Acta Chim. Slov. 2002, 49, 605-611.                                605
A NEW SYNTHESIS OF SUBSTITUTED BENZALDEHYDE N-[(E)-PHENYLMETHYLIDENE]HYDRAZONES
Aleš Obrezaa and Uroš Urlebab*
aUniversity of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia bLek d.d., Verovškova 57, 1000 Ljubljana
Received 06-11-2001
Abstract
Reaction of substituted tert-butyl 2-(phenylmethylidene)-1-hydrazinecarboxylates with gaseous HCl in various anhydrous solvents affords benzaldehyde N-(phenylmethylidene)-hydrazones in very good yields. A series of substituted benzaldehydes was used for the preparation of this type of compounds. The structure of the resulting compounds was investigated by 1H-NMR, IR and MS spectra.
Introduction
In the course of our research on the design of   serine protease inhibitors para
substituted benzaldehyde hydrazones would be interesting synthons that can be easily functionalized on both nitrogen atoms.1,2 To prevent the formation of bis substituted hydrazones the series of substituted tert-butyl 2-(phenylmethylidene)-1-hydrazinecarboxylates 2 were prepared from corresponding benzaldehydes 1 and tert-butyl 1-hydrazinecarboxylate.3
Results and discussion
In this paper we report the unexpected reaction that took place during the
deprotection of Boc-group in compounds 2a-i. After two minutes of influx of gaseous hydrogen chloride in solution of 2a-i in anhydrous tetrahydrofurane, dichloromethane or acetic acid at room temperature or with slight cooling benzaldehyde N-(phenylmethylidene)hydrazones 3a-i were formed as yellow or orange precipitates.
Concerning the mechanism of the reaction we at first stipulated that the first step was the removal of Boc-protecting group, followed by the hydrolysis of imino bond. Substituted benzaldehydes and protonated hydrazine would be the corresponding intermediates that take part in condensation reaction. Reaction between benzaldehydes
A. Obreza, U.Urleb: A new synthesis of substituted benzaldehyde N-[(E)-phenylmethylidene]hydrazones
606
Acta Chim. Slov. 2002, 49, 605-611.
and hydrazine hydrate has been known for a long time and is the standard procedure in the synthesis of benzaldehyde N-(phenylmethylidene) hydrazones.4,5
CHO
N
O_NH
T O
\\,O
T Y
I         n
R
2
a: NHNHBoc, EtOH, 5h; b: HCl/AcOH, r.t., 2 min
1,2,3	a	b	c	d	e	f	g	h	i
R	H	4-Me	4-NO2	3-NO2	4-COOH	4-CONH2	4-CH2NHCOCH3	4-NMe2	4-CN
Scheme 1
To prove the above-mentioned mechanism various reaction conditions were used. Substituted benzaldehydes were dissolved in different solvents saturated with gaseous hydrogen chloride. Hydrazine in the form of hydrazine hydrate, hydrazine chloride or boc-karbazate was added and the reaction mixture was stirred at room temperature. In neither case the product was formed as proved by NMR-spectra and mass spectrometry.
Probably during the removal of Boc-group benzaldehyde hydrazones are formed. One resulting molecule reacts with another to yield the final product.
Experimental Synthesis of compounds 2a-2i (General procedure): The mixture of substituted
benzaldehyde (10 mmol) and tert-butyl 1-hydrazinecarboxylate (10 mmol) in absolute
ethanol (25 ml) was refluxed for 5 hours. The solution was diluted with water and the
resulting precipitate filtered to yield compounds 2a-i as white or pale yellow solids.
R
R
R
a
b
1
3
A. Obreza, U.Urleb: A new synthesis of substituted benzaldehyde N-[(E)-phenylmethylidene]hydrazones
Acta Chim. Slov. 2002, 49, 605-611.
