Hypervalent iodine(III)-mediated benzannulation of enamines with alkynes for the synthesis of polysubstituted naphthalene derivatives

Article abstract of DOI:10.1021/ol401206g

A series of functionalized 1-amino-2-naphthalenecarboxylic acid derivatives were synthesized from enamines and alkynes via a benzannulation strategy mediated by iodosylbenzene and BF₃·Et₂O. The advantages of this novel benzannulation process include broad substrate scope, good functional group tolerance, and mild reaction conditions without the use of heavy metals.

Full text of DOI:10.1021/ol401206g

ORGANIC
LETTERS
2013
Vol. 15, No. 11
2872–2875
Hypervalent Iodine(III)-Mediated
Benzannulation of Enamines with Alkynes
for the Synthesis of Polysubstituted
Naphthalene Derivatives
Peng Gao, Jinjian Liu, and Yunyang Wei*
School of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing 210094, P. R. China
ywei@mail.njust.edu.cn
Received April 29, 2013
ABSTRACT
A series of functionalized 1-amino-2-naphthalenecarboxylic acid derivatives were synthesized from enamines and alkynes via a benzannulation
strategy mediated by iodosylbenzene and BF3 Et2O. The advantages of this novel benzannulation process include broad substrate scope, good
functional group tolerance, and mild reaction conditions without the use of heavy metals.
3
Hypervalent iodine(III) reagents were used extensively
in organic synthesis as a result of their unique properties,
such as readily availability, environmental benignity, and
high reactivity.1 Under metal-free conditions, the utiliza-
tion of hypervalent iodine(III) reagents for CÀN,2 CÀO,3
or NÀN4 bond formation has been thoroughly investi-
gated. In recent years, it was found that hypervalent
iodine(III) reagents also showed remarkable reactivies
for CÀC bond formation. Following these strategies,
biaryl compounds,5 spirodienones,6 or heterocycles7 could
be obtained successfully. Nevertheless, hypervalent iodine-
(III)-mediated intermolecular cyclization procedures via
CÀC bond formation have been seldom reported, espe-
cially in the synthesis of carbocycles.8
€
(5) (a) Mirk, D.; Willner, A.; Frohlich, R.; Waldvogel, S. R. Adv.
Synth. Catal. 2004, 346, 675. (b) Dohi, T.; Morimoto, K.; Maruyama,
K.; Kita, Y. Org. Lett. 2006, 8, 2007. (c) Dohi, T.; Ito, M.; Morimoto, K.;
Iwata, M.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 1301. (d) Kita, Y.;
Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem. Soc.
2009, 131, 1668.
(1) For selected reviews, see: (a) Stang, P. J.; Zhdankin, V. V. Chem.
Rev. 1996, 96, 1123. (b) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 2002,
102, 2523. (c) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656. (d)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (e) Dohi, T.;
Kita, Y. Chem. Commun. 2009, 45, 2073.
(6) (a) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T.
J. Am. Chem. Soc. 1992, 114, 2175. (b) Kita, Y.; Takada, T.; Gyoten, M.;
Tohma, H.; Zenk, M. H.; Eichhorn, J. J. Org. Chem. 1996, 61, 5857. (c)
ꢀ
Traore, M.; Maynadier, M.; Souard, F.; Choisnard, L.; Vial, H.; Wong,
(2) (a) Cho, S.; Yoon, H. J.; Chang, S. J. Am. Chem. Soc. 2011, 133,
5996. (b) Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.;
DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960. (c) Antonchick, A. P.;
Samanta, R.; Kulikov, K.; Lategahn, J. Angew. Chem., Int. Ed. 2011, 50,
ꢀ
Y. S. J. Org. Chem. 2011, 76, 1409. (d) Beaulieu, M. A.; Guerard, K. C.;
Maertens, G.; Sabot, C.; Canesi, S. J. Org. Chem. 2011, 76, 9460.
