Multicomponent domino reaction promoted by Mg(ClO4)2: Highly efficient access to functionalized 1,4-dihydropyridines

Article abstract of DOI:10.1002/ejoc.200800422

An efficient, one-pot multicomponent synthetic protocol toward substituted 1,4-dihydropyridines from aromatic amines, β-keto derivatives, and ethyl propiolate mediated by Mg(ClO₄)₂ is described. When ortho- or meta-substituted arylam

Full text of DOI:10.1002/ejoc.200800422

FULL PAPER
DOI: 10.1002/ejoc.200800422
Multicomponent Domino Reaction Promoted by Mg(ClO4)2: Highly Efficient
Access to Functionalized 1,4-Dihydropyridines
Giuseppe Bartoli,[a] Marcella Bosco,[a] Patrizia Galzerano,[a] Roberto Giri,[a]
Andrea Mazzanti,[a] Paolo Melchiorre,[a] and Letizia Sambri*[a]
Keywords: Multicomponent reactions / Magnesium perchlorate / Nitrogen heterocycles / Solvent-free conditions / Atrop-
isomers
An efficient, one-pot multicomponent synthetic protocol to-
ward substituted 1,4-dihydropyridines from aromatic amines,
β-keto derivatives, and ethyl propiolate mediated by
ated. An NMR spectroscopic study of the energy barrier in-
volved in the interconversion of the isomers is reported.
Mg(ClO4)2 is described. When ortho- or meta-substituted (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
arylamines are used, two conformational isomers are gener- Germany, 2008)
Introduction
Multicomponent reactions[1] involving one-pot domino
processes[2] are one of the most powerful tools to easily ob-
tain complex molecular skeletons from simple substrates.
Current literature continues to report new protocols for the
preparation of 1,4-dihydropyridines (1,4-DHPs), which ex-
hibit important pharmacological and biological activities.[3]
Scheme 1.
Studying the reaction with other α,β-unsaturated sys-
tems, we obtained a surprising result. In fact, the reaction
In fact, 1,4-DHPs are among the most widely used drugs
for the treatment of vascular disorders, and they find appli-
cations as calcium antagonists, vasodilators, bronchodila-
tors, and anticancer agents. Moreover, they are NADH
of enamino ester 1a with ethyl propiolate (4) did not give
expected pyridone[9] 5 or Michael adduct 6, but a consider-
able amount (20% yield after 70 h at r.t.) of dihydropyridine
7a derived from a double conjugate addition of 1a to 4 fol-
lowed by an intramolecular condensation with elimination
of aniline 8a (Scheme 2). Given the importance of the 1,4-
DHP system, a study to optimize this procedure by de-
veloping a useful synthesis of systems like 7a would seem
appropriate.
mimics[4] and can be involved in hydrogen-transfer reac-
tions. The best known procedure for the synthesis of 1,4-
DHP systems is the Hantzch condensation, which was set
up more than one century ago.[5] However, due to their rele-
vance, many efforts have been devoted to find new protocols
for the synthesis of wide libraries of such important com-
pounds.[6]
Results and Discussion
During our studies on the application of perchlorate salts
as powerful Lewis acids,[7] we recently reported a new
method for the synthesis of asymmetric 1,4-DHPs by a
Mg(ClO4)2 promoted addition–condensation reaction of β-
enamino carbonylic derivatives and α,β-unsaturated alde-
hydes (Scheme 1).[8]
[a] Università di Bologna, Dipartimento di Chimica Organica “A.
Mangini”,
Scheme 2.
Viale Risorgimento 4, 40136 Bologna, Italy
Fax: +39-051-2093654
E-mail: letizia.sambri@unibo.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
In the reaction depicted in Scheme 2, 1 equiv. of aniline
8a was recovered, and as such, a one-pot procedure to ob-
3970
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3970–3975

Multicomponent Domino Reaction Promoted by Mg(ClO4)2
Table 1. Reaction of ethyl acetoacetate (9a; 2 equiv.) with aniline 8a (1 equiv.) and ethyl propiolate (4; 1.2 equiv.) under various reaction
conditions.
Entry
Catalyst
Solvent
T [°C]
Time [h]
Conversion [%][a]
1
2
3
4
5
6
7
Mg(ClO4)2 (10 mol-%)/MgSO4 (20 mol-%)
Mg(ClO4)2 (10 mol-%)/MgSO4 (20 mol-%)
Mg(ClO4)2 (10 mol-%)/MgSO4 (20 mol-%)
Mg(ClO4)2 (10 mol-%)/MgSO4 (20 mol-%)
Mg(ClO4)2 (10 mol-%)/MgSO4 (20 mol-%)
Mg(ClO4)2 (5 mol-%)/ MgSO4 (20 mol-%)
Mg(ClO4)2 (10 mol-%)
CH2Cl2
CH2Cl2
THF
neat
neat
neat
r.t.
40
50
40
50
50
50
90
54
54
24
24
24
24
3
70
71
69
95
85
81
neat
1
[a] Calculated by H NMR spectroscopy.
tain 7a by starting from 2 equiv. of ethyl acetoacetate, Table 2. Reaction of keto derivatives 9 (2 equiv.) with amines 8
(1 equiv.) and ethyl propiolate (4; 1.2 equiv.).
