Metal-free sp3 C-H bond dual-(Het)arylation: I 2-promoted domino process to construct 2,2-bisindolyl-1-arylethanones

Article abstract of DOI:10.1021/ol301366p

A molecular I₂-promoted sp³ C-H bond dual-(het)arylation protocol was developed for the synthesis of 2,2-bisindolyl-1-arylethanones. Through a logical design, three mechanism-different reactions (iodination, Kornblum oxidation, and F

Full text of DOI:10.1021/ol301366p

ORGANIC
LETTERS
Metal-Free sp3 CÀH Bond
2012
Vol. 14, No. 13
3392–3395
Dual-(Het)arylation: I2-Promoted Domino
Process to Construct 2,2-Bisindolyl-
1-arylethanones
Yan-ping Zhu, Mei-cai Liu, Feng-cheng Jia, Jing-jing Yuan, Qing-he Gao, Mi Lian, and
An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Hubei, Wuhan 430079, P. R. China
chwuax@mail.ccnu.edu.cn
Received May 17, 2012
ABSTRACT
A molecular I2-promoted sp3 CÀH bond dual-(het)arylation protocol was developed for the synthesis of 2,2-bisindolyl-1-arylethanones. Through a
logical design, three mechanism-different reactions (iodination, Kornblum oxidation, and FriedelÀCrafts reaction) were assembled in a single
reactor. A variety of 2,2-bisindolyl-1-aryl ethanones were synthesized from simple and readily available aryl methyl ketones and indoles. In the
reaction, metal, base, and ligand were all avoidable.
In recent years, direct arylation of the CÀH bond has
emerged as a hot theme in organic synthetic chemistry.1
Many impressive results have been achieved for arylation
of CspÀH and Csp2ÀH bonds during the past several
years.2 However, reactions involving the Csp3ÀH bond
have suffered inherent problems due to inertia and weak
coordination. Some efforts have been made to overcome
the challenges (Scheme 1). The most widely used method is
the coupling of Csp3ÀH bonds with aryl halide or aryl
metal. This method was demonstrated very well by Yu,
Daugulis, Corey, Sames, Sanford, and Chen (Scheme 1,
pathways A and B).3 The intramolecular direct arylation
was closely studied by Fagnou, Fujii and Ohno, and Chen
(Scheme 1, pathway C).4 The cross-dehydrogenative
coupling (CDC) reaction is an excellent method for
CÀH arylation, which was efficiently launched by Li and
others (Scheme 1, pathway D).5 However, the scope of the
substrates was limited since the sp3 CÀH bond must be
(3) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7,
3657. (c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965.
(d) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (e) Pastine, S. J.; Gribkov, D. V.; Sames, D.
J. Am. Chem. Soc. 2006, 128, 14220. (f) Giri, R.; Maugel, N.; Li, J. J.;
Wang, D. H.; Breazzano, S. P.; Saunders, L. B.; Yu, J. Q. J. Am. Chem.
Soc. 2007, 129, 3510. (g) Wang, D. H.; Wasa, M.; Giri, R.; Yu, J. Q.
J. Am. Chem. Soc. 2008, 130, 7190. (h) Wasa, M.; Engle, K. M.; Yu, J. Q.
J. Am. Chem. Soc. 2009, 131, 9886. (i) Reddy, S. V. S.; Reddy, L. R.;
Corey, E. J. Org. Lett. 2006, 8, 3391. (j) Zhao, Y. S.; Chen, G. Org. Lett.
2011, 13, 4850.
(1) Do, H. Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Huang, J. K.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.;
Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674. (c) Liu,
W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H. B.;
Kwong, F. Y.; Lei, A. W. J. Am. Chem. Soc. 2010, 132, 16737. (d) Shuai,
ꢀ
Q.; Yang, L.; Guo, X. Y.; Basle, O.; Li, C. J. J. Am. Chem. Soc. 2010, 132,
12212. (e) Wei, Y.; Su, W. P. J. Am. Chem. Soc. 2010, 132, 16377.
(f) Daugulis, O.; Do, H. Q.; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074. (g) Engle, K. M.; Mei, T. S.; Wasa, M.; Yu, J. Q. Acc. Chem. Res.
2012, 45, 788.
(2) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.
(c) Truong, T.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 4243. (d) Cao,
H.; Zhan, H. Y.; Lin, Y. G.; Lin, X. L.; Du, Z, D.; Jiang, H. F. Org. Lett.
2012, 14, 1688. (e) Suarez, L. L.; Greaney, M. F. Chem. Commun. 2011,
47, 7992.
(4) (a) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2007, 129, 14570. (b) Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.;
Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am.
Chem. Soc. 2010, 132, 10706. (c) Watanabe, T.; Oishi, S.; Fujii, N.;
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Landgraf, B.; Liu, S.; Chen, G. Org. Lett. 2010, 12, 3414.
r
10.1021/ol301366p
Published on Web 06/26/2012
2012 American Chemical Society

