TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 5591±5595
A new synthetic approach to N-substituted 1,4-dihydropyridines
Ana I. De Lucas,a Javier FernaÂndez-Gadea,b Nazario MartõÂna,p and Carlos Seoanea,p
a
Facultad de QuõÂmica, Departamento de QuõÂmica OrgaÂnica, Universidad Complutense, E-28040 Madrid, Spain
Departamento de InvestigacioÂn BaÂsica, Janssen-Cilag S.A., C/Jarama s/n, PolõÂgono Industrial, E-45007 Toledo, Spain
b
Received 13 February 2001; revised 27 March 2001; accepted 20 April 2001
AbstractÐSome novel N-substituted 1,4-dihydropyridines (DHPs) (15a±d) have been synthesized by reaction of 2-amino-5-formyl-4Hpyran (10) with primary amines. Formation of 1,4-DHPs involves ring cleavage of the 4H-pyran ring by nucleophilic attack of the respective
amine and subsequent 6-exo-dig cyclization. Treatment of the pyran system 10 with hydrazines under the same reaction conditions leads,
however, to the corresponding hydrazone derivatives 12a,b. Two different reaction routes are observed depending whether the amine or
hydrazine derivative is used as nucleophilic reagent. A competition between 1,4 versus 1,2 addition reaction pathway is proposed. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
Since Nifedipine (1) was successfully introduced in the
market at the beginning of 1975 for the treatment of
coronary diseases,1 there has been a great deal of attention
in the study of 4-aryl-1,4-dihydropyridines (DHPs) as a
consequence of their pharmacological activity as the most
important class of the calcium channel modulators.2±4 To
this day, many chemical modi®cations have been carried out
on the DHP ring looking for drugs with longer bioavailability or greater tissue selectivity. The presence of different
substituents5 or heteroatoms6 (2) has allowed an expansion
of the structure±activity relationship thus getting a better
insight into the molecular interactions at the receptor
level. The knowledge of stereochemical/conformational
requirements for activity7 requires the study of other related
analogues of the DHP ring. In this regard, it has been
reported8 the synthesis of modi®ed structures bearing nitro
and fused lactone groups on the DHP ring (3,4). These
exhibit calcium agonist effects opposite to those of the
calcium antagonists 1 and 2.
Starting from a pyran ring suitably functionalyzed with a
reactive conjugated carbonyl system (10) and different
primary amines, we report in this paper a novel simple
one-step synthesis of previously unknown DHPs (15a±d)
with a substituted nitrogen atom. A complex mechanistic
pathway is proposed to explain this transformation. The
synthesis of hydrazone derivatives (12a,b) starting from
the same pyran system 10 and hydrazines is also discussed
(Chart 1).
Keywords: 1,4-dihydropyridines; cyclization; hydrazines; 4H-pyrans.
p
Corresponding authors. Tel.: 134-91-3944227; fax: 134-91-3944103;
e-mail:
[email protected]
Chart 1.
2. Results and discussion
The preparation of the new 5-formyl-4H-pyran 10 is
depicted in Scheme 1. The synthetic sequence starts from
commercially available propargylic alcohol (5) by oxidation
with cromium trioxide/sulfuric acid in butanone at 08C to
afford propynal (6) which was obtained in a considerably
lower yield than described in the literature (91%),9 despite
different attempts carried out in order to optimize this
reaction step (solvents with higher boiling point such as
pentanone, different Vigreux columns in the puri®cation
process, mechanical stirring instead of magnetic stirring,
PCC as the oxidizing reagent).
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0040-402 0(01)00463-X
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A. I. De Lucas et al. / Tetrahedron 57 (2001) 5591±5595
Scheme 1.
Addition of dry dimethylamine to a solution of propynal (6)
in dry methanol yielded 3-dimethylaminopropenal (7),10
which on reaction with dimethylamine perchlorate gave
3-dimethylaminopropenylidenedimethylammonium
perchlorate (8).10 Treatment of 8 with benzaldehyde in acetic
anhydride at 08C using perchloric acid as the catalyst,
followed by acidic hydrolysis afforded benzylidenemalonaldehyde (9).11 Finally, Michael addition of malononitrile to
the dialdehyde 9 led to 5-formyl-4H-pyran (10) in a
moderate yield (46%).
