A straightforward synthesis and structure of unprecedented iminium salts of dihydropyrido[3,2-e][1,3]thiazines

Tetrahedron 62 (2006) 1365–1371

A straightforward synthesis and structure of unprecedented iminium salts of dihydropyrido[3,2-e][1,3]thiazines Margarita Sua´rez,a,* Hector Novoa,b,* Yamila Verdecia,a Estael Ochoa,a Amaury Alvarez,a,c Rolando Pe´rez,c Roberto Martı´nez-Alvarez,d Dolores Molero,e Carlos Seoane,d Norbert M. Blaton,b Oswald M. Peetersb and Nazario Martı´nd,* a

Laboratorio de Sı´ntesis Orga´nica, Facultad de Quı´mica, Universidad de La Habana, 10400-Ciudad Habana, Cuba b Laboratorium voor Analytische Chemie en Medicinale Fysicochemie, Faculteit Farmaceutische Wetenschappen, K.U. Leuven, Van Evenstraat 4, B-3000 Leuven, Belgium c Instituto Cubano de Investigaciones de los Derivados de la Can˜a de Azu´car, 10400-Ciudad Habana, Cuba d Departamento de Quı´mica Orga´nica, Facultad de Ciencias Quı´micas, Universidad Complutense, E-28040 Madrid, Spain e CAI de Resonancia Magne´tica Nuclear, Facultad de Ciencias Quı´micas, Universidad Complutense, E-28040 Madrid, Spain Received 29 September 2005; revised 8 November 2005; accepted 16 November 2005 Available online 19 December 2005

Abstract—Unprecedented 2-iminium chloride salts of 5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazines derivatives (8) were easily synthesized in one step from the corresponding o-chloroformyl-1,4-dihydropyridine (2) and thiourea. The structural study has been carried out by X-ray crystallography and theoretical calculations at the B3LYP/6-31G* levels and reveal that the new salts exhibit appropriate structural features to behave as calcium channel modulators. q 2005 Elsevier Ltd. All rights reserved.

1. Introduction 1,3-Thiazines are an important type of heterocycles showing a wide variety of pharmacological properties. Thus, 1,3thiazine derivatives have recently been reported as cholecystokinin antagonists1 or antimycobacterial agents.2 Fused thiazines such as those incorporating a pyridine nucleus have shown anticancer,3 antitumor,4 and antioxidant activities.5 On the other hand, 1,4-dihydropyridine derivatives (1,4DHPs) form a class of heterocyclic compounds with interesting pharmacological and biological properties.6 The systematic structural modification of the 1,4-DHP ring yields different compounds used in the treatment of hypertension and angina pectoris.7 The most prominent of these compounds is Nifedipine, which was the first generation calcium channel blocker marketed by Bayer.8 Keywords: 2-Imino pyrido[3,2-e][1,3]thiazines; X-ray analysis; 1,4Dihydropyridines; Iminium salts. * Corresponding authors. Tel.: C53 7 878 1398; fax: C53 7 873 5737 (M.S.); tel.: C32 16 323427; fax: C32 16 323469 (H.N.); tel.: C34 91 394 4332; fax: C34 91 394 4103 (N.M.); e-mail addresses: [email protected]; [email protected]; [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.11.054

Since then, a wide variety of novel compounds belonging to the second and third generations of new biological active substances from 1,4-DHP class have been developed in order to obtain larger bioavailability or greater tissue selectivity.9 Up to now, 1,4-DHPs are still the most potent group of calcium channel modulators and, therefore, the design and study of this class of compounds remains highly desirable.10 Very recently, new 4-aryl-1,4-dihydropyridines have been investigated as P-glycoprotein inhibitors11 and N-alkoxycarbonylmethyl derivatives of 1,4-dihydropyridine-3,5dicarboxylate were reported to act as a new carrier system for delivering drugs to the brain.12 The above studies clearly show that the 1,4-DHP nucleus appears to be a unique structure interacting with a wide variety of channels and receptors, thus being considered as a class of privileged pharmacophoric structures.9 Pyridothiazine derivatives have been synthesized by tedious multi-step procedures,13 and were patented as pharmacological agents.14 Recently, the antiepileptic properties of pyrido-1,3-thiazin-4-one derivative have been reported.15 In previous works we have reported the synthesis of 6-chloro-5-formyl-1,4-dihydropyridines (2), which were

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obtained from the corresponding 2(1H)pyridone 1.16 1,4Dihydropyridine 2 proved to be an excelent candidate for further transformations into other heterocyclic-fused 1,4dihydropyridines such as pyrazolo[3,4-b]pyridines 316 and 4,7-dihydrothieno[2,3-b]pyridines 4.17 Recently, we carried out the synthesis of novel fulleropyrrolidines 5 bearing biologically active 1,4-DHPs covalently connected to the fullerene core, from the corresponding 1,4-DHP 218 (see Chart 1).

