Intramolecular alkene electrophilic bromination initiated ipso -bromocyclization for the synthesis of functionalized azaspirocyclohexadienones

Article abstract of DOI:10.1021/ol301531z

Intramolecular alkene electrophilic bromination initiated dearomative cyclization has been realized in the presence of DBDMH to provide functionalized azaspirocyclohexadienones in excellent yields under mild conditions.

Full text of DOI:10.1021/ol301531z

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3526–3529
Intramolecular Alkene Electrophilic
Bromination Initiated
ipso-Bromocyclization for the
Synthesis of Functionalized
Azaspirocyclohexadienones
Qin Yin and Shu-Li You*
State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received June 4, 2012
ABSTRACT
Intramolecular alkene electrophilic bromination initiated dearomative cyclization has been realized in the presence of DBDMH to provide
functionalized azaspirocyclohexadienones in excellent yields under mild conditions.
Spirocycles have attracted great attention in organic
synthesis because of the challenge toward their synthesis
and their extensive existence as a key structural unit in
functional molecules. Among them, azaspirocyclohexadie-
nones are of particularly significant importance in organic
synthesis (Figure 1).1 To date, various methods have been
developed to construct this core motif, including intramo-
lecular cyclization reactions such as radical cyclization,2
electrophilic substitution on N-acyliminium or thionium
ions,3 metal-catalyzed (Pd, Ir, Ru, Cu) dearomatization
reactions,4 methods basedon hypervalent iodinereagents,5
an ipso-FriedelꢀCrafts/Michael addition cascade strategy,6
and others.7 However, many of the reported methods were
restricted to relatively harsh reaction conditions, a limited
(4) (a) Pigge, F. C.; Coniglio, J. J.; Rath, N. P. Org. Lett. 2003, 5,
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Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 4455.
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S. V.; Piutti, C. Angew. Chem., Int. Ed. 2002, 41, 2194. (b) Baxendale,
I. R.; Ley, S. V.; Nessi, M.; Piutti, C. Tetrahedron 2002, 58, 6285. (c)
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Zhang, H. Org. Lett. 2009, 11, 2820. (h) Andrez, J.-C.; Giroux, M.-A.;
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r
10.1021/ol301531z
Published on Web 06/22/2012
2012 American Chemical Society

