Rhodium-Catalyzed Regioselective C7-Functionalization of N-Pivaloylindoles

Article abstract of DOI:10.1002/anie.201508117

An efficient rhodium-catalyzed method for direct C-H functionalization at the C7 position of a wide range of indoles has been developed. Good to excellent yields of alkenylation products were observed with acrylates, styrenes, and vinyl phenyl sulfones, whereas the saturated alkylation products were obtained in good yield with α,β-unsaturated ketones. Both the N-pivaloyl directing group and the rhodium catalyst proved to be crucial for high regioselectivity and conversion.

Full text of DOI:10.1002/anie.201508117

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201508117
German Edition: DOI: 10.1002/ange.201508117
CÀH Activation
Rhodium-Catalyzed Regioselective C7-Functionalization of
N-Pivaloylindoles
Lanting Xu, Chao Zhang, Yupeng He, Lushi Tan,* and Dawei Ma*
Abstract: An efficient rhodium-catalyzed method for direct
CÀH functionalization at the C7 position of a wide range of
indoles has been developed. Good to excellent yields of
alkenylation products were observed with acrylates, styrenes,
and vinyl phenyl sulfones, whereas the saturated alkylation
products were obtained in good yield with a,b-unsaturated
ketones. Both the N-pivaloyl directing group and the rhodium
catalyst proved to be crucial for high regioselectivity and
conversion.
T
he indole ring system is one of the most ubiquitous
heterocycles in nature and plays an essential role in medicinal
[1]
chemistry. Numerous studies have shown that diverse
substituent patterns around the indole nucleus impart
a wide range of interesting biological properties to these
[
2]
compounds, and as a result, great effort has been made to
develop synthetic methods for the direct functionalization of
indoles over the past decades. To date, a number of
approaches have been reported for the regioselective intro-
duction of a functional group at the 2-, 3-, 5-, or 6-position of
Scheme 1. Regioselectivity in the metal-catalyzed direct functionaliza-
tion of N-protected indoles.
take place exclusively at the 2-position through the formation
[3]
[5c,e,6k–m]
indoles. However, selective direct functionalization at the
-position remains challenging, owing to the inherently poor
of a five-membered metallocycle 2 (Scheme 1).
For
7
direct functionalization at the 7-position, two methods have
been frequently used. One is to protect or block the indole
reactivity of this carbon center. Solutions to this problem are
highly desirable as they would enable access to an important
range of natural and unnatural products containing a 7-
[
8a,c,10]
2-position,
and the other is the use of indoline deriva-
[11]
tives as alternative substrates.
Hartwig and co-workers
[4]
substituted indole moiety.
described the first regioselective C7-functionalization, in
In the last decade, substantial progress has been made in
which CÀH bond cleavage gave a five-membered metallo-
[8b]
the field of transition-metal-catalyzed CÀH bond functional-
cycle 4 from N-silylindole 3.
During our studies on the
ization, which has provided a general and straightforward
synthesis of unnatural amino acid derivatives through direct
[
5–8]
[12]
approach for the assembly of substituted indoles.
On
CÀH bond functionalization, we discovered that regiose-
account of the higher electron density at the 2- and 3-
positions, direct metal-catalyzed functionalization is possible
at these positions even without the assistance of a directing
lective 7-olefination of indoles could be promoted by tuning
metal catalysts and using N-pivaloyl as a directing group. This
unprecedented observation could be rationalized by a prefer-
ence for the formation of a six-membered intermediate 7 over
a five-membered intermediate 6 owing to the bulkiness of the
tert-butyl group.
[5b, 9]
group.
When a directing group is introduced at the indole
1
-position, CÀH bond cleavage has been demonstrated to
Initially, we used 1-acyl indoles 1a as the substrate. The
treatment of 1a with methyl acrylate in the presence of
[{Cp*RhCl } ], AgSbF , and Cu(OAc) ·H O gave the 2-
[
*] Dr. L. Xu, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
2
2
6
2
2
olefination product 11a and the 7-olefination product 9a in
2 and 7% yield, respectively (Table 1, entry 1). This result
3
54 Fenglin Lu, Shanghai 200032 (China)
1
E-mail: madw@mail.sioc.ac.cn
prompted us to explore the possible determining factors for
regioselectivity. We speculated that the size of the directing
group might play an important role. To our delight, with
larger acyl groups, higher selectivity for the 7-position and
conversion were observed (Table 1, entries 1–4). With 1-
pivaloylindole, 10a and 12a were obtained in 60% combined
yield with 9:1 regioselectivity favoring C7-olefination
C. Zhang, Dr. Y. He
Liaoning Shihua University
Dandong Lu West 1, Fushun 113001 (China)
Dr. L. Tan
Merck Research Laboratories
P.O. Box 2000, RY800-D280, Rahway, NJ 07065-0900 (USA)
E-mail: lushi_tan@merck.com
(
Table 1, entry 4). These results clearly demonstrated that
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508117.
