Microwave-assisted direct esterification of cyclic phosphinic acids in the presence of ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2016.01.044

The efficiency of the microwave-assisted direct esterification of cyclic phosphinic acids was significantly enhanced by adding 10% of an ionic liquid to the reaction mixture prior to irradiation. In the presence of [bmim][PF₆] most of the esterifications were complete within 30 min at 180 °C.

Full text of DOI:10.1016/j.tetlet.2016.01.044

Accepted Manuscript
Microwave-assisted direct esterification of cyclic phosphinic acids in the pres-
ence of ionic liquids
Nóra Zsuzsa Kiss, György Keglevich
PII:
S0040-4039(16)30044-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.044
TETL 47208
Reference:
Tetrahedron Letters
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13 November 2015
7 January 2016
12 January 2016
Please cite this article as: Kiss, N.Z., Keglevich, G., Microwave-assisted direct esterification of cyclic phosphinic
acids in the presence of ionic liquids, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.01.044
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1
Tetrahedron Letters
Microwave-assisted direct esterification of cyclic phosphinic acids in the presence of
ionic liquids
Nóra Zsuzsa Kiss and György Keglevich
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The efficiency of the microwave-assisted direct esterification of cyclic phosphinic acids was
significantly enhanced by adding 10% of an ionic liquid to the reaction mixture prior to
irradiation. In the presence of [bmim][PF6] most of the esterifications were complete within 30
min at 180 °C.
Available online
Keywords:
2013 Elsevier Ltd. All rights reserved.
Phosphinic acids
Phosphinates
Direct esterification
Ionic liquids
Microwave
The most frequent method for the synthesis of phosphinates
involves the reaction of phosphinic chlorides with alcohols.1–3
However, the use of acid chlorides introduces cost, and the
hydrochloric acid formed needs to be removed by a base. On the
whole, this esterification is not atom efficient. It is known that
phosphinic acids typically do not undergo direct esterification
with alcohols, and this reaction is possible only in special
cases.4,5 We have found that under microwave (MW) irradiation,
phosphinic acids react with alcohols when used in a 15–20-fold
molar excess to afford the corresponding phosphinates in variable
yields.6–8 The use of less volatile alcohols (bp ≥ 118 °C) was
more efficient, as in these cases, the optimum temperature of
200–220 °C could be ensured considering the pressure limit of
the MW reactor of ca. 20 bar. According to our theory, MW
irradiation is helpful in overcoming the relatively high enthalpy
barrier9,10 because of the beneficial effect of the local
overheating11 appearing statistically in the bulk of the mixture.12
presence of 15 equivalents of various C1–C12 alcohols at 160–230
°C in a closed vessel under MW irradiation (Scheme 1). The data
whose major part was published earlier6,8,9 are listed in Table 1.
The esterifications with C1–C4 alcohols were not efficient, and a
maximum conversion of ca. 38–62% could be obtained in five
out of the six cases (Table 1, entries 1–6). The main reason was
that the volatility of these alcohols prevented the application of
temperatures >200 °C. Using n-pentanol, isopentanol, n-octanol,
2-ethylhexanol and dodecyl alcohol, quantitative conversions
could be obtained as a consequence of the higher (220–235 °C)
reaction temperature. However, with one exception, there was a
need for 2–3 h irradiation. The corresponding phosphinates 2g,
2h and 2j-l were prepared in yields of 82%, 76%, 71%, 76% and
95%, respectively (Table 1, entries 7, 8, 10–12). The
esterification of phosphinic acid (1) with 3-pentanol could only
be attempted at a maximum temperature of 210 °C allowed by its
volatility. This temperature, together with the steric hindrance
resulted in a rather low conversion of 36% after 4 h irradiation
(Table 1, entry 9).
The obvious disadvantage of our MW-assisted esterification
was the relatively high reaction temperature (optimally 200–235
°C) required. In a few cases, the reaction times reached 4 h.
When alcohols with low boiling points were used, the yields of
the phosphinates remained low. We wished to develop a more
efficient esterification method utilizing ionic liquids (ILs) as
additives. It has recently been found that certain organic chemical
transformations became more efficient in the presence of ILs.13–18
In
a few cases, ILs were applied together with MW
irradiation.13,17,18
Our model reaction was the MW-assisted esterification of 1-
Scheme 1.
hydroxy-3-phospholene 1-oxide (1) which was carried out in the
———
 Corresponding author. Tel.: +36 1 463 1111/5883; fax: +36 1 463 3648; E-mail address: gkeglevich@mail.bme.hu (G. Keglevich).

