Magnesium perchlorate as efficient Lewis acid: A simple and convenient route to 1,4-dihydropyridines

Article abstract of DOI:10.1055/s-2007-990839

A new protocol for the synthesis of various 1,2,3,4-tetrasubstituted 1,4-dihydropyridines from enamino or carbonylic derivatives promoted by Mg(ClO₄)₂ is presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990839

LETTER
2897
Magnesium Perchlorate as Efficient Lewis Acid: A Simple and Convenient
Route to 1,4-Dihydropyridines
S
imple and Conve
i
nient
R
u
oute to 1,4-D
s
ihydropy
e
ridines ppe Bartoli, Krzysztof Babiuch,1 Marcella Bosco, Armando Carlone, Patrizia Galzerano, Paolo Melchiorre,
Letizia Sambri*
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, V. le Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2093654; E-mail: letizia.sambri@unibo.it
Received 31 July 2007
not dangerous chemicals if not employed under highly
Abstract: A new protocol for the synthesis of various 1,2,3,4-tetra-
substituted 1,4-dihydropyridines from enamino or carbonylic deriv-
atives promoted by Mg(ClO4)2 is presented.
acidic conditions and not exposed to high temperatures
(>300–500 °C).10
We report here that a new synthesis of 1,2,3,4-tetrasub-
stituted 1,4-dihydropyridines like 3 promoted by metal
perchlorates is possible.
Key words: magnesium perchlorate, 1,4-dihydropyridines, domi-
no reaction, Michael addition, cyclization
A few years ago, we set up a convenient procedure to ob-
tain b-enaminoesters and b-enaminoketones by condensa-
tion of b-ketoesters and b-diketones with amines in the
presence of Zn(ClO4)2·6H2O and MgSO4 as catalyst.11
Owing to the nucleophilic character of b-enaminoesters
and b-enaminoketones, a Michael addition to a,b-unsatur-
ated carbonylic compounds could occur in the presence of
a perchlorate salt, whose ability to activate b-bidentate
substrates is actually well known.12 If this is the case, a
domino procedure could also be set up.
1,4-Dihydropyridine (1,4-DHP) derivatives continue to
be subject of notable interest and studies as analogues of
NADH coenzymes that could be involve in hydrogen-
transfer reactions.2 In addition, the DHP heterocyclic ring
is part of the fundamental skeleton of important classes of
drugs.2,3 1,4-DHP derivatives, in fact, find application as
calcium antagonists, as vasodilators, bronchodilators,
antitumor agents and in the treatment of cardiovascular
diseases.
The first 1,4-DHP systems were obtained more than one
century ago by Hantzsch via a one-pot condensation of an
aldehyde, ammonia and a ketoester.4 Various modifica-
tion of the original procedure have been set up during the
years in order to improve the yields and the reaction con-
ditions.5 However, this strategy can not be considered
general for the synthesis of all types of 1,4-dihydropyr-
idines leading to completely substituted 1,4-DHP units.
In order to evaluate the practicability of the reaction,
preliminary experiments were carried out by reacting the
starting enamino derivatives 1a and 1b with a slight ex-
cess (1.2 equiv) of (E)-4-methyl-2-pentenal (2a) in
CH2Cl2, in the presence of different catalytic systems. Af-
ter 24 hours at room temperature, the mixture was filtered
on celite, the solvent was evaporated and the conversion
was determined by NMR analysis of the crude product.
The results are reported in Table 1.
On the contrary, to the best of our knowledge, only few
methods are available for the synthesis of unsymmetrical
tetrasubstituted derivatives.6,7 Most of these procedures
are based on a Michael addition on an a,b-unsaturated
system promoted by a Lewis acid catalyst [LiI,6a
Sc(OTf)3,6b CAN6c].
Depending on the activity of the catalyst, together with the
desired product 3, variable amounts of the pyridinium salt
4 could be detected. Zn(ClO4)2·6H2O proved to be very ef-
ficient since the reaction was complete after 24 hours.
However, the reaction led to a mixture of the desired prod-
uct 3aa and a 25% yield of 4aa (Table 1, entry 1). LiClO4
seemed to be a good choice for the reaction of 1a, giving
3aa in 85% conversion without traces of the pyridinium
salt (Table 1, entry 2), but it was not suitable for the less
reactive b-enaminoketone 1b, which was converted into
3ba in only 33% yield (Table 1, entry 3). Mg(ClO4)2
proved to be the best choice among the selected perchlor-
ates: enaminoester 1a reacted almost completely giving
3aa in 90% yield, and only a small amount of 4aa (8%).