O

Ar

H3C

N H

O

CHO

H3C

N H

H3C

1

2 Ar

Ar ROOC

ROOC

COOEt

N H3C

N H

N H

H3C

N H

3

S

CHO

RO

N H 1

H3C

O

N H 2

Cl

S H 2N

H 3C

Cl

Ar

ultrasound 2h at 70°C

Ar

O N

RO

Ar ROOC

POCl3/DMF/DCM

RO

O

ROOC

O

Ar

N H

S 8

NH2

Ar N

RO NH2 Cl

6

.. H 3C

N H

Cl S

..NH2

7 a, b, c, d, e, f, g,

Ar = C6H5 Ar = 3-NO2C6H4 Ar = 4-COOCH3C6H4 Ar = C6H5 Ar = 2-ClC6H4 Ar = 3-NO2C6H4 Ar = 4-COOCH3C6H4

R = CH2CH3 R = CH2CH3 R = CH2CH3 R = CH3 R = CH3 R = CH3 R = CH3

4 COOR

Ar H3C N

CH3 N Cl

H

5

Chart 1.

2. Results and discussion In this paper, we report on the synthesis of novel 2-iminodihyropyrido[3,2-e][1,3]thiazines (8), a class of unprecedented compounds, which are readily available from 6-chloro-5-formyl 1,4-dihydropyridines (2) by reaction with thiourea. Compounds 2 were obtained as previously reported,16 from the corresponding methyl 2-oxo-1,2,3,4-tetrahydropyridine-5-carboxylate (1) via Vilsmeier-Haack chloroformylation. Even though this procedure allows the preparation of the desired 6-chloro-5-formyl 1,4-DHP in a straightforward fashion, we have made some modifications in order to simplify the experimental work. The new chloroformylation methodology involved the interaction of the halomethylenium salt, formed in situ from POCl3 and DMF, with alkyl 4-aryl-6-methyl-2-oxo1,3,3,4-tetrahydropyridine-5-carboxylate 1 in DCM at room temperature. Further irradiation of the reaction mixture in an ultrasonic bath at 70 8C for 2 h and subsequent hydrolysis afforded the desired 6-chloro-5formyl 1,4-DHP derivative 2 in good yields (Scheme 1). After washing twice with small portions of cold ether, the crude solid was obtained with excellent purity, as determined by TLC and RP-HPLC (O98%, based on the integration peak area at 226 nm).

Scheme 1. 2-Iminopyrido[3,2-e][1,3]thiazines synthesized 8a–g.

The ultrasonic-based methodology possesses important improvements over our previously reported conventional Vilsmeier-Haack chloroformylation. The reaction times were notably reduced, the final product was obtained with an excellent purity, and hence, it could be used in further synthetic steps without the need of wasteful purification. The structures of compounds 2 were confirmed by spectroscopic methods and are in agreement with previously reported data.16 The synthesis of the 2-iminopyrido[3,2-e][1,3]thiazines 8a–g was readely accomplished by refluxing the appropriate alkyl 4-aryl-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3carboxylate 2a–g with an equivalent amount of thiourea in dry ethanol under an inert atmosphere (Scheme 1). After a few minutes, the iminium chloride that precipitated from the reaction medium, was filtered off and washed with hot ethanol and dried. Formation of the 1,3-thiazine ring can be accounted for by nucleophilic attack of the amino group in the thiourea at the formyl group in 2, followed by a dehydration to yield the intermediate 7. Subsequent attack of the sulfur atom with loss of a HCl molecule affords compounds 8, via a 6-endotrig cyclization,19 as stable crystaline solids in moderate to good yields (Scheme 1). Compounds 8a–g show a satisfactory analytical and spectroscopic data. The FTIR spectra of compounds 8 present the amino and carbonyl signals at 3360 and 3200 cm K1 (NH) and 1690–1700 cm K1 (C]O). In addition, the C]N signal appears at 1645 cmK1. The 1H NMR (300 MHz) spectra of 2-iminiumpyrido[3,2e][1,3]thiazine chloride derivatives 8a–g show a very similar pattern. Assignment of the signals was ascertained by 1D and 2D NMR experiments. The NH and –C]NHC 2 protons appear as broad singlets at w12.6, 10.6 and w10.3 ppm. The vinyl proton on C4, H5 and the methyl