1 equiv. of amine, and a slight excess amount of ethyl pro-
piolate (1.2 equiv.) seemed possible. In Table 1, preliminary
results to optimize the procedure are reported. Best results
were obtained when the reaction was carried out under sol-
vent-free conditions at 50 °C. In fact, the addition of a sol-
vent and/or a lower temperature decreased the reaction rate
(Table 1, Entries 1–5). As in various other procedures we
set up, the catalytic system Mg(ClO4)2 (10 mol-%)/MgSO4
(20 mol-%) proved to be the best combination: a decrease
Entry R1
Ar
Time
[h]
Product Yields of 7 (10)[a]
in the amount of Mg(ClO4)2 or the absence of MgSO4 led
to worse results (Table 1, Entries 6 and 7).
[%]
1
OEt
Ph
24
24
24
24
24
48
27
48
48
32
52
50
78
76
7a
7b
95
92
With optimal conditions in hands, the scope of the reac-
tion was investigated. The reaction worked with differently
substituted anilines. The presence of an electron-donating
substituent on the aromatic ring did not influenced the re-
activity (Table 2, Entries 1 and 2), whereas a weak deacti-
vating group diminished the yields in the desired product
(Table 2, Entries 4 and 5). In contrast, with hindered
amines, such as 1-naphthylamine or 2-substituted aniline, a
dramatic decrease in the yields of product 7 was observed
and variable amounts of side product 10 were detected
(Table 2, Entries 6–9). In particular, in the case of 2-tert-
butylaniline, only 10i was isolated and 7i was not detected
(Table 2, Entry 9).
2
3
4
5
6
7
8
9
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
(4-OMe)C6H4
(4-iPr)C6H4
(3-Cl)C6H4
(3-OH)C6H4
(2-I)C6H4
1-naphthyl
(2-Ph)C6H4
(2-tBu)C6H4
7c
7d
7e
7fA+7fS
7gA+7gS
7hA+7hS
7i
76
73 (9)
60 (7)
50 (17)
55 (22)
39 (25)
0 (27)
71
10
11
12
13
14
OtBu Ph
OtBu (4-OMe)C6H4
OtBu (3-Cl)C6H4
Me
Me
7j
7k
7l
7m
7n
70
45[b]
Ph
55[b]
(4-OMe)C6H4
57[b]
[a] Isolated yields. [b] Conversion yields almost complete.
The reaction can be performed with different keto esters,
like tert-butyl acetoacetate, obtaining comparable yields of
Concerning the reaction mechanism, a plausible explana-
7 (Table 2, Entries 10–12). Other 1,3-bidentate systems, like tion is depicted in Scheme 3. In the presence of magnesium
acetylacetone, worked well (Table 2, Entries 13 and 14), but perchlorate, which is known to be able to coordinate 1,3-
some problems arose with the purification step. Although bidentate compounds,[10] carbonyl derivative 9 rapidly con-
NMR spectroscopic analysis of the crude reaction mixture densed with the amine eliminating water and forming en-
pointed out the almost exclusive presence of the desired amino derivative 1. Compound 1 added to ethyl propiolate
product, after column chromatography, 7m,n were isolated (4) to give Michael adduct 11, as an intermediate, which
in moderate yields. Very likely, these derivatives are not very underwent a second conjugate addition from 1 to give 12.
stable on silica gel and oxidation to the pyridine salt oc- An intramolecular condensation (path a) gave desired 1,4-
curred, as in the case of 1,4-dihydropyridines such as 3.[8] DHP 7 and 1 equiv. of amine 8, which can restart the reac-
An analogous explanation can be given for the yield of tion cycle. However, when the N-substituent is too hin-
compound 7l. Unsatisfying results were obtained with ali- dered, the N-atom resulted too crowded to perform intra-
phatic amines. The reaction of 9a with benzylamine gave molecular attack on intermediate 12. Therefore, the con-
only 31% of the desired product, together with a complex densation could occur through the addition of the methyl
mixture of unidentified byproducts.
group (path b) giving rise to byproduct 10.
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L. Sambri et al.
FULL PAPER
(Figure 1). The lack of saturation transfer during the NOE
experiments confirms that the energy barrier for the in-
terconversion of the two atropisomers is larger than
20 kcalmol–1 (DFT calculations indicate an Ar–N rota-
tional barrier of about 27 kcalmol–1). The two isomers
could be separated by HPLC, and the energy barrier for the
anti–syn conversion was derived by following the rising of
the more stable isomer starting from the pure minor one.
From the first-order kinetics equation for a process at the
equilibrium, the appropriate rate constant was obtained
(details are reported in Figure S2 in the Supporting Infor-
mation) and the barrier for exchanging the more-stable
(anti) into the less-stable (syn) isomer was derived (∆G϶
23.3 kcalmol–1 at +23 °C).
=
The same approach was used in the case of iodo deriva-
tive 7f, where, at a variance with 7g, the syn isomer was
determined by NOE spectra to be the more stable isomer
Scheme 3. A plausible mechanism proposed for the reaction.
The second Michael addition on 11 very likely occurs by (Supporting Information, Figure S3). The process leading
1 and not by 9, as the first reaction, in which the formation to the interconversion of the isomers of 7f was followed by
of 7a was observed, was performed by starting from β-en- monitoring the time dependence of the NMR signal of the
amino ester 1a in an anhydrous medium; therefore, 1a could CH2 in the 4-position of the DHP ring of the pure anti
not be hydrolyzed to 9a.
isomer in CD3CN at +35 °C. The intensity of the CH2 line
It is interesting to observe that, due to the steric hin- of the anti isomer decreases, whereas that of the syn isomer
drance exerted by the two methyl groups, the plane of 1,4- begins to appear at lower field with an intensity that in-
DHP and the plane of the aromatic ring are forced to be creases until an equilibrium, corresponding to a syn:anti ra-
orthogonal to each other. When ortho- or meta-substituted tio of 60:40 (in CD3CN), is reached. In this case, the barrier
arylamines are employed in the reaction, two conformers, is higher (∆G϶ = 24.2 kcalmol–1 at +35 °C; see Figure S4
in which the substituent can be in a syn or anti relationship in the Supporting Information for details) than that of com-
with respect to the CH2 in the 4-position of the DHP ring pound 7g. Even if the two isomers are not completely stable
(see Figure 1), can thus be generated. In the cases of ortho- at room temperature (lifetime ≈19 h at +25 °C), the present
substituted amines, the energy barrier involved in the in- case represents one of the few examples of stable atropiso-
terconversion of these two isomers is sufficiently high to mers not containing a biaryl moiety.[12]
allow the observation of separate NMR signals at ambient
temperature.
