Catalyst-free P-C coupling reactions of halobenzoic acids and secondary phosphine oxides under microwave irradiation in water

Article abstract of DOI:10.1016/j.tetlet.2015.02.015

4-Bromo and 3-bromobenzoic acids along with 4-iodobenzoic acid underwent P-C coupling reactions with diarylphosphine oxides in the absence of any catalyst in water as the solvent under microwave irradiation. The phosphinoylbenzoic acids obtained were conv

Full text of DOI:10.1016/j.tetlet.2015.02.015

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Tetrahedron Letters 56 (2015) 1638–1640
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free P–C coupling reactions of halobenzoic acids and
secondary phosphine oxides under microwave irradiation in water
⇑
Erzsébet Jablonkai, György Keglevich
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Bromo and 3-bromobenzoic acids along with 4-iodobenzoic acid underwent P–C coupling reactions
with diarylphosphine oxides in the absence of any catalyst in water as the solvent under microwave irra-
diation. The phosphinoylbenzoic acids obtained were converted into the corresponding ethyl esters in
yields of 59–82%.
Received 1 December 2014
Revised 15 January 2015
Accepted 4 February 2015
Available online 12 February 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
P–C coupling
Hirao reaction
Catalyst-free
Microwave-assisted
Secondary phosphine oxide
Triarylphosphine oxide
A widely used method for the synthesis of arylphosphonates is
the Hirao reaction involving the P–C coupling of bromoarenes and
dialkyl phosphites in the presence of Pd(PPh3)4 as the catalyst and
triethylamine as the base.1,2 Subsequently, the reaction was
extended to other aryl derivatives and different >P(O)H reagents
including H-phosphinates and secondary phosphine oxides using
Pd(0)-, Pd(II)- and Ni(II)-catalysts with mono- and bidentate
P-ligands.3,4
diphenylphosphine oxide with aryl bromides was also described
in water at 70 °C in the presence of NiCl2ꢀ6H2O as the catalyst
and Zn along with 2,20-bipyridine as the additives to afford
aryl(diphenyl)phosphine oxides in yields of 78–97%.8 A recent
exciting development was that halobenzoic acids and
diphenylphosphine oxide undergo P–C coupling in water at
180 °C under microwave (MW) irradiation in the presence of Pd/C
as the catalyst, and K2CO3 as the base.9 Interestingly, the authors
of this communication found that the Hirao reaction of aryl
bromides and different >P(O)H species, such as dialkyl phosphites
and secondary phosphine oxides took place in the presence of
P-ligand-free Pd(OAc)2 under solvent-free and MW-assisted condi-
tions.10,11 Recently, we have aimed at the simplification of different
It is a significant challenge to carry out the Hirao reaction under
‘green’ chemical conditions. The first step was taken when a cat-
alytic amount of water was added to a somewhat related coupling
reaction of dialkyl phosphites and substituted benzyl halides using
Pd(OAc)2/Xantphos and N,N-diisopropylethylamine in THF. The
corresponding benzylphosphonates were obtained in 71–98%
catalytic systems under MW irradiation.12,13 Thus, it was
challenge for us to try to elaborate catalyst-free MW-
assisted variation of the Hirao reaction in water as the solvent.
a
yields.5 It was
a
valuable observation that the coupling of
a
4-iodotoluene and diethyl phosphite was quantitative in MeCN–
H2O (1:1) at 25 °C applying Pd(PPh2(m-C6H4SO3M))3 (M = Na+ or
K+) as the catalyst, and triethylamine as the base.6 Next, the cou-
pling of substituted aryl halides and diisopropyl phosphite was
performed successfully in water (containing three molar equiva-
The first model reaction was the coupling of 4-bromobenzoic
acid (1A) and diphenylphosphine oxide (2a) or di(4-methyl-
phenyl)phosphine oxide (2b)14–16 in water in the presence of three
equivalents of K2CO3 at 180 °C under MW irradiation. It was neces-
sary to carry out the P–C coupling reactions under a nitrogen atmo-
sphere to avoid the oxidation of the secondary phosphine oxide
reagents (2a and 2b). For the two cases (1. 1A+2a, and 2. 1A+2b),
the reaction times were 1 h and 3 h, respectively, and the products,
which were prepared and identified as the ethyl esters 4a and 4b,
were obtained in 78% and 73% yields, respectively, (Scheme 1,
entries 1 and 2).17,18 The esterification of the 4-phosphinoyl-
benzoic acids 3a and 3b, which had been isolated by precipitation,
lents of iPrOH) using
a ferrocene-based palladacycle with a
P- and an N-ligand, and applying KF at reflux temperature. One
equivalent of tetrabutylammonium bromide was also present in
the mixture as an additive and the yields of the arylphosphonates
fell in the range of 53–94%.7 The coupling of reactive
⇑
Corresponding author. Tel.: +36 1 463 1111/5883; fax: +36 1 463 3648.