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with puckering parameters (N8–C7–C6–C5–C4a–C8a)23 ˚ , qZ105.9(19)8 and 4Z8(2)8 and a weighted QZ0.185(6) A ˚ . The ring conformation average bond distance of 1.420(3) A represents 31% of puckering in ideal cyclohexane chair (17% chair with N8 pointing up, 24% twist boat with axis through C8A and C4A pointing up, and 59% boat with bowsprit at N8 pointing down). The bisection of the aromatic ring at C5 with respect to the DHP, described by torsion angle C6–C5–C1 0 –C2 0 , displays a value of 71.2(8)8, showing that the plane of the phenyl ring bisects the pyridine ring. The torsion angle C1 0 –C5–C4a–C8a of 106.7(6)8 shows that the phenyl ring is in axial position. The ester group at C6 was found to be nearly coplanar with the nearest endocyclic double bond in the DHP ring and having the carbonyl group at C10 in a trans (ap) disposition with respect it.

group on C7 were observed as a singlet at d 8.4–8.8, w5 and w2.4 ppm, respectively. The signals between 7.0–8.5 ppm correspond to the protons of the aromatic ring on C5, showing the characteristic multiplicity depending on the position of the substituent. The 13C NMR spectra of these compounds (8a–g) exhibit signals in the carbonyl, aromatic and aliphatic region. In order to unequivocally assign the signals corresponding to the heterocyclic ring, we used 1D and 2D techniques: DEPT(135), HMQC and HMBC. The signals corresponding to the carbon atoms of the bicyclic ring are relatively insensitive to the nature of the substituent on the phenyl ring. Around 165–166 ppm appears the signal corresponding to the carbonyl group, and the signal corresponding to C4 and C2 at 166–167 and w155 ppm, respectively. C4a (106–107 ppm) and C6 (107–108 ppm) appear at lower d values than those expected for typical olefinic carbon atoms, whereas C7 and C8a appear at higher d values, 143–144 and w167 ppm, respectively. These findings have been accounted for by the strong push–pull effect of the groups linked to the olefinic double bond, similarly to that observed previously in other related molecules.20 C5 appears at 39–40 ppm and the rest of signals are in agreement with the nature of each particular aromatic or aliphatic carbon atoms (see Section 4).

The thiazine ring has puckering parameters (S1–C2– ˚ , qZ70(3)8 and 4Z N3–C4–C4a–C8a):23 QZ0.117(5) A 31(3)8 and can be described as screw boat with axis through N3 and C4 pointing up. This ring conformation represents 18% puckering of an ideal cyclohexane chair (22% chair with S1 pointing up, 76% twist boat with axis through N3 and C4 pointing up, and 2% boat with bowsprit at C2 pointing down). The weighted average bond distance in this ˚ . The distances involving the S atom in ring is 1.526(3) A ˚ and the heterocyclic ring are: d(S1-C2(sp2))Z1.757(6) A 2 ˚ d(S1-C2(sp ))Z1.726(6) A. The bond angles around C2 shows the sp2 character of this atom [S1–C2–N3: 123.3(5)8, S1–C2–N9: 116.8(5)8, N3–C2–N9: 119.8(6)8. Figure 1 shows the solid state conformation of 8a, together with the atomic numbering scheme. Figure 2 shows the projection of the molecules of 8a in the unit cell, denoting the hydrogen bonds that involves the Cl atom. The molecules are packed by means of hydrogen bonds. The Cl atom is involved in three hydrogen bonds of the type N/ Cl, one intramolecular (Fig. 1) and the others with two neighboring host molecules, resembling a propeller shape arrangement with the Cl atom in the centre and forming an infinite one-dimensional chain along the [001] direction. Intramolecular hydrogen bonds: N8–H8/Cl with N8/ ˚ and N8–H8/ClZ1718. Intermolecular ClZ3.145(5) A hydrogen bonds: N9–H9A/Cl (xC1, y, z) with N9/ ˚ and N9–H9A/ClZ1718, and N9–H9B/ ClZ3.235(6) A ˚ and A ˚ Cl (xC1/2, KyK1/2, Kz) with N9/ClZ3.126(5) A and N9–H9B/ClZ1708.

