Niobium pentachloride catalyzed multicomponent povarov reaction

Article abstract of DOI:10.1055/s-0032-1316587

A single-step method for the synthesis of furan- and pyranoquinoline derivatives through multicomponent Povarov reactions between aniline derivatives, benzaldehyde and two different enol ethers (2,3-dihydrofuran and 3,4-dihydropyran) using niobium pentach

Full text of DOI:10.1055/s-0032-1316587

LETTER
▌1973
lNettierobium Pentachloride Catalyzed Multicomponent Povarov Reaction
Multicomponent Povarov Reaction
Bruno Henrique Sacoman Torquato da Silva, Lucas Michelão Martins, Luiz Carlos da Silva-Filho*
Department of Chemistry, São Paulo State University (UNESP), 17033-360 Bauru, São Paulo State, Brazil
Fax +55(14)31036099; E-mail: lcsilva@fc.unesp.br
Received: 26.03.2012; Accepted after revision: 08.06.2012
The tetrahydroquinoline derivatives can be easily synthe-
sized through Povarov multicomponent reactions (MCRs)
using several catalysts9 (Lewis acids), such as, InCl3,
LiBF4, BF3OEt2 and others, in which, usually, a pair of
Abstract: A single-step method for the synthesis of furan- and py-
ranoquinoline derivatives through multicomponent Povarov reac-
tions between aniline derivatives, benzaldehyde and two different
enol ethers (2,3-dihydrofuran and 3,4-dihydropyran) using niobium
pentachloride as catalyst under mild conditions, providing good diastereoisomers with cis and trans stereochemistry (Fig-
yields and high diastereoselectivity, is described.
ure 2) is formed between the hydrogens H-1 and H-2, pro-
viding different ratios between these isomers, depending
on the conditions used.
Key words: niobium pentachloride, multicomponent Povarov re-
action, furanoquinolines, pyranoquinolines, Lewis acid
O
O
H
H
(CH2)n
H
(CH2)n
H
The tetrahydroquinoline derivatives, compounds that
have the basic structure of quinolines, are an important
class of natural products and have several important bio-
logical activities,1 such as psychotropic,2 antiallergic,3
anti-inflammatory4 and estrogenic activity.5 Pyranoquino-
line and furanoquinoline derivatives have pharmacologi-
cal potential.6 Among these compounds we can mention
the simulenoline (1) and the huajiaosimuline7 (2 ; Figure
1), extracted from the Zanthoxylum simulans, a bush
found in China and Taiwan, compounds that act as strong
platelet inhibitors.
2
2
R1
R1
1
1
N
N
R2
R2
H
H
H
H
cis
trans
Figure 2 Stereochemistry of the tetrahydroquinoline derivatives
Some of the Lewis acids are not easily available or are ex-
pensive. In addition, they require longer reaction times
and form the products with poor yields. Therefore, devel-
oping simple and efficient synthetic methods for prepar-
ing this type of compound becomes increasingly
important.
OH
Niobium pentachloride, which is a low-cost and commer-
cially available reagent, has been used by our group and
other researchers as an effective catalyst in synthetic
methodologies in a variety of reactions.10,11
O
O
O
N
O
N
O
In the present report, we describe a highly efficient one-
pot method for the synthesis of furano- and pyranoquino-
lines using NbCl5 as catalyst. We reacted aniline deriva-
tives 3a–g, benzaldehyde (4) and different dienophile
types [2,3-dihydrofuran (5) and 3,4-dihydropyran (6)], in
the presence of NbCl5 as catalyst (Scheme 1), producing
the tetrahydroquinoline derivatives 7–9 and 10a–g, in a
typical Povarov multicomponent reaction.
Me
Me
1
2
Figure 1 Structures of the simulenoline (1) and the huajiaosimuline
(2)
In addition to this good applicability observed for the
simulenoline and the huajiaosimuline, some recent studies
found in the literature8 show other possible applications
for tetrahydroquinoline derivatives. Among them, their
application as an anticancer drug, acting as mitotic kinesin
inhibitors (enzyme responsible for cell division) and also
for Alzheimer’s disease treatment, inhibiting the acetyl-
cholinesterase enzyme (an enzyme necessary for the
transmission of nerve impulses and also responsible for
acetylcholine degradation, an important neurotransmit-
ter).