When the ortho position is substituted by a phenyl group
(compound 7h), a 92:8 ratio of the two conformers is ob-
served. Again, the syn isomer was found to be more stable
by NOE experiments. DFT calculations also confirm the
lower energy of the syn conformer, even if it would appear
to be the more sterically hindered conformation. Unfortu-
nately, this compound has a lower interconversion barrier
(21.3 kcalmol–1, obtained by 1D-EXSY at +40 °C; Sup-
porting Information, Figure S5), and a physical separation
of the two conformer is not feasible.
Conclusions
Figure 1. DFT calculated syn and anti conformers of 7g. Hydrogen
atoms and OEt groups are omitted for clarity.
We developed a new and simple multicomponent domino
reaction for the synthesis of symmetric 1,4-dihydropyridines
In the case of compound 7g, the 1H NMR spectrum indi- mediated by Mg(ClO4)2. The reported process is a one-pot
cates that the two atropisomers are present in a 66:34 pro- procedure, it works under solvent free conditions, and high
portion (see spectra in the Supporting Information). DFT atom economy is observed; water is the only byproduct of
calculations[11] predict that the DHP ring resembles a pseu- the reaction. This methodology can be successfully applied
doboat conformation, and that the anti isomer should be to various β-keto derivatives and aromatic amines. When
slightly more stable than the syn isomer. NOE spectra ob- hindered amines are employed, two diastereomeric con-
tained on saturation of the CH2 in the 4-position of the formers are obtained, and they can be, in some cases, iso-
DHP ring (Supporting Information, Figure S1) confirm lated. Efforts to explore the differences in the reactivities of
that the anti isomer, where the CH2 is close to 2-H of the diastereoisomeric 1,4-DHPs and to obtain conformation-
naphthalene ring, is the more stable atropisomer in solution ally stable atropisomers are in progress in our laboratory.
3972
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3970–3975

Multicomponent Domino Reaction Promoted by Mg(ClO4)2
(q, J = 7.1 Hz, 4 H), 4.36 (t, J = 6.0 Hz, 1 H), 7.10–7.15 (m, 1 H),
7.25–7.28 (m, 1 H), 7.40–7.45 (m, 2 H) ppm. 13C NMR: δ = 14.0
(CH3), 14.1 (CH3), 18.3 (CH3), 31.1 (CH), 41.5 (CH2), 59.88 (CH2),
59.91 (CH2), 104.5 (C), 128.6 (CH), 128.9 (CH), 130.1 (CH), 130.4
(CH), 134.8 (C), 141.3 (C), 147.6 (C), 167.5 (C), 171.8 (C) ppm.
HRMS (EI): calcd. for C23H28ClNO6 449.1605; found 449.1602.
Experimental Section
General Remarks: All reactions were carried out in an air atmo-
sphere. Reagents were purchased from commercial sources and
used as received.
General Procedure for the Synthesis of 1,4-Dihydropyridines 7:
Mg(ClO4)2 (0.1 equiv., 0.075 mmol), MgSO4 (0.2 equiv.,
0.15 mmol), β-keto derivative 9 (2 equiv., 1.5 mmol), aromatic
amine 8 (1 equiv., 0.75 mmol), and ethyl propiolate (4; 1.2 equiv.,
0.9 mmol) were mixed together and heated at 50 °C. The mixture
was left to stir until TLC and GC–MS analysis revealed the reac-
tion was finished. After cooling, CH2Cl2 (10 mL) was added, and
the catalyst was filtered off. The solvent was evaporated, and the
crude mixture was purified by column chromatography on silica
gel (petroleum ether/Et2O).
Diethyl 4-(2-Ethoxy-2-oxoethyl)-1-(3-hydroxyphenyl)-2,6-dimethyl-
1
1,4-dihydropyridine-3,5-dicarboxylate (7e): Yield: 194 mg, 60%. H
NMR: δ = 1.27 (t, J = 7.2 Hz, 3 H), 1.31 (t, J = 7.2 Hz, 6 H), 1.99
(s, 6 H), 2.42 (d, J = 6.5 Hz, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 4.16–
4.28 (m, 4 H), 4.38 (t, J = 6.5 Hz, 1 H), 6.60–6.65 (m, 1 H), 6.73–
6.77 (m, 1 H), 6.90–6.95 (m, 1 H), 7.20–7.25 (m, 1 H), 8.18 (br. s,
1 H) ppm. 13C NMR: δ = 14.0 (CH3), 14.2 (CH3), 18.3 (CH3), 31.4
(CH), 41.5 (CH2), 60.1 (CH2), 60.6 (CH2), 103.2 (C), 115.8 (CH),
117.2 (CH), 121.5 (CH), 129.7 (CH), 140.8 (C), 149.0 (C), 157.8
(C), 168.0 (C), 173.2 (C) ppm. HRMS (EI): calcd. for C23H29NO7
431.1944; found 431.1946.
