Solvent-free synthesis of diphenyl [2-(aminocarbonyl)-1,2- dihydroisoquinolin-1-yl]phosphonates from isoquinoline, isocyanates, and diphenyl phosphonate

Article abstract of DOI:10.1002/hlca.200900247

The 1:1 intermediates generated by addition of isoquinoline to isocyanates were trapped by diphenyl phosphonate to yield diphenyl [2-(aminocarbonyl)-1,2- dihydroisoquinolin-1-yl]phosphonates in good yields under solvent-free conditions.

Full text of DOI:10.1002/hlca.200900247

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Helvetica Chimica Acta – Vol. 93 (2010)
Solvent-Free Synthesis of Diphenyl [2-(Aminocarbonyl)-1,2-
dihydroisoquinolin-1-yl]phosphonates from Isoquinoline, Isocyanates, and
Diphenyl Phosphonate
by Issa Yavari*, Anvar Mirzaei, and Gholamhossein Khalili
Chemistry Department, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-82883465; fax: þ 98-21-82883455; e-mail: yavarisa@modares.ac.ir)
The 1:1 intermediates generated by addition of isoquinoline to isocyanates were trapped by
diphenyl phosphonate to yield diphenyl [2-(aminocarbonyl)-1,2-dihydroisoquinolin-1-yl]phosphonates
in good yields under solvent-free conditions.
Introduction. – Phosphonate-containing molecules are an important class of active
compounds, and their use and synthesis have received attention during the last two
decades [1 – 4]. Among these, a-aminophosphonates are key compounds as analogues
of a-amino acids in medicinal chemistry and pharmaceutical industries [5].
As part of our current studies on the synthesis of alkylphosphonates [6 – 8], we
report the results of our studies involving the reactions of zwitterions derived from
isoquinoline, isocyanates, and diphenyl phosphonate, which constitute a synthesis of
diphenyl a-aminophosphonates 4.
Results and Discussion. – The reaction of isoquinoline (1), isocyanate (or
isothiocyanate) 2, and diphenyl phosphonate (3) proceeded smoothly and was
1
complete within 4 – 10 min. The H- and 13C-NMR spectra of the crude products
clearly indicated the formation of diphenyl [2-(aminocarbonyl)- or [2-(aminothioxo-
methyl)-1,2-dihydroisoquinolin-1-yl]phosphonates 4 in 96 – 99% yield (Scheme 1 and
Table).
Scheme 1
1
The structures of compounds 4a – 4f were deduced from their IR and H- and
13C-NMR spectra. For example, the 1H-NMR spectrum of 4a exhibited olefinic (d(H)
5.47 and 6.80), CH (d(H) 6.30), and NH (d(H) 7.92) H-atoms, along with ms for the
1
aromatic H-atoms. The H-decoupled 13C-NMR spectrum of 4a showed 22 distinct
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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655
Table. Reaction of Isoquinoline (1) with Isocyanates 2a – 2e, 2g, and 2h or with Isothiocyanate 2f in the
Presence of Diphenyl Phosphonate (3) under Solvent-Free Conditions
Entry RꢀN¼C¼X
Product
Time [min] Yield [%]
1
2
3
4
PhꢀN¼C¼O (2a)
4a 10
98
99
97
97
3-Clꢀ4-MeꢀC6H3ꢀN¼C¼O (2b)
cHexꢀN¼C¼O (2c)
4b 4
4c
7
BuꢀN¼C¼O (2d)
4d 8
5
6
EtꢀN¼C¼O (2e)
PhꢀN¼C¼S (2f)
4e 10
97
96
4f
6
7
8
4-NO2ꢀC6H4ꢀN¼C¼O (2g)
4-ClꢀC6H4ꢀN¼C¼O (2h)
no reaction
no reaction
–
–
–
–
resonances that confirmed the proposed structure. The IR spectrum of 4a displayed
characteristic NH, amide C¼O, and P¼O bands. The 1H- and 13C-NMR spectra of 4b –
4f were similar to those of 4a, except for the amide moieties, which exhibited
characteristic resonances in appropriate regions of the spectrum.
