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Synthesis of N-Tosylguanidines by Ring Cleavage of 1,2-Dihydro-2-tosyliminopyrimidines Synthesi ofN-Tosylguanidnes Lasri,a M. Eugenia González-Rosende,b José Sepúlveda-Arques*a Jamal a
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia, Avda. Vicent Andres Estelles s/n, 46100 Burjassot, Valencia, Spain Fax +34(96)3864939; E-mail:
[email protected] b Departamento de Química, Bioquímica y Biología Molecular, Universidad Cardenal Herrera-CEU, 46113 Moncada, Valencia, Spain Received 6 February 2003
Abstract: The present communication discloses a new synthetic method for the preparation of N-tosylguanidines in high yields by ring cleavage of 1,2-dihydro-2-tosyliminopyrimidines with methylamine.
H N
NTs N
N
HN
Ar H2N
O
O
Ι
ΙΙ
Figure 1
In a previous paper4 we reported that imidazo[1,2-c]pyrimidines I were obtained from 2-tosylimino-1-carbamoylmethylpyrimidines II by intramolecular Michael addition of the carboxamide group to the a,b-unsaturated imino system (Figure 1).
NTs
Ar
Key words: imines, ring opening, nucleophilic addition, sulfonamides, cleavage
Numerous natural and non-natural guanidine derivatives have shown biological activity, making these compounds targets for drug design and discovery,1 sulfonylguanidines are specially of great interest in medicinal chemistry.2 Classically, guanidines are obtained through intermediates such as thioureas, carbodiimides, chloroformamidines, dichloroisocyanides, carboxamidines or cyanamides and through Mitsunobu protocol.3 Here, we describe a novel procedure for the synthesis of N-tosylguanidines in excellent yields from 2-tosyliminopyrimidines as precursors.
N
Structures of pyrimidines I and II
We were intrigued to see if intermolecular Michael additions with primary amines would take place on similar 1,2-dihydropyrimidine systems. The substrates for this study were the pyrimidine-2-imines 1a and 1b–f (containing a 1,4-disubstituted benzene ring) which were prepared for pharmacological screening as anti-inflammatory compounds,5 according to procedures described in the literature.4,6 The reaction of 1a–f with methylamine did not afford the six-membered heterocycle 2 resulting from the nucleophilic addition to the a,b-unsaturated imino system but rather the guanidine derivatives 3a–f along with (Z)3-methylaminoprop-2-enal (4) (Scheme 1). The reaction of the alkylated products 1a–f with methylamine was performed by bubbling an excess of the amine through an acetonitrile solution of the corresponding compound 1 at –40 °C and allowing the reaction mixture to stir H N
NTs N CH (C H ) CONHR 2 6 4 n
NHCH3 N
NTs
2
H2NCH3
N CH2(C6H4)nCONHR 1
H2N
NTs
+ HN CH2(C6H4)nCONHR 3
CH3 NH H O 4
a: n = 0, R = H; b: n = 1, R = C6H5; c: n = 1, R = p-FC6H4; d: n = 1, R = p-FC6H4CH2CH2; e: n = 1, R = 2,4-Cl2C6H3; f: n = 1, R = 2,4-Cl2C6H3CH2CH2
Scheme 1
Synthesis 2003, No. 6, Print: 29 04 2003. Art Id.1437-210X,E;2003,0,06,0845,0848,ftx,en;P01203SS.pdf. © Georg Thieme Verlag Stuttgart · New York ISSN 0039-7881
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overnight at room temperature. Crystallization of the crude from ethanol provided the corresponding guanidines 3 in high yields (70–90%). The mother liquor was evaporated to dryness and the resulting crude was purified by column chromatography (EtOAc–MeOH, 7:3) affording (Z)-3-methylaminoprop-2-enal (4) (8–12%). Structural assignment of compounds 3 and 4 is supported by analytical and spectroscopic data. Thus, 1H NMR spectra of compounds 3 show one set of signals in the aromatic region indicating the AB system of the p-toluenesulfonyl group and loss of the typical AMX pattern of the original derivatives 1 consistent with the ring fragmentation. The 13 C NMR spectra also agree with the