Direct esterification of phosphinic acids under microwave conditions: Extension to the synthesis of thiophosphinates and new mechanistic insights

Article abstract of DOI:10.1016/j.tetlet.2012.11.054

The direct esterification of phosphinic acids has been extended to the preparation of thiophosphinates using thiols, but the conversions are only ca. 50%. The outcome is in agreement with the unexpectedly high enthalpy of activation and endothermicity sug

Full text of DOI:10.1016/j.tetlet.2012.11.054

Tetrahedron Letters 54 (2013) 466–469
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Tetrahedron Letters
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Direct esterification of phosphinic acids under microwave conditions:
extension to the synthesis of thiophosphinates and new mechanistic insights
György Keglevich a, , Nóra Zsuzsa Kiss a, László Drahos b, Tamás Körtvélyesi c
⇑
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
b Hungarian Academy of Sciences, Chemical Research Center, 1525 Budapest, Hungary
c Department of Physical Chemistry and Material Science, University of Szeged, 6701 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct esterification of phosphinic acids has been extended to the preparation of thiophosphinates
using thiols, but the conversions are only ca. 50%. The outcome is in agreement with the unexpectedly
high enthalpy of activation and endothermicity suggested by quantum chemical calculations. At the same
time, formation of the thiophosphinates confirms the AAC2 (phosphinylation) mechanism and excludes
the SN reaction paths. Formation of an olefinic intermediate under the reaction conditions is also
excluded experimentally.
Received 26 September 2012
Revised 25 October 2012
Accepted 13 November 2012
Available online 23 November 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Phosphinic acids
Thiophosphinates
Esterification
Microwave
Theoretical calculations
Mechanism
It is well-known that phosphinic acids do not undergo esterifi-
cation with alcohols under traditional thermal conditions. For this
reason, phosphinates are usually prepared by the reaction of phos-
phinic chlorides with alcohols in the presence of a base.1 We, how-
ever, found that the direct esterification of phosphinic acids is
possible under microwave (MW) conditions2,3 as a consequence
of the beneficial effect of MW irradiation.4 We assumed that the
statistically occurring local overheating effect4 can overcome the
barrier corresponding to the high values of the enthalpy of activa-
tion (102–161 kJ molꢀ1).4 It was also found that the esterifications
under discussion are virtually thermoneutral.5 Quantum chemical
calculations suggested that four-membered transition states (TSs)
are involved in the rate-determining step of the esterifications
and amidations.5 The proposed mechanism for the esterification
is shown in Scheme 1.
analogous mechanism to that for the esterification of carboxylic
acids, this step is followed by proton transfer, converting interme-
diate 6 into 7. Dehydration of species 7 leads to the protonated
form of the phosphinate 4. Scheme 1 also shows the ‘AAC2’ route
suggested by quantum chemical calculations.5 According to this,
the protonated product 4 is formed via the above mentioned
four-membered TS (3). The relevance of a cyclic TS in the phosph-
inylation mechanism theory is a novel discovery. But how is it pos-
sible to exclude the ‘SN2’ and ‘SN1’ mechanisms involving
protonation of the alcohol (by the phosphinic acid) in the first step,
which is followed by nucleophilic attack by the hydroxy group of
the phosphinic acid on the a-carbon atom of the protonated alco-
hol to furnish the protonated phosphinate 9 via TS 8 (SN2), or by
dehydration and subsequent reaction of the cation (RCH2CH2+) so
formed with the phosphinic acid 1? The result of the ‘SN1’ route
is, of course, the same (species 9, and after deprotonation, 5).
To answer the above question, we studied the reaction of 3-
phospholene 1-oxides 12 and 13 with thiols, such as 1-butanethiol
and 1-pentanethiol under MW conditions. As in earlier cases, the
thiols were applied in 14-fold excess and the reactions were
accomplished at ca. 200–220°C over 4–8 h in sealed tubes.6 It
was a question of whether the esterification takes place, and if
so, whether the monothiophosphinates 14/15, or the phosphinates
16 are formed. It was found that the reaction had occurred in all
cases with conversions of ca. 51%. The work-up procedure, com-
prising the removal of the volatile components followed by purifi-
cation by chromatography, led to the monothiophosphinates 14/15
The theoretically possible mechanistic pathways leading to the
phosphinic ester 5 are shown in general in Scheme 2.