NMR Spectroscopy: If not specified, NMR spectra were recorded
at 400 MHz for 1H and 100.6 MHz for 13C in CDCl3. Assignments
1
of the H and 13C signals of 7f–h were obtained by bidimensional
Diethyl 4-(2-Ethoxy-2-oxoethyl)-1-(2-iodophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (7f): Yield: 203 mg, 50%. 1H
NMR (600 MHz, CDCl3): δ = 1.22 (tA, J = 7.1 Hz, 1.33 H), 1.25
(tS, J = 7.1 Hz, 1.67 H), 1.32 (tS + tA, J = 7.1 Hz, 6 H), 1.92 (sS,
3.35 H), 2.04 (sA, 2.65 H), 2.47 (dA, J = 5.4 Hz, 0.9 H), 2.64 (dS, J
= 6.6 Hz, 1.1 H), 4.07 (mS+A, 2 H), 4.15–4.25 (mS+A, 4 H), 4.37
(tA, J = 5.4 Hz, 0.45 H), 4.42 (tS, J = 6.8 Hz, 0.55 H), 7.10–7.15
(mS+A, 1 H), 7.10–7.15 (mS+A, 1 H), 7.21 (ddS, J = 7.8, 1.5 Hz, 0.55
H), 7.39 (ddA, J = 7.7, 1.5 Hz, 0.45 H), 7.42–7.45 (mS+A, 1 H), 7.93
(ddA, J = 8.0, 1.3 Hz, 0.45 H), 7.96 (ddS, J = 7.8 Hz, 1.5 0.55 H)
ppm. 13C NMR (150.8 MHz, CDCl3): δ = 14.21 (CH3,S), 14.24
(CH3,A), 14.28 (2 CH3,S), 14.33 (2 CH3,A), 18.0 (2 CH3,A), 18.7 (2
CH3,S), 31.3 (CHS), 31.5 (CHA), 42.2 (CH2,A), 44.0 (CH2,S), 59.91
(CH2,A), 59.97 (CH2,A), 59.98 (CH2,S), 60.1 (2 CH2,S), 102.2 (CA),
103.5 (CS), 104.0 (CA), 104.5 (CS), 128.9 (CHS), 130.0 (CHA), 130.1
(CHA), 130.2 (CHS), 130.7 (CHA), 132.0 (CHS), 139.97 (CHS),
139.99 (CHA), 142.6 (CS), 143.7 (CA), 146.5 (2 CS), 147.9 (2 CA),
167.8 (2 COA), 167.9 (2 COS), 171.7 (COS), 172.3 (COA) ppm.
HRMS (EI): calcd. for C23H28INO6 541.0961; found 541.0962.
experiments (g-COSY, gs-HSQC, and gs-HMBC sequences). The
NOE experiments were obtained at 600 MHz by means of the
DPFGSE-NOE[13] sequence. To selectively irradiate the desired sig-
nal, a 50-Hz wide shaped pulse was calculated with a refocusing-
SNOB shape and a pulse width of 37 ms. Mixing time was set to
1.5 to 2.0 s. 1D-EXSY spectra of 7h were obtained by using the
same DPFGSE pulse sequence, and rising the mixing time from
0.025 to 1.2 s.
Diethyl
4-(2-Ethoxy-2-oxoethyl)-2,6-dimethyl-1-phenyl-1,4-dihy-
1
dropyridine-3,5-dicarboxylate (7a): Yield: 296 mg, 95%. H NMR:
δ = 1.23 (t, J = 7.2 Hz, 3 H), 1.32 (t, J = 7.3 Hz, 6 H), 2.02 (s, 6
H), 2.44 (d, J = 6.5 Hz, 2 H), 4.08 (q, J = 7.2 Hz, 2 H), 4.21 (q, J
= 7.3 Hz, 4 H), 4.38 (t, J = 6.5 Hz, 1 H), 7.05–7.10 (m, 2 H), 7.20–
7.30 (m, 3 H) ppm. 13C NMR: δ = 14.1 (CH3), 14.2 (CH3), 18.3
(CH3), 31.2 (CH), 41.6 (CH2), 59.87 (CH2), 59.91 (CH2), 103.8 (C),
128.5 (CH), 129.2 (CH), 130.1 (CH), 140.1 (C), 148.3 (C), 167.7
(C), 171.7 (C) ppm. HRMS: calcd. for C23H29NO6 415.1994;,
found 415.1992.