E-mail address: gkeglevich@mail.bme.hu (G. Keglevich).
http://dx.doi.org/10.1016/j.tetlet.2015.02.015
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
E. Jablonkai, G. Keglevich / Tetrahedron Letters 56 (2015) 1638–1640
1639
MW
N2
The reaction of 4-bromobenzoic acid (1A) and diphenyl-phos-
phine oxide (2a) was also attempted under conventional heating
and similar conditions, but the desired P–C coupling reaction was
reluctant and incomplete. After heating for three hours at 180 °C,
the conversion was only 43%.
In the next stage, the analogous coupling reaction of 3-bro-
mobenzoic acid (5) with diarylphosphine oxides 2a and 2b was
investigated. Under similar conditions, longer reaction times (3 h
and 6 h, respectively) were required,17 and after the esterification
of intermediates 6a and 6b, the corresponding 3-phosphinoylben-
zoic acid esters 7a and 7b were obtained in 70% and 59% yields,
respectively18 (Scheme 2, entries 1 and 2). It is noted that the P–
C couplings discussed took place in a homogeneous (water) medi-
um. In the latter cases, a minor debromination side reaction also
occurred under the conditions applied.
O
O
78 °C, 6 h
SOCl2
PAr2
X
PAr2
180 °C, time
K2CO3
EtOH
+
Ar2P(O)H
H2O
2
CO2H
CO2H
CO2Et
4
3
1A: X = Br
1B: X = I
Ar = Ph (a), 4-MeC6H4 (b)
Entry
Aryl halide
P reagent
Time (h)
Yield of estera (%)
78 (4a)
1
2
3
4
1A
1A
1B
1B
2a
2b
2a
2b
1
3
1
3
73 (4b)
82 (4a)
80 (4b)
a Regarding the transformation 1 → 4.
Scheme 1. Reactions of 4-halobenzoic acids with diarylphosphine oxides.
Finally,
a
mixed diarylphosphine oxide, phenyl-(4-
methylphenyl)phosphine oxide (8), prepared by us for the first
time,14 was reacted with 4-iodobenzoic acid (1B) under similar
conditions to those applied above. After the usual esterification
of the intermediate 9, the corresponding 4-phosphinoylbenzoic
acid ester 10 was obtained in a yield of 62% (Scheme 3). The pro-
duct 10 is a triarylphosphine oxide with three different aryl groups.
The intermediates, diarylphosphinoylbenzoic acids 3a, 3b, 6a,
6b and 9 were identified by 31P NMR and IR spectroscopy and by
MW
N2
78 °C, 6 h
SOCl2
O
O
Br
PAr2
PAr2
180 °C, time
K2CO3
EtOH
+
Ar2P(O)H
H2O
2
CO2H
CO2H
CO2Et
5
6
7
Ar = Ph (a), 4-MeC6H4 (b)
HRMS, as shown in Table 1. The mP@O and mC@O stretching vibrations
appeared at around 1180 cmꢁ1 and 1684 cmꢁ1, respectively.
The phosphinoylbenzoic acid esters 4a, 4b, 7a, 7b and 10 were
characterized by 31P, 13C and 1H NMR spectroscopy, as well as by
HRMS. With one exception (4a19), the triarylphosphine oxides 4,
7 and 10 are new compounds.
