A simple access to 2-acyl- and 2,5-diacyl- phospholide ions

Article abstract of DOI:10.1055/s-2001-18747

Depending on the reaction conditions (rate of addition, temperature, stoichiometry), the reaction of acyl chlorides with 3,4-dimethylphospholide ion in THF gives the 2-acyl- and 2,5-diacylphospholides.

Full text of DOI:10.1055/s-2001-18747

LETTER
1977
A Simple Access to 2-Acyl- and 2,5-Diacyl- Phospholide Ions
A
Simple
Acc
a
c
t
r
2,5-Diac
i
yl Pho
c
spholide Io
k
ns Toullec, François Mathey*
Laboratoire 'Hétéroéléments et Coordination', URA CNRS 1499, DCPH, Ecole Polytechnique, 91128 Palaiseau Cedex, France
Fax +33(169)333990; E-mail: francois.mathey@polytechnique.fr
Received 16 July 2001
Z+, THF
∆, [1,5]
Abstract: Depending on the reaction conditions (rate of addition,
temperature, stoichiometry), the reaction of acyl chlorides with 3,4-
dimethylphospholide ion in THF gives the 2-acyl- and 2,5-diacyl-
phospholides.
Z
P
P
Z
P
- H+
Key words: acyl chlorides, 3,4-dimethylphospholide, sigmatropic
shift
tBuOK
Z
P
Scheme 1
The synthesis of functionalized phospholes is a recurrent
problem, which has not received fully satisfactory solu-
tions until now.1 Electrophilic substitution reactions are
indeed impossible except in a few special cases2 because
phospholes are pyramidal and essentially non-aromatic.
Besides, the aromatic phospholides ions react with elec-
trophiles exclusively at phosphorus as a result of the high
concentration of negative charge at the heteroatom. At the
moment, the most versatile solution to get 2-functional-
ized phospholes involves the reaction of electrophiles
with 2-lithiophospholes.3 Unfortunately, this process re-
lies on the cumbersome synthesis of the appropriate 2-
bromophosphole precursors. Besides, it cannot be used
for the preparation of reactive 2,5-bis-functionalized de-
rivatives, which are key intermediates en route to poly-
phosphole macrocycles and chains.
H) = 38.4 Hz) together with the AX system of the 2H-
phosphole dimer 35 ( 31P –24 and –63, 1J(P-P) = 185 Hz).
The functional phospholide 2a was also characterized by
negative ion mass spectrometry and derivatization leading
to phosphole 4a and its sulfide 5a.6 Similar results were
observed with benzoyl chloride.7 The overall reaction se-
quence is depicted in Scheme 2.
Me
Me
RC(O)Cl (0.5 eq.)
THF, -78°C, 10 min.
Me
Me
Me
Me
[1,5]
C(O)R
P
P
P
Li+
1
C(O)R
Me
Me
Me
Me
BrCH2CH2CO2Et
1 h, RT
1
Recently, we have discovered a practical access to 2-func-
tional phospholide ions4 which is shown in Scheme 1. The
functionalized electrophile Z+ is grafted at P, then a ther-
mal [1,5] sigmatropic shift, is induced by heating and the
resulting 2-functionalized 2H-phosphole is deprotonated
by a base. A limited number of electrophiles have been
used, the most interesting in the context of this work being
ClCO2Et, which yields both the mono- and the bis-ethox-
ycarbonyl phospholides under mild conditions. The ex-
treme simplicity of this one-pot process encouraged us to
investigate its generality more deeply. Thus, we decided
to study the reaction of 3,4-dimethylphospholide 1 with
acyl chlorides.
C(O)R
P
P
Li+
2a,b
Me
Me
[4+2]
a: R = Me
b: R = Ph
C(O)R
P
4a,b
Me
Me
P
CO2Et
Me
Me
S8, 80°C
toluene
P
Me
Me
3
C(O)R
P
S
CO2Et
5a (32% from 1)
5b (38% from 1)
Scheme 2
In view of the high reactivity of acyl chlorides towards 1,
a first series of experiments was carried out at –78 °C in
THF. The reaction of 1 with acetyl chloride goes to com-
pletion in 10 minutes. Monitoring the reaction mixture by
31P NMR shows the replacement of the resonance of 1 (
31P +59, t, 2J(P-H) = 40 Hz) by a new resonance correspond-
From a mechanistic standpoint, this means that the sigma-
tropic shift of the acyl groups from P to C is fast even at
–78 °C. The resulting 2H-phospholes are very acidic and
easily deprotonated by the starting phospholide 1 to give
the functionalized phospholides 2a,b. According to 31P
NMR, the reactions are almost quantitative in line with the
yields of 5a,b as measured on the isolated products (32
and 38 vs 50% max.). From a practical standpoint, we then
tried to modify the technique in order to make a better use
of 1. A more efficient procedure relies on the very fast ad-
2
ing to the 2-acetylphospholide 2a ( 31P +135, d, J(P-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1977,1979,ftx,en;G14501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1978
P. Toullec, F. Mathey
LETTER
(2) (a) Keglevich, G.; Böcskei, Z.; Keserü, G. M.; Ujszaszy, K.;
Quin, L. D. J. Am. Chem. Soc. 1997, 119, 5095.
dition of the acyl chloride to the phospholide (in ca. 5 sec),
followed by the addition of t-BuOK.6 The overall yields of
sulfides 5a,b from 1 were boosted to 70% (R = Me) and
78% (R = Ph). This approach can also be modified to get
the 2,5-diacyl derivatives. The slow addition of ca. one
equivalent of acyl chloride to 1 at 50 °C leads to a mixture
of mono- and diacyl-phospholides. After alkylation, the
resulting phospholes 4 and 7 can be separated by chroma-
tography, then sulfurized8 (Scheme 3). Since two mole-
cules of 1 are successively used for the deprotonation of
the mono- and difunctionalized 2H-phospholes, the max-
imum theoretical yield of 7 and 8a,b from 1 is only 33%.
In practice, we have obtained the sulfides 8a and 8b in 10
and 13% yields, respectively after chromatographic puri-
fication. No attempt has been made to optimize these
yields, although this is certainly possible. Anyhow, the
extreme simplicity of this procedure is attractive even at
this stage of development. Finally, it is interesting to no-
tice that 6b displays, by far, the most deshielded 31P reso-
nance of all presently known monophospholides at +209
ppm.
(b) Keglevich, G.; Chuluunbaatar, T.; Dobo, A.; Töke, L. J.
Chem. Soc., Perkin Trans. 1 2000, 1495.
(3) (a) Deschamps, E.; Mathey, F. Bull. Soc. Chim. Fr. 1992,
129, 486. (b) Deschamps, E.; Ricard, L.; Mathey, F. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1158. (c)Niemi, T.-A.;Coe,
P. L.; Till, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 1519.
(4) (a) Holand, S.; Jeanjean, M.; Mathey, F. Angew. Chem., Int.
Ed. Engl. 1997, 36, 98. (b) Holand, S.; Maigrot, N.;
Charrier, C.; Mathey, F. Organometallics 1998, 17, 2996.
(5) Charrier, D.; Bonnard, H.; de Lauzon, G.; Mathey, F. J. Am.
Chem. Soc. 1983, 105, 6871.
