A novel and convenient method for synthesis of carbamoyl and thiocarbamoyl phosphonates

Article abstract of DOI:10.1002/hc.20538

A simple, efficient, and general method has been developed for the synthesis of carbamoyl and thiocarbamoyl phosphonic esters using CaCl ₂ as an efficient Lewis base catalyst. Carbamoyl and thiocarbamoyl phosphonic esters were obtained in good

Full text of DOI:10.1002/hc.20538

Heteroatom Chemistry
Volume 20, Number 4, 2009
A Novel and Convenient Method
for Synthesis of Carbamoyl and
Thiocarbamoyl Phosphonates
Babak Kaboudin and Hazegh Zahedi
Department of Chemistry, Institute for Advanced Studies in Basic Sciences, Gava Zang,
Zanjan 45195-1159, Iran
Received 18 February 2009; revised 4 May 2009
have been reported as a new zinc-binding group
ABSTRACT: A simple, efficient, and general method
for selective matrix metalloproteinases (MMP)
has been developed for the synthesis of carbamoyl and
inhibitors [6,7]. In contrast to the widely studied
thiocarbamoyl phosphonic esters using CaCl2 as an
α-functional phosphonic acid derivatives [8–12],
efficient Lewis base catalyst. Carbamoyl and thiocar-
relatively few papers have reported on the chemistry
bamoyl phosphonic esters were obtained in good yield
of carbamoylphosphonates, although there is
(37%–65%) and purity under mild conditions by the
evidence that carbamoylphosphonates are phar-
reaction of diethyl phosphite with isocyanates and
maceutically active [13–16]. The base-catalyzed
isothiocyanates in the presence of CaCl2. This method
reaction of dialkyl phosphite with isocyanates and
is easy, rapid, and good-yielding reaction for the syn-
isothiocyanates by alkali metals or their alkox-
thesis of carbamoyl and thiocarbamoyl phosphonic
ides has been reported in the literature for the
ꢀ
C
esters. 2009 Wiley Periodicals, Inc. Heteroatom Chem
preparation of carbamoylphosphonates [17,18]. The
Arbuzov reaction of cabamoyl chlorides with trialkyl
phosphite also reported as an applicable method
20:250–253, 2009; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20538
for the preparation carbamoylphosphonates [19].
However, these highly reactive reagents suffer from
INTRODUCTION
high toxicity and low selectivity that limit its general
use. Recently, phosphonoformylation of primary
amine by triethyl phosphonothiolformate has been
reported as a novel method for the synthesis of
carbamoylphosphonates [6].
In recent years, the development of a more
economical and environment friendly conversion
processes has gaining interest. Calcium chloride
is inexpensive, commercially available and has re-
cently been shown to act as a very excellent Lewis
base catalyst in organic transformation [20–22]. In
continuation of our interest in developing novel
methodologies for the synthesis of organophospho-
rous compounds [23–31], herein we report an ef-
ficient, practical, environmentally benign, and good
yielding method for the synthesis of carbamoylphos-
phonates from isocyanates and isothiocyanates.
Phosphorus-carbon bond formation has attracted
growing attention due to their novel application
in organic synthesis and bio-organic chemistry.
α-Functionalized phosphonic acids are valuable
intermediates for the preparation of medicinal
compounds and synthetic intermediates [1–5].
Among α-functional phosphonic acids, car-
bamoylphosphonates are important class of
compounds that exhibit a variety of interesting and
useful properties. Recently, carbamoylphosphonates
Correspondence to: Babak Kaboudin; e-mail: kaboudin@iasbs.
ac.ir.
Contract grant sponsor: Institute for Advanced Studies in Basic
Sciences.
c
ꢀ
2009 Wiley Periodicals, Inc.
250

A Novel and Convenient Method for Synthesis of Carbamoyl and Thiocarbamoyl Phosphonates 251
O O
O
P
and aliphatic isocyanates with diethyl phosphite
in dichloromethane at room temperature under
Ar atmosphere afforded the corresponding car-
bamoylphosphonates in good yields (2a–2c). The re-
actions also proceeded with isothiocyanates using
calcium chloride as catalyst to give corresponding
thiocarbamoylphosphonates in moderate to good
yield (2d–2g). Dibenzyl phosphite also reacted with
isocyanates and isothiocyanates to give correspond-
ing phosphonates in good yields (2h–2j). The reac-
tions were clean with no tar formation (Scheme 2).