Entry
1
2
P reagent
2a
2b
Time (h)
Yield of estera (%)
70 (7a)b
3
6
59 (7b)b
a Regarding the transformation 5 → 7.
b Benzoic acid was obtained as a by-product.
In conclusion, an environmentally friendly catalyst-free and
MW-assisted variation of the Hirao reaction is described, which
allows the synthesis of new phosphinoylbenzoic acid derivatives
in water.
Scheme 2. Reaction of 3-bromobenzoic acid with diarylphosphine oxides.
Acknowledgement
was carried out using thionyl chloride in boiling ethanol. Starting
from 4-iodobenzoic acid (1B), the outcomes were similar but the
overall yields of the two-step procedure were somewhat higher.
4-Phosphinoylbenzoic acid esters 4a and 4b were prepared in
yields of 82% and 80%, respectively (Scheme 1, entries 3 and 4).17,18
This project was supported by the Hungarian Scientific
Research Fund (OTKA K83118). The advice of Professor Dr Harry
R. Hudson (London Metropolitan University, London, UK) is
appreciated.
MW
N2
78 °C, 6 h
O
I
O
P
O
P
180 °C, 3 h
K2CO3
SOCl2
H
CO2H
P
CO2Et
EtOH
+
H2O
CO2H
1B
Me
Me
Me
10 (62% [from 1B])
9
8
Scheme 3. The synthesis of triarylphosphine oxides with three different aryl groups.
Table 1
Selected spectral data for the diarylphosphinoylbenzoic acid intermediates 3a, 3b, 6a, 6b and 9
Intermediate
31P NMR (D2O)a
dP (DMSO-d6)
[M+H]+found
[M+H]+required
IR (cmꢁ1
)
3a
3b
6a
6b
9
23.6
23.6
24.1
24.0
23.9
26.49
26.59
—
—
—
323.0837
323.0844
351.1154
351.1157
337.0997
323.0832
323.0832
351.1145
351.1145
337.0988
760, 696, 1181, 1682
751, 694, 1180, 1687
750, 704, ꢂ1180, 1687
751, 695, 1180, 1687
758, 695, 1179, 1680
a
Obtained using a Bruker AV-300 spectrometer at 121.5 MHz.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
1640
E. Jablonkai, G. Keglevich / Tetrahedron Letters 56 (2015) 1638–1640
18. General procedure for the esterification of the diarylphosphinoylbenzoic acids 3a,
3b, 6a, 6b and 9: 0.11 mL (1.5 mmol) of SOCl2 was added slowly to a suspension
of ca. 0.40–0.45 mmol of the phosphinoylbenzoic acid 3a, 3b, 6a, 6b and 9
obtained above in 10 mL of EtOH. The solution was stirred under reflux until
HCl formation was complete (ꢂ6 h). Evaporation of the solvent provided a
residue that was purified by column chromatography (silica gel, 3% MeOH in
CH2Cl2) to give products 4a, 4b, 7a, 7b and 10 as dense oils.
References and notes
1. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Tetrahedron Lett. 1980, 21, 3595–
3598.
2. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Synthesis 1981, 56–57.
3. Jablonkai, E.; Keglevich, G. Curr. Org. Synth. 2014, 11, 429–453.
4. Jablonkai, E.; Keglevich, G. Org. Prep. Proced. Int. 2014, 46, 281–316.
5. Lavén, G.; Stawinski, J. Synlett 2009, 225–228.
6. Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112, 4324–4330.
7. Xu, K.; Yang, F.; Zhang, G.; Wu, Y. Green Chem. 2013, 15, 1055–1060.
8. Zhang, X.; Liu, H.; Hu, X.; Tang, G.; Zhu, J.; Zhao, Y. Org. Lett. 2011, 13, 3478–
3481.
9. Rummelt, S. M.; Ranocchiari, M.; van Bokhoven, J. A. Org. Lett. 2012, 14, 2188–
2190.
10. Jablonkai, E.; Keglevich, G. Tetrahedron Lett. 2013, 54, 4185–4188.
11. Keglevich, G.; Jablonkai, E.; Balázs, L. B. RSC Adv. 2014, 4, 22808–22816.
12. Keglevich, G.; Novák, T.; Vida, L.; Greiner, I. Green Chem. 2006, 8, 1073–1075.
13. Keglevich, G.; Grün, A.; Bálint, E. Curr. Org. Synth. 2013, 10, 751–763.
14. General procedure for the synthesis of diarylphosphine oxides 2b and 8: The
Grignard reagent (20.0 mmol) formed from Mg (0.48 g, 20.0 mmol) and 4-
bromotoluene (3.4 g, 20.0 mmol) in Et2O (15 mL) was added dropwise to the
>P(O)H reagent (diethyl phosphite: 0.9 mL, 6.7 mmol or ethyl phenyl-H-
phosphinate: 2 mL, 13.3 mmol) in Et2O (10 mL) at 0 °C. The resulting mixture
was stirred at 26 °C for 1.5 h. The mixture was hydrolyzed with 10% HCl
solution (20 mL) and the aqueous phase was extracted with Et2O (2 ꢃ 50 mL).
The combined organic phases were dried (Na2SO4). Evaporation of the solvent
provided a residue that was purified by column chromatography using silica
gel and 1% MeOH in CH2Cl2 as the eluent to give secondary phosphine oxides
2b and 8.
Ethyl 4-(diphenylphosphinoyl)benzoate (4a): 31P NMR (121.5 MHz, CDCl3) d 28.6,
dP (CDCl3)19 28.2; 13C NMR (75.5 MHz, CDCl3) d 14.3 (CH2CH3), 61.5 (OCH2),
128.7 (d, J = 12.2 Hz, C20)a, 129.4 (d, J = 12.2 Hz, C2)b, 131.9 (d, J = 104.8 Hz,
C10), 132.1 (d, J = 10.0 Hz, C30)b, 132.2 (d, J = 10.1 Hz, C3)b, 132.3 (d, J = 2.8 Hz,
C40), 133.6 (d, J = 2.8 Hz, C4), 137.5 (d, J = 100.9 Hz, C1), 165.8 (C@O),a,b
tentative assignments; 1H NMR (300 MHz, CDCl3) d 1.38 (t, 3H, J = 7.1 Hz,
CH2CH3), 4.39 (q, 2H, J = 14.2 Hz, OCH2), 7.80–7.31 (m, 12H, ArH), 7.95–8.18
(m, 2H, ArH); IR (neat) 694, 750, 1193, 1270, 1440, 1715 cmꢁ1; HRMS: m/z
[M+H]+ = 351.1145, C21H20O3P requires 351.1145.
Ethyl 4-[di(4-methylphenyl)phosphinoyl]benzoate (4b): 31P NMR (121.5 MHz,
CDCl3) d 28.7; 13C NMR (75.5 MHz, CDCl3) d 14.1 (CH2CH3), 21.5 (C40-Me), 61.3
(OCH2), 128.7 (d, J = 107.2 Hz, C10), 129.1 (d, J = 12.0 Hz, C2)a, 129.2 (d,
J = 12.6 Hz, C20)b, 131.9 (d, J = 10.3 Hz, C3 and C30)a,b, 133.2 (d, J = 2.7 Hz, C4),
138.0 (d, J = 100.8 Hz, C1), 142.5 (d, J = 2.8 Hz, C40), 165.7 (C@O),a,b tentative
assignments; 1H NMR (300 MHz, CDCl3) d 1.39 (t, 3H, J = 7.1 Hz, CH2CH3), 2.40
(s, 6H, C40-CH3), 4.39 (q, 2H, J = 14.1 Hz, OCH2), 7.21–7.31 (m, 4H, ArH), 7.49–
7.60 (m, 4H, ArH), 7.70–7.82 (m, 2H, ArH), 8.06–8.16 (m, 2H, ArH); IR (neat)
700, 757, 1197, 1270, 1438, 1720 cmꢁ1
23H24O3P requires 379.1458.
