Metal-Free N–H/C–H Coupling for Efficient Asymmetric Synthesis of Chiral Dihydroquinoxalinones from Readily Available α-Amino Acids

Article abstract of DOI:10.1002/ejoc.201800012

We have developed a method for the synthesis of dihydroquinoxalinones via intramolecular N–H/C–H coupling using hypervalent iodine. The starting materials were prepared from inexpensive and readily available aniline and amino acid derivatives. Various functional groups were tolerated to give multisubstituted dihydroquinoxalinones in moderate to excellent yields. The chirality of the amino acid was transferred to the desired target compound without a loss of enantiomeric excess. Preliminary mechanistic studies indicated that the reaction proceeds via an ionic mechanism.

Full text of DOI:10.1002/ejoc.201800012

A Journal of
Accepted Article
Title: Metal-Free N-H/C-H Coupling for Efficient Synthesis of Chiral
Dihydroquinoxalinones From Readily Available α-Amino Acids
Authors: Kyalo Stephen Kanyiva, Masashi Horiuchi, and Takanori
Shibata
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800012
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800012
Supported by

10.1002/ejoc.201800012
European Journal of Organic Chemistry
COMMUNICATION
Metal-Free N-H/C-H Coupling for Efficient Asymmetric Synthesis
of Chiral Dihydroquinoxalinones From Readily Available α-Amino
Acids
Kyalo Stephen Kanyiva,*[a] Masashi Horiuchi,[b] and Takanori Shibata,*[b]
Dedication ((optional))
Abstract: We have developed a method for the synthesis of
dihydroquinoxalinones via intramolecular N-H/C-H coupling using
hypervalent iodine. The starting materials were prepared from
inexpensive and readily available aniline and amino acid derivatives.
Various functional groups were tolerated to give multisubstituted
dihydroquinoxalinones in moderate to excellent yields. The chirality
of the amino acid was transferred to the desired target compound
without a loss of enantiomeric excess. Preliminary mechanistic
studies indicated that the reaction proceeds via an ionic mechanism.
reaction suffers from a limited substrate scope, because the
starting materials are often expensive or difficult to prepare for
substituted dihydroquinoxalinones. The second major class of
synthesis is the transition metal-catalyzed asymmetric
hydrogenation of quinoxalinone derivatives.[4] Representative
examples are the Ir- and Ir-catalyzed hydrogenations reported
by Vidal-Ferran[4a] and Xu,[4b] respectively. Other approaches
such as Rh-catalyzed asymmetric arylation of aldimines[2c] and
the use of Jocie-type reactions have been reported. Although
these methods are promising, the toxicity and cost of the
transition metals, as well as the difficulty of obtaining the starting
materials may limit their practical use on a large scale. Therefore,
the development of new routes for the effective synthesis of
substituted dihydroquinoxalinones from readily available
materials is needed.
Dihydroquinoxalinones are common structural motifs in bioactive
compounds.[1] For example, bioactive dihydroquinoxalinones
having anticancer, anti-HIV and absorption-inhibitory properties
have been reported (Figure 1). Moreover, dihydroquinoxalinones
are useful synthetic intermediates for the preparation of complex
organic molecules.[2]
(1) Use of ortho-substituted aniline derivatives
H
R2
R2
O
Z
R2N
N
i-PrO
O
R1
R1
+
R1
H
N
ref. 3
Y
Y
HO
O
F
N
NHNH2
O
Cl
Cl
N
N
R
Y = NO2, NH2, etc.; Z = I, F, Br, etc.
N
H
O
N
H
N
H
O
(2) Synthesis by asymmetric hydrogenation
H
N
NH2
NH2
R3
O
R3
O
GW420867X
(anti-HIV drug)
WO 2011103028
(anticancer agent)
WO 2014195695
(absorption inhibitor)
N
Ir, Rh cat., H2
R1
*
R1
R1
ref. 4
N
N
R2
R2
Figure 1. Examples of bioactive dihydroquinoxalinones.