(6) 2a: A solution of 1-phenyl-3,4-dimethylphosphole (0.94 g,
5
10–3 mol) in distilled THF (25 mL) was stirred with
lithium wire (70 mg, 1 10–2 mol) for 2 h at 25 °C. The
complete transformation of the phosphole into the
phospholide was checked by 31P NMR. The remaining
lithium wire was removed, tert-butyl chloride (0.55 mL) was
added, and the solution was refluxed for 30 min. The
resulting reaction mixture was cooled to –78 °C and acetyl
chloride (0.36 mL, 5 10–3 mol) was added over 5 sec. After
warming to r.t., potassium tert-butoxide (0.784 g) was added
to the solution which turned from orange to red. 31P NMR
(THF): = +135, 1J(P-H) = 38.4 Hz; mass (ICN, NH3): m/z
(%) = 153(100) [M–]. 4a: 31P NMR (CDCl3): = +3.3; 13
C
Me
Me
NMR (CDCl3): = 61.11 (s, OCH2), 151.24 (d, 2J(C-P) = 5.3
Hz, C ), 157.81 (d, 2J(C-P) = 12.1 Hz, C ), 173.21 (d,
3J(C-P) = 5.3 Hz, CO2Et), 196.60 (d, 2J(C-P) = 21.9 Hz,
COMe). 5a: Purified by chromatography on silica gel with
hexane/ether 70/30: 31P NMR (CDCl3): = +48.6; 1H NMR
(CDCl3): = 1.25 (t, 3J(H-H) = 7.2 Hz, CH3-CH2), 2.13 (dd,
CH3 cycle), 2.38 (d, CH3 cycle), 2.57 (s, COCH3), 4.13 (q,
CH2O), 6.19 (dd, 2J(H-P)) = 30.8 Hz, CH-P); 13C NMR
(CDCl3): = 14.15 (s, CH3(Et)), 16.32 (d, 3J(C-P) = 12.1 Hz,
CH3 cycle), 17.70 (d, 3J(C-P) = 15.8 Hz, CH3 cycle), 26.78
(d, 1J(C-P) = 51.3 Hz, CH2P), 28.04 (s, COCH3), 32.01 (s,
COCH2), 61.13 (s, OCH2), 125.98 (d, 1J(C-P) = 77.7 Hz,
P-CH), 134.28 (d, 1J(C-P) = 70.2 Hz, P-CCO) 153.17 (d,
2J(C-P) = 15.1 Hz, C ), 160.24 (d, 2J(C-P) = 21.1 Hz, C ),
171.66 (d, 3J(C-P) = 13.6 Hz, CO2Et), 194.55 (d, 2J(C-P) = 15.8
Hz, CO); mass (ICP, NH3): m/z (%) = 287(100) [M+ + H].
(7) 2b: 31P NMR (THF): = +151.5, 1J(P-H) = 36.6 Hz; mass:
m/z (%) = 215(100) [M–]. 4b: 31P NMR (CDCl3): = +10.3;
mass (ICP, NH3): m/z (%) = 316(6) [M+], 216(24) [M+ –
CH2CHCO2Et], 105 (100). 5b: 31P NMR (CDCl3): = +58.8;
1H NMR (CDCl3): = 1.25 (t, CH3 (Et)), 1.86 (d, CH3 cycle),
2.12 (dd, CH3 cycle), 4.14 (q, 3J(H-H) = 7.2 Hz, CH2O), 6.23
(dd, 2J(H-P) = 32.3 Hz, CH-P); 13C NMR (CDCl3): = 14.84
(s, CH3 (Et)), 17.01 (d, 3J(C-P) = 13.4 Hz, CH3 cycle), 18.13
(d, 3J(C-P) = 16.5 Hz, CH3 cycle), 27.71 (d, 1J(C-P) = 50.8 Hz,
CH2-P), 28.66 (s, COCH2), 61.59 (s, OCH2), 125.90 (d,
1J(C-P) = 77.2, P-CH), 153.00 (d, 2J(C-P) = 20.3 Hz, C ),
153.41 (d, 2J(C-P) = 15.1 Hz, C ), 172.74 (d, 3J(C-P) = 14.2 Hz,
CO2Et), 194.07 (d, 2J(C-P) = 10.2 Hz, CO); mass (IE): m/z (%)
= 348(3) [M+], 248(91) [M+ – CH2CHCO2Et], 105 (100).
(8) 6a: 31P NMR (THF): = +188.9. 6b: The solution of 3,4-
dimethylphospholide was prepared as for 2a. The reaction
mixture was warmed to 50 °C and benzoyl chloride (0.58
mL, 5 10–3 mol) was added dropwise over 1 min. A
condenser was used to avoid THF evaporation. 31P NMR
(THF): = +209.6. 7a: 31P NMR (THF): = +13.2. 7b :
Purified by chromatography on silica gel with hexane/ether
70/30. 31P NMR (CDCl3): = +23; 13C NMR (CDCl3):
= 14.64 (s, CH3 (Et)), 17.54 (s, CH3 cycle), 18.09 (d,
1J(C-P) = 24.5 Hz, CH2-P), 31.27 (s, CH2CO), 61.24 (s,
OCH2), 148.33 (d, 1J(C-P) = 7.8 Hz, C ), 153.92 (d, 2J(C-
RC(O)Cl dropwise (ca 1-5 min.)
