methylamine in ethanol was stirred until complete dissolution
(25 min). After concentration to dryness and scratching with a
glass rod to induce crystallization, the product was rinsed with
ether (Found C, 43.4; H, 4.4; N, 10.1. C15H18N3O5PS2 requires
C, 43.3; H, 4.3; N, 10.1%); mmax 3380, 3320, 3180; dH (DMSO-
d6) 2.39 (3H, dd, J 5.6 and 13.6, CH3), 3.21 (2H, m, NCH2),
4.93 (2H, dt (apparent q), J 7.8, OCH2), 5.26 (1H, dq (apparent
sext.), J 5.6 and 11.2, NHCH3), 7.41–8.42 max 8.3 (10H, m,
C6H5 + C6H4 + NHSO2); dC (DMSO-d6) 27.3 (d, J 2.2, CH3),
42.6 (d, J 8.9, NCH2), 62.2 (d, J 5.6, OCH2), 124.3 and 128.5
(2 C ortho, 2 C meta C6H4NO2), 128.2 (d, J 12.9, 2 C ortho
PhPS), 130.2 (d, J 10.9, 2 C meta PhPS), 131.3 (d, J 3, C para
PhPS), 133.9 (d, J 141.5, C ipso), 146.1 and 149.4 (2 quat.C
C6H4NO2); dP (DMSO-d6) +77.9. After dissolution in DMF
containing an excess of ∼40% aqueous methylamine solution
the reaction reached completion in less than 5 min (dP +78
(90%): 11a, + 65 (10%): 9a).
Illustrative procedure no. 2 (crystallization in the presence
of citric acid): benzylamide 13f. A dichloromethane (20 cm3)
solution of 8c (5.13 g, 12.08 mmol) and benzylamine (1.5 cm3, 1.1
eq.) was concentrated to dryness after 2 h (31P NMR: the single
signal of 13f d +15.2). The residue was triturated ∼5 min in a
∼10% acid solution (a few cm3). After addition of ∼1 volume of
alcohol the product soon crystallized (Found: C, 56.5; H, 5.7; N,
7.9. C25H30N3O6PS requires: C, 56.7; H, 5.7; N, 7.8%); mmax 3260,
3170, 1730; dH (DMSO-d6) 1.14 (3H, t, J 7.1, CH2CH3), 2.31
(3H, s, CCH3), 2.52 (3H, d, J 9.4, NCH3), 3.74 (2H, apparent dd
(ABX spectrum), CH2 sarcosine), 3.93–4.19 max 4.02 (4H, m, 2
CH2: benzylic and ethyl), 5.58 (1H, dt, J 10.4 and 6.5, NHCH2),
6.96–7.67 max 7.34 (13H, m, C6H5 + 2 C6H4), 9.1 (1H, s, NH
tosyl).
salt, + 75.7 (75%): aminolysis product attributed by comparison
with d of 11a.) Similarly with potassium alaninate (∼8 eq.) and
water (∼100 eq.) after 5 min 31P NMR showed 3 signals: d =
+66.79 (60%): hydrolysis, +75.9 (20%), +75.0 (20%): aminolysis
(two diastereoisomers).
Alcoholysis—illustrative procedure: methyl ester 10a. To a
DMF solution of 6a, triethylamine (∼1.9 eq.), then methanol
(∼40 eq.) were added. After 30 min (31P NMR control: a single
signal d +88.6), the solution was concentrated to dryness and the
product crystallized quantitatively in a mixture of ethyl acetate–
ether (1/1), mp 102–104 ◦C (Found: C, 43.3; H, 4.1; N, 6,7.
