Radical cation salt induced tandem cyclization between anilines and N-vinyl amides: Synthesis of 2-methyl-4-anilino-1,2,3,4-tetrahydroquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.10.106

A tandem cyclization of imines with N-vinyllactams induced by TBPA ⁺ was investigated, and a series of 2-methyl-4-anilino-1,2,3,4- tetrahydroquinolines were synthesized based on a domino process in which N-vinyllactams serve as an acetaldehyde

Full text of DOI:10.1016/j.tetlet.2010.10.106

Tetrahedron Letters 51 (2010) 6779–6782
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Tetrahedron Letters
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Radical cation salt induced tandem cyclization between anilines and N-vinyl
amides: synthesis of 2-methyl-4-anilino-1,2,3,4-tetrahydroquinoline derivatives
Xiao-dong Jia a,b, , Yan Ren a, Cong-de Huo a, Wen-Juan Wang a, Xiang-Ning Chen a, Xiao-Lan Xu a,
⇑
Xi-cun Wang a,
⇑
a Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education of China, Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
A tandem cyclization of imines with N-vinyllactams induced by TBPA+Å was investigated, and a series of
2-methyl-4-anilino-1,2,3,4-tetrahydroquinolines were synthesized based on a domino process in which
N-vinyllactams serve as an acetaldehyde surrogate. A single electron transfer mechanism was proposed
and radical cation salt acts as both a Lewis acid and one electron oxidant to induce such transformation.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 11 August 2010
Revised 13 October 2010
Accepted 22 October 2010
Available online 28 October 2010
1. Introduction
shortcomings based on such methodology also exist. In most cases,
more than stoichiometric amounts of the catalysts are required
Tetrahydroquinoline scaffold is present in various biologically
active alkaloids and many tetrahydroquinoline derivatives exhibit
numerous biological activities. Among those efficient protocols to-
wards the synthesis of tetrahydroquinoline derivatives, the aza-
Diels–Alder reaction between N-arylimines and electron-rich
dienophiles is probably a most powerful synthetic tool for the con-
struction of nitrogen-containing heterocyclic compounds including
tetrahydroquinolines,1,2 due to its efficiency and the ready avail-
ability of starting materials. Recently, new progress including
three-component reaction among aldehydes, anilines and alkenes
based on one-pot procedure has been achieved.2 However, some
and furthermore, most of the imines are hygroscopic, unstable at
high temperatures and are difficult to purify by distillation or col-
umn chromatography. It is necessary to develop more simple, con-
venient and efficient catalysts to synthesize tetrahydroquinolines
under mild conditions.
According to Batey and other groups’ research, tetrahydroquin-
oline skeleton can be built via 1:2 coupling of substituted anilines
with vinyl ethers (such as dihydrofuran, ABB pattern, see Fig. 1).3
Batey and co-workers also reported such reaction could occur be-
tween N-vinyllactams (such as dihydropyrrole) and substituted
anilines. It is well-known that enamines are tautomer of imines
X
NH2
X
B
X
Cat.
Cat.
R
+
+
R
R
ABB pattern
Cyclization
N
N
H
A
B
NH2
X
R
R
R
N
HN
A
B
Cyclization
ABAB pattern
R
R
N
H
N
H
Figure 1. Routes to tetrahydroquinolines via different patterns.
⇑
Corresponding authors. Tel.: +86 931 7975550; fax: +86 931 7971989 (X.-d.J.).
E-mail addresses: jiaxd1975@163.com, jiaxd75@sohu.com (X.-d. Jia).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.106

6780
X.-d. Jia et al. / Tetrahedron Letters 51 (2010) 6779–6782
when there is
a
-H in imines, and enamines are also good dieno-
was obtained when the ratio of aniline: N-vinyllactam was raised
to 2:1 (entry 2). Next, a solvent screening was performed to iden-
tify the best reaction conditions. From Table 1 we also can see, a
remarkable solvent effect was found to exist in TBPA+Å initiated
cycloaddition. The best result was obtained with CH2Cl2 as solvent
while CHCl3, CH2ClCH2Cl and CH3CN resulted in lower yields of the
desired products (entries 3–5). We also tried the reaction in the
presence of one molar excess of DBP (2,6-di-tert-butylpyridine)
as acid scavenger and the efficiency of the reaction did not change
obviously (entry 6). Furthermore, N-vinylcaprolactam can also par-
ticipate in this transformation (entries 7 and 8). Based on such re-
sults, in our later experiments, CH2Cl2 was chosen as the organic
solvent to conduct the radical cation induced reactions.
philes which can participate in construction of tetrahydroquino-
lines. So we wondered if substituted anilines could react with N-
vinyllactams producing imines intermediates which react with
its enamine tautomers via ABAB pattern to achieve the synthesis
of 4-anilino-tetrahydroquinoline skeleton (Fig. 1).4 If our hypothe-
sis is feasible, the N-vinyllactams can serve as acetaldehyde equiv-
alent participating in such domino coupling reaction to synthesize
tetrahydroquinolines avoiding the isolation of the unstable acetal-
dehyde imines.
Commercially available, stable radical cation salt tris(4-bromo-
phenyl)aminium hexachloroantimonate (TBPA+Å) induced reactions
have been investigated for more than 20 years, and many valuable
reactions initiated by such catalyst have been discovered to accom-
plish kinds of interesting transformations in organic chemistry.5 As
part of our ongoing research program on exploring the synthetic
potentials of such catalyst,6 we recently found that imino-Diels–
Alder reaction could be efficiently induced by TBPA+Å to accomplish
[4+2] cycloaddition of aromatic imines with electron-rich alkenes
such as styrene derivatives and N-vinyllactams.6b,c Herein, we wish
to report a novel synthesis of 2-methyl-4-anilino-1,2,3,4-tetrahy-
droquinoline derivatives via a tandem cyclization of imine with
its enamine isomer induced by radical cation salts.
Table 2
Substituent effect on the synthesis of tetrahydroquinolines
R1
O
NH2
R2
HN
TBPA+. ( 5mol %)
R3
N
R1
+
anhydrous CH2Cl2
reflux
(trans and cis)
R1
N
H
2
1
3
O
O
O
H
H
N
H
N
O
N
N
N
2b
O
2. Results and discussion
2a
2e
2c
2d
Our studies began with the reaction of aniline 1a and N-vinyl-
pyrrolidinone (2a) catalysed by TBPA+Å. Initially, a solution of 1a
(1 mmol) and 2a (1 mmol) was added dropwise to a CH2Cl2 solu-
tion (10 mL) of a catalytic amount of tris(4-bromophenyl)aminium
hexachloroantimonate (TBPA+Å SbClÀ6 , 0.05 mmol, 5 mol %) at ambi-
ent temperature under stirring. Unfortunately, no cycloaddition
products were isolated. Next we performed this reaction under
refluxing. After column chromatographic purification, a novel 2-
methyl-4-anilino-1,2,3,4-tetrahydroquinoline derivative 3a was
isolated in good yield as a mixture of two stereoisomers that were
fully identified and the configuration was evaluated by 1H NMR
spectroscopy.7 With these results in hand, we then conducted a
brief optimization of reaction conditions and the results are sum-
marized in Table 1.
b
Entry
R1
H
2
Time (min)
Product
Yielda (%)
trans:cis
1
2
3
4
5
2a
2b
2c
2d
2e
60
30
60
60
30
3a
85
87
56
71
93
2.1
2.0
3.5
1.7
1.9
6
7
8
9
10
p-Cl
o-Cl
p-Br
2a
2b
2c
2d
2e
60
30
60
60
30
3b
3c
3d
3e
3f
70
68
90
90
98
2.6
2.6
1.8
2.3
3.3
11
12
13
14
15
2a
2b
2c
2d
2e
60
60
60
60
30
97
64
NR
97
98
1.9
1.8
NR
1.0
1.8
Initially, we added same amounts of the reactants to the reac-
tion solution, but the yield was moderate (entry 1). Higher yield
16
17
18
19
20
2a
2b
2c
2d
2e
60
30
60
60
30
47
73
82
87
95
1.7
3.3
2.6
1.9
1.2
Table 1
Optimization of the reaction conditions
21
22
23
24
25
p-CH3
2a
2b
2c
2d
2e
60
30
60
60
30
NR
72
NR
39
74
NR
2.0
NR
1.9
2.2
R
NH2
n
HN
TBPA+. (5 mol %)
O
N
+
R
anhydrous CH2Cl2
reflux
R
26
27
28
29
30
p-CO2CH3
2a
2b
2c
2d
2e
60
30
60
60
30
25
25
69
65
73
2.4
1.2
2.2
1.4
4.2
N
H
2
1a
n = 1, 2a
3a
2b
n = 3,
(trans and cis)
Entry
Solvent
Substrates
Timea (h)
Yieldb (%)
31
32
33
34
35
p-F
2a
2b
2c
2d
2e
60
30
60
60
30
3g
3h
NR
81
NR
NR
80
NR
1.3
NR
NR
1.7
1
2
3
CH2Cl2
CH2Cl2
CHCl3
CH2ClCH2Cl
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
1:1 (2a)
2:1 (2a)
2:1 (2a)
2:1 (2a)
2:1 (2a)
2:1 (2a)
1:1 (2b)
2:1 (2b)
1
1
1
1
1
1
0.5
0.5
53
85
82
80
33
79
61
87
4
5
36
37
38
39
40
p-NO2
2a
2b
2c
2d
2e
360
No reaction
6c
7
8
a
b
c
Monitored by TLC.
Detected by chromatography.
DBP (10 mol %) was added as acid scavenger.
a
Detected by chromatography.
Determined by 1H NMR.
b

X.-d. Jia et al. / Tetrahedron Letters 51 (2010) 6779–6782
6781
We then examined the scope of aniline substrates by varying
the substituents on the aromatic ring to explore the generality of
this tandem cyclization. The results are summarized in Table 2.
As it can be seen from Table 2, the substituents of 1 exert
remarkable effect on the reaction. Most of the anilines acted well
in this reaction producing the desired tetrahydroquinolines in good
yields (entries 1–20). But when anilines bearing strong electron-
donating or electron-withdrawing groups, the reaction did not pro-
ceed smoothly and the yields of tetrahydroquinolines decreased. It
is easy to know that when those strong electron-withdrawing
groups are connected on anilines (entries 26–40), the nucleophilic-
ity of anilines decreases, resulting in the difficulty of the formation
of intermediate C (Scheme 1). Among our previous Letters, the oxi-
dation potential of the dienophiles must be low enough to be pref-
erentially oxidized.6b This criterion is also supported in the
reaction. While bearing strong electron-donating groups (such as
CH3 and OCH3), anilines are more easier to be oxidized by TBPA+Å,
thus the reaction was fully inhibited (entries 21 and 23). We also
tried the reaction between p-methoxylaniline with all the five N-
vinyl amides, no desired reaction occurred except for the oxidation
of p-methoxylaniline.
According to the structure of the products, N-vinyl amides serve
as acetaldehyde equivalents involved in this reaction. So we chose
five different N-vinyl amides (2a–e) to test the influence of the sur-
rogates of acetaldehyde. From Table 2 we can see that the best
yields were obtained when N-methyl-N-vinyl-acetamide 2e was
used as an acetaldehyde equivalent. To confirm the reaction pro-
cess, we also directly performed the reaction of aniline (2a) with
acetaldehyde under the standard condition but the desired product
3a was isolated in lower yield (34%), which implied that it is nec-
essary to use N-vinyl amides as surrogates of acetaldehyde.
It is well-known that TBPA+Å can also induce acid-catalysed
reactions, and in some cases the role of aminium salts was ascer-
tained as a latent source of SbCl5 (to rule out the possible process
induced by SbCl5, we also tried the reaction under SbCl5-catalysed
conditions, but no any reaction occurred).8 Generally, addition of
DBP can inhibit SbCl5-catalysed reactions (from Table 1, entry 6,
we can see addition of DBP does not affect the efficiency of this
reaction)8,9 but Lewis acidity of TBPA+Å cannot be inhibited com-
pletely. So a possible mechanism was proposed in which TBPA+Å
acts as both Lewis acid and one electron oxidant to induce such
transformation (Scheme 1).
Firstly, TBPA+Å as a Lewis acid was added to the double bond of
N-vinylamides to form transition substrate A that was attacked by
aniline. After subsequent elimination of the corresponding amide,
Schiff base B was generated which underwent enamine tautomer-
ism forming enamine D. Enamine D was further oxidized by TBPA+Å
producing its radical cation, followed by addition to another Schiff
base B. After cyclization and back electron transfer (D lost an elec-
tron to F, producing D+Å) to propagate the chain reaction, 2-methyl-
4-anilino-1,2,3,4-tetrahydroquinoline was produced in a stereose-
lective way.
Different from most literatures’ results, the products 2-methyl-
4-lactam-1,2,3,4-tetrahydroquinolines (via ABB pattern) were not
isolated. The main reason lies in that in the presence of single elec-
tron oxidant, enamine D prefers to be oxidized by TBPA+Å than the
corresponding N-vinyllactams (the anilino group in enamine D is
stronger electron-donating substituent than amide), which is the
critical factor resulting in the formation of the products via ABAB
pattern.10
In summary, we have executed a novel approach in which the
tandem cyclization between substituted anilines and N-vinyllac-
tams occurred via ABAB pattern to achieve the synthesis of a series
of tetrahydroquinoline derivatives. We are currently focused on
promoting this novel transformation and further exploring the
use in construction of more variable heterocycle compounds. Fur-
ther investigations in the mechanism of this reaction are also
underway in this laboratory.
Acknowledgements
We thank Project 20096203120002 supported by the Ministry
of Education of the People’s Republic of China and the third Knowl-
edge and Technological Innovation Project (NWNU-KJCXGC-03-75
and NWNU-KJCXGC-03-64) of Northwest Normal University for
supporting our research.
NH2
O
O
O
R3
R3
R3
R2
TBPA+.
-H+
R2
R2
N
N
N
Supplementary data
N
H
TBPA
+H+
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.106.
TBPA
O
A
R3
R2
O
-
N
H
R3
N
References and notes
R2
N
1. (a) Crousse, B.; Bégué, J.-P.; Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009–
5013; (b) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128,
13070–13071; (c) Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G. Org. Lett. 2002, 4,
4411–4414; (d) Shi, M.; Shao, L.-X.; Xu, B. Org. Lett. 2003, 5, 579–582; (e)
Sundararajan, G.; Prabagaran, N.; Varghese, B. Org. Lett. 2001, 3, 1973–1976; (f)
Xue, Z.; Samanta, A.; Whittlesey, B. R.; Mayer, M. F. Tetrahedron Lett. 2009, 50,
6064–6067; (g) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357–
7360; (h) Crousse, B.; Bégué, J.-P.; Bonnet-Delpon, D. Tetrahedron Lett. 1998, 39,
5765–5768; (i) Fadel, F.; Titouani, S. L.; Soufiaoui, M.; Ajamay, H.; Mazzah, A.
Tetrahedron Lett. 2004, 45, 5905–5908.
2. (a) Lavilla, R.; Bernabeu, M. C.; Carranco, I.; Díaz, J. L. Org. Lett. 2003, 5, 717–
720; (b) Muhuhi, J.; Spaller, M. R. J. Org. Chem. 2006, 71, 5515–5526; (c)
Gaddam, V.; Nagarajan, R. J. Org. Chem. 2007, 72, 3573–3576; (d) Desrat, S.; van
de Weghe, P. J. Org. Chem. 2009, 74, 6728–6734; (e) Gaddam, V.; Nagarajan, R.
Org. Lett. 2008, 10, 1975–1978; (f) Savitha, G.; Perumal, P. T. Tetrahedron Lett.
2006, 47, 3589–3593; (g) Nagaiah, K.; Sreenu, D.; Rao, R. S.; Vashishta, G.;
Yadav, J. S. Tetrahedron Lett. 2006, 47, 4409–4413; (h) Xia, M.; Lu, Y.-D. Synlett
2005, 2357–2361; (i) Nagarajan, R.; Magesh, C. J.; Perumal, P. T. Synthesis 2004,
69–74; (j) Kouznetsov, V. V.; Bohórquez, A. R. R.; Stashenko, E. E. Tetrahedron
Lett. 2007, 48, 8855–8860; (k) Smith, C. D.; Gavrilyuk, J. I.; Lough, A. J.; Batey, R.
A. J. Org. Chem. 2010, 75, 702–715.
N
B
H
C
TBPA+.
N
N
H
NH
HN
N
D
D+.
D
D
Ph
NHPh
HN
N
H
N
H
F
3. (a) Kumar, A.; Srivastava, S.; Gupta, G. Tetrahedron Lett. 2010, 51, 517–520; (b)
Lin, X.-F.; Cui, S.-L.; Wang, Y.-G. Tetrahedron Lett. 2006, 47, 4509–4512; (c)
Scheme 1. Proposed mechanism of tandem cyclization.

6782
X.-d. Jia et al. / Tetrahedron Letters 51 (2010) 6779–6782
Batey, R. A.; Powell, D. A.; Acton, A.; Lough, A. J. Tetrahedron Lett. 2001, 42,
133.0, 143.9, 144.9; EI-MS m/z (relative intensity, %): 398 (0.7%), 396 (1.5%),
394 (0.8%), 226 (29.0%), 224 (45.5%), 210 (86.9%), 208 (94.4%), 173 (89.5%), 171
(85.1%), 145 (19.4%), 143 (24.8%), 129 (57.9%), 65 (100%); ESI-HRMS: m/z calcd
for C16H14N2Br2+H: 392.9597, found: 392.9603. syn-3d: 1H NMR (300 MHz,
CDCl3): d 1.22 (d, J = 6.3 Hz, 3H), 1.45 (q, J = 11.7 Hz, 1H), 2.31 (ddd, J = 2.1, 5.1,
12.9 Hz, 1H), 3.58 (ddd, J = 2.4, 5.7, 11.1 Hz, 1H), 3.78 (br, NH, 2H), 4.70 (dd,
J = 5.4, 11.1 Hz, 1H), 6.38 (d, J = 9.0 Hz, 1H), 6.55 (d, J = 9.0 Hz, 2H), 7.11 (dd,
J = 2.4, 8.4 Hz, 1H), 7.25–7.30 (m, 2H), 7.43 (s, 1H); 13C NMR (100.6 MHz,
CDCl3): d 22.2, 37.1, 46.9, 50.2, 109.0, 114.7, 115.5, 124.6, 129.6, 130.9, 132.1,
143.8, 146.4, one 13C signal lost for overlap; EI-MS m/z (relative intensity, %):
398 (1.6%), 396 (3.1%), 394 (1.6%), 226 (66.0%), 224 (77.1%), 210 (100%), 208
(91.6%), 173 (82.7%), 171 (85.2%); ESI-HRMS: m/z calcd for C16H14N2Br2+H:
392.9597, found: 392.9601.
7935–7939; (d) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A. J.
Chem. Commun. 1999, 651–652; (e) Zhang, J.; Li, C.-J. J. Org. Chem. 2002, 67,
3969–3971; (f) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–2916; (g)
Powell, D. A.; Batey, R. A. Tetrahedron Lett. 2003, 44, 7569–7573.