Ethyl 3-(diphenylphosphinoyl)benzoate (7a): 31P NMR (121.5 MHz, CDCl3)
;
HRMS: m/z [M+H]+ = 379.1455,
C
d
28.7; 13C NMR (75.5 MHz, CDCl3) d 14.2 (CH2CH3), 61.4 (OCH2), 128.6 (d,
J = 12.3 Hz, C20)⁄, 130.9 (d, J = 12.0 Hz, C2), 131.97 (d, J = 104.7 Hz, C10), 132.03
(d, J = 10.0 Hz, C30)⁄, 132.2 (d, J = 2.8 Hz, C40), 132.8 (d, J = 14.2 Hz, C6), 132.9 (d,
J = 2.7 Hz, C4), 133.0 (d, J = 12.5 Hz, C5), 133.3 (d, J = 102.6 Hz, C1), 136.1 (d,
J = 9.9 Hz, C3), 165.6 (C@O), ⁄tentative assignments; 1H NMR (300 MHz, CDCl3)
d 1.35 (t, 3H, J = 7.1 Hz, CH2CH3), 4.34 (q, 2H, J = 14.2 Hz, OCH2), 7.41–7.73 (m,
11H, ArH), 7.80–7.94 (m, 1H, ArH), 8.21 (d, 1H, J = 7.6 Hz, ArH), 8.36 (d, 1H,
J = 12.2 Hz, ArH); IR (neat) 690, 751, 1183, 1264, 1446, 1716 cmꢁ1; HRMS: m/z
[M+H]+ = 351.1156, C21H20O3P requires 351.1145.
Di(4-methylphenyl)phosphine oxide (2b): Yield: 61%; white crystals; mp.: 98–
99 °C, mp15: 95–96 °C; 31P NMR (121.5 MHz, CDCl3) d 20.7, dP (CDCl3)16 21.2;
HRMS: m/z [M+H]+ = 231.0920, C14H16OP requires 231.0933.
Phenyl-(4-methylphenyl)phosphine Oxide (8): Yield: 42%; dense oil; 31P NMR
(121.5 MHz, CDCl3) d 21.9; 13C NMR (75.5 MHz, CDCl3) d 21.5 (CH3), 127.7 (d,
J = 104.1 Hz, C10)a, 128.7 (d, J = 12.8 Hz, C20)b, 129.5 (d, J = 13.3 Hz, C2)b, 130.3
(d, J = 103.9 Hz, C1)a, 130.5 (d, J = 11.5 Hz, C30)b, 130.6 (d, J = 11.9 Hz, C3)b,
132.3 (d, J = 2.8 Hz, C40), 143.1 (d, J = 2.9 Hz, C40),a,b tentative assignments; 1H
NMR (300 MHz, CDCl3) d 2.42 (s, 3H, CH3), 7.28–7.77 (m, 9H, ArH), 8.06 (d,
J = 480.6 Hz, 1H, PH); HRMS: m/z [M+H]+ = 217.0776, C13H14OP requires
217.0777.
Ethyl 3-[di(4-methylphenyl)phosphinoyl]benzoate (7b): 31P NMR (121.5 MHz,
CDCl3) d 28.7; 13C NMR (75.5 MHz, CDCl3) d 14.2 (CH2CH3), 21.6 (C40-Me), 61.3
(OCH2), 128.5 (d, J = 11.6 Hz, C2), 128.9 (d, J = 107.4 Hz, C10), 129.3 (d, J = 12.6 Hz,
C20)⁄, 130.8 (d, J = 11.9 Hz, C5), 132.0 (d, J = 10.3 Hz, C30)⁄, 132.7 (d, J = 2.4 Hz, C4),
132.9 (d, J = 10.7 Hz, C6), 133.9 (d, J = 103.2 Hz, C1), 136.1 (d, J = 9.8 Hz, C3),
142.6 (d, J = 2.8 Hz, C40), 165.7 (C@O), ⁄tentative assignments; 1H NMR
(300 MHz, CDCl3) d 1.36 (t, 3H, J = 7.1 Hz, CH2CH3), 2.40 (s, 6H, C40-CH3), 4.35
(q, 2H, J = 14.2 Hz, OCH2), 7.20–7.31 (m, 5H, ArH), 7.48–7.60 (m, 5H, ArH), 8.20
(d, 1H, J = 7.7 Hz, ArH), 8.36 (d, 1H, J = 12.1 Hz, ArH); IR (neat) 697, 763, 1182,
1270, 1446, 1715 cmꢁ1; HRMS: m/z [M+H]+ = 379.1470, C23H24O3P requires
379.1458.