C15H17N2O6PS2 requires C, 42.9; H, 4.1; N, 6.4%); mmax 3214,
1348, 1166, 1529, 1311; dH (CDCl3) 3.31 (2H, dt, J 5.1 and 5.5,
NCH2), 3.66 (3H, d, J 13.8, CH3), 4.11 (2H, dt, J 5.5 and 10,
OCH2), 6.9–7.3 max 7.2 (5H, m, C6H5), 7.9 (4H, qAB, J 9.1,
C6H4); dC (CDCl3) 43.5 (d, J 7.3, NCH2), 53.5 (d, J 5.3, OCH3),
64.6 (d, J 5.5, OCH2), 124.4 (2 C ortho C6H4NO2), 128.3 (2 C
meta C6H4NO2), 128.3 (d, J 15.1, 2 C ortho PhPS), 131 (d, J
11.9, 2 C meta PhPS), 132.9 (d, J 2,8, C para PhPS), 131.5 (d, J
151.2, C ipso), 145.9 and 149.9 (2 quat.C C6H4NO2); dP (CDCl3)
+91.4.
Acknowledgements
The authors thank Mrs A. Colomer for the IR measurements
and formatting the manuscript.
References
1 M. Mulliez, Tetrahedron, 1981, 37, 2027–2041; also: N. E. Jacobsen
and P. A. Bartlett, J. Am. Chem. Soc., 1983, 105, 1613–1619.
2 M. Mulliez and M. Wakselman, Phosphorus Sulfur Relat. Elem.,
1980, 8, 41–50.
3 F. Dujols, P. Jollet and M. Mulliez, Phosphorus Sulfur Silicon Relat.
Elem., 1998, 134–135, 231–254.
4 F. Dujols and M. Mulliez, J. Heterocycl. Chem., 2001, 38, 475–480.
5 F. Dujols and M. Mulliez, Phosphorus Sulfur Silicon Relat. Elem.,
2000, 157, 165–191.
6 M. Mulliez, Participation of sulfonamides in the reactions of
phosphorylation, in preparation; F. Dujols’ thesis (Universite´ Paul
Sabatier, Toulouse (France), 4-10-99), chapter VII.
7 J. Devillers, L. T. Tran and J. Navech, Bull. Soc. Chim. Fr., 1970,
182–183.
8 C. Brown, J. A. Boudreau, B. Hewitson and R. F. Hudson, J. Chem.
Soc., Perkin Trans. 2, 1976, 888–895.
9 D. B. Cooper, C. R. Hall, J. M. Harrisson and T. D. Inch, J. Chem.
Soc., Perkin Trans. 1, 1977, 1969–1980.
Illustrative procedure no. 3 (purification by acid–base extrac-
tions): glycine ethyl ester derivative 13b. To a pyridine (3 cm3)
solution of 8a (0.48 g, 1.15 mmol) and glycine ethyl ester
hydrochloride (0.16 g, 1.15 mmol), triethylamine (0.17 cm3,
1.2 eq.) was added after 17 h. 31P NMR control: after 16 h: d +
64.3 (10%): 13b, + 59.7 (90%): 8a; after 17 h 45: d +65 (100%).
The solution was concentrated to a small volume, diluted with
ether (∼20 cm3) extracted with ∼10% citric acid and ∼5%
bicarbonate solutions (3 × ∼15 cm3 each) and dried (Na2SO4).
After concentrating to dryness and diluting in absolute ethanol
(a few cm3) the product soon crystallized (Found: C, 53.1; H,
4.8; N, 5.4. C23H25N2O6PS2 requires C, 53.3; H, 4.9; N, 5.3%);
dH (DMSO-d6) 1.19 (3H, t, J 7.1, CH2CH3), 2.29 (3H, s, CH3
tosyl), 3.85 (2H, d, J 14.9, CH2 glycine), 4.04 (2H, q J 7.1,
CH2CH3), 7–7.69 max 7.24 (15H, m, C6H5 + 2 C6H4 + 2 NH);
dC (CDCl3) 14.2 (CH3 ethyl), 21.6 (CH3 tosyl), 44 (CH2 gly), 62.2
(CH2 ethyl), 121.1 (d, J 4.3), 122.3, 125.2, 125.8, 127.3, 129.6,
129.9 (CH, 9 expected), 129.1 (d, J 6.1), 136.5, 141.6 (d, J 7.5),
143.9, 150.4 (d, J 7.2) (quat C, 5 expected), 170.8 (d, J 6.9, CO);
dP (CDCl3) +63.6.
10 See particularly: R. J. Edmundson and T. A. Moran, J. Chem. Soc.,
1971, 3437–3441. However with prior silylation a clean acylation
occurs: M. Mulliez, Bull. Soc. Chim. Fr., 1985, 1211–1218.
11 P. Cazabonne, F. Dujols and M. Mulliez, Synthesis of constrained
N-sulfonylated amino-alcohols, in preparation; F. Dujols’ thesis
(Universite´ Paul Sabatier, Toulouse (France), 4-10-99), chapter VI.
12 P. Jacob, W. Ritcher and I. Ugi, Liebigs Ann. Chem., 1991, 519–522.
13 M. Mulliez, Phosphorus Sulfur Relat. Elem., 1980, 9, 209–220.
14 For example with the heterocycles incorporating a glycol moiety: M.
Revel, J. Navech and F. Mathis, Bull. Soc. Chim. Fr., 1971, 105–110.
15 T. Koizumi, Y. Watanabe, Y. Yoshida and E. Yoshii, Tetrahedron
Lett., 1974, 1075–1078.
Hydrolysis—illustrative procedure: dicyclohexylammonium
salt 9a. To a suspension of 6a in a ∼2 : 1 (v/v) DMF–water
mixture, triethylamine (1.5 eq.) was added after 2 h 15 min, and
dicyclohexylamine (1.1 eq.) after complete solubilization (4 h
15 min). 31P NMR control: after 2 h: d +85.8 (70%): 6a; +74.2
(30%): acid corresponding to 9a; after 4 h: a single signal d
+66.2: triethylammonium salt. After concentration to dryness,
the product was crystallized in a methanol–water mixture, mp
85–87 ◦C (Found: C, 51.9; H, 6.7; N, 6.7. C26H38N3O6PS2. H2O
requires C, 51.7; H, 6.5; N, 6.6%); dH (DMSO-d6) 1–1.9, max
1.64 (20H, m, 10 CH2 DCHA), 3.16 (2H, t, J 5.3, NCH2), 3.16
(2H, m, 2 CH DCHA), 3.7 (2H, s, H2O), 3.9 (2H, m, OCH2),
7.32–8 max 7.36 (7H, m, C6H5 + NH2), 8.25 (4H, qAB, J 9,
C6H4); dP (DMSO-d6) +67.5.
16 F.H. Westheimer, Acc. Chem. Res., 1968, 1, 70–78.
17 The lack of pseudorotation implies that the reaction, as with non
sulfonylated heterocycles9 occurs with inversion of the phosphorus
configuration. A priori the access to the requisite chiral heterocycles
should be easy (simple separation of diastereoisomers), using chiral
aminoacids instead of sarcosine (in 8c) and N phenylglycine (in 8d).
18 One should note that generally hydrolysis or alcoholysis are favoured
over aminolysis: thermodynamically P–O bonds are stronger than P–
N bonds and usually amino P(V) intermediates are less stable. For a
discussion of this problem see: J. M. Gre´vy and M. Mulliez, J. Chem.
Soc., Perkin Trans. 2, 1995, 1809–1815.
19 R. F. Hudson and R. J. Greenhalgh, J. Chem. Soc., 1969, 325–329.
20 L. Horner, J. Prakt. Chem., 1992, 334, 645–655.
21 R. Hirschmann, K. M. Yager, C. M. Taylor, J. Witherington, P. A.
Sprengler, B. W. Phillips, W. Moore and A. B. Smith, J. Am. Chem.
Soc., 1997, 119, 8177–8190.
The reaction of tetrabutylammonium glycinate (∼15 eq.) and
water (∼200 eq.) in DMF solution went to completion in less
than 5 min. (31P NMR: two signals d = + 66.5 (25%): potassium
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 7 – 2 3 2
2 3 1