The mass spectra under EI conditions of the 2-iminiumpyrido[3,2-e][1,3]thiazine chlorides (8) show the [MKHCl]C ions with low intensity. The loss of the aryl substituent on C5 gives the pyrylium ion as the base peak of the spectra in m/zZ250 for 8a–c and m/zZ236 for 8d–g. This spectrometric behaviour under EI conditions is similar to those reported for analogous structures.21 In order to gain a better understanding of the novel compounds, and to confirm their molecular structure, we have carried out X-ray diffraction studies. Single crystals of 8a were obtained from slow evaporation in methanol solution. From a search in the latest version of the Cambridge Crystallographic Database (CSD, version 5.26),22 no crystal structure was found having the 2-imino-dihydropyrido[3,2-e][1,3]thiazine moiety, being the crystal structure of 8a the first of this type of compounds. The molecules of 8a crystallized as a hydrochloride salt. In the solid state, the DHP ring has a screw boat conformation (a)

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(b) C4'

C5'

C3'

C6' O11 C13

C1' C5 C6

C2' C4A

C4

N3

C10 C14

C2

O12 C7 C15

C8A

N9 S1

N8

Cl

Figure 1. (a) Most stable conformation for compound 8a calculated by B3LYP/6-31G*. (b) ORTEP diagram of the crystal structure of 8a showing its atomic numbering scheme. Displacement ellipsoids are drawn at 50% probability level for non-H atoms.

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diffraction. The data for the remaining compounds are collected in the Supplementary material.

Figure 2. Projection of the molecules of 8a in the unit cell along the [001] direction and denoting the hydrogen bonds that involves the Cl atom.

Also, the main geometrical characteristics of the synthesized compounds were obtained from B3LYP/6-31G*24 ab initio calculations using the Gaussian 9825 program. The optimized geometry for compound 8a is shown in Figure 1. Table 1 shows geometrical data calculated for compound 8a (B3LYP/6-31G*) as well as those determined by X-ray

˚ ) valence angles (8) and torsion Table 1. Most relevant bond distances (A angles (8) for the most stable conformation of compound 8a, obtained by B3LYP/6-31G*, as well as by X-ray diffraction

˚) Bond distrances (A S1–C2 C2–N3 N3–C4 C4–C4a C4a–C8a C8a–S1 C2–N9 C4a–C5 C8a–N8 C5–C6 C6–C7 C7–N8 C5–C1 0 Bond angles (8) C8a–S1–C2 S1–C2–N3 C2–N3–C4 C4a–C5–C6 C7–N8–C8a C4a–C5–C1 0 Torsion angles (8) N8–C8a–C4a–C5 C8a–C4a–C5–C6 C4a–C5–C6–C7 C5-C6-C7-N8 C6-C7-N8-C8a C7–N8–C8a–C4a Sjrj C8a–S1–C2–N3 S1–C2–N3–C4 C2–N3–C4–C4a N3–C4–C4a–C8a C4–C4a–C8a–S1 C4a–C8a–S1–C2 C4a–C5–C1 0 –C2 0 C6–C5–C1 0 –C2 0 C5–C6–C10–O11

B3LYP/6-31G*

X-ray

1.783 1.311 1.340 1.393 1.394 1.759 1.337 1.532 1.344 1.524 1.353 1.419 1.533

1.757(6) 1.349(8) 1.332(8) 1.388(8) 1.379(8) 1.726(6) 1.292(8) 1.530(8) 1.349(7) 1.506(8) 1.351(9) 1.410(8) 1.515(9)

100.3 125.3 122.2 111.5 123.7 110.3

101.6(3) 123.3(5) 122.1(6) 111.1(5) 122.2(5) 111.4(5)

7.3 K18.0 17.1 K4.9 K8.4 7.1 62.8 K1.8 2.7 K0.4 K2.7 3.2 K1.1 K52.5 72.6 8.8

7.4(9) K18.3(8) 16.3(8) K3.1(9) K10.4(9) 8.0(9) 63.5(9) K11.5(6) 9.3(8) 1.0(10) K6.0(10) 1.5(8) 6.1(6) K53.5(8) 71.2(8) 19.5(9)