(3) Present strategy: direct N-H/C-H coupling
PG
R3
O
HN
HO
PG
N
PG
hypervalent
iodine
R3
O
R3
O
HN
Several methods have been developed for the synthesis of
dihydroquinoxalinones, and these can be grouped into two major
classes. One class uses ortho-substituted aniline derivatives,
which are reacted with amino acid derivatives (Scheme 1).[1e,3]
For example, Jiang and coworkers reported the copper-
catalyzed Ullmann-type N-arylation of aliphatic amines with
amino acids, followed by reduction with SnCl2.[3b] Another
excellent example is the copper-catalyzed synthesis of
quinoxalinones by coupling of 2-bromoanilines with α-amino
acids, reported by Tanimori and coworkers.[3f] This class of
R1
R1
R1
This work
NH
R2
N
N
R2
R2
readily available substrates
Scheme 1. Synthetic approaches to dihydroquinoxalinones.
Hypervalent iodine[6] has emerged as an effective and
environmentally alternative to transition metal catalysts[7] for the
construction of C-N bonds. For example, Kikugawa developed
an electrophilic aromatic substitution reaction for the synthesis of
dihydroquinolines,[8a] Zhao synthesized indoles,[8b] Nishiyama
and Kita pioneered the synthesis of spirolactams and phenol
ethers,[8c,8e] Tellitu and Domínguez achieved the synthesis of
pyrrolodiazepines,[8d] and Togo synthesized sulfonamides using
hypervalent iodine reagents.[8f] Moreover, recently, our group
and others reported the synthesis of heteroaromatic compounds
[a]
[b]
K. S. Kanyiva
Global Center for Science and Engineering
School of Advanced Science and Engineering
Waseda University, Shinjuku, Tokyo 169-8555, Japan
E-mail: kanyiva.skm@aoni.waseda.jp
M. Horiuchi, T. Shibata
Department of Chemistry and Biochemistry
School of Advanced Science and Engineering
Waseda University, Shinjuku, Tokyo 169-8555, Japan
E-mail: tshibata@waseda.jp
such
as
benzimidazoles,[8g,8i-8k]
carbazoles,[8h]
and
azahelicenes.[8l]
Inspired by these studies and our interest in the efficient
synthesis of organic compounds using amino acid derivatives,[9]
we conceived that dihydroquinoxalinones could be synthesized
http://www.chem.waseda.ac.jp/shibata/
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800012
European Journal of Organic Chemistry
COMMUNICATION
using hypervalent reagents by direct oxidative cyclization.
Herein we report a metal-free method for the synthesis of
dihydroquinoxalinones from commercially or readily available
starting materials that do not require prefunctionalization or a
directing group before the N-H/C-H coupling reaction. We also
briefly discuss preliminary studies on the mechanism of
intramolecular N-H/C-H coupling.
Under the optimum conditions for entry 9 in Table 1, we first
screened the effect of the N-substituent on the aryl amide (R2).
Although unprotected substrate 1b was not tolerated in this
reaction, a benzyl group gave the desired product 2c in good
yield (Scheme 2). When a N-phenyl substrate was used, the
reaction was slow, and the product underwent further C-H bond
cleavage/cyclization to give a product 2d having a carbazole
core. We next examined the effect of substituents (R1) at the
para, meta and ortho positions of the aryl moiety. As a result,
bromo, chloro, alkyl, cyano and phenyl groups were tolerated to
afford the desired dihydroquinoxalinones 2e-2m in moderate to
high yields. Apparently, in this N-H/C-H coupling, electron-
donating groups at the para position gave comparatively higher
yields than electron-withdrawing groups. When 3-phenyl-
substituted substrate 1k was subjected to the reaction conditions,
a 1:1 mixture of regioisomers was obtained in excellent yield. A
substrate containing a 3-cyano group also gave a 1:1 mixture of
regioisomers in 51% yield. 2-Methyl substrate 1l also
participated in the reaction to afford 2l in 53% yield due to
moderate conversion of the starting material. Additionally, a
multisubstituted dihydroqunoxalinone could also be accessed in
high yield by the current metal-free synthesis, as exemplified by
the synthesis of 2j. Finally, a substrate containing a pyridyl core
was also tolerated under the oxidative coupling conditions to
provide 2n in moderate yield.