4. This process is known as Doebner–von Miller reaction. Refs see: (a) Turner, A.
B.; McBain, B. I.; Howie, R. A.; Cox, P. J. J. Chem. Soc., Perkin Trans. 1 1986, 1151–
1155; (b) Westerwelle, U.; Keuper, R.; Risch, N. J. Org. Chem. 1995, 60, 2263–
2266; (c) Talukdar, S.; Chen, C.-T.; Fang, J.-M. J. Org. Chem. 2000, 65, 3148–
3153; (d) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem. 1995, 60, 7631–
7640.
5. (a) Bauld, N. L. Tetrahedron 1989, 45, 5307–5363; (b) Schmittel, M.; Burghart, A.
Angew. Chem., Int. Ed. 1997, 36, 2550–2589; (c) Nelsen, S. F. Acc. Chem. Res.
1987, 20, 269–276.
8. (a) Gassman, P. G.; Singleton, D. A. J. Am. Chem. Soc. 1984, 106, 6085–6086; (b)
Bordwell, F. G.; Bausch, M. J. J. Am. Chem. Soc. 1986, 108, 2473–2474; (c)
Lapouyade, R.; Villeneuve, P.; Nourmamode, A.; Morand, J. P. J. Chem. Soc.,
Chem. Commun. 1987, 776–778; (d) Ciminale, F.; Lopez, L.; Paradiso, V.; Nacci,
A. Tetrahedron 1996, 52, 13971–13980; (e) Ciminale, F.; Lopez, L.; Nacci, A.;
D’Accolti, L.; Vitale, F. Eur. J. Org. Chem. 2005, 70, 1597–1604; (f) Ciminale, F.;
Lopez, L.; Farinola, G. M.; Sportelli, S.; Nacci, A. Eur. J. Org. Chem. 2002, 67,
3850–3854; (g) Ciminale, F.; Lopez, L.; Farinola, G. M.; Sportelli, S. Tetrahedron
Lett. 2001, 42, 5685–5687.
6. (a) Jia, X.-D.; Wang, X.-E.; Yang, C.-X.; Huo, C.-D.; Wang, W.-J.; Ren, Y.; Wang,
X.-C. Org. Lett. 2010, 12, 732–735; (b) Jia, X.-D.; Lin, H.-C.; Huo, C.-D.; Zhang,
W.; Lu, J.-M.; Yang, L.; Zhao, G.-Y.; Liu, Z.-L. Synlett 2003, 1707–1709; (c) Jia, X.-
D.; Han, B.; Zhang, W.; Jin, X.-L.; Yang, L.; Liu, Z.-L. Synthesis 2006, 2831–2836;
(d) Jia, X.-D.; Wang, X.-E.; Yang, C.-X.; Da, Y.; Yang, L.; Liu, Z. L. Tetrahedron
2009, 65, 2334–2338; (e) Jia, X.-D.; Da, Y.; Yang, C.; Yang, L.; Liu, Z.-L.
Tetrahedron Lett. 2008, 49, 1786; (f) Huo, C.; Jia, X.; Zhang, W.; Yang, L.; Lu, J.;
Liu, Z. Synlett 2004, 251–254.
7. Representative spectral data of the products. trans-3d: 1H NMR (400 MHz, CDCl3):
d 1.21 (d, J = 5.6 Hz, 3H), 1.50 (t, J = 10.8 Hz, 1H), 2.09 (d, J = 13.2 Hz, 1H), 3.38
(br s, 1H), 3.89 (br, NH, 2H), 4.43 (br s, 1H), 6.43 (d, J = 8.8 Hz, 1H), 6.52 (d,
J = 8.4 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.27 (br, 3H); 13C NMR (100.6 MHz,
CDCl3): d 21.8, 34.4, 42.3, 48.6, 108.4, 108.8, 114.2, 116.1, 122.4, 131.4, 132.0,
9. (a) Schmittel, M. Top. Curr. Chem. 1994, 169, 183–230; (b) Schmittel, M.;
Abufarag, A.; Luche, O.; Levis, M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1144–
1146.
10. During the course of reaction, Ar3N, the reduction product of TBPA+Å, was
produced, which suggested that redox reactions occurred.