Dearomatization strategy of β-enamino ester: Construction of indenoazepines via tandem Michael addition/polycyclization

Article abstract of DOI:10.1021/ol401553n

A dearomatization strategy of β-enamino esters was developed to construct indenoazepine derivatives. The oxidative dearomatization was combined with a base-promoted tandem Michael addition/polycyclization and an acid-catalyzed aromatization. The nonaromatic structure of the Michael adducts might be essential to the realization of the 7-endo-dig cyclization.

Full text of DOI:10.1021/ol401553n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Dearomatization Strategy of β‑Enamino
Ester: Construction of Indenoazepines via
Tandem Michael Addition/Polycyclization
Min Yang,† Jie Tang,*,† and Renhua Fan*,‡
Shanghai Engineering Research Center of Molecular Theraputics and New Drug
Development, East China Normal University, Shanghai 200062, China, and Department
of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
rhfan@fudan.edu.cn; jtang@chem.ecnu.edu.cn
Received June 3, 2013
ABSTRACT
A dearomatization strategy of β-enamino esters was developed to construct indenoazepine derivatives. The oxidative dearomatization was
combined with a base-promoted tandem Michael addition/polycyclization and an acid-catalyzed aromatization. The nonaromatic structure of the
Michael adducts might be essential to the realization of the 7-endo-dig cyclization.
The rapid and economic construction of architecturally
complex molecules from simple aromatic compounds using
a dearomatization strategy has been intensively explored
and utilized by organic chemists.1 Recently, dearomatiza-
tion of aniline derivatives has drawn significant attention.2
The Kerr,3 Quideau,4 and Canesi5 groups have developed a
variety of dearomatization methods to convert anilines into
useful molecules. In our previous works, we developed a
dearomatization strategy to convert N-Ts protected
o-alkynylanilines to 3,4-dihydro-cyclopenta[c,d] indoles.6
Polycyclization is the key step to build the tricyclic
structure.7 In this current study, we have sought to further
extend the utility of this process by exploring the dearo-
matization of β-enamino esters 1.8 In particular, we were
interested in the selectivity of the reaction between the
generated cyclohexadienimine intermediate 2 and acti-
vated methylene compounds 3 (Scheme 1).
† East China Normal University.
‡ Fudan University.
(1) For reviews on dearomatization, see: (a) Bach, T. Angew. Chem.,
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E. P. Chem. Rev. 2000, 100, 2917. (d) Magdziak, D.; Meek, S. J.; Pettus,
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Organometallics 2005, 24, 1786. (f) Lopez Ortiz, F.; Iglesias, M. J.;
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Fernandez, I.; Andujar Sanchez, C. M.; Gomez, G. R. Chem. Rev. 2007,
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1993, 115, 10416. (b) Swenton, J. S.; Biggs, T. N.; Clark, W. M. J. Org.
Chem. 1993, 58, 5607. (c) Engler, T. A.; Wanner, J. J. Org. Chem. 2000,
65, 2444. (d) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L.
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r
10.1021/ol401553n
XXXX American Chemical Society