Our initial attempts to realize catalytic N-H/C-H coupling using
in situ-generated PhI(OAc)2 with or without additives such as
acids, inorganic bases or Lewis acids provided the desired
dihydroquinoxalinones in poor yields due to low conversion of
the starting material.[10] Therefore, we turned our attention to
screening stoichiometric amounts of hypervalent iodine. When
substrate 1a was treated with two equivalents of PhI(OAc)2 in
HFIP as a solvent at 84 ºC (oil bath temp.) for 18 h, the desired
dihydroquinoxalinone 2a was obtained in 43% isolated yield
(Table 1). The reaction was carried out using a variety of organic
solvents, and DCE gave the highest yield of 71% (entries 1-5).
Meanwhile, other commercially available hypervalent iodines
afforded lower yields, probably due to their rapid decomposition
(entries 6 and 7). After further tuning of the reaction parameters
such as concentration and temperature, we found that the
reaction under 2.0 M concentration of 1a at 90 ºC for 24 h
afforded the desired product in 91% yield after purification using
silica gel chromatography (entry 9). A reduction in the amount of
PhI(OAc)2 to 1.0 equivalent resulted in a significant decrease in
the yield (entry 10). Notably, the reaction proceeded with perfect
retention of the enantiomeric excess of the alanine derivative as
confirmed by HPLC analysis using a chiral column.
PG
HN
PG
N
Me
O
Me
O
PhI(OAc)2 (2.0 equiv)
R1
R1
DCE, 90 ºC, 24 h
Z = CH, N
Z
N
Z
N
R2
R2
1b-1n
2b-2n
Table 1. Screening of reaction conditions for N-H/C-H coupling using 1a.[a]
Ts
N
Ts
Ts
N
Ts
HN
Ts
N
N
PhI(X)(Y) (2.0 equiv)
N
O
N
H
O
N
O
solvent (Z M), 84 ºC, 18 h
N
O
Bn
N
O
Me
Me
2b, N.D.
2c, 75%
2d, 20%
1a
2a
Ts
N
Ts
N
Ts
N
Entry
Solvent
PhI(A)(B)
X (M)
Yield (%)
Br
Cl
Me
1
2
3
4
5
6
7
HFIP
DCE
PhCl
TFE
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OTf)2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
43
71
32
49
68
34
49
N
O
N
O
N
O
O
Me
Me
Me
2g, 84%
2e, 82%
2f, 45%
Me
Ts
Ts
Ts
t-Bu
N
NC
N
N
MeCN
DCE
DCE
N
O
N
O
Me
N
Me
Me
Me
2j, 82%
2h, 68%
2i, 74%
PhI(OH(OTs)
Ts
N
Ph
Ts
N
Ts
N
8b
DCE
DCE
DCE
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
2.0
2.0
2.0
87
91
53
+
9b,c
N
O
N
O
Ph
N
O
Me
Me
Me
Me
10b,c,d
2k + 2k’: 92% (1:1)
2m, 53%
CN
[a] Conditions: 1a (0.20 mmol), PhI(OAc)2 (0.4 mmol), solvent (0.10 mmol), [b]
Run at 90 ºC. [c] Run for 24 h. [d] PhI(OAc)2 (0.20 mmol, 1.0 equiv) was used.
HFIP: Hexafluoroisopropanol; DCE: 1,2-dichloroethane, TFE: 2,2,2-
trifluoroethanol.