Phosphinate 5 may be formed by acylation/phosphinylation of
the alcohol (as shown by the ‘AAC2’ routes in red), or by alkylation
of the phosphinic acid (1) (as shown by the ‘SN2’ and ‘SN1’ routes in
green and blue, respectively). Considering the ‘AAC2’ protocol, the
first step is the protonation of the phosphinic acid 1 (that is, auto-
protonation in our case). Then, the alcohol attacks the electrophilic
P=O moiety of the protonated phosphinic acid 2. Envisaging an
⇑
Corresponding author. Tel.: +36 1 463 1111/5883; fax: +36 1 463 3648.
E-mail address: gkeglevich@mail.bme.hu (G. Keglevich).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.054

G. Keglevich et al. / Tetrahedron Letters 54 (2013) 466–469
467
MW
MW
HO
H
R1
autoprotonation
H
Me
Me
Me
R1
R1
O
R1
O
R1
O
R2OH
O
OH
OH
200 °C
R1
HO
200 °C
R2SH
P
P
P
OR2
R2SH
4
3
R1
R1
OH
5
2
1
R1
1
2
P
P
P
− H2O
− H2S
OR2
OH
SR2
3
R1, R2 = alkyl
16
R1
H
R1
R2
nBu 14a7
14b8
− H2O
12
H
H
nPent
Me 13
R1
R1
OH
OR2
O
OR2
− H
Me nPent 159
P
P
R1
R1
5
4
Scheme 3. MW-assisted direct esterification of 1-hydroxy-3-phospholene 1-oxides
with thiols.
Scheme 1. Mechanism for the MW-assisted direct esterification of phosphinic
acids.
sulfur atom instead of oxygen into the product somewhat resem-
bles isotopic labeling.
in yields of 36–40%. No phosphinates 16 were formed (Scheme 3).
The unreacted phosphinic acids 12 and 13 were recovered. Thi-
ophosphinates 14a,b and 15 were identified by 31P, 13C and 1H
NMR spectroscopy, as well from mass spectral data.7–9
On the other hand, the question arises as to why the conver-
sions in the reactions of phosphinic acids 12 and 13 with thiols
are incomplete? To answer this, B3LYP/6-31++G(d,p) calculations
were carried out on the reaction of 1-hydroxy-3-methyl-3-phos-
pholene 1-oxide (12) with thiobutanol, and as a comparison, also
on the reaction of the same hydroxy-phospholene (12) with buta-
nol. We wished to map the energetics of these reactions. The struc-
tures of the two respective TSs (17 and 18) together with selected
geometries are shown in Figures 1 and 2.
It can be seen, that the O–>S exchange in the four-membered TS
17/18 is associated with a bond elongation of 28%, while the O–P–X
(X = O and S) angle in the four-membered ring changes only
slightly (71.7 vs 74.4 deg.) The energy diagrams for the 12 ? 14a
and 12 ? 1-butoxy-3-methyl-3-phospholene 1-oxide (19) trans-
formations are shown in Figures 3 and 4, respectively.
On conventional heating at 200°C for 6 h, the conversions of the
reactions of phosphinic acid 12 with the thiols were below 10%.
The 1-thioalkoxy-3-phospholene 1-oxides 14 and 15 can also be
synthesized by the conventional approach via the 1-chloro-3-
phospholene 1-oxides10 prepared in a separate step from the cor-
responding phosphinic acids 12 and 13. However, it is a disadvan-
tage that, in this case, the thioesterification involves two steps.
On the one hand, our experiments on direct esterifications
unambiguously justified the AAC2 mechanism during the reaction
of phosphinic acids and thiols. Accordingly, the thiol is phosphiny-
lated by the cyclic phosphinic acid, meaning that the phosphinic
acid is not alkylated by the thiol in an SN2 or SN1 mechanism. It fol-
lows that the phosphinylation (acylation) mechanism, which is
obviously valid also for the reaction of phosphinic acids with alco-
hols, is supported by experimental proof. The incorporation of a
It can be seen that the direct esterification of 1-hydroxy-3-
phospholene oxide (12) with 1-butanethiol involves a significantly
higher enthalpy of activation, than that with butanol (DH
# = 145.4
vs 101.7 kJ molꢀ1). It is also significant that while the reaction with
R1
O
+
R2CH2CH2 OH
P
R1
OH
1
H
H
− H
R1
R1
R2CH2CH2 OH2
R2CH2CH2
R2CH CH2
H
OH
OH
OH
OH
P
− H2O
P
R1
via
R1
2
2'
olefin
formation
SN2
SN1
R2CH CH3
A
Ac2
R2
R2CH2CH2
R1
O
H
#
#
HO
P
R1
H
O
R1
O
CH3
CH
R2
R1
R1
P
O
CH2
CH2CH2R2
P
OH
P
R1
δ
δ
O
H
R1
6
R1
HO
O
CH2 OH2
OH
H
3
8
10
H
− H2O
− H2O
R2CH2CH2
R1
O
P
− H
R1
O
R1
O
CH2CH2R2
P
P
OH
P
P
O
H
CH2CH2R2
R1
R1
R1
− H2O
OH
OH2
4
9
7
− H
R1
O
O
CH3
CH
R2
R1
R1
O
CH2CH2R2
R1
R1
P
O
O
− H
R1
CH2CH2R2
5
OH
R1, R2 = alkyl
4'
11
Scheme 2. Possible reaction paths for the formation of phosphinates.