Also enaminoketone 1b gave the product 3ba with 82%
conversion, with no traces of 4ba (Table 1, entries 4 and
5). Carrying out the reaction under an inert atmosphere
did not change the reactivity and the proportion of the
reaction products.
During our studies on the ability of metal perchlorates to
work as Lewis acids, we proved that metal perchlorates
can behave as powerful Lewis acids, and their activity is
comparable, and in some cases superior,8 to that of metal
triflates, which, however, are much more expensive.
Moreover, the high activity is typical not only of heavy
metal perchlorates, but also of perchlorate salts of alkaline
and alkaline earth metals.9 This is a very important pecu-
liarity that makes the synthetic methodologies more eco-
friendly. Finally, it has been demonstrated that, despite
the common opinion, Li, Mg, Zn and Ni perchlorates are
SYNLETT 2007, No. 18, pp 2897–2901
x
x
.x
x
.2
0
0
7
Advanced online publication: 12.10.2007
DOI: 10.1055/s-2007-990839; Art ID: G26107ST
© Georg Thieme Verlag Stuttgart · New York

2898
G. Bartoli et al.
LETTER
Carrying out the reaction with cinnamaldehyde at 40 °C
could improve the conversion (Table 2, entry 17). The
presence of an aromatic moiety on the ketone (R1 = Ph)
makes the b-enaminoketone completely unreactive
(Table 2, entry 24).
Table 1 Reaction of b-Enamino Derivatives 1 with (E)-4-Methyl-
pentenal 2a (1.2 equiv) under Various Reaction Conditions
O
R1
The amount of the pyridinium salt 4 increased when both
b-enaminoesters and b-enaminoketones were reacted with
cinnamaldehyde. We were able to isolate and characterize
the pyridinium salt 4 only in two cases: compound 4db,
which crystallized from the crude reaction mixture, and
compound 4ea, from the column chromatography.
N
R2
4
–
ClO4
O
R2
catalyst
O
HN
+
H
+
CH2Cl2, 0.5 M, r.t.
24 h
R1
O
1
2a
R1
The synthesis of dihydropyridine 3 could be also be
achieved through a domino reaction starting from b-keto-
esters or b-diketones 5 by adding one equivalent of amine,
in the presence of Mg(ClO4)2 (10%) and MgSO4 (20%),
and subsequently the aldehydes when the formation of the
enamino derivative was complete, generally after 1–2
hours. The results obtained via the domino reaction are re-
ported in Table 3. The yields and times are comparable
with those obtained starting from b-enamino deriva-
tives.13
N
R2
3
1a: R1 = OtBu, R2 = Ph
1b: R1 = Me, R2 = Ph
3aa: R1 = OtBu, R2 = Ph
3ba: R1 = Me, R2 = Ph
Entry Substrate Catalyst
(equiv)
Conversion
(%) 3 (4)
1
2
3
4
5
6
7
1a
1a
1b
1a
1b
1a
1b
Zn(ClO4)2·6H2O (0.1), MgSO4 (0.2) >74 (25)
LiClO4 (0.1), MgSO4 (0.2)
LiClO4 (0.1), MgSO4 (0.2)
Mg(ClO4)2 (0.1), MgSO4 (0.2)
Mg(ClO4)2 (0.1), MgSO4 (0.2)
Mg(ClO4)2 (0.1)
85 (0)
33 (0)
90 (8)
74 (8)
85 (0)
50 (0)
1
Although the conversion yields calculated from the H
NMR spectra of the crude of the reactions were generally
very high, we found various difficulties in the isolation of
the pure products (see Table 3). Although we found in the
literature that this kind of compound can be purified by a
simple column chromatography on SiO2, without any pre-
caution, in our hand this technique did not work and the
yields of the purified products 3 were generally much
lower than the 1H NMR conversions.14
Mg(ClO4)2 (0.1)
After trying various conditions for the column chromatog-
raphy (the solvent with or without the addition of Et3N)
and various stationary phases (SiO2, Florosil, neutral
Al2O3, basic Al2O3), we found that the best condition to
obtain a good separation and the best yield for the dihy-
dropyridine 3 was to carry out the column chromatogra-
phy on SiO2, using a petroleum ether–acetone solvent
mixture with 5% Et3N added during the conditioning pro-
cess, and then the solvent mixture alone for the separation
step. The column should be preferentially short (40 g of
SiO2 for 1 g of product) and the separation should be
quickly carried out under a nitrogen atmosphere. To ex-
clude the possibility that traces of magnesium perchlorate
could be responsible for the low yields, the pure isolated
product 3aa was subjected to another column chromatog-
raphy. The yield was low again, demonstrating that these
products are very labile, and, probably, traces of oxygen
are sufficient to oxidize them on the solid support. More-
over, even if the workup step was carried out by adding
water and extracting the product with CH2Cl2, instead of
a filtration on celite, the results are exactly the same.