(2a) performed smoothly with 50% yield in the presence
of I2 (1.1 mmol) and CuO (1.1 mmol) at 80 °C in DMSO.
Thus, we screened a series of Brønsted acids for this
reaction, such as HOAc, MeSO3H, CF3SO3H, TFA,
PTSA (Table 1, entries 2À6), but the desired product
3aa was obtained in a low yield. Alternatively, the diver-
sity of Lewis acids were also investigated for the reaction.
Gratifyingly, the reaction occurred in good yield by use of
Ti(i-PrO)4 and ZnCl2 (Table 1, entries 7 and 9). However,
other Lewis acids, such as AlCl3, FeCl3, InCl3, and
Cu(OTf)2, only promoted this reaction in moderate yield.
To our surprise, the reaction could perform in good yield
in the absence of CuO and Lewis acid (Table 1, entry 13).
However, the reaction could not perform at all without I2
(Table 1, entry 14). After several experimental optimizations,
we found that 1a (1.0 mmol) could react with 2a (2.0 mmol)
in the presence of I2 (1.0 mmol) in DMSO at 95 °C to afford
the desired product in 76% yield (Table 1, entry 16).
Scheme 1. Protocols for sp3 CÀH Bond Arylation
adjacent to a nitrogen or an oxygen atom. Recently,
MacMillan proposed a graceful photoredox amine CÀH
arylation, which provides a new insight into CÀH arylation
(Scheme 1, pathway E).6 The previous studies mainly
focused on Pd-, Ru-, Cu-catalyzed arylation. Therefore,
development of ametal-free CÀH and CÀH bond coupling
protocol is still greatly desired for sp3 CÀH bond arylation.
Indoles are important molecules and exist widely in
natural products and pharmaceuticals.7 In addition, they
have been known to be useful in agricultural chemistry and
material science. Accordingly, synthesis and functionaliza-
tion of indoles have attracted considerable attention over
one and a half centuries.8 Among them, bisindoles as
molecular stars were pursued by many synthetic chemists
and pharmacologists.9 However, direct sp3 CÀH bond
dual heteroarylation has not yet been proposed for the
synthesis of bisindoles. As a part of our program aimed at
constructing diverse heterocycles, we herein report a mo-
lecular I2-promoted sp3 CÀH bond dual-(het)arylation
protocol for accessing 2,2-bisindolyl-1-arylethanones from
aryl methyl ketones and indoles.
Table 1. Optimization Studies for the Synthesis of 2,2-
Bis(1-methyl-1H-indol-3-yl)-1-phenylethanonea,b
I2
CuO
temp time yield
entry (mmol)
(mmol)
cat.
(°C)
(h)
(%)
1
2
3
4
5
6
7
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
80
80
80
80
80
80
80
10
12
12
12
12
8
50
<15
<15
<15
<15
0
HOAc
MeSO3H
CF3SO3H
PTSA
TFA
Ti(i-
5
72
PrO)4
8
9
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0) CuO (1.0)
I2 (1.0)
AlCl3
80
80
80
80
80
90
90
100
95
95
6
4
50
74
55
58
56
70
0
Initially, the reaction conditions were optimized for dual
heteroarylation of aryl methyl ketone (1a) with N-methy-
lindole (2a). Various catalysts, additives, and temperatures
were examined in DMSO, and all cases are shown in Table 1.
To our delight, the reaction of 1a with N-methylindole
ZnCl2
InCl3
10
11
12
13
14
15
16
17
8
Cu(OTf)2
FeCl3
6
10
5
12
2
I2 (1.0)
I2 (1.0)
I2 (1.5)
68
76
75
3
(5) (a) Li, Z. P.; Li, C. J. J. Am. Chem. Soc. 2005, 127, 6968. (b) Li,
Z. P.; Bohle, D. S.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928.
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(c) Basle, O.; Li, C. J. Org. Lett. 2008, 10, 3661. (d) Li, C. J. Acc. Chem.
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), catalyst (0.03
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(f) Wang, P.; Rao, H. H.; Hua, R. M.; Li, C. J. Org. Lett. 2012, 14, 902.
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mmol, 30 mol %), heated in 3 mL of DMSO. b Isolated yield.
€
76, 1759. (h) Ghobrial, M.; Schnurch, M.; Mihovilovic, M. D. J. Org.
Chem. 2011, 76, 8781.
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334, 1114.
Under the optimal conditions, a wide range of aryl
methyl ketones was investigated. As shown in Scheme 2,
the substituted aryl methyl ketones performed smoothly
with N-methylindole 2a to afford the desired products in
moderate togood yields (58À85%). The electron-donating
groups, such as 4-Me, 4-OMe, 2,4-(OMe)2, and 3,4-
OCH2O, attached to phenyl rings of aryl methyl ketones
exhibited good reactivity (Scheme 2, 3baÀea). The electron-
withdrawing groups, such as Cl, Br, and NO2, could
(7) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1996; p 113. (b) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep.
2000, 17, 175. (c) Hibino, S.; Chozi, T. Nat. Prod. Rep. 2001, 18, 66.
(d) Zaimoku, H.; Taniguchi, T.; Ishibashi, H. Org. Lett. 2012, 14, 1656.
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2011, 111, PR215.
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2012, 112, 3508.
Org. Lett., Vol. 14, No. 13, 2012
3393