the introduction of a bulky acyl group on the indole nitrogen
Angew. Chem. Int. Ed. 2016, 55, 321 –325
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
321

Angewandte
Communications
Chemie
[
a]
Table 1: Alkenylation of N-acyl indoles with methyl acrylate.
Entry
Y
Catalyst
Solvent
CH Cl
Product
yield [%)])
[b]
(
1
2
3
4
5
6
7
8
9
Me [{Cp*RhCl } ]
Et
iPr
tBu [{Cp*RhCl } ]
tBu [{Cp*RhCl } ]
tBu [{Cp*IrCl } ]
tBu [{Ru(p-cymene)Cl } ] CH Cl
tBu Pd(OAc)2
tBu [{Cp*RhCl } ]
tBu [{Cp*RhCl } ]
tBu [{Cp*RhCl } ]
tBu [{Cp*RhCl } ]
tBu [{Cp*RhCl } ]
tBu [{Cp*RhCl } ]
tBu [{Cp*RhCl } ]
9a (7)/11a (12)
9b (9)/11b (14)
9c (15)/11c (20)
10a (54)/12a (6)
10a (92)/12a (3)
10a (28)/12a (3)
10a (16)/12a (41)
10a (0)/12a (0)
10a (94)/12a (3)
10a (80)/12a (1)
2
2
2
2
2
2
2
2
2
2
2
[{Cp*RhCl } ]
[{Cp*RhCl } ]
CH Cl
2
2
2
CH Cl
2
2
2
CH Cl
2
2
2
CH Cl
2
2
2
CH Cl
2
2
2
2
2
2
[c]
CH Cl
2
tAmOH
dioxane
2
2
1
1
1
1
1
1
0
1
2
3
4
5
2
2
Cl(CH ) Cl 10a (64)/12a (1)
2
2
2
2
C H CF
3
10a (78)/12a (18)
10a (70)/12a (7)
10a (25)/12a (5)
10a (13)/12a (3)
2
2
6
5
[
[
[
d]
e]
f]
CH Cl
2
2
2
2
2
2
CH Cl
2
2
2
CH Cl
2
2
2
[
(
a] Reaction conditions: 1 (0.2 mmol), 8a (1.0 mmol), catalyst
4 mol%), AgSbF (16 mol%; for entries 1–4) or AgNTf (16 mol%; for
6
2
.
entries 5–16), Cu(OAc) H O (0.42 mmol), solvent (1.5 mL), 808C, 36 h.
2
2
[
b] Yield of the isolated product. [c] The 3-alkenylation product was
isolated in 30% yield. [d] AgOAc was used as the oxidant. [e] Ag CO was
2
3
used as the oxidant. [f] No oxidant was added. t-AmOH=2-methyl-2-
butanol, Cp*=1,2,3,4,5-pentamethylcyclopentadienyl.
[13]
atom not only facilitated CÀH bond functionalization, but
also dramatically enhanced the regioselectivity. To improve
the conversion, we tried different additives and were pleased
to find that complete conversion occurred with 92:3 regiose-
lectivity when AgNTf was used in place of AgSbF (Table 1,
2
6
entry 5). Further screening revealed that metal catalysts also
had a remarkable influence on both regioselectivity and
conversion (Table 1, entries 5–8). When [{Cp*RhCl } ] was
2
2
exchanged for [{Cp*IrCl } ], only slightly lower regioselec-
2
2
tivity was observed, but much lower conversion (Table 1,
entry 6). By contrast, [{Ru(p-cymene)Cl } ] provided the 2-
2
2
olefination product 12a as the major regioisomer (Table 1,
entry 7), whereas Pd(OAc) delivered the 3-olefination prod-
2
uct exclusively (entry 8). Among the solvents examined, 2-
methyl-2-butanol gave a similar result (Table 1, entry 9),
dioxane and 1,2-dichloroethane gave slightly better selectivity
but significantly lower conversion (entry 10 and 11), and
trifluoromethylbenzene led to significant decrease in both
conversion and regioselectivity (entry 12). Furthermore, the
use of Cu(OAc) ·H O as an oxidant proved to be important
Scheme 2. C7-functionalization of N-pivaloylindoles. Reaction condi-
tions: 5 (0.2 mmol), 8 (1.0 mmol), catalyst (4 mol%), AgNTf2
2
2
(
16 mol%), Cu(OAc) ·H O (0.42 mmol), CH Cl (1.5 mL), 808C, 36 h.