2
Tetrahedron Letters
entries 2, 3). The application of 10% [bmim][PF6] had a marked
The direct esterifications of 1-hydroxy-3-phospholene oxide 1
effect and the conversion was complete after 30 min, with
phosphinate 2g being isolated in 92% yield (Table 2, entry 4).
[Emim][HSO4] performed less well (Table 2, entry 5). The use of
[emim][MeSO4], [emim][EtSO4] and [emim][Cl] resulted in
conversions around 60% after 60–75 min irradiation (Table 2,
entries 6–8). [Emim][Ac] did not seem to be useful as an additive
(Table 2, entry 9).
with n-pentanol at 180 °C in the presence of catalytic amounts of
ILs was examined as a model reaction. Seven different
imidazolium salts were tried, mostly in 10% loading (Scheme 2).
These results are listed in Table 2. The control experiment carried
out at 180 °C for 2 h led to a conversion of 82% (Table 2, entry
1). The use of 10% and 20% of [bmim][BF4] together with a
reaction time of 45 min resulted in the formation of phosphinate
2g with conversions of 55% and 81%, respectively (Table 2,
Table 1. Direct esterification of 1-hydroxy-3-methyl-3-phospholene 1-oxide (1) in the absence or presence of 10% [bmim][PF6].
Entry
R
IL
T (°C)
160
160
180
180
200
200
220
235
210
220
220
230
160
160
180
180
180
180
180
210
180
180
180
p (bar)
18
17
15.5
16
16
16.5
9
t (h)
Conversion (%)a MW (Δb)
Yield (%)
Ref.
Phosphinatec
1
Me
–
4
38
32
2a
2b
2c
2d
2e
2f
2
Et
–
4
38
30
3
nPr
–
4
40
30
4
iPr
–
4
28
22
5
nBu
–
2
62 (11)
53
58
[6]
6
iBu
–
4
45
7
nPent
iPent
3-Pent
nOct
iOct
nDodecyl
Me
–
2.5
3
100
100
36
82d
[8]
[8]
2g
2h
2i
8
–
14
12
2
76
9
–
4
25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
–
2
100
100 (28)
100
62
71
[9]
[8]
[9]
2j
–
3
1
76
2k
2l
–
2
2
95
10%
10%
10%
10%
10%
10%
10%
10%
10%
10%
10%
18
17
15.5
16
14
5
3
38
2a
2b
2c
2d
2e
2g
2h
2i
Et
3
86
60
nPr
3
98
68
iPr
3
66
60
nBu
0.5
0.5
0.5
2
90 (19)
100 (52)
100
55
83
nPent
iPent
3-Pent
nOct
iOct
nDodecyl
94
5
95
12
1.5
2
45
0.33
0.33
0.33
100
100 (75)
100
85
2j
84
2k
2l
1
94
a On the basis of relative 31P NMR intensities.
b Comparative thermal experiment.
c The phosphinates (2a–l) described earlier were identified by 31P NMR and HRMS.
d As a result of new measurements.
Scheme 2