The addition of a catalytic amount of MgSO4 as dehydra-
tion agent was necessary; in fact, on carrying out the reac-
tion in the absence of MgSO4, a decrease in the conversion
was observed (Table 1, entries 6 and 7).
The protocol was applied to various b-enaminoesters and
b-enaminoketones with various aldehydes. The results are
reported in Table 2. The reaction works well, both with b-
enaminoesters and b-enaminoketones, even if the former
substrates are generally more reactive.
b-Enaminoesters 1a and 1c–f were totally reactive and
were predominantly converted into the corresponding di-
hydropyridines 3, and partially into the pyridinium salt 4.
They showed the same reactivity irrespective of the nature
of the ester group (R1 = OEt, Ot-Bu) and of the N-substit-
uent (R2 = Ph, Bz, Bu) (Table 2, entries 1–13), whereas
the nature of the aldehyde affected the rate of the reaction.
In fact the reactions with cinnamaldehyde (R3 = Ph,
Table 2, entries 2, 5, 8 and 12) required longer reaction
times; the presence of an electron-withdrawing group on
the phenyl ring, such as a 2-NO2 substituent, increased the
rate (Table 2, entries 6 and 13).
In order to evaluate the possibility of increasing the scale
of application of our methodology we carried out the se-
quential synthesis of dihydropyridine 3da starting from
10 mmol of ethyl acetoacetate. The conversion yield of
3da calculated from the 1H NMR spectra was almost the
same as that from the small-scale (0.3 mmol) run, but the
On the other hand, b-enaminoketones 1b and 1g were less
reactive, giving the corresponding dihydropyridines 3
with conversions ranging from 50% to >99%. Even in this
case, with aromatic a,b-unsaturated aldehydes, longer
reaction times were required (Table 2, entries 16 and 23).
Synlett 2007, No. 18, 2897–2901 © Thieme Stuttgart · New York

LETTER
Simple and Convenient Route to 1,4-Dihydropyridines
2899
Table 2 Reaction of Enamino Derivatives 1 (1 equiv) with Various Enals 2 (1.2 equiv) in the Presence of Mg(ClO4)2 and MgSO4 in CH2Cl2
at Room Temperature
R3
O
R3
O
R2
Mg(ClO4)2 (10 mol%)
O
HN
R1
R1
R3
+
+
O
MgSO4 (20 mol%)
CH2Cl2, 0.5 M, r.t.
R1
–
N
2
N
ClO4
1
R2
R2
3
4
Entry
Starting 1
R1
R2
Ph
R3
Product
Time
Conversion (%)a,b of
3 (4)
Yield (%)c of 3
1
2
1a
1a
1c
1c
1c
1c
1d
1d
1e
1f
Ot-Bu
Ot-Bu
i-Pr
3aa
3ab
3ca
3cc
3cb
3cd
3da
3db
3ea
3fa
24
70
24
24
70
48
24
70
24
24
24
70
48
24
24
70
70d
48
70
24
24
48
70
70
95 (5)
75 (10)
75 (24)
82 (18)
70 (30)
89 (11)
90 (0)
71 (19)
96 (4)
93 (7)
93 (7)
75 (12)
96 (4)
80 (2)
64 (6)
54 (10)
70 (nd)
90 (nd)
95 (nd)
99 (nd)
74 (11)
62 (nd)
50 (nd)
0
75
58
63
67
52
64
67
55
64
66
59
65
72
65
47
40
55
68
62
60
52
44
32
Ph
3
Bu
i-Pr
4
Pr
5
Ph
6
2-O2NC6H4
7
OEt
Ph
i-Pr
8
Ph
9
OEt
OEt
Bn
Bu
i-Pr
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
i-Pr
1f
Pr
3fc
1f
Ph
3fb
3fd
3ba
3bc
3bb
3bb
3bd
3be
3bf
3ga
3gc
3gb
3ha
1f
2-O2NC6H4
1b
1b
1b
1b
1b
1b
1b
1g
1g
1g
1h
Me
Ph
i-Pr
Pr
Ph
Ph
2-O2NC6H4
4-O2NC6H4
CO2Et
i-Pr
Me
Ph
Bn
Ph
Pr
Ph
i-Pr
a Conversion calculated from the 1H NMR spectra.
