The influence of ring size on the selectivity of phosphorus heterocycle aminolysis in the presence of water or alcohols - Case of 2-oxo- or 2-thioxo-3-sulfonyl-1,3,2-oxazaphosphorinanes

Article abstract of DOI:10.1002/ejoc.200500743

Seven phosphorus heterocycles 2 were synthesized in one step by condensing P^IV dichlorides 3 with N-sulfonyl-3-aminopropanols 4. In the presence of water, they react selectively with the less bulky amines. No change in selectivity of aminolysis

Full text of DOI:10.1002/ejoc.200500743

FULL PAPER
DOI: 10.1002/ejoc.200500743
The Influence of Ring Size on the Selectivity of Phosphorus Heterocycle
Aminolysis in the Presence of Water or Alcohols – Case of 2-Oxo- or
2-Thioxo-3-sulfonyl-1,3,2-oxazaphosphorinanes[‡]
Frédéric Dujols*[a] and Michel Mulliez[a]
Keywords: Amino alcohols / Sulfonamides / Phosphorus heterocycles / Phosphorylation / Chemoselectivity
Seven phosphorus heterocycles 2 were synthesized in one
step by condensing PIV dichlorides 3 with N-sulfonyl-3-ami-
nopropanols 4. In the presence of water, they react selec-
tively with the less bulky amines. No change in selectivity
of aminolysis was observed when using these six-membered
heterocycles 2 instead of their five-membered analogs 1.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Results
Recently[1] we reported the first observed selective ami-
nolysis of phosphorus heterocycles, namely 1, in the pres-
ence of water. This was attributed to the effect of the good
sulfonamide leaving group (pKa Ϸ 10[2,3]). However, it may
also result from the five-membered-ring size effect, as phos-
phorus displays an extraordinary reactivity in heterocycles
of this kind.[4] In that case, the mechanism of phosphoryl-
ation is of the addition–elimination (A.E.) type, while with
six-membered heterocycles, as with the common acyclic
phosphorus compounds, a different SN2P mechanism is op-
erative.[5] We describe in this paper the previously unre-
ported synthesis and reactivity of the six-membered hetero-
cycles 2. This should enable us to discriminate between the
leaving group and the size (mechanism) effect for heterocy-
cles 1 and eventually to discover an improved aminolysis
for heterocycles 2 relative to that for 1 (Figure 1).
Synthesis and Characterization
In a straightforward manner and in analogy with the
synthesis of heterocycles 1, PIV dichlorides 3 and γ-N-sulfo-
nylamino alcohols 4 were used, the latter being easily pre-
pared[6] by the selective sulfonylation of 3-aminopropanol.
Among the three methods selected for the synthesis of 1,
only using the disodium salts of the N-sulfonyl amino
alcohols 4 (prepared in situ in anhydrous THF) proved to
be satisfactory (Figure 2).
Figure 2. Synthesis of the heterocycles 2.
The NaCl formed was eliminated either by filtration or
by aqueous extraction without any significant loss of het-
erocycles 2 by hydrolysis. These heterocycles (seven repre-
sentatives shown in Table 1) are all crystalline in racemic
form except 2f. As expected, they display correct elemental
analyses and mass spectra, no OH or NH vibration in the
IR spectra, a noticeable deshielding of the O and N methyl-
Figure 1. Phosphorous heterocycles 1, 2, 8, and 9.
1
ene groups, both in H- and 13C NMR spectra, relative to
those in compound 4, and a characteristic complexity of
the H NMR spectra due to the magnetic nonequivalence
[‡] Intramolecular Catalysis of Phosphorus Heterocycles Incorpo-
rating an α-Aminoamide Moiety, V. Part IV: Ref.[1]
[a] Laboratoire de Synthèse et Physico-chimie de Molécules
d’Intérêt Biologique, Unité Mixte de Recherche no. 5068
associée au Centre National de la Recherche Scientifique, Uni-
versité Paul Sabatier,
1
of the two protons of each methylene group.[7] Of interest
are the shielded values (∆δ Ϸ 10 ppm) of the 31P NMR
spectra compared with those of the five-membered analogs
1, a phenomenon which can be attributed to the reduced
strain in 6-membered heterocycles 2.
118 route de Narbonne, 31062 Toulouse cedex 09, France
Fax: + 33-5-61558255
E-mail: candre@chimie.ups-tlse.fr
Eur. J. Org. Chem. 2006, 1959–1964
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1959

F. Dujols, M. Mulliez
FULL PAPER
Table 1. Heterocycles 2.
it appears that the selectivity of heterocycles 2 is compar-
able to that of 1.[1] For example, with the heterocycle 1 cor-
responding to 2d (same environment around phosphorus,
numbered[1] 6a), the ratio aminolysis/hydrolysis in aqueous
solutions of methylamine, potassium glycinate, and potas-
sium alaninate is 90:10, 75:25, and 60:40, respectively.[1,17]
N°
Y
R
RЈ
M.p. [°C] (solvent of
Yield[%]
recrystallization)
Table 2. Products of hydrolysis, alcoholysis, and aminolysis of the
heterocycles 2.
2a
2b
2c
2d
2e
2f
S
S
S
S
O
O
O
Me Me
95–97 (Et2O-iPr2O)
70
65
61
68
65
63
59
Me NO2 117–119 (MeOH)
Ph Me 145–147 (Et2O)
Ph NO2 154–156 (Et2O)
Me Me
Ph Me
OPh Me
123–125 (EtOAc/Et2O)
oil
94–96 (CHCl3–Et2O)
N°[a]
Y
R
RЈ
R"
Yield[%]
2g
5a
S
O
S
S
S
S
S
S
S
S
Me
Me
Me
Ph
Ph
Me
Ph
Me
Me
Ph
Me
Me
Me
Me
NO2 OMe
Me
Me
NO2 OBn
Me
NO2 NHMe
OH DCHA salt
OH DCHA salt
OMe
87
5e
82
6a1
6c1
6d1
6a2
6c2
6b2
7a1
7d1
100[b]
Reactivity
OMe
100[b]
100[b]
Heterocycles 2 are less reactive than their analogs 1 most
probably because of the reduced strain discussed in the pre-
vious section (for an example, see the reactivity of com-
pound 2a shown in Figure 3). They are rather resistant to
hydrolysis even in the presence of bases, which leads to ac-
ids 5, isolated as dicyclohexylammonium (DCHA) salts.
