Divergent construction of nitrogen-containing polycyclic compounds with a dearomatization strategy

Article abstract of DOI:10.1021/ol301282p

The oxidative dearomatization of para-substituted o-alkynylanilines afforded 2-alkynyl cyclohexadienimines, which can act as active substrates for reaction with electron-rich styrenes. The reaction is metal-controlled. Bi(OTf)₃-catalyzed reactions afforded 3,4-dihydro-cyclopenta[c,d] indoles, and AgOTf-catalyzed reactions provided tricyclic pyrrole derivatives.

Full text of DOI:10.1021/ol301282p

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3596–3599
Divergent Construction of Nitrogen-
Containing Polycyclic Compounds with
a Dearomatization Strategy
Linfei Wang and Renhua Fan*
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433,
China
rhfan@fudan.edu.cn
Received May 9, 2012
ABSTRACT
The oxidative dearomatization of para-substituted o-alkynylanilines afforded 2-alkynyl cyclohexadienimines, which can act as active substrates
for reaction with electron-rich styrenes. The reaction is metal-controlled. Bi(OTf)3-catalyzed reactions afforded 3,4-dihydro-cyclopenta-
[c,d]indoles, and AgOTf-catalyzed reactions provided tricyclic pyrrole derivatives.
Dearomatization of aromatic compounds provides an
economical and efficient way to build architecturally com-
plex molecules as a result of the inherent functionalities
stored within the aromatic systems.1 The appeal of such an
approach has drawn significant attention in the past
decades. Most of the reports focus on the oxidative
dearomatization of phenols and their derivatives.2,3 An-
other family of significance in aromatic compounds, ani-
lines, is also interesting using materials in organic
synthesis. Dearomatization of anilines will provide a
powerful tool to construct complex nitrogen-containing
molecules. However, to date the dearomatization of ani-
lines has been concentrated on the oxidation of para-
or ortho-aminophenols or phenylenediamines4 and the
subsequent conversion of the corresponding quinonemo-
noimides and diimides.5 Compared with the extensive
investigation of reactions of para-substituted phenols,
ꢀ
(1) Reviews, see: (a) Quideau, S.; Pouysegu, L. Org. Prep. Proced. Int.
€
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Tetrahedron 2001, 57, 8203. (d) Magdziak, D.; Meek, S. J.; Pettus,
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T. R. R. Chem. Rev. 2004, 104, 1383. (e) 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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107, 1580. (f) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467.
(g) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235.
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(h) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068.
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Chem. Soc. 2006, 128, 15625. (b) Dohi, T.; Maruyama, A.; Takenaga,
N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita,
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Ed. 2008, 47, 4366. (g) Garcıa-Fortanet, J.; Kessler, F.; Buchwald, S. L.
J. Am. Chem. Soc. 2009, 131, 6676. (h) Gu, Q.; Rong, Z.-Q.; Zheng, C.;
You, S.-L. J. Am. Chem. Soc. 2010, 132, 4056. (i) Wu, Q.-F.; Liu, W.-B.;
Zhuo, C.-X.; Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed.
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Buffeteau, T.; Cavagnat, D.; Chenede, A. Angew. Chem., Int. Ed.
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Soc. 2009, 131, 6674. (f) Guerard, K. C.; Sabot, C.; Racicot, L.; Canesi,
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Covell, D. G.; Beutler, J. A.; Porco, J. A., Jr. Angew. Chem., Int. Ed.
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(4) Recent developments in the chemistry of quinoneimides, see:
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r
10.1021/ol301282p
Published on Web 07/10/2012
2012 American Chemical Society

the dearomatization of para-substituted anilines has only
been investigated in a few cases.6 Under oxidizing condi-
tions, dearomatization of para-substituted anilines results
in cyclohexadienimines. Compared with cyclohexadie-
nones, cyclohexadienimines are less reactive for further
conversion due to the existence of the carbonꢀnitrogen
double bond. In our dearomatization strategy (Scheme 1),
an alkynyl group is introduced at the ortho-position of
para-substituted anilines. The corresponding dearomati-
zation product could be stabilized by the conjugated effect.
More importantly, the dearomatization might be followed
by a transition metal catalyzed cyclization to afford a more
reactive intermediate I.7 The coexistence of an electrophilic
center (C-4) and a nucleophilic center (C-3) in its structure
could makeintermediateI act asa 1,3-dipole. For example,
it might react with alkenes via a cycloaddition8 to access
3,4-dihydro-cyclopenta[c,d] indole, which is structurally
related to the orchid alkaloid dendrobine.9,10 Additionally,
this scaffold appears as the core structure in some organic
electroluminescent components.11
Scheme 1. Synthesis of 3,4-Dihydro-cyclopenta[c,d]indoles
Table 1. Selection of Catalyst for the Cascade Reactiona
To test the feasibility of our strategy, compound 1a was
selected as the standard substrate. After screening various
oxidants, nucleophiles (ROH), temperature and solvents,
the optimized dearomatization condition was established
(eq 1).
4aa 5aa
4aa
(%)b
5aa
(%)b
entry catalyst (%)b (%)b entry catalyst
1
2
3
4
5
6
7
8
9
AuCl3
AuCl
39
0
0
17
0
12 Yb(OTf)3
13 In(OTf)3
14 Bi(OTf)3
15 AgOTf
16 Rh(OAc)2
17 Pd(OAc)2
18 PdCl2
0
38
62
0
0
0
CuCl
0
0
CuI
0
0
91
0
CuCl2
CuBr2
Cu(OAc)2
0
0
0
The reaction between 1-methoxy-4-vinylbenzene 3a and
compound 2a was done in order to investigate the cascade
reaction. Gold(III) chloride was tested as the first catalyst.
We were pleased to observe that the reaction proceeded
well, and the desired product 4aa was isolated in a
39% yield (Table 1, entry 1). Interestingly, the formation
of compound 4aa was not observed from the reaction
0
0
46
38
20
48
52
0
0
0
0
0
Cu(OTf)2 49
0
19 PtCl2
0
Zn(OTf)2
0
0
0
0
20 RuCl3
0
10 Ni(OTf)3
11 Sc(OTf)3
0
21 FeCl3
0
0
22 FeCl2
0
a General reaction conditions:reactions performed on 0.1 mmol scale
using 2 equiv of 3a, 20 mol % catalyst in CH3CN (2 mL) at 25 °C.
b Reported yields are of the isolated product based on compound 2a.
(5) Examples on the reactions of quinoneimides, see: (a) Engler,
T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444. (b) Parker, K. A.;
Mindt, T. L. Org. Lett. 2002, 4, 4265. (c) Nair, V.; Dhanya, R.; Rajesh,
C.; Bhadbhade, M. M.; Manoj, K. Org. Lett. 2004, 6, 4743. (d) Tichenor,
M. S.; Kastrinsky, D. B.; Boger, D. L. J. Am. Chem. Soc. 2004, 26, 8396.
(e) Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7, 1215.
(6) (a) Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7,
catalyzed by gold(I) chloride. Instead, a new fused hetero-
cyclic compound 5aa was obtained in a 17% yield (Table 1,
entry 2). The structures of compounds 4aa and 5aa were
confirmed by their single-crystal diffraction analysis (see
the Supporting Information). Encouraged by these results,
a variety of metal salts were explored. For various copper
catalysts (Table 1, entries 3ꢀ8), only Cu(OTf)2 proved
effective to catalyze the formation of compound 4aa, and
the yield was improved to 49%. Further screening of other
metal triflates revealed that Bi(OTf)3 and AgOTf were the
best catalysts for generating products 4aa and 5aa, respec-
tively (Table 1, entries 9ꢀ15). Some other Lewis acids
[Pd(II), Pt(II), Ru(III), and Fe(III)] exhibited lower cata-
lytic activities in the formation of compound 4aa, but
they could not catalyze the generation of compound 5aa
(Table 1, entries 17ꢀ21).
ꢀ
1215. (b) Quideau, S.; Pouysegu, L.; Ozanne, A.; Gagnepain, J. Mole-
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cules 2005, 10, 201. (c) Giroux, M.-A.; Guerard, K. C.; Beaulieu, M.-A.;
Sabot, C.; Canesi, S. Eur. J. Org. Chem. 2009, 3871. (d) Salomon, R. J.;
Todd, M. A.; Sabat, M.; Myers, W. H.; Harman, W. D. Organometallics
2010, 29, 707.
(7) (a) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 11164. (b) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70,
7679.
(8) (a) Dohi, T.; Hu, Y.; kamitanaka, T.; Washimi, N.; Kita, Y. Org.
Lett. 2011, 13, 4814. (b) Fan, R.; Li, W.; Ye, Y.; Wang, L. Adv. Synth.
Catal. 2008, 350, 1531.
(9) (a) Inubushi, Y.; Sasaki, Y.; Tsuda, Y.; Yasui, B.; Konita, T.;
Matsumoto, J.; Katarao, E.; Nakano, J. Tetrahedron 1964, 20, 2007. (b)
Onaka, R.; Kamata, S.; Maeda, T.; Kawazoe, Y.; Natsume, M.;
Okamoto, T.; Uchimaru, F.; Shimizu, M. Chem. Pharm. Bull. 1964,
12, 506.
(10) The synthesis of 3,4-dihydro-cyclopenta[c,d]indole, see:Rousseaux,
S.; Davi, M.; Sofack-Kreutzer, J.; Pierre, C.; Kefalidis, C. E.; Clot, E.;
Fagnou, K.; Baudoin, O. J. Am. Chem. Soc. 2010, 132, 10706.
(11) Takahashi, H.; Iizumi, Y. Organic Electroluminescent Compo-
nent. Jpn. Kokai Tokkyo Koho JP 2000268961 A 20000929, 2000.
In an attempt to make this approach more efficient,
oxidative dearomatization and the subsequent cascade
Org. Lett., Vol. 14, No. 14, 2012
3597

Table 2. Reaction Scope Investigationa
entry
R1
R2
C6H5
R3
R4
R5
R6 condition A product (%)b condition B product (%)b
1
4-MeC6H4SO2
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
4aa (63)
4ba (50)
4ca (62)
4da (0)
5aa (93)
2
4-NO2C6H4SO2 C6H5
5ba (51)
3
MeSO2
C6H5
C6H5
C6H5
5ca (92)
4
CF3SO2
5da (0)
5
C6H5CO
4ea (0)
5ea (0)
6
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeC6H4SO2
4-MeOC6H4 Me
4fa (52)
4ga (54)
4ha (47)
4ia (50)
4ja (0), 7ja (45)
4ka (0)
5fa (81)
7
4-MeC6H4
4-ClC6H4
2-thiophyl
2-pyridyl
cyclopropyl
H
Me
Me
Me
Me
Me
Me
Et
5ga (84)
8
5ha (80)
9
5ia (92)
10
11
12
13
14
15
16
17
18
19
20
21
5ja (76)
5ka (72)
4la (0)
5la (75)
C6H5
4ma (60)
4na (55)
4oa (60)
4ab (0)
5ma (0), 6m (88)
5na (0), 6n (85)
5oa (0)
C6H5
n-Bu
Me
Me
Me
Me
Me
Me
Me
C6H5
Me 4-MeOC6H4
C6H5
H
H
H
H
H
H
C6H5
5ab (0)
C6H5
4-BnOC6H4
3,4-(MeO)2C6H3
2-Br-4,5-(MeO)2-C6H2
4-MeOC6H4
4-MeC6H4
4ac (53)
4ad (55)
4ae (39)
4af (70)
4ag (74)
5ac (82)
C6H5
5ad (85)
C6H5
5ae (92)
C6H5
5af (0), 4af (71)
5ag (0), 4ag (70)
C6H5
a Reactions performed on 0.1 mmol scale. b Reported yields are of the isolated products based on compound 1 over two steps.
reaction were conducted in a one-pot fashion. However,
the formation of compound 4aa or 5aa was not observed,
and 4-methoxy substituted indole 6a was isolated as the
major product from both Bi(OTf)3 and AgOTf catalyzed
reactions. After a workup process to remove methanol,
the crude oxidative dearomatization mixture was used in
the cascade reaction. Either Bi(OTf)3 or AgOTf catalyzed
cascade proceeded well and afforded compound 4aa or
5aa in a 58 or 85% yield over two steps, respectively.
Further optimization of the cascade processes revealed
that acetonitrile was the best solvent for both conversions.
Compared with Bi(OTf)3-catalyzed reaction (the opti-
mized conditions: 0.2 equiv of Bi(OTf)3, 3 equiv of 3a,
CH3CN, 0 °C, 30 min), a higher reaction temperature
(15 °C) and a longer reaction time (24 h) were required for
AgOTf-catalyzed reaction.
The protecting group of nitrogen atoms played a sig-
nificant role on the transformations (Table 2, entries 1ꢀ5).
Ts and Ms groups proved to be the best choices. When
N-Tf protected substrate 1d was used, it was unreactive
toward the oxidant under the dearomatization conditions.
When N-Bz protected substrate 1e was used, the oxidative
dearomatization proceeded well, but further conversions
did not occur. The substituent at the alkynyl group also
affected the reactions. Compounds 1fꢀ1i bearing an aryl
group or a thiophen group as the R2 substituent were
suitable substrates for both conversions (Table 2, entries
6ꢀ9). When the R2 group was a pyridine, a cyclopropyl, or
a hydrogen, the formation of products 4ja, 4ka, and 4la
were not observed from Bi(OTf)3-catalyzed reactions, but
AgOTf-catalyzed reaction proceeded well and afforded
products 5ja, 5ka, and 5la in good yields (Table 2, entries
10ꢀ12). When the methyl group at the para position was
replaced by an ethyl or a butyl group, AgOTf-catalyzed
reaction did not afford the desired product 5ma or 5na.
However, this change had no influence on the Bi(OTf)3-
catalyzed reactions (Table 2, entries 13 and 14). When the
5-position of compound 1 was blocked by a methyl group,
the formation of compound 5oa was not observed in the
AgOTf-catalyzed reaction (Table 2, entry 15). Electron-
rich styrenes are suitable partners in this process, as we
expected (Table 2, entries 16ꢀ19). When 1-methoxy- or
1-methyl-4-(prop-1-en-2-yl)benzene 3f or 3g was utilized,
AgOTf-catalyzed reaction also provided compounds 4af
or 4ag as the major products (Table 2, entries 20 and 21).
Notably, the formation of products 4 or 5 is completely
selective under the conditions A or B, respectively.
4-Methoxy substituted indole 6 or acyclic addition pro-
duct 7 was isolated from the reaction as the major by-
product when AgOTf or Bi(OTf)3 was used as the catalyst,
3598
Org. Lett., Vol. 14, No. 14, 2012

Scheme 2. Control Experiments
Scheme 3. Plausible Reaction Pathway
respectively. For example, Bi(OTf)3-catalyzed reaction
of substrate 1j provided compound 7ja in a 45% yield. In
the AgOTf-catalyzed reactions of substrates 1m and 1n,
4-methoxy substituted indoles 6m and 6n were isolated as
the major products (Table 2, entries 13 and 14).
Treatment of compound 2a with 1 equiv of AgOTf in
acetonitrile at 25 °C led to the complete conversion to
compound 6a. But the conversion was not observed in the
presence of Bi(OTf)3 under the same conditions (Scheme 2,
eq 1). When the alkynyl group was removed from com-
pound 2a, Bi(OTf)3 could still catalyze the corresponding
reaction to afford meta-substituted aniline derivative 10;12
however, AgOTf failed (Scheme 2, eq 2). These results
indicatedthatthe activatingmodeof Bi(OTf)3 or AgOTf in
the cascade reaction was different.
A plausible reaction pathway is depicted in Scheme 3.
The reaction between 2-alkynyl cyclohexadienimine and
the electron-richalkene proceeds in two different pathways
depending on the employed Lewis acid.7 In path a, Bi-
(OTf)3 works as a Lewis acid to promote the Michael
addition of the electron-rich alkene to compound 2 to
generate intermediate B. After a tandem cyclization and a
succeeding Bi(OTf)3-catalyzed aromatization, compound
4 is formed. In path b, AgOTf acts as a π acid to coordinate
with the triple bond of compound 2 and facilitates the
intramolecular nucleophilic attack of the nitrogen on the
triple bond to yield an iminium ion D. The nucleophilic
attack by the electron-rich alkene at the C-4 position of
intermediate D yields an intermediate E, which undergoes
a cyclization atthe C-6positiontoproduceanintermediate
F. Alternatively, the intermediate D can also undergo a
5 þ 2 (4π þ 2π) cycloaddition with the electron-rich alkene
to afford the intermediate F (path c).13 In the presence of a
trace amount of water in the reaction system, intermediate
F is hydrolyzed to form compound 5 and regenerate the
silver catalyst. In the case of 1-(prop-1-en-2-yl)benzene 3f
or 3g, the 4π þ 2π cycloaddition or the cyclization at the
C-6 position is not preferred due to steric factors, and the
corresponding AgOTf-catalyzed reaction also provided
compound 4af or 4ag as the major product.
In summary, we have explored a strategy of building
nitrogen-containing polycyclic compounds from simple
aniline derivatives. Our strategy relies on the dearomatiza-
tion of para-substituted o-alkynylanilines and the subse-
quent metal-controlled cascade reactions of the cor-
responding 2-alkyny cyclohexadienimines. Two fine-tuned
metal-controlled conditions were established. Further stu-
dies on the reaction mechanism and synthetic applications
of this methodology are currently under investigation at
our laboratory.
Acknowledgment. Financial support from National
Natural Science Foundation of China (No. 21072033), is
gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, copies of H NMR and
13C NMR of new compounds, and crystallographic data
of compounds 4aa and 5aa (CIF). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(12) Meta-substitution of anilines, see:Phipps, R. J.; Gaunt, M. J.
Science 2009, 323, 1593.
(13) Engler, T. A.; Iyengar, R. J. Org. Chem. 1998, 63, 1929.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3599