slightly decrease the reactivity (Scheme 2, 3faÀja).
Furthermore, 2-naphthyl methyl ketone (1k) and biphenyl
methyl ketone (1l) also reacted with N-methylindole 2a to
obtain satisfying results (76% and 70% yields). Encour-
aged by the results, the heteroaryl methyl ketones were
investigated under the optimal conditions. To our delight,
the substrates with heterocycle, such as furanyl (1m),
thiophene-yl (1n, 1o), and benzofuryl (1p), could obtain
the corresponding products 3maÀpa in moderate to good
yields (68%-81%). As we know, compounds with multi-
heterocyclic scaffolds are novel and important that would
have enhanced biological activity or vagarious property.
The bisindole molecules containing furan or thiophene or
benzofuran were rarely reported in the literature.
turned our attention to the indole derivatives (2eÀi), in
which the substituted groups attached to the phenyl rings.
Notably, the electronic properties of indole derivatives
(2eÀi) have strong influence on the yield. The electron-
withdrawing groups attached to the phenyl rings of indole
derivatives 2h,i could give good yields (Scheme 3, 3ae and
3af). However, the electron-donating groups, such as 6-Me
and 6-OMe, could largely decrease the reactivity to afford
the desired products in very low yields (3ah and 3ai).
Furthermore, the target compounds 3ca and 3db were
further determined by X-ray crystallographic analysis
(Figures S1 and S2, Supporting Information).
Scheme 3. Scope of Aryl Methyl Ketones and Indoles
Scheme 2. Scope of Aryl Methyl Ketones and N-Methylindole
To further expand the scope of the substrates, diversity of
indole derivatives were examined. To our disappointment,
the reaction of acetophenone 1a with indole 2b provided a
low yield. We observed that the desired products were
obtained in moderate yield for the first 2 h, but some of
the desired product decomposed over time. After several
experimental iterations, we found that heating acetophe-
none 1a in the presence of I2 (1.4 mmol) at 95 °C for 2 h,
then adding indole 2b (2.0 mmol) and stirring at 25 °C for 2
h yielded the desired product in good yield (88%).
Under the optimal conditions, a series of indole de-
rivatives was examined. Gratifyingly, indole 2b could
smoothly react with aryl methyl ketones to afford the
corresponding products in good yields (Scheme 3, Entries
3abÀhb). Both electron-donating and electron-withdraw-
ing groups attached to the phenyl rings of 1a could afford
the corresponding products in moderate to good yields
(65À88%). The N-allylindole 2c and N-benzylindole 2d
could also perform smoothly to afford the corresponding
products under these conditions (Scheme 3, entries
3acÀad, 60À72%). Encouraged by the above results, we
To gain some insights intothe mechanism ofthe reaction
process, the following experiments were performed. The
reaction of aryl methyl ketone 1a (1.0 mmol) with I2 (1.1
mmol) and CuO (1.1 mmol) was refluxed for 1.0 h in
MeOH, and R-iodo ketone 1aa was obtained in 96% yield
(Scheme 4 (a)).10 When aryl methyl ketone 1a (1.0 mmol)
was heated with I2 (1.5 mmol) in DMSO at 95 °C, the
substrate could be transformed to phenylglyoxal (1ab) or
hydrated hemiacetal (1ac) in quantitative conversion
(Scheme 4 (b)). Substrates 1aa (1.0 mmol) and 2a (2.0
mmol) were treated with I2 (1.0 mmol) at 95 °C in DMSO,
and the desired product 3aa was obtained in 85% yield.
This reaction of 1ac and 2a was treated with iodide (1.0
mmol) in DMSO at 95 °C, and the product 3aa was
obtained in excellent yield (>95%). This result clearly
confirmed the intermediacy of phenacyl iodine 1aa and
phenylglyoxal 1ab in the transformation.
(10) Yin, G. D.; Gao, M.; She, N. F.; Hu, S. L.; Wu, A. X.; Pan, Y. J.
Synthesis 2007, 20, 3113.
3394
Org. Lett., Vol. 14, No. 13, 2012