The Povarov multicomponent reactions were carried out
under an inert atmosphere of N2, at room temperature and
using anhydrous MeCN as solvent. NbCl5 was used as cat-
alyst, at the proportions of 10 mol% and 25 mol% for each
aniline derivative used. The products obtained were puri-
fied by column chromatography on silica gel and charac-
terized by spectroscopic methods,12 whenever possible.
The results obtained are described in Tables 1 and 2.
Through the analysis of Tables 1 and 2, it is possible to ob-
serve the high efficiency of niobium pentachloride as a
catalyst in the reactions between aniline derivatives, benz-
aldehyde and enol ethers for the tetrahydroquinoline de-
rivatives synthesis, presenting short reaction times and
SYNLETT 2012, 23, 1973–1977
Advanced online publication: 26.07.2012
DOI: 10.1055/s-0032-1316587; Art ID: ST-2012-S0277-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1974
B. H. S. T. da Silva et al.
LETTER
O
O
H
H
O
(CH2)n
H
(CH2)n
H
R
R
NH2
O
NbCl5
+
+
+
H
MeCN
r.t.
(CH2)n
N
N
R
H
H
H
H
4
5 n = 1
6 n = 2
3a R = H
3b R =OMe
3c R = Br
3d R = n-Bu
3e R = F
7a–g n = 1
9a–g n = 2
8a–g n = 1
10a–g n = 2
3f R = Cl
3g R = I
Scheme 1 Povarov multicomponent reaction catalyzed by NbCl5
good yields in both cases. Also, a high diastereoselectivity selectivity in some of the cases, especially with lower mo-
can be verified when using 3,4-dihydropyran (6) as dieno- lar concentrations of NbCl5. These notable features make
phile. The diastereoselectivity of the products formed was this procedure a useful and attractive process for the syn-
determined by comparing the integrals of the vicinal hy- thesis of furano- and pyranoquinolines, compounds with
1
drogens to nitrogen atom, for both products, in the H high biological interest, evidenced in a recent research.8
NMR spectrum of crude product.
Recent reports13 in the literature suggest that multicompo-
It was also possible to observe that, even when we nent Povarov reaction occur by formal aza-Diels–Alder
changed the aniline substituent, the reactions took place cycloaddition with inverse electron demand by a noncon-
rapidly and presented good yield when compared with certed process, and a possible explanation to the high dia-
other catalysts largely used in organic syntheses.9 It was stereoisomeric difference found, is that in the moment of
also observed in Tables 3 and 4 that high diastereoselec- the Schiff base formation, the Lewis acid bonds with the
tivity was obtained when low concentrations of the cata- nitrogen causing an steric impediment in the reaction,
lyst were used.
making the formation of the cis adduct difficult. On the
formation of the trans adduct this impediment has no in-
fluence, favoring then the formation of this adduct in a
larger proportion (Scheme 2).
In Tables 3 and 4, the results obtained in this work are
compared with other studies described in the literature.
When compared with other Lewis acids,9 niobium penta-
chloride is more effective, requiring shorter reaction
times, providing competitive yields and high diastereo-
This affirmation can be confirmed by NMR analyses used
to determine the relative stereochemistry of the products.
Table 1 Multicomponent Povarov Reaction Catalyzed by Niobium
Pentachloride for the Synthesis of Furanoquinolines 7a–g and 8a–g
Table 2 Multicomponent Povarov Reaction Catalyzed by Niobium
Pentachloride for the Synthesis of Piranoquinolines 9a–g and 10a–g
Aniline
NbCl5 (mol%) Time (min)
Yield (%)
Ratioa 7/8
Aniline
NbCl5 (mol%) Time (min) Yield (%)
Ratioa 9/10
3a
10
25
10
25
10
25
10
25
10
25
10
25
10
25
30
15
60
20
50
30
70
40
50
20
50
10
90
30
70
71
69
70
77
77
77
70
65
60
75
83
67
70
11:89
25:75
30:70
20:80
30:70
35:65
08:92
15:85
10:90
12:88
18:82
27:73
30:70
34:66
3a
10
25
10
25
10
25
10
25
10
25
10
25
10
25
30
20
60
20
120
60
60
30
40
10
50
10
80
30
85
80
69
75
88
83
68
65
70
75
61
70
83
90
5:95
15:85
2:98
5:95
3:97
7:93
2:98
5:95
3:97
6:94
5:95
8:92
10:90
11:89
3b
3c
3d
3e
3f
3b
3c
3d
3e
3f
3g
3g
a The products ratios were determined by 1H NMR analysis of the
crude product.
a The products ratios were determined by 1H NMR analysis of the
crude product.