In all cases, the distortion from planarity of the atoms comprising the 1,4-DHP ring can be clearly seen from the torsion angles calculated about the ring bonds. The greatest displacement from zero occurs from N1 and C4, indicating that the largest degree of puckering occurs at these positions, the distortion being greatest at the C4 position, as found in the solid state structure. The magnitude and sign of this torsion angles indicate that both C5 and N8 (Table 1) lie above of the plane formed by C8a, C4a, C6 and C7, which imparts a boat-like conformation to the DHP ring. Calculations predicted that the substituent on C5 is in a pseudoaxial position (torsion C8a–C4a–C5–C1 0 between 96 and 1028) and bisecting the plane containing the 1,4-DHP ring (torsion angles C4a–C5–C1 0 –C2 0 with values between 100 and 1118). It is important to note that B3LYP/6-31G* calculations predict the 1,3-thiazine ring planar as can be seen from the values of the corresponding dihedral angles. Also the condensation of the 1,4-DHP ring to the 1,3thiazine ring makes the former more planar in comparison to the monocyclic 1,4-DHP.26 The sum, Sjrj, of the absolute values of the internal torsion angles is a measure of the planarity of the 1,4-DHP ring. Different from the solid state structure, the geometry at the calculated minimum energy in the gas phase shows the exocyclic ester at C6 in a cis conformation with respect to the C6]C7 double bond (Fig. 1). 3. Conclusions In summary, we have carried out the synthesis and characterization of unprecedented pyrido[3,2-e][1,3]thiazin-2-iminium chloride and determined their structure by X-ray analysis. It has been found that the 1,4-dihidropyridine shows a screw boat conformation with a pseudoaxial orientation of the aryl ring in C5 position. The geometrical features of the studied compounds are quite similar to the structurally related 1,4-dihydropyridines and, therefore, they exhibit appropriate structural features to act as potential calcium channel modulators. 4. Experimental 4.1. General Reagents and solvents were purchased from Fluka or Aldrich. Alkyl 4-aryl-6-methyl-2-oxo-1,2,3,4-tetrahydropyridine-5-carboxylate were obtained as previously reported16 from commercial reagents. The progress of the reaction and the purity of compounds were monitored by TLC analytical silica gel plates (Merck 60F250). Column chromatographies were carried out with silica gel 60 (70–230 mesh ASTM). Melting points were determined in capillary tubes in an Electrothermal 9100 apparatus and are uncorrected. A Decon (U.K.) ultrasonic bath equipped with 40 KHz frequency transducer was used for ultrasonically irradiated reactions. Analytical HPLC runs were performed in an Amersham Bioscience Akta 10 equipment; gradient: 5–40% of ACN (0.05% TFA) in 15 min; acquisition/

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processing data was accomplished with the UNICORN 4.11 program. Spectra were obtained as follow: FTIR were recorded on a FTIR 8300 spectrometer; 1H NMR spectra were recorded at 300 MHz, and 13C NMR at 75.5 MHz, on a Bruker Avance-300 instrument, the one-bond heteronuclear correlation (HMQC) and the long range 1H–13C correlation (HMBC) spectra were obtained using the inv4gs and the inv4gslplrnd programs, respectively, with the Bruker software. Mass spectrawere obtained with a Hewlett Packard 5989A spectrometer. Microanalysis was performed in a Perkin-Elmer 2400 CHN by the Servicio de Microana´lisis de la Universidad Complutense de Madrid. DFT calculations were performed using B3LYP/6-31G* basis set.24 All calculations were carried out using the Gaussian 98 program.25 4.2. Synthesis of ethyl 4-aryl-6-chloro-5-formyl-2methyl-1,4-dihydropyridine-3-carboxylates (2) under ultrasound irradiation To a stirred mixture of ethyl 4-aryl-6-methyl-2-oxo-1,2,3,4tetrahydropyridine-5-carboxylate 1 (7 mmol) and 1.4 mL (18.2 mmol) of DMF in 15 mL of dry DCM under a nitrogen atmosphere, 1.1 mL (12.2 mmol) of POCl3 was slowly added. The mixture was sonicated at 70 8C during 2 h. An aqueous sodium acetate solution was added (12 g in 21 mL of water) and stirred for 0.5 h. The reaction mixture was partitioned between water and DCM, and the aqueous phase was extracted with ethyl acetate. The organic phases were collected and dried under MgSO4. The organic solvent was removed in vacuo and the solid residue was washed twice with small portions of cold ether to afford 2. 4.3. General procedure for 6-alkoxycarbonyl-7-methyl5-phenyl-5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazin-2iminium chloride (8a–g) A mixture of the appropriate alkyl 4-aryl-6-chloro-5formyl-2-methyl-1,4-dihydropyridine-3-carboxylate 2a–g (2 mmol) and thiourea 6 (2 mmol) in dry ethanol (10 ml) was refluxed for 30 min. The precipitated solid was filtered, washed with hot ethanol (3!5 mL) and dried. 4.3.1. 6-Ethoxycarbonyl-7-methyl-5-phenyl-5,8-dihydro2H-pyrido[3,2-e][1,3]thiazin-2-iminium chloride (8a). Prepared from ethyl 6-chloro-4-phenyl-5-formyl-2-methyl1,4-dihydropyridine-3-carboxylate (2a). Yield, 71%; mp 286–287 8C; IR (KBr) nmax 3360 and 3210 (nNH), 1692 (nC]O), 1643 (nC]N) cmK1; 1H NMR (DMSO-d6) d: 12.72 (1H, s, NH), 10.58 (1H, s, NH), 10.30 (1H, s, NH), 8.39 (1H, s, H4), 7.33–7.19 (5H, m, Ph), 5.03 (1H, s, H5), 4.05–3.97 (2H, m, OCH2), 2.41 (3H, s, CH3), 1.07 (3H, t, CH3); 13C NMR (DMSO-d6) d 167.2 (C8a), 166.3 (C4), 165.5 (COO), 155.4 (C2), 146.2 (C1 0 ), 143.3 (C7), 128.9 (C2 0 , C6 0 ), 127.2 (C4 0 ), 126.9 (C3 0 , C5 0 ), 108.4 (C6), 107.3 (C4a), 60.1 (OCH2), 40.1 (C5), 17.8 (CH3), 13.9 (CH3); MSEI m/z (%): 327 ([MKHCl]%C, 21), 312 (7), 298 (31), 250 (100), 223 (40), 195 (23). Anal. Calcd for C17H18ClN3O2S (363.86): C: 56.12; H: 4.99; N: 11.55; S: 8.81. Found: C: 56.01; H: 4.91; N: 11.58; S: 8.97.