substrate scope, and expensive catalytic systems. Recently,
intramolecular electrophilic ipso-halocyclization of alkynes8
has emerged as an important method for the construc-
tion of spiro-carbocycles and heterocycles, allowing facile
installation of a halo group and quaternary spirocenter.
This method, to our knowledge, is limited to substrates
containing an alkyne group and has not yet been expanded
to alkene substrates. On the other hand, the functionalization
of alkenes represents a commonly employed strategy for the
construction of molecular complexity in organic synthesis.
Catalytic enantioselective olefin halocyclization reactions such
as halo-O-cyclizations (e.g., lactonization, etherification) and
halo-N-cyclizations (e.g., lactamization, aminocyclization)
have gained rapid development in recent years.9 However,
an intramolecular halo-C-spirocyclization procedure based
on alkene group has not been reported to date.10
We envisaged that suitable para-alkene substituted
anisole derivatives (1) under electrophilic halogenation in-
itiated dearomative spirocyclization would provide functio-
nalized azaspirocyclohexadienones (Scheme 1). In this paper,
we report such an efficient synthesis of highly functionalized
azaspirocyclohexadienones via the intramolecular alkene
electrophilic bromination initiated ipso-bromocyclization.
Figure 1. Representative azaspirocycle-based nature products.
Scheme 1. Proposed Electrophilic Halogenation Initiated
Dearomative Spirocyclization
ꢀ
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Fanghanel, E. Eur. J. Org. Chem. 2003, 47. (b) Zhang, X.; Larock,
We began our exploration by testing model substrate
1a with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH)
as the halide electrophile. To our delight, the reaction in
dichloromethane at rt proceeded very fast (<5 min) to
afford the desired product 2a in 20% yield (entry 1, Table 1).
The anti stereochemistry of product 2a was established by
X-ray analysis (see the Supporting Information). The reac-
tion at ꢀ20 °C was found to afford a much improved yield
(72%, entry 2, Table 1). As summarized in Table 1, several
halide electrophiles were further evaluated in this reaction.
Compared to the high activity of DMDBH, other halide
electrophiles such as N-bromoacetamide, DCDMH,
and NIS gave low conversions even at rt (entries 3ꢀ6,
Table 1).
N. A. M.; Baumeister, U.; Hartung, H.; Kluge, R.; Strohl, D.;
€
R. C. J. Am. Chem. Soc. 2005, 127, 12230. (c) Tang, B.-X.; Yin, Q.; Tang,
R.-Y.; Li, J.-H. J. Org. Chem. 2008, 73, 9008. (d) Yu, Q.-F.; Zhang,
Y.-H.; Yin, Q.; Tang, B.-X.; Tang, R.-Y.; Zhong, P.; Li, J.-H. J. Org.
Chem. 2008, 73, 3658. (e) Tang, B.-X.; Tang, D.-J.; Tang, S.; Yu, Q.-F.;
Zhang, Y.-H.; Liang, Y.; Zhong, P.; Li, J.-H. Org. Lett. 2008, 10, 1063.
(f) Tang, B.-X.; Zhang, Y.-H.; Song, R.-J.; Tang, D.-J.; Deng, G.-B.;
Wang, Z.-Q.; Xie, Y.-X.; Xia, Y.-Z.; Li, J.-H. J. Org. Chem. 2012, 77, 2837.
(9) For recent representative examples, see: (a) Kang, S. H.; Lee,
S. B.; Park, C. M. J. Am. Chem. Soc. 2003, 125, 15748. (b) Wang, M.;
Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem.
2004, 69, 2874. (c) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445,
900. (d) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B.
J. Am. Chem. Soc. 2010, 132, 3298. (e) Zhang, W.; Zheng, S.; Liu, N.;
Werness, J. B.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664.
(f) Veitch, G. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 7332.
(g) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura,
M.; Fujioka, H. Angew. Chem., Int. Ed. 2010, 49, 9174. (h) Denmark,
S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20655. (i)
Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am. Chem.
Soc. 2010, 132, 15474. (j) Yousefi, R.; Whitehead, D. C.; Mueller, J. M.;
Staples, R. J.; Borhan, B. Org. Lett. 2011, 13, 608. (k) Tan, C. K.; Zhou,
L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738. (l) Zhou, L.; Chen, J.; Tan,
C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164. (m) Jaganathan,
A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.; Borhan, B. Angew.
Chem., Int. Ed. 2011, 50, 2593. (n) Lozano, O.; Blessley, G.; Martinez del
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Borman, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105. (o)
With DBDMH as the halide electrophile, the reac-
tion conditions were further optimized. The results are
summarized in Table 2. Various solvents (CHCl3, DCE,
toluene, CF3CH2OH, CH3CN) were tested, and all led to
the formation of the desired azaspirocyclohexadienone
(entries 1ꢀ6, Table 2). The reaction in CH3CN gave the
best yield (entry 6, Table 2). Elevating the reaction tem-
perature to 0 °C caused a slightly decreased yield (70%,
€
€
Hennecke, U.; Muller, C. H.; Frohlich, R. Org. Lett. 2011, 13, 860. (p)
Huang, D.; Wang, H.; Xue, F.; Guan, H.; Li, L.; Peng, X.; Shi, Y. Org.
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Decloux, K.; Zheng, S.; Werness, J. B.; Tang, W. Chem.;Eur. J.
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77, 999.
˚
entry 7, Table 2). Then different additives such as 4 A MS,
a Brønsted acid, a base, and KBr (entries 7ꢀ12, Table 2)
(10) Intramolecular halo-C-cyclizations of alkenes using malonate as
the nucleophile have been reported; for account, see: Kitagawa, O.;
Taguchi, T. Synlett 1999, 1191 and reference therein.
Org. Lett., Vol. 14, No. 13, 2012
3527