Although the mechanistic details of the reaction are not known, a plausible
rationalization may be advanced to explain the product formation. Presumably, the
zwitterionic intermediate 5 [9][10], formed from 1 and 2, is protonated by 3 to furnish
intermediate 6, which is attacked by 7 to produce 4 (Scheme 2).
In summary, we report a ꢂgreenꢃ synthesis of diphenyl [2-(aminocarbonyl)- or [2-
(aminothioxomethyl)-1,2-dihydroisoquinolin-1-yl]phosphonates in good yields under

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2
solvent-free conditions. The present procedure has the advantage that the reaction
takes place under noncatalytic conditions, and that the reactants can be mixed without
any prior activation or modification.
Experimental Part
General. Compounds 1 – 3 were obtained from Merck and used without further purification. M.p.:
Electrothermal-9100 apparatus; uncorrected. IR Spectra: Shimadzu-IR-460 spectrometer; ˜n in cmꢀ1. 1H-,
13C-, and 31P-NMR Spectra: Bruker-DRX-500-Avance instrument; in CDCl3 at 500.1, 125.7, and 202 MHz,
resp.; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: Finnigan-MAT-8430 mass spectrometer at
70 eV; in m/z (rel. %). Elemental analyses: Heraeus-CHN-O-Rapid analyzer.
Compounds 4: General Procedure. To a stirred mixture of 3 (0.47 g, 2 mmol) and heterocumulene 2
(2 mmol) was added isoquinoline (1; 0.26 g, 2 mmol) at r.t. After a short time (4 – 10 min), solidification
occurred, and the solid was washed with cold MeCN (10 ml) to afford the pure desired products.
Diphenyl 1,2-Dihydro-{2-[(phenylamino)carbonyl]isoquinolin-1-yl}phosphonate (4a): Yield 0.47 g
(98%). White powder. M.p. 148 – 1508. IR (KBr): 3295 (NH), 3035, 1658 (C¼O), 1618, 1585, 1475, 1235
(P¼O), 1205, 927, 740. 1H-NMR: 5.47 (d, 3J(H,H) ¼ 7.3, CH); 6.30 (d, 2J(P,H) ¼ 13.4, CH); 6.80 (d,
3
3
3J(H,H) ¼ 7.3, CH); 6.92 (d, J(H,H) ¼ 7.7, 2 CH); 7.00 (d, J(H,H) ¼ 7.7, 2 CH); 7.03 – 7.12 (m, 4 CH);
7.18 – 7.26 (m, 9 CH); 7.34 (d, 3J(H,H) ¼ 7.5, 2 CH); 7.92 (br. s, NH). 13C-NMR: 55.2 (d, 1J(P,C) ¼ 156.6,
CHꢀP); 110.5 (CH); 120.0 (d, 3J(C,P) ¼ 2.6, 2 CH); 120.1 (d, 3J(C,P) ¼ 2.6, 2 CH); 123.5 (2 CH); 124.0
3
(C); 124.8 (CH); 125.0 (d, J(C,P) ¼ 2.9, CH); 125.1 (2 CH); 125.2 (C); 127.2 (CH); 127.3 (CH); 127.4
3
(C); 128.7 (CH); 128.9 (CH); 129.0 (CH); 129.4 (2 CH); 129.6 (2 CH); 131.4 (d, J(C,P) ¼ 3.3, CH);
150.1 (d, J(C,P) ¼ 10.5, C); 150.2 (d, J(C,P) ¼ 10.5, C); 152.3 (C¼O). 31P-NMR: 11.1. EI-MS: 482 (2,
Mþ), 234 (20), 170 (10), 130 (50), 129 (100), 119 (52), 94 (95), 92 (40), 77 (42), 65 (48), 51 (51), 39 (80).
Anal. calc. for C28H23N2O4P (482.47): C 69.71, H 4.80, N 5.81; found: C 69.80, H 4.75, N 5.72.
Diphenyl {2-{[(3-Chloro-4-methylphenyl)amino]carbonyl}-1,2-dihydroisoquinolin-1-yl}phospho-
nate (4b): Yield 0.52 g (99%). White powder. M.p. 157 – 1598. IR (KBr): 3285 (NH), 3000, 1654
2
2
1
3
(C¼O), 1620, 1578, 1506, 1480, 1208 (P¼O), 932, 756. H-NMR: 2.31 (s, Me); 5.94 (d, J(H,H) ¼ 7.5,
2
3
3
CH); 6.27 (d, J(P,H) ¼ 12.9, CH); 6.79 (d, J(H,H) ¼ 7.6, CH); 6.92 (d, J(H,H) ¼ 8.4, 2 CH); 7.02 (d,
3J(H,H) ¼ 8.0, 2 CH); 7.09 – 7.15 (m, 4 CH); 7.20 – 7.31 (m, 8 CH); 7.42 (s, 1 CH); 7.96 (br. s, NH).
13C-NMR: 28.4 (Me); 47.5 (d, 1J(P,C) ¼ 160.5, CHꢀP); 110.8 (CH); 118.5 (CH); 120.2 (d, 3J(C,P) ¼ 4.0,
3
2 CH); 120.8 (d, J(C,P) ¼ 2.0, 2 CH); 124.9 (CH); 125.0 (CH); 125.1 (CH); 125.2 (CH); 125.3 (CH);
2
127.5 (C); 128.0 (d, J(C,P) ¼ 2, C); 129.2 (CH); 129.6 (2 CH); 129.8 (CH); 130.9 (2 CH); 131.2 (CH);
131.5 (C); 134.4 (C); 135.2 (C); 137.2 (CH); 150.1 (d, J(C,P) ¼ 11, C); 150.2 (C); 152.4 (C¼O). 31P-
2
NMR: 11.6. EI-MS: 530 (1, Mþ), 234 (22), 170 (12), 167 (52), 140 (38), 130 (51), 129 (100), 113 (47), 94
(92), 77 (44), 51 (50), 39 (75). Anal. calc. for C29H24ClN2O4P (530.95): C 65.60, H 4.56, N 5.28; found: C
65.52, H 4.61, N, 5.35.
Diphenyl {2-[(Cyclohexylamino)carbonyl]-1,2-dihydroisoquinolin-1-yl}phosphonate (4c): Yield
0.47 g (97%). White powder. M.p. 143 – 1458. IR (KBr): 3330 (NH), 2910, 1661 (C¼O), 1619, 1583,
1478, 1248 (P¼O), 1211, 945, 764. 1H-NMR: 1.20 (m, 3 CH); 1.39 (m, 2 CH); 1.61 – 1.70 (m, 3 CH); 1.95
(m, 2 CH); 3.72 (m, CHꢀN); 5.35 (br. s, NH); 5.92 (d, 3J(H,H) ¼ 5.7, CH); 6.30 (d, 2J(P,H) ¼ 15.0, CH);
3
3
6.71 (d, J(H,H) ¼ 7.4, CH); 6.98 – 7.01 (m, 4 CH); 7.09 (d, J(H,H) ¼ 7.5, CH); 7.11 – 7.16 (m, 2 CH);

Helvetica Chimica Acta – Vol. 93 (2010)
657
7.24 – 7.29 (m, 5 CH); 7.32 – 7.34 (m, 2 CH). 13C-NMR: 24.8 (CH2); 24.9 (CH2); 25.6 (CH2); 33.3 (CH2);
1
3
33.5 (CH2); 50.0 (CHꢀN); 54.9 (d, J(P,C) ¼ 155.0, CꢀP); 110.0 (CH); 120.2 (d, J(C,P) ¼ 3.8, 2 CH);
120.4 (d, 3J(C,P) ¼ 3.8, 2 CH); 124.7 (CH); 125.0 (d, 3J(C,P) ¼ 2.5, CH); 125.1 (CH); 125.2 (CH); 127.3
3
3
(CH); 127.9 (d, J(C,P) ¼ 5.0, C); 128.9 (d, J(C,P) ¼ 2.5, CH); 129.0 (C); 129.5 (2 CH); 129.6 (2 CH);
131.9 (d, 3J(C,P) ¼ 3.8, CH); 150.3 (d, 2J(C,P) ¼ 10.0, C); 150.4 (d, 2J(C,P) ¼ 11.3, C); 153.7 (C¼O). 31P-
NMR: 11.4. EI-MS: 488 (2, Mþ), 234 (18), 170 (11), 130 (52), 129 (100), 125 (48), 98 (37), 94 (89), 77
(40), 71 (45), 51 (46), 39 (71). Anal. calc. for C28H29N2O4P (488.52): C 68.84, H 5.98, N 5.73; found: C
68.70, H 5.90, N 5.67.