Some of the carbamoylphosphonates prepared by
this method have been used as MMP inhibitors [6,7].
In summary, simple work-up, fast reaction rates,
mild reaction conditions, good yields, and the rela-
tively clean reactions with no tar formation make
this method an attractive and a useful contribution
to present methodologies. Indeed, a wide range of
isocyanates and isothiocyanates were converted into
the corresponding carbamoyl and thiocarbamoyl
phosphonates using this method.
H
N
OEt
CaCl2 (0.1 equiv)
Ph
C P(OEt)2
Ph
N C O + H
OEt CH2Cl2, Ar, 12 h
1a
2a
SCHEME 1
Synthesis of diethyl anilinocarbonylphos-
phonate from phenylisocyanates.
X O
O
H
OR′
CaCl2 (0.1 equiv)
CH2Cl2, Ar, 6-24 h
R
N C P(OR′)2
H
N C X +
P
R
OR′
1
2
X=O, S
SCHEME 2 Synthesis of carbamoyl and thiocarbamoyl-
phosphonates.
RESULTS AND DISCUSSION
Initially, we have carried out the reaction of phenyl
isocyanate, as a model compound, with diethyl phos-
phite in the presence of calcium chloride as a cat-
alyst in a variety of solvents. Conversion of phenyl
isocyanate to corresponding carbamoylphosphonate
was generally completed in chlorinated solvents
compared with protic solvents such as methanol and
ethanol. We found that reaction of phenyl isocyanate
with diethyl phosphite for 12 h in dichloromethane
gave diethyl phenyl carbamoylphosphonate in 65%
yield (Scheme 1).
EXPERIMENTAL
Chemicals were either prepared in our laboratories
or purchased from Merck, Fluka, and Aldrich Chem-
ical Companies. NMR spectra were taken with a 250
Brucker Avance instrument with the chemical shifts
being reported as δ ppm and couplings expressed in
hertz. Silica gel column chromatography was carried
out with Silica gel 100 (Merck no. 10184).
In the absence of any catalyst, phenyl isocyanate
did not undergo the conversion reaction with diethyl
phosphite in dichloromethane at room temperature
for 48 h.
To study the scope and limitation of the reac-
tion, various isocyanates and isothiocyanates were
subjected to treatment with dialkyl phosphite in the
presence of calcium chloride in dichloromethane
at room temperature. As shown in Scheme 2 and
Table 1, the reaction of a mixture of aromatic
General Procedure for the Synthesis of
Carbamoyl and Thiocarbamoyl Phosphonates
from Isocyanates and Isothiocyanates (2)
Calcium chloride (0.25 mmol) was added to a
stirred mixture of dialkylphosphite (3 mmol) in
TABLE 1 Synthesis of Carbamoyl and Thiocarbamoylphosphonates from Isocyanates and Isothiocyanates in the Presence
of Dialkyl Phosphite Using Calcium Chloride as Catalyst
Product
R
X
R ꢁ
Reaction Time (h)
Yield (%)a
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5−
O
O
O
S
S
S
S
O
O
S
Et−
12
12
18
24
6
12
18
12
12
24
65
55
62
45
56
52
61
60
58
37
4-Me-3-ClC6H3−
Cyclohexyl
C6H5−
Et−
Et−
Et−
p-NO2C6H4−
p-CH3C6H4−
Ph-CH2−CH2−
Cyclohexyl
Ph-CH2−
Et−
Et−
Et−
PhCH2−
PhCH2−
PhCH2−
2j
C6H5−
aConversions were monitored by TLC analysis.
bYields refer to the isolated pure products after column chromatography.
Heteroatom Chemistry DOI 10.1002/hc

252 Kaboudin and Zahedi
dichloromethane (5 mL) at room temperature. Iso-
cyanate or isothiocyanate (2.5 mmol) was added to
the reaction mixture, and the mixture was stirred
for 6–24 h at room temperature under Ar atmo-
sphere. Evaporation of the mixture under reducing
pressure gave oily mixture. The oily mixture residue
was purified by column chromatography on alumina
(hexane/EtOAc = 5:1) to give pure product in 37%–
65% yield. All products gave satisfactory spectral
data in accordance with the assigned structures and
literature reports.
CDCl3): 16.20 (d, JPC = 6.3 Hz), 65.7 (d, JPC = 6.3 Hz),
121.8, 124.8, 129.8, 147.2, 192.8 (d, JPC = 186.7 Hz).
Anal. Calcd for C11H15N2O5PS. C, 41.50; H, 4.75; N,
8.80. Found: C, 41.35; H, 4.63; N, 8.52.
Diethyl [(4-Methylphenyl)amino]carbonothioyl-
phosphonate (2f). 1H NMR (250 MHz, CDCl3): 1.39
(t, 6H, J = 7.0 Hz), 2.37 (s, 3H), 4.20–4.38 (m,
4H), 7.23 (d, 1H, J = 7.5 Hz), 7.85 (d, 1H, J = 7.5
Hz), 10.40–10.60 (br, 1H, NH). 31P NMR (101.2
MHz, CDCl3, H3PO4): −0.84 ppm. 13C NMR (62.9
MHz, CDCl3): 16.2 (d, JPC = 6.3 Hz), 21.2, 65.3 (d,
JPC = 6.3 Hz), 121.9, 127.5, 129.1, 137.6 (d, JPC = 15.7
Hz), 192.3 (d, JPC = 186.4 Hz). Anal. Calcd for
C12H18NO3PS. C, 50.61; H, 6.32; N, 4.88. Found: C,
50.50; H, 6.20; N, 4.71.
Diethyl anilinocarbonylphosphonate (2a) [17].
1H NMR (250 MHz, CDCl3): 1.37 (t, 6H, J = 7.0 Hz),
4.15–4.38 (m, 4H), 7.15 (t, 1H, J = 7.2 Hz), 7.33 (t, 2
H, J = 7.5 Hz), 7.67 (d, 2H, J = 7.5 Hz), 9.39 (s, 1H,
NH). 31P NMR (101.2 MHz, CDCl3, H3PO4): −1.26
ppm;
Diethyl
[(2-Phenylethyl)amino]carbonothioyl-
phosphonate (2g). 1H NMR (250 MHz, CDCl3):
1.31 (t, 6H, J = 7.0 Hz), 3.00 (t, 2H, J = 7.5 Hz),
3.85–4.05 (m, 2H), 4.10–4.35 (m, 4H), 7.10–7.45
(m, 5H), 9.40–9.60 (br, 1H, NH). 31P NMR (101.2
MHz, CDCl3, H3PO4): −1.13 ppm. 13C NMR (62.9
MHz, CDCl3): 16.2 (d, JPC = 6.3 Hz), 33.4, 46.1 (d,
JPC = 8.8 Hz), 65.0 (d, JPC = 6.3 Hz), 126.8, 128.7,
129.8, 137.9, 192.5 (d, JPC = 181.1 Hz). Anal. Calcd
for C13H20NO3PS. C, 51.81; H, 6.69; N, 4.65. Found:
C, 51.65; H, 6.42; N, 4.60.
Diethyl [(3-Chloro-4-methylphenyl)amino] car-
bonylphosphonate(2b). 1H NMR (250 MHz, CDCl3):
1.39 (t, 6H, J = 7.0 Hz), 2.33 (s, 3H), 4.18–4.40 (m,
4H), 7.18 (d, 1H, J = 8.25 Hz), 7.49 (d, 1H, J = 8.25
Hz), 7.81 (s, 1H), 9.48 (s, NH). 31P NMR (101.2
MHz, CDCl3, H3PO4): −1.58 ppm. 13C NMR (62.9
MHz, CDCl3): 16.2 (d, JPC = 5.7 Hz), 19.6, 64.7 (d,
JPC = 6.9 Hz), 118.5, 120.8, 131.0, 133.2, 134.5, 135.5
(d, JPC = 13.8 Hz), 164.2 (d, JPC = 227.7 Hz). Anal.
Calcd for C12H17ClNO4P. C, 47.20; H, 5.62; N, 4.59.
Found: C, 46.95; H, 5.52; N, 4.39.