b When the conversion was not complete, starting material 1 was also detected.
c Isolated yields.
d The reaction was carried out at 40 °C.
isolated yield increased (94%, Table 3, entry 4). There- In conclusion, we have demonstrated an another interest-
fore we could observe that the separation step was better ing application of MgClO4 to act as a Lewis acid in pro-
when a reasonable amount of the crude material was moting the synthesis of 1,2,3,4-tetrasubstituted 1,4-
present. Yields reported in the Table 2 refer to those ob- dihydropyridines 3, by addition of enamino esters and
tained from the reactions carried out on a 0.3–3.0 mmol ketones to enals. Considering the ability of perchlorates to
scale of starting material.
catalyze the formation of the enamino derivatives from
Synlett 2007, No. 18, 2897–2901 © Thieme Stuttgart · New York

2900
G. Bartoli et al.
LETTER
Table 3 Sequential One-Pot Synthesis of 1,4-Dihydropyridines 3 from b-Keto Derivatives 5, Amines and Enals 2
1) R2NH2 (1.1 equiv)
Mg(ClO4)2 (10 mol%),
MgSO4 (20 mol%),
R3
O
R3
O
O
O
R1
R1
CH2Cl2, 0.5 M, r.t., 1–2 h
R1
R1 = alkyl, OR
+
5
2)
R3
–
N
R2
O
N
R2
ClO4
(1.2 equiv)
2
4
3
Entry
R1
R2
R3
Product
Time (h)
Isolated yield (%) of
3 (4a)
1
2
3
4
5
6
7
8
9
Ot-Bu
Bu
i-Pr
3ca
3cb
3if
25
64
26
26
25
30
26
70
26
65 (11)
58 (23)
71 (8)
94b (4)
78 (10)
70 (0)
61
Ph
Ot-Bu
OEt
OEt
OEt
Me
Bn
Ph
Bn
Bu
Ph
Bn
CO2Et
i-Pr
3da
3ea
3fd
3ba
3gb
3gc
i-Pr
2-O2NC6H4
i-Pr
Me
Ph
45 (0)
51 (5)
Pr
a Calculated from 1H NMR.
b Reaction carried out starting from 10 mmol of 4.
(4) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 1, 215.
(5) For some recent examples, see: (a) Wang, G.-W.; Xia, J.-J.;
Miao, C.-B.; Wu, X.-L. Bull. Chem. Soc. Jpn. 2006, 79, 454.
(b) Maheswara, M.; Siddaiah, V.; Raob, Y. K.; Tzeng, Y.-
M.; Sridhar, C. J. Mol. Catal. A: Chem. 2006, 260, 179.
(c) Zolfigol, M. A.; Safaiee, M. Synlett 2004, 827.
carbonyl derivatives and amines, a more convenient
sequential procedure to obtain 3 is also possible. Notably,
the only by-product of the reaction is water.
Studies are in progress in our laboratories to apply this
procedure to other carbonyl derivatives, such as b-keto-
amides, and to obtain enantiomerically pure 1,4-dihydro-
pyridine.
(d) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A.
V. Green Chem. 2003, 5, 60. (e) Sabitha, G.; Reddy, G. S.
K. K.; Reddy, C. S.; Yadav, J. S. Tetrahedron Lett. 2003, 44,
4129.
(6) (a) Geirsson, J. F. K.; Johannesdottir, J. F. J. Org. Chem.
1996, 61, 7320; and previous works cited therein.