468
G. Keglevich et al. / Tetrahedron Letters 54 (2013) 466–469
−1
ΔH (kJ mol
)
BuSH
12
14a
#
ΔH = 145.4
0
ΔH = 48.5
Figure 1. TS 17 for the esterification of 1-hydroxy-3-methyl-3-phospholene 1-
oxide (12) and 1-butanethiol calculated by the B3LYP/6-31++G(d,p) method.11
Selected geometries (bond distances, bond angles, and torsion angles) are given in Å
and deg. P–S 2.278, P–O1 1.975, P–O2 1.614, P–C2 1.869, C2–C3 1.513, C3–C4 1.344,
C4–C5 1.505, P–C5 1.849, S. . .H 1.469, O1. . .H 1.452, S–C10 1.867, C10–C20 1.532,
C20–C30 1.541, C30–C40 1.533, P–S. . .H 74.73, P–O1. . .H 85.75, P–C2–C3 105.33, C2–
C3–C4 115.91, C3–C4–C5 118.47, C5–P–C2 94.13, S–P–O1 74.41, S–P–O2 115.41, P–
S–C10 104.85, S–C10–C20 109.47, C10–C20–C30 110.75, C20–C30–C40 112.12, O1–P–
S. . .H ꢀ5.18, P–C2–C3–C4 ꢀ8.01, P–C2–C3–Me 173.83, C2–C3–C4–C5 1.11, C3–C4–
C5–P 6.47, P–S–C10–C20 165.22, S–C10–C20–C30 177.95, C10–C20–C30–C40 179.56. (For
the numbering of the five-membered hetero ring, see Scheme 3, in P(O1-H)O2-H,
O1 is the ring O, while O2 is the exocyclic O, C10–C20–C30–C40 represent the atoms of
the Bu group).
reaction coordinate
Figure 3. Enthalpy profile for the esterification of 1-hydroxy-3-phospholene oxide
(12) with 1-butanethiol.
−1
ΔH (kJ mol
)
Me
Me
BuOH
P
P
n
O
OH
O
O Bu
12
19
#
ΔH = 101.7
0
ΔH = 3.3
reaction coordinate
Figure 4. Enthalpy profile for the esterification of 1-hydroxy-3-phospholene oxide
(12) with butanol.
Figure 2. TS 18 for the esterification of 1-hydroxy-3-methyl-3-phospholene 1-
oxide (12) and butanol calculated by the B3LYP/6-31++G(d,p) method.11 Selected
geometries (bond distances, bond angles, and torsion angles) are given in Å and deg.
P–O 1.778, P–O1 1.947, P–O2 1.607, P–C2 1.853, C2–C3 1.518, C3–C4 1.343, C4–C5
1.506, P–C5 1.842, O. . .H 1.095, O1. . .H 1.371, O–C10 1.502, C10–C20 1.517, C20–C30
1.541, C30–C40 1.533, P–O. . .H 88.88, P–O1. . .H 74.96, P–C2–C3 104.04, C2–C3–C4
115.81, C3–C4–C5 118.27, C4–C5–P 103.74, O–P–O1 71.69, O–P–O2 116.55, P–O–
C10 127.94, O–C10–C20 108.39, C10–C20–C30 110.79, C20–C30–C40 112.13, O1–P–O. . .H
1.43, P–C2–C3–C4 13.27, P–C2–C3–Me –167.41, C2–C3–C4–C5 ꢀ1.314, C3–C4-C5-P
ꢀ11.43, P–O–C10–C20 ꢀ156.20, O–C10–C20–C30 ꢀ177.94, C10–C20–C30–C40 ꢀ179.68.
(For atom numbering see the caption to Fig. 1.).