2
2
2
2
for complete conversion (Table 1, entry 5 vs. entries 13–15).
Having optimized the reaction conditions, we next
explored the scope of the reaction with respect to the
substrates and functional-group tolerance. A series of indole
derivatives with various substituents were subjected to
olefination with methyl acrylate, and good to excellent
yields were observed in most cases (Scheme 2). Generally,
substrates with electron-donating groups at either the 4- or
the 5-position gave the 7-olefination products with full
Yields are for the isolated product. [a] The reaction was conducted at
08C in 2-methyl-2-butanol. [b] The reaction was conducted on
a 1 mmol scale with 1 mol% of the catalyst and 4 mol% of AgNTf2.
7
[c] The reaction was conducted in CH Cl at 1008C. [d] The correspond-
2
2
ing 2-alkenylation product was isolated in about 50% yield. [e] 1-Pival-
oylindole was recovered in 59% yield. Bn=benzyl, Phth=phthaloyl,
TBS=tert-butyldimethylsilyl.
3
22
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 321 –325

Angewandte
Communications
Chemie
conversion and higher than 90% yield at 708C in 2-methyl-2-
butanol (products 10b–e, 10i, and 10j). Those substrates with
a halogen at either the 4- or the 5-position required 808C in
dichloromethane for full conversion, and again the desired
products were obtained in excellent yield (products 10 f, 10g
and 10k–m). In contrast, under similar conditions, substrates
with an electron-withdrawing group reacted sluggishly, and
the reaction did not proceed to completion. For example, the
reaction of 4-cyano-1-pivaloylindole was slow even at 1008C,
and the olefination product 10h was obtained in only 40%
yield. When 6-substituted indoles were used, the desired 7-
olefination products 10n and 10o were not observed, but
instead the corresponding 2-olefination products were iso-
lated in about 50% yield. This result provides additional
evidence that steric effects are important for the regioselec-
tivity of the reaction.
Both the 2-methyl- and 3-methyl-substituted indoles were
good substrates, and 10p and 10q were formed in good yield.
More importantly, pharmaceutically useful compounds, such
as tryptamine, tryptophol, and tryptophan derivatives, also
reacted smoothly at the C7 position to provide 10r–u in 68–
9
0% yield. Direct functionalization of N-pivaloylcarbazole
and an analogue also successfuly provided products 10v and
Scheme 3. Deprotection of the alkenylation products.
1
0w in 95 and 84% yield, respectively.
We also examined the scope of the reaction with respect to
the alkene coupling partner. Benzyl and n-butyl acrylate
reacted just as well as methyl acrylate to give the desired 7-
olefination products 10x and 10y in 94 and 93% yield,
respectively. Vinyl phenyl sulfone and even weakly activated
styrene were compatible with this reaction, which delivered
the corresponding alkenylation products 10z, 10ab, and 10ac
in good yield. Interestingly, the alkylation products 10aa,
of the pivaloyl group. The pivaloyl group of the resulting
intermediate was then removed by Et N-mediated cleavage
3
to afford the fully deprotected compound 14 in 80% overall
yield. Compound 14 is a valuable building block for the
synthesis of terezine D, an antifungal diketopiperazine alka-
loid that was isolated from liquid cultures of the coprophilous
[15]
1
7
0ad–af without an alkene double bond were obtained in 38–
8% yield when a,b-unsaturated ketones were used. This
fungus Spwormiella teretispora.