Acknowledgment
This work was carried out in the framework of the National Project
‘Stereoselezione in Sintesi Organica: Metodologie e Applicazioni’
supported by MIUR, Rome.
(b) Vohra, R. K.; Bruneau, C.; Renaud, J.-L. Adv. Synth.
Catal. 2006, 348, 2571. (c) Sridharan, V.; Perumal, P. T.;
Avendaño, C.; Menéndez, J. C. Tetrahedron 2007, 63, 4407.
(7) Taylor, M. D.; Himmelsbach, R. J.; Kornberg, B. E.; Quin,
J. III.; Lunney, E.; Michel, A. J. Org. Chem. 1989, 54, 5585.
(8) (a) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Massaccesi, M.; Sambri, L. Eur. J. Org. Chem. 2003, 4611.
(b) Bartoli, G.; Bosco, M.; Carlone, A.; Dalpozzo, R.;
Locatelli, M.; Melchiorre, P.; Sambri, L. J. Org. Chem.
2006, 71, 9580. (c) Shivani, ; Pujala, B.; Chakraborti, A. K.
J. Org. Chem. 2007, 72, 3713. (d) Bhagat, S.; Chakraborti,
A. K. J. Org. Chem. 2007, 72, 1263.
References and Notes
(1) Erasmus student from Uniwersytet Jagielloński, ul. Golebia
24, 31-007 Cracow, Poland
(2) (a) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141.
(b) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269.
(3) (a) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamatsu, Y.;
Nagaoka, A. Chem. Pharm. Bull. 1985, 33, 3787.
(b) Triggle, D. J. Cell. Mol. Neurobiol. 2003, 23, 293.
(c) De Simone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow,
J. W.; Pippin, D. A. Comb. Chem. High Throughput
Screening 2004, 7, 473. (d) Loev, B.; Ehrreich, S. J.;
Tedeschi, R. E. J. Pharm. Pharmacol. 1972, 24, 917.
(e) Harrold, M. In Foye’s Principles of Medicinal Chemistry,
5th ed.; Williams, D. A.; Lemke, T. L., Eds.; Lippincott
Williams and Wilkins: Baltimore, 2002, 533. (f) Mojarrad,
J. S.; Vo, D.; Velázquez, C.; Knaus, E. E. Bioorg. Med.
Chem. 2005, 13, 4085.
(9) Bartoli, G.; Locatelli, M.; Melchiorre, P.; Sambri, L. Eur. J.
Org. Chem. 2007, 2037; and references therein cited.
(10) (a) Long, J. Chem. Health Safety 2002, 9, 12. (b) El-Awad,
A. M.; Gabr, R. M.; Girgis, M. M. Thermochim. Acta 1991,
184, 205.
(11) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Melchiorre, P.; Sambri, L. Synlett 2004, 239.
(12) (a) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Massaccesi, M.; Melchiorre, P.; Sambri, L. Synlett 2004,
1794. (b) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni,
Synlett 2007, No. 18, 2897–2901 © Thieme Stuttgart · New York

LETTER
E.; Melchiorre, P.; Sambri, L. Org. Lett. 2005, 7, 427.
Simple and Convenient Route to 1,4-Dihydropyridines
2901
(CH), 134.0 (CH), 141.7 (C), 143.3 (C), 147.7 (C), 149.2
(C), 199.0 (C). HRMS: m/z calcd for C20H18N2O3: 334.1317;
found: 334.1315.
tert-Butyl 1-Butyl-2-methyl-4-(2-nitrophenyl)-1,4-
dihydropyridine-3-carboxylate (3cd): 1H NMR: d = 0.95
(t, JH,H = 7.3 Hz, 3 H), 1.10 (s, 9 H), 1.35–1.40 (m, 2 H),
1.55–1.60 (m, 2 H), 2.49 (s, 3 H), 3.20–3.30 (m, 1 H), 3.40–
(c) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Massaccesi, M.; Rinaldi, S.; Sambri, L. Synlett 2003, 39.
(d) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
Marcantoni, E.; Melchiorre, P.; Palazzi, P.; Sambri, L. Eur.
J. Org. Chem. 2006, 4429. (e) Khatik, G. L.; Kumar, R.;
Chakraborti, A. K. Synthesis 2007, 541. (f) Shivani, R. G.;
Chakraborti, A. K. J. Mol. Catal. A: Chem. 2007, 264, 208.