3
Table 2
Direct esterification of hydroxy-phospholene oxide 1 by pentyl alcohol at 180 °C in the presence of ionic liquids
Entry
Catalyst
IL (%)
t (min)
120
45
Conversiona (%)
Yield of ester 2g (%)
1
2
3
4
5
6
7
8
9
–
–
82
75
[bmim][BF4]
[bmim][BF4]
[bmim][PF6]
[emim][HSO4]
[emim][MeSO4]
[emim][EtSO4]
[emim][Cl]
[emim][Ac]
10
55
20
45
81
70
92
10
30
100
30b
57b
63b
56b
40b
10
30
10
60
51
58
10
75
10
60
10
30
a On the basis of relative 31P NMR intensities.
b No change upon further irradiation.
On the basis of the above results, we applied [bmim][PF6] as
an additive in further esterifications.
corresponding phosphinates 2j-l were obtained in yields of 85%,
84% and 94%, respectively (Table 1, entries 21–23).
In the next stage, the target esterifications of 1-hydroxy-3-
phospholene oxide 1 with different alcohols were carried out at a
temperature range of 160–210 °C under MW irradiation, in the
presence of 10% [bmim][PF6] as the catalyst (Scheme 3).19
It can be seen that the addition of 10% [bmim][PF6] to the
reaction mixtures was indeed advantageous. The esterifications
became significantly faster and more complete even at a lower
temperature. This is rather obvious using linear and iso alcohols
with carbon atom number ≥4. While the reaction temperatures
could be decreased from 200–235 °C to 180 °C, and the reaction
times from 2–3 h to 20–30 min, the yields of the corresponding
phosphinates 2 were increased, with three exceptions, by 12–38%
(averaging 19%).
To see the role of MW vs traditional thermal heating, the IL-
catalyzed esterification of 1-hydroxy-3-phospholene 1-oxide 1
was also carried out by conventional heating. In reactions with
butanol, n-pentanol and 2-ethylhexanol at 180 °C for 30 min, the
conversions were 19%, 52% and 75%, respectively (Table 1,
entries 17, 18 and 22). The presence of 10% [bmim][PF6] was
also beneficial for thermal esterifications; however, upon
prolonged heating, the reactions remained incomplete.
Scheme 3.
These results can be found in Table 1 (entries 13–23). The
esterifications with the most volatile alcohols MeOH and EtOH
were performed at 160 °C for 3 h, and conversions of 62% and
86% were obtained (Table 1, entries 13, 14). The next reactions
The positive effect of ILs as an additive may be a consequence
of their polarity causing a much better absorption of the MW
energy, hence bringing about more significant local overheating
in the bulk of the mixture.
n
i
with PrOH and PrOH were run at 180 °C for 3 h leading to
conversions of 98% and 66%, respectively (Table 1, entries 15,
16). The methyl ester 2a was obtained in a lower yield (38%),
while the ethyl and propyl products (2b-d) could be isolated in
yields of 60–68%. The butylation was almost complete after
irradiation at 180 °C for 30 min. The 1-butoxy-3-phospholene
oxide 2e was prepared in 83% yield (Table 1, entry 17). The
esterification of phosphinic acid 1 readily took place with n-
pentanol and isopentanol at 180 °C after 30 min, giving complete
conversions and yields around 94% (Table 1, entries 18, 19). At
the same time, the derivatization with 3-pentanol was not
complete even at 210 °C after 2 h irradiation, leading to a
conversion of 55% and a yield of 45% (Table 1, entry 20). The
decreased reactivity is a consequence of steric hindrance. The
phosphinoylation of n-octanol, isooctanol and dodecanol was
complete at 180 °C after irradiation for 20 min, and the
In summary, it was found that the MW-assisted direct
esterifications of 1-hydroxy-3-methyl-3-phospholene oxide 1
became much more efficient in the presence of 10% [bmim][PF6]
in respect to temperature, reaction time and outcome.
Moreover, the IL catalysis seemed to be of more general
value, as it was also effective for the derivatization of other
phosphinic acids, such as 1-hydroxy-3,4-dimethyl-3-phospholene
oxide (3A), monomethyl- and dimethyl-hydroxyphospholane
oxides (3B and 3C) and a hydroxy-hexahydrophosphinine oxide
(3D) (Scheme 4).19 The results of the extension obtained using n-
pentanol as the alcohol are summarized in Table 3.

