Synthesis of n-butyl ester and n-butylamide of methyl-phenylphosphinic acid: Two case studies

Article abstract of DOI:10.1080/00397911.2016.1171361

n-Butyl methyl-phenylphosphinate and methyl-phenylphosphinic n-butylamide were synthesized by different methods: the reaction of methyl-phenylphosphinic chloride withⁿBuOH orⁿBuNH₂, respectively, the T3P-promoted derivatiz

Full text of DOI:10.1080/00397911.2016.1171361

Synthetic Communications
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Synthesis of the N-Butyl Ester and N-Butylamide of
Methyl-Phenylphosphinic Acid – Two Case Studies
Nóra Zsuzsa Kiss, Réka Henyecz, Erzsébet Jablonkai & György Keglevich
To cite this article: Nóra Zsuzsa Kiss, Réka Henyecz, Erzsébet Jablonkai & György Keglevich
(2016): Synthesis of the N-Butyl Ester and N-Butylamide of Methyl-Phenylphosphinic Acid –
Two Case Studies, Synthetic Communications, DOI: 10.1080/00397911.2016.1171361
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Date: 15 April 2016, At: 06:16

Synthesis of the N-Butyl Ester and N-Butylamide of Methyl-Phenylphosphinic Acid
–
Two Case Studies
1
1
1
1
Nóra Zsuzsa Kiss , Réka Henyecz , Erzsébet Jablonkai , György Keglevich
1
Department of Organic Chemistry and Technology, Budapest University of Technology
and Economics, Budapest, Hungary
Address correspondence to György Keglevich, Department of Organic Chemistry and
Technology, Budapest University of Technology and Economics, 1521 Budapest,
Hungary. E-mail: gkeglevich@ mail.bme.hu
Received 11 February 2016, in revised form 18 March 2016.
Abstract
n-Butyl methyl-phenylphosphinate and methyl-phenylphosphinic n-butylamide were
synthesized by different methods comprising the reaction of methyl-phenylphosphinyl
n
n
®
chloride with BuOH or BuNH , respectively, the T3P -promoted derivatization of
2
n
n
methyl-phenylphosphinic acid with BuOH or BuNH , the microwave-assisted direct
2
esterification of the model phosphinic acid, and finally the alkylating esterification with
n-butyl bromide under phase transfer catalytic and MW-assisted conditions. The different
methods, mostly elaborated by us, were compared from practical and environmentally-
friendly points of view.
1

®
KEYWORDS: phosphinic acid; esterification; amidation; T3P reagent; microwave;
phase transfer catalysis
INTRODUCTION
Most often, phosphinates and phosphinic amides are synthesized from the corresponding
[
1–5]
phosphinic chloride intermediates.
Even industrial syntheses are based on this
approach. However, phosphinic chlorides are relatively expensive, and the hydrochloric
acid formed from them on phosphinylation means an environmental burden, and should
be removed by a base, in most cases by a tertiary amine. Not speaking about the by far
not quantitative atomic efficiency. Direct derivatization of phosphinic acids is, in general,
not possible. Two authors of this paper were, who elaborated the microwave (MW)-
assisted direct esterification of phosphinic acids. Using the alcohols in 15-fold quantity,
and performing the reactions at 200–220 °C in a closed vessel, especially with longer
carbon atom chain alcohols (n≥4), the phosphinates were obtained in most cases in 70–
[
6–9]
9
5% yields.
The esterification of phosphinic acids is thermoneutral, and has a rather
-1
[10]
high (≥100 kJ mol ) enthalpy of activation. Such reactions may be promoted by the
beneficial effect of the statistically occurring local overheatings appearing on MW
[
11,12]
irradiation.
It is noteworthy that the MW-assisted direct amidations remained
[
13]
incomplete that is the consequence of the endothermicity of the reactions. Another
[
14]
possibility for the preparation of phosphinates is the alkylating esterification. A MW-
assisted version was developed for the solid–liquid phase reaction of phosphinic acids
with alkyl halides in the presence of K CO , and in the absence of any solvent. It was
2
3
found that the alkylations with alkyl halides of normal reactivity were enhanced by the
2