Ts
Ts
Ts
N
N
N
+
N
O
NC
N
O
MeO
N
N
O
Me
Me
Me
2l + 2l’: 51% (1:1)
2n, 49%
Scheme 2. Scope of N-arylpropanamides.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800012
European Journal of Organic Chemistry
COMMUNICATION
Next, we investigated the scope of amino acid derivatives
(Scheme 3). When a glycine derived substrate 1o was treated
with hypervalent iodine under the standard conditions,
intramolecular N-H/C-H coupling proceeded smoothly to give the
corresponding product 2o in 82% yield. Substrates 1p and 1q
prepared from L-valine and L-leucine also reacted to give the
desired dihydroquinoxalinones 2p and 2q in respective yields of
72% and 83%. When L-phenylalanine and tyrosine derivatives 1r
and 1s were used, the reaction proceeded regioselectively to
afford 6-membered N-H/C-H coupling product in high yields, as
opposed to the formation of a 5-membered heterocycle from a
phenyl ring of the respective amino acid. A substrate 1t
prepared from the unnatural amino acid 2-methylalanine also
participated in the reaction to give the corresponding desired
products 2t in 62% yield.
(Table 2). Since 2,6-di-tert-butyl-4-methylphenol (BHT) and 1,1-
diphenylethene (DPE) had almost no effect on the yield, we
considered that radical species were not generated in the
reaction. In contrast, TEMPO led to a decrease of yield probably
due to the competitive reaction of TEMPO with PhI(OAc)2.[12]
Table 2. Addition of various radical scavengers.
Ts
HN
PhI(OAc)2 (2.0 equiv)
additive (1.1 equiv)
Ts
N
DCE (2.0 M), 90 ºC, 24 h
N
Me
O
N
Me
O
1a
2a
Entry
Additive
Yield (%)
1
2
3
4
None
BHT
91
91
87
53
Ts
HN
Ts
N
R1
R2
R1
R2
PhI(OAc)2 (2.0 equiv)
DPE
DCE (2.0 M), 90 ºC, 24 h
TEMPO
N
O
N
O
Me
Me
1o-1t
2o-2t
Ts
Ts
N
Ts
N
Based on the above mechanism studies, we propose a
reaction mechanism initiated by the reaction of 1a with
PhI(OAc)2 to give N-I intermediate A, followed by the elimination
of PhI and acetate anion (Scheme 3). Aromatic nucleophilic
attack of the phenyl ring to the nitrenium center of B gives
intermediate C. Aromatization promoted by hydrogen abstraction
using acetate anion affords the desired dihydroquinoxalinone 2a.
However, a radical mechanism can not be completely ruled out.
N
N
O
N
O
N
O
Me
Me
Me
2o, 82%
2p, 72%
2q, 83%
Ts
N
Ts
N
Ts
Me
N
Me
N
O
N
O
OTs
N
O
Me
2r, 71%
Me
Me
2s, 80%
2t, 62%
OAc
Scheme 3. Scope of amino acids.
Ts
Ts
N
I
PhI(OAc)2
HOAc
HN
Ts
N
N
Me
O
N
Me
1a
O
To demonstrate the practicality of the reaction, the oxidative
cyclization reaction was carried out using 1.0 mmol (0.41g) of 1c
under the standard conditions. The reaction proceeded smoothly
to deliver 2c without a decrease in yield (Eq. 1). Moreover, the
tosyl group was easily removed in excellent yield using
magnesium turnings under ultrasonic irradiation (Eq. 2).[11] The
enantiomeric excess of the starting material was also maintained
during deprotection.
PhI, –OAc
N
B
O
Me
A
–OAc
Ts
N
Ts
N
H
N
Me
2a
O
N
Me
O
HOAc
C
Scheme 3. Plausible reaction mechanism.
Ts
HN
Ts
N
PhI(OAc)2 (2.0 equiv)
DCE, 90 ºC, 24 h
Eq. 1
N
Bn
O
N
Bn
O
In summary, we have developed a metal-free synthesis of
dihydroquinoxalinones from inexpensive and/or readily available
aniline and amino acid derivatives. The reaction tolerates
various functional groups to afford the desired multisubstituted
dihydroquinoxalinones in moderate to excellent yields. The
chirality of the amino acid is transferred to the desired product
without a loss of enantiomeric excess. Preliminary mechanistic
studies indicated that the reaction proceeded via an ionic
mechanism. Further synthetic applications of amino acids as
building blocks for the synthesis of potentially bioactive
compounds are in progress in our laboratory.