Diethyl 4-(2-Ethoxy-2-oxoethyl)-2,6-dimethyl-1-(naphthalen-1-yl)-
1,4-dihydropyridine-3,5-dicarboxylate (7g): Yield: 192 mg, 55%. H
Diethyl 4-(2-Ethoxy-2-oxoethyl)-1-(4-methoxyphenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (7b): Yield: 307 mg, 92%. H
1
1
NMR (600 MHz, CDCl3): δ = 1.25 (tA, J = 7.2 Hz, 2 H), 1.24 (tS,
J = 7.2 Hz, 1 H), 1.32 (tS + tA, J = 7.1 Hz, 6 H), 1.921 and 1.923
(sA + sS, 6 H), 2.52 (dA, J = 6.0 Hz, 1.3 H), 2.65 (dS, J = 6.4 Hz,
0.7 H), 4.11 (qA, J = 7.2 Hz, 1.3 H), 4.13 (qS, J = 7.1 Hz, 0.7 H),
4.17–4.26 (mA + mS, 4 H), 4.46 (tA, J = 6.0 Hz, 0.65 H), 4.53 (tS,
J = 6.4 Hz, 0.35 H), 7.29 (ddS, J = 7.1, 1.0 Hz, 0.35 H), 7.43 (ddA,
J = 7.1, 1.2 Hz, 0.65 H), 7.51–7.62 (mA + mS, 3 H), 7.68 (mA, 0.65
H), 7.90–7.96 (mA + mS, 2.35 H) ppm. 13C NMR (150.8 MHz,
CDCl3): δ = 14.23 (CH3,A), 14.31 (CH3,S), 14.34 (CH3,A+S), 17.4
(CH3,A), 18.7 (CH3,S), 31.4 (CHA), 31.8 (CHS), 42.0 (CH2,A), 43.3
(CH2,S), 59.98 (2 OCH2,A), 60.01 (2 OCH2,S) 60.06 (OCH2,A), 60.11
(OCH2,S), 103.5 (CA), 104.1 (CS), 122.3 (CHS), 123.2 (CHA), 124.9
(CHS), 125.7 (CHA), 126.7 (CHA), 126.9 (CHS), 127.5 (CHA), 127.7
(CHA), 127.8 (CHS), 128.5 (CHS), 128.6 (CHA), 128.8 (CHS), 129.2
(CHS), 129.4 (CHA), 132.0 (CS), 132.6 (CA), 134.1 (CA), 134.3 (CS),
136.4 (CS), 137.5 (CA), 148.2 (2 CS), 149.1 (2 CA), 167.9 (2 COA),
168.0 (2 COS), 171.8 (COS), 172.2 (COA) ppm. HRMS (EI): calcd.
for C27H31NO6 465.2151; found 465.2154.
NMR: δ = 1.23 (t, J = 7.1 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 6 H), 2.04
(s, 6 H), 2.43 (d, J = 6.7 Hz, 2 H), 3.85 (s, 3 H), 4.08 (q, J = 7.1 Hz,
2 H), 4.23 (q, J = 7.1 Hz, 4 H), 4.38 (t, J = 6.7 Hz, 1 H), 6.90–7.00
(m, 2 H), 7.10–7.15 (m, 2 H) ppm. 13C NMR: δ = 14.0 (CH3), 14.1
(CH3), 18.1 (CH3), 31.1 (CH), 41.4 (CH2), 55.2 (CH3), 59.7 (CH2),
59.8 (CH2), 103.6 (C), 114.2 (CH), 130.9 (CH), 130.6 (C), 148.7
(C), 159.1 (C), 167.6 (C), 171.9 (C) ppm. HRMS (EI): calcd. for
C24H31NO7 445.2100; found 445.2100.
Diethyl 4-(2-Ethoxy-2-oxoethyl)-1-(4-isopropylphenyl)-2,6-dimethyl-
1
1,4-dihydropyridine-3,5-dicarboxylate (7c): Yield: 260 mg, 76%. H
NMR: δ = 1.23 (t, J = 7.2 Hz, 3 H), 1.28 (d, J = 6.8 Hz, 6 H), 1.31
(t, J = 7.1 Hz, 6 H), 2.02 (s, 6 H), 2.41 (d, J = 6.4 Hz, 2 H), 2.96
(h, J = 6.8 Hz, 1 H), 4.07 (q, J = 7.2 Hz, 2 H), 4.15–4.25 (m, 4 H),
4.37 (t, J = 6.4 Hz, 1 H), 7.05–7.10 (m, 2 H), 7.25–7.30 (m, 2 H)
ppm. 13C NMR: δ = 14.2 (CH3), 14.3 (CH3), 18.4 (CH3), 23.9
(CH3), 31.2 (CH), 33.7(CH), 59.9 (CH2), 60.0 (CH2), 103.8 (C),
127.2 (CH), 139.9 (CH), 137.7 (C), 148.7 (C), 149.4 (C), 167.8 (C),
172.0 (C) ppm. HRMS (EI): calcd. for C26H35NO6 457.2464; found
457.2465.
Diethyl 1-(Biphenyl-2-yl)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (7h): Yield: 144 mg, 39%. 1H
Diethyl
1,4-dihydropyridine-3,5-dicarboxylate (7d): Yield: 250 mg, 73%. H
NMR: δ = 1.23 (t, J = 7.2 Hz, 3 H), 1.31 (t, J = 7.1 Hz, 6 H), 2.03 7.1 Hz, 0.5 H), 1.50 (dS, J = 7.2 Hz, 1.84 H), 1.92 (sA, 0.24 H),
(s, 6 H), 2.44 (d, J = 6.0 Hz, 2 H), 4.08 (q, J = 7.2 Hz, 2 H), 4.21 2.07 (sS, 2.76 H), 2.45 (dA, J = 5.2 Hz, 0.16 H), 3.99 (qS, J = 7.1 Hz,
1-(3-Chlorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethyl- NMR (600 MHz, CDCl3): δ = 1.21 (tA, J = 7.1 Hz, 0.24 H), 1.23
1
(tS, J = 7.1 Hz, 2.76 H), 1.27 (tS, J = 7.1 Hz, 5.5 H), 1.28 (tA, J =
Eur. J. Org. Chem. 2008, 3970–3975
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3973