It should be pointed out that formation of the corresponding
1,2-addition product to the carbonyl group was not observed
to any extent, which is in agreement with other previously
reported results.12
Pyran 10 shows in the IR spectrum the presence of the
p-conjugated formyl and cyano groups at 1665 and
2210 cm21, respectively. In the 1H NMR spectrum the aldehyde group appears as a singlet at 9.36 ppm. The amino
group gives rise to a signal at 4.58 ppm as a broad singlet.
The hydrogen atom at position C-6 in the 4H-pyran ring
appears in the aromatic region at 7.31±7.22 ppm. The signal
at 4.42 ppm reveals the presence of the proton (H-4)
attached to the sp3 carbon atom of the 4H-pyran ring.
Scheme 2.
Due to the scarcity of available information on the 13C NMR
spectra of these compounds,13 we have carried out the
assignments of the signals of the pyran system 10 based
on a 13C NMR study of 4H-pyran derivatives14 and by
recording off-resonance and DEPT experiments. It is
worth mentioning the signal at 57.6 ppm due to the ole®nic
carbon C-3 of the pyran ring. The chemical shift of this
carbon is rather unusual for a sp2 carbon, as a result of the
combined effects of the O, NH2 and CN groups, and is
probably among the lowest ever observed for an ethylenic
carbon. This ®nding has been previously observed in other
related molecules.15
The novel 2-amino-4H-pyran bearing an easily
functionalizable carboxaldehyde group at C-5 position
(10) can be considered as a key compound for further
derivatizations. In this regard, we decided to study the
behavior of such 4H-pyran ring in the presence of
different hydrazine and amine derivatives. Thus, treatment of formyl containing pyran 10 with hydrazines
(11a,b) in re¯uxing ethanol led to the corresponding
hydrazone derivatives 12a,b by means of a 1,2 addition
process to the conjugated carbonyl system (Scheme 2).
Compounds 12a±b were obtained as stable solids in
moderate yields (41±65%).
A. I. De Lucas et al. / Tetrahedron 57 (2001) 5591±5595
5593
Scheme 3.
The IR spectra of derivatives 12a,b show several bands at
3480±3180 cm21 corresponding to both hydrazone and
amino groups. The stretching vibration of the conjugated
cyano group appears at 2200 cm21. The protons HCvN
and HCvC can be observed as multiplets in the aromatic
region of the 1H NMR spectra. Compound 12b shows the
NH2 protons at 6.89 ppm as a broad singlet. The proton on
C-4 appears at 4.40±4.13 ppm. Off-resonance and DEPT
experiments have allowed the assignments of the signals
of the 13C NMR spectra. Neither of the above techniques
allows us to establish unambiguously the signals corresponding to both C-6 and HCvN, which appear in the
off-resonance spectrum, as doublets with a coupling
constant 160±196 Hz. The ®nal assignment has been
achieved taking into account the theoretical values which
predict a higher deshielding for the HCvN proton.
In view of the fact that reaction with hydrazines brings
about the formation of hydrazone derivatives 12, treatment of pyran 10 with different amines (13a±d) should
lead to the corresponding Schiff bases. However, in this
case, the novel 1,4-dihydropyridines 15a±d were
isolated as the only reaction products in 30±51% yields
(Scheme 3).
The reaction can be rationalized by the cleavage of the
pyran ring by nucleophilic attack of the amine at the
electron de®cient C-6 position, followed by the favored
6-exo-dig cyclization.16 This cyclization involves nucleophilic attack by the amino group at the cyano group in the
non-isolated open-chain intermediate 14. The ®nal imino±
enamino tautomerism gives the dihydropyridine systems
15a±d.
The different behavior of the pyran system 10 towards
hydrazines 11 and amines 13 can be explained considering
the nature of the nucleophilic reagent employed in the
reaction. Thus, when hydrazine compounds are used, a 1,2
addition process to the carbonyl system takes place due to
the high stability of the corresponding hydrazones which
quickly precipitate from the reaction mixture. On the
other hand, the Schiff bases resulting from the 1,2 addition
of amines to the formyl containing pyran 10 should not be as
stable as the hydrazones and a 1,4 competitive conjugated
addition is preferred, yielding the ®nal 1,4-dihydropyridines
15a±d.