1
2a,b + 3 +
R(O)C
C(O)R
Li+
THF, 50°C
P
6a,b
Me
Me
BrCH2CH2CO2Et
4a,b +
R(O)C
C(O)R
CO2Et
60°C, 16 h
P
7a,b
S8, 80°C,
toluene
Me
Me
R(O)C
C(O)R
CO2Et
P
S
8a,b
Scheme 3
Acknowledgement
One of us (P. Toullec) thanks BASF for financial support.
References
(1) Recent reviews : (a) Quin, L. D.; Phospholes, In
Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996, 757. (b) Dillon, K. B.; Mathey, F.;
Nixon, J. F. Phosphorus: The Carbon Copy, Chap. 8, 203;
Wiley: Chichester, 1998. (c) Mathey, F. In Science of
Synthesis, Vol. 9; Maas, G., Ed.; Thieme: Stuttgart, 2001,
Chap. 14, 553. (d) Quin, L. D. In Phosphorus-Carbon
Heterocyclic Chemistry; Mathey, F., Ed.; Elsevier: Oxford,
2001, Chap. 4, 219.
Synlett 2001, No. 12, 1977–1979 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Simple Access to 2-Acyl- and 2,5-Diacyl Phospholide Ions
1979
P) = 12.4 Hz, C ), 172.55 (d, 3J(C-P) = 6.8 Hz, CO2Et), 194.51
(d, 3J(C-P) = 13.6 Hz, CO2Et), 195.69 (d, 2J(C-P) = 15.1 Hz,
CO); mass (ICP, NH3): m/z (%) = 345(27) [M+ + NH3],
328(100) [M+]. 8b: 31P NMR (CDCl3): +63.7; 1H NMR
(CDCl3): = 1.10 (t, CH3 (Et)), 1.77 (s, CH3 cycle), 2.54 (m,
CH2), 2.69 (m, CH2), 3.99 (q, 3J(H-H) = 7.2 Hz, OCH2);
13C NMR (CDCl3): = 13.67 (s, CH3 (Et)), 15.78 (d,
3J(C-P) = 12.8 Hz, CH3 cycle), 27.80 (d, 1J(C-P) = 52.1 Hz,
CH2P), 60.40 (s, OCH2), 135.62 (d, 1J(C-P) = 67.9 Hz, C ),
150.64 (d, 2J(C-P) = 17.4 Hz, C ), 171.25 (d, 3J(C-P) = 21.9 Hz,
CO2Et), 192.28 (d, 2J(C-P) = 10.6 Hz, CO).
(d, 2J(C-P) = 16.6 Hz, CO); mass (IE): m/z (%) = 421(4) [M+
+ H], 256 (67) 105 (100, PhCO). 8a: Purified by chromato-
graphy on silica gel with hexane/ether 50/50. 31P NMR
(CDCl3): +57.9; 1H NMR (CDCl3): = 1.21 (t, CH3 (Et)),
2.35 (d, 4J(H-P) = 2.3 Hz, CH3 cycle), 2.59 (s, COCH3), 4.07
(q, 3J(H-H) = 7.1 Hz, OCH2); 13C NMR (CDCl3): = 14.12 (s,
CH3 (Et)), 16.08 (d, 3J(C-P) = 11.3 Hz, CH3 cycle), 27.65 (d,
1J(C-P) = 50.6 Hz, CH2P), 27.85 (d, 3J(C-P) = 2.6 Hz, COCH3),
32.38 (s, COCH2), 61.30 (s, OCH2), 135.08 (d, 1J(C-P) = 68.7
Hz, C ), 157.66 (d, 2J(C-P) = 18.1 Hz, C ), 171.22
Synlett 2001, No. 12, 1977–1979 ISSN 0936-5214 © Thieme Stuttgart · New York