Carbamoylphosphonates part 7. An efficient method for the synthesis of hindered carbamoylphosphonates using 4-nitrophenoxycarbonylphosphonate diesters

Article abstract of DOI:10.1016/j.tetlet.2008.03.036

Hindered primary amines that resist other reagents can be converted to carbamoylphosphonates by means of 4-nitrophenoxycarbonylphosphonate diesters in high yields and under mild conditions.

Full text of DOI:10.1016/j.tetlet.2008.03.036

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Tetrahedron Letters 49 (2008) 2875–2877
Carbamoylphosphonates Part 7. An efficient method for the
synthesis of hindered carbamoylphosphonates using
4-nitrophenoxycarbonylphosphonate diesters
Irena Beylis a, Julia Frant a, Naama Mussai a, Reuven Reich b, Eli Breuer a,*
a Department of Medicinal Chemistry, School of Pharmacy, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel
b Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel
Received 31 January 2008; revised 22 February 2008; accepted 6 March 2008
Available online 18 March 2008
Abstract
Hindered primary amines that resist other reagents can be converted to carbamoylphosphonates by means of 4-nitro-
phenoxycarbonylphosphonate diesters in high yields and under mild conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
We have recently reported that some carbamoylphos-
phonic acids (CPOs, 1, R0 = H) are capable of inhibiting
matrix metalloproteinases (MMPs) in vitro,1 and in vivo.2,3
Carbamoylphosphonates have been known for almost a
century. The first compound of this class, the parent diethyl
carbamoylphosphonate, H2NCOP(O)(OEt)2, was prepared
by reacting triethyl phosphonoformate and anhydrous
ammonia in an alcohol solvent for several weeks (5a,
Method B, Scheme 1).4 Later, substituted carb-
amoylphosphonates were prepared by the Arbuzov reac-
tions of carbamoyl chlorides with trialkyl phosphites5 or
by the addition of dialkyl H-phosphonates 3 to alkyl or
aryl isocyanates6 (2, Method A, Scheme 1). Subsequently,
it was found that this reaction could be accelerated signifi-
cantly by base catalysis.7
Another convenient synthetic approach to compounds 1
is based on the reaction of trialkyl phosphonothiol-
formates8 5b with ammonia9 or an amine (4, Method B,
Scheme 1). The latter approach is particularly convenient
when a series of N-substituted carbamoylphosphonates
are required as it uses a common, phosphorus-containing,
starting material, 5b, which can be reacted with many
primary and secondary amines, instead of needing the
synthesis of isocyanates
2
(Scheme 1). Triethyl
phosphonothiolformate (5b, R = R0 = Et) reacts with
amines via the cleavage of the S-acyl bond,9 as opposed
Method A
Method B
O
O
O
O
R'
R'
O
R'
R'
R'
R'
base
R
C
R
O
O
P
+
O
O
R NH2
+
N
N
P
H
X
P
O
-HX
H
O
O
5a, X = R-O-
5b, X = R-S-
1
3
4
2
6, X = 4-O2N-C6H4-O-
Scheme 1.
*
Corresponding author. Tel.: +972 2 675 8704; fax: +972 2 675 8934.
E-mail address: eli.breuer@huji.ac.il (E. Breuer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.036

