Accessing bridged bicyclic compounds or meta carbon-functionalized anilines from the dearomatization of anilines

Article abstract of DOI:10.1039/c3ra23224g

The oxidative dearomatization of anilines was combined with a domino Michael addition, providing a series of nitrogen-containing bridged bicyclic compounds in moderate to excellent yields. The bridged bicyclic compound could be converted into the correspo

Full text of DOI:10.1039/c3ra23224g

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Accessing bridged bicyclic compounds or meta
carbon-functionalized anilines from the
Cite this: RSC Advances, 2013, 3, 5775
dearomatization of anilines3
Linfei Wang,a Shuo-En Wang,a Weibin Wang*b and Renhua Fan*a
Received 7th December 2012,
Accepted 25th February 2013
DOI: 10.1039/c3ra23224g
www.rsc.org/advances
The oxidative dearomatization of anilines was combined with a
domino Michael addition, providing a series of nitrogen-contain-
ing bridged bicyclic compounds in moderate to excellent yields.
The bridged bicyclic compound could be converted into the
corresponding meta carbon-functionalized aniline derivative via a
quinine-catalyzed tandem retro-oxa-Michael addition–aromatiza-
tion reaction.
Scheme 1 Building 3-D molecules from flat anilines.
The rapid and economic construction of architecturally complex
molecules from simple starting materials is a crucial aspect in
organic synthesis. The dearomatization of aromatic compounds, a
powerful tool in organic synthesis, has been intensively explored
and utilized by organic chemists in complex syntheses.1 Due to the
significance of aromatic amines as attractive starting materials in
organic synthesis, some of our recent efforts have led to the
development of new reactions based on the dearomatization of
aniline derivatives.2 Utilising this work, we are interested in
exploring the possibility of building 3-D molecules from flat
anilines through a domino reaction3,4 (Scheme 1). The resulting
bridged bicyclic compound could be a potential precursor to many
biologically active compounds, such as gelsemine and huperzine
A.5
We initially evaluated the reaction between pentane-2,4-dione
3a and cyclohexadienimines6 2a–e (Scheme 2). The nitrogen
protecting group played a significant role in the transformation.
No reaction was observed when an N-Boc, N-Bz or N-COCF3
protected substrate was used. Ms and Ts groups proved to be
suitable nitrogen protecting groups for the double Michael
addition. The desired bridged bicyclic compounds 4da and 4ea
were obtained in 12% and 23% yields, respectively. The structure
of compound 4ea was confirmed by single-crystal diffraction
analysis (Fig. 1, see ESI for details).7 With this promising lead in
3
hand, the effects of various solvents, temperatures and ratios of
reagents were examined (see ESI ). The yield of compound 4ea was
3
improved to 98% when the reaction was conducted in methanol,
with 3 equiv. of pentane-2,4-dione and 0.5 equiv. of CH3ONa at
room temperature, for 4 h. When the reaction was conducted on a
5 mmol scale, compound 4ea was obtained in an 87% yield.
After optimising the reaction conditions, the scope of this
domino Michael addition was explored, and the results are
summarized in Table 1. Since some of the cyclohexadienimines
were sensitive to hydrolysis, the crude dearomatization reaction
mixtures were directly used in the domino Michael addition. The
C-4 substitution of cyclohexadienimines could be an alkyl, phenyl
or methoxy group. The 4-alkoxy group could also be an ethoxy
group. When the C-3 or C-2 positions of cyclohexadienimine were
blocked by a methyl or a phenyl group, the reaction still proceeded
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: rhfan@fudan.edu.cn; Fax: 86-21-6510-2412; Tel: 86-21-6564-2019
bDepartment of General Surgery, Peking Union Medical College Hospital, Chinese
Academy of Medical Science and Peking Union Medical College, No. 1 Shuai Fu Yuan,
Dongcheng District, Beijing, 100730, China. E-mail: wwb_xh@yahoo.com.cn
Electronic supplementary information (ESI) available: Evaluation of reaction
3
conditions, experimental procedures, characterization data, copies of 1H NMR and
13C NMR spectra of new compounds. CCDC reference number 891422. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra23224g
Scheme 2 Reaction between pentane-2,4-dione 3a and cyclohexadienimines 2a–e.
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Scheme 3 Formation of the 4,5,6,7-tetrahydro-1H-indole derivative 5ma.