According to our experience,9 the attack of the activated
methylene compounds to cyclohexadienimine might
occur at the C-3 position to form a Michael adduct. This
intermediate contains two nucleophilic centers in the
β-enamino ester moiety: the nitrogen atom and the
R-carbon of the R,β-unsaturated system. Potentially, it
Scheme 1. Dearomatization Strategy of β-Enamino Esters
might undergo a polycyclization via a 5-endo-dig,10
a
6-exo-dig,11 or a 7-endo-dig manner to generate compound
4, 5, or 6. Normally, compared with the 5-endo or the
6-exo cyclization, the 7-endo cyclization is often hindered
by entropic factors and transannular interactions.12 Inter-
estingly, in the course of this study, a 7-endo process was
preferred over the 5-endo or the 6-exo process.
For the purpose of our investigation, we examined the
oxidative dearomatization of β-enamino ester 1a, which
was prepared from the corresponding β-keto ester and
2-alkynyl aniline. When 1.1 equiv of PhI(OAc)2 was used
as the oxidant,13 the dearomatization in methanol gave
rise to cyclohexadienimine 2a in a 90% isolated yield
(Scheme 2, eq 1). When the dearomatization was con-
ducted in other organic solvents in the presence of 5 equiv
of methanol, cyclohexadienimine 2a was produced in
much lower yields (<30%). The initial test on the reaction
of cyclohexadienimine 2a with dimethyl malonate using
methanol as the solvent and sodium methoxide as the base
failed to give any desired annulation products. When THF
was used as the solvent, although a complex reaction was
observed, the isolated compound was identified as product
7aa (Scheme 2, eq 2). This product was supposed to be
formed from a decarboxylation of the expected product 6aa.
Treatment of compound 7aa with 4 equiv of 4-methylben-
zenesulfonic acid led to an indenoazepine14 derivative 8aa
(Scheme 2, eq 3). The structure of compound 8aa was con-
firmed by its single-crystal diffraction analysis (Figure 1).15
Scheme 2
(9) (a) Yang, M.; Tang, J.; Fan, R. Chem. Commun. 2012, 48, 11775.
(b) Zhang, L.; Li, Z.; Fan, R. Org. Lett. 2012, 14, 6076. (c) Zhang, L.;
Wang, W.; Fan, R. Org. Lett. 2013, 15, 2018.
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2007, 9, 1687. (b) Murai, K.; Nakatani, R.; Kita, Y.; Fujioka, H.
Tetrahedron 2008, 64, 11034. (c) Murai, K.; Hayashi, S.; Takaichi, N.;
Kita, Y.; Fujioka, H. J. Org. Chem. 2009, 74, 1418.
(11) (a) Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E.; Sferrazza, A.
Synlett 2009, 1245. (b) Peng, C.; Wang, Y.; Liu, L.; Wang, H.; Zhao, J.;
Zhu, Q. Eur. J. Org. Chem. 2010, 818. (c) Toh, K. K.; Wang, Y.-F.; Ng,
E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011, 133, 13942. (d) Toh, K. K.;
Sanjaya, S.; Sahnoun, S.; Chong, S. Y.; Chiba, S. Org. Lett. 2012, 14,
2290. (e) Xia, X.-F.; Zhang, L.-L.; Song, X.-R.; Liu, X.-Y.; Liang, Y.-M.
Org. Lett. 2012, 14, 2480.
(12) For reviews on 7-endo cyclization, see: (a) Illuminati, G.;
Mandolini, L. Acc. Chem. Res. 1981, 14, 95. (b) Evans, P. A.; Holmes,
A. B. Tetrahedron 1991, 47, 9131. (c) Hoberg, J. O. Tetrahedron 1998, 54,
12631. (d) Molander, G. A. Acc. Chem. Res. 1998, 31, 603. (e) Yet, L.
Chem. Rev. 2000, 100, 2963. (f) Galli, C.; Mandolini, L. Eur. J. Org.
Chem. 2000, 3117. (g) Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed.
2006, 45, 5740. (h) Sharma, A.; Appukkuttan, P.; Eycken, E. V. Chem.
Commun. 2012, 48, 1623.
(13) For reviews on hypervalent iodines, see: (a) Zhdankin, V. V.;
Stang, P. J. Chem. Rev. 2002, 102, 2523. (b) Wirth, T. Hypervalent Iodine
Chemistry: Modern Developments in Organic Synthesis. Top. Curr.
Chem. 2003, 224. (c) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer,
M.; Chang, J.; Chai, D. Synthesis 2007, 3759. (d) Zhdankin, V. V.; Stang,
P. J. Chem. Rev. 2008, 108, 5299.
In an attempt to make this approach more efficient, the
tandem Michael addition/polycyclization and the aroma-
tization reaction were combined in one pot. Various bases
were used to promote the formation of compound 7aa
(Table 1, entries 1À5). While inorganic bases such as
potassium tert-butoxide, cesium carbonate, or sodium
hydride exhibited higher activities, no reaction was ob-
served when organic bases such as triethylamine or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were used. For the
aromatization reaction, a variety of Brønsted acids or
Lewis acids were examined, and BF3 Et2O proved to be
3
the best catalyst (Table 1, entries 6À12). A screening of
solvents revealed that 1,4-dioxane was the best reaction
mediaforthistwo-step/one-pot procedure(Table1, entries
13À17). The best ratio of compound 2a, dimethyl mal-
onate, sodium hydride, and BF3 Et2O was 1:4:3:4, increas-
(14) Evans, D. D.; Weale, J.; Weyell, D. J. Aust. J. Chem. 1973, 26,
1333.
(15) Crystallographic data for compounds 8aa and 14ah are available
free of charge from the Cambridge Crystallographic Data Centre,
accession numbers CCDC 935280 and CCDC 935279.
3
ing the yield to 83% (Table 1, entry 19).
A possible intermediate was isolated and identified as
the Michael adduct 9aa. When compound 9aa was treated
B
Org. Lett., Vol. XX, No. XX, XXXX

