Bioinspired construction of a spirocyclohexadienone moiety via sodium nitrite catalyzed aerobic intramolecular oxidative phenol coupling

Article abstract of DOI:10.1021/ol400388j

An efficient and green intramolecular oxidative phenol coupling for the direct construction of spirocyclohexadienones has been developed, which uses environment-friendly sodium nitrite as the catalyst and oxygen in the air as the terminal oxidant. Hydroxy-containing substituted phenanthrenes and dibenzoazepines could be easily obtained from the dienone-phenol rearrangement.

Full text of DOI:10.1021/ol400388j

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1606–1609
Bioinspired Construction of a
Spirocyclohexadienone Moiety via
Sodium Nitrite Catalyzed Aerobic
Intramolecular Oxidative Phenol Coupling
Bo Su,† Meng Deng,† and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
wang98h@263.net; wangqm@nankai.edu.cn
Received February 8, 2013
ABSTRACT
An efficient and green intramolecular oxidative phenol coupling for the direct construction of spirocyclohexadienones has been developed, which
uses environment-friendly sodium nitrite as the catalyst and oxygen in the air as the terminal oxidant. Hydroxy-containing substituted
phenanthrenes and dibenzoazepines could be easily obtained from the dienoneꢀphenol rearrangement.
Intramolecular oxidative phenol coupling has long been
recognized as the key step in the biosynthesis of phenolic
alkaloids and other natural products (Scheme 1),1 among
which amaryllicaceae,2 morphine and aporphine,3 and
phenanthroindolizidine alkaloids4 were widely examined.
The biogenesis of these natural products has inspired a
number of elegant total syntheses5 and led to extensive
exploration of oxidizing reagents, mainly focusing on heavy
metal reagents such as Tl(III),6 Fe(III),7 Pb(IV),8 and V(V)
salts.9 In the past two decades, a nonmetal oxidizing reagent,
a hypervalent iodine(III) reagent, has also been widely
explored and applied in the oxidative coupling reactions.10
However, large excess amounts of usage (at least stoichio-
metric equivalent), high toxicity, severe conditions, and/or
low yield also largely limited their applications, especially
(6) (a) Schwartz, M. A.; Rose, B. F.; Vishnuvajjala, B. J. Am. Chem.
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G. J. H.; McKillop, A. J. Am. Chem. Soc. 1980, 102, 6513–6519.
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T. J. Am. Chem. Soc. 2010, 132, 13633–13635. (b) Egami, H.; Katsuki, T.
J. Am. Chem. Soc. 2009, 132, 6082–6083. (c) Wang, K. L.; Lu, M. Y.; Yu,
A.; Zhu, X. Q.; Wang, Q. M. J. Org. Chem. 2009, 74, 935–938.
(8) Feldman, K. S.; Ensel, S. M. J. Am. Chem. Soc. 1994, 116, 3357–
3366.
† These authors contributed equally.
(1) (a) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004,
104, 1383–1430. (b) Swenton, J. S. In The Chemistry of Quinonoid
Compounds, Vol. 2, Part 2; Patai, S., Rappoport, Z., Eds.; Wiley: New
York, 1988; p 899. (c) Humphries, S. G. In Biogenesis of Natural
Products; Bernfeld, P., Ed.; McMillan: New York, 1963; p 617.
(2) (a) Bhandarkar, J. G.; Kirby, G. W. J. Chem. Soc. 1970, 1224–
1227. (b) Eichhorn, J.; Takada, T.; Kita, Y.; Zenk, M. H. Phytochem-
istry 1998, 49, 1037–1047.
(3) (a) Kutchan, T. M. In The Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; San Diego, 1997; Vol. 50, p 257. (b) Eichhorn, J.;
Takada, T.; Kita, Y.; Zenk, M. H. Phytochemistry 1998, 49, 1037.
(4) (a) Mulchandani, N. B.; Iyer, S. S.; Badheka, L. P. Phytochem-
istry 1969, 8, 1931–1935. (b) Mulchandani, N. B.; Iyer, S. S.; Badheka,
L. P. Phytochemistry 1971, 10, 1047–1050.
(9) (a) Schwartz, M. A.; Holton, R. A.; Scott, S. W. J. Am. Chem. Soc.
1969, 91, 2800–2800. (b) Schwartz, M. A.; Holton, R. A. J. Am. Chem.
Soc. 1970, 92, 1090–1092.
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2584. (b) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178.
(c) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh, S.;
Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684–3691. (d) Kita,
Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J.
J. Org. Chem. 1996, 61, 5857–5864. (e) Takada, T.; Arisawa, M.;
Gyoten, M.; Hamada, R.; Tohma, H.; Kita, Y. J. Org. Chem. 1998,
63, 7698–7706.
(5) (a) Node, M.; Kodama, S.; Hamashima, Y.; Baba, T.; Hamamichi,
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r
10.1021/ol400388j
Published on Web 03/11/2013
2013 American Chemical Society