Me
MW
~220 °C
P
O
O
OCH2CH2R
20
12
+
58−95%
RCH2CH2OH
Me
MW
~220 °C
thiobutanol is clearly endothermic (
butanol is only slightly so, being rather near to thermoneutral
H0 = 3.3 kJ molꢀ1). Our experience is that the beneficial effect
D
H0 = 48.5 kJ molꢀ1), that with
P
OCH(Me)R
(D
R = Et, C6H13, C10H21
21
of MW irradiation, that is the statistically occurring local overheat-
ing effect, may overcome the relatively high enthalpy of activation
values,4 but the endothermicity works against this positive impact
leading eventually to incomplete conversions. Hence, the theory
and practice (incomplete conversions) are in good agreement for
the cases under discussion.
Returning to Scheme 2 showing the possible routes leading to
phosphinate 5: there is still a possibility that has not been men-
tioned. This is the route in which the protonated alcohol is con-
verted into an olefin, R2CH@CH2, and this species acts as the
alkylating agent after protonation. This approach would lead to
Scheme 4. MW-assisted direct esterification of 1-hydroxy-3-phospholene 1-oxide
(12) with various alcohols.
the ester with a branched alkyl group 21 according to the Mark-
ovnikov orientation. However, this route can be excluded, as only
cyclic phosphinates with linear alkyl groups 20 were obtained.3,5
A few examples are shown in Scheme 4.
Two additional experimental observations are also against the
involvement of an olefin-type intermediate. Using benzyl alcohol

G. Keglevich et al. / Tetrahedron Letters 54 (2013) 466–469
469
sealed under nitrogen. The pressure developed was in the range of 6–7 bar).
The excess thiol was removed under reduced pressure, and the residue so
obtained purified by flash column chromatography using silica gel and 3%
MeOH in CHCl3 as the eluant to afford phosphinate 14a, 14b, or 15 as oils. All
operations with thiophosphinates were carried out under nitrogen.
A
B
MW
MW
Me
Me
170 °C/~15 bar
tBuOH
180 °C/6 bar
BnOH
12
7. Compound 14a: Yield: 38%; 31P NMR (121.5 MHz, CDCl3) d 75.2; 13C NMR
(75.5 MHz, CDCl3) d 12.8 (CH2CH3), 19.6 (3J = 11.8, C3–CH3), 21.0 (CH2CH3), 27.6
(CH2), 32.6 (SCH2), 36.7 (1J = 66.0, C2), 39.4 (1J = 69.1, C5), 119.5 (2J = 9.5, C4),
135.5 (2J = 15.1, C3); 1H NMR (300 MHz, CDCl3) d 0.88 (t, J = 7.3, 3H, CH2CH3),
1.31–1.47 (m, 2H, CH2CH3), 1.60–1.72 (m, 2H, CH2), 1.76 (s, 3H, C3–CH3), 2.45–
2.83 (m, 4H, PCH2), 2.83–2.96 (m, 2H, SCH2), 5.48 (d, J = 35.4, 1H, CH);
[M+H]+found = 205.0821, C9H18OPS requires 205.0816.
P
P
O
OBn
22 (55%)
O
OtBu
23 (0%)
Scheme 5. MW-assisted direct esterification of 1-hydroxy-3-phospholene 1-oxide
(12) with benzyl alcohol and tert-butanol.
8. Compound 14b: Yield: 40%; 31P NMR (121.5 MHz, CDCl3) d 74.5; 13C NMR
(75.5 MHz, CDCl3) d 13.2 (CH2CH3), 19.6 (3J = 12.0, C3–CH3), 21.4 (CH2CH3), 27.9
(CH2), 30.1 (SCH2CH2), 30.2 (2J = 3.5, SCH2), 36.7 (1J = 65.9, C2), 39.4 (1J = 69.1,
C5), 119.5 (2J = 9.7, C4), 135.5 (2J = 15.2, C3); 1H NMR (300 MHz, CDCl3) d 0.90
(t, J = 7.0, 3H, CH2CH3), 1.25–1.47 (m, 4H, 2 ꢁCH2), 1.64–1.77 (m, 2H, SCH2CH2),
1.82 (s, 3H, C3–CH3), 2.50–2.88 (m, 4H, PCH2), 2.88–3.02 (m, 2H, SCH2), 5.53 (d,
J = 36.0, 1H, CH); [M+H]+found = 219.0977, C10H20OPS requires 219.0973.