2c, 78% (0.32 g)
1c,1.0 mmol (0.41 g)
Ts
N
H
N
Mg (10 equiv)
Eq. 2
ultrasonic,
MeOH, 0 ºC, 30 min
N
Bn
O
N
Bn
O
2c, 99% ee
3, 91ꢀ, 99% ee
This N-H/C-H coupling may proceed through either ionic[8d,8g] or
radical[8b,8j] mechanism. To elucidate the mechanism, we carried
out the reaction in the presence of several radical scavengers
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800012
European Journal of Organic Chemistry
COMMUNICATION
Carbain, E. Schütznerová, A. Přibylka, V. Krchňák, Adv. Synth. Catal.
2016, 358, 701–706.
Acknowledgements
[4]
a) J. L. Núñez-Rico, A. Vidal-Ferran, Org. Lett. 2013, 15, 2066–2069; b)
L. Zhang, R. Qiu, X. Xue, Y. Pan, C. Xu, H. Li, L. Xu, Adv. Synth. Catal.
2015, 357, 3529–3537.
This work was supported in part by a Waseda University Grant
for Special Research Projects (for K.S.K., Project Number:
2016-B145), and a JSPS Grant-in-Aid for Young Scientists for
K.S.K., No. 16K21435).
[5]
[6]
M. S. Perryman, M. E. Harris, J. L. Foster, A. Joshi, G. J. Clarkson, D. J.
Fox, Chem. Commun. 2013, 49, 10022–10024.
For selected reviews, see: a) R. M. Moriarty, O. Prakash Acc. Chem.
Rev. 1986, 19, 244–250; b) Y. Kita, T. Takada, H. Tohma, Pure Appl.
Chem., 1996, 68, 627–630; c) P. Stang, V. V. Zhdankin, Chem. Rev.
1996, 96, 1123–1178; d) P. J. Stang, V. V. Zhdankin, V. V. Chem. Rev.
2002, 102, 2523–2584; e) T. Wirth, Angew. Chem., Int. Ed. 2005, 44,
3656–3665; f) M. Ochiai, K. Miyamoto, Eur. J. Org. Chem. 2008, 4229–
4239; g) T. Dohi, Y. Kita, Chem. Commun. 2009, 2073–2085; h) A.
Yoshimura, V. V. Zhdankin, Chem. Rev. 2016, 116, 3328–3435.
For selected recent reviews, see: a) P. Ruiz-Castillo, S. L. Buchwald,
Chem. Rev. 2016, 116, 12564–12649; b) H. Kim, S. Chang, ACS Catal.
2016, 6, 2341–2351; c) Q. Wang, Y. Su, L. Lia, H. Huang, Chem. Soc.
Rev. 2016, 45, 1257–1272; d) V. Ritleng, M. Henrion, M. J. Chetcuti,
ACS Catal. 2016, 6, 890–906; e) J. Li, Y. Hu, D. Zhang, Q. Liu, Y. Dong,
H. Liu, Adv. Synth. Catal. 2017, 359, 710–771.
Keywords: dihydroquinoxalinones • C-N coupling • hypervalent
iodine • amino acids • C-H functionalization
[1]
a) J. P. Kleim, R. Bender, R. Kirsch, C. Meichsner, A. Rosner, H.
Rubsamen-Waigmann, R. Kaiser, M. Wichers, K. E. Scheneweis, I.
Winker, G. Riess, Antimicrob. Agents Chemother. 1995, 39, 2253–
2257; b) U. J. Ries, H. W. M. Priepke, N. H. Hauel, S. Handschuh, G.