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4.4. Crystal structure determination of 8a Crystals suitable for X-ray diffraction were grown by slow evaporation from absolute methanol solution. The crystallographic and experimental data for these compounds are summarised in Table S1. Measurements were carried out using a Siemens P4 four-circle diffractometer with graphite monochromated and Cu Ka1 radiation. The intensity data were collected using u–2q scans, with u scan width equal to the low range plus the high range plus the separation between the Ka1 and Ka2 positions; 4522 reflections measured. Empirical absorption correction, via j scan was applied.27 Three standard reflections were monitored every 100 reflections (intensity decay: none). The structure was solved by direct methods and Fourier synthesis. Non-H atoms were refined anisotropically by full-matrix leastsquares techniques. H atoms were calculated geometrically and included in the refinement, but were restrained to ride on their parent atoms. The isotropic displacement parameters of the H atoms were fixed to 1.3 times Ueq of their parent atoms. Data collection: XSCANS.28 Cell refinement: XSCANS.28 Data reduction: XSCANS.28 Program used to solve structure: SIR92.29 Program used to refine structure: SHELXL97.30 Molecular graphics: DIAMOND.31 Software used to prepare material for publication: PLATON.32 Detailed crystallographic data for have been deposited at the Cambridge Crystallographic Data Centre (CCDC 265438) and are available on request. 4.4.1. 6-Ethoxycarbonyl-7-methyl-5-(3 0 -nitrophenyl)5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazin-2-iminium chloride (8b). Prepared from ethyl 6-chloro-4-(3-nitrophenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2b). Yield 53%; mp 273–275 8C; IR (KBr) nmax 3392 and 3260 (nNH), 1690 (nC]O), 1645 (nC]N), 1530 and 1355 (nNO2) cmK1; 1H NMR (DMSO-d6) d 12. 74 (1H, s, NH), 10.68 (1H, s, NH), 10.37 (1H, s, NH), 8.47 (1H, s, H4), 8.16 (1H, t, H2 0 , JZ1.8 Hz), 8.09 (1H, ddd, H4 0 , JZ 8.0, 1.8, 1.0 Hz), 7.60 (1H, dt, H6 0 , JZ8.0, 1.0 Hz), 7.62 (1H, t, H5 0 , JZ8.0 Hz), 5.27 (1H, s, H5), 4.06–3.97 (2H, m, OCH2), 2.43 (3H, s, CH3), 1.08 (3H, t, CH3); 13C NMR (DMSO-d6) d 167.9 (C8a), 167.1 (C4), 165.5 (COO), 156.0 (C2), 148.3 (C3 0 ), 148.2 (C1 0 ), 144.8 (C7), 134.5 (C2 0 ), 131.0 (C4 0 ), 122.6 (C6 0 ), 122.2 (C5 0 ), 107.2 (C6), 106.7 (C4a), 60.6 (OCH2), 40.0 (C5), 18.3 (CH3), 14.2 (CH3); MSEI m/z (%): 372 ([MKHCl]%C, 12), 355 (34), 250 (100), 223 (40) 195 (25). Anal. Calcd for C17H17ClN4O4S (408.86): C: 49.94; H: 4.19; N: 13.70; S: 7.84. Found: C: 49.92; H: 4.18; N: 13.82; S: 7.88. 4.4.2. 6-Ethoxycarbonyl-5-(4-metoxycarbonylphenyl)-7methyl-5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazin-2-iminium chloride (8c). Prepared from ethyl 6-chloro-4-(4 0 methoxycarbonylphenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2c). Yield 50%; mp 287–288 8C; IR (KBr) nmax 3384 and 3250 (nNH), 1728 and 1692 (nC]O), 1647 (nC]N) cmK1; 1H NMR (DMSO-d6) d: 12.72 (1H, s, NH), 10.63 (1H, s, NH), 10.34 (1H, s, NH), 8.41 (1H, s, H4), 7.89 (2H, d, JZ7.5 Hz, H3 0 , H5 0 ), 7.42 (2H, d, JZ7.5 Hz, H2 0 , H4 0 ), 5.15 (1H, s, H5), 4.05–3.95 (2H, m, OCH2), 3.81 (3H, s, OCH3), 2.42 (3H, s, CH3), 1.06 (3H, t, CH3); 13C NMR (DMSO-d6) d: 167.4 (C8a), 166.5 (C4), 165.9 (COO), 165.3 (COO), 155.6 (C2), 151.1 (C1 0 ), 144.0 (C7), 129.9