L. Sambri et al.
FULL PAPER
2.76 H), 4.06 (qS, J = 7.1 Hz, 0.24 H), 4.08–4.19 (mS+A, 4 H), 4.21
(tS, J = 7.2 Hz, 0.92 H), 4.34 (tA, J = 5.2 Hz, 0.08 H), 7.17 (m, 2.7
H), 7.29–7.51 (m, Ar, 6.2 H), 7.57 (ddA, J = 7.8, 1.6 Hz, 0.1 H)
ppm. 13C NMR (150.8 MHz, CDCl3; only the signals of the major
(m, 6 H), 6.06 (br. q, J = 1.5 Hz, 1 H), 6.85–6.90 (m, 1 H), 6.95–
7.05 (m, 1 H), 7.05–7.10 (m, 1 H), 7.22 (t, J = 8.0 Hz, 1 H),10.35
(br. s, 1 H) ppm. 13C NMR: δ = 14.1 (CH3), 14.2 (CH3), 14.4
(CH3), 24.3 (CH3), 32.7 (CH), 36.9 (CH2), 48.2 (CH), 59.6 (CH2),
conformer are reported): δ = 14.2 (CH3), 14.25 (2 CH3), 19.0 (2 60.4 (CH2), 61.1 (CH2), 94.1 (C), 118.5 (CH), 121.1 (CH), 122.8
CH3), 30.6 (CH), 41.3 (CH2), 43.9 (CH2), 59.7 (CH2), 59.9 (CH2), (CH), 123.7 (CH), 129.9 (CH), 134.5 (C), 141.0 (C), 142.1 (C),
103.6 (C), 127.8 (CH), 128.1 (CH), 128.4 (2 CH), 128.7 (2CH),
129.0 (CH), 131.4 (CH), 131.8 (CH), 137.8 (C), 138.4 (C), 142.2
(C), 147.8 (2 C), 167.9 (2CO), 171.6 (CO) ppm. HRMS (EI): calcd.
for C29H33NO6 491.2308; found 491.2306.
149.8 (C), 169.3 (C), 171.3 (C), 172.2 (C) ppm. HRMS (EI): calcd.
for C23H28ClNO6 449.1605; found 449.1603.
Diethyl 2-(2-Ethoxy-2-oxoethyl)-4-(3-hydroxyphenylamino)-6-meth-
ylcyclohexa-3,5-diene-1,3-dicarboxylate (10e): Yield: 23 mg, 7%. 1H
NMR: δ = 1.25–1.35 (m, 9 H), 1.97 (d, J = 1.5 Hz, 3 H), 2.29 (dd,
J = 14.5, 10.5 Hz, 1 H), 2.42 (dd, J = 14.5, 4.6 Hz, 1 H), 3.14 (d,
J = 1.4 Hz, 1 H), 3.87 (ddd, J = 4.5, 10.5, 1.5 Hz, 1 H), 4.10–4.25
(m, 6 H), 6.14 (br. q, J = 1.5 Hz, 1 H), 6.50–6.60 (m, 3 H), 7.13 (t,
J = 8.0 Hz, 1 H), 10.30 (br. s, 1 H) ppm. 13C NMR: δ = 14.1 (CH3),
14.2 (CH3), 14.5 (CH3), 24.3 (CH3), 32.8 (CH), 37.1 (CH2), 48.2
(CH), 59.5 (CH2), 60.4 (CH2), 61.2 (CH2), 92.6 (C), 110.3 (CH),
111.2 (CH), 115.3 (CH), 119.2 (CH), 129.9 (CH), 140.6 (C), 141.5
(C), 150.7 (C), 156.7 (C), 169.4 (C), 172.0 (C), 172.4 (C) ppm.
HRMS (EI): calcd. for C23H29NO7 431.1944; found 4311.1942.
Di-tert-butyl 4-(2-Ethoxy-2-oxoethyl)-2,6-dimethyl-1-phenyl-1,4-di-
hydro-pyridine-3,5-dicarboxylate (7j): Yield: 251 mg, 71%. 1H
NMR: δ = 1.23 (t, J = 7.0 Hz, 3 H), 1.52 (s, 18 H), 1.99 (s, 6 H),
2.41 (d, J = 6.2 Hz, 2 H), 4.09 (q, J = 7.0 Hz, 2 H), 4.32 (t, J =
6.2 Hz, 1 H), 7.15–7.20 (m, 2 H), 7.35–7.45 (m, 3 H) ppm. 13C
NMR: δ = 14.4 (CH3), 18.6 (CH3), 28.5 (CH3), 32.2 (CH), 41.9
(CH2), 60.1 (CH2), 79.9 (C), 105.5 (C), 128.7 (CH), 129.5 (CH),
130.6 (C), 140.7 (C), 147.5 (C), 167.4 (C), 172.3 (C) ppm. HRMS
(EI): calcd. for C27H37NO6 471.2621; found 471.2621.
Di-tert-butyl 4-(2-Ethoxy-2-oxoethyl)-1-(4-methoxyphenyl)-2,6-di-
methyl-1,4-dihydropyridine-3,5-dicarboxylate (7k): Yield: 263 mg,
Diethyl 2-(2-Ethoxy-2-oxoethyl)-4-(2-iodophenylamino)-6-methylcy-
clohexa-3,5-diene-1,3-dicarboxylate (10f): Yield: 69 mg, 17%. 1H
NMR: δ = 1.20–1.35 (m, 9 H), 1.96 (d, J = 1.5 Hz, 3 H), 2.31 (dd,
J = 14.5, 10.9 Hz, 1 H), 2.45 (dd, J = 14.5, 4.3 Hz, 1 H), 3.15 (d,
J = 1.5 Hz, 1 H), 3.88 (ddd, J = 4.3, 10.9, 1.5 Hz, 1 H), 4.10–4.30
(m, 6 H), 5.78 (dq, J = 1.5 Hz, 1 H), 6.75–6.80 (m, 1 H), 7.10–7.05
(m, 1 H), 7.25–7.30 (m, 1 H), 7.80–7.85 (m, 1 H), 10.24 (br. s, 1 H)
ppm. 13C NMR: δ = 14.4 (CH3), 14.5 (CH3), 14.8 (CH3), 24.5
(CH3), 33.1 (CH), 37.1 (CH2), 48.4 (CH), 59.9 (CH2), 60.6 (CH2),
61.2 (CH2), 94.0 (C), 95.0 (C), 119.3 (CH), 124.2 (CH), 125.5 (CH),
128.9 (CH), 139.6 (CH), 141.6 (C), 141.7 (C), 149.6 (C), 169.3 (C),
171.6 (C), 172.5 (C) ppm. HRMS (EI): calcd. for C23H28NO6I
541.0961; found 541.0961.