607
tert-Butyl 2-[(E)-phenylmethylidene]-1-hydrazinecarboxylate (2a). 1H NMR (300 MHz, CDCl3): ? 1.55 (s, 9H, C(CH3)3), 7.36 (d, 2H, J=2.38 Hz, Ar-H), 7.38 (m, 1H, Ar-H), 7.68 (m, 2H, Ar-H), 7.86 (s, 1H, Ar- CH), 8.06 (s, 1H, NH) ppm; MS (FAB+): m/z (%): 221 (MH+, 16), 165 (100); IR (KBr): ? 3250, 2982, 1690, 1529, 1372, 1272, 1165, 1058, 861, 759, 693 cm-1; Anal. Calcd for C12H15N2O2×1/3 H2O: 63.70% C, 6.98% H, 12.38% N; Found: 63.78% C, 7.27% H, 12.47% N. mp = 151 °C. Yield = 94%.
tert-Butyl 2-[(E)-(4-nitrophenyl)methylidene]-1-hydrazinecarboxylate (2c). 1H NMR (300 MHz, CDCl3): ? 1.56 (s, 9H, C(CH3)3), 7.83 (d, 2H, J=8.84 Hz, Ar-H), 7.98 (s, 1H, Ar-CH), 8.22 (d, 2H, J=8.84 Hz, Ar-H), 8.40 (s, 1H, NH) ppm; MS (FAB+): m/z (%): 266 (MH+,24), 210 (100); IR (KBr): ? 3281, 2987, 1705, 1528, 1347, 1252, 1144, 1060, 850, 614 cm-1; Anal. Calcd for C12H15N3O4: 54.33% C, 5.70% H, 15.84% N; Found: 54.17% C, 5.84% H, 15.51% N. mp = 169-171 °C. Yield = 90%.
tert-Butyl 2-[(E)-(3-nitrophenyl)methylidene]-1-hydrazinecarboxylate (2d). 1H NMR (300 MHz, CDCl3): ? 1.56 (s, 9H, C(CH3)3), 7.56 (t, 1H, J=7.98 Hz, Ar-H), 8.00 (s, 1H, Ar-CH), 8.08 (d, 1H, J=7.81 Hz, Ar-H), 8.20 (m, 1H, Ar-H), 8.27 (s, 1H, NH), 8.43 (m, 1H, Ar-H) ppm; MS (FAB+): m/z (%): 266 (MH+, 7), 210 (100); IR (KBr): ? 3221, 2980, 1713, 1530, 1354, 1270, 1165, 1054, 870, 680 cm-1; Anal. Calcd for C12H15N3O4: 54.33% C, 5.70% H, 15.84% N; Found: 54.33% C, 5.70% H, 15.74% N. mp= 158-159 °C. Yield = 90%.
4-{[(E)-2-(tert-Butoxycarbonyl)hydrazono]methyl}benzoic acid (2e). 1H NMR (300 MHz, DMSO-d6): ? 1.48 (s, 9H, C(CH3)3), 7.66 (d, 2H, J=7.78 Hz, Ar-H), 7.91 (d, 2H, J=7.78 Hz, Ar-H), 8.02 (s, 1H, Ar-CH), 10.85 (s, 1H, NH), 13.00 (s, 1H, COOH) ppm; MS (FAB+): m/z (%): 265 (MH+, 17), 209 (100); IR (KBr): ? 3491, 3286, 2986, 1708, 1678, 1356, 1266, 1161, 1059, 858, 775, 608 cm-1; Anal. Calcd for C13H16N2O4: 59.08% C, 6.10% H, 10.60% N; Found: 59.12% C, 6.07% H, 10.36% N. mp = 322-325 °C. Yield = 94%.
A. Obreza, U.Urleb: A new synthesis of substituted benzaldehyde N-[(E)-phenylmethylidene]hydrazones
608
Acta Chim. Slov. 2002, 49, 605-611.
tert-Butyl 2-{(E)-[4-(aminocarbonyl)phenyl]methylidene}-1-hydrazinecarboxylate (2f).
1H NMR (300 MHz, DMSO-d6): ? 1.48 (s, 9H, C(CH3)3), 7.37 and 7.99 (2s, 2H, CONH2), 7.66 (d, 2H, J=8.28 Hz, Ar-H), 7.90 (d, 2H, J=8.28 Hz, Ar-H), 8.04 (s,1H, ArCH), 10.99 (s,1H, NH) ppm; MS (FAB+): m/z (%): 264 (MH+, 34), 154 (100); IR (KBr): ? 3378, 3282, 3175, 2985, 1707, 1654, 1622, 1533, 1419, 1360, 1269, 1159, 1059, 946, 854, 760, 609, 536 cm-1; Anal. Calcd for C13H17N3O3: 59.30% C, 6.51% H, 15.96% N; Found: 59.17% C, 6.62% H, 16.21% N. mp = 204-206 °C. Yield = 92%.
tert-Butyl 2-((E)-{4-[(acetylamino)methyl]phenyl}methylidene)-1-hydrazine-carboxylate (2g).