(13) General Procedure for the Synthesis of Dihydropyridine
3 from Enamino Derivatives 1: In a two-necked flask
equipped with a magnetic stirring bar, Mg(ClO4)2 (0.10
mmol), MgSO4 (0.20 mmol), and the enamino derivative 1
(1.0 mmol) were suspended in anhyd CH2Cl2 (2 mL) and the
aldehyde 2 (1.2 mmol) was added. The mixture was stirred
at r.t. until completion of the reaction or for 70 h. The crude
reaction mixture was filtered on celite and the solvent was
removed by rotary evaporation. The dihydropyridine 3 was
purified by flash chromatography on silica gel pretreated
with the solvent mixture of PE–acetone (95:5) added with
5% Et3N.
3.50 (m, 1 H), 5.04 (d, JH,H = 4.9 Hz, 1 H), 5.15 (dd, JH,H
=
4.9, 7.7 Hz, 1 H), 5.82 (d, JH,H = 7.7 Hz, 1 H), 7.10–7.15 (m,
1 H), 7.55–7.60 (m, 2 H), 7.80–7.85 (m, 1 H). 13C NMR: d =
13.8 (Me), 15.3 (Me), 19.8 (CH2), 27.8 (3 × Me), 32.4 (CH2),
37.3 (CH), 50.1 (CH2), 78.9 (C), 99.7 (C), 106.2 (CH), 123.4
(CH), 126.2 (CH), 129.3 (CH), 130.9 (CH), 133.2 (CH),
144.2 (C), 147.4 (C), 149.6 (C), 167.8 (C). HRMS: m/z calcd
for C21H28N2O4: 372.2049; found: 372.2048.
Ethyl 1-Butyl-2-methyl-4-propyl-1,4-dihydropyridine-3-
carboxylate (3fc): 1H NMR: d = 0.87 (t, JH,H = 6.8 Hz, 3 H),
0.93 (t, JH,H = 7.3 Hz, 3 H), 1.26 (t, JH,H = 7.1 Hz, 3 H), 1.20–
1.40 (m, 6 H), 1.45–1.55 (m, 2 H), 2.36 (s, 3 H), 3.10–3.20
(m, 1 H), 3.30–3.40 (m, 1 H), 3.40–3.50 (m, 1 H), 4.05–4.20
General Procedure for the Synthesis of Dihydropyridine
3 from Carbonyl Derivatives 5: In a two-necked flask
equipped with a magnetic stirring bar, Mg(ClO4)2 (0.10
mmol), MgSO4 (0.20 mmol), and the carbonyl derivative 5
(1.0 mmol) were suspended in anhyd CH2Cl2 (2 mL) and the
amine (1.1 mmol) was added. When the reaction was
completed (check with TLC), the aldehyde 2 (1.2 mmol) was
added. The mixture was stirred at r.t until completion of the
reaction or for 70 h. The crude reaction mixture was filtered
on celite and the solvent was removed by rotary evaporation.
The dihydropyridine 3 was purified by flash
(m, 2 H), 4.86 (dd, JH,H = 6.3, 7.4 Hz, 1 H), 5.84 (d, JH,H =
7.4 Hz, 1 H). 13C NMR: d = 14.0 (Me), 14.5 (Me), 14.6 (Me),
15.8 (Me), 18.2 (CH2), 20.0 (CH2), 32.6 (CH2), 33.0 (CH),
41.6 (CH2), 50.0 (CH2), 59.2 (CH2), 99.7 (C), 107.5 (CH),
130.0 (CH), 149.3 (C), 169.7 (C). HRMS: m/z calcd for
C16H27NO2: 265.2042; found: 265.2043.