The IR spectra of compounds 15a±d show two bands at
1680±1625 cm21 corresponding to both formyl and
carbamoyl groups. 1H NMR and 13C NMR data of the
novel compounds 15a±d are given in Tables 1 and 2,
respectively.
Table 1. 1H NMR spectroscopic data of N-substituted 1,4-dihydropyridines (15a±d)
Compound
15a
15b
15c
15d
NH2
CONH2
CHO
H-4
Arom/H-6
4.98 (s)
5.00 (s)
5.00 (s)
4.95 (s)
6.84 (s)
6.82 (s)
6.83 (s)
6.83 (s)
9.15 (s)
9.18 (s)
9.15 (s)
9.17 (s)
4.82 (s)
4.83 (s)
4.80 (s)
4.80 (s)
7.53±7.24 (m)
7.57±7.26 (m)
7.51±7.26 (m)
7.43±7.21 (m)/6.78 (s)
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A. I. De Lucas et al. / Tetrahedron 57 (2001) 5591±5595
Table 2. 13C NMR spectroscopic data of N-substituted 1,4-dihydropyridines (15a±d)
Compounds
15a
15b
15c
15d
a
C-2
C-3
C-4
C-5
C-6
149.9
150.5
151.0
150.2
80.7
80.7
80.1
80.9
34.8
36.6
36.6
34.4
120.4
121.3
120.7
120.0
147.9
145.6
146.4
148.8
CONH2 CHO
Cipsoa
171.4
172.1
172.3
164.4
146.6
144.8
145.1
146.3
188.7
188.3
188.4
171.3
Carbon atom of the R group directly linked to the nitrogen atom of the
1,4-dihydropyridine.
The signals of the 13C NMR spectra have been unambiguously assigned by off-resonance and DEPT experiments
and, in some cases, by HMBC techniques.
In summary, we report the synthesis of N-substituted 1,4dihydropyridines 15a±d as novel modi®ed DHP rings by
ring transformation of the formyl-containing 2-amino 4Hpyran 10 by reaction with amines. This pyran system,
synthesized for the ®rst time by means of a multi-step
reaction procedure, has also been allowed to react with
hydrazines to form the respective hydrazone derivatives
(12a,b) in which the pyran skeleton is preserved.
The novel N-substituted 1,4-DHPs are suitably functionalized for further chemical transformations.
3. Experimental
3.1. General
Melting points were determined in a capillary tube in a
Thermolab apparatus and are uncorrected. 1H and 13C
NMR spectra were measured with a Varian Unity XL-300
and a Bruker AC-200. The IR spectra were recorded with a
Perkin±Elmer 781 Spectrophotometer. Microanalyses were
performed by the Servicio de MicroanaÂlisis of Universidad
Complutense de Madrid.
3.1.1. 2-Amino-3-cyano-4-phenyl-4H-pyran-5-carboxaldehyde (10). A solution of benzylidenemalonaldehyde11
(0.01 mol) in ethanol (30 mL) containing a few drops of
piperidine was treated with malononitrile (0.66 g,
0.01 mol). The reaction mixture was stirred for a few
minutes. The solid product so formed, was collected by
®ltration and crystallized from ethanol. 46% yield, mp
1928C (dec.). IR (KBr disk) n (cm21): 3360, 3310, 3195
(N±H), 2880, 2210 (CuN), 1665 (CvO), 1605, 1495,
1455, 1405, 1380, 1300, 1225, 1195. 1H NMR (CDCl3,
300 MHz) d : 9.36 (s, 1H, CHO), 7.31±7.22 (m, 6H, 5
ArH and HCvC), 4.58 (s broad, 2H, NH2), 4.42 (s, 1H,
H-4). 13C NMR (DMSO, 75 MHz) d : 189.7 (CHO), 158.7
(C-2), 157.3 (C-6), 143.6 (C-1 0 ), 128.4 (C-2 0 ), 127.4 (C-3 0 ),
126.9 (C-4 0 ), 121.6 (C-5), 119.6 (CN), 57.6 (C-3), 34.9 (C4). C13H10O2N2: calcd. C 69.02; H 4.46; N 12.38; found C
68.54; H 4.61; N 12.30.