cyclization of β-enamino ester 1a only gave rise to a 6-exo-
dig cyclization product 11a (Scheme 3, eq 6).
Moreover, to specify the influence of the second ring
closure on the 7-endo-dig C-cyclization, malononitrile was
used instead of dimethyl malonate. The reaction produced
two 7-endo-dig cyclization products, benzoazepine 12ab
and indenoazepine 13ab (Scheme 4). The above results
indicated that the nonaromatic structure of the corre-
sponding Michael addition product might be essential to
the realization of the 7-endo-dig C-cyclization.
Scheme 3. Control Experiments
Figure 1. X-ray diffraction structure of compound 8aa.
Table 1. Evaluation of Conditions for the Two-Step/One-Pot
Procedurea
base
acid
8aa
entry
(equiv)
(equiv)
solvent
THF
(%)b
1
t-BuOK (2)
Cs2CO3 (2)
NaH (2)
Et3N (2)
DBU (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
NaH (3)
TsOH H2O (4)
28
43
44
3
2
TsOH H2O (4)
THF
3
3
TsOH H2O (4)
THF
3
c
4
TsOH H2O (4)
THF
À
3
c
5
TsOH H2O (4)
THF
À
3
Scheme 4. Reaction between Cyclohexadienimine 2a and
Malononitrile
6
TfOH (4)
THF
12
d
7
CH3COOH (4)
Cu(OTf)2 (0.2)
Zn(OTf)2 (0.2)
AgOTf (0.2)
Bi(OTf)3 (0.2)
THF
À
d
8
THF
À
d
9
THF
À
d
10
11
12
13
14
15
16
17
18f
19f,g
THF
À
d
THF
À
BF3 Et2O (2)
THF
53
23
42
3
3
3
3
3
3
3
3
BF3 Et2O (2)
ClCH2CH2Cl
toluene
DMSO
DMF
BF3 Et2O (2)
e
BF3 Et2O (2)
À
e
BF3 Et2O (2)
À
BF3 Et2O (2)
1,4-dioxane
1,4-dioxane
1,4-dioxane
59
64
83
BF3 Et2O (2)
BF3 Et2O (4)
a General reaction conditions: reactions performed on 0.2 mmol
scale in t-BuOH (2 mL). b Isolated yield. c No reaction was observed,
and compound 2a was recovered. d The aromatization was not observed,
and compound 7aa was isolated. e The reaction was complex, the forma-
tion of compound 7aa was not observed. f The reaction was conducted at
reflux. g 4 equiv of dimethyl malonate was used.
The reaction using other activated methylene com-
pounds under the optimized conditions afforded the
corresponding indenoazepine derivatives in moderate
yields (Scheme 5). When acetoacetate or benzoylacetate
was used, the second cyclization occurred at the ketone
group. The structure of compound 14ah was confirmed by
its single-crystal diffraction analysis (Figure 2).15 After a
workup process to remove methanol and the generated
acetic acid, the crude oxidative dearomatization product
could be used in the two-step/one-pot reaction (Table 2).
For most β-enamino esters, the reaction proceeded
smoothly. When the R2 group was a cyclopropyl group,
with sodium hydride under the optimized reaction condi-
tions, it could be converted to compound 7aa (Scheme 3,
eq 4). However, its aromatization product 10aa could
not be converted to the desired compound 8aa under
the same conditions (Scheme 3, eq 5). This reaction was
complex, and all isolated compounds did not have a seven-
membered ring structure. As a control experiment, the
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Substrate Scope Investigation
Scheme 5. Construction of Indenoazepine Derivatives
from Cyclohexadienimine 2 and Activated Methylene
Compounds
entry
R1
R2
R3
8 (%)a
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
8aa (75)
8ba (71)
8ca (58)
8da (81)
8ea (69)
8fa (55)
8ga (40)
8ha (63)
8ia (69)
8ja (45)
8ka (0)
2
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
CF3
3
4
5
6
7
8
Ph
4-MeC6H4
4-MeOC6H4
4-ClC6H4
cyclopropyl
Ph
9
Ph
10
11
12
13
14
Ph
Ph
Ph
8la (65)
8ma (63)
8na (0)
Ph
Ph
n-Bu
Ph
Ph
Ph
a Reported yields are of the isolated product based on compound 1.
corresponding reaction with dimethyl malonate was com-
plex (Table 2, entries 11 and 14).
In conclusion, we have developed a method to construct
indenoazepine derivatives from β-enamino esters using
a dearomatization strategy. A 7-endo-dig polycyclization
was the key step. Currently, efforts are focused toward
extending its scope and exploring its reaction mechanism
and possible synthetic applications, and these results will
be reported in due course.
Acknowledgment. Financial support from National
Natural Science Foundation of China (No. 21072033)
and Shanghai Science and Technology Council (No.
12142200802) are gratefully acknowledged.
Supporting Information Available. Experimental proce-
dures, characterization data, copies of 1H and 13C NMR of
new compounds, and crystallographic data of compounds
8aa and 14ah in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
Figure 2. X-ray diffraction structure of compound 14ah.
or when the R3 group was a phenyl group, the oxidative
dearomatization reaction proceeded well, but the
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX