Esterification of five-membered cyclic phosphinic acids under mild conditions using propylphosphonic anhydride (T3P)

Article abstract of DOI:10.1016/j.tetlet.2013.08.082

1-Hydroxy-phospholene 1-oxides (1 and 3) and 1-hydroxy-phospholane oxides (5 and 7) undergo fast and efficient esterification with a series of alcohols, at room temperature, in the presence of 1.1 equiv of propylphosphonic anhydride (T3P).

Full text of DOI:10.1016/j.tetlet.2013.08.082

Tetrahedron Letters 54 (2013) 5873–5875
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Tetrahedron Letters
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Esterification of five-membered cyclic phosphinic acids under mild
conditions using propylphosphonic anhydride (T3PÒ)
Erzsébet Jablonkai a, Mátyás Milen a,b, László Drahos c, György Keglevich a,
⇑
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
b Egis Pharmaceuticals PLC., Division for Chemical Research, POB 100, 1475 Budapest, Hungary
c Research Centre for Natural Sciences, Hungarian Academy of Sciences, POB 17, 1525 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2013
Revised 24 July 2013
Accepted 21 August 2013
Available online 29 August 2013
1-Hydroxy-phospholene 1-oxides (1 and 3) and 1-hydroxy-phospholane oxides (5 and 7) undergo fast
and efficient esterification with a series of alcohols, at room temperature, in the presence of 1.1 equiv
of propylphosphonic anhydride (T3PÒ).
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
P-heterocycles
Phosphinic acid
Phosphinate
T3P reagent
Green synthesis
Phosphinates are usually synthesized by the reaction of phos-
phinic chlorides with alcohols (Scheme 1A).1 This method works
well, but it utilizes rather expensive chlorides and cannot be re-
garded as being environmentally friendly due to the formation of
hydrochloric acid. It is well-known that phosphinic acids do not
undergo direct esterification with alcohols on conventional heating
(Scheme 1B). However, under microwave irradiation, direct ester-
ification of phosphinic acids does take place (Scheme 1C).2
Although these esterifications are ‘green’ from the point of view
of the starting materials, the reaction temperature of ca. 200 °C is
a disadvantage.
Δ
B
C
A
ROH
O
O
O
ROH
− HCl
P
P
P
MW
ROH
Cl
OR
OH
Scheme 1. Synthetic routes to phosphinates utilizing alcohols.
O
O
O
P
There are alternative possibilities for the esterification of phos-
phinic acids. Such reactions require specialized reagents, such as
orthoesters,3a chloroformates,3b,c and orthosilicates.3d Direct ester-
ification of phosphinic acids has not been reported, but phenyl-
phosphinodithioates were prepared by heating PhP(S)(SH)H with
primary alcohols.3e
P
P
®
Pr
Pr
T3P
O
O
O
Pr
The propylphosphonic anhydride (T3PÒ) reagent is a powerful
coupling (dehydrating/condensing) agent applied in a wide range
of reactions,4 including peptide syntheses,5 polyamidations,6 ami-
dations,7 and esterifications,8 as examples of only acylation reac-
tions among the great variety of the reactions studied.
Me
Me
25 °C, time
1) T3P (1.1 equiv.)/EtOAc
P
P
2) ROH
O
OH
O
OR
2
1
i
i
s
a
h
b
c
d
e
f
g
R= Me ( ), Et ( ), Pr ( ), Pr ( ), Bu ( ), Bu ( ), Bu ( ),
i
c
i
j
k
l
Pent ( ), Pent ( ), 3-pentyl ( ), Hexyl ( ), Bn ( ),
2-phenylethyl (m), 2-(1-naphthyl)ethyl (n), menthyl (o)
⇑
Corresponding author. Tel.: +36 1 463 1111/5883; fax: +36 1 463 3648.
E-mail address: gkeglevich@mail.bme.hu (G. Keglevich).
Scheme 2. Esterification of 1-hydroxy-3-methyl-3-phospholene 1-oxide (1) in the
presence of T3PÒ
.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.082

5874
E. Jablonkai et al. / Tetrahedron Letters 54 (2013) 5873–5875
Table 1
Esterification of 2-hydroxy-3-methyl-3-phospholene 1-oxide (1)
31P NMR (121.5 MHz, CDCl3)
½M þ Hꢀþfound
½M þ Hꢀþrequires
dLPit
Entry
ROH
Time (h)
Yield (%)
1
2
3
4
5
6
7
MeOH
EtOH
0.5
0.5
0.5
3
0.5
0.5
3
80 (2a)
77 (2b)
80 (2c)
76 (2d)
82 (2e)
86 (2f)11c
88 (2g)
76.8
74.7
72.5
73.0
74.7
74.6
73.23 (50%)
73.24 (50%)
74.8
74.7
73.6
73.1
75.9
75.5
75.7
73.32 (50%)
73.36 (50%)
77.011a
74.711b
74.511b
73.211b
74.62a
–
147.0575
161.0730
175.0888
175.0888
189.1045
189.1045
147.0575
161.0731
175.0888
175.0888
189.1044
189.1044
PrOH
iPrOH
BuOH
iBuOH
sBuOH
8
9
PentOH
0.5
0.5
3
94 (2h)
91 (2i)
79 (2j)
75.42d
203.1200
203.1201
203.1201
215.1201
223.0889
237.1044
287.1201
271.1828
203.1201
203.1201
203.1201
215.1201
223.0888
237.1044
287.1201
271.1827
iPentOH
74.72d
10
11
12
13
14
15
3-Pentyl alcohol
—
—
cHexylOH
2
89 (2k)
95 (2l)
BnOH
0.5
0.5
0.5
3
76.011b
2-Phenylethanol
2-(1-Naphthyl)ethanol
Menthol
90 (2m)11c
93 (2n)
95 (2o)
—
—
73.28 (50%)
73.33 (50%)11d
reaction times, typically three hours. With tert-butanol there was
no reaction at all. The corresponding phosphinates 2a–o where ob-
tained in yields of 76–95% after flash column chromatography
(Scheme 2, Table 1).10 Phosphinates 2g and 2o were obtained as
1:1 mixtures of two isomers.
Me
Me
P
Me
Me
25 °C, 0.5 h
1) T3P (1.1 equiv.)/EtOAc
P
The T3PÒ promoted esterification was then extended to 1-hy-
droxy-3,4-dimethyl-3-phospholene 1-oxide (3),9 and 1-hydroxy-
3-methyl- and 1-hydroxy-3,4-dimethyl-phospholane 1-oxides (5
and 7)2b with butanol as the alcohol component. Carrying out the
esterifications as described for the 1?2 transformation, phosphi-
nates 4, 6, and 8 were obtained in yields of 81%, 70%, and 75%,
respectively (Schemes 3–5). 1-Butoxy-3-methyl-phospholane 1-
oxide (6) was obtained as a mixture of two isomers (on the basis
of GC–MS), while the dimethyl analogue 8 was isolated as a mix-
ture of three isomers. The isomers 8A, 8B1, and 8B2 were identified
on the basis of our earlier study.2b The major isomer (8A) was sep-
arated by column chromatography in a yield of 42%.
2) BuOH
O
OH
O
OBu
4
3
Scheme 3. Esterification of 1-hydroxy-3,4-dimethyl-3-phospholene 1-oxide (3) in
the presence of T3PÒ
.
Me
Me
25 °C, 1 h
1) T3P (1.1 equiv.)/EtOAc
P
P
2) BuOH
O
OH
O
OBu
6
5
The known phosphinates (2a–e, 2h, 2i, 2l, 2o, 4, 6, and 8) were
identified by 31P NMR spectroscopy and HRMS (Tables 1 and 2),
while the new products (2f, 2g, 2j, 2k, 2m, and 2n) were also char-
acterized by 13C and 1H NMR spectroscopy.
1:1 mixture of two isomers
Scheme 4. Esterification of 1-hydroxy-3-methyl-phospholane 1-oxide (5) in the
presence of T3PÒ
.
The role of the T3PÒ reagent is to form a reactive anhydride type
intermediate (9) from the phosphinic acid, which may then under-
go reaction with the alcohol at room temperature. The by-product
HOP(O)(Pr)OP(O)(Pr)OP(O)(Pr)OH formed was removed by extrac-
tion from the organic phase with water.
We herein describe the esterification of cyclic phosphinic acids
with alcohols in the presence of the T3PÒ reagent.
Initially, the model compound, 1-hydroxy-3-methyl-3-phos-
pholene 1-oxide (1),9 was reacted with 1.1 equiv of T3PÒ in ethyl
acetate at 25 °C for 10 min. Next, 1.5–3 equiv of an alcohol was
added and the mixture was stirred further. With simple alcohols,
such as methanol, ethanol, propanol, butanol, i-butanol, pentanol,
i-pentanol, benzyl alcohol, 2-phenylethanol, and 2-(1-naph-
thyl)ethanol, the esterification was complete after 30 min, while
the use of sterically hindered alcohols (i-propanol, sec-butanol,
3-pentyl alcohol, cyclohexanol, and menthol) required longer
P(O)OP(O)(Pr)OP(O)(Pr)OP(O)(Pr)OH
9
The T3PÒ-mediated reaction of phosphinic acids with alcohols
is obviously of more general value.
Me
Me
Me
Me
Me
Me
25 °C, 1 h
1) T3P (1.1 equiv.)/EtOAc
+
P
P
P
2) BuOH
O
OBu
O
OBu
8B1 and 8B2
O
OH
8A
7
3:2 mixture of two isomers
3:1:1 mixture of three isomers
Scheme 5. Esterification of 1-hydroxy-3,4-dimethyl-phospholane 1-oxide (7) in the presence of T3PÒ
.

E. Jablonkai et al. / Tetrahedron Letters 54 (2013) 5873–5875
5875
Table 2
Selected spectral data for phosphinates 4, 6, and 8
½M þ Hꢀþfound
½M þ Hꢀþrequires
d2Pb
Product
31P NMR (121.5 MHz, CDCl3)
4
6
68.5
79.4 (broad)
68.6
203.1203
191.1204
203.1201
191.1201
79.40 (50%)
79.38 (50%)
72.5 (60%)
78.4 (20%)
79.0 (20%)
8A
8B1
8B2
72.4 (92%)
78.3 (7%)
79.9 (5%)
205.1350
205.1357
1-Isobutoxy-3-methyl-3-phospholene 1-oxide (2f): 31P NMR and HRMS: Table 1;
13C NMR (75.5 MHz, CDCl3) d 18.8 (2 ꢂ CHCH3), 20.9 (d, J = 12.9, C3–CH3), 29.3
(d, J = 6.2, OCH2CH), 30.8 (d, J = 88.3, C2), 33.5 (d, J = 92.3, C5), 70.8 (d, J = 7.0,
OCH2), 120.4 (d, J = 10.8, C3), 136.4 (d, J = 16.9, C4); 1H NMR (300 MHz, CDCl3) d
0.95 (d, 6H, J = 6.7, CHCH3), 1.80 (s, 3H, C3–CH3), 1.86–2.03 (m, 1H, OCH2CH),
2.28–2.55 (m, 4H, 2 ꢂ PCH2), 3.79 (t, 2H, J = 6.7, OCH2), 5.53 (d, 1H, J = 35.9,
C4–H).
In summary, a mild and efficient esterification of a series of five-
membered cyclic phosphinic acids was elaborated utilizing the
T3PÒ reagent.
Acknowledgment
1-(1-Methylpropoxy)-3-methyl-3-phospholene 1-oxide (2g): 31P NMR and HRMS:
Table 1; 13C NMR (75.5 MHz, CDCl3) d 9.5 (CH2CH3), 20.6 (d, J = 12.9, C3–CH3),
21.6 (OCHCH3), 30.6 (d, J = 5.0, OCHCH2), 31.3 (d, J = 88.6, C2, isomer A), 31.7 (d,
J = 88.6, C2, isomer B), 34.0 (d, J = 92.5, C5, isomer A), 34.4 (d, J = 92.5, C5,
isomer B), 74.3 (d, J = 6.9, OCH), 120.1 (d, J = 11.1, C3, isomer A), 120.3 (d,
J = 11.0, C3, isomer B), 136.1 (d, J = 16.9, C4, isomer A), 136.2 (d, J = 16.8, C4,
isomer B); 1H NMR (300 MHz, CDCl3) d 0.87 (t, 3H, J = 7.4, CH2CH3), 1.27 (d, 3H,
J = 6.2, OCHCH3), 1.42–1.71 (m, 2H, OCHCH2), 1.73 (s, 3H, C3–CH3), 2.15–2.50
(m, 4H, 2 ꢂ PCH2), 4.32–4.53 (m, 1H, OCH), 5.46 (d, 1H, J = 35.8, C4–H).
1-(1-Ethylpropoxy)-3-methyl-3-phospholene 1-oxide (2j): 31P NMR and HRMS:
Table 1; 13C NMR (75.5 MHz, CDCl3) d 9.5 (CH2CH3), 20.9 (d, J = 12.9, C3–CH3),
28.0 (d, J = 3.6, OCHCH2), 31.8 (d, J = 88.8, C2), 34.5 (d, J = 92.6, C5), 79.4 (d,
J = 7.4, OCH), 120.5 (d, J = 10.9, C3), 136.4 (d, J = 16.9, C4); 1H NMR (300 MHz,
CDCl3) d 0.94 (t, 6H, J = 7.4, CH2CH3), 1.51–1.71 (m, 4H, 2 ꢂ OCHCH2), 1.80 (s,
3H, C3–CH3), 2.28–2.59 (m, 4H, 2 ꢂ PCH2), 4.25–4.41 (m, 1H, OCH), 5.53 (d, 1H,
J = 35.7, C4–H).
This project was supported by the Hungarian Scientific and Re-
search Fund (OTKA K83118).
References and notes
1. Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley: New York, 2000.
2. (a) Kiss, N. Zs.; Ludányi, K.; Drahos, L.; Keglevich, Gy. Synth. Commun. 2009, 39,
}
2392; (b) Keglevich, Gy.; Bálint, E.; Kiss, N. Zs.; Jablonkai, E.; Hegedus, L.; Grün,
A.; Greiner, I. Curr. Org. Chem. 2011, 15, 1802; (c) Keglevich, Gy.; Kiss, N. Zs.;
Mucsi, Z.; Körtvélyesi, T. Org. Biomol. Chem. 2012, 10, 2011; (d) Kiss, N. Zs.;
Böttger, É.; Drahos, L.; Keglevich, Gy. Heteroat. Chem. 2013, 7, 99.
3. (a) Yoshino, T.; Imori, S.; Togo, H. Tetrahedron 2006, 62, 1309; (b) Hewitt, D. G.
Aust. J. Chem. 1979, 32, 463; (c) Afarinkia, K.; Yu, H.-W. Tetrahedron Lett. 2003,
44, 781; (d) Dumond, Y. R.; Baker, R. L.; Montchamp, J.-L. Org. Lett. 2000, 2,
3341; (e) Hopkins, T. R.; Vogel, P. W. J. Am. Chem. Soc. 1956, 78, 4447.
4. Basavaprabhu; Vishwanatha, T. M.; Rao Panguluri, N.; Sureshbabu, V. V.
Synthesis 2013, 1569.
1-Cyclohexyloxy-3-methyl-3-phospholene 1-oxide (2k): 31P NMR and HRMS:
Table 1; 13C NMR (75.5 MHz, CDCl3) d 20.6 (d, J = 13.0, C3–CH3), 23.6 (C30), 24.9
(C40), 31.6 (d, J = 88.5, C2), 33.79 and 33.83 (d, J = 2.9, C20), 34.3 (d, J = 92.5, C5),
74.6 (d, J = 6.8, C10), 120.2 (d, J = 11.0, C3), 136.1 (d, J = 16.9, C4); 1H NMR
(300 MHz, CDCl3) d 1.01–1.94 (m, 13H, C3–CH3, 5 ꢂ CH2), 2.18–2.52 (m, 4H,
2 ꢂ PCH2), 4.20–4.40 (m, 1H, C10–H), 5.44 (1H, J = 35.9, C4–H).
5. Wissmann, H.; Kleiner, H.-J. Angew. Chem. 1980, 92, 129.
6. Ueda, M.; Honma, T. Polym. J. 1988, 20, 477.
7. (a) Scaravelli, F.; Bacchi, S.; Massari, L.; Curcuruto, O.; Westerduin, P.; Maton,
W. Tetrahedron Lett. 2010, 51, 5154; (b) Sharnabai, K. M.; Nagendra, G.;
Vishwanatha, T. M.; Sureshbabu, V. V. Tetrahedron Lett. 2013, 54, 478.
8. (a) Wissmann, H.; König, W.; Teetz, V.; Geiger, R. 16th Peptides Processing
European Peptide, Symposium, 1980; 174.; (b) Kessler, H.; Kühn, M.; Löschner,
T. Liebigs Ann. Chem. 1986, 1.
1-(2-Phenylethoxy)-3-methyl-3-phospholene 1-oxide (2m): 31P NMR and HRMS:
Table 1; 13C NMR (75.5 MHz, CDCl3) d 20.8 (d, J = 12.9, C3–CH3), 30.8 (d,
J = 88.1, C2), 33.4 (d, J = 91.8, C5), 37.2 (d, J = 5.8, OCH2CH2), 65.4 (d, J = 6.8,
OCH2), 120.3 (d, J = 10.9, C3), 126.7 (C40), 128.6 (C20), 129.1 (C30), 136.3 (d,
J = 17.0, C4), 137.5 (C10); 1H NMR (300 MHz, CDCl3) d 1.73 (s, 3H, C3–CH3),
2.00–2.60 (m, 4H, 2 ꢂ PCH2), 2.99 (t, 2H, J = 6.6, OCH2CH2), 4.12–4.33 (m, 2H,
OCH2), 5.46 (1H, J = 36.0, C4–H), 7.12–7.40 (m, 5H, ArH).