Synlett 2012, 23, 1973–1977
© Georg Thieme Verlag Stuttgart · New York

LETTER
Multicomponent Povarov Reaction
1975
Small values of H–1H scalar coupling constant between
the hydrogens H-3a and H-9b (J3a,9b), in the adducts ob-
tained in the reaction with 2,3-dihydrofuran (5), and be-
tween hydrogens H-4a and H-10b (J4a,10b), in the adducts
obtained through reaction with 3,4-dihydropyran (6), are
characteristic of cis conformation between these hydro-
gens, confirming the mechanism proposed. The product
with trans orientation between these hydrogens was not
isolated (Figure 3).
1
H
N
O
Ar
Nb
••
O
••
O
••
••
n
n
Nb N
H
N
Nb
H
Ar
Ar
Table 3 Comparison of this Work with Literature Results; Furano-
quinoline Derivatives
O+
O+
Aniline Lewis acid mol% Time (min) Yield (%) Ratio 7/8
n
n
NbCl5
3a
25
25
20
50
10
50
15
180
120
150
60
71
96
88
68
69
53
25:75
24:76
15:85
47:53
30:70
38:62
Nb N
H
N
Nb
9e
H
GdCl3
Ar
Ar
9q
VCl3
9r
CuBr2
O
H
O
NbCl5
H
3b
n
n
9r
CuBr2
288
H
H
N
N
H
H
H
H
Table 4 Comparison of this Work with Literature Results; Pyrano-
cis
trans
quinoline Derivatives
Scheme 2 Mechanistic proposal for Povarov multicomponent reac-
tion catalyzed by NbCl5
Aniline Lewis acid mol% Time (min) Yield (%) Ratio
9/10
NbCl5
3a
25
20
25
20
50
25
20
25
50
25
25
20
50
25
20
25
25
20
25
20
600
720
150
120
20
80
88
84
90
76
75
95
62
46
83
82
82
57
75
76
70
70
74
82
15:85
27:73
61:39
20:80
21:79
02:98
02:98
03:97
37:63
07:93
18:82
25:75
26:74
06:94
11:89
18:82
08:92
09:91
20:80
J2,6 value: 2.0–5.0 Hz
J2,6 value: 2.3–5.0 Hz
9m
SmI2
9e
GdCl3
O
O
9q
9b or 10bH
VCl3
9b or 10bH
(CH2)n
(CH2)n
9r
CuBr2
H
H
3a or 4a
3a or 4a
N
N
NbCl5
3b
3c
H
H
H
H
4 or 5
4 or 5
9m
SmI2
300
2160
135
60
J1,2 value: 5.5–5.7 Hz
cis
J1,2 value: 8.1–11.1 Hz
9e
9r
GdCl3
CuBr2
trans
Figure 3 Coupling constant values used for determining stereo-
chemistry
NbCl5
9e
GdCl3
1800
180
270
10
Another important information obtained through NMR
analyses to determine the relative stereochemistry is that
on the position of furan or pyran ring. The cis adducts,
show smaller coupling constants J4/3a or J5/4a (5.5–5.7 Hz),
typical for a gauche conformation. This is consistent with
an orientation where the furan or pyran ring and the phe-
nyl group are on the same side (Figure 3). In trans ad-
ducts, the coupling constants are significantly higher, J4/3a
or J5/4a between 8.1 and 11.1 Hz, indicative of the anti ori-
entation of H-4/H-3a and H-5/H-4a, which is only possi-
ble when the furan or pyran ring and the phenyl group are
on opposite sides of the quinoline ring.
9q
VCl3
9r
CuBr2
NbCl5
3e
3f
9m
SmI2
300
2160
10
9e
GdCl3
NbCl5
9m
SmI2
300
1800
9e
GdCl3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1973–1977

1976
B. H. S. T. da Silva et al.
LETTER
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(l) Kudale, A. A.; Kendall, J.; Miller, D. O.; Collins, J. L.;
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In summary, we have developed an efficient, rapid and
good-yielding procedure to synthesize tetrahydroquino-
lines derivatives. Notable features of this protocol are
mild reaction conditions, good selectivity, cleaner reac-
tion profiles, short reaction times, and operational sim-
plicity.