Dibenzyl
(Cyclohexylamino)carbonylphospho-
nate (2h). 1H NMR (250 MHz, CDCl3): 1.05–1.45
(m, 5H), 1.50–1.95 (m, 5H), 3.60–3.90 (m, 1H), 5.15
(dd, 4H, JHH = 2.2 Hz and JHP = 8.25 Hz), 6.80–6.90
(br, 1H, NH), 7.35 (s, 10H). 31P NMR (101.2 MHz,
CDCl3, H3PO4): −0.29 ppm. 13C NMR (62.9 MHz,
CDCl3): 24.7, 25.2, 32.5, 48.6 (d, JPC = 6.9 Hz),
69.5 (d, JPC = 6.9 Hz), 128.1, 128.7, 128.6, 135.3 (d,
JPC = 6.3 Hz), 164.3 (d, JPC = 223.3 Hz). Anal. Calcd
for C21H26NO4P. C, 65.09; H, 6.77; N, 3.62. Found:
C, 64.85; H, 6.58; N, 3.60.
Diethyl (Cyclohexylamino)carbonylphosphonate
(2c) [13]. 1H NMR (250 MHz, CDCl3): 1.05–1.95
(m, 16H), 3.70–3.85 (m, 1H), 4.05–4.30 (m, 4H),
6.90–7.10 (br, 1H, NH). 31P-NMR (101.2 MHz,
CDCl3, H3PO4): −0.24 ppm. 13C NMR (62.9 MHz,
CDCl3): 16.2 (d, JPC = 6.3 Hz), 24.7, 25.2, 32.6, 48.5
(d, JPC = 6.9 Hz), 64.2 (d, JPC = 6.3 Hz), 165.5 (d,
JPC = 224.3 Hz).
Diethyl Anilinocarbonothioylphosphonate (2d)
[16]. 1H NMR (250 MHz, CDCl3): 1.39 (t, 6H, J = 7.0
Hz), 4.15–4.38 (m, 4H), 7.28 (t, 1H, J = 7.2 Hz),
7.46 (t, 2H, J = 7.5 Hz), 7.98 (d, 2H, J = 7.5 Hz),
10.50–10.70 (br, 1H, NH). 31P NMR (101.2 MHz,
CDCl3, H3PO4): −1.05 ppm. 13C NMR (62.9 MHz,
CDCl3): 16.3 (d, JPC = 6.3 Hz), 65.3 (d, JPC = 7.5 Hz),
122.0, 127.5, 129.1, 137.9 (d, JPC = 15.7 Hz), 193.5 (d,
JPC = 185.3 Hz).
Dibenzyl
(Benzylamino)carbonylphosphonate
(2i). 1H NMR (250 MHz, CDCl3): 4.43 (d, 2H,
J = 5.5 Hz) (m, 1H), 5.15 (dd, 4H, JHH = 1.75 and
JHP = 8.25 Hz), 7.35 (s, 10H), 7.50–7.80 (br, 1H, NH).
31P NMR (101.2 MHz, CDCl3, H3PO4): −0.70 ppm.
13C NMR (62.9 MHz, CDCl3): 43.3 (d, JPC = 8.2 Hz),
69.7 (d, JPC = 6.9 Hz), 127.8, 128.0, 128.2, 128.6,
128.8, 135.2, 135.3, 136.7, 165.3 (d, JPC = 225.2 Hz).
Anal. Calcd for C22H22NO4P. C, 66.81; H, 5.61; N,
3.54. Found: C, 66.60; H, 5.45; N, 3.38.
Diethyl
[(4-Nitrophenyl)amino]carbonothioyl-
phosphonate (2e). 1H NMR (250 MHz, CDCl3): 1.39
(t, 6H, J = 7.0 Hz), 4.10–4.38 (m, 4H), 8.15–8.35 (m,
4H), 10.90–11.10 (br, 1H, NH). 31P NMR (101.2 MHz,
CDCl3, H3PO4): −2.21 ppm. 13C NMR (62.9 MHz,
Dibenzyl Anilinocarbonothioylphosphonate (2j).
1H NMR (250 MHz, CDCl3): 5.20–5.33 (m, 4H), 7.25–
7.47 (m, 13H), 7.89 (d, 2H, J = 8.0 Hz), 10.35–10.60
Heteroatom Chemistry DOI 10.1002/hc

A Novel and Convenient Method for Synthesis of Carbamoyl and Thiocarbamoyl Phosphonates 253
(br, 1H, NH). 31P NMR (101.2 MHz, CDCl3, H3PO4):
[13] Breuer, E.; Katz, Y.; Hadarb, R.; Reich, R. Tetrahe-
−1.80 ppm. 13C NMR (62.9 MHz, CDCl3): 70.8 (d,
JPC = 6.4 Hz), 122.0, 128.2–129.1 (m, Ar), 137.8 (d,
JPC = 15.5 Hz), 191.5 (d, JPC = 181.3 Hz). Anal. Calcd
for C21H20NO3PS. C, 63.46; H, 5.07; N, 3.53. Found:
C, 63.55; H, 4.90; N, 3.37.
dron: Asymmetry 2004, 15, 2415.