3.2. Synthesis of hydrazone and p-tosylhydrazone
derivatives (12a,b). General procedure
A suspension of 2-amino-3-cyano-4-phenyl-4H-pyran-5carboxaldehyde (10) (100 mg, 0.44 mmol) in ethanol
(15 mL) was heated until total solution of the starting
material. The corresponding hydrazine derivative (11a,b)
(0.44 mmol) was added and the reaction mixture was
re¯uxed for a variable time (2±5 h), then allowed to cool
to room temperature. The solid product formed was
collected by ®ltration in good purity.
3.2.1. Phenylhydrazone of 2-amino-3-cyano-4-phenyl4H-pyran-5-carboxaldehyde (12a). 65% yield, mp 215±
2178C. IR (KBr disk) n (cm21): 3480, 3380, 3290 (N±H and
NH2), 2200 (CuN), 1670 (CvC), 1625, 1590 (CvN and
H2N±CvCuN), 1575, 1495, 1400, 1260, 1240, 1180,
1125, 910. 1H NMR (DMSO, 300 MHz) d : 9.99 (s, 1H,
NH), 7.35±6.65 (m, 14H, 10 ArH, NH2, HCvN and
HCvC), 4.40 (s, 1H, H-4). 13C NMR (DMSO, 75 MHz)
d : 159.1 (C-2), 144.8, 144.7 (arom), 140.0 (HCvN),
132.5 (C-6), 128.5, 127.7, 126.9, 125.9 (arom), 119.9
(CN), 117.9 (arom), 117.6 (C-5), 111.2 (arom), 57.0 (C3), 36.7 (C-4). C19H16ON4: calcd C 72.15; H 5.06; N
17.72; found C 72.04; H 5.10; N 17.79.
3.2.2. p-Tosylhydrazone of 2-amino-3-cyano-4-phenyl4H-pyran-5-carboxaldehyde (12b). 41% yield, mp 198±
1998C. IR (KBr disk) n (cm21): 3440, 3340, 3180 (N±H and
NH2), 2200 (CuN), 1670 (CvC), 1640, 1600 (CvN and
H2N±CvCuN), 1500, 1410, 1320, 1235, 1170, 1060, 960.
1
H NMR (DMSO, 300 MHz) d : 11.10 (s, 1H, NH), 7.45±
7.01 (m, 11H, 9 ArH, HCvN and HCvC), 6.89 (s broad,
2H, NH2), 4.13 (s, 1H, H-4), 2.35 (s, 3H, CH3). 13C NMR
(DMSO, 75 MHz) d : 159.0 (C-2), 144.1, 143.5, 143.4
(arom), 142.5 (HCvN), 135.5 (C-6), 129.0, 127.8, 126.7,
126.5, 126.1 (arom), 119.6 (CN), 116.3 (C-5), 56.7 (C-3),
35.9 (C-4), 20.1 (CH3). C20H18O3N4S: calcd C 60.91; H
4.57; N 14.21; found C 60.88; H 4.79; N 14.08.
3.3. Synthesis of N-substituted 1,4-dihydropyridine
derivatives (15a±d). General procedure
A suspension of 2-amino-3-cyano-4-phenyl-4H-pyran-5carboxaldehyde (10) (100 mg, 0.44 mmol) in ethanol
(15 mL) was heated until total solution. The corresponding
amine (13a±d) (0.44 mmol) was added and the reaction
mixture was re¯uxed for 2±6 h, then allowed to cool to
room temperature. The solid that precipitated was isolated
by ®ltration with high purity.
3.3.1. 2-Amino-3-carbamoyl-5-formyl-1,4-diphenyl-1,4dihydropyridine (15a). 38% yield, mp 209±2118C. IR
(KBr disk) n (cm21): 3480, 3400, 3310, 2870, 2840, 1675,
1650, 1585, 1470, 1385, 1255, 1190, 1180, 1080. 1H NMR
(CDCl3, 300 MHz) d : 9.15 (s, 1H, CHO), 7.53±7.24 (m,
11H, 10 ArH and H-6), 6.84 (s, 2H, CONH2), 4.98 (s, 2H,
NH2), 4.82 (s, 1H, H-4). 13C NMR (DMSO, 50 MHz) d :
188.7 (CHO), 171.4 (CONH2), 149.9 (C-2), 147.9 (C-6),
146.6 (Carom ±N), 139.0, 129.8, 128.4, 127.7, 127.4, 127.3,
125.7 (arom), 120.4 (C-5), 80.7 (C-3), 34.8 (C-4).