Acknowledgment
The authors would like to thank the Fundação de Amparo à Pesqui-
sa do Estado de São Paulo (FAPESP) (Procs. 2010/18022-2), the
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq), the Coordenadoria de Aperfeiçoamento de Pessoal do
Nível Superior (CAPES) and the Pró-Reitoria de Pesquisa da
UNESP (PROPe-UNESP) for their financial support. We would
also like to thank CBMM, Companhia Brasileira de Mineralogia e
Mineração, for the NbCl5 samples. We express our special thanks to
L.A.B. de Moraes, N.P. Lopes and J.C. Tomaz at the University of
São Paulo in Ribeirão Preto for the MS and HRMS analyses.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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(12) General Procedure for the Multicomponent Povarov
Reaction of Benzaldehyde, Aniline Derivatives and Enol
Synlett 2012, 23, 1973–1977
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ether with NbCl5: To a solution of niobium pentachloride
Multicomponent Povarov Reaction
1977
(CH), 76.63 (CH), 65.6 (CH2), 58.2 (CH), 43.8 (CH), 29.3
(CH2). IR (film): 3348, 2975, 2855, 1615, 1480, 1039 cm–1.
MS: m/z = 251 [M]+, 220, 206, 174, 130, 115, 91, 77.
(4aS,5S,10bS)-5-Phenyl-3,4,4a,5,6,10b-hexahydro-2H-
pyran[3,2-c]quinoline (9a): 1H NMR (300 MHz, CDCl3):
δ = 7.35–7.44 (m, 5 H), 7.30 (m, 1 H), 7.09 (dt, 1 H, J1 = 7.7
Hz, J2 = 0.8 Hz), 6.79 (dt, 1 H, J1 = 7.7 Hz, J2 = 1.0 Hz), 6.60
(dd, 1 H, J1 = 7.7 Hz, J2 = 0.8 Hz), 5.33 (d, 1 H, J = 5.6 Hz),
4.69 (d, 1 H, J = 2.3 Hz), 3.85 (NH, 1 H), 3.58 (m, 1 H), 3.43
(dt, 1 H, J1 = 11.6 Hz, J2 = 2.5 Hz), 2.16 (m, 1 H), 1.47–1.58
(m, 2 H), 1.43 (m, 1 H), 1.31 (m, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 145.6 (C), 141.5 (C), 129.2 (CH), 128.8 (CH),
128.7 (CH), 128.5 (CH), 128.0 (CH), 127.9 (CH), 127.2
(CH), 120.3 (C), 118.7 (CH), 114.8 (CH), 73.2 (CH), 61.0
(CH2), 59.7 (CH), 39.3 (CH), 25.8 (CH2), 18.4 (CH2). IR
(film): 3312, 2941, 2865, 1608, 1486, 1317, 1265, 1069, 737
cm–1. MS: m/z = 265 [M]+, 234, 220, 194, 129, 117, 91, 77.
(4aS,5R,10bS)-5-Phenyl-3,4,4a,5,6,10b-hexahydro-2H-
pyran[3,2-c]quinoline (10a): 1H NMR (300 MHz, CDCl3):
δ = 7.30–7.44 (m, 5 H), 7.22 (dd, 1 H, J1 = 7.7 Hz, J2 = 1.3
Hz), 7.09 (dt, 1 H, J1 = 7.7 Hz, J2 = 1.3 Hz), 6.71 (dt, 1 H,
J1 = 7.3 Hz, J2 = 0.7 Hz), 6.53 (dd, 1 H, J1 = 7.7 Hz, J2 = 0.7
Hz), 4.72 (d, 1 H, J = 10.9 Hz), 4.39 (d, 1 H, J = 2.8 Hz), 4.10
(dt, 1 H, J1 = 11.4 Hz, J2 = 2.3 Hz), 3.72 (dt, 1 H, J1 = 11.4
Hz, J2 = 2.5 Hz), 2.11 (m, 1 H), 1.84 (tdt, 1 H, J1 = 13.4 Hz,
J2 = 12.4 Hz, J3 = 4.5 Hz), 1.65 (tt, 1 H, J1 = 13.4 Hz, J2 =
4.5 Hz), 1.47 (m, 1 H), 1.33 (m, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 145.1 (C), 142.7 (C), 131.3 (CH), 129.8 (CH),
129.0 (2 × CH), 128.3 (2 × CH), 128.2 (CH), 121.0 (C),
117.9 (CH), 114.5 (CH), 74.9 (CH), 69.0 (CH2), 55.2 (CH),
39.3 (CH), 24.5 (CH2), 22.4 (CH2). IR (film): 3360, 2940,
2865, 1610, 1488, 1315, 1265, 1070, 737 cm–1. MS: m/z =
265 [M]+, 234, 220, 194, 129, 117, 91, 77.