Table 1. Optimization of Conditionsa
Scheme 1. Oxidative Phenol Coupling and DienoneꢀPhenol
Rearrangement in the Biosynthesis of Phenanthroindolizidine
and Aporphine Alkaloids
NaNO2
(equiv)
solvents
(6 mL)
time
convb
(%)
yieldb
(%)
entry
(min)
1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.02
0.2
0.2
TFA
20
20
20
20
20
20
20
20
35
35
35
10
20
20
100
100
100
100
100
100
100
100
100
70
86
0
2
AcOH
3
DMF/TFA 5:1
EtOAc/TFA 5:1
toluene/TFA 5:1
MeCN/TFA 5:1
DCM/TFA 5:1
DCM/TFA 1:1
DCM/TFA 23:1
DCM/TFA 79:1
DCM/TFA 5:1
DCM/TFA 5:1
DCM/TFA 5:1
DCM/TfOH 5:1
2
4
33
89
90
96
95
93
49
90
97
79
5
5
6
when the concepts of environmental friendliness and atom
economy were taken into consideration. In addition, the
nonenzymic analog of this reaction in the laboratory often
results in large amounts of polymeric materials. In the past
decade, great effort has been focused toward the catalytic
version of hypervalent idion reagents, but auxiliary oxi-
dants are also indispensable.11 Therefore, a catalytic oxi-
dative phenol coupling reaction is very appealing but is
also very challenging.
Spirocyclohexadienone, containing a quaternary carbon
center, is of high importance and ubiquitously presented in
many bioactive molecules. Because it was also proposed to
be a key intermediate in the biosynthesis of some natural
occurring products, much attention has been given to the
direct construction through oxidative phenol coupling
reactions.12 Recently, we reported a novel sodium nitrite
catalyzed aerobic oxidative coupling of phenol ether deriv-
atives, in which polymethoxyl-substituted phenanthrenes
and biaryls could be synthesized efficiently.13 As a con-
tinuation of our interest in developing efficient and envi-
ronmentally benign catalytic oxidative coupling reactions,
we report herein on the construction of a spirocyclohexa-
dienone moiety using sodium nitrite as the catalyst and
oxygen in the air as the terminal oxidant at room temperature.
Initially, substrate 1a was selected to investigate suitable
reaction conditions, and the results are summarized in
Table 1. It was found that spirocyclohexadienone 2a (con-
firmed by single crystal X-ray diffraction analysis) was
obtained in 86% yield when 0.2 equiv of NaNO2 in TFA
was used in the presence of air, while no desired product
was detected when AcOH was used (entries 1 and 2). To make
7
8
9
10
11
12c
13d
14
100
100
100
100
a General reaction conditions: 1a (187 mg, 0.5 mmol), solvents
(6 mL), at room temperature and under an atmosphere of air unless
noted. b Conversion and yield were determined by HPLC. c Reaction was
carried out under an atmosphere of O2. d Reaction was carried out at 0 °C.
the reaction conditions much milder and to decrease by-
products, different solvents were screened, among which
CH2Cl2 showed the best result (entries 3ꢀ7). The concen-
tration effect of the trifluoacetic acid on the oxidative
coupling reaction was not very significant (entries 8 and 9);
49% desired product 2a could also be obtained when only
5 equiv of trifluoacetic acid was used (entry 10). When the
usage of NaNO2 was reduced to 0.1 equiv, a relatively long
reaction time was needed (entry 11). But if the reaction was
run under an atmosphere of oxygen, 0.02 equiv of NaNO2
is sufficient (entry 12), which demonstrates the fact that the
concentration of oxygen is of high importance for both the
rate and efficiency of the reaction. Byproducts increased
when the reaction was run at a lower temperature (entry 13),
and only trace amounts of the desired product were ob-
tained (entry 14) when the much stronger acid TfOH was
used.
With the optimized reaction conditions in hand, the
substrate scope was briefly investigated first (Scheme 2).
Substrates 1aꢀ1f, which have two methoxyl groups on the
phenol, were found to react smoothly and give the corre-
sponding spirocyclohexadienones 2aꢀ2f in good to excel-
lent yields. With only one methoxyl group on the phenol,
substrates 1gꢀ1j also gave the desired products 2gꢀ2j
efficiently, but substrate 1k, of which the lower aryl is less
nucleophilic, onlygavethe desiredcoupled product in22%
(11) (a) Dohi, T.; Minamitsuji, Y.; Maruyama, A.; Hirose, S.; Kita,
Y. Org. Lett. 2008, 10, 3559–3562. (b) Dohi, T.; Maruyama, A.;
Minamitsuji, Y.; Takenaga, N.; Kita, Y. Chem. Commun. 2007, 45,
1224. (b) Dohi, T.; Maruyama, A.; Yoshimura, M.; Morimoto, K.;
Tohma, H.; Kita, Y. Angew. Chem., Int. Ed. 2005, 44, 6193–6196. (c)
Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamato, K.
J. Am. Chem. Soc. 2005, 127, 12244.
(12) For recent reviews, see: Magdziak, D.; Meek, S. J.; Pettus,
T. R. R. Chem. Rev. 2004, 104, 1383–1430 and references cited therein.
(13) Su, B.; Li, L.; Hu, Y.; Liu, Y.; Wang, Q. Adv. Synth. Catal. 2012,
354, 383–387.
Org. Lett., Vol. 15, No. 7, 2013
1607

yield. Similar results were also observed for substrate 1l
and 1m. Ascan be seenfromthe results above, the electron-
donating substituents on both the phenol and the lower
arylarehighlyimportantforthe reaction, and theinfluence
of the oxy substituents on the phenol was crucial for the
formation of the desired spirocyclohexadienones.
see Supporting Information), which suggests the config-
uration of the alkene has little effect on the reaction. The
reaction of substrates 1rꢀ1t, which contain a nitrogen in
the tether, also proceeded smoothly and offered valuable
nitrogen-containing spirocyclohexadienones 2rꢀ2t respec-
tively in good yields.
Scheme 2. Effects of Oxy Substituents on the Arylsa
Scheme 3. Effects of Tether between Arylsa
a Unless otherwise noted, the reaction was carried out with 1 (0.5 mmol)
and solvents (6 mL), and yields in the parentheses referred to isolated yields.
On the basis of the preliminary studies, a plausible mech-
anism for the present oxidative coupling was proposed in
Scheme 4. The reaction proceeds with a typical radical
mechanism via the one-electron transfer from substrate 1
to the NOþ cation and subsequent deprotonation, giving
hexadienone radical 3 and a NO radical. Radical inter-
mediate 4, whichresultsfromintramolecular radical attack
of species 3, was further oxidized and deprotonated to give
spirocyclohexadienone 2.
Scheme 4. Plausible Mechanism for the Oxidative Phenol
Coupling Reaction
a Unless otherwise noted, the reaction was carried out with 1 (0.5 mmol)
and solvents (6 mL), and yields in the parentheses referred to isolated yields.
Furthermore, the influence of the tether between the
phenol and the lower aryl on the reaction was also in-
vestigated (Scheme 3). It was found that when the tether is
ethylene, an electron-withdrawing group at the double
bond is necessary. Substrates 1nꢀ1p worked well to give
the spirocyclohexadienones 2nꢀ2p respectively in good
yields, while substrate 1q gave complex unidentified by-
products. It is worth noting that Z-1a could also give the
desired spirocyclohexadienone 2a in 50% yield (not shown,
1608
Org. Lett., Vol. 15, No. 7, 2013

alkenyl migration) in 96% combined yield. 2s and 2t, when
subjected to the same conditions, gave two valuable di-
benzoazepines 3s and 3t in excellent yield respectively. It is
noteworthy that the construction of seven-membered di-
benzoazepines usually required multiple steps, often involving
palladium catalyzed biaryl coupling as one of the key steps.14
In summary, the bioinspired sodium nitrite catalyzed
oxidative phenol coupling for the direct construction of the
spirocyclohexadienone moiety was developed using O2 in
the air as the terminal oxidant at room temperature. The
resulting spirocyclohexadienones could lead to diverse
valuable scaffolds via Lewis acid catalyzed hexadienoneꢀ
phenol rearrangement.
Scheme 5. SpirocyclohexadienoneꢀPhenol Rearrangement
Acknowledgment. We are grateful to the National Key
Project for Basic Research (2010CB126100), the National
Natural Science Foundation of China (21132003, 21121002),
Tianjin Natural Science Foundation (11JCZDJC20500),
National Key Technology Research and Development Pro-
gram (2011BAE06B05, 2012BAK25B03-3), and Specialized
Research Fund for the Doctoral Program of Higher Educa-
tion (20120031110010) for generous financial support for our
programs. We also thank China Agricultural University for
the supply of some chemical reagents.
Spirocyclohexadienoneꢀphenol rearrangement has also
been a well-known biogenetic process (Scheme 1) and
contributes greatly to the structural diversity of natural
products.1ꢀ4 Spirocyclohexadienone 2g was selected to
investigate the rearrangement (Scheme 5). Among the
Lewis acids and Brønsted acids screened for promoting the
reaction, BF3 Et2O was found to be the best choice, resulting
3
Supporting Information Available. Detailed experime-
1
tal procedures, copies of H and 13C NMR spectra for
in 3-hydroxyphenanthryl ester 3g (formed via aryl migra-
tion) and 4-hydroxyphenanthryl ester 3gg (formed through
compounds 1aꢀ1t, 2aꢀ2t, 3g, 3gg, 3s, and 3t; crystal
structure data and cif file for 2a. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) (a) Pan, X.; Wilcox, C. S. J. Org. Chem. 2010, 75, 6445–6451. (b)
Tabata, H.; Suzuki, H.; Akiba, K.; Takahashi, H.; Natsugari, H. J. Org.
ꢀ
Chem. 2010, 75, 5984–5993. (c) Baudoin, O.; Cesario, M.; Guenard, D.;
ꢀ
Gueritte, F. J. Org. Chem. 2002, 67, 1199–1207.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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