[
7,15]
use of triethylbenzylammonium chloride (TEBAC) as the phase transfer catalyst.
®
Recently, the trimeric n-propylphosphonic anhydride (T3P )–promoted esterification and
[
16,17]
amidation of phosphinic acids were also described by us.
In our earlier
derivatizations, mainly phenyl-H-phosphinic acid and cyclic phosphinic acids, such as 1-
hydroxy-phospholene 1-oxides, 1-hydroxy-phospholane oxides, and a 1-hydroxy-
[
7,18]
1
,2,3,4,5,6-hexahydrophosphinine oxide served as the starting phosphinic acids.
In this paper, we wished to compare the different possibilities for the derivatizations
(esterification and amidation) of methyl-phenylphosphinic acid and its chloride.
RESULTS AND DISCUSSION
1
.) Synthesis Of N-Butyl Methyl-Phenylphosphinate (3a) And Methyl-
Phenylphosphinic N-Butylamide (4) Via Methyl-Phenylphosphinic Chloride
First, the traditional method starting from methyl-phenylphosphinic chloride (2) was
followed during the preparation of the target compounds (Scheme 1). In our case, the
phosphinic chloride 2 was obtained from methyl-phenylphosphinic acid (1) by reaction
with thionyl chloride in dichloromethane. Then, the intermediate (2) was reacted with 2
equivalents of n-butanol (Scheme 1/(1)) and with 1.1 equivalents of n-butylamine
(Scheme 1/(2)) in boiling toluene, in both cases, in the presence of 1 equivalent of
triethylamine, and for 2 h. After removing the amine salt by filtration, the organic phase
was concentrated. The crude products were purified by flash column chromatography to
afford the phosphinate (3a) or the phosphinic amide (4) in yields of 93% and 89%,
respectively.
3

®
2
.) The T3P -Assisted Esterification And Amidation Of Methyl-Phenylphosphinic
Acid (1) (Scheme 2 And 3)
®
Methyl-phenylphosphinic acid (1) was first reacted with 1.1 equivalents of the T3P
reagent in ethyl acetate. In this stage, the mixed anhydride shown by formula 5 was
formed. This way of activation is well-known, and the reaction sequence has been
[
19]
evaluated by us by quantum chemical calculations. Then, 3 equivalents of n-butanol
was added to intermediate 5 at 25 °C. After a 1 h’s stirring, the purification of the crude
®
product obtained after removing the T3P reagent by hydrolysis and evaporation of the
volatiles led to ester 3a in a yield of 81% (Table 1, entry 1). Carrying out the
esterification at 85 °C, either on conventional heating for 30 min, or on MW irradiation
for 20 min, the yields of phosphinate 3a were similar (~78%) (Table 1, entries 2 and 3).
In order to make the synthesis more atom-economical and cheaper, we tried to decrease
®
the quantity of the T3P reagent. For this, the previous protocols were repeated using
®
only 0.66 equivalents of the T3P . No matter if a longer reaction (1.5 h) was allowed, at
2
5 °C the yield was only 52% (Table 1, entry 4). The thermal and the MW-assisted
variations at 85 °C led to a yield of 61% and 80%, respectively (Table 1, entries 5 and 6).
It can be seen that the experiments covered by entries 1, 3 and 6 gave practically the same
results. One may conclude that increasing the temperature from 25 to 85 °C, MW
irradiation allows a faster esterification. At the same time, decreasing the quantity of the
®
T3P reagent from 1.1 to 0.66 equivalents, application of a temperature of 85 °C and a
somewhat longer reaction time leads to a similar result under MW.
4

