Continuous flow esterification of a H-phosphinic acid, and transesterification of H-phosphinates and H-phosphonates under microwave conditions

Article abstract of DOI:10.3390/molecules25030719

The microwave (MW)-assisted direct esterification of phenyl-H-phosphinic acid, transesterification of the alkyl phenyl-H-phosphinates so obtained, and the similar reaction of dibenzyl phosphite (DBP) were investigated in detail, and the batch accomplishme

Full text of DOI:10.3390/molecules25030719

molecules
Article
Continuous Flow Esterification of a H-Phosphinic
Acid, and Transesterification of H-Phosphinates and
H-Phosphonates under Microwave Conditions
Nóra Zsuzsa Kiss, Réka Henyecz and György Keglevich *
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
1111 Budapest, Hungary; zsnkiss@mail.bme.hu (N.Z.K.); henyecz.reka@mail.bme.hu (R.H.)
* Correspondence: gkeglevich@mail.bme.hu; Tel.: +36-1-463-1111/5883
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 14 January 2020; Accepted: 4 February 2020; Published: 7 February 2020
Abstract: The microwave (MW)-assisted direct esterification of phenyl-H-phosphinic acid,
transesterification of the alkyl phenyl-H-phosphinates so obtained, and the similar reaction of
dibenzyl phosphite (DBP) were investigated in detail, and the batch accomplishments were translated
into a continuous flow operation that, after optimization of the parameters, such as temperature
and flow rate, proved to be more productive. Alcoholysis of DBP is a two-step process involving an
intermediate phosphite with two different alkoxy groups. The latter species are of synthetic interest,
as precursors for optically active reagents.
Keywords: H-phosphinic acid; esterification; H-phosphinates; H-phosphonates; transesterification;
microwave flow reactor
1. Introduction
It has been a great challenge in the pharmaceutical industry to transform batch realizations of
organic chemical reactions into continuous flow methods [
chemists who have elaborated flow chemical accomplishments that are welcome by the pharmaceutical
industry in order to introduce up to date techniques, in the first approach, in the R&D segment [ ].
1–3]. Kappe is one of the most prominent
1
However, the “sine qua non” of the realization of the flow techniques is that the mixtures should
be homogenous and non-viscous that represents a limitation. Due to the dynamical development
in the field, up-to-date models of MW reactors have appeared on the market. The application of
the MW technique embraces above all organic chemical syntheses, the preparation of nanomaterials,
and broadly understood material processing [
include multicomponent reactions, condensations, eliminations, and substitutions as exemplified by
esterifications, C–C cross couplings, dehydrations and the Mannich condensation [ ]. The combination
of the flow technique with MW irradiation represents a big step further, as it broadens the sphere
of reactions that can be performed [ ]. We have had interests in converting batch MW-promoted
reactions involving organophosphorus transformations into flow operation [ 11]. Ionic liquids (ILs)
4–6]. The most suitable reactions for MW assistance
7
8
9–
are regarded as green solvents [12]. However, there is a vision that ILs might cause a real breakthrough
as additives or catalysts [13,14].
P-esters, like phosphinates and phosphonates may be important building blocks in synthetic
organic chemistry [15
for the Hirao P–C coupling reactions and the Kabachnik–Fields condensations resulting in the
formation of aryl-phosphinates/phosphonates and -aminophosphonates, respectively [17 19].
-Amino-phosphonates are important due to their potential biological activity connected to their
enzyme inhibitory effect. A novel preparation of phosphinates involves the microwave (MW)-assisted
,16]. H-Phosphinates and H-phosphonates are typical starting materials
α
–
α
Molecules 2020, 25, 719; doi:10.3390/molecules25030719
www.mdpi.com/journal/molecules