way of Kornblum oxidation in the presence of DMSO.11
The aldehyde group of phenylglyoxal (1ab) was activated
by excess or regenerated Lewis acid I2.12 Then, N-methy-
lindole 2a could attack the activated aldehyde group of
phenylglyoxal (1ab) to give the 3-alkylidene-3H-indolium
cation A. Finally, another N-methylindole2a could further
trap the cation A to give the desired product 3aa.
Scheme 4. Control Experiments
Scheme 6. Proposed Mechanism
The intermolecular kinetic isotope (KIE) was also mea-
sured through a competition process of 2a with a mixture
of 1a and 1a-d8 (1:1) (1a-d8, D > 95%) in the presence of I2
in DMSO at95 °C (Scheme 5). The relativerate constant of
KH/KD was determined to be 6.0. The result indicates that
CÀH bond cleavage of CH3 in aryl methyl ketone 1a is
involved the rate-determining step (RDS) during the dom-
ino process.
In conclusion, we developed a molecular I2-promoted
sp3 CÀH bond dual-(het)arylation protocol for the synthe-
sis of 2,2-bisindolyl-1-arylethanones from simple and read-
ily available aryl methyl ketones and indole derivatives. In
the transformation, three mechanism-different reactions
(iodination, Kornblum oxidation, and FriedelÀCrafts
alkylation) were assembled in a single reactor. It is notable
that the reaction performs well in the absence of any metal,
base, or ligand. Because of the above-mentioned charac-
teristics of this reaction, it should be of great utility in
organic chemistry. Further studies on the applications of
this strategy will be reported in due course.
Scheme 5. Intermolecular Kinetic Isotope Experiment
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (Grant
21032001) and PCSIRT (No. IRT0953). We also thank
Dr. Chuanqi Zhou, Hebei University, for analytical
support.
On the basis of the above results, a possible mechanism
of the present reaction was proposed using acetophenone
(1a) and N-methylindole (2a) as an example (Scheme 6).
Initially, the substrate acetophenone 1a reacted with I2 to
afford the intermediate R-iodo ketone 1aa, Subsequently,
intermediate 1aa convergented to phenylglyoxal (1ab) by
Supporting Information Available. Spectrascopic data
and general procedure. This material is available free of
charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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