4
Tetrahedron Letters
Comparing the reactions carried out in the absence and
presence of [bmim][PF6], one can see that the IL-promoted
experiments could be performed under milder conditions (lower
temperature and shorter reaction time), and in a more efficient
way (higher conversions and yields). It is noted, however, that
phosphinate 4D could only be obtained in a lower yield of 42%
(Table 3, entry 8). Esters 4B-D were formed as mixtures of
isomers due to the P and C stereogenic centers.
Scheme 4.
Table 3
Direct esterification of cyclic phosphinic acids 3A-D with n-pentanol
Entry
Phosphinic
acid
IL
T (°C)
p (bar)
t (h)
Conversion (%)
MW
Ratio of
diastereomers
(%)
Yield (%)
Ref.
Phosphinatea
1
2
3
4
5
6
7
8
3A
3A
3B
3B
3C
3C
3D
3D
–
235
200
235
220
235
220
220
200
11
6
3
1
3
1
5
2
4
2
90
67
72
79
89
60
84
31
42
8
8
8
4A
4A
4B
4B
4C
4C
4D
4D
10%
–
95
11
9
~85
~100
~72
~95
~45
~60
50 – 50
10%
–
52 – 48
11
9
70 – 15 – 15
65 – 18 – 17
50 – 50
10%
–
9
10%
9
50 – 50
a Phosphinates 4A-C described in the literature were identified by 31P NMR and HRMS. Species 4D was fully characterized.22
14. Olivier-Bourbigou, H.; Magna, L.; Morvan, D. Appl. Cat. A: Gen.
2010, 373, 1–56.
Acknowledgements
15. Zhang, Q.; Zhang, S.; Deng, Y. Green Chem. 2011, 13, 2619-2637.
16. Yang, X.; Yang, L. Wu, L. Bull. Korean Chem. Soc. 2012, 714-716.
17. Arfan, A.; Paquin, L.; Bazureau, J. P. Russ. J. Org. Chem. 2007, 43,
1058-1064.
18. Chen, Y.; Zu, Y.; Fu, Y.; Zhang, X.; Yu, P.; Sun, G.; Efferth, T.
Molecules 2010, 15, 9486-9495.
This project was supported by the Hungarian Scientific
Research Fund (OTKA K83118 and K115421). G. K. is grateful
to Professor Emeritus Dr Harry R. Hudson (London Metropolitan
University) for his advice.
19. General procedure for the MW-assisted direct esterification of
phosphinic acids: A mixture of the phosphinic acid (0.76 mmol) and
the alcohol (11 mmol) was measured in a sealed tube and irradiated in
a CEM Discover microwave reactor equipped with a stirrer and a
pressure controller using 50–150 W irradiation in the presence of
[bmim][PF6] (0.08 mmol, 15.5 μL) at the temperature and times shown
in Tables 1 and 3. (The pressure developed was in the range of 1–18
bar.) The excess of alcohol was removed under reduced pressure, and
the residue purified by silica flash column chromatography using ethyl
acetate as the eluent to afford phosphinates (2a–e, 2g–l and 4A–D) as
oils in a purity of ~98% according to GC.
The direct esterifications marked by Table 1, entries 1–12 and Table 3,
entries 1, 3, 5, 7 were carried out similarly in the absence of IL.
20. Jablonkai, E.; Milen, M.; Drahos, L.; Keglevich, G. Tetrahedron Lett.
2013, 54, 5873-5875.
21. Bálint, E.; Jablonkai, E.; Bálint, M.; Keglevich, G. Heteroatom Chem.
2010, 21, 211-214.
Supplementary data
Supplementary data (characterization data for compounds 2a-l
and 4A-C described earlier) are provided.
References and notes
1.
Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley: New
York, 2000.
2.
3.
Kiss, N. Z.; Keglevich, G. Curr. Org. Chem. 2014, 18, 2673-2690.
Keglevich, G., Kiss, N. Z., Mucsi, Z.: Chem. Sci. J. 2014, 5, 1-14. Doi:
10.4172/2150-3494.1000088
4.
5.
Mais, A.; McBride, J. J., US3092650 A, 1963.
Cherbuliez, E.; Weber, G.; Rabinowitz, J. Helv. Chim. Acta 1963, 46,
2464-2470.
22. Compound 4D: Yield: 42%; 31P NMR (CDCl3)  48.2 and 49.5; 13C
NMR (CDCl3)  13C NMR (CDCl3) δ 13.8 (CH2CH3), 22.0 (CH2CH3),
21.8 (J = 3.7) and 22.7 (J = 5.1) C3, 23.9 (J = 16.2) and 24.1 (J = 16.5)
C3–CH3, 25.6 (J = 85.8) and 26.2 (J = 86.4) C6, 27.5 and 27.6 (CH2),
30.28 (J = 5.0) and 30.32 (J = 2.5) C4, 30.2 (J = 5.8) and 31.3 (J = 4.6)
C5, 34.5 (J = 6.5) and 34.9 (J = 6.2) OCH2CH2, 34.9 (J = 83.9) and
6.
7.
8.
9.
Kiss, N. Z.; Ludányi, K.; Drahos, L.; Keglevich, G. Synth. Commun.
2009, 39, 2392-2404.
Keglevich, G.; Bálint, E.; Kiss, N. Z.; Jablonkai, E.; Hegedűs, L.;
Grün, A.; Greiner, I. Curr. Org. Chem. 2011, 15, 1802-180.
Kiss, N. Z.; Böttger, É.; Drahos, L.; Keglevich, G. Heteroatom Chem.
2013, 24, 283-288.
1
35.1 (J = 84.1) C2, 63.3 (J = 6.4) and 63.9 (J = 6.6) OCH2; H NMR
Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Körtvélyesi, T. Org. Biomol.
Chem. 2012, 10, 2011-2018.
(CDCl3)  0.89 (t, J = 7.0) and 0.90 (t, J = 6.9) CH2CH3 overlapped,
total intensity 3H, 1.01 (dd, J1 = 6.5, J2 = 3.1) and 1.02 (dd, J1 = 6.4, J2
= 2.9) C3–CH3, 0.13–2.03 (m, 15H, CH2, CH), 3.92–4.01 (m, 2H,
OCH2); [M+H]+found = 219.1512, C11H24O2P requires 219.1514.
10. Mucsi, Z.; Kiss, N. Z.; Keglevich, G. RSC Adv. 2014, 4, 11948-11954.
11. Kranjc, K.; Kočevar, M. Curr. Org. Chem. 2010, 14, 1050-1074.
12. Keglevich, G.; Greiner, I.; Mucsi, Z. Curr. Org. Chem. 2015, 19, 1436-
1440.
13. Martínez-Palou, R. J. Mex. Chem. Soc. 2007, 51, 252-264.

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Microwave-assisted direct esterification of
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Nóra Zsuzsa Kiss, György Keglevich*