Likewise, with the more bulky alcohols, no reaction leading
to esters 6 was observed in the absence of a base or on
addition of pyridine or dimethylaminopyridine at room
temperature. Only diazabicycloundecene (DBU) promotes
alcoholysis at a reasonable rate. The reaction of heterocy-
cles 2 with amines, leading to amides 7, is rapid with me-
thylamine (a few hours) but rather slow with benzylamine
(a few days) and indefinite (no reaction) with secondary
amines. More significantly, using methylamine, the selectiv-
OBn
OBn
89
100[b]
100[b]
NHMe
80, 95[b,c], 100[b,d]
100, 100[b,c]
100,[b,d]
60[c]
,
7e1
7a2
7d2
7g2
7e2
7a3
7a4
O
S
S
O
O
S
Me
Me
Ph
Me
Me
NHMe
NHBn
75, 70[c]
NO2 NHBn
100[b]
OPh Me
NHBn
NHBn
67
Me
Me
Me
Me
Me
Me
77[c]
NHCH2COOK
72[b,c]
S
NHCHMeCOOK 40[b,c]
[a] Numbering is as follows: 5, 6, and 7 are the products of hydroly-
sis, alcoholysis, and aminolysis, respectively; the subscript indicates
the reacting heterocycle; the following number (for alcoholysis or
aminolysis) is 1 for Me, 2 for Bn (benzyl), 3 for potassium glycinate,
ity of aminolysis is complete in the presence of an alcohol and 4 for potassium alaninate. [b] By 31P NMR spectroscopy, in
the reaction mixture. [c] Reaction performed in the presence of ex-
cess water. [d] Reaction performed in the presence of excess meth-
and very high (Ͼ 85%) in the presence of water. However,
with more sterically hindered amines such as benzylamine,
anol.
glycine, or alanine, hydrolysis is more pronounced as the
bulkiness of the amine increases (for example with 2a, the
yield is 70, 72, and 40%, respectively; see Table 2). In fact,
isolated as oils with the exception of the crystalline phos-
All the products synthesized (Table 2), 5, 6, and 7, were
phonamides 7a1 and 7g2. The latter compound did not
show subsequent loss of phenol (i.e. no recyclization), a fact
of some importance in light of the postulated participation
of the sulfonamide group in the reactions of phosphoryl-
ation.[8]
Discussion and Conclusion
A considerable number of studies have been devoted to
the reactivity of phosphorus, particularly when it is in-
cluded in cyclic structures.[4] They are very well documented
for hydrolysis, but fewer examples exist for aminolysis[9,10]
and even fewer for the selectivity of aminolysis over hydrol-
ysis.[11] However, this is of particular interest from two
points of view: (1) general: how to explain, independently
of catalysis, the paradox of the usually higher reactivity of
water and alcohols relative to that of the better nucleo-
philes, amines, with activated phosphorus compounds (just
Figure 3. Reactions of the heterocycle 2a.
1960
the opposite of the cases with carbonyl- and sulfonyl-acti-
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Eur. J. Org. Chem. 2006, 1959–1964

Selectivity of Phosphorus Heterocycle Aminolysis in the Presence of Water
FULL PAPER
1
vated compounds);[12] (2) particular: the applicability of a
scheme of intramolecular peptide synthesis[13] requiring the
selective aminolysis in water of phosphorus heterocycles 8
(Figure 1). The purpose of the series of studies we have un-
dertaken[14] is precisely to solve this problem.
Similarly 2b was obtained. H NMR (CDCl3): δ = 1.70–2.0 (m, 1
H, CCH2C), 2.09–2.18 (m, 1 H, CCH2C), 2.33 (d, J = 15.7 Hz, 3
H, PCH3), 3.10–3.30 (m, 1 H, NCH2), 3.60–3.80 (m, 1 H, NCH2),
3.90–4.10 (m, 1 H, OCH2), 4.30–4.50 (m, 1 H, OCH2), 8.26 (qAB,
J = 8.8 Hz, 4 H, C6H4NO2) ppm. 13C NMR (CDCl3): δ = 26.12
(d, J = 101.5 Hz, PCH3), 26.27 (d, J = 3.1 Hz, CCH2C), 44.80
(NCH2), 63.46 (d, J = 7.5 Hz, OCH2), 123.89 (2 CH), 130.42 (2
CH), 141.68 (SO2Cquat.), 150.87 (NO2Cquat.) ppm. 31P NMR
For this work (part V of the series[1,14,16,18]), all heterocy-
cles 2 react with cleavage of the P–N bonds, therefore with
attack of the nucleophiles opposite to the sulfonamide leav-
ing group. Of particular interest is the case of 2g; there is
(CDCl ): δ = +87.22 ppm. IR: ν = 1351, 1172 (νSO ), 1530, 1355
˜
3
2
(νNO2) cm–1. C10H13N2O5PS2 (336.33): calcd. C 35.71, H 3.89, N
no loss of phenol, and the cyclic structure is retained, prod- 8.33; found C 35.46, H 3.78, N 8.34.