1H NMR (300 MHz, CDCl3): ? 1.54 (s, 9H, C(CH3)3), 2.04 (s, 3H, COCH3), 4.42 (d, 2H, J=5.84 Hz, Ar-CH2), 6.19 (s, 1H, NHCO), 7.23 (d, 2H, J=8.17 Hz, Ar-H), 7.59 (d, 2H, J=8.17 Hz, Ar-H), 7.83 (s, 1H, Ar-CH), 8.27 (s, 1H, NHCOO) ppm; MS (FAB+): m/z (%): 292 (MH+, 16), 236 (100); IR (KBr): ? 3315, 3194, 2976, 1718, 1657, 1555, 1364, 1278, 1180, 1058, 882, 805, 714, 664 cm-1; Anal. Calcd for C15H21N3O3×1/6 H2O: 61.20% C, 7.41% H, 14.27% N; Found: 61.08% C, 7.24% H, 13.92% N. mp = 183-187 °C. Yield = 87%.
tert-Butyl 2-{(E)-[4-(dimethylamino)phenyl]methylidene}-1-hydrazinecarboxylate (2h).
1H NMR (300 MHz, CDCl3): ? 1.54 (s, 9H, C(CH3)3), 3.01 (s, 6H, N(CH3)2), 6.68 (d, 2H, J=8.51 Hz, Ar-H), 7.56 (d, 2H, J=8.51 Hz, Ar-H), 7.42 (s, 1H, Ar-CH), 7.74 (s, 1H, NH) ppm; MS (FAB+): m/z (%): 263 (M+, 100); IR (KBr): ? 3253, 2982, 1688, 1615, 1518, 1369, 1272, 1166, 1056, 866, 817 cm-1; Anal. Calcd for C14H21N3O2: 63.85% C, 8.04% H, 15.96% N; Found: 63.93% C, 7.89% H, 16.23% N. mp = 156-157 °C. Yield = 92%.
Synthesis of compounds 3a-3i (General procedure): 9.5 mmol of compounds 3a-3i was dissolved in 15 ml of anhydrous acetic acid (or appropriate amount of other above mentioned anhydrous solvents) and gaseous hydrogen chloride was bubbled in for 2
A. Obreza, U.Urleb: A new synthesis of substituted benzaldehyde N-[(E)-phenylmethylidene]hydrazones
Acta Chim. Slov. 2002, 49, 605-611.
609
minutes. The resulting yellow or orange precipitates were filtered, washed with ether and crystalized from ethanol to yield benzaldehyde N-[(E)-phenylmethylidene]-hydrazones 3a-i.
Benzaldehyde N-[(E)-phenylmethylidene]hydrazone (3a).
1H NMR (300 MHz, DMSO-d6): ? 7.51 (2d, 6H, J=7.16 Hz, Ar-H), 7.89 (2d, 4H, J=7.16 Hz, Ar-H), 8.72 (s, 2H, Ar-CH) ppm; MS (70 eV, EI): m/z (%): 208 (M+, 23), 77 (100); IR (KBr): ? 2914, 2063, 1941, 1815, 1709, 1482, 1239, 1088, 882 cm-1; Anal. Calcd for C14H12N2: 80.74% C, 5.81% H, 13.45% N; Found: 80.59% C, 6.03% H, 13.34% N. mp = 92-94 °C (lit.5: 93 °C). Yield = 92%.
4-Methylbenzaldehyde N-[(E)-(4-methylphenyl)methylidene]hydrazone (3b). 1H NMR (300 MHz, DMSO-d6): ? 2.33 (s, 6H, CH3), 7.76 (d, 4H, J=8.24 Hz, Ar-H), 8.01 (d, 4H, J=8.24 Hz, Ar-H), 8.67 (s, 2H, Ar-CH) ppm; MS (70 eV, EI): m/z (%): 236 (M+, 44), 77 (100); IR (KBr): ? 2951, 2069, 1945, 1816, 1483, 1094, 876 cm-1; Anal. Calcd for C16H16N2: 81.32% C, 6.82% H, 11.85% N; Found: 81.02% C, 7.10% H, 11.59% N. mp= 151-153 °C (lit.4: 153 °C). Yield = 79%.