9. Quin, L. D. The Heterocyclic Chemistry of Phosphorus: Systems Based on the
Phosphorus–Carbon Bond; Wiley: New York, 1981. p 37.
10. General procedure for the esterification of phosphinic acids in the presence of T3PÒ: a
mixture of 0.76 mmol of phosphinic acid (1-hydroxy-3-methyl-3-phospholene
1-oxide: 0.10 g, 1-hydroxy-3,4-dimethyl-3-phospholene 1-oxide: 0.11 g,
1-hydroxy-3-methyl-phospholane 1-oxide: 0.10 g, 1-hydroxy-3,4-dimethyl-
phospholane 1-oxide: 0.11 g) and 0.55 mL (50 wt %, 0.84 mmol) of T3PÒ in
EtOAc was stirred for 10 min. To the resulting mixture was added 2.3 mmol (or,
in the case of non-volatile reagents, 1.1 mmol) of the alcohol [methanol:
0.09 mL, ethanol: 0.13 mL, propanol: 0.17 mL, isopropanol: 0.18 mL, butanol:
0.21 mL, isobutanol: 0.21 mL, sec-butanol: 0.21 mL, pentanol: 0.25 mL,
isopentanol: 0.25 mL, 3-pentyl alcohol: 0.25 mL, cyclohexanol: 0.12 mL,
benzyl alcohol: 0.12 mL, 2-phenylethanol: 0.14 mL, 2-(1-naphthyl)ethanol:
0.20 g or (1R,2S,5R)-(ꢁ)-menthol: 0.18 g] and the contents of the flask were
stirred at 25 °C for the appropriate amount of time. The excess T3P reagent was
hydrolyzed with 7 mL of 10% NaHCO3 solution and the aqueous phase was
extracted with EtOAc (2 ꢂ 15 mL). The combined organic phase was dried
(Na2SO4), filtered, and evaporated to provide a crude residue that was passed
through a thin (ca. 3–4 cm) layer of silica gel using 3% MeOH in CH2Cl2 as the
eluent to give the products (2a–p, and 4, 6, and 8) in P99% purity, as oils.
1-[2-(1-Naphthyl)ethoxy]-3-methyl-3-phospholene 1-oxide (2n): 31P NMR and
HRMS: Table 1; 13C NMR (75.5 MHz, CDCl3) d 20.8 (d, J = 12.9, C3–CH3), 30.8 (d,
J = 87.9, C2), 33.5 (d, J = 91.9, C5), 34.4 (d, J = 5.6, OCH2CH2), 65.0 (d, J = 6.8,
OCH2), 120.3 (d, J = 10.9, C3), 123.7 (C20)a, 125.6 (C30)a, 125.8 (C10)a, 126.3
(C40)a, 127.3 (C90)a, 127.6 (C80)b, 128.9 (C100)b, 132.1 (C70)b, 133.5 (C60)b, 134.0
(C50)b, 136.3 (d, J = 16.9, C4),a,b may be reversed; 1H NMR (300 MHz, CDCl3) d
1.67 (s, 3H, C3–CH3), 2.01–2.45 (m, 4H, 2 ꢂ PCH2), 3.47 (t, 2H, J = 7.0,
OCH2CH2), 4.35 (q, 2H, J = 7.2, OCH2), 5.37 (1H, J = 35.4, C4–H), 7.26–7.56 (m,
4H, ArH), 7.74 (d, 1H, J = 7.6, C50–H)c, 7.84 (d, 1H, J = 7.7, C40–H)c; 8.04 (d, 1H,
J = 8.1, C80–H)c, cmay be reversed.
Spectral data for the additional products (4, 6 and 8) are listed in Table 2.
11. (a) Arbuzov, A. B.; Visel, A. O.; Sukina, L. J.; Giniatullin, R. C. Dokl. Akad. Nauk.
SSSR 1980, 253, 879; (b) Bálint, E.; Jablonkai, E.; Bálint, M.; Keglevich, G.
Heteroat. Chem. 2010, 21, 211; (c) Arbuzov, A. B.; Visel, A. O.; Ivanovskaja, K. M.
Dokl. Akad. Nauk. SSSR 1966, 170, 585; (d) Keglevich, G.; Dvorszki, J.; Ujj, V.;
Ludányi, K. Heteroat. Chem. 2010, 21, 271.