1
uct 7g2 (cf. Figure 3, bottom, left) being isolated. This me-
ans either that there is no pseudorotation of the initial ad-
dition product resulting from the reaction of amines with
phosphorus (A.E. mechanism) or, more probably, that the
SN2P mechanism of phosphorylation is involved (a penta-
coordinated transition state and not, as in the A.E. mecha-
nism, an intermediate compound of sufficient lifetime,
which can solely be subject to a pseudorotation), in accord-
ance with the literature.[5] As with acyclic phosphorus com-
pounds comparable to 2 (also SN2P mechanism) with good
leaving groups and similar crowding around phosphorus,
selective aminolysis has been observed with rather hindered
amines such as cyclohexylamine or isopropylamine,[15] one
should expect an improvement of the selectivity of aminoly-
sis of the heterocycles 2. However, this is not the case. The
conclusion is therefore reached that neither the mechanism
nor the size, as previously observed[16] with heterocycles 8
and 9 (Figure 1), significantly influences the selectivity of
aminolysis observed with either 1 or 2, and that the selectiv-
ity is fundamentally related to the presence of the good sul-
fonamide leaving group.
Similarly 2c was obtained. H NMR (CDCl3): δ = 1.80–2.00 (m, 1
H, CCH2C), 2.10–2.30 (m, 1 H, CCH2C), 2.42 (s, 3 H, tos CH3),
3.30–3.50 (m, 1 H, NCH2), 3.70–3.90 (m, 1 H, NCH2), 4.10–4.30
(m, 1 H, OCH2), 4.40–4.60 (m, 1 H, OCH2), 7.52 (qAB, J = 8.1 Hz,
4 H, C6H4Me), 7.50–7.60 (m, 3 H, C6H5), 8.00–8.20 (m, 2 H,
C6H5) ppm. 13C NMR (CDCl3): δ = 21.42 (tos CH3), 26.21 (d, J
= 3.8 Hz, CCH2C), 45.38 (NCH2), 64.08 (d, J = 7.5 Hz, OCH2),
128.19 (d, J = 15.7 Hz, 2 CH), 128.76 (CH), 129.53 (CH), 130.56
(d, J = 154.5 Hz, PCquat.), 132.08 (d, J = 12.3 Hz, 2 CH), 133.10
(d, J = 2.9 Hz, CH), 134.41 (MeCquat.), 144.52 (SO2Cquat.) ppm.
31P NMR (CDCl ): δ = +76.29 ppm. IR: ν = 1352, 1164 (νSO )
˜
3
2
cm–1. MS (DCI/CH4): m/z (%) = 368 (100) [MH]+. C16H18NO3PS2
(367.43): calcd. C 52.30, H 4.94, N 3.81; found C 52.03, H 4.98, N
3.57.
1
Similarly 2d was obtained. H NMR (CDCl3): δ = 1.90–2.10 (m, 1
H, CCH2C), 2.20–2.40 (m, 1 H, CCH2C), 3.40–3.60 (m, 1 H,
NCH2), 3.80–4.00 (m, 1 H, NCH2), 4.20–4.40 (m, 1 H, OCH2),
4.40–4.60 (m, 1 H, OCH2), 7.50–7.70 (m, 3 H, C6H5), 8.00–8.20
(m, 2 H, C6H5), 8.18 (qAB, J = 8.9 Hz, 4 H, C6H4NO2) ppm. 13C
NMR (CDCl3): δ = 26.27 (d, J = 3.7 Hz, CCH2C), 45.86 (NCH2),
64.33 (d, J = 7.4 Hz, OCH2), 123.91 (2 CH), 128.42 (d, J = 16.1 Hz,
2 CH), 129.23 (d, J = 154.7 Hz, PCquat.), 130.09 (2 CH), 132.19
(d, J = 12.8 Hz, 2 CH), 133.6 (d, J = 2.9 Hz, CH), 142.76 (SO2C-
quat.), 150.55 (NO2Cquat.) ppm. 31P (CDCl3): δ = +76.34 ppm.
IR:
ν =
˜
1311, 1162 (νSO2), 1533, 1350 (νNO2) cm–1.
C15H15N2O5PS2 (366.33): calcd. C 45.22, H 3.80, N 7.03; found C
45.29, H 3.64, N 6.76.
Experimental Section[17]
The general conditions are the same as in the preceding article of
this series.[1]
1
Similarly 2e was obtained. H NMR (CDCl3): δ = 1.60–1.90 (m, 2
H, CCH2C), 1.87 (d, J = 17.7 Hz, 3 H, PCH3), 2.33 (s, 3 H, tos
CH3), 2.90–3.20 (m, 1 H, NCH2), 3.50–3.60 (m, 1 H, NCH2), 3.90–
4.20 (m, 2 H, OCH2), 7.56 (qAB, J = 7.9 Hz, 4 H. C6H4Me) ppm.
13C NMR (CDCl3): δ = 16.34 (d, J = 135.7 Hz, PCH3), 21.59 (tos
CH3), 25.53 (d, J = 5.2 Hz, CCH2C), 44.75 (NCH2), 64.99 (d, J =
7.9 Hz, OCH2), 128.35 (2 CH), 129.75 (2 CH), 134.97 (MeCquat.),
144.66 (SO2Cquat.) ppm. 31P NMR (CDCl3): δ = +25.34 ppm. IR:
Synthesis of the Heterocycles 2
2-Methyl-3-p-methylbenzenesulfonyl-2-thioxo-1,3,2-oxazaphosphori-
nane (2a) – Illustrative Procedure: A THF (50 mL) solution of 4a
[6]
(1 g, 4.36 mmol) was heated to reflux first for 1 h in the presence
of NaH (95%, 0.22 g, 9.16 mmol) and finally for 3 h after addition
of methanethiophosphonyl dichloride (3a) (0.715 g, 4.75 mmol).
The cooled suspension was centrifuged (10 min, 6000 rpm), and the
supernatant concentrated to dryness. Alternatively, after concentra-
tion, the residue was taken up in chloroform (50 mL), and the or-
ganic layer was extracted with water (3×50 mL), dried (Na2SO4),
and concentrated to dryness. In each case the product was easily
ν = 1210 (νPO), 1341, 1162 (νSO ) cm–1. MS (DCI/CH ): m/z (%)
˜
2
4
= 290 (100) [MH]+. C11H16NO4PS (289.29): calcd. C 45.67, H 5.57,
N 4.84; found C 45.84, H 5.34, N 4.81.