4-Nitrobenzaldehyde N-[(E)-(4-nitrophenyl)methylidene]hydrazone (3c). 1H NMR (300 MHz, DMSO-d6): ? 8.17 (d, 4H, J=8.85 Hz, Ar-H), 8.38 (d, 4H, J=8.85 Hz, Ar-H), 8.87 (s, 2H, Ar-CH) ppm; MS (70 eV, EI): m/z (%): 298 (M+, 63), 271 (13), 251 (34), 205 (17), 176 (100), 149 (15), 130 (39), 103 (37), 89 (17), 76 (51), 63 (23); IR (KBr): ? 2967, 2564, 2070, 1946, 1597, 1519, 1483, 1346, 1093, 952, 839, 952, 839, 746, 684 cm-1; Anal. Calcd for C14H10N4O4: 56.38% C, 3.38% H, 18.78% N; Found: 56.29% C, 3.51% H, 18.62% N. mp = 296-298 °C (lit.5: 297-298 °C). Yield = 93%.
3-Nitrobenzaldehyde N-[(E)-(3-nitrophenyl)methylidene]hydrazone (3d). 1H NMR (300 MHz, DMSO-d6): ? 7.83 (t, 2H, J=7.98 Hz, Ar-H), 8.33 (d, 2H, J=7.81 Hz, Ar-H), 8.37 (m, 2H, Ar-H), 8.72 (m, 2H, Ar-H), 8.93 (s, 2H, Ar-CH) ppm; MS (70 eV, EI): m/z (%): 298 (M+, 67), 176 (100); IR (KBr): ? 2961, 2729, 2558, 1947, 1625, 1525, 1482, 1354, 1092, 809, 736 cm-1; Anal. Calcd for C14H10N4O4: 56.38% C, 3.38%
A. Obreza, U.Urleb: A new synthesis of substituted benzaldehyde N-[(E)-phenylmethylidene]hydrazones
610
Acta Chim. Slov. 2002, 49, 605-611.
H, 18.78% N; Found: 56.17% C, 3.65% H, 18.57% N. mp= 175-179 °C (lit.5: 196-197 °C). Yield = 95%.
4-({(E)-2-[(E)-(4-Carboxyphenyl)methylidene]hydrazono}methyl)benzoic acid (3e). 1H NMR (300 MHz, DMSO-d6): ? 7.87 (d, 4H, J=8.27 Hz, Ar-H), 8.06 (d, 4H, J=8.27 Hz, Ar-H), 8.80 (s, 2H, Ar-CH), 12.03 (s,2H, COOH) ppm; MS (70 eV, EI): m/z (%): 296 (M+, 39), 124 (100); IR (KBr): ? 3408, 2982, 1685, 1626, 1428, 1292, 1217, 1097, 952, 769 cm-1; Anal. Calcd for C16H12N2O4: 64.86% C, 4.08% H, 9.46% N; Found: 65.00% C, 4.23% H, 9.18% N. mp = 287-289 °C. Yield = 98%.
4-[((E)-2-{(E)-[4-(Aminocarbonyl)phenyl]methylidene}hydrazono)methyl]-benzamide (3f).
1H NMR (300 MHz, DMSO-d6): ? 7.73 (d, 4H, J=8.16 Hz, Ar-H), 8.02 (d, 4H, J=8.16 Hz, Ar-H), 8.74 (s, 2H, Ar-CH), 9.33 and 6.84 (2s,4H, CONH2) ppm; MS (70 eV, EI): m/z (%):294 (M+,46), 122 (100); IR (KBr): ? 3384, 2967, 2034, 1662, 1534, 1430, 1276, 1199, 1087, 966, 784 cm-1; Anal. Calcd for C16H14N4O2: 65.30% C, 4.79% H, 19.04% N; Found: 65,18% C, 4,81% H, 19,20% N. mp = 236-238 °C. Yield = 83%. N-(4-{[(E)-2-((E)-{4-[(acetylamino)methyl]phenyl}methylidene)hydrazono]methyl}-benzyl)acetamide (3g).
1H NMR (300 MHz, DMSO-d6): ? 1.91 (s, 6H, CH3), 4.31 (d,4H, J=5.78 Hz, CH2), 4.88 (s, 2H, NH), 7.37 (d, 4H, J=8.09 Hz, Ar-H), 7.83 (d, 4H, J=8.09 Hz, Ar-H), 8.45 (s, 2H, Ar-CH) ppm; MS (FAB+): m/z (%): 351 (MH+,52) 154 (100); IR (KBr): ? 3422, 2904, 2731, 2580, 1945, 1655, 1560, 1425, 1187, 1096, 1030, 821, 663, 602cm-1; Anal. Calcd for C20H22N4O2: 68.55% C, 6.33% H, 15.99% N; Found: 68.27% C, 6.51% H, 11.59% N. mp = 230-232 °C. Yield = 91%.