(7) (a) Arisawa, M.; Ramesh, N. G.; Nakajima, M.; Tohma, H.; Kita,
Y. J. Org. Chem. 2001, 66, 59. (b) Ye, Y.; Zheng, C.; Fan, R. Org. Lett.
2009, 11, 3156. (c) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417. (d)
Liang, J.; Chen, J.; Du, F.; Zeng, X.; Li, L.; Zhang, H. Org. Lett. 2009,
11, 2820. (e) Wang, J.; Yuan, Y.; Xiong, R.; Zhang-Negrerie, D.; Du, Y.;
Zhao, K. Org. Lett. 2012, 14, 2210.
ꢀ
~
8605. (d) Souto, J. A.; Becker, P.; Iglesias, A.; Muniz, K. J. Am. Chem.
Soc. 2013, 135, 1550.
(3) (a) Dohi, T.; Takenaga, N.; Goto, A.; Maruyama, A.; Kita, Y.
Org. Lett. 2007, 9, 3129. (b) Zhao, F.; Liu, X.; Qi, R.; Zhang-Negrerie,
D.; Huang, J.; Du, Y.; Zhao, K. J. Org. Chem. 2011, 76, 10338. (c)
Zheng, Y.; Li, X.; Ren, C.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J. Org.
Chem. 2012, 77, 10353.
(4) (a) Correa, A.; Tellitu, I.; Domınguez, E.; SanMartin, R. J. Org.
Chem. 2006, 71, 3501. (b) Correa, A.; Tellitu, I.; Domınguez, E.;
SanMartin, R. Tetrahedron 2006, 62, 11100. (c) Wang, K.; Fu, X.;
Liu, J.; Liang, Y.; Dong, D. Org. Lett. 2009, 11, 1015.
(8) (a) Hamamoto, H.; Anilkumar, G.; Tohmaa, H.; Kita, Y. Chem.
Commun. 2002, 38, 450. (b) Hamamoto, H.; Anilkumar, G.; Tohmaa,
H.; Kita, Y. Chem.;Eur. J. 2002, 8, 5377. (c) Rodrıguez, A.; Moran,
W. J. Org. Lett. 2011, 13, 2220. (d) Desjardins, S.; Andrez, J.-C.; Canesi,
ꢀ
S. Org. Lett. 2011, 13, 3406. (e) Jacquemot, G.; Menard, M.-A.;
L’Homme, C.; Canesi, S. Chem. Sci. 2013, 4, 1287.
r
10.1021/ol401206g
Published on Web 05/15/2013
2013 American Chemical Society

Polysubstituted naphthalenes are important raw mate-
rials both in medicinal chemistry and industrial chemistry
not only because of their remarkable biological and pharma-
cological activities but also because of their electro-
chemical and photochemical properties.9 Apart from these
interesting activities, some naphthalene derivatives also
find application in the design of chiral catalysts, ligands,
and metal complexes.10 Therefore, development of new
methods for the synthesis of naphthalene derivatives,
especially the polysubstituted ones, is of great importance.
For the preparation of naphthalene derivatives, many
efficient benzannulation strategies have been reported.11
For example, Yamamoto and co-workers had developed a
variety of benzannulations of enynals with alkynes or
enols leading to naphthalenes with transition metals as
catalyst.11aÀc The benzannulation reaction of the Fischer
HPF6 water solution, or 40% HBF4 water solution
instead of BF3 Et2O led to a decrease of the product yield
3
(entries 5À7). There was no increase in yield of 3aa when
the dosage of BF3 Et2O increased from 1.2 to 1.8 equiv.
Decreasing the dosage of BF3 Et2O to 0.6 equiv dramati-
3
3
cally reduced the yield of product 3aa, and only a trace
amount of the product was detected (entries 8 and 9).