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(C3 0 , C5 0 ), 128.5 (C4 0 ), 127.5 (C2 0 , C6 0 ), 107.6 (C6), 106.6 (C4a), 60.2 (OCH2), 52.2 (OCH3), 40.2 (C5), 17.9 (CH3), 13.9 (CH3); MSEI m/z (%): 385 ([MKHCl]%C, 16), 356 (29), 312 (25), 250 (100), 223 (37), 195 (25). Anal. Calcd for C19H20ClN3O4S (421.90): C: 54.09; H: 4.78; N: 9.96; S: 7.60. Found: C: 53.87; H:4.75; N: 10.07; S: 7.59. 4.4.3. 6-Methoxycarbonyl-7-methyl-5-phenyl-5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazin-2-iminium chloride (8d). Prepared from methyl 6-chloro-4-phenyl-5-formyl-2methyl-1,4-dihydropyridine-3-carboxylate (2d). Yield, 73%; mp 241–243 8C; IR (KBr) nmax 3360 and 3220 (nNH), 1690 (nC]O), 1645 (nC]N) cmK1; 1H NMR (DMSO-d6) d: 12.61 (1H, s, NH), 10.57 (1H, s, NH), 10.32 (1H, s, NH), 8.45 (1H, s, H4), 7.35–7.22 (5H, m, Ph), 5.06 (1H, s, H5), 3.58 (3H, s, OCH3); 2.43 (3H, s, CH3); 13C NMR (DMSO-d6) d 167.3 (C8a), 166.4 (C4), 166.0 (COO), 155.3 (C2), 145.9 (C1 0 ), 143.5 (C7), 129.0 (C2 0 , C6 0 ), 127.3 (C4 0 ), 126.7 (C3 0 , C5 0 ), 108.0 (C6), 107.4 (C4a), 51.5 (OCH3), 39.7 (C5), 17.8 (CH3); MSEI m/z (%): 313 ([MKHCl]%C, 21); 298 (17), 236 (100), 209 (62), 177 (8). Anal. Calcd for C16H16ClN3O2S (349.84): C: 54.93; H: 4.61; N: 12.01; S: 9.17. Found: C: 54.87; H: 4.65; N: 12.03; S: 9.19. 4.4.4. 5-(2-Chlorophenyl)-6-methoxycarbonyl-7-methyl5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazin-2-iminium chloride (8e). Prepared from methyl 6-chloro-4-(2-chlorophenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2e). Yield 69%; mp 304–306 8C; IR (KBr) nmax 3370 and 3225 (nNH), 1692 (nC]O), 1648 (nC]N) cmK1; 1H NMR (DMSO-d6) d: 12.68 (1H, s, NH), 10.58 (1H, s, NH), 10.35 (1H, s, NH), 8.15 (1H, s, H4), 7.44 (1H, m, H3 0 ), 7.33–7.24 (3H, m, H5 0 , H4 0 ,H6 0 ), 5.50 (1H, s, H5), 3.51 (3H, s, OCH3); 2.40 (3H, s, CH3); 13C NMR (DMSO-d6) d 167.1 (C8a), 165.7 (COO), 165.3 (C4), 155.9 (C2), 144.3 (C7), 142.9 (C1 0 ), 130.80 (C2 0 ), 130.7 (C6 0 ), 129.9 (C3 0 ), 129.1 (C4 0 ), 128.2 (C5 0 ), 107.3 (C6), 106.6 (C4a), 51.4 (OCH2), 37.3 (C5), 17.9 (CH 3); MSEI m/z (%): 347/349 ([MKHCl]%C, 14/6); 332/334 (25/9), 288/290 (21/8), 236 (100), 209 (61), 177 (9). Anal. Calcd for C16H15Cl2N3O2S (384.28): C: 50.01; H: 3.93; N: 10.93; S: 8.34. Found: C: 49.83; H: 3.92; N: 11.00; S: 8.32. 4.4.5. 6-Methoxycarbonyl-7-methyl-5-(3 0 -nitrophenyl)5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazin-2-iminium chloride (8f). Prepared from methyl 6-chloro-4-(3-nitrophenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2f). Yield 58%; mp 250–252 8C; IR (KBr) nmax 3390 and 3255 (nNH), 1690 (nC]O), 1645 (nC]N), 1535 and 1350 (nNO2) cmK1; 1H NMR (DMSO-d6) d 12.70 (1H, s, NH), 10.64 (1H, s, NH), 10.38 (1H, s, NH), 8.52 (1H, s, H4), 8.13 (1H, t, H2 0 , JZ1.8 Hz), 8.09 (1H, ddd, H4 0 , JZ 7.9, 1.8, 1.0 Hz), 7.73 (1H, dt, H6 0 , JZ7.9, 1.0 Hz), 7.62 (1H, t, H5 0 , JZ7.9 Hz), 5.28 (1H, s, H5), 3.57 (3H, m, OCH3), 2.45 (3H, s, CH3); 13C NMR (DMSO-d6) d 167.6 (C8a), 166.7 (C4), 165.8 (COO), 155.6 (C2), 148.1 (C3 0 ), 147.6 (C1 0 ), 144.7 (C7), 133.9 (C2 0 ), 130.6 (C4 0 ), 122.3 (C6 0 ), 121.6 (C5 0 ), 106.9 (C6), 106.4 (C4a), 51.6 (OCH3), 39.3 (C5), 18.0 (CH3); MSEI m/z (%): 358 ([MKHCl]%C, 13); 341 (22), 236 (100), 209 (61), 177 (9). Anal. Calcd for C16H15ClN4O4S (394.83): C: 48.67; H: 3.83; N: 14.19; S: 8.12. Found: C: 48.56; H: 3.89; N: 14.22; S: 8.15.