Molecules 2020, 25, 719
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direct esterification of phosphinic acids with alcohols [20
–
22]. The similar esterification of phosphonic
acids was a more difficult task [23]. We found that a suitable IL additive may promote the esterification
of phosphinic acids [24 25], and the monoesterification of phosphonic acids [25]. It was found
,
that alkylation was more suitable to convert the second hydroxy group into an alkoxy unit [26].
The senior author of this article together with co-workers developed the MW-assisted transesterification
(alcoholysis) of dialkyl phosphites [27,28]. It was possible to conduct the reactions to afford the dialkyl
phosphites with two different alkyl groups as the predominating products.
In this article we summarize our experience acquired during the translation of batch MW
preparations of H-phosphinates and H-phosphonates into flow processes. Esterifications and
transesterifications were chosen as suitable model reactions, as, in these cases, MW irradiation
and IL additives proved to be useful in our earlier studies.
2. Results and Discussion
2.1. MW-Assisted Direct Esterification of Phenyl-H-Phosphinic Acid (1)
Before the flow chemical attempts, let us survey the precedents on the batch MW synthesis of alkyl
phenyl-H-phosphinates (
or branched C3–C5 and C8 alcohols applied in a 15-fold quantity at 160–200 ◦C to afford the esters 2a
2b 2d in yields of 73–90% (Table 1/Entries 1, 3, 7–9, 11, 13, 15, 17 and 19). More developed syntheses
were performed in the presence of 10% of [bmim][PF6] at a lower temperature of 140–160 ◦C providing
the products 2a 2b 2d after a short reaction time of 30 min in somewhat higher yields of 82–94%
2). In the first round, phosphinic acid 1 was reacted with ethyl and other linear
,
,
–i
,
,
–I
(Table 1/Entries 2, 4, 10, 12, 14, 16, 18 and 20). It was found earlier that a catalytic amount (5–10%) of
the IL is beneficial in the direct esterifications. A few ILs were tested as additives. Although all tested
ILs enhanced the esterifications, [bmim][PF6] was the best one [24]. In the small-scale reactions it was
appropriate to apply 10% of the IL. The basic role of the IL additive may be to enhance the absorption
of MWs due to its polar nature. The results with i-propanol referred to steric hindrance, as an almost
complete conversion could only be attained at 180 ◦C in the presence of the IL (Table 1/Entries 5 and 6).
Most of the results were reported earlier [20
4, 6, 8, 9, 15, 16, 19 and 20).
,26] that were completed by a few new data (Table 1/Entries
Next, we tried to convert the esterification into a flow method. The sketch of the continuous flow
system used in our experiments is shown in Figure 1. A commercially available flow cell (Figure 2)
was inserted into the CEM reactor, and the transport of the PhP(O)H(OH)/ROH mixture was ensured
by a HPLC pump. The pressure was maintained by a back pressure regulator.
Figure 1. Sketch of the continuous flow system used.
Figure 2. The commercial continuous flow cell.

Molecules 2020, 25, 719
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Table 1. Direct esterification of phenyl-H-phosphinic acid (1) in a batch MW reactor.
Entry
R
IL
T (◦C)
t (min) Conversion * (%)
Yield (%)
Product
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Et
Et
–
160
140
160
160
180
180
160
180
200
140
160
140
190
140
190
150
180
140
180
150
60
30
60
30
120
120
60
30
10
30
60
30
30
30
30
30
30
30
30
30
100
100
100
100
58
80
94
73
84
48
80
85
90
89
94
75
93
89
92
87
94
84
88
75
82
2a
2a
2b
2b
2c
2c
2d
2d
2d
2d
2e
2e
2f
[20]
[26]
[20]
10% [bmim][PF6]
nPr
–
nPr
10% [bmim][PF6]
iPr
–
[20]
[20]
iPr
10% [bmim][PF6]
96
nBu
nBu
nBu
nBu
iBu
–
–
–
100
100
100
100
100
100
100
100
100
100
100
100
100
100
10% [bmim][PF6]
[26]
[20]
[26]
[26]
[26]
–
iBu
10% [bmim][PF6]
nPent
nPent
iPent
iPent
nOct
nOct
iOct
iOct
–
10% [bmim][PF6]
2f
–
2g
2g
2h
2h
2i
10% [bmim][PF6]
–
[26]
[26]
10% [bmim][PF6]
–
10% [bmim][PF6]
2i
* On the basis of relative 31P-NMR integrals.
During the continuous flow esterification of phenyl-H-phosphinic acid (
solutions were prepared, and fed in the reactor at different temperatures (160–200 ◦C) and flow rates
(Table 2). The unstationary phase that was comparable with the residence time (at = 0.15 mL/min and
1), 0.10 g 1/mL alcohol
V
V
=0.25 mL/min t = 67 min and t = 40 min, respectively) was followed by the steady state operation.
The esterifications were monitored by 31P-NMR measurements. The reaction of phosphinic acid
1
n
with BuOH was investigated in detail. In this particular case, the 0.1 g/mL concentration means
15-fold quantity of the alcohol. Increasing the temperature from 160 ◦C to 180 ◦C, and then to 200 ◦C,
at a flow rate of 0.25 mL/min, the conversions were 50%, 53% and 63%, respectively (Table 2/Entries
1, 3 and 5). At the same temperatures, but setting a lower flow rate of 0.15 mL/min that allows a
longer residence time in the reactor, somewhat higher conversions of 54%, 64% and 72%, respectively,
were detected (Table 2/Entries 2, 4 and 6). The addition of 5% of [bmim][PF6] to the mixture of the
reagents prior to irradiation was helpful to attain higher conversions. It has to be mentioned that
◦
◦
◦
5% of the IL was sufficient. Applying a flow rate of 0.25 mL/min at 160 C, 180 C and 200 C,
the conversions were 66%, 83% and 100%, respectively (Table 2/Entries 7, 9 and 11). At a lower rate of
0.15 mL/min, the conversions were somewhat higher 72% (160 ◦C) and 95% (180 ◦C) (Table 2/Entries
8 and 10) than setting 0.25 mL/min. In the next step, the volatile alcohols EtOH, nPrOH and iPrOH
were reacted at the possible maximum temperatures of 160–180 ◦C applying the lower flow rate of
0.15 mL/min. In these cases, the conversions were 65%, 71% and 68%, respectively (Table 2/Entries
12–14). Recycling the mixture from the esterification with EtOH, and re-reacting it under the same
conditions (160 ◦C/0.15 mL/min), the conversion became quantitative (see footnote “e” of Table 2).
◦
The comparative thermal esterification of phosphinic acid
1
with EtOH at 160 C applying a flow
rate of 0.15 mL/min proceeded until a conversion of 35% (see footnote “d” of Table 2). Using iBuOH
(160 ◦C, 0.15 mL/min), the conversion was quantitative (Table 2/Entry 15). PentOH, iPentOH, nOctOH
n
and iOctOH allowed the application of a somewhat higher temperature of 180–200 ◦C. In these cases,