1
Similarly 2f was obtained. H NMR (CDCl3): δ = 1.60–2.10 (m, 2
H, CCH2C), 2.36 (s, 3 H, tos CH3), 3.35–3.85 (m, 2 H, NCH2),
3.80–4.45 (m, 2 H, OCH2), 7.20–7.90 (m, 5 H, PC6H5), 7.59 (qAB
J = 8.4 Hz, 4 H, C6H4Me) ppm. 13C NMR (CDCl3): δ = 21.66 (tos
CH3), 25.66 (d, J = 5.4 Hz, CCH2C), 45.43 (NCH2), 65.76 (d, J =
7.9 Hz, OCH2), 128.32 (2 CH), 128.49 (d, J = 16.6 Hz, 2 CH),
129.74 (2 CH), 131.24 (d, J = 151.6 Hz, PCquat.), 132.10 (d, J =
11.1 Hz, 2 CH), 132.93 (d, J = 2.7 Hz, CH), 135.48 (MeCquat.),
144.59 (SO2Cquat.) ppm. 31P NMR (CDCl3): δ = +11.92 ppm. IR:
1
crystallized. H NMR (CDCl3): δ = 1.73–1.85 (m, 1 H, CCH2C),
2.01–2.20 (m, 1 H, CCH2C), 2.31 (d, J = 14.7 Hz, 3 H, PCH3),
2.42 (s, 3 H, tos CH3), 3.10–3.26 (m, 1 H, NCH2), 3.50–3.70 (m, 1
H, NCH2), 3.90–4.20 (m, 1 H, OCH2), 4.30–4.50 (m, 1 H, OCH2),
7.59 (qAB J = 8.1 Hz, 4 H, tos C6H4) ppm. 13C NMR (CDCl3): δ
= 21.75 (tos CH3), 26.18 (d, J = 102.2 Hz, PCH3), 26.34 (d, J =
2.7 Hz, CCH2C), 44.39 (NCH2), 63.22 (d, J = 7.2 Hz, OCH2),
129.02 (2 CH), 129.42 (2 CH), 133.49 (MeCquat.), 144.82 (SO2C-
quat.) ppm. 31P NMR (CDCl3): δ = +87.12 ppm. IR: 1343, 1164
ν
˜
= C
1339, 1165 (νSO2) cm–1. C16H18NO4PS (351.36):
54.69,H5.16, N 3.98; found C 54.31, H 5.01, N 3.63.
(νSO2) cm–1. MS (DCI/CH4): m/z (%)
C11H16NO3PS2 (305.36): calcd. C 43.27, H 5.28, N 4.59; found C
42.93, H 5.25, N 4.43.
=
306 (100) [MH]+.
1
Similarly 2g was obtained. H NMR (CDCl3): δ = 1.80–2.00 (m, 2
H, CCH2C), 2.41 (s, 3 H, tos CH3), 3.50–3.70 (m, 1 H, NCH2),
Eur. J. Org. Chem. 2006, 1959–1964
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1961

F. Dujols, M. Mulliez
FULL PAPER
3.80–4.00 (m, 1 H, NCH2), 4.30–4.50 (m, 2 H, OCH2), 7.10–7.40 2.38 (s, 3 H, tos CH3), 3.02 (t, J = 6.2 Hz, 2 H, NCH2), 3.66 (d, J
(m, 5 H, OC6H5), 7.59 (qAB, J = 8.3 Hz, 4 H, C6H4Me) ppm. 13C
= 13.7 Hz, 3 H, OCH3), 3.95–4.31 (m, 2 H, OCH2), 7.19–7.96 (m,
NMR (CDCl3): δ = 21.70 (tos CH3), 25.90 (d, J = 5.4 Hz, CCH2C), 5 H, PC6H5), 7.47 (qAB, J = 8.4 Hz, 4 H, C6H4NO2) ppm. 13C
46.93 (NCH2), 69.90 (d, J = 8.4 Hz, OCH2), 120.24 (d, J = 4.8 Hz, NMR (CDCl3 + D2O): δ = 21.59 (tos CH3), 30.13 (d, J = 6.5 Hz,
2 CH), 125.49 (CH), 127.89 (CH), 129.65 (CH), 129.82 (CH), CCH2C), 39.50 (NCH2), 63.69 (d, J = 5.7 Hz, OCH2), 53.33 (d, J
136.60 (MeCquat.), 144.69 (NO2Cquat.), 150.22 (d, J = 7.6 Hz,
= 4.9 Hz, OCH3), 127.13 (2 CH), 128.50 (d, J = 14.7 Hz, 2 CH),
129.77 (2 CH), 131.03 (d, J = 11.7 Hz, 2 CH), 132.64 (d, J =
OCquat.) ppm. 31P NMR (CDCl ): δ = –13.71 ppm. IR: ν = 1246
˜
3
(νPO), 1336, 1167 (νSO2) cm–1. C16H18NO5PS (367.36): calcd. C 2.9 Hz, CH), 136.88 (MeCquat.), 143.45 (SO2Cquat.) ppm. 31P
52.32, H 4.94, N 3.81; found C 52.13, H 4.82, N 3.80.
NMR (CDCl ): δ = +87.97 ppm. IR: ν = 1331, 1158 (νSO ), 3288
˜
3 2
(νNH) cm–1.
Reactions of the Heterocycles 2
Similarly 6d1 was obtained after 24 h in acetonitrile. The sulfonic
acid Amberlyst 15 resin was used for the removal of DBU. 1H
NMR (CDCl3): δ = 1.6–1.9 (m, 2 H, CCH2C), 3.03 (t, J = 6.4 Hz,
2 H, NCH2), 3.65 (d, J = 13.7 Hz, 3 H, OCH3), 3.95–4.22 (m, 2
H, OCH2), 7.35–7.88 (m, 5 H, C6H5C), 8.10 (qAB, J = 9.2 Hz, 4
H, C6H4NO2) ppm. 13C NMR (CDCl3): δ = 30.72 (d, J = 7 Hz,
CCH2C), 40.05 (NCH2), 53.34 (d, J = 5.5 Hz, OCH3), 63.98 (d, J
= 5.9 Hz, OCH2), 123.88 (2 CH), 128.24 (2 CH), 128.49 (d, J =
15 Hz, 2 CH), 130.98 (d, J = 11.8 Hz, 2 CH), 132.65 (d, J = 2.7 Hz,
CH), 132.07 (d, J = 151 Hz, PCquat.), 147.49 (MeCquat.), 149.52
Hydrolysis – Illustrative Procedure: A DMF (2 g) solution of 2a
(0.20 g, 0.6 mmol), water (0.22 g, 12.2 mmol), and triethylamine
(0.19 g, 1.9 mmol) were kept at room temperature. After 4 weeks,
only 25% reaction was observed by 31P NMR spectroscopy. After
addition of more water (0.86 g) and triethylamine (0.82 g) and heat-
ing to 60 °C, the reaction was terminated in less than a week. The
reaction mixture was concentrated to dryness, diluted with an
aqueous solution (20 mL) of mono-dicyclohexylammonium citrate
(0.54 g, 1.45 mmol), and extracted with chloroform (3×20 mL).
The organic extracts were dried (Na2SO4) and concentrated to dry-
1
(SO2Cquat.) ppm. 31P NMR (CDCl ): δ = +89.83 ppm. IR: ν =
˜
3
ness. H NMR (CDCl3): δ = 0.9–1.9 (m, 22 H, 10 CH2 DCHA +
1311,165 (νSO2), 1530, 1349 (νNO2), 3286 (νNH) cm–1. In the pres-
ence of a large excess of methanol in little DMF, the reaction is
accelerated by DBU (2 equiv.): t1/2 Ϸ 2 h and is very slow with
DMAP (1 equiv.): t1/2 Ϸ 7 weeks.
CCH2C), 1.60 (d, J = 14.5 Hz, 3 H, PCH3), 2.39 (s, 3 H, tos CH3),
2.90–3.20 (m, 4 H, 2 CH DCHA + NCH2), 3.60–4.10 (m, 2 H,
OCH2), 7.48 (qAB, J = 8.4 Hz, 4 H, C6H4Me) ppm. 13C NMR
(CDCl3): δ = 21.52 (tos CH3), 24.75 (4 CH2 DCHA), 25.05 (2 CH2
DCHA), 29.18 (4 CH2 DCHA), 30.08 (d, J = 6.9 Hz, CCH2C),
39.59 (NCH2), 53.08 (2 CH DCHA), 60.87 (d, J = 5.8 Hz, OCH2),
127.07 (2 CH), 129.56 (2 CH), 137.63 (MeCquat.), 142.92 (SO2C-
Similarly 6a2 was obtained after 3 weeks. 1H NMR (CDCl3
+
D2O): δ = 1.71 (pseudo q, J = 6.5 Hz, 2 H, CCH2C), 1.72 (d, J =
15.5 Hz, 3 H, PCH3), 2.37 (s, 3 H, tos CH3), 2.94 (t, J = 6.5 Hz, 2
H, NCH2), 3.70–4.20 (m, 2 H, OCH2), 4.94–5.11 (m, 2 H, OCH2),
7.19–7.32 (m, 5 H, C6H5CH2), 7.48 (qAB, J = 8.3 Hz, 4 H,
C6H4Me) ppm. 13C NMR (CDCl3): δ = 21.54 (tos CH3), 21.59 (d,
J = 115.3 Hz, PCH3), 30.17 (d, J = 7.2 Hz, CCH2C), 39.53 (NCH2),
63.13 (d, J = 6.7 Hz, OCH2), 68.16 (d, J = 6.2 Hz, benzylic CH2),
127.13 (2 CH), 128.68 (CH), 128.68 (2 CH), 129.68 (2 CH), 129.77
(2 CH), 136.31 (d, J = 6.3 Hz, CH2Cquat.), 137.03 (MeCquat.),
quat.) ppm. 31P NMR (CDCl ): δ = +75.29 ppm. IR: ν = 1327,
˜
3
1158 (νSO2), 2800–2400 (νN+H), 3245 (νNH) cm–1.
Similarly 5e was obtained. 1H NMR (CDCl3): δ = 1.10–2.05 (m, 22
H, 10 CH2 DCHA + CCH2C), 1.27 (d, J = 10.5 Hz, 3 H, PCH3),
2.37 (s, 3 H, tos CH3), 2.65–3.12 (m, 4 H, 2 CH DCHA + NCH2),
3.70–4.05 (m, 2 H, OCH2), 7.46 (qAB, J = 8.3 Hz, 4 H,
C6H4Me) ppm. 13C NMR (CDCl3): δ = 12.47 (d, J = 140 Hz,
PCH3), 21.53 (tos CH3), 24.73 (4 CH2 DCHA), 25.11 (2 CH2
DCHA), 29.17 (4 CH2 DCHA), 29.17 (4 CH2 DCHA), 30.26 (d, J
= 4.5 Hz, CCH2C), 39.31 (NCH2), 52.96 (2 CH DCHA), 60.85 (d,
J = 5.7 Hz, OCH2), 126.99 (2 CH), 129.58 (2 CH), 137.91 (MeC-
143.44 (SO2Cquat.) ppm. 31P (CDCl ): δ = +97.52. IR: ν = 1327,
˜
3
1159 (νSO2), 3277 (νNH) cm–1.
Similarly 6 2 was obtained after 11 days. IR: ν = 1327, 1159 (νSO ),
˜
c
2
3317 (νNH). 1H NMR (CDCl3 + D2O): δ = 1.73 (pseudo q, J =
6.2 Hz, 2 H, CCH2C), 2.37 (s, 3 H, tos CH3), 2.85–2.99 (m, 2 H,
NCH2), 3.88–4.12 (m, 2 H, OCH2), 4.98–5.15 (m, 2 H, OCH2),
7.45 (qAB, J = 8.1 Hz, 4 H, C6H4Me), 7.10–8.00 (m, 10 H, 2
C6H5) ppm. 13C NMR (CDCl3): δ = 21.59 (tos CH3), 30.12 (d, J
= 7.2 Hz, CCH2C), 39.54 (NCH2), 63.68 (d, J = 5.9 Hz, OCH2),
68.44 (d, J = 5.3 Hz, benzylic CH2), 127.12 (2 CH), 128.19 (2 CH),
128.51 (d, J = 15.4 Hz, 2 CH), 128.56 (CH), 128.66 (CH), 129.78
(2 CH), 131.01 (d, J = 11.8 Hz, 2 CH), 132.56 (d, J = 153.5 Hz,
PCquat.), 132.61 (d, J = 2.9 Hz, CH), 136.10 (d, J = 7.7 Hz,
CH2Cquat.), 141.06 (MeCquat.), 143.39 (SO2Cquat.) ppm. 31P
quat.), 142.90 (SO2Cquat.) ppm. 31P NMR (CDCl3):
δ =
–25.48 ppm. IR: ν = 1326 (et), 1159 (νSO ), 1198 (νPO), 2800–2400
˜
2
(νNH+), 3244 (νNH) cm–1.
Alcoholysis – Illustrative Procedure: To a DMF (0.8 g) solution of
2a (0.1 g, 0.33 mmol), were added methanol (0.12 g, 3.74 mmol)
and DBU (0.05 g, 0.33 mmol). After completion of the reaction (Ϸ
3 weeks), the reaction mixture was diluted with chloroform
(10 mL), and the organic layer was extracted with citric acid solu-
tion (10%, 2×10 mL), dried (MgSO4), and concentrated to dry-
ness, leaving 6a1 as as a colorless oil. 1H NMR (CDCl3): δ = 1.67–
2.00 (m, 2 H, CCH2C), 1.73 (d, J = 15.5 Hz, 3 H. PCH3), 2.39 (s,
3 H, tos CH3), 2.70–3.20. max 2.99 (m, 2 H, NCH2), 3.65 (d, J =
13.8 Hz, 3 H, OCH3), 3.60–4.20 (m, 2 H, OCH2), 7.49 (qAB, J =
8.3 Hz, 4 H, C6H4Me) ppm. 13C NMR (CDCl3): δ = 20.83 (d, J =
114.9 Hz, PCH3), 21.56 (tos CH3), 30.29 (d, J = 6.9 Hz, CCH2C),
39.53 (NCH2), 53.02 (d, J = 6.6 Hz, OCH3), 65.18 (d, J = 6.6 Hz,
OCH2), 127.13 (2 CH), 129.77 (2 CH), 137.02 (MeCquat.), 143.46
NMR (CDCl ): δ = +88.71 ppm. IR: ν = 1327, 1159 (νSO ), 3317
˜
3
2
(νNH) cm–1. No reaction was observed in the presence of excess
benzyl alcohol and a catalytic amount of DMAP after 2 months at
65 °C.
Similarly 6b2 was obtained after 3 days in benzyl alcohol as solvent.
1H NMR (CDCl3 + D2O): δ = 1.77 (pseudo q, J = 6.2 Hz, 2 H,
CCH2C), 3.01 (t, J = 6.2 Hz, 2 H, NCH2), 3.88–4.20 (m, 2 H,
OCH2), 4.95–5.14 (m, 2 H, OCH2), 7.06–7.70 (m, 5 H, C6H5), 8.07
(qAB, J = 9 Hz, 4 H, C6H4NO2) ppm. 13C NMR (CDCl3): δ =
30.05 (d, J = 7.2 Hz, CCH2C), 39.46 (NCH2), 63.29 (d, J = 5.9 Hz,
OCH2), 68.65 (d, J = 5.3 Hz, benzylic CH2), 124.37 (2 CH), 127.67
(2 CH), 127.92 (CH), 128.39 (2 CH), 128.45 (d, J = 14.2 Hz, 2
CH), 128.97 (2 CH), 130.97 (d, J = 11.7 Hz, 2 CH), 132.53 (d, J =
(SO2Cquat.) ppm. 31P NMR (CDCl ): δ = +98.86 ppm. IR: ν =
˜
3
1328, 1159 (νSO2), 3279 (νNH) cm–1. Only 56% reaction was ob-
served after 18 days in the presence of NEt3 (5 equiv.) in place of
DBU.
Similarly 6c1 was obtained after 2 days in acetonitrile. 1H NMR
(CDCl3 + D2O): δ = 1.80 (pseudo q, J = 6.2 Hz, 2 H, CCH2C),
1962
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Selectivity of Phosphorus Heterocycle Aminolysis in the Presence of Water
FULL PAPER
151 Hz, CH), 132.76 (d, J = 3 Hz, CH2Cquat.), 135.92 (d, J = 9.1 Hz, 4 H, C6H4NO2) ppm. 31P NMR (CDCl3): δ = +77.64 ppm.
7.3 Hz, CH2Cquat.), 145.89 (SO2Cquat.), 149.99 (NO2C-
IR: ν = 1324, 1157 (νSO ), 3276 (νNH) cm–1.
˜
2
quat.) ppm. 31P NMR (CDCl ): δ = +88.82 ppm. IR: ν = 1311,
˜
3
Similarly 7g2 was obtained after 5 days. M.p. 183–185 °C. 1H NMR
([D6]DMSO): δ = 1.70–2.20 max 1.80 (m, 2 H, CCH2C), 2.36 (s, 3
H, tos CH3), 2.60–2.80, max 2.76 (m, 2 H, NCH2), 3.25–3.60 (m,
2 H, OCH2), 3.87 (broad s, 2 H, benzylic CH2), 7.00–7.40 (m, 5 H,
OC6H5), 7.61 (qAB, J = 7.9 Hz, 4 H, C6H4Me) ppm. 13C NMR
([D6]DMSO): δ = 20.89 (tos CH3), 26.09 (CCH2C), 42.96 (NCH2),
44.01 (benzylic CH2), 49.92 (OCH2), 120.85 (d, J = 4.3 Hz, 2 CH),
122.85 (CH), 127.62 (CH), 128.54 (CH), 128.88 (CH), 129.46 (CH),
132.56 (CH2Cquat.), 138.21 (MeCquat.), 142.55 (SO2Cquat.),
152.8 (d, J = 7.5 Hz, OCquat.) ppm. 31P NMR ([D6]DMSO): δ = –
1165 (νSO2), 1529, 1348 (νNO2), 3282 (νNH) cm–1.
