMS (ESI): calcd. for C17H15NO2Na [M + Na]+
288.0995; found 288.1002.
[7] The oxidative “homo” dehydrogenative coupling of thiols to
disulfides by using the NaI/H2O2 system has been reported,
see: M. Kirihara, Y. Asai, S. Ogawa, T. Noguchi, A. Hatano,
Y. Hirai, Synthesis 2007, 3286–3289.
[8] For a review on oxidative coupling by using the halide salt/
ROOH system, see: M. Uyanik, K. Ishihara, ChemCatChem
2012, 4, 177–185.
[9] L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu, X.
Wan, Chem. Eur. J. 2011, 17, 4085–4089.
[10] T. Froehr, C. P. Sindlinger, U. Kloeckner, P. Finkbeiner, B.
Nachtsheim, Org. Lett. 2011, 13, 3754–3757.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data of the prod-
1
ucts, and copies of the H and 13C NMR spectra.
[11] L. Ma, X. Wang, W. Yu, B. Han, Chem. Commun. 2011, 47,
11333–11335.
[12] A. Rodríguez, W. J. Moran, Org. Lett. 2011, 13, 2220–2223.
[13] Needless to say, halogen should not be incorporated into the
product.
Acknowledgments
The work at Kochi was supported by the Japanese Ministry of Edu-
cation, Culture, Sports, Science and Technology (MEXT) through
a Grant-in-aid for Young Scientists B (grant number 23750042).
The work at Guangzhou was supported by the National Natural
Science Foundation of China (NSFC) (grant number 20972198).
T. N. acknowledges Mitsubishi Tanabe Pharma for financial sup-
port.
[14] Z. He, H. Li, Z. Li, J. Org. Chem. 2010, 75, 4636–4639.
[15] Z. He, W. Liu, Z. Li, Chem. Asian J. 2011, 6, 1340–1343.
[16] For other examples of the synthesis of indole derivatives by
intramolecular oxidative coupling, see: a) Y. Du, R. Liu, G.
Linn, K. Zhao, Org. Lett. 2006, 8, 5919–5922; b) W. Yu, Y. Du,
K. Zhao, Org. Lett. 2009, 11, 2417–2420; c) S. Würtz, S. Rak-
shit, J. J. Neumann, T. Dröge, F. Glorius, Angew. Chem. 2008,
120, 7340–7343; Angew. Chem. Int. Ed. 2008, 47, 7230–7233;
d) R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi, Angew.
Chem. 2009, 121, 8222–8225; Angew. Chem. Int. Ed. 2009, 48,
8078–8081; e) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui,
N. Jiao, Angew. Chem. 2009, 121, 4642–4646; Angew. Chem.
Int. Ed. 2009, 48, 4572–4576; f) Y.-X. Jia, P. Kündig, Angew.
Chem. 2009, 121, 1664–1667; Angew. Chem. Int. Ed. 2009, 48,
1636–1639; g) A. Perry, R. J. K. Taylor, Chem. Commun. 2009,
3249–3251.
[1] P. T. Anastas, J. C. Warner, Green Chemistry, Theory and Prac-
tice, Oxford University Press, Oxford, UK, 1998.
[2] For recent reviews on the CDC reaction, see: a) C.-J. Li, Acc.
Chem. Res. 2009, 42, 335–344; b) C. J. Scheuermann, Chem.
Asian J. 2010, 5, 436–451; c) C. S. Yeung, V. M. Dong, Chem.
Rev. 2011, 111, 1215–1292; d) A. E. Wendlandt, A. M. Suess,
S. S. Stahl, Angew. Chem. 2011, 123, 11256–11283; Angew.
Chem. Int. Ed. 2011, 50, 11062–11087; e) A. N. Campbell, S. S.
Stahl, Acc. Chem. Res. 2012, 45, 851–863; f) C. Zhang, C.
Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464–3484.
[3] T. Nagano, Z. Jia, X. Li, M. Yan, G. Lu, A. S. C. Chan, T.
Hayashi, Chem. Lett. 2010, 39, 929–931.
[17] Li and co-workers reported that the substrate possessing the
isopropyl group at the R2 position gave the product in a yield
of 36%, see ref.[15]
.
[18] Ishihara and co-workers proposed the formation of (hypo)iod-
[4] M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science 2010,
ite from the reaction of the iodide ion and hydroperoxide (I– +
–
328, 1376–1379.
ROOH h IO– + ROH or I– + 2ROOH h IO2 + 2ROH) in
[5] M. Uyanik, D. Suzuki, T. Yasui, K. Ishihara, Angew. Chem.
2011, 123, 5443–5446; Angew. Chem. Int. Ed. 2011, 50, 5331–
5334.
[6] For recent reviews on hypervalent organoiodane-catalyzed
metal-free oxidations originally developed by Kita and Ochiai,
see: a) M. Ochiai, K. Miyamoto, Eur. J. Org. Chem. 2008,
4229–4239; b) V. V. Zhdankin, J. Org. Chem. 2011, 76, 1185–
1197; c) R. D. Richardson, T. Wirth, Angew. Chem. 2006, 118,
4510–4512; Angew. Chem. Int. Ed. 2006, 45, 4402–4404.
their study of oxidative coupling reactions, see ref.[4,5]
.
[19] Wan and co-workers recently proposed that the reaction of
TBHP and I– in the absence of acid produces the tert-butoxyl
and tert-butylperoxyl radicals, see: a) W. Wei, C. Zhang, Y. Xu,
X. Wan, Chem. Commun. 2011, 47, 10827–10829; b) Z. Liu, J.
Zhang, S. Chen, E. Shi, Y. Xu, X. Wan, Angew. Chem. 2012,
124, 3285–3289; Angew. Chem. Int. Ed. 2012, 51, 3231–3235.
Received: November 24, 2012
Published Online: ᭿
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21585
/KAP1
Date: 03-01-13 17:42:46
Pages: 5
Synthesis of Indole Derivatives
Cross-Dehydrogenative Coupling
Z. Jia, T. Nagano,* X. Li,*
A. S. C. Chan .................................... 1–5
Iodide-Ion-Catalyzed
Carbon–Carbon
Bond-Forming Cross-Dehydrogenative
Coupling for the Synthesis of Indole De-
rivatives
We have found that the intramolecular oxi-
dative coupling of N-arylenamines pro-
ceeds well in the presence of catalytic am-
ounts of nBu4NI (TBAI) using tert-butyl
hydroperoxide as oxidant to afford the cor-
responding 1H-indole derivatives. This is
one of the rare examples of TBAI-cata-
lyzed C–C bond-forming CDC reactions.
Keywords: Synthetic methods
/ Homo-
geneous catalysis / Oxidation / Cross-coup-
ling / Nitrogen heterocycles / Iodine
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5