Among the solvents tested, including 2,2,2-trifluoroethanol
(TFE), CH2Cl2, CH3CN, and EtOAc, TFE gave the best
result (entries 10À12). Thus, the optimized procedure was
chosen as follows: carried out the reaction in TFE in the
presence of 1.1 equiv (PhIO)n and 1.2 equiv BF3 Et2O at
3
0 °C to room temperature for 5 h (entry 4).
Table 1. Optimization of Iodine(III)-Mediated Benzannulation
of Methyl 3-Amino-3-phenylacrylate and Phenylacetylene for
the Synthesis of Methyl 1-Amino-4-phenyl-2-naphthoatea
€
carbene complexes, named the WulffÀDotz reaction, was
another important approach to naphthalene derivatives.11dÀg
However, most of these methodologies started from
multistep-prepared materials and relied heavily on transi-
tion-metal catalysts. To develop simple methods for the
preparation of naphthalene derivatives and in continua-
tion of our efforts on the development of hypervalent
iodine(III) mediated oxidative reactions,12 herein we re-
port a new benzannulation strategy for the synthesis of
1-amino-2-naphthalenecarboxylic acid derivatives from
readily available enamines and alkynes mediated by
entry
oxidant
solvent
additive (equiv)
yieldb (%)
1
PIDA
TFE
BF3 OEt2 (1.2)
21
3
2
PIFA
TFE
BF3 OEt2 (1.2)
26
3
3
HTIB
TFE
BF3 OEt2 (1.2)
trace
85
3
(PhIO)n and BF3 Et2O.
3
4
(PhIO)n
(PhIO)n
(PhIO)n
(PhIO)n
(PhIO)n
(PhIO)n
(PhIO)n
(PhIO)n
(PhIO)n
TFE
BF3 OEt2 (1.2)
3
Initial expieriments were carried out using enamine 1a
and phenylacetylene as the model substrates to test the
feasibility of this transformation. As seen from Table 1,
phenyliodine diacetate (PIDA), phenyliodine bis-trifluoro-
acetate (PIFA) or hydroxy(tosyloxy)iodobenzene (HTIB)
showed low reactivity in this reaction. In the presence of
these oxidants, 3aa was obtained in low yield (entries 1À3).
Toour delight, by changingtheoxidantto(PhIO)n, yield of
3aa was greatly improved to 85% (entry 4). Use of other
additives, such as p-toluenesulfonic acid (PTSA), 60%
5
TFE
PTSA (1.2)
HPF6 (1.2)c
HBF4 (1.2)d
trace
76
6
TFE
7
TFE
68
8
TFE
BF3 OEt2 (1.8)
84
3
9
TFE
BF3 OEt2 (0.6)
trace
63
3
10
11
12
CH2Cl2
CH3CN
EtOAc
BF3 OEt2 (1.2)
3
BF3 OEt2 (1.2)
trace
trace
3
BF3 OEt2 (1.2)
3
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), oxidant (0.55
mmol), additive, in solvent (5 mL), 0 °C to rt, 5 h. b Isolated yield. c 60%
HPF6 water solution was used. d 40% HBF4 water solution was used.
(9) (a) Ukita, T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Takahashi,
M.; Kotera, J.; Ikeo, T. J. Med. Chem. 1999, 42, 1293. (b) de Koning, C. B.;
Michael, J. P.; van Otterlo, W. A. L. J. Chem. Soc., Perkin Trans. 1 2000,
799. (c) Xie, X.; Kozlowski, M. C. Org. Lett. 2001, 3, 2661. (d) Pozharskii,
With the optimized conditions in hand, different sub-
strates were tested for the synthesis of substituted 1-amino-
2-naphthalenecarboxylic acid derivatives (Scheme 1).