Aminolysis – Illustrative Procedure: After 3 hours (no more 2a by
31P NMR), the initial solution of methylamine (0.24 g, 7.41 mmol)
and 2a (0.19 g, 0.62 mmol) in anhydrous pyridine (10.9 g) was con-
centrated and taken up with chloroform (20 mL). The organic solu-
tion was extracted with citric and hydrogen carbonate (5%) solu-
tions, dried (Na2SO4), and concentrated to dryness. The product
7a1 was crystallized: m.p. 69–71 °C (EtOAc/iPr2O). Alternatively,
the product was obtained (95% yield by NMR, 75% isolated yield)
in a 1:1 DMF/methylamine(40% aqueous solution, 45 equiv.) mix-
ture after 2 h. 1H NMR (CDCl3): δ = 1.65 (d, J = 13 Hz, 3 H,
PCH3), 1.46–1.67 (m, 2 H, CCH2C), 2.33 (s, 3 H, tos CH3), 2.51
(d, J = 13.1 Hz, 3 H, NCH3), 2.60–2.99 (m, 2 H, NCH2), 3.60–4.08
(m, 2 H, OCH2), 7.45 (qAB, J = 8.2 Hz, 4 H, C6H4Me) ppm. 13C
NMR (CDCl3): δ = 19.57 (d, J = 106.6 Hz, PCH3), 21.55 (tos
CH3), 27.93 (d, J = 2.8 Hz, NCH3), 29.96 (d, J = 7.5 Hz. CCH2C),
39.57 (NCH2), 60.65 (d, J = 6.3 Hz, OCH2), 127.07 (2 CH), 129.76
(2 CH), 139.61 (MeCquat.), 143.36 (SO2Cquat.) ppm. 31P NMR
8.23 ppm. IR:
ν =
˜
1322, 1154 (νSO2), 3271 (νNH) cm–1.
C23H27N2O5PS:(474.52): calcd. C 58.21, H 5.73, N 5.90; found C
57.91, H 5.58, N 5.71.
Similarly 7e2 was obtained after 20 days. 1H NMR (CDCl3 + D2O):
δ = 1.41 (d, J = 17.7 Hz, 3 H, PCH3), 1.79 (pseudo q, J = 6.4 Hz,
2 H, CCH2C), 2.38 (s, 3 H, tos CH3), 3.01 (t, J = 6.4 Hz, 2 H,
NCH2), 3.99–4.45 (m, 4 H, benzylic CH2 + OCH2), 7.15–7.40 (m,
5 H,C6H5), 7.48 (qAB, J = 8.3 Hz, 4 H, C6H4Me) ppm. 13C NMR
(CDCl3): δ = 12.88 (d, J = 132.3 Hz, PCH3), 21.52 (tos CH3), 39.21
(d, J = 5.9 Hz, CCH2C), 39.20 (NCH2), 44.64 (benzylic CH2), 60.47
(d, J = 6.3 Hz, OCH2), 127.51 (CH), 126.99 (2 CH), 127.74 (2 CH),
128.69 (2 CH), 129.68 (2 CH), 137.36 (CCquat.), 139.74 (d, J =
5.2 Hz, CH2Cquat.), 143.15 (SO2Cquat.) ppm. 31P NMR (CDCl3
(CDCl ): δ = +85.66. IR: ν = 1324, 1158 (νSO ), 3275 (νNH) cm–1.
˜
3
2
C11H19N2O3PS2 (290.32): calcd. C 40.98, H 5.94, N 8.69; found C
40.77, H 5.92, N 8.48. With excess diethylamine (28 equiv.) no reac-
tion was observed after 1 month.
Similarly 7d1 was obtained after 30 min in DMF. 1H NMR (CDCl3
+ D2O): δ = 1.91 (pseudo q, J = 5.9 Hz, 2 H, CCH2C), 2.46 (d, J
= 13.3 Hz, 3 H, NCH3), 3.05–3.20 (m, 2 H, NCH2), 3.95–4.30 (m,
2 H, OCH2), 7.35–7.80 (m, 5 H, PC6H5), 8.11 (qAB, J = 9.2 Hz, 4
H, C6H4Me) ppm. 13C NMR (CDCl3): δ = 28.15 (d, J = 2.4 Hz,
NCH3), 30.09 (d, J = 6.9 Hz, CCH2C), 39.46 (NCH2), 60.99 (d, J
= 5.8 Hz, OCH2), 124.35 (2 CH), 128.39 (2 CH), 128.63 (d, J =
14.5 Hz, 2 CH), 130.65 (d, J = 11.1 Hz, 2 CH), 132.03 (d, J =
2.6 Hz, CH), 132.94 (d, J = 118.2 Hz, PCquat.), 145.70 (SO2C-
quat.), 149.95 (NO2Cquat.) ppm. 31P NMR (CDCl3): δ = +79.18.
+ D O): δ = +32.41 ppm. IR: ν = 1194 (νPO), 1319, 1157 (νSO ),
˜
2
2
3252 (νNH) cm–1.
Similarly 7a3 was obtained after 3 days at 60 °C in a mixture of
DMF with a solution of potassium glycinate (8 equiv.) in water
(5.6 equiv.). 31P NMR: δ = +83.5 ppm.
Similarly 7a4 was obtained after 5 days at 60 °C in a mixture of
DMF with a solution of potassium alaninate (8 equiv.) in water
(64 equiv.). 31P NMR: δ = +83.9, + 83.3 ppm (2 couples of dia-
stereoisomers, 1:1 ratio).