[14] Skarpos, H.; Vorobeva, D. V.; Osipov, S. N.; Odinets,
I. L.; Breuer, E.; Roschenthaler, G.-V. Org Biomol
Chem 2006, 4, 3669.
[15] Canac, Y.; Aniol, G. E.; Conejero, S.; Donnadieu, B.;
Bertrand, G. Eur J Inorg Chem 2006, 5076.
[16] Bulpin, A.; Le, S.; Gourvennec, R.; Masson, S. Phos-
phorus Sulfur Silicon 1994, 89, 119.
[17] Fox, R. B.; Venezky, D. L. J Am Chem Soc 1956, 78,
1661.
REFERENCES
[18] Tashma, Z. J Org Chem 1982, 47, 3012.
[19] Reetz, T.; Chadwick, D. H.; Hardy, E. E.; Kaufman,
S. J Am Chem Soc 1955, 77, 3813.
[1] Engel, R. Chem Rev 1977, 77, 349.
[2] Kaboudin, B. Phosphorus Sulfur Silicon Relat Elem
2002, 177, 1749.
[20] Miura, K.; Nakagawa, T.; Hosomi, A. J Am Chem Soc
2002, 124, 536.
[21] Gangadasu, B.; Narender, P.; China, R. B.;
Jayathirtha, R. V. Indian J Chem, Sect B 2006, 45,
1259.
[3] Afarinkia, K.; Rees, C. W. Tetrahedron 1990, 46, 7175.
[4] Kaboudin, B.; Haghighat, H.; Yokomatsu, T. J Org
Chem 2006, 71, 6604.
[5] Blazis, V. J.; Koeller, K. J.; Spilling, C. D. J Org Chem
1995, 60, 931.
[22] Kaboudin, B.; Zahedi, H. Chem Lett 2008, 37,
540.
[23] Kaboudin, B.; Haruki, T.; Yamaghishi, T.;
Yokomatsu, T. Tetrahedron 2007, 63, 8199.
[24] Kaboudin, B.; Haruki, T.; Yamagishi, T.; Yokomatsu,
T. Synthesis 2007, 3226.
[6] Farkas, E.; Katz, Y.; Rhusare, S.; Reich, R.;
Roschenthaler, G.-V.; Konigsmann, M.; Breuer, E.
J Biol Inorg Chem 2004, 9, 307.
[7] Breuer, E.; Salomon, C. J.; Katz, Y.; Chen, W.; Lu,
S.; Roschenthaler, G.-V.; Hadar, R.; Reich, R. J Med
Chem 2004, 47, 2826.
[25] Kaboudin, B.; Jafari, E. Synthesis 2006, 3063.
[26] Kaboudin, B.; Elhamifar, D. Synthesis 2006,
224.
[27] Kaboudin, B.; Sorbiun, M. Tetrahedron Lett 2007,
48, 9015.
[28] Kaboudin, B.; Jafari, E. Synthesis 2007, 1823.
[29] Kaboudin, B.; Haghighat, H.; Yokomatsu, T. Tetra-
hedron: Asymmetry 2008, 19, 862.
[8] Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahe-
dron: Asymmetry 1993, 4, 1779.
[9] Kaboudin, B.; Rahmani, A. Synthesis 2003, 2705.
[10] Kukhar, V. P.; Hudson, H. R. (Eds.). Aminophospho-
nic and Aminophosphinic Acids: Chemistry and Bio-
logical Activity; Wiley: Chichester, UK, 2000.
[11] For a review, see: Collinsova´, M.; Jira´cek, J. Curr Med
Chem 2000, 7, 629.
[30] Kaboudin, B.; Jafari, E. Synlett 2008, 1837.
[31] Kaboudin, B.; Jafari, E. Synthesis 2008, 2683.
[12] Matziari, M.; Georgiadis, D.; Dive, V.; Yiotakis, A. Org
Lett 2001, 3, 659.
Heteroatom Chemistry DOI 10.1002/hc