Meta substitution of aromatic amines by carbon functional groups
remains a challenge in organic synthesis.9 It is noteworthy that the
reaction of 2,4,6-trimethylbenzenamine, which was sluggish at
room temperature, gave rise to a meta carbon-functionalized
aniline derivative 6na in a 78% yield when the reaction was
conducted under reflux. Meta functionalization of p-toluidine was
also observed when 5,5-dimethylcyclohexane-1,3-dione (3h),
4-hydroxy-2H-chromen-2-one (3i), or 4,4,4-trifluoro-3-oxobutanoate
(3f) was used as the nucleophile (Scheme 4).
A plausible reaction pathway is depicted in Scheme 5. The
domino sequence is initiated by the 1,4-conjugate addition of the
bis-nucleophile10 to the cyclohexadienimine at the less hindered
position. Because of the steric hindrance of the R1 group (R1 =
alkyl or phenyl), this reaction is diastereoselective from the face of
the OR4 group leading to the Michael adduct A. In the presence of
a base, the intermediate B undergoes an intramolecular 1,4-
conjugate addition to form the bridged bicyclic compound 4.
When the C-2 and C-6 positions of cyclohexadienimine were
blocked by methyl groups, or when 5,5-dimethylcyclohexane-1,3-
dione or 4- hydroxy-2H-chromen-2-one was used, the second
Michael addition failed due to the steric hindrance effect or the
constrained conformation of the cyclic bis-nucleophiles.11 In the
case of ethyl 4,4,4-trifluoro-3-oxobutanoate, the strong electron-
Fig. 1 X-ray diffraction structure of compound 4ea.
smoothly, and provided product 4ka or 4la in 83% and 63% yields,
respectively. With respect to other bis-nucleophiles, methyl or
ethyl acetoacetate and 1-(methylsulfonyl)propan-2-one were also
suitable reaction partners. When methyl 3-aminobut-2-enoate 3e
was used,8 bridged aza-bicyclic products 4ee and 4he were formed
in moderate yields.
When N-Ts-4-methyl-2-(2-phenylethynyl)benzenamine 1m was
employed, the resulting bridged bicyclic compound 4ma could be
converted to the 4,5,6,7-tetrahydro-1H-indole derivative 5ma via a
silver-catalyzed cyclization (Scheme 3).
As an electron-donating substituent, the amine group normally
directs incoming substituents to the ortho and para positions.
Table 1 Construction of bridged bicyclic compounds via dearomatization and
domino Michael additiona
Entry R1
R2 R3 R4 R5
R6
X
Yield of 4 (%)
1
2
3
4
5
6
7
8
Me
Et
n-Bu
Ph
H
H
H
H
H
H
Me
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me Me
Me Me
Me Me
Me Me
Me Me
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOEt
SO2Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4ea (91)
4fa (50)
4ga (62)
4ha (81)
4ia (80)
4ja (61)
4ka (83)
4la (63)
4eb (88)
4hb (91)
4jb (62)
4kb (61)
4lb (70)
4ec (79)
4ed (71)
OMe
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Ph
Et
Me
Me Me
Ph Me Me
9
H
H
H
H
Me Me
Me Me
10
11
12
13
14
15
16
17
18
19
Et
Me
Me Me
Ph Me Me
H
H
H
H
H
H
Me Me
Me Me
Me Me
Me Me
Me CF3
COOMe NH 4ee (47)
COOMe NH 4he (51)
COOEt
Ph
Ph
O
O
4ef (0)
4eg (0)
Me OMe COOMe
a
Isolated yield based on compound 1.
Scheme 4 Formation of 3-substituted anilines.
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Scheme 6 Aromatization of bridged bicyclic compound 4ea, forming the meta
carbon-functionalized aniline derivative 6ea.
Conclusions
In summary, we have explored a route to build nitrogen-
containing bridged bicyclic compounds from simple anilines via
an oxidative dearomatization and a domino Michael addition. An
advantage of this methodology is that meta carbon-functionalized
aniline derivatives can be prepared with significant regiocontrol.
Further studies on the synthetic applications of this methodology
are currently under investigation at our laboratory.
Financial support from National Natural Science Foundation of
China (21072033) is gratefully acknowledged.
Notes and references
Scheme 5 A plausible reaction pathway.
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compound to the corresponding meta carbon-functionalized
aniline derivative, compound 4ea was treated with CH3ONa in
methanol under reflux. The formation of compound 6ea was not
detected, and a 96% yield of compound 4ea was recovered after 1
h. Since compound 4ea was stable under basic conditions, various
Lewis acids or Brønsted acids were examined as catalysts to
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of 0.5 equiv. of trifluoromethanesulfonic acid (TfOH) or 4-methyl-
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