We used deuterium labeling to gain evidence for the
proposed mechanism (Scheme 1). A 1:1 mixture of 1-piva-
loylindole and its 2-deuterated derivative was treated with
a stoichiometric amount of the catalyst in the absence of an
alkene, and then the reaction was quenched with water
(Scheme 4). The H/D ratio at the 2-position of the recovered
starting material was still 1:1, thus implying that intermediate
7 was produced exclusively during CÀH bond activation.
result indicated that the coupling reaction might involve the
protonolysis of an alkyl rhodium species, which might be
generated by the insertion of the aryl rhodium intermediate
into the C=C double bond. Similar phenomena have been
observed in other metal-catalyzed CÀH bond-activation
studies with a,b-unsaturated ketones as the coupling part-
[
7f, 14]
ner.
Several reactions (to form 10b, 10m, 10r, 10s, and 10ae)
were scaled up successfully to a 1 mmol scale with only
1
mol% of the catalyst and 4 mol% of the additive. Complete
conversion was still observed for all reactions, although the
yields were slightly lower. To further demonstrate the robust-
ness and utility of the method, we conducted a gram-scale
reaction with the relatively complex tryptophan derivative 5t.
The desired product 10t was isolated in 76% yield
Scheme 4. Deuterium-labeling test.
(
Scheme 3).
A remarkable aspect of the present method is that the
directing group was readily removed under very mild
conditions. The treatment of 10t with triethylamine in
methanol left the Boc group and methyl ester intact and
provided the 7-functionalized tryptophan derivative 13 in
In conclusion, we have developed a highly efficient
method for the rhodium-catalyzed, C7-selective functionali-
zation of N-pivaloylindole derivatives. This protocol features
low catalyst loading, mild reaction conditions, and compati-
bility with diverse functional groups, and provides a straight-
forward strategy for the introduction of a wide variety of side
chains at the C7 position of indole derivatives.
9
4% yield (Scheme 3). Compound 13 is potentially useful for
the development of peptidomimetics for biological studies.
On the other hand, the Boc protecting group in 10u could be
removed selectively with trifluoroacetic acid in the presence
Angew. Chem. Int. Ed. 2016, 55, 321 –325
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
323

Angewandte
Communications
Chemie
[
5] For the palladium-catalyzed direct CÀH bond functionalization
of indoles, see: a) E. Capito, J. M. Brown, A. Ricci, Chem.
Commun. 2005, 1854 – 1856; b) N. P. Grimster, C. Gauntlett,
C. R. A. Godfrey, M. J. Gaunt, Angew. Chem. Int. Ed. 2005, 44,
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (grant 21132008) and Merck for their financial
support.
3
125 – 3129; Angew. Chem. 2005, 117, 3185 – 3189; c) N. R.
Deprez, D. Kalyani, A. Krause, M. S. Sanford, J. Am. Chem.
Soc. 2006, 128, 4972 – 4973; d) D. R. Stuart, E. Villemure, K.
Fagnou, J. Am. Chem. Soc. 2007, 129, 12072 – 12073; e) N.
Lebrasseur, L. Larrosa, J. Am. Chem. Soc. 2008, 130, 2926 – 2927;
f) A. García-Rubia, R. G. Arrayµs, J. C. Carretero, Angew.
Chem. Int. Ed. 2009, 48, 6511 – 6515; Angew. Chem. 2009, 121,
Keywords: alkenylation · CÀH activation ·
homogeneous catalysis · indoles · rhodium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 321–325
Angew. Chem. 2016, 128, 329–333
6
2
1
633 – 6637; g) P. Y. Choy, C. P. Lau, F. Y. Kwong, J. Org. Chem.
011, 76, 80 – 84; h) Q. Liu, Q. Li, Y. Ma, Y. Jia, Org. Lett. 2013,
5, 4528 – 4531.
[
[
1] For books and reviews, see: a) R. J. Sundberg, Indoles, Academic
Press, New York, 1970; b) Y. Ban, Y. Murakami, Y. Iwasawa, M.
Tsuchiya, N. Takano, Med. Res. Rev. 1988, 8, 231 – 308; c) R. J.
Sundberg, Indoles, Academic Press, San Diego, 1996; d) U.
Pindur, T. Lemster, Curr. Med. Chem. 2001, 8, 1681 – 1698; e) A.
Ramirez, S. Garcia-Rubio, Curr. Med. Chem. 2003, 10, 1891 –
[
6] For the rhodium-catalyzed direct CÀH bond functionalization of
indoles, see: a) D. J. Schipper, M. Hutchinson, K. Fagnou, J. Am.
Chem. Soc. 2010, 132, 6910 – 6911; b) F. W. Patureau, T. Besset,
F. Glorius, Angew. Chem. Int. Ed. 2011, 50, 1064 – 1067; Angew.
Chem. 2011, 123, 1096 – 1099; c) J. Shi, B. Zhou, Y. Yang, Y. Li,
Org. Biomol. Chem. 2012, 10, 8953 – 8955; d) J. Zhou, B. Li, F.
Hu, B.-F. Shi, Org. Lett. 2013, 15, 3460 – 3463; e) B. Zhou, Y.
Yang, S. Lin, Y. Li, Adv. Synth. Catal. 2013, 355, 360 – 364; f) X.
Qin, H. Liu, D. Qin, Q. Wu, J. You, D. Zhao, Q. Guo, X. Huang,
J. Lan, Chem. Sci. 2013, 4, 1964 – 1969; g) F. Xie, Z. Qi, S. Yu, X.
Li, J. Am. Chem. Soc. 2014, 136, 4780 – 4787; h) J. Shi, G. Zhao,
X. Wang, H. E. Xu, W. Yi, Org. Biomol. Chem. 2014, 12, 6831 –
1
915; f) A. J. Kochanowska-Karamyan, M. T. Hamann, Chem.
Rev. 2010, 110, 4489 – 4497.
2] a) R. J. Sundberg in Comprehensive Heterocyclic Chemistry,
Vol. 4, Pergamon, Oxford, 1984, pp. 313 – 376; b) J. F. Austin,
D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124, 1172 – 1173;
c) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003,
1
03, 893 – 930; d) F.-E. Chen, J. Huang, Chem. Rev. 2005, 105,
6
836; i) L. Zhang, R. Qiu, X. Xue, Y. Pan, C. Xu, D. Wang, X.
4
671 – 4706; e) F. R. de Sa Alves, E. J. Barreiro, M. Fraga, C.
Wang, L. Xu, H. Li, Chem. Commun. 2014, 50, 12385 – 12388;
j) M.-Z. Lu, P. Lu, Y.-H. Xu, T.-P. Loh, Org. Lett. 2014, 16, 2614 –
Alberto, Mini-Rev. Med. Chem. 2009, 9, 782 – 793; f) H. Xu, M.
Lv, Curr. Pharm. Des. 2009, 15, 2120 – 2148; g) V. Sharma, P.
Kumar, D. Pathak, J. Heterocycl. Chem. 2010, 47, 491 – 502; h) S.
Lal, T. J. Snape, Curr. Med. Chem. 2012, 19, 4828 – 4837.
2
617; k) L. Zhang, X. Xue, C. Xu, Y. Pan, G. Zhang, L. Xu, H. Li,
Z. Shi, ChemCatChem 2014, 6, 3069 – 3074; l) M. Chaitanya, P.
Anbarasan, J. Org. Chem. 2015, 80, 3695 – 3700; m) N. K.
Mishra, T. Jeong, S. Sharma, Y. Shin, S. Han, J. Park, J. S. Oh,
J. H. Kwak, Y. H. Jung, I. S. Kim, Adv. Synth. Catal. 2015, 357,
[
3] For books and reviews, see: a) S. Cacchi, G. Fabrizi, Chem. Rev.
2
005, 105, 2873 – 2920; b) G. R. Humphrey, J. T. Kuethe, Chem.
Rev. 2006, 106, 2875 – 2911; c) M. Bandini, A. Eichholzer,
Angew. Chem. Int. Ed. 2009, 48, 9608 – 9644; Angew. Chem.
1
2
293 – 1298; n) L. Wang, X. Qu, Z. Li, W. Peng, Tetrahedron Lett.
015, 56, 3754 – 3757; o) T. Jeong, S. Han, N. K. Mishra, S.
2
009, 121, 9786 – 9824; d) L. Joucla, L. Djakovitch, Adv. Synth.
Sharma, S. Lee, J. S. Oh, J. H. Kwak, Y. H. Jung, I. S. Kim, J. Org.
Chem. 2015, 80, 7243 – 7250.
Catal. 2009, 351, 673 – 714; e) G. W. Gribble, J. C. Badenock,
Heterocyclic Scaffolds II: Reactions and Applications of Indoles,
Springer, Berlin, 2010; f) S. Cacchi, G. Fabrizi, Chem. Rev. 2011,
[
7] For the ruthenium-catalyzed direct CÀH bond functionalization
of indoles, see: a) V. Lanke, K. Ramaiah Prabhu, Org. Lett. 2013,
1
11, PR215 – PR283.
1
5, 6262 – 6265; b) B. Li, J. Ma, W. Xie, H. Song, S. Xu, B. Wang,
[
4] a) L. G. Humber, E. Ferdinandi, C. A. Demerson, S. Ahmed, U.
Shah, D. Mobilio, J. Sabatucci, B. De Lange, F. Labbadia, J. Med.
Chem. 1988, 31, 1712 – 1719; b) B. Zhang, G. Salituro, D.
Szalkowski, Z. Li, Y. Zhang, I. Royo, D. Vilella, M. T. Díez, F.
Pelaez, C. Ruby, R. L. Kendall, X. Mao, P. Griffin, J. Calaycay,
J. R. Zierath, J. V. Heck, R. G. Smith, D. E. Moller, Science 1999,
J. Org. Chem. 2013, 78, 9345 – 9353; c) L. Liang, S. Fu, D. Lin, X.
Zhang, Y. Deng, H. Jiang, W. Zeng, J. Org. Chem. 2014, 79,
9
472 – 9480; d) W. Zhang, J. Wei, S. Fu, D. Lin, H. Jiang, W.
Zeng, Org. Lett. 2015, 17, 1349 – 1352; e) V. K. Tiwari, N. Kamal,
M. Kapur, Org. Lett. 2015, 17, 1766 – 1769; f) S. Li, H. Lin, X.
Zhang, L. Dong, Org. Biomol. Chem. 2015, 13, 1254 – 1263; g) T.
Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh, M.
Miura, Org. Lett. 2011, 13, 706 – 708.
2
84, 974 – 977; c) R. A. Jones, Inflammopharmacology 2001, 9,
6
3 – 70; d) X. Teng, A. Degterev, P. Jagtap, X. Xing, S. Choi, R.
Denu, J. Yuan, G. D. Cuny, Bioorg. Med. Chem. Lett. 2005, 15,
039 – 5044; e) M. C. Pirrung, Y. Liu, L. Deng, D. K. Halstead, Z.
[
8] For the iridium-catalyzed direct CÀH bond functionalization of
5
indoles, see: a) S. Paul, G. A. Chotana, D. Holmes, R. C. Reichle,
Li, J. F. May, M. Wedel, D. A. Austin, N. J. G. Webster, J. Am.
Chem. Soc. 2005, 127, 4609 – 4624; f) A. Omachi, K. Ishioka, A.
Uozumi, A. Kamikawa, C. Toda, K. Kimura, M. Saito, Res. Vet.
Sci. 2007, 83, 5 – 11; g) A. Degterev, J. Hitomi, M. Germscheid,
I. L. Chꢀen, O. Korkina, X. Teng, D. Abbott, G. D. Cuny, C.
Yuan, G. Wagner, S. M. Hedrick, S. A. Gerber, A. Lugovskoy, J.
Yuan, Nat. Chem. Biol. 2008, 4, 313 – 321; h) M. Fujita, T. Ueda,
M. Iwata, Int. J. Pharm. 2010, 386, 195 – 200; i) K.-S. Yeung, Z.
Qiu, Q. Xue, H. Fang, Z. Yang, L. Zadjura, C. J. DꢀArienzo, B. J.
Eggers, K. Riccardi, P. -Y. Shi, Y.-F. Gong, M. R. Browning, Q.
Gao, S. Hansel, K. Santone, P. -F. Lin, N. A. Meanwell, J. F.
Kadow, Bioorg. Med. Chem. Lett. 2013, 23, 198 – 202; j) K.-S.
Yeung, Z. Qiu, Z. Yin, A. Trehan, H. Fang, B. Pearce, Z. Yang, L.
Zadjura, C. J. DꢀArienzo, K. Riccardi, P. -Y. Shi, T. P. Spicer, Y.-F.
Gong, M. R. Browning, S. Hansel, K. Santone, J. Barker, T.
Coulter, P.-F. Lin, N. A. Meanwell, J. F. Kadow, Bioorg. Med.
Chem. Lett. 2013, 23, 203 – 208.
R. E. Maleczka, M. R. Smith, J. Am. Chem. Soc. 2006, 128,
1
5552 – 15553; b) D. W. Robbins, T. A. Boebel, J. F. Hartwig, J.
Am. Chem. Soc. 2010, 132, 4068 – 4069; c) R. P. Loach, O. S.
Fenton, K. Amaike, D. S. Siegel, E. Ozkal, M. Movassaghi, J.
Org. Chem. 2014, 79, 11254 – 11263; d) S. Zhou, Y. Jia, Org. Lett.
2014, 16, 3416 – 3418.
[9] a) Y. Murakami, Y. Yokoyama, T. Aoki, Heterocycles 1984, 22,
1493 – 1496; b) C. Jia, W. Lu, T. Kitamura, Y. Fujiwara, Org. Lett.
1999, 1, 2097 – 2100; c) Y. Yokoyama, K. Tsuruta, Y. Murakami,
Heterocycles 2002, 56, 525 – 529; d) J. Takagi, K. Sato, J. F.
Hartwig, T. Ishiyama, N. Miyaura, Tetrahedron Lett. 2002, 43,
5649 – 5651; e) A. Maehara, H. Tsurugi, T. Satoh, M. Miura, Org.
Lett. 2008, 10, 1159 – 1162; f) S. R. Neufeldt, M. S. Sanford, Acc.
Chem. Res. 2012, 45, 936 – 946.
[10] C. G. Hartung, A. Fecher, B. Chapell, V. Snieckus, Org. Lett.
2003, 5, 1899 – 1902.
3
24
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 321 –325

Angewandte
Communications
Chemie
[
11] a) B. Urones, R. G. Arrayas, J. C. Carretero, Org. Lett. 2013, 15,
[12] a) M. Fan, D. Ma, Angew. Chem. Int. Ed. 2013, 52, 12152 – 12155;
1
5
1
120 – 1123; b) L. Jiao, M. Oestreich, Org. Lett. 2013, 15, 5374 –
377; c) Z. Song, R. Samanta, A. P. Antonchick, Org. Lett. 2013,
5, 5662 – 5665; d) M. Kim, N. K. Mishra, J. Park, S. Han, Y. Shin,
Angew. Chem. 2013, 125, 12374 – 12377; b) Y. He, C. Zhang, M.
Fan, Z. Wu, D. Ma, Org. Lett. 2015, 17, 496 – 499.
[13] A similar effect was observed in iridium-catalyzed CÀH
S. Sharma, Y. Lee, E. Lee, J. H. Kwak, I. S. Kim, Chem.
Commun. 2014, 50, 14249 – 14252; e) S. Pan, T. Wakaki, N.
Ryu, T. Shibata, Chem. Asian J. 2014, 9, 1257 – 1260; f) W. Ai, X.
Yang, Y. Wu, X. Wang, Y. Li, Y. Yang, B. Zhou, Chem. Eur. J.
amination with anilines: H. Kim, K. Shin, S. Chang, J. Am.
Chem. Soc. 2014, 136, 5904 – 5907.
[14] G. Rouquet, N. Chatani, Chem. Sci. 2013, 4, 2201 – 2208.
[15] Y. Wang, J. B. Gloer, J. A. Scott, D. Mallpch, J. Nat. Prod. 1995,
58, 93 – 99.
2
014, 20, 17653 – 17657; g) S. Pan, N. Ryu, T. Shibata, Adv. Synth.
Catal. 2014, 356, 929 – 933; h) Y. Wu, Y. Yang, B. Zhou, Y. Li, J.
Org. Chem. 2015, 80, 1946 – 1951; i) X. Yang, X. Hu, T. Loh, Org.
Lett. 2015, 17, 1481 – 1484; j) N. Jin, C. Pan, H. Zhang, P. Xu, Y.
Cheng, C. Zhu, Adv. Synth. Catal. 2015, 357, 1149 – 1153; k) W.
Hou, Y. Yang, W. Ai, Y. Wu, X. Wang, B. Zhou, Y. Li, Eur. J. Org.
Chem. 2015, 395 – 400.
Received: August 30, 2015
Published online: October 29, 2015
Angew. Chem. Int. Ed. 2016, 55, 321 –325
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
325