®
The T3P -assisted amidation of methyl-phenylphosphinic acid (1) was performed
similarly applying 1.1 equivalents of the activating agent and 3 equivalents of n-
buthylamine. After a 1 h’s stirring at 25 °C, the work-up afforded the phosphinic amide
(4) in a yield of 65%.
3
.) Direct Esterification Of Methyl-Phenylphosphinic Acid (1)
As was mentioned in the Introduction, the direct esterification of phosphinic acids is
possible under MW conditions. n-Butanol is, however, not a too efficient reagent due to
its volatility. At a temperature of 220 °C, the pressure is ~18 bar that is close to the limit
of the MW reactor applied. Regarding the direct esterification of methyl-
phenylphosphinic acid 1 and n-butanol measured in 15-fold excess, the conversion was
only 15% after a reaction time of 3 h (Table 2, entry 1). Performing the esterification at a
lower temperature of 180 °C, but in the presence of 10% of [bmim][PF ] as an additive,
6
the conversion was 100% after 1.5 h, and the target phosphinate (3a) was isolated in a
yield of 73% (Table 2, entry 2). As a matter of fact, ionic liquids used in catalytic
[20,21]
quantities may have a positive influence on the course of different reactions
[
22]
including esterifications.
To use a more efficient alcohol, the esterification was also performed with n-octanol.
Irradiation at 200 °C for 2 h, or at 180 °C for 20 min, this latter in the presence of 10% of
[
bmim][PF ], resulted in the formation of n-octyl phosphinate 3b in conversions of 32%
6
and 100%, respectively (Table 2, entries 3 and 4). In the latter case, the yield of 3b was
2%.
9
5

4
.) Alkylating Esterification Of Methyl-Phenylphosphinic Acid (1)
The next option was the synthesis of the phosphinate (3a) by alkylating esterification.
Methyl-phenylphosphinic acid (1) was reacted with 1.2 equivalents of n-buthyl bromide
in the presence of K CO and 5% of TEBAC in acetonitrile, at 100 °C on MW irradiation.
2
3
Allowing a reaction time of 2 h, phosphinate 3a was obtained in a yield of 89% after the
work-up comprising filtration, concentration in vacuum, and purification by flash
chromatography (Table 3, entry 1). In the absence of the phase transfer catalyst, the yield
was decreased by 44% (Table 3, entry 2). On conventional heating at 100 °C for a longer
reaction time of 5 h in the presence of 5% of TEBAC, the yield was only 67% (Table 3,
entry 3) referring to the beneficial effect of MW irradiation. In the last case, the
alkylating esterification was carried out using triethylamine as the base, but without any
solvent. The yield of this homogeneous accomplishment was 89% (Table 3, entry 4). It
can be seen that the heterogeneous phase transfer catalytic approach (Table 3, entry 1)
and the homogeneous variation (entry 4), both under MW conditions, led to the best
results.
The comparison of the different methods for the preparation of n-butyl methyl-
phenylphosphinate (3a) are shown in Table 4. The classical synthesis involving the
n
phosphinylation of BuOH by reaction with MePhP(O)Cl is rather efficient (the yield of
3
a is 93%), but the use of a P-chloride may mean a drawback regarding cost,
environmental burden, and atomic efficiency that is only 47%. Moreover, there was need
for toluene as the solvent.
6

The preparation of phosphinate 3a from methyl-pehylphosphinic acid 1 via its activation
®
by reaction with the T3P reagent can be realized under mild conditions, and with a
®
rather good yield (81%). At the same time, the T3P reagent is expensive, and the atomic
®
efficiency is as low as 37%, if 1 equivalent of the T3P reagent is used. It is, however,
®
possible to reduce the quantity of T3P to 0.66 equivalents, but in this case a somewhat
higher temperature (85 °C) is needed under MW conditions.
The third possibility comprises the MW-assisted IL-catalyzed direct esterification of
phosphinic acid 1, providing the phosphinate (3a) in a yield of 73%. The excess of the
alcohol served as the solvent. An obvious advantage of this method is the good atomic
efficiency of 92% that is the best in the series discussed. The need for 180 °C as the
optimum temperature is compensated by a relatively short reaction time.
The synthesis via O-alkylation of phosphinic acid 1 with n-butyl bromide was performed
in two ways. In the first variation, the esterification was performed under solid-liquid
phase transfer catalytic conditions applying TEBAC as the catalyst, and K CO as the
2
3
base in acetonitrile, under MW-assisted conditions. The other way included the use of
triethylamine in a homogeneous phase accomplishment. Both protocols led to good yields
of 89%. However, the need for n-butyl bromide as the reagent, and the atomic efficiency
of 54% (in case of TEA) or 49% (in case of K CO ) may be problematic.
2
3
7