proposed guanidine structure, with the carboxamidine carbon atom at d = ca. 157 ppm and the carboxamide carbon atom at d = ca. 166– 170 ppm. The observed results can be explained by a nucleophilic addition of methylamine at the ring carbon (C-6) of the 2tosyliminopyrimidines 1. Concomitant ring opening and further attack of the amine at C-4 followed by N-3–C-4 bond cleavage would give guanidines 3 and the intermediate N-methyl-(Z)-3-methyliminoprop-1-en-1-amine (5), isolated as the hydrolyzed product (Z)-3-methylaminoprop-2-enal (4) (Scheme 2). Inspection of the literature has shown that ring fission of pyrimidine systems was extensively studied in the sixties.7 A close analogy with our result is the reaction of 1,2dihydro-2-imino-1-methylpyrimidine with butylamine, studied by Brown,8 who obtained 1,3-dibutyliminopropane and ‘postulated’, the loss of methylguanidine, which was ‘not isolated’ (Scheme 3). In the present work, we have presented the transformation of the 1,2-dihydro-2-toluenesulfonyliminopyrimidines 1a–f into guanidines 3a–f by treatment with methylamine, which constitutes a simple and efficient route to important substituted tosylguanidine derivatives. Extension of these fragmentations to other functionalized dihydropyrimidine
Bu N
NH
NH
H2NBu
N
H2N H
NHCH3
CH3 NBu
Not isolated
Scheme 3
systems, as well as their scope and limitations are currently under investigation. All reagents were purchased from Aldrich and used without purification, unless stated otherwise. All experiments were conducted under N2. Melting points were determined with a Kofler hot-stage apparatus and are uncorrected. Flash column chromatography was performed using silica gel (Merck 60, 70–230 mesh). 1H and 13C NMR spectra were recorded on a Bruker AC-300 instrument in CDCl3, unless otherwise indicated. Chemical shifts (d values) and coupling constants (J values) are given in ppm and Hz respectively. MS and HRMS were obtained using a VG Autospec TRIO 1000 instrument. The ionization mode used in mass spectra was electron impact (EI) or fast atom bombardment (FAB). 1H and 13C NMR assignments have been confirmed by homonuclear two dimensional correlations and DEPT experiments. Elemental analyses were recorded by the ‘Servicio de Microanálisis’ of the University of Valencia (SCSIE). Compounds 1a–f were prepared as described in the literature.4,5 Reaction of Compounds 1a–f with Methylamine; General Procedure The reaction was performed by bubbling an excess of methylamine through an MeCN solution of the corresponding compound 1a–f at –40 °C. The reaction mixture was allowed to stir overnight at r.t. and then concentrated under reduced pressure. The resulting solid was crystallized from EtOH affording the corresponding guanidines 3. Compound 4 was isolated from the mother liquor in low yield (8– 12%).
H2NCH3 3 N
6
NTs
H N
N
NTs
H2NCH3 N R´
N 1 R´
H N
NTs
NTs NHR´
NHR´
NHCH3
1
NCH3
NHCH3
2
R´ = CH2(C6H4)nCONHR CH3 H2N
NTs
NH
3
Scheme 2 ISSN 0039-7881
H2O
CH3 NH
+
© Thieme Stuttgart · New York
H
H
NHR´
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NH
+
NCH3
O
5
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Synthesis of N-Tosylguanidines
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N2-(Amino{[(4-methylphenyl)sulfonyl]imino}methyl)glycinamide (3a) Yield: 75%; mp 200–203 °C.
Anal. Calcd for C24H25FN4O3S: C, 61.52; H, 5.33; N, 11.95; S, 6.84. Found: C, 61.33; H, 5.61; N, 11.99; S, 6.67.
1 H NMR (DMSO-d6): d = 2.34 (s, 3 H), 3.70 (d, 2 H, J = 4.9 Hz), 6.81–6.87 (br s, 2 H, NH), 7.13 (br s, 1 H, NH), 7.27 (d, 2 H, J = 8.1 Hz), 7.44 (br s, 1 H, NH), 7.64 (d, 2 H, J = 8.1 Hz), 10.2 (br s, 1 H, NH).
N-(2,4-Dichlorophenyl)-4-{[(amino{[(4-methylphenyl)sulfonyl]imino}methyl)amino]methyl}benzamide (3e) Yield 85%; mp 209–211 °C.