C25H22ON4: calcd C 76.11; H 5.62; N 14.21; found C
75.97; H 5.29; N 13.97.
3.3.2. 2-Amino-3-carbamoyl-1-(p-chlorophenyl)-5-formyl4-phenyl-1,4-dihydropyridine (15b). 40% yield, mp 188±
1898C. IR (KBr disk) n (cm21): 3480, 3460, 3140, 2830,
1680, 1655, 1580, 1480, 1400, 1250, 1190, 1095, 1020. 1H
A. I. De Lucas et al. / Tetrahedron 57 (2001) 5591±5595
NMR (CDCl3, 300 MHz) d : 9.18 (s, 1H, CHO), 7.57±7.26
(m, 10H, 9 ArH and H-6), 6.82 (s, 2H, CONH2), 5.00 (s, 2H,
NH2), 4.83 (s, 1H, H-4). 13C NMR (CDCl3, 75 MHz) d :
188.3 (CHO), 172.1 (CONH2), 150.5 (C-2), 145.6 (C-6),
144.8 (Carom ±N), 137.0, 135.7, 130.7, 129.1, 128.8, 127.6,
127.1 (arom), 121.3 (C-5), 80.7 (C-3), 36.6 (C-4).
C19H16O2N3Cl: calcd C 64.59; H 4.53; N 11.90; found C
64.28; H 4.38; N 11.89.
3.3.3. 2-Amino-3-carbamoyl-5-formyl-4-phenyl-1-(p-tolyl)1,4-dihydropyiridine (15c). 30% yield, mp 199±2008C. IR
(KBr disk) n (cm21): 3440, 3360, 1650, 1570, 1510, 1475,
1410, 1375, 1330, 1255, 1190, 1110, 1030. 1H NMR
(CDCl3, 300 MHz) d : 9.15 (s, 1H, CHO), 7.51±7.26 (m,
10H, 9 ArH and H-6), 6.83 (s, 2H, CONH2), 5.00 (s, 2H,
NH2), 4.80 (s, 1H, H-4), 2.45 (s, 3H, CH3). 13C NMR
(CDCl3, 75 MHz) d : 188.4 (CHO), 172.3 (CONH2), 151.0
(C-2), 146.4 (C-6), 145.1 (Carom ±N), 140.0, 135.8, 131.0,
128.7, 127.6, 127.5, 127.0 (arom), 120.7 (C-5), 80.1
(C-3), 36.6 (C-4), 21.3 (CH3). C20H19O2N3: calcd C 72.07;
H 5.71; N 12.61; found C 71.76; H 6.06; N 12.44.
3.3.4. 2-Amino-1-benzyl-3-carbamoyl-5-formyl-4-phenyl1,4-dihydropyridine (15d). 51% yield, mp 200±2028C. IR
(KBr disk) n (cm21): 3450, 3340, 3160, 1670, 1625, 1490,
1460, 1390, 1260, 1205, 1190, 1150, 1100. 1H NMR
(CDCl3, 300 MHz) d : 9.17 (s, 1H, CHO), 7.43±7.21 (m,
10H, ArH), 6.83 (s, 2H, CONH2), 6.78 (s, 1H, H-6), 4.95
(s, 2H, NH2), 4.87 (d, 1H, J26.4 Hz, CH2), 4.82 (d, 1H,
J26.4 Hz, CH2), 4.80 (s, 1H, H-4). 13C NMR (DMSO,
75 MHz) d : 171.3 (CHO), 164.4 (CONH2), 150.2 (C-2),
148.8 (C-6), 146.3 (Carom ±CH2N), 136.6, 128.1, 127.2,
127.1, 126.9, 126.8, 125.3 (arom), 120.0 (C-5), 80.9
(C-3), 51.3 (CH2N), 34.4 (C-4). C20H19O2N3: calcd C
72.07; H 5.71; N 12.61; found C 71.82; H 5.88; N 12.28.
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Carlos Seoane