Diphenyl {2-[(Butylamino)carbonyl]-1,2-dihydroisoquinolin-1-yl}phosphonate (4d): Yield 0.50 g
(97%). White powder. M.p. 133 – 1358. IR (KBr): 3350 (NH), 2925, 1641 (C¼O), 1615, 1523, 1478, 1243
1
3
(P¼O), 1207, 920, 755. H-NMR: 0.95 (t, J(H,H) ¼ 7.0, Me); 1.39 (m, CH2); 1.52 (m, CH2); 3.32 (t,
3J(H,H) ¼ 7.1, CH2N); 5.45 (br. s, NH); 5.94 (d, 3J(H,H) ¼ 5.0, CH); 5.27 (d, 2J(P,H) ¼ 15.0, CH); 6.71 (d,
3
3
3J(H,H) ¼ 7.5, CH); 6.97 (d, J(H,H) ¼ 7.6, 2 CH); 7.02 (d, J(H,H) ¼ 7.6, 2 CH); 7.09 – 7.15 (m, 3 CH);
7.24 – 7.33 (m, 7 CH). 13C-NMR: 13.7 (Me); 20.1 (CH2); 32.0 (CH); 42.8 (CH2N); 55.1 (d, 1J(P,C) ¼ 153.8,
3
3
CꢀP); 110.0 (CH); 120.2 (d, J(C,P) ¼ 5.0, 2 CH); 120.4 (d, J(C,P) ¼ 3.8, 2 CH); 124.6 (C); 125.0 (d,
3J(C,P) ¼ 2.4, CH); 125.1 (CH); 127.3 (CH); 127.4 (CH); 127.9 (d, J(C,P) ¼ 5.0, C); 128.9 (CH); 129.0
3
3
2
(CH); 129.5 (2 CH); 129.6 (2 CH); 131.8 (d, J(C,P) ¼ 3.8, CH); 150.3 (d, J(C,P) ¼ 10.0, C); 150.4 (d,
2J(C,P) ¼ 11.3, C); 154.6 (C¼O). 31P-NMR: 12.3. EI-MS: 462 (1, Mþ), 234 (19), 170 (13), 130 (48), 129
(100), 99 (48), 94 (87), 77 (40), 72 (30), 57 (10), 51 (46), 45 (46), 39 (71). Anal. calc. for C26H27N2O4P
(462.48): C 67.52, H 5.88, N 6.06; found: C 67.39, H 5.78, N 6.10.