In summary, the MW-assisted direct esterification may be the method of choice if the
phosphinate (3a) is prepared in a small (0.5 g) scale. The larger scale realization justifies
the utilization of the classical method starting from the phosphinic chloride (2).
Regarding the preparation of methyl-phenylphosphinic n-butylamide (4), the synthesis
via phosphinylation of n-butylamine with MePhP(O)Cl (2) remains the practical method
®
of choice, but the approach utilizing T3P -activated phosphinic acid (1) may also be a
good possibility. The atomic efficiency of the two methods mentioned is 47% and 36%,
respectively.
In conclusion, four methods for the preparation of n-butyl methyl-phenylphosphinate (3a)
were applied, and critically evaluated. From among the four protocols, three methods
[15,16,22]
were based on synthetic approaches developed by us.
The direct MW-assisted
esterification seemed to be the best. In respect of the target amide, it may be synthesized
by both methods starting either from the P-chloride (2) and n-butylamine, or from the
®
acid (1), the T3P reagent and butylamine.
EXPERIMENTAL
3
1
13
1
The P, C, H NMR spectra were taken on a Bruker DRX-300 spectrometer operating
at 202.4, 125.7 and 500 MHz, respectively. The couplings are given in Hz. Mass
spectrometry was performed on a ZAB-2SEQ instrument.
GC was carried out on an HP5890 series 2 GC-FID chromatograph, using a 15 m ×
0
.18 mm Restek, Rtx-5 column with a film layer of 0.20 m. The temperature of the
8

column was initially held at 40 °C for 1 min, followed by programming at 25 °C/min up
to 300 °C, and a final period at 300 °C (isothermal) for 10 min. The temperature of the
injector was 290 °C, and of the FID detector 300 °C. The carrier gas was H2.
The MW-assisted reactions were carried out in a CEM Discover microwave reactor
equipped with a stirrer and a pressure controller applying 100–300 W irradiation.
Procedure For The Traditional Esterification And Amidation Via Phosphinic
Chloride 2
To 0.50 g (3.2 mmol) of methyl-phenylphosphinic acid (1) in 5 mL of dry
dichloromethane was added 0.28 mL (3.8 mmol) of thionyl chloride and the mixture was
stirred at 26 °C for 24 h. Then the solvent was evaporated, and the volatiles were
removed in vacuum. The 0.55 g (~100%) of methyl-phenylphosphinic acid chloride (2)
so obtained was taken up in 3 mL of dry toluene, and the resulting solution was added
dropwise to a mixture of 0.32 mL (3.5 mmol) of n-butanol (or 0.35 mL (3.5 mmol) of n-
butylamine) and 0.45 mL (3.2 mmol) of triethylamine in 3 mL of toluene at 60 °C. The
contents of the flask were stirred at reflux for 2 h. Then, the amine-hydrochloride salt was
removed by filtration, and the filtrate evaporated. The crude product so obtained was
purified by column chromatography (3% methanol in chloroform, silica gel) to afford
0
.63 g (93%) of n-butyl methyl-phenylphosphinate (3a) (or 0.60 g (89%) of methyl-
phenylphosphinic n-butylamide (4)).
9

Procedure For The Esterification And Amidation Of Methyl-Phenylphosphinic Acid
®
(
1) In The Presence Of T3P Reagent (Table 1/Entry 1 And Scheme 3)
A mixture of 0.12 g (0.75 mmol) methyl-phenylphosphinic acid (1) and 0.55 mL (0.84
®
mmol) of T3P reagent (50 wt.% ethyl acetate solution) was stirred for 10 min. To the
resulting mixture 0.21 mL (2.3 mmol) of n-butanol or 0.23 mL (2.3 mmol) of n-
butylamine was added, and the contents of the flask were stirred for 1 h. The excess of
®
the T3P reagent was hydrolyzed with 7 mL of 10% NaHCO solution, and after
3
separation the aqueous phase was washed with 15 mL of ethyl acetate. The combined
organic phases were dried (Na SO ), and concentrated in vacuum. The crude product so
2
4
obtained was passed through a thin (ca. 3–4 cm) layer of silica gel using ethyl acetate as
the eluent to give 0.13 g (81%) of phosphinate 3a or 0.11 g (65%) of phosphinic amide 4
as colourless oils.
Procedure For The MW-Assisted Direct Esterification Of Methyl-Phenylphosphinic
Acid (1) (Table 2/Entries 2 And 4)
A mixture of 0.12 g (0.75 mmol) of methyl-phenylphosphinic acid (1), 11.0 mmol of the
alcohol (1.0 mL of n-butanol or 1.8 mL of n-octanol), and 10% (15.5 μL) of [bmim][PF6]
was measured in a sealed tube that was irradiated in the MW reactor equipped with a
pressure controller at 180 °C for 1.5 h and 20 min, respectively. (The pressure developed
was 18 and 2 bar, respectively.) Then, the excess of the alcohol was removed under
reduced pressure, and the residue so obtained purified by flash column chromatography
using silica gel and ethyl acetate as the eluent to afford phosphinates 3a [0.12 g (73%)]
and 3b [0.19 g (92%)] as oils.
1
0