Mihn, J. M. Stassen, W. Mienen, H. Nar, Bioorg. Med. Chem. Lett. 2003,
13, 2297–2302; c) Y. Mori, T. Hirokawa, K. Aoki, H. Satomi, S. Takeda,
M. Aburada, K. Miyamoto, Chem. Pharm. Bull. 2008, 56, 682–687; d) B.
Xu, Y. Sun, Y. Guo, Y. Cao, T. Yu, Bioorg. Med. Chem. 2009, 17,
2767–2774; e) D. V. Smil, S. Manku, Y. Chantgny, S. Leit, A. Wahhab,
T. P. Yan, M. Fournel, C. Maroun, Z. Li, A.-M. Lemiex, A. Nicolescu, J.
Rahil, S. Lefebvre, A. Panetta, J. M. Besterman, R. Deziel, Bioorg. Med.
Chem. Lett. 2009, 19, 688–692; f) S. A. Galal, A. S. Abdelsamie, S. M.
Soliman, J. Mortier, G. Wohber, M. M. Ali, H. Tokuda, N. Suzuki, A.
Lida, R. A. Ramadan, H. I. Diwani, Eur. J. Med. Chem. 2013, 69, 115–
124; g) Y. Wang, T.-Y. Wach, P. Sheehan, C. Zhong, C. Zhan, R.
Harris, S. C. Almo, J.; Bishop, S. J. Haggarty, A. Ramek, K. N. Berry, C.
O’Herin, A. N. Koehler, A. W. Hung, D. W. Young, Med. Chem. Lett.
2016, 7, 852–856.
[7]
[8]
Examples: a) Y. Kikugawa, M. Kawase, Chem. Lett. 1990, 581–582; b)
Y. Du, R. Liu, G. Linn, K. Zhao, Org. Lett. 2006, 8, 5919–5922; c) Y.
Amano, S. Nishiyama, Tetrahedron Lett. 2006, 47, 6505–6507; d) A.
Correa, I. Tellitu, E. Domínguez, I. Moreno, R. SanMartin, J. Org. Chem.
2005, 70, 2256–2264; e) T. Dohi, A. Maruyama, Y. Minamitsuji, N.
Takenaga, Y. Kita, Chem. Commun. 2007, 1224–1226; f) A. Moroda, H.
Togo, Synthesis 2008, 1257–1261; g) J. Zhu, H. Xie, Z. Chen, S. Li, Y.
Wu, Synlett. 2009, 3299–3302; h) A. P. Antonchick, R. Samanta, K.
Kulikov, J. Lategahn, Angew. Chem., Int. Ed. 2011, 50, 8605–8608; i) N.
Kunsumura, S. Kunimatsu, K. Kagawa, T. Otani, T. Saito, Synthesis
2011, 3235–3240; j) J. Huang, Y. He, Y. Wang, Q. Zhu, Chem. Eur. J.
2012, 18, 13964–13967; k) S. K. Alla, R. K. Kumar, P. Sadhu, T.
Punniyamurthy, Org. Lett. 2013, 15, 1334–1337; l) T. Otani, A. Tsuyuki,
T. Iwachi, S. Someya, K. Tateno, H. Kawai, T. Saito, K. S. Kanyiva, T.
Shibata, Angew. Chem., Int. Ed. 2017, 56, 3906–3910.
[2]
For recent examples, see: a) T. P. C. Rooney, P. Filippakopoulos, O.