Diphenyl {2-[(Ethylamino)carbonyl]-1,2-dihydroisoquinolin-1-yl}phosphonate (4e): Yield 0.42 g
(97%). White powder. M.p. 123 – 1258. IR (KBr): 3345 (NH), 3025, 1620 (C¼O), 1619, 1582, 1468, 1293
(P¼O), 1210, 915, 763. 1H-NMR: 1.61 (t, 3J(H,H) ¼ 7.2, Me); 3.33 (m, CH2N); 5.44 (2J(P,H) ¼ 28.0, CH);
3
3
5.92 (br. d, CH); 6.28 (br. s, NH); 6.68 (d, J(H,H) ¼ 7.5, CH); 6.95 (d, J(H,H) ¼ 8.0, 2 CH); 6.98 (d,
3J(H,H) ¼ 7.9, 2 CH); 7.06 – 7.11 (m, 3 CH); 7.21 – 7.29 (m, 7 CH). 13C-NMR: 15.2 (Me); 36.1 (CH2N);
54.9 (d, 1J(P,C) ¼ 155.1, CꢀP); 110.2 (CH); 120.2 (d, 3J(C,P) ¼ 4.3, 2 CH); 120.4 (d, 3J(C,P) ¼ 4.3, 2 CH);
3
4
124.6 (C); 124.8 (d, J(C,P) ¼ 3.0, CH); 124.9 (CH); 125.0 (CH); 127.3 (d, J(C,P) ¼ 2.5, CH); 127.9 (d,
3J(C,P) ¼ 5.8, C); 128.9 (CH); 129.0 (CH); 129.5 (2 CH); 129.6 (2 CH); 131.8 (d, J(C,P) ¼ 3.3, CH);
3
150.3 (d, J(C,P) ¼ 10.5, C); 150.5 (d, J(C,P) ¼ 10.6, C); 154.5 (C¼O). 31P-NMR: 13.1. EI-MS: 434 (2,
Mþ), 234 (18), 170 (14), 130 (46), 129 (100), 71 (49), 94 (88), 73 (30), 44 (15), 44 (30), 39 (71). Anal.
calc. for C24H23N2O4P (434.43): C 66.35, H 5.34, N 6.45; found: C 66.22, H 5.29, N 6.36.
2
2
Diphenyl 1,2-Dihydro-2-[(phenylamino)thioxomethyl]isoquinolin-1-yl]phosphonate (4f): Yield
0.48 g (96%). White powder. M.p. 152 – 1548. IR (KBr): 3344 (NH), 3015, 1582, 1479, 1253 (P¼O),
1208, 933, 764. 1H-NMR: 4.94 (d, 2J(P,H) ¼ 17.4, CH); 6.88 (d, 3J(H,H) ¼ 7.8, 2 CH); 7.05 (t, 3J(H,H) ¼
7.4, CH); 7.10 – 7.18 (m, 6 CH); 6.19 – 6.23 (m, 5 CH); 7.25 – 7.28 (m, 6 CH); 7.56 (d, 3J(H,H) ¼ 7.19, CH);
1
3
7.92 (br. s, NH). 13C-NMR: 54.1 (d, J(P,C) ¼ 128.5, CꢀP); 120.4 (d, J(P,C) ¼ 4.0, 2 CH); 120.5 (CH);
120.6 (d, 3J(C,P) ¼ 4.1, 2 CH); 120.7 (2 CH); 120.7 (CH); 125.1 (CH); 125.3 (2 CH); 126.4 (C); 126.5 (d,
3J(C,P) ¼ 3.4, CH); 127.9 (d, 4J(C,P) ¼ 3, CH); 128.1 (C); 128.6 (d, 3J(C,P) ¼ 3.9, CH); 129.5 (CH); 129.6
3
3
(CH); 129.7 (2 CH); 129.8 (2 CH); 133.6 (d, J(C,P) ¼ 6.8, CH); 133.7 (d, J(C,P) ¼ 6.7, C); 150.2 (d,
2J(C,P) ¼ 10.2, C); 150.3 (C¼S); 150.4 (d, J(C,P) ¼ 10.5, C). 31P-NMR: 12.5. EI-MS: 498 (2, Mþ), 234
2
(23), 186 (11), 130 (50), 129 (100), 135 (50), 94 (85), 92 (38), 77 (40), 65 (44), 51 (38), 39 (65). Anal.
calc. for C28H23N2O3PS (498.53): C 67.46, H 4.65, N 5.62; found: C 67.20, H 4.55, N 5.55.
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Received June 29, 2009