1,4-Diphenyl-3-(ethoxycarbonyl)-2-methylpyridinium
Perchlorate (4db): 1H NMR (CD2Cl2): d = 1.06 (t, JH,H = 7.2
Hz, 3 H), 2.60 (s, 3 H), 4.25 (q, JH,H = 7.2 Hz, 2 H), 7.60–
7.70 (m, 7 H), 7.75–7.80 (m, 3 H), 8.11 (d, JH,H = 6.6 Hz, 1
H), 8.78 (d, JH,H = 6.6 Hz, 1 H). 13C NMR (CD2Cl2): d = 13.6
(Me), 19.9 (Me), 63.8 (CH2), 125.7 (CH), 127.1 (CH), 128.5
(CH), 129.7 (CH), 131.3 (CH), 131.7 (CH), 132.3 (CH),
134.0 (C), 135.3 (C), 140.8 (C), 146.3 (CH), 153.6 (C),
158.3 (C), 164.6 (C). MS (ESI+): m/z = 318. MS (ESI–):
m/z = 99.
chromatography on silica gel pre-treated with the solvent
mixture of PE–acetone (95:5) added with 5% Et3N.
Spectroscopic data for selected compounds are as follows:
1-(4-Isopropyl-2-methyl-1-phenyl-1,4-dihydropyridin-3-
yl)ethanone (3ba): 1H NMR: d = 0.91 (d, JH,H = 6.9 Hz, 6
H), 1.50–1.60 (m, 1 H), 2.00 (s, 3 H), 2.27 (s, 3 H), 3.41 (dd,
JH,H = 4.4, 6.0 Hz, 1 H), 4.93 (dd, JH,H = 6.2, 7.5 Hz, 1 H),
6.30 (d, JH,H = 7.5 Hz, 1 H), 7.05–7.15 (m, 2 H), 7.25–7.30
(m, 1 H), 7.35–7.45 (m, 2 H). 13C NMR: d = 16.8 (Me), 18.6
(Me), 19.1 (Me), 29.0 (Me), 35.5 (CH), 40.6 (CH), 103.5
(CH), 111.1 (C), 126.96 (CH), 126.99 (CH), 129.3 (CH),
131.3 (CH), 143.6 (C), 146.4 (C), 200.9 (C). HRMS: m/z
calcd for C17H21NO: 255.1623; found: 255.1623.
1-[2-Methyl-4-(2-nitrophenyl)-1-phenyl-1,4-dihydro-
pyridin-3-yl]ethanone (3bd): 1H NMR: d = 1.99 (s, 3 H),
2.18 (s, 3 H), 5.26 (dd, JH,H = 5.5, 7.5 Hz, 1 H), 5.32 (d, JH,H
= 5.5 Hz, 1 H), 6.10 (d, JH,H = 7.5 Hz, 1 H), 7.15–7.20 (m, 2
H), 7.35–7.40 (m, 2 H), 7.40–7.45 (m, 2 H), 7.60–7.65 (m, 2
H), 7.80–7.85 (m, 1 H). 13C NMR: d = 19.6 (Me), 29.8 (Me),
37.3 (CH), 106.4 (CH), 108.9 (C), 124.3 (CH), 127.4 (CH),
127.8 (CH), 128.1 (CH), 130.0 (CH), 130.3 (CH), 131.1
1-Benzyl-3-(ethoxycarbonyl)-2-methyl-4-isopropyl-
pyridinium Perchlorate (4ea): 1H NMR: d = 1.33 (t, JH,H
=
7.1 Hz, 6 H), 1.40 (t, JH,H = 7.0 Hz, 3 H), 2.72 (s, 3 H), 3.00–
3.10 (m, 1 H), 4.48 (q, JH,H = 7.1 Hz, 2 H), 5.83 (s, 2 H),
7.25–7.30 (m, 2 H), 7.35–7.45 (m, 3 H), 7.93 (d, JH,H = 7.0
Hz, 1 H), 8.92 (d, JH,H = 7.0 Hz, 1 H). 13C NMR: d = 13.8
(Me), 18.2 (Me), 22.3 (2 × Me), 47.3 (CH), 61.9 (CH2), 63.4
(CH2), 123.7 (CH), 127.9 (CH), 129.5 (CH), 129.6 (CH),
131.2 (C), 134.7 (C), 146.5 (CH), 151.8 (C), 164.2 (C),
165.4 (C). MS (ESI+): m/z = 298. MS (ESI–): m/z = 99.
(14) We compared our results with those from the previously
reported procedure, employing Sc(OTf)3 as Lewis acid (see
ref. 6b) and we found conversion yields similar to those
obtained with our method facing the same separation
problems. These results mean that the perchlorate anion is
not responsible in any way for the low recovered yields.
Synlett 2007, No. 18, 2897–2901 © Thieme Stuttgart · New York

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