Fedorov, S. Picaud, W. A. Cortopassi, D. A. Hay, S. Martin, A. Tumber,
C. M. Rogers, M. Philpott, M. Wang, A. L. Thompson, T. D. Heightman,
D. C. Pryde, A. Cook, R. S. Paton, S. Müller, S. Knapp, P. E. Brennan,
S. J. Conway, Angew. Chem. 2014, 126, 6240–6244; b) Y. Yang, L.
Zhao, B. Xu, L. Yang, J. Zhang, H. Zhang, J. Zhou, Biorg. Chem. 2016,
68, 236–244; c) X. Zhang; B. Xu, M.-H. Xu, Org. Chem. Front. 2016, 3,
944–948; d) T. Fogeron, P. Retailleau, L.-M. Chamoreau, M. Fontecave,
Y. Li, Dalton Trans. 2017, 46, 4161–4164.
[9]
a) Y. Tahara, M. Ito, K. S. Kanyiva, T. Shibata, Chem. Eur. J. 2015, 21,
11340–11343; b) Y. Tahara, M. Michino, M. Ito, K. S. Kanyiva, T.
Shibata, Chem. Commun. 2015, 51, 16660–16663; c) Y. Tahara, S.
Obinata, K. S. Kanyiva, T. Shibata, A. Mandi, T. Taniguchi, K. Monde,
Eur. J. Org. Chem. 2016, 1405–1413; d) Kanyiva, S. K.; Makino, S.
Shibata, T. Chem. Asian J. 10.1002/asia.201701739.
[3]
a) C. Hulme, J. Peng, G. Morton, J. M. Salvino, T. Herpin, R.
Labaudiniere, Tetrahedron Lett. 1998, 39, 7227–7230; b) Q. Jiang, D.
Jiang, Y. Jiang, Y. Zhao, Synlett 2007, 72, 1836–1842; c) J.-L. Li, B.
Han, K. Jiang, W. Du, Y.-C. Chen, Bioorg. Med. Chem. Lett. 2009, 19,
3952–3954; d) S. Tanimori, T. Nishimura, M. Kirihata, Biorg. Med.
Chem. 2009, 19, 4119–4121; e) S. Tanimori, H. Kashiwagi, T.
Nishimura, M. Kirihara, Adv. Synth. Catal. 2010, 352, 2531–2537; f) W.
Nasir, M. A. Munawar, E. Ahmed, A. Sharif, S. Ahmed, A. Ayub, M. A.
Khan, F. H. Nasim, Arch. Pharm. Res. 2011, 34, 1605–1614; g) Y. Kim,
K. J. Park, Y. S. Park, Bull. Korean Chem. Soc. 2012, 33, 3853–3856;
h) C. Neagoie, V. Krchňák, Comb. Sci. 2012, 14, 399–402; i) B.
[10] a) T. Dohi, A. Maruyama, M. Yoshimura, K. Morimoto, H. Tohma, Y.
Kita, Angew. Chem., Int. Ed. 2005, 44, 6193–6196; b) M. Ochiai, Y.
Takeuchi, T. Katayama, T. Sueda, K. Miyamoto, J. Am. Chem. Soc.
2005, 127, 12244–12245; c) Y. Yamamoto; H. Togo, Synlett 2006,
798–800.
[11] B. Nyasse, L. Grehnb, U. Ragnarsson Chem. Commun. 1997, 1017–
1018.
[12] A. Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli, J. Org.
Chem. 1997, 62, 6974–6977.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800012
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
Kyalo Stephen Kanyiva,* Masashi
Horiuchi, and Takanori Shibata*
PG
PG
N
R3
O
R3
O
HN
PhI(OAc)2 (2.0 equiv)
R1
R1
Page No. – Page No.
DCE, 90 ºC, 24 h
Z = CH, N
Z
N
Z
N
R2
R2
Metal-Free N-H/C-H Coupling for
Efficient Asymmetric Synthesis of
Chiral Dihydroquinoxalinones From
Readily Available α-Amino Acids
>99% ee
up to 92% yield,
>99% ee
N-H/C-H coupling
We have developed a method for the synthesis of dihydroquinoxalinones via
intramolecular N-H/C-H coupling using hypervalent iodine from inexpensive and
readily available aniline and amino acid derivatives. Various functional groups were
tolerated to give multisubstituted dihydroquinoxalinones in moderate to excellent
yields. The chirality of the amino acid was transferred to the desired target
compound without loss of enantiomeric excess.
This article is protected by copyright. All rights reserved.