Procedure For The Alkylating Esterification Of Methyl-Phenylphosphinic Acid (1)
Table 3/Entries 1 And 4)
Method A: A mixture of 0.12 g (0.75 mmol) of methyl-phenylphosphinic acid, 0.10 mL
0.90 mmol) of n-butyl bromide, 0.11 g (0.83 mmol) of K CO and 8.6 mg (0.038 mmol)
(
(
2
3
of TEBAC in 1 mL of acetonitrile was stirred under MW irradiation at 100 °C for 2 h.
The reaction mixture was then taken up in 50 mL of ethyl acetate, and the suspension was
filtrated. The solid was washed with 5 mL of ethyl acetate. Evaporation of the combined
organic phases provided the crude product that was passed through a thin (ca. 3-4 cm)
layer of silica gel using ethyl acetate as the eluent to give 0.15 g (89%) of phosphinate 3a
as an oil.
Method B: A mixture of 0.12 g (0.75 mmol) of methyl-phenylphosphinic acid (1), 0.10
mL (0.90 mmol) of n-butyl bromide and 0.12 mL (0.83 mmol) of triethylamine was
stirred under MW irradiation at 100 °C for 0.5 h. The crude product was passed through a
thin (ca. 3-4 cm) layer of silica gel using ethyl acetate as the eluent to give 0.15 g (89%)
of phosphinate 3a as a colourless oil.
SUPPLEMENTARY INFORMATION
3
1
13
1
Supplementary data ( P, C, H NMR and HRMS characterization data for compounds
a,b and 4) associated with this article can be found via the “Supplementary Content”
section of this article’s webpage.
3
1
1

ACKNOWLEDGEMENT
Support from the Hungarian Research Development and Innovation Fund (K119202) is
acknowledged.
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1
2
.
.
Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley: New York, 2000.
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Traditional Versus up-to-Date Synthetic Procedures, Chem. Sci. J., 2014, 5, 1–14. doi:
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0.4172/2150-3494.1000088.
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Comprehensive Organic Functional Group Transformations II; Katritzky, A. R., Taylor,
R. J. K., Eds.; Elsevier: Oxford, 2005, p 853–907.
5
.
Product Class 40: Arylphosphinic Acids and Derivatives (2007). In: Ramsden CA,
Bellus D (eds) Science of Synthesis: Houben–Weyl Methods of Molecular
Transformations, vol 31b. 1st Edition edn. Georg Thieme Verlag, Stuttgart.
doi:10.1055/sos-SD-031-02233
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.
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Phosphinates by the Microwave-Assisted Esterification of Phosphinic Acids Synth.
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Greiner, I. Microwave-Assisted Esterification of Phosphinic Acids. Curr. Org. Chem.
2
011, 15, 1802–180.
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8
Esterification of Cyclic Phosphinic Acids. Heteroatom Chem. 2013, 24, 283–288.
Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Körtvélyesi, T. Insights into a surprising
9
.
reaction: The microwave-assisted direct esterification of phosphinic acids. Org. Biomol.
Chem. 2012, 10, 2011–2018.
1
0.
Mucsi, Z.; Kiss, N. Z.; Keglevich, G. A quantum chemical study on the
mechanism and energetics of the direct esterification, thioesterification and amidation of
1
1
-hydroxy-3-methyl-3-phospholene 1-oxide. RSC Adv. 2014, 4, 11948–11954.
1. Kranjc, K.; Kočevar, M. Microwave-assisted organic synthesis: General
considerations and transformations of heterocyclic compounds. Curr. Org. Chem. 2010,
1
4, 1050–1074.
2. Keglevich, G.; Greiner, I.; Mucsi, Z. An interpretation of the rate enhancing effect
1
of microwaves – modelling the distribution and effect of local overheating – A case study.
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1
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Keglevich, G.; Kiss, N. Z.; Körtvélyesi, T. Microwave-Assisted Functionalization
of Phosphinic Acids: Amidations versus Esterifications. Heteroatom Chem. 2013, 24, 91–
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1
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4.
Golubski, Z. E. Alkylation of phosphinic acid salts in the presence of crown
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1
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1
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Bálint, E.; Jablonkai, E.; Bálint, M.; Keglevich, G. Alkylating Esterification of 1-
Hydroxy-3-phospholene Oxides under Solventless MW Conditions. Heteroatom Chem.
2
010, 21, 211–214.
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1
membered cyclic phosphinic acids under mild conditions using propylphosphonic
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1
7.
esterification and amidation of phosphinic acids. Tetrahedron 2014, 70, 8280–8285.
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phosphinates: traditional versus green chemical approaches. Green Proc. and Synth. 2014,
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1
3
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1
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2
2
1
4