Table 1. Screening of Halide Electrophiles and Reaction
Conditions Using 1a
Table 3. Substrate Scope
entrya
Z
1, R
1a, H
product
yield (%)b
1
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NNs
O
2a
2b
2c
2d
2e
2f
91
84
93
68
93
85
91
94
92
90
95
93
89
2
1b, 2-Me
1c, 4-Me
1d, 4-MeO
1e, 2-Cl
1f, 3-Cl
3
4
entrya
t (°C)
Xþ
time
yield (%)b
5
6
1
2
3
4
5
6
rt
DBDMH
DBDMH
NBS
<5 min
10 h
20
7
1g, 4-Cl
1h, 2-Br
1i, 4-Br
1j, 3-NO2
1k, 4-CO2Me
1l, H
2g
2h
2i
ꢀ20
ꢀ20
rt
72
8
48 h
15
9
AcNHBr
DCDMH
NIS
20 h
trace
trace
trace
10
11
12
13
2j
rt
72 h
2k
2l
rt
72 h
1m, H
2m
a Reactions were performed with 1a (0.1 mmol), Xþ (1.1 equiv).
b Isolated yield.
a Reactions were performed with 1 (0.1 mmol), DBDMH (1.1 equiv).
b Isolated yield.
Table 2. Screening of Solvents, Additives, and Temperature
Scheme 2. Extension of the Substrate Scope
t
time
(h)
yield
(%)b
entrya
solvent
CH2Cl2
(°C)
additive
1
2
3
4
5
6
7
8
9
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
/
10
72
73
45
71
35
80
70
58
30
CHCl3
/
/
/
/
/
/
24
toluene
DCE
48
10
were tested; however, none of them displayed positive
effects on the reaction outcome. Finally, to our delight,
water was found to be an effective additive, and the
reaction with 0.05 mL of water could lead to a 91% yield
(entry 13, Table 2). Increasing the amount of water further
did not improve the yield (entry 14, Table 2).
CF3CH2OH
CH3CN
CH3CN
CH3CN
CH3CN
72
0.2
0.1
0.1
0.4
˚
ꢀ20
ꢀ20
4 A MS
BzOH
(10 mol %)
DBACO
(20 mol %)
NaHCO3
(1 equiv)
KBr
10
11
12
13
14
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
15
56
45
45
91
90
With the optimized reaction conditions in hand, the
scope of the ipso-halocyclization reaction was explored.
The results are summarized in Table 3. For the alkene
substituted phenyl ring, either an electron-donating group
(2-Me, 4-Me, 4-MeO, 6-BnO) or an electron-withdrawing
group (2-Cl, 3-Cl, 4-Cl, 2-Br, 4-Br, 3-NO2, 4-CO2Me)
could be well tolerated. In most cases, good to excellent
yields were achieved (68ꢀ95%, entries 2ꢀ11, Table 3). For
the protection group on the N-linkage, when 4-nitrobenzene
sulfonyl (Ns) was used, a 93% yield was obtained (entry 12,
Table 3). Notably, when the N-linker was replaced with an
O-linker, the ipso-halocyclization reaction also proceeded
0.3
0.2
0.5
0.5
(1 equiv)
H2O
(0.05 mL)
H2O
(0.1 mL)
a Reactions were performed with 1a (0.1 mmol), DBDMH (1.1 equiv).
b Isolated yield.
3528
Org. Lett., Vol. 14, No. 13, 2012

substrate 1o and cis-alkene substrate 1p were also tested,
however, no dearomatiztion product was isolated.
The products obtained by this intramolecular electro-
philic ipso-halocyclization reaction could be subjected
to various transformations. As shown in Scheme 3, from
treatment of azaspirocyclohexadienone 2a under different
reduction conditions, chemoselective reduction could
be realized (eqs 1 and 2). Under Pd/C hydrogenation
conditions, the two double bonds were hydrogenated,
while the ketone moiety was converted to alcohol by Luche
reduction. When 2a was treated with p-toluenesulfonic
acid, a fragmentation product 3d was isolated in 73%
yield (eq3). Thisfragmentation occursvia aretro-Mannich
reaction catalyzed by acid and then hydrolysis of the
resulted N-Ts iminium ion.3b,11 In addition, the intramo-
lecular Heck reaction could be conducted with 2h under
conditions utilizing Pd(OAc)2 and TBAB, providing aza-
spirotricyclic product 3e in moderate yield (eq 4).8f
In summary, we have developed an efficient method
to provide functionalized azaspirocyclohexadienones
via intramolecular alkene electrophilic bromination ini-
tiated dearomative cyclization. The method features a
wide substrate scope, a high yield, and mild conditions.
The products obtained here are compatible with various
transformations.
Scheme 3. Transformations of the Products
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2009CB825300),
the National Natural Science Foundation of China
(20923005, 21025209, 21121062), and the Chinese Acad-
emy of Sciences for generous financial support.
well to afford oxospirocyclohexadienone in 89% yield
(entry 13, Table 3).
To further examine the substrate scope, naphthalene
skeleton-based substrate 1n was tested (Scheme 2). The
reaction proceeded smoothly to afford the desired product
2n in 92% yield (dr = 3.6:1). Methyl substituted alkene
Supporting Information Available. Detailed experi-
mental procedures and spectroscopic data for all new
compounds and X-ray crystal data of 2a. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(11) (a) Padwa, A.; Kuethe, J. T. J. Org. Chem. 1998, 63, 4256. (b)
Yokosaka, T.; Nemoto, T.; Hamada., Y. Chem. Commun. 2012, 48,
5431.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3529