The modified 'phosphine imide' reaction: A safe and soft alternative ureas synthesis

Article abstract of DOI:10.1016/j.tetlet.2004.05.002

In this work we present a new way for the direct and general synthesis of urea compounds from primary amines by the modified 'phosphine imide' reaction. A large panel of amine structures are compatible with the smooth reaction conditions. Particularly in the case of sensitive L-aminoesters, it is interesting to note that the stereochemistry at the asymmetric centre was unmodified in the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2004.05.002

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5027–5029
The modified ‘phosphine imide’ reaction: a safe and soft alternative
ureas synthesis
Stanislaw Porwanski,a Stephane Menuel,b Xavier Marsurab and Alain Marsurab,*
aDepartment of Organic and Applied Chemistry, University of Lodz, ul.Naturowicza 68, 90-136 Lodz, Poland
bG.E.V.S.M. Unitꢀe Mixte de Recherche du CNRS 7565, Structure et Rꢀeactivitꢀe des Systꢁemes, Molꢀeculaires Complexes,
Facultꢀe des Sciences Pharmaceutiques 5, rue A. lebrun 5400, B.P. 403 Nancy cedex, France
Received 20 February 2004;revised 30 April 2004;accepted 3 May 2004
Abstract—In this work we present a new way for the direct and general synthesis of urea compounds from primary amines by the
modified ‘phosphine imide’ reaction. A large panel of amine structures are compatible with the smooth reaction conditions. Par-
ticularly in the case of sensitive L-aminoesters, it is interesting to note that the stereochemistry at the asymmetric centre was
unmodified in the reaction conditions.
Ó 2004 Elsevier Ltd. All rights reserved.
It is obvious that new methods and strategies leading to
the efficient formation of amide or urea bonds remain
very important in peptide or pseudopeptide synthesis.1
An interesting approach earlier reported in the literature
described a first one-step modified reaction enabling the
obtention of isocyanates from primary amines and
phenylalanine methyl ester using the Mitsunobu chem-
istry.2 Very recently, the so-called ‘phosphine imide’
strategy has been intensively employed to achieve simple
and direct access to sophisticated cyclodextrin host
derivatives (including preparation of Cds monoisocya-
nate), via the formation of urea or thiourea bonds from
azides.3
O
i
ii
R1-N=P(Ph)3
R1-NH2
1-7
R1-HN
NH-R1
8 - 14
COOBn
COOEt
COOEt
CH
HO
CH
R1
=
CH
3
2
1
H2
C
COOMe
CH
4
6
5
7
Scheme 1. Reagents and conditions: (i) CCl4/P(Ph)3/Et3N/CH2Cl2/Ar;
(ii) R1-NH2 (1 equiv)/CO2/24 h/rt.
In the present work, the extension of the latter to pri-
mary amines or L-aminoacid esters in place of azides is
As previously reported in the case of the phosphine
imide reaction,3 the new synthesis presented here could
also run in a ‘one-pot’ manner.7 As illustrated in Scheme
1, pseudoureido dipeptide esters 8–11 and bis-ureas 12–
14 are obtained in medium to good yields (see Table 1)
proposed. As demonstrated earlier by Appel,4 we sug-
gest a new approach, which combines an amino phos-
phonium salt step formation obtained by the reaction of
an amine with the triphenylphosphine/CCl4 reagent,
then followed by its in situ base dehydrohalogenation.
This should give an iminophosphorane intermediate
(Scheme 1) and will finally be able to give, through the
phosphine imide route, the expected ureido derivatives.5
from L-aminoacid esters 1–4 and primary amines 5–7 by
reaction with: triphenylphosphine/CCl4, Et3N, then
24 h, rt, CO2 bubbling in anhydrous CH2Cl2 or DMF.
However, the reaction with less reactive aromatic
amines, for example, naphthylamine 7 works poorly and
a large amount of the starting product was recovered.8
The spectroscopic data6 are in perfect agreement with
the proposed structures. It is interesting to point out
Keywords: Urea formation;Modified phosphine imide reaction.