2876
I. Beylis et al. / Tetrahedron Letters 49 (2008) 2875–2877
Table 1
Comparison of the efficiency of 4-nitrophenoxycarbonylphosphonate (6) and phosphonothiolformate (5) as reagents in carbamoylphosphonate synthesis
R-NH2 + X-CO-P(O)(OR’)2 → R-NH-CO-P(O)(OR’)2 + H-X
4
5 or 6
1
Reagent
6 X = 4-O2N–C6H4O–
5b, X = EtS–
Starting material
Solvent
Product yielda (%) (reaction time, 1 h)b
Solvent (catalyst)
Product Yielda (%) (reaction time h)b
4, R–NH2 tert-Bu–NH2
1-Adamantyl–NH2
MeCN
DMF
65
83
MeCN
DMF
30 (48)
0 (24)
CH2NH2
MeCN
50
MeCN (DMAP)
0 (72)
0 (24)
NHBoc
CH2NH2
DCM
85
MeCN
NHBoc
a
Yields were determined by 31P NMR spectral examination of the crude reaction mixtures.
All reactions were performed at room temperature.
b
to P-acyl fission, which is the characteristic behavioral
nated hydrocarbons, ethers, amides (e.g., DMF) nitriles,
amines and pyridine. An advantage of the reactions is that
the salts of amines can also be used, as the free bases can be
generated in situ by adding a strongly basic tertiary amine
such as diisopropylethylamine to the reaction mixture.
The onset of the reaction usually occurs instantly after mix-
ing the reagents at room temperature as indicated by the
appearance of the intense yellow color of the 4-nitropheno-
late anion. Another convenient aspect of the method is that
the difference in 31P NMR chemical shifts between reagent 6
(d = ꢀ6 to ꢀ8 ppm) and the CPO products (d = ꢀ2 to
ꢀ4 ppm) is sufficiently large to allow monitoring the pro-
gress of the reaction directly by 31P NMR spectroscopy.
At the end of the reaction, the 4-nitrophenol byproduct
can be removed from the reaction mixture by extraction
with 0.5 M NaOH solution. If the solvent used for the reac-
tion is water soluble it must be replaced with dichlorometh-
ane. All the carbamoylphosphonate esters prepared are new
compounds. They have been dealkylated by a treatment
with TMSBr11 to give the corresponding carbamoylphos-
phonic acids, which have been characterized by elemental
pattern of simple acylphosphonate diesters toward nucleo-
philes.10 The phosphonate diesters 1 (R0 = alkyl) can subse-
quently be dealkylated with bromotrimethylsilane11
(TMSBr) in chloroform12 followed by methanolysis to
the corresponding N-(cyclo)alkylcarbamoylphosphonic
acids CPOs, 1, R0 = H). As has been pointed out, some
CPOs are active as MMP inhibitors, and are potentially
useful in the treatment of various diseases such as cancer
metastasis,2,3,13 arthritis, and several other connective
tissue-related disorders that have been shown to be medi-
ated by MMPs.13
For our further studies we required CPOs derived from
sterically hindered, tertiary alkyl- or 2-substituted cyclo-
alkylamines. Attempts to obtain these using reagent 5b
(Method B, Scheme 1), however, were unsuccessful even
under harsh conditions, and in the presence of 4-N,N-
dimethylaminopyridine (DMAP) as catalyst, apparently
due to its poor reactivity. We considered that the problem
could be overcome by increasing the electrophilicity of the
carbonyl group in 5b, simply by substituting ‘X’ with a
stronger electron-withdrawing group. Comparison of the
pKa values of the two leaving groups EtSH (pKa = 10.6)
with that of 4-nitrophenol (pKa = 7.15) revealed three
orders of magnitude difference between the two values.
Therefore, we examined 4-nitrophenylphosphonoformate
diethyl14 and diisopropyl15 esters, (abbreviated as Et–
NPPF and iPr–NPPF, respectively) 6a, and 6b as reagents
in these syntheses. Indeed, we found that reagents 6 reacted
rapidly with sterically hindered amines (that reacted only
sluggishly or not at all with 5b) to give the corresponding
CPOs under mild conditions. The results of the reactions
of four representative sterically hindered amines with the
two reagents 5b and 6 are shown in Table 1. The applica-
tion of ‘NPPF’ esters 6 for the synthesis of CPOs has not
been reported previously.
1
analysis and by H and 31P NMR spectroscopy.
Acknowledgements
This work was supported in part by the Ministry of Sci-
ence of Israel and in part by The German Israeli Founda-
tion for Scientific Research and Development (GIF) to
E.B. and R.R. and, in part, by the Grass Center for Drug
Design and Synthesis of Novel Therapeutics. R.R. and
E.B. are affiliated with the David R. Bloom Center of Phar-
macy, in the School of Pharmacy, Faculty of Medicine,
The Hebrew University of Jerusalem.
Supplementary data
The reactions were carried out by mixing the reactants in
a wide variety of solvents, such as hydrocarbons, haloge-
Experimental procedures and analytical data of the
compounds shown in Table 1 and of additional CPOs syn-

I. Beylis et al. / Tetrahedron Letters 49 (2008) 2875–2877
2877
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6, can be found in the Supplementary data associated with
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2008.03.036.
11. Salomon, C. J.; Breuer, E. Tetrahedron Lett. 1995, 36, 6759.
12. Following our publication11 we found that using chloroform as
solvent, the reactions are faster and cleaner, and result in higher
yields.
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2007, 2, 152–171; (b) Hu, J.; Van den Steen, P. E.; Sang, Q.-X. A.;
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