15. Christiansen, A.; Li, C.; Garland, M.; Selent, D.; Ludwig, R.; Spannenberg, A.;
Baumann, W.; Franke, R.; Börner, A. Eur. J. Org. Chem. 2010, 2733–2741.
16. Goto, M.; Yamano, M. Patent WO 2003048174, 2003; Chem. Abstr., 2003, 139,
36636.
17. General procedure for the reaction of halobenzoic acids 1A, 1B and
5 and
secondary phosphine oxides 2a, 2b and 8: A mixture of a halobenzoic acid
(0.50 mmol) [4-bromobenzoic acid or 3-bromobenzoic acid (0.10 g) or
iodobenzoic acid (0.12 g)], the secondary phosphine oxide (0.50 mmol)
[diphenylphosphine oxide (0.10 g), di(4-methylphenyl)phosphine oxide
(0.12 g), phenyl-(4-methylphenyl)phosphine oxide (0.11 g)] and K2CO3
(0.21 g, 1.5 mmol) in degassed H2O (2.5 mL) was irradiated under an N2
atmosphere in a closed vial using a 300 W CEM Discover reactor (operating
at 20–30 W) at 180 °C for the appropriate time (see Schemes 1–3). After
cooling to 25 °C, H2O (20 mL) was added to the mixture. A dilute (18%) HCl
solution (ca. 1.9 mL) was added dropwise until pH 3–4. The tertiary
phosphine oxides 3a, 3b, 6a, 6b and 9 were obtained as white precipitates
and were filtered and dried under vacuum. Selected spectral data of
Ethyl 4-[phenyl(4-methylphenyl)phosphinoyl]benzoate (10): 31P NMR (121.5 MHz,
CDCl3) d 28.8; 13C NMR (75.5 MHz, CDCl3) d 14.2 (CH2CH3), 21.6 (C40-Me), 61.4
(OCH2), 128.4 (d, J = 103.9 Hz, C100), 128.5 (d, J = 2.9 Hz, C400), 128.6 (d, J = 12.2 Hz,
C200)a, 129.3 (d, J = 12.1 Hz, C20)b, 129.4 (d, J = 12.7 Hz, C2)c, 131.97 (d, J = 10.0 Hz,
C3)c, 132.03 (d, J = 10.1 Hz, C30 and C300)a,b, 132.1 (d, J = 104.7 Hz, C10), 133.4 (d,
J = 2.8 Hz, C4), 137.7 (d, J = 100.9 Hz, C1), 142.8 (d, J = 2.8 Hz, C40), 165.7 (C@O),a–c
tentative assignments; 1H NMR (300 MHz, CDCl3) d 1.40 (t, 3H, J = 7.1 Hz,
CH2CH3), 2.41 (s, 3H, C40-CH3), 4.40 (q, 2H, J = 14.0 Hz, OCH2), 7.21–7.32 (m, 3H,
ArH), 7.43–7.85 (m, 9H, ArH), 8.11 (d, 1H, J = 7.9 Hz, ArH); IR (neat) 695, 764,
;
1184, 1270, 1437, 1716 cmꢁ1 HRMS: m/z [M+H]+ = 365.1310, C22H22O3P
requires 365.1301.
the products 3a, 3b, 6a, 6b and
diarylphosphinoylbenzoic acids 3a, 3b, 6a, 6b and 9 were characterized as
the corresponding ethyl esters. See next procedure.
9 are shown in Table 1. The
19. Berger, O.; Petit, C.; Deal, E. L.; Montchamp, J.-L. Adv. Synth. Catal. 2013, 355,
1361–1373.