* Corresponding author. Tel.: +33-03-8368-2324;fax: +33-03-8368-
2345;e-mail: alain.marsura@pharma.uhp-nancy.fr
that no racemization occurs at the asymmetric centre of
1
L
-aminoacid esters as confirmed by H- and 13C NMR.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.002

5028
S. Porwanski et al. / Tetrahedron Letters 45 (2004) 5027–5029
Table 1. Pseudoureido dipeptide derivatives and ureas 8–14
€
5. Appel, R.;Blaser, B.;Kleinst uck, R.;Ziehn, K. D. Chem.
Ber. 1971, 104, 1847–1854;Appel, R.;Blaser, B.;Siege-
mund, G. Z. Anorg. Allg. Chem. 1968, 363, 176–
182.
Amine
Urea
Yield (%)
1
2
3
4
5
6
7
L
L
L
L
-Phenylalanine ethylestera
-Serine ethylesterb
-Valine benzylesterc
-Valine methylesterc
8
9
89
41
47
65
96
79
17
6. Structure of all compounds were assigned by 1H and 13C
NMR on a Bruker-DRX 400 spectrometer, FTIR spectra
were recorded on a Bruker–Vector 22 spectrometer. The
solvents were purified by standard methods.
10
11
12
13
14
Cyclohexylamined
Benzylamined
Naphtylamined
7. Ureas 8–11. Carbon tetrachloride (0.6 equiv) was added to
a mixture of triphenylphosphine (1.1 equiv) and amine
(1 equiv) in anhydrous CH2Cl2. The mixture was stirred
and heated at reflux under argon for 24 h. The solution was
concentrated to dryness. Anhydrous CH2Cl2 was added to
the residue. Then triethylamine (1 equiv) was added to the
solution and the mixture was stirred 2 h at rt. After,
the mixture was stirred at rt under CO2 for 24 h more. The
solution was concentrated to dryness and the residue was
chromatographed on a silica gel column.
a Conditions: amine (mmol) ¼ 8, P(Ph)3 (equiv) ¼ 1.2, CCl4
(equiv) ¼ 0.6;Et 3N ¼ 3 mL.
b Conditions: amine (mmol) ¼ 5.1, P(Ph)3 (equiv) ¼ 5.7, CCl4
(equiv) ¼ 2.8, Et3N ¼ 1.5 mL.
c Conditions: amine (mmol) ¼ 6, P(Ph)3 (equiv) ¼ 6.6, CCl4
(equiv) ¼ 0.6;Et 3N ¼ 3 mL.
d Conditions: amine (mmol) ¼ 8, P(Ph)3 (equiv) ¼ 1.1, CCl4
(equiv) ¼ 1.1;Et 3N ¼ 3 mL.
N,N0-2-[Di-(phenylethylpropanoate)]-urea 8. Yield (%) 89
(3.8 mmol, 1.58 g);TLC SiO 2;CH 2Cl2/MeOH 93/7;
1
Rf ¼ 0:34;IR (KBr) m ¼ 3357 (NH);1625 (NH– C@O); H
Moreover, the primary alcohol side group in L-serine,
needs no protection and remains unchanged in the
reaction conditions.
NMR (CD3OD) d ¼ 1:23 (t, CH3, J ¼ 6:9 Hz);3.03 (d, 4H,
CH2Bn, J ¼ 5:7 Hz);4.12 (m, 4H, CH );4.79 (m, 2H,CH);
2
5.26 (m, 2H, NH);7.11–7.28 (10H, arom); 13C NMR
(CD3OD) ¼ 14.0 (CH3);38.72 (CH 2Bn);54.0 (CH);61.28
(CH2–CH3);126.8 (C arom);128.3 (C arom);129.4 (C
In conclusion, we have shown the in situ modified
‘phosphine imide’ reaction could be applied successfully
to primary amines in place of azides in a ‘one-pot’
procedure to afford symmetrical ureas. We argued this
method could be also considered as a valuable alterna-
tive to recently described methods, for example, obten-
tion of ureas using Mitsunobu reagent, or hazardous
phosgene or triphosgene.9 Future work to apply the
reaction to dissymmetric ureas and in the solid phase to
free aminoacids or, for example, to protected peptides
intermolecular coupling is under investigation.
4
3
2
arom);136.2 (C
arom);156.2 (NH–C @O);172.8 (O–
1
C@O). ESI-MS m=z (%) ¼ 413.3 (100) [MþH]þ.
N,N0-2-[Di-(methyl-2-hydroxymethylethanoate)]-urea
9.
Yield (%) 41 (2.43 mmol, 0.324 g);TLC (SiO 2;AcOEt/
MeOH 4/1); Rf ¼ 0:27;IR (KBr) m ¼ 3100–3500 (OH);
1735 (NH–C@O); 1H NMR (DMSO) d ¼ 1:11 (t, 6H, CH3,
J ¼ 7:05 Hz);3.57 (d, 4H, CH , J ¼ 7:05 Hz);4.12 (m, 4H,
2
CH–CH3);3.76 (m, 2H, CH);3.88 (m, 4H, CH 2–OH); 13C
NMR (DMSO) d ¼ 17:2 (CH3);57.7 (CH 2);60.5 (CH);
63.2 (CH2OH);168.5 (O–C @O);172.5 (NH–C @O).
N,N0-2-[Di-(benzylisopentanoate)]-urea 10. Yield (%) 47
(2.82 mmol, 0.584 g);TLC (SiO ;AcOEt/hexane/CH Cl2 1/
2
2
1/1); Rf ¼ 0:80;IR (KBr) m ¼ 3332 (NH);1740 (NH–C @O);
1H NMR (CDCl3) d ¼ 0:89 (d, 6H, CH3, J ¼ 6:9 Hz);0.95
(d, 6H, CH3, J ¼ 6:9 Hz);2.15 (m, 2H, CH(CH 3)2);4.51
(dd, 2H, CH, J ¼ 4:6 Hz, J ¼ 8:8 Hz);5.19 (dd, 2H, NH,
J ¼ 12:2 Hz, J ¼ 37:2 Hz);7.32–7.39 (m, 8H, arom); 13C
NMR (CDCl3) d ¼ 17:9 (CH3);19.5 (CH 3);31.9
Acknowledgements
ꢀ
We are grateful to the University Henri Poincare Nancy-
I, MRES and to the CNRS for the financial support.
The authors wish to thank Mrs. N. Marshall for cor-
recting the manuscript.
(CH(CH3)2);58.4 (CH);67.4 (C
arom);128.7 (C arom);
3
1
128.9 (C2 arom);135.8 (C
arom);157.9 (O–C @O);
4
173.97(NH–C@O).
N,N0-2-[Di-(methylisopentanoate)]-urea 11. Yield (%) 65
(3.89 mmol, 1.12 g);TLC (SiO 2;CH 2Cl2/AcOEt/MeOH/
hexane2/1/1/1); Rf ¼ 0:50;IR (KBr) m ¼ 3382 (NH);1736
(NH–C@O); 1H NMR (CDCl3) d ¼ 0:9 (6H, d, CH3,
J ¼ 6:9 Hz);2.21 (m, 2H, CH(CH 3)2);2.96 (s, 2H, NH);
3.31 (dd, 2H, CH, J ¼ 4:6 Hz, J ¼ 8:8 Hz);3.74 (m, 6H,
CH3); 13C NMR (CDCl3) d ¼ 17:6 (C3);19.6 ( C3);32.6
(CH(CH3)2);52.1 (CH);60.4 (CH 3);162.9 (O–C @O);176.4
(NH–C@O).
References and notes
1. Nowick, J. S. Acc. Chem. Res. 1999, 32, 287–296 (and
references cited therein);Semetey, V.;Hemmerlin, C.;
Didierjean, C.;Schaffner, A. P.;Giner, A. G.;Aubry, A.;
Briand, J. P.;Marraud, M.;Guichard, G. Org. Lett. 2001,
3, 3843–3846;Rincon, A. M.;Prados, P.;de Mendoza, J. J.
Am. Chem. Soc. 2001, 123, 3493–3498.
2. Saylick, D.;Horwath, M. J.;Elmes, P. S.;Jackson, W. R. J.
Org. Chem. 1999, 64, 3940–3946.
ꢀ
3. Sallas, F.;Marsura, A.;Petot, V.;Pint er, I.;Kov acs, J.;
Jicsinszky, L. Helv. Chim. Acta 1998, 81, 632–645;Char-
8. Ureas 12–14. Carbon tetrachloride (0.88 mL;1.1 equiv) was
added to a mixture of triphenylphosphine (2.26 g, 1.1 equiv)
and corresponding amine (1 equiv) in anhydrous CH2Cl2
(20 mL/mmol of amine). The mixture was stirred and
heated at reflux under argon for 24 h. The solution was
concentrated to dryness. Anhydrous CH2Cl2 was added to
the residue with triethylamine (1 equiv) and the mixture was
stirred at rt. After 2 h, amine (1 equiv) was added and the
mixture was stirred at rt under CO2 for 24 h. The solution
was concentrated to dryness and mixture of diethylether
and water (3:1) was added to the residue at 0 °C. The
resulting precipitate was filtered and washed thoroughly
with diethylether and cold water.
ꢀ
ꢀ
ꢀ
bonnier, F.;Marsura, A.;Roussel, K.;Kov acs, J.;Pint er, I.
Helv. Chim. Acta 2001, 84, 535–551;Heck, R.;Dumarcay,
F.;Marsura, A. Chem. Eur. J. 2002, 8, 2438–2445;
Porwanski, S.;Kryczka, B.;Marsura, A. Tetrahedron Lett.
2002, 43, 8441–8443.
4. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801–811;
Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 87, 863–874.

S. Porwanski et al. / Tetrahedron Letters 45 (2004) 5027–5029
5029
N,N0-Dicyclohexylurea 12. Yield (%) 96 (7.1 mmol, 1.59 g);
mp ¼ 233–234 °C;IR (KBr) m ¼ 3328 (NH);1655 (N–
C@O); 1H NMR (CF3COOD) d ¼ 3:50 (2H, m, CH–
CH2–);2.20–1.00 (m, 20H, –CH 2–); 13C NMR (CDCl3)
d ¼ 25:3 (C4);26.0 (C );34.3 (C );49.7 (C );155.0 (NH–
2H, NH, J ¼ 5:8 Hz);7.20–7.38 (m, 8H, arom); 13C NMR
(CDCl3) d ¼ 43:9 (CH2);127.4 (C 4 arom);127.9 (C 2 arom);
129.1
(C3
arom);141.8
(C
arom);158.9
1
(N–C@O).
N,N0-Dinaphtylurea 14. Yield (%) 17 (1.4 mmol, 0.430 g);
mp ¼ 275–280 °C decomposition;IR (KBr) m ¼ 3377 (NH);
1637 (NH–C@O); 1H NMR (CDCl3) d ¼ 5:31 (2H, s, NH);
7.48–7.96 (m, 14H, arom).
3
2
1
C@O).
N,N0-Dibenzylurea 13. Yield (%) 79 (6.3 mmol, 1.52 g);
mp ¼ 170–171 °C;TLC (SiO 2;CH 2Cl2/MeOH 96/4);
1
Rf ¼ 0:34;IR (KBr) m ¼ 3323 (NH);1627 (NH–C @O); H
9. Maya, I.;Lopez, O.;Maza, S.;Fernandez-Bolanos, J. G.;
Fuentes, J. Tetrahedron Lett. 2003, 44, 8539–8543.
NMR (CDCl3) d ¼ 4:24 (d, 4H, CH2, J ¼ 5:91 Hz);6.43 (t,