IR: ν = 1309, 1163 (νSO ), 1529, 1347 (νNO ), 3287 (νNH) cm–1.
˜
2
2
1
Similarly 7e1 was obtained after 5 h in DMF. H NMR (CDCl3):
δ = 1.37 (d, J = 16.5 Hz, 3 H, PCH3), 1.76 (pseudo q, J = 6 Hz, 2
H. CCH2C), 2.36 (s. 3 H, tos CH3), 2.51 (d, J = 11.8 Hz, 3 H,
NCH3), 2.95 (t, J = 6.0 Hz, 2 H, NCH2), 3.65–4.05 (m, 2 H,
OCH2), 7.47 (qAB, J = 8.3 Hz, 4 H, C6H4Me) ppm. 13C NMR
(CDCl3): δ = 11.54 (d, J = 132.7 Hz, PCH3), 21.51 (tos. CH3), 27.02
(NCH3), 30.29 (d, J = 5.5 Hz, CCH2C), 39.21 (NCH2), 60.31 (d, J
= 6.3 Hz, OCH2), 127.02 (2 CH), 129.65 (2 CH), 137.44 (MeC-
[1] F. Dujols, L. Marty, M. Mulliez, Org. Biomol. Chem. 2005, 3,
227–232.
[2] F. G. Bordwell, F. G. Algrim, J. Org. Chem. 1976, 41, 2507–
2508.
[3] G. Dauphin, A. Kergomard, Bull. Soc. Chim. France 1961,
486–492.
[4] See inter alia: F. H. Westheimer, Acc. Chem. Res. 1968, 1, 70–
78.
[5] J. Emsley, D. Hall, The Chemistry of Phosphorus, Harper and
Row, London, 1976, pp. 329–336.
[6] P. Cazabonne, F. Dujols, M. Mulliez, Synthesis of Constrained
N-Sufonylated Amino Alcohols, in preparation; F. Dujols’ doc-
toral thesis [Université Paul Sabatier, Toulouse (France), 4–10–
99], ch. VI.
quat.), 143.07 (SO2Cquat.) ppm. 31P NMR (CDCl3):
δ =
+36.98 ppm. IR: ν = 1208 (νPO), 1321, 1163 (νSO ), 3266 (νNH)
˜
2
cm–1.
1
Similarly 7a2 was obtained after 4 weeks. H NMR (CDCl3): δ =
1.71 (d, J = 15 Hz, 3 H, PCH3), 1.6–1.86 (m, 2 H, CCH2C), 2.36
(s, 3 H, tos CH3), 2.60–3.00 (m, 2 H, NCH2), 3.45–4.30 (m, 4 H,
OCH2 + benzylic CH2), 7.25 (s, 5 H, C6H5), 7.46 (qAB, J = 8.3 Hz,
4 H, C6H4Me) ppm. 13C NMR (CDCl3): δ = 20.93 (d, J =
106.3 Hz, PCH3), 21.57 (tos CH3), 29.99 (d, J = 7.7 Hz, CCH2C),
39.49 (NCH2), 60.87 (d, J = 6.4 Hz, OCH2), 127.36 (CH), 127.62
(2 CH), 127.78 (2 CH), 128.76 (2 CH), 129.77 (2 CH), 137.07
(MeCquat.), 139.37 (d, J = 5.5 Hz, CH2Cquat.), 143.38 (SO2C-
[7] No definite structure, such as chair or boat, could be deter-
mined.
[8] M. Mulliez, Participation of Sulfonamides in the Reactions of
Phosphorylation, in preparation; F. Dujols’ doctoral thesis
[Université Paul Sabatier, Toulouse (France), 4–10–99], ch. VII.
[9] For acyclic compounds, see for example: V. E. Belskii, L. S.
Novikova, L. A. Kudryatseva, B. E. Ivanov, Bull. Acad. Sci.
USSR, Div. Chem. Sci., (Izv. Akad. Nauk SSSR, Ser. Khim
Transl.) 1977, 1188–1202.
[10] For cyclic compounds, see for example: M. Revel, J. Navech,
F. Mathis, Bull. Soc. Chim. France 1971, 105–112.
[11] See particularly: L. Horner, J. Prakt. Chem. 1992, 234, 645–
6553 and references cited therein.
quat.) ppm. 31P NMR (CDCl ): δ = +84.47 ppm. IR: ν = 1323,1156
˜
3
(νSO2), 3276 (νNH) cm–1.
1
Similarly 7d2 was obtained after 2 weeks. H NMR (CDCl3): δ =
1.84 (pseudo q, J = 6 Hz, 2 H, CCH2C), 2.36 (s, 3 H, tos CH3),
3.05 (t, J = 6 Hz, 2 H, NCH2), 3.85–4.20 (m, 4 H, OCH2 + CH2),
7.18–7.85 (m, 5 H, C6H5), 8.09 (m, 5 H, PC6H5), 8.09 (qAB, J =
[12] J. M. Grévy, M. Mulliez, J. Chem. Soc., Perkin Trans. 2 1995,
1809–1816.
Eur. J. Org. Chem. 2006, 1959–1964
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1963

F. Dujols, M. Mulliez
FULL PAPER
[13] M. Mulliez, Tetrahedron 1981, 37, 2027–2041.
[14] F. Dujols, P. Jollet, M. Mulliez, Phosphorus Sulfur Silicon 1998,
134–135, 231–254.
[15] G. Sosnovsky, M. Konieczny, Synthesis 1977, 618–619.
[16] F. Dujols, M. Mulliez, Phosphorus Sulfur Silicon 2000, 157,
165–191.
[17] More details are available in: F. Dujols’ doctoral thesis: no.
3497, 1999, Université Paul Sabatier, Toulouse (France) .
[18] F. Dujols, M. Mulliez, J. Heterocycl. Chem. 2001, 38, 475–480.
Received: September 30, 2005
Published Online: February 6, 2006
1964
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Eur. J. Org. Chem. 2006, 1959–1964