(10 mol% or 25 mol%) in anhyd MeCN (2.0 mL),
maintained at r.t. under a nitrogen atmosphere, was added a
solution of the benzaldehyde (1.0 mmol), 2,3-dihydrofuran
or 3,4-dihydropyran (1.0 mmol) and the respective aniline
(3a–g; 1.0 mmol) in anhyd MeCN (3.0 mL). After
completion of the addition, stirring was continued at r.t. The
reaction mixture was quenched with H2O addition (3.0 mL).
The mixture was extracted with EtOAc (10.0 mL). The
organic layer was separated and washed with sat. NaHCO3
solution (3 × 10.0 mL), sat. brine (2 × 10.0 mL), and then
dried over anhyd MgSO4. The solvent was removed under
vacuum and the products were purified by column
chromatography through silica gel using mainly a mixture
of hexane and EtOAc (9.0:1.0) as eluent.
(3aS,4S,9bS)-4-Phenyl-2,3,3a,4,5,9b-hexahydrofuran-
[3,2-c]quinoline (7a): 1H NMR (300 MHz, CDCl3): δ = 7.47
(d, 1 H, J1 = 7.6 Hz), 7.40–7.43 (m, 5 H), 7.10 (dd, 1 H, J1 =
8.0 Hz, J2 = 7.0 Hz), 6.82 (dd, 1 H, J1 = 7.6 Hz, J2 = 7.0 Hz),
6.61 (d, 1 H, J = 8.0 Hz), 5.29 (d, 1 H, J = 7.9 Hz), 4.71 (d,
1 H, J = 2.4 Hz), 3.70–3.88 (m, 2 H), 2.80 (m, 1 H), 2.21 (m,
1 H), 1.55 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 143.9
(C), 141.2 (C), 129.1 (CH), 127.6 (2 × CH), 127.3 (CH),
126.6 (CH), 125.5 (2 × CH), 121.7 (C), 118.2 (CH), 113.9
(CH), 74.9 (CH), 65.8 (CH2), 56.5 (CH), 44.8 (CH), 23.7
(CH2). IR (film): 3348, 2975, 2855, 1615, 1480, 1039 cm–1.
MS: m/z = 251 [M]+, 220, 206, 174, 130, 115, 91, 77.
(3aS,4R,9bS)-4-Phenyl-2,3,3a,4,5,9b-hexahydrofuran-
[3,2-c]quinoline (8a): 1H NMR (300 MHz, CDCl3): δ = 7.37
(d, 1 H, J = 7.0 Hz), 7.27–7.35 (m, 5 H), 7.06 (dd, 1 H, J1 =
8.3 Hz, J2 = 7.0 Hz), 6.73 (dd, 1 H, J1 = 8.3 Hz, J2 = 7.7 Hz),
6.56 (d, 1 H, J = 7.7 Hz), 4.54 (d, 1 H, J = 4.9 Hz), 3.96 (m,
1 H), 3.77 (m, 1 H), 3.74 (d, 1 H, J = 11.2 Hz), 2.40 (m, 1 H),
1.95 (m, 1 H), 1.65 (m, 1 H). 13C NMR (75 MHz, CDCl3):
δ = 145.8 (C), 142.1 (C), 131.6 (CH), 129.6 (CH), 129.1
(CH), 128.7 (CH), 128.6 (CH), 120.5 (CH), 118.8 (C), 115.1
(13) (a) Bello, D.; Ramón, R.; Lavilla, R. Curr. Org. Chem. 2010,
14, 332. (b) Jiménez, O.; de la Rosa, G.; Lavilla, R. Angew.
Chem. Int. Ed. 2005, 44, 6521.
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Synlett 2012, 23, 1973–1977

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