1
70%. H NMR: δ = 1.23 (t, J = 7.1 Hz, 3 H), 1.51 (s, 18 H), 1.99
(s, 6 H), 2.39 (d, J = 6.2 Hz, 2 H), 3.85 (s, 3 H), 4.08 (q, J = 7.1 Hz,
2 H), 4.30 (t, J = 6.2 Hz, 1 H), 6.90–6.95 (m, 2 H), 7.05–7.10 (m,
2 H) ppm. 13C NMR: δ = 14.1 (CH3), 18.2 (CH3), 28.2 (CH3), 31.9
(CH), 41.6 (CH2), 55.4 (CH3), 59.8 (CH2), 79.6 (C), 105.1 (C),
114.2 (CH), 131.1 (CH), 133.0 (C), 147.8 (C), 159.2 (C), 167.1 (C),
172.1 (C) ppm. HRMS (EI): calcd. for C28H39NO7 501.2726; found
501.2728.
Di-tert-butyl
1-(3-Chlorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,6-di-
methyl-1,4-dihydropyridine-3,5-dicarboxylate (7l): Yield: 170 mg,
1
45%. H NMR: δ = 1.22 (t, J = 7.3 Hz, 3 H), 1.49 (s, 18 H), 1.98
(s, 6 H), 2.40 (d, J = 6.0 Hz, 2 H), 4.07 (q, J = 7.3 Hz, 2 H), 4.27
(t, J = 6.0 Hz, 1 H), 7.08–7.13 (m, 1 H), 7.35–7.40 (m, 2 H) ppm.
13C NMR: δ = 14.2 (CH3), 18.3 (CH3), 28.2 (CH3), 32.0 (CH), 41.7
(CH2), 60.0 (CH2), 79.9 (C), 105.9 (C), 128.9 (2 CH), 130.1 (CH),
130.7 (CH), 134.9 (C), 141.8 (C), 146.7 (C), 167.0 (C), 172.1 (C)
ppm. HRMS: calcd. for C27H36ClNO6 505.2231; found 505.2233.
Diethyl 2-(2-Ethoxy-2-oxoethyl)-6-methyl-4-(naphthalen-1-ylamino)-
cyclohexa-3,5-diene-1,3-dicarboxylate (10g): Yield: 22 mg, 77%. H
1
NMR: δ = 1.20–1.40 (m, 9 H), 1.92 (d, J = 1 Hz 5, 3 H), 2.35 (dd,
J = 14.6, 10.4 Hz, 1 H), 2.51 (dd, J = 14.4, 4.2 Hz, 1 H), 3.17 (d,
J = 1.7 Hz, 1 H), 3.949 (ddd, J = 4.2, 10.4, 1.6 Hz, 1 H), 4.10–4.30
(m, 6 H), 5.78 (br. q, J = 1.5 Hz, 1 H), 7.10–7.15 (m, 1 H), 7.40–
7.55 (m, 2 H), 7.60–7.75 (m, 2 H), 7.80–7.85- (m, 1 H), 8.05–8.10
(m, 1 H), 10.79 (br. s, 1 H) ppm. 13C NMR: δ = 14.2 (CH3), 14.3
(CH3), 14.6 (CH3), 24.3 (CH3), 32.9 (CH), 37.3 (CH2), 48.3 (CH),
59.4 (CH2), 60.3 (CH2), 61.0 (CH2), 92.5 (C), 119.1 (CH), 121.4
(CH), 122.6 (CH), 125.0 (CH), 125.4 (CH), 126.30 (CH), 126.33
(CH), 128.1 (CH), 134.3 (C), 135.4 (C), 139.4 (C), 141.7 (C), 151.7
(C), 169.7 (C), 171.5 (C), 172.3 (C) ppm. HRMS (EI): calcd. for
C27H31NO6 465.2151; found 465.2153.
Ethyl 2-(3,5-Diacetyl-2,6-dimethyl-1-phenyl-1,4-dihydropyridin-4-
yl)acetate (7m): Yield: 146 mg, 55%. 1H NMR: δ = 1.24 (t, J =
7.3 Hz, 3 H), 1.98 (s, 6 H), 2.35 (d, J = 7.1 Hz, 2 H), 2.41 (s, 6 H),
4.09 (q, J = 7.1 Hz, 2 H), 4.32 (t, J = 7.1 Hz, 1 H), 7.15–7.20 (m,
2 H), 7.40–7.50 (m, 3 H) ppm. 13C NMR: δ = 14.1 (CH3), 18.7
(CH3), 29.9 (CH3), 31.7 (CH), 41.3 (CH2), 60.6 (CH2), 114.0 (C),
128.9 (CH), 129.5 (CH), 130.1 (CH), 139.8 (C), 146.2 (C), 171.6
(C), 198.8 (C) ppm. HRMS (EI): calcd. for C21H25NO4 355.1783;
found 355.1781.