®
Table 1. T3P –promoted esterification of methyl-phenylphosphinic acid (1) with n-
butanol
®
T3P (eq.) T (°C) Mode of heating t (h) Yield (%) Entry
1
1
1
0
0
.1
25
85
85
25
85
85
–
1
81
1
2
3
4
5
6
.1
Δ
0.5 77
0.33 79
.1
MW
–
a
.66
.66
.66
1.5 52
b
Δ
0.5 61
0
MW
0.5 80
a
No change on further stirring.
No change on further heating.
b
1
5

Table 2. Direct esterification of methyl-phenylphosphinic acid (1) with n-butanol
T (°C) t (h) p (bar) Catalyst Conversion (%) Yield (%) Entry
R
Bu 220
Bu 180
Oct 200
Oct 180
3
18
1.5 14
2.5
0.33 2
–
15
–
1
2
3
4
10% [bmim][PF ] 100
73 (3a)
–
6
2
-
32
10% [bmim][PF ] 100
92 (3b)
6
1
6

Table 3. Alkylating esterification of methyl-phenylphosphinic acid (1) with n-butyl
bromide
Base
TEBAC Solvent Mode of heating t (h) Yield (%) Entry
K CO3 5%
MeCN MW
MeCN MW
2
2
5
89
45
67
1
2
3
4
2
a
K CO3
2
–
b
K CO3 5%
2
MeCN
Δ
Et N
–
–
MW
0.5 89
3
a
No change on further irradiation.
No change on further heating.
b
1
7

n
Table 4. Comparison of the different methods for the preparation of PhMeP(O)O Bu
Reaction
Reagents
Phosphinylation Phosphinylation Phosphinylation
O-alkylation
PhMeP(O)Cl
BuOH
PhMeP(O)OH
PhMeP(O)OH
PhMeP(O)OH
®
n
n
T3P
BuOH
BuBr
n
NEt (1 equiv.)
BuOH
[bmim][PF6]
NEt3*
3
(cat.)
*
Solvent
PhMe
EtOAc
25
BuOH
180
–
Temperature 110
°C]
100
MW
0.5
[
Mode of
heating
Δ
MW
1.5
73
Reaction time 2
h]
0.33
81
[
Yield [%]
Adventage
93
89
Efficient
synthesis
Mild conditions good atomic
efficiency
Efficient
synthesis
need for
Disadvantage need for P-
chloride
need for
relatively high
temperature
n
expensive T3P
BuBr
*
or TEBAC (cat.)/K CO (1 equiv.)/MeCN leading to a yield of 89%
2 3
1
8

Scheme 1.
1
9

Scheme 2.
2
0

Scheme 3.
2
1

Scheme 4
2
2

Scheme 5.
2
3