9. Compound 15: Yield: 36%; 31P NMR (121.5 MHz, CDCl3) d 67.5; 13C NMR
(75.5 MHz, CDCl3) d 13.7 (CH2CH3), 16.2 (3J = 12.0, C3–CH3), 21.9 (CH2CH3), 28.4
(3J = 2.6, SCH2CH2), 30.6 (CH2), 30.8 (2J = 3.9, SCH2), 42.2 (1J = 68.1, C2), 127.1
(2J = 11.2, C3); 1H NMR (300 MHz, CDCl3) d 0.82 (t, J = 7.0, 3H, CH2CH3), 1.17–
1.40 (m, 4H, 2ꢁCH2), 1.59–1.73 (m, total intensity 8H, 2ꢁC3–CH3, CH2), 2.48–
2.64 (m, 2H, SCH2), 2.66–2.94 (m, 4H, PCH2); [M+H]+found = 233.1130,
as the reactant, the expected benzyl phosphinate 2212 was formed
(Scheme 5A). At the same time, there was no reaction with tert-
butanol (Scheme 5B).
The fact that the benzyl phosphinate 22 was formed is of prin-
cipal importance in excluding the mechanism via olefin formation.
The lack of the formation of the tert-butyl phosphinate 23 at a reac-
tion temperature of 170°C confirms the lack of 2-methylprop-1-
ene formation under such conditions, and at the same time shows
that the phosphinylation cannot take place due to steric hindrance.
In conclusion, the MW-assisted direct esterification was ex-
tended to the synthesis of new cyclic monothiophosphinates. For-
mation of these products proved the phosphinylation mechanism
and that the incomplete conversions could be explained by the cal-
culated energetics.
C
11H22OPS requires 233.1129.
}
10. Keglevich, G.; Kovács, A.; Toke, L.; Újszászy, K.; Argay, G.; Czugler, M.; Kálmán,
A. Heteroat. Chem. 1993, 4, 329.
11. All computations were carried out using the GAUSSIAN 03 program package
(G03). The transition states were calculated by the semi-empirical PM6
method13 The structures were used as initial structures in the density
functional calculations at the B3LYP/6-31++G(d,p) level in the gas phase.14
12. Compound 22: Yield: 55%; 31P NMR (121.5 MHz, CDCl3) d 76.3; 13C NMR
(75.5 MHz, CDCl3) d 20.6 (3J = 13.0, C3–CH3), 30.9 (1J = 87.6, C2), 33.5 (1J = 91.6,
C5), 66.2 (2J = 6.4, OCH2), 120.2 (2J = 11.0, C4), 127.8 (C20), 128.3 (C40), 128.5
(C30), 136.1 (2J = 17.0, C3), 136.2 (3J = 5.5, C10); 1H NMR (300 MHz, CDCl3) d 1.75
(s, 3H, C3–CH3), 2.22–2.53 (m, 4H, PCH2), 5.08 (d, J = 8.8, 2H, OCH2), 5.49 (d,
J = 37.1, 1H, CH), 7.29–7.40 (m, 5H, C6H5); [M+H]+found = 223.0883, C12H16O2P
requires 223.0888.
Acknowledgements
This project was supported by the Hungarian Scientific and Re-
search Fund (OTKA K83118). G.K. is indebted to Professor Harry R.
Hudson (London Metropolitan University) for his advice.
13. Stewart, J. J. P. J. Mol. Mod. 2007, 13, 1173.
14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03, Revision E.01, GAUSSIAN, Inc., Wallingford CT, 2004.
References and notes
1. Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley: New York, 2000.
2. Kiss, N. Z.; Ludányi, K.; Drahos, L.; Keglevich, G. Synth. Commun. 2009, 39, 2392.
3. Keglevich, G.; Bálint, E.; Kiss, N. Z.; Jablonkai, E.; Hegedus, L.; Grün, A.; Greiner,
}
I. Curr. Org. Chem. 2011, 15, 1802.
ˇ
4. Kranjc, K.; Kocevar, M. Curr. Org. Chem. 2010, 14, 1050.
5. Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Körtvélyesi, T. Org. Biomol. Chem. 2012, 10,
2011.
6. General procedure for the direct thioesterification of 1-hydroxy-3-methyl-3-
phospholene 1-oxide (12) under MW irradiation.
A mixture of 0.76 mmol of the phosphinic acid (0.1 g of 12, 0.11 g of 13) and
11.4 mmol of the thiol (1.2 mL of 1-butanethiol or 1.4 mL of 1-pentanethiol) in
a sealed tube was irradiated in a 300 W CEM Discover focused MW reactor
equipped with a pressure controller at 200°C for 6 h. (The reaction vessel was