Diethyl 4-(Biphenyl-2-ylamino)-2-(2-ethoxy-2-oxoethyl)-6-methylcy-
clohexa-3,5-diene-1,3-dicarboxylate (10h): Yield: 92 mg, 25%. 1H
NMR: δ = 1.15–1.30 (m, 9 H), 1.95 (d, J = 1.3 Hz, 3 H), 2.20 (dd,
J = 14.4, 10.5 Hz, 1 H), 2.37 (dd, J = 14.4, 4.1 Hz, 1 H), 3.10 (br.
s, 1 H), 3.89 (br. dd, J = 4.1, 10.5 Hz, 1 H), 4.05–4.25 (m, 6 H),
5.78 (m, 1 H), 7.05–7.10 (m, 1 H), 7.15–7.25 (m, 1 H), 7.25–7.45
(m, 7 H), 10.01 (br. s, 1 H) ppm. 13C NMR: δ = 14.1 (CH3), 14.2
(CH3), 14.4 (CH3), 24.3 (CH3), 32.8 (CH), 37.2 (CH2), 48.2 (CH),
59.2 (CH2), 60.2 (CH2), 60.9 (CH2), 93.0 (C), 119.1 (CH), 124.6
(CH), 125.4 (CH), 127.2 (CH), 127.8 (CH), 128.4 (CH), 129.2
(CH), 130.7 (CH), 136.2 (C), 136.9 (C), 138.9 (C), 141.4 (C), 150.3
(C), 168.9 (C), 171.4 (C), 172.3 (C) ppm. HRMS (EI): calcd. for
C29H33NO6 491.2308; found 491.2310.
Ethyl
2-[3,5-Diacetyl-1-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihy-
dropyridin-4-yl]acetate (7n): Yield: 164 mg, 57%. 1H NMR: δ =
1.25 (t, J = 7.0 Hz, 3 H), 1.99 (s, 6 H), 2.34 (d, J = 7.1 Hz, 2 H),
2.41 (s, 6 H), 3.86 (s, 3 H), 4.10 (q, J = 7.2 Hz, 2 H), 4.31 (t, J =
7.0 Hz, 1 H), 6.95–7.00 (m, 2 H), 7.05–7.10 (m, 2 H) ppm. 13C
NMR: δ = 14.4 (CH3), 18.9 (CH3), 30.1 (CH3), 31.9 (CH), 41.5
(CH2), 55.8 (CH3), 60.8 (CH2), 114.2 (C), 114.8 (CH), 131.1 (CH),
132.5 (C), 146.9 (C), 159.8 (C), 171.8 (C), 199.0 (C) ppm. HRMS
(EI): calcd. for C22H27NO5 385.1889; found 385.1887.
Diethyl 4-(3-Chlorophenylamino)-2-(2-ethoxy-2-oxoethyl)-6-methyl-
cyclohexa-3,5-diene-1,3-dicarboxylate (10d): Yield: 30 mg, 9%. 1H
NMR: δ = 1.20–1.35 (m, 9 H), 2.00 (d, J = 1.5 Hz, 3 H), 2.28 (dd,
J = 14.5, 10.5 Hz, 1 H), 2.42 (dd, J = 14.5, 4.5 Hz, 1 H), 3.15 (d,
J = 1.5 Hz, 1 H), 3.86 (ddd, J = 4.5, 10.5, 1.5 Hz, 1 H), 4.10–4.25
Diethyl
4-(2-tert-Butylphenylamino)-2-(2-ethoxy-2-oxoethyl)-6-
methylcyclohexa-3,5-diene-1,3-dicarboxylate (10i): Yield: 95 mg,
3974
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3970–3975

Multicomponent Domino Reaction Promoted by Mg(ClO4)2
1
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27%. H NMR: δ = 1.20–1.35 (m, 9 H), 1.40 (s, 9 H), 1.89 (d, J =
1.3 Hz, 3 H), 2.31 (dd, J = 14.4, 10.5 Hz, 1 H), 2.49 (dd, J = 14.4,
4.6 Hz, 1 H), 3.11 (d, J = 1.3 Hz, 1 H), 3.89 (ddd, J = 4.6, 10.5,
1.3 Hz, 1 H), 4.10–4.25 (m, 6 H), 5.78 (d, J = 1.3 Hz, 1 H), 6.85–
6.95 (m, 1 H), 7.10–7.20 (m, 2 H), 7.35–7.45 (m, 1 H), 10.34 (br. s,
1 H) ppm. 13C NMR: δ = 14.4 (CH3), 14.5 (CH3), 14.8 (CH3), 24.5
(CH3), 30.7 (CH3), 33.2 (CH), 35.2 (C), 37.9 (CH2), 48.7 (CH),
59.4 (CH2), 60.5 (CH2), 61.1 (CH2), 91.2 (C), 119.1 (CH), 126.0
(CH), 126.6 (CH), 126.9 (CH), 129.7 (CH), 138.1 (C), 142.1 (C),
145.4 (C), 151.9 (C), 169.9 (C), 171.7 (C), 172.6 (C) ppm. HRMS
(EI): calcd. for C27H37NO6 471.2621; found 471.2623.
Calculations: Computations were carried out at the B3LYP/6-
31G(d) level by means of the Gaussian 03 series of programs:[11]
the standard Berny algorithm in redundant internal coordinates
and default criteria of convergence were employed. The reported
energy values are not ZPE corrected. Harmonic vibrational fre-
quencies were calculated for all the stationary points. For each opti-
mized ground state the frequency analysis showed the absence of
imaginary frequencies.
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C
Acknowledgments
This research was carried out within the framework of the National
Project “Stereoselezione in Sintesi Organica” supported by MIUR,
Rome.
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Received: April 29, 2008
Published Online: July 9, 2008
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Eur. J. Org. Chem. 2008, 3970–3975
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