4-(Dimethylamino)benzaldehyde N-{(E)-[4-(dimethylamino)phenyl]methylidene}-hydrazone (3h).
1H NMR (300 MHz, DMSO-d6): ? 3.02 (s, 12H, N(CH3)2), 7.12 (d, 4H, J=8.43 Hz, Ar-H), 7.89 (d, 4H, J=8.43 Hz, Ar-H), 8.13 (s, 2H, Ar-CH) ppm; MS (FAB+): m/z (%): 295 (MH+, 100); IR (KBr): ? 3401, 2908, 2571, 1607, 1551, 1432, 1197, 1094 cm-1; Anal.
A. Obreza, U.Urleb: A new synthesis of substituted benzaldehyde N-[(E)-phenylmethylidene]hydrazones
Acta Chim. Slov. 2002, 49, 605-611.
611
Calcd for C18H22N4: 73.44% C, 7.53% H, 19.03% N; Found: 73.20% C, 7.71% H, 18.82% N. mp = 226-228 °C (lit.6: 228-229 °C). Yield = 97%.
4-({(E)-2-[(E)-(4-Cyanophenyl)methylidene]hydrazono}methyl)benzonitrile (3i). 1H NMR (300 MHz, DMSO-d6): ? 7.86 (d, 4H, J=8.60 Hz, Ar-H), 8.07 (d, 4H, J=8.60 Hz, Ar-H), 8.79 (s, 2H, Ar-CH) ppm; MS (70 eV, EI): m/z (%): 258 (M+, 52), 156 (100); IR (KBr): ? 2922, 2565, 2226, 1944, 1670, 1610, 1482, 1411, 1286, 1214, 1094, 1020, 833, 549 cm-1; Anal. Calcd for C16H10N4: 74.40% C, 3.90% H, 21.69% N; Found: 74.62 % C, 4.11% H, 21.25% N. mp = 316-319 °C (lit.7: 318-320 °C). Yield = 100%.
Acknowledgements
This work was supported by the Ministry of Science and Technology of the
Republic of Slovenia, through grant P1-505-002-00.
References and Notes
1.   Zega, A.; Mlinšek, G.; Šepic, P.; Golič-Grdadolnik, S.; Šolmajer, T.; Tschopp, T.; Steiner, B.; Kikelj, D.; Urleb, U. Bioorg. Med. Chem. 2001, 9, 2745–2756.
2.   Zega, A.; Trampuš-Bakija, A.; Fortuna, M.; Stegnar, M.; Tschopp, T.; Steiner, B.; Urleb, U. Pharmazie 2001, 56, 683–685.
3.    Fässler,A.; Bold, G.; Capraro,H.G.; Cozens, R.; Mestan, J.; Poncioni, B.; Rösel, J.; Titelnot-Blomley, M.; Lang, M. J. Med. Chem. 1996, 39, 3203–3216.
4.   Bandlish, B. K.; Garner, A.W.; Hodges, M. L.; Timberlake, J.W. J. Am. Chem. Soc. 1975, 97, 5856– 5862.
5.    Blout, E. R.; Gofstein, J. J. Am. Chem. Soc. 1945, 67, 13–18.
6.    Curtius, T.; Bertho, A. J. Prakt. Chem. 1930, 125, 23–39.
7.    Barber, H. J.; Slack, R. J. J. Am. Chem. Soc. 1943, 65, 1776–1777.
Povzetek
Pri reakciji substituiranih terc-butil 2-(fenilmetiliden)-1-hidrazinkarboksilatov s plinastim HCl v različnih brezvodnih topilih dobimo benzaldehid N-(fenilmetiliden)hidrazone z zelo visokimi izkoristki. Za sintezo spojin tega tipa smo uporabili vrsto različnih, substituiranih benzaldehidov. Strukturo nastalih produktov smo dokazali z uporabo 1H-NMR in IR spektroskopije ter masne spektrometrije.
A. Obreza, U.Urleb: A new synthesis of substituted benzaldehyde N-[(E)-phenylmethylidene]hydrazones