To our satisfaction, phenyl enamines bearing electron-
donating or electron-withdrawing groups in the phenyl
ring were all reacted well and the corresponding products
were isolated with high yields (3aaÀia). To our surprise,
when 3-amino-3-(2-methylphenyl)acrylic acid methyl ester
(1c) was used as a substrate, benzannulation took place at
the meta position of the methyl group of the aromatic ring
to lead to product 3ca in good yield and no steric effect of
the o-methyl group was observed. Naphthyl enamine 1j also
reacted well, and the corresponding phenanthrene derivative
3ja was obtained in good yield. However, when heterocyclic
enamine 1k was used as substrate, the reaction was compli-
cated and only trace amount of the product 3ka were detected.
Reactions of the enamine 1l bearing cyano as an electron-
withdrawing group with phenylacetylene also proceeded
smoothly and gave the desired product (3la) in moderate yield.
€
A. F. Russ. Chem. Rev. 1998, 67, 1. (e) Watson, M. D.; Fechtenkotter, A.;
€
Mullen, K. Chem. Rev. 2001, 101, 1267.
(10) (a) Matsunaga, S.; Ohshima, T.; Shibasaki, M. Adv. Synth.
Catal. 2002, 344, 3. (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev.
2002, 102, 2187. (c) Hara, K.; Tosaki, S.; Gnanadesikan, V.; Morimoto,
H.; Harada, S.; Sugita, M.; Yamagiwa, N.; Matsunaga, S.; Shibasaki,
M. Tetrahedron 2009, 65, 5030. (d) Shibasaki, M.; Matsunaga, S. In
BINOL. In Privileged Chiral Ligands and Catalysts; Zhou, Q. L., Ed.;
Wiley: New York, 2011; pp 295À332.
(11) (a) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 10921. (b) Asao, N.; Aikawa, H. J. Org. Chem. 2006, 71,
5249. (c) Asao, N.; Sato, K.; Yamamoto, Y. J. Org. Chem. 2005, 70,
3682. (d) Vorogushin, A. V.; Wulff, W. D.; Hansen, H. J. Am. Chem.
Soc. 2002, 124, 6512. (e) Wu, C.; Berbasov, D. O.; Wulff, W. D. J. Org.
Chem. 2010, 75, 4441. (f) Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am.
Chem. Soc. 2011, 133, 6557. (g) Majumdar, N.; Korthals, K. A.; Wulff,
W. D. J. Am. Chem. Soc. 2012, 134, 1357.
(12) (a) Zhu, C.; Wei, Y. ChemSusChem 2011, 4, 1082. (b) Zhu, C.;
Wei, Y. Adv. Synth. Catal. 2012, 354, 313. (c) Zhu, C.; Xu, D.; Wei, Y.
Synthesis 2011, 43, 711. (d) Zhu, C. J.; Yoshimura, A.; Solntsev, P.; Ji, L.;
Wei, Y. Y.; Nemykin, V. N.; Zhdankin, V. V. Chem. Commun. 2012, 48,
10108. (e) Zhu, C.; Yoshimura, A.; Ji, L.; Wei, Y.; Nemykin, V. N.;
Zhdankin, V. V. Org. Lett. 2012, 14, 3170.
Org. Lett., Vol. 15, No. 11, 2013
2873

Scheme 1. Scope of Enamine Substrates for
Iodine(III)-Mediated Benzannulation with Phenylacetylenea
Scheme 2. Synthesis of 1-Amino-2-naphthalenecarboxylic Acid
Derivatives from Different Alkynesa
a Reaction conditions: 1(0.5 mmol), 2a (0.5 mmol), (PhIO)n (0.55 mmol),
BF3 OEt2 (0.6 mmol), in TFE (5 mL), 0 °C to rt, 5 h, isolated yield.
3
In light of the above encouraging results, our further
study was aimed at the scope of alkynes in this reaction. As
seen from Scheme 2, substituted phenyl terminal alkynes
all smoothly converted to the desired products in moderate
to good yields (3abÀad). Nonterminal alkynes, such as
1-(but-1-ynyl)benzene (2e) and 1,2-diphenylethyne (2f),
also gave the corresponding products (3ae, 3af) in mod-
erate to good yields. The relatively lower yield of 3af may
bedue tothe decreasedreactivityofthe alkyne group orthe
steric effect of the two phenyl groups in 1,2-diphenylethyne.