C NMR (DMSO-d6): d = 21.0 (CH3), 43.1 (CH2), 125.7 (CH), 129.0 (CH), 141.2 (C), 141.5 (C), 156.6 (C=N), 170.2 (C=O).
13
HRMS (FAB+): m/z calcd for C10H15N4O3S (MH+), 271.0864; found, 271.0862. Anal. Calcd for C10H14N4O3S: C, 44.46; H, 5.18; N, 20.73; S, 11.87. Found: C, 44.61; H, 5.79; N, 20.33; S, 11.94. 4-{[(Amino{[(4-methylphenyl)sulfonyl]imino}methyl)amino]methyl}-N-phenylbenzamide (3b) Yield: 82%; mp 218–220 °C. H NMR (DMSO-d6): d = 2.33 (s, 3 H), 4.38 (d, 2 H, J = 5.3 Hz), 6.82 (br s, 1 H, NH), 7.09 (t, 1 H, J = 7.35 Hz), 7.25 (m, 4 H), 7.29 (d, 2 H, J = 8.2 Hz), 7.35 (t, 2 H, J = 7.7 Hz), 7.55 (br s, 2 H, NH), 7.77 (d, 2 H, J = 7.7 Hz), 7.86 (d, 2 H, J = 8.2 Hz), 10.2 (br s, 1 H, NH). 1
C NMR (DMSO-d6): d = 20.9 (CH3), 43.4 (CH2), 120.3 (CH), 123.6 (CH), 125.6 (CH), 126.8 (CH), 127.7 (CH), 128.6 (CH), 129.0 (CH), 131.0 (C), 133.5 (C), 139.2 (C), 141.0 (C), 141.1 (C), 156.7 (C=N), 165.2 (C=O).
13
HRMS (EI+): m/z calcd for C22H22N4O3S (M+), 422.1413; found, 422.1414. N-(4-Fluorophenyl)-4-{[(amino{[(4-methylphenyl)sulfonyl]imino}methyl)amino]methyl}benzamide (3c) Yield: 65%; mp 242–244 °C. H NMR (DMSO-d6): d = 2.33 (s, 3 H), 4.37 (d, 2 H, J = 6 Hz), 6.80 (br s, 1 H, NH), 7.19 (t, 2 H, J = 8.85 Hz), 7.26 (m, 4 H), 7.28 (d, 2 H, J = 8 Hz), 7.54 (br s, 2 H, NH), 7.78 (dd, 2 H, J = 8.85, 5.1 Hz), 7.84 (d, 2 H, J = 8 Hz), 10.26 (br s, 1 H, NH). 1
13 C NMR (DMSO-d6): d = 21.1 (CH3), 43.4 (CH2), 115.4 (d, J = 22 Hz, CH), 122.5 (d, J = 7.5 Hz, CH), 125.8 (CH), 127.1 (CH), 127.9 (CH), 129.3 (CH), 131.5 (C), 135.5 (C), 138.0 (C), 141.5 (C), 141.5 (C), 156.9 (C=N), 160.5 (d, J = 240 Hz, C), 165.4 (C=O).
HRMS (EI): m/z calcd for C22H21FN4O3S, 440.1318; found, 440.1323. Anal. Calcd for C22H21FN4O3S: C, 59.99; H, 4.77; N, 12.71; S, 7.28. Found: C, 59.74; H, 5.10; N, 12.46; S, 7.42. N-[2-(4-Fluorophenyl)ethyl]-4-{[(amino{[(4-methylphenyl)sulfonyl]imino}methyl)amino]methyl}benzamide (3d) Yield: 70%; mp 177–179 °C. H NMR (DMSO-d6): d = 2.33 (s, 3 H), 2.83 (t, 2 H, J = 6.8, Hz), 3.45 (q, 2 H, J = 6.8 Hz), 4.33 (d, 2 H, J = 5 Hz), 6.81 (br s, 1 H, NH), 7.10 (t, 2 H, J = 8.8 Hz), 7.22 (m, 8 H), 7.54 (br s, 2 H, NH), 7.71 (d, 2 H, J = 8 Hz), 8.51 (br s, 1 H, NH). 1
C NMR (DMSO-d6): d = 20.9 (CH3), 34.2 (CH2), 40.8 (CH2), 43.3 (CH2), 115.0 (d, J = 20.7 Hz, CH), 125.6 (CH), 126.8 (CH), 127.1 (CH), 129.0 (CH), 130.4 (d, J = 7.5 Hz, CH), 134.3 (C), 134.5 (C), 136.5 (C), 141.1 (C), 141.1 (C), 158.4 (C=N), 162.4 (d, J = 244 Hz, C), 165.9 (C=O). 13
HRMS (EI+): m/z calcd for C24H25FN4O3S, 468.1631; found, 468.1633.