4.4.6. 6-Methoxycarbonyl-5-(4-metoxycarbonylphenyl)7-methyl-5,8-dihydro-2H-pyrido[3,2-e][1,3]thiazin-2iminium chloride (8g). Prepared from methyl 6-chloro-4(4 0 -methoxycarbonylphenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2g). Yield 52%; mp 242– 244 8C; IR (KBr) nmax 33890 and 3255 (nNH), 1725 and 1690 (nC]O), 1647 (nC]N) cmK1; 1H NMR (DMSO-d6) d: 12.76 (1H, s, NH), 10.64 (1H, s, NH), 10.35 (1H, s, NH), 8.45 (1H, s, H4), 7.89 (2H, d, H3 0 , H5 0 , JZ8.4 Hz), 7.42 (2H, d, H2 0 , H4 0 , JZ8.4 Hz), 5.16 (1H, s, H5), 3.81 (3H, s, OCH3), 3.56 (3H, s, OCH3, overlaping with de H2O signal), 2.42 (3H, s, CH3); 13C NMR (DMSO-d6) d: 167.5 (C8a), 166.5 (C4), 165.9 (COO), 165.8 (COO), 155.5 (C2), 150.8 (C1 0 ), 144.2 (C7), 129.9 (C3 0 , C5 0 ), 128.5 (C4 0 ), 127.3 (C2 0 , C6 0 ), 107.2 (C6), 106.6 (C4a), 52.1 (OCH3), 51.5 (OCH3), 39.1 (C5), 17.9 (CH3); MSEI m/z (%): 371 ([MKHCl]%C, 16); 356 (25), 236 (100), 209 (62), 177 (8). Anal. Calcd for C18H17ClN3O4S (406.06): C: 53.14; H: 4.21; N: 10.33; S: 7.88. Found: C: 53.01; H: 4.17; N: 10.42; S: 7.89.

Acknowledgements Supports of this work by Proyectos Alma Mater (CUBA) and MEC of Spain (PQU2002-00855 and CTQ2004-03760) are gratefully acknowledged. M. Sua´rez is grateful to SAB2003-0161 from Secretarı´a de Estado de Universidades e Investigacio´n del Ministerio de Educacio´n y Ciencia de Espan˜a. H. Novoa is indebted to the Postdoctoral Mandate fellowship of the Research Funds/Onderzoeksfunds, K.U. Leuven (Belgium).

Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tet.2005.11. 054. The main geometrical characteristics of compounds 8b–g obtained from B3LYP/6-31G*24 ab initio are collected in the supplementary material.

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