However, only a trace amount of product (3ag) was
detected when methyl propiolate (2g) was used as the
alkyne partner. The decreased reactivity of the alkyne by
ester group maybe cause the failure to get product 3ag.
When 1-hexyne (2h), an aliphatic terminal alkyne, was
used as substrate, the corresponding benzannulation
products (3ah, 3dh) were also obtained in good yields.
Reaction of substituted phenylalkynes with various en-
amines also gave corresponding 1-amino-2-naphthalene-
carboxylic acid derivatives 3bb, 3fb, and 3bc in good to
excellent yields.
a Reaction conditions: 1(0.5mmol),2a (0.5mmol),(PhIO)n (0.55mmol),
BF3 OEt2 (0.6 mmol), in TFE (5 mL), 0 °C to rt, 5 h, isolated yield.
3
On the basis of the properties of (PhIO)n13 and literature
reports about the reaction of hypervalent iodine(III) re-
agents with enamine compounds,7d,e,14 a possible mecha-
nism is proposed in Scheme 3. First, depolymerization of
(PhIO)n with BF3 OEt2 generates the iodine(III) reagent
3
A. Reaction of A with enamine 1 gives the intermediate B.
Nucleophilic attack of alkyne 2 on B generates C. The final
benzannulation product 3 is then formed by intramolecular
(13) (a) Ochiai, M.; Fujita, E.; Arimoto, M.; Yamaguchi, H. Tetra-
hedron Lett. 1983, 24, 777. (b) Ochiai, M.; Sumi, K.; Nagao, Y.; Fujita,
E.; Arimoto, M.; Yamaguchi, H. J. Chem. Soc., Chem. Commun. 1985,
697. (c) Ochiai, M.; Kunishima, M.; Sumi, K.; Nagao, Y.; Fujita, E.
Tetrahedron Lett. 1985, 26, 4501. (d) Zhdankin, V. V.; Tykwinski, R.;
Caple, R. Tetrahedron Lett. 1988, 29, 3717.
(14) (a) Papoutsis, I.; Spyroudis, S.; Varvoglis, A. Tetrahedron 1998,
54, 1005. (b) Wang, Y.; Liu, S. P.; Yu, W. Synlett 2009, 15, 2529. (c)
Wang, J. Y.; Wang, X. P.; Yu, Z. S.; Yu, W. Adv. Synth. Catal. 2009, 351,
2063. (d) Li, X.; Du, Y.; Liang, Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett.
2009, 11, 2643.
1
All of the isolated products were identified by H, 13C
NMR and HR-MS. The crystal structure of 3aa was
determined by X-ray crystallography (Figure 1).
2874
Org. Lett., Vol. 15, No. 11, 2013

Scheme 3. Possible Mechanism of the Hypervalent
Iodine(III)-Mediated Benzannulation of Enamines with Alkynes
synthesisof usefulnaphthalene derivatives. Furtherstudies
to clearly understand the mechanism and extension of the
scope of the protocol are currently under investigation in
our laboratory.
Figure 1. X-ray crystal structure of 3aa.
Acknowledgment. This work was funded by the Priority
Academic Program Development of Jiangsu Higher Edu-
cation Institutions.
electrophilic attack of the cationic carbon of C on the
aromatic ring.
In summary, an efficient, direct oxidative benzannula-
tion procedure was developed. This novel protocol afforded
1-amino-2-naphthalenecarboxylic acid derivatives in high
yields from easily available enamines and alkynes in the
Supporting Information Available. Experimental details
and characterization data for products. This material
is available free of charge via the Internet at http://
pubs.acs.org.
presence of (PhIO)n and BF3 OEt2. Broad substrate scope,
good functional group tolerance, and mild reaction con-
ditions make the protocol a potential approach to the
3
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 11, 2013
2875