H NMR (DMSO-d6): d = 2.33 (s, 3 H), 4.38 (d, 2 H, J = 5 Hz), 6.87 (br s, 1 H, NH), 7.24 (d, 2 H, J = 7 Hz), 7.30 (d, 2 H, J = 8 Hz), 7.48 (m, 3 H), 7.63 (d, 1 H, J = 8 Hz), 7.74 (d, 1 H, J = 2 Hz), 7.88 (d, 2 H, J = 8 Hz), 10.02 (br s, 1 H). 1
C NMR (DMSO-d6): d = 20.9 (CH3), 43.4 (CH2), 125.6 (CH), 127.0 (CH), 127.6 (CH), 127.7 (CH), 128.9 (CH), 129.0 (CH), 129.5 (CH), 129.6 (C), 130.0 (C), 130.4 (C), 134.3 (C), 141.0 (C), 141.1 (C), 156.7 (C=N), 165.1 (C=O). 13
HRMS (EI+): m/z calcd for C22H20Cl2N4O3S, 490.0633; found, 490.0647. N-[2-(2,4-Dichlorophenyl)ethyl]-4-{[(amino{[(4-methylphenyl)sulfonyl]imino}methyl)amino]methyl}benzamide (3f) Yield: 80%; mp 187–190 °C. 1 H NMR (DMSO-d6): d = 2.33 (s, 3 H), 2.95 (t, 2 H, J = 6.7 Hz), 3.50 (q, 2 H, J = 6.7 Hz), 4.33 (d, 2 H, J = 5.1 Hz), 7.02 (br s, 1 H, NH), 7.22 (m, 4 H), 7.35 (m, 2 H), 7.53 (br s, 2 H, NH), 7.58 (s, 1 H), 7.70 (d, 2 H, J = 8.1 Hz), 7.80 (m, 2 H), 8.53 (t, 1 H, J = 5.1 Hz, NH).
C NMR (DMSO-d6): d = 20.9 (CH3), 32.3 (CH2), 39.5 (CH2), 43.3 (CH2), 125.6 (CH), 126.7 (CH), 127.1 (CH), 127.3 (CH), 128.6 (CH), 128.9 (CH), 131.7 (C), 132.4 (CH), 134.1 (C), 136.2 (C), 139.4 (C), 141.1 (C), 141.1 (C), 142.5 (C), 156.8 (C=N), 166.0 (C=O). 13
HRMS (EI+): m/z calcd for C24H24Cl2N4O3S, 518.0946; found, 518.0931. Anal. Calcd for C24H24Cl2N4O3S: C, 55.44; H, 4.62; N, 10.78; S, 6.17. Found: C, 55.39; H, 4.96; N, 10.79; S, 5.51. (Z)-3-Methylaminoprop-2-enal (4) H NMR (MeOH-d4): d = 2.81 (s, 3 H), 5.26 (dd, 1 H, J = 12, 9 Hz), 7.47 (d, 1 H, J = 12 Hz), 8.85 (d, J = 9 Hz, 1 H). 1
C NMR (MeOH-d4): d = 30.4 (CH3), 100.1 (CH), 162.4 (CH), 192.2 (CH). 13
HRMS (EI+): m/z calcd for C4H7NO, 85.0528; found, 85.0527.
Acknowledgments We are indebted to the Ministery of Science and Technology (Project PB98-1451) for financial support. We thank Dr. Gurnos Jones (University of Keele) and Dr. Rafael Ballesteros (Universidad de Valencia) for helpful discussion. We wish to thank SCSIE (Universidad de Valencia) for elemental analyses and Dr. Rossella Mello for HRMS.
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