Molecules 2020, 25, 719
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the higher rate of 0.25 mL/min was efficient at 190 ◦C (and in one case at 200 ◦C) as the conversions were
quantitative (Table 2/Entries 17, 19, 21 and 23). Applying a lower flow rate of 0.15 mL/min at somewhat
lower temperature of 180 ◦C, the conversion was 100%, or almost quantitative (Table 2/Entries 16, 18,
20 and 22). The yields of the phosphinates 2a–i prepared from the best experiments fell in the range of
63–91%. If there is a time frame for the preparation of the esters (2), it is worth choosing the parameter
set of 190 ◦C/0.25 mL/min against 180 ◦C/0.15 mL/min.
Table 2. Direct esterification of phenyl-H-phosphinic acid (1) with different alcohols in a flow MW
reactor in a concentration of 0.1 g/mL.
Conversion a,b (%)
Entry
R
IL
T (◦C)
V (mL/min)
Yield c (%) Product
1
2
3
4
5
6
160
160
180
180
200
200
0.25
0.15
0.25
0.15
0.25
0.15
50
54
53
64
63
72
–
–
–
–
–
–
2d
2d
2d
2d
2d
2d
–
nBu
7
8
9
10
11
160
160
180
180
200
0.25
0.15
0.25
0.15
0.25
66
72
83
95
100
–
–
–
–
81
2d
2d
2d
2d
2d
5% [bmim][PF6]
12
13
14
15
Et
5% [bmim][PF6]
5% [bmim][PF6]
5% [bmim][PF6]
5% [bmim][PF6]
0.15
0.15
0.15
0.15
65 e
–
63
–
2a
2b
2c
2e
160 d
nPr
iPr
iBu
160
71
180
68
160
100
91
16
17
180
190
0.15
0.25
100
100
–
85
2f
2f
nPent
5% [bmim][PF6]
5% [bmim][PF6]
5% [bmim][PF6]
5% [bmim][PF6]
18
19
180
200
0.15
0.25
97
100
–
90
2g
2g
iPent
nOct
20
21
180
190
0.15
0.25
100
100
82
84
2h
2h
22
23
180
190
0.15
0.25
100
100
86
85
2i
2i
iOct
a
On the basis of relative 31P-NMR integrals; b After reaching the steady state; c After an operation of 45 or 75 min
belonging to 0.25 mL/min and 0.15 mL/min, respectively; d The comparative thermal experiment led to a conversion
of 35%; e Recycling this mixture, and reacting under the same conditions, the final conversion was 100%. 2a was
isolated in a yield of 79%.
Comparing the batch and continuous flow preparation of the butyl-(2d) or pentyl phosphinate
2f) (Table 1/Entries 10 and 14 vs. Table 2/Entries 11 and 17), one can conclude that the flow operation
(
afforded products 2d and 2f in a 4.5-fold and 6.9-fold higher quantity, respectively, as compared to the
corresponding batch method. Of course, during the comparison, the operation time of the flow reactor
should be equal to the reaction time applied in the batch reactor. It can be said that the batch method
provides ca. 0.10 g ester/30 min, while the flow preparation may give ca. 0.75 g product after the same
time. It can be concluded that the batch approach is more limited in respect of scale. If more alkyl
phenyl-H-phosphinate is needed, it is worth choosing the flow operation. It is noteworthy that the
quantity of the IL (that is the most expensive component) could be halved, as 5% was enough.

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2.2. MW-Assisted Transesterification of Ethyl-Phenyl-H-Phosphinate (2a)
As an alternative method to direct esterification, transesterification (alcoholysis) is another option
for the preparation of esters, and seemed to be a suitable model for MW application. For this, we wished
to investigate the reaction of ethyl phenyl-H-phosphinate (2a) (a commercially available P-ester) with
simple alcohols under MWs to prepare other representatives of this family of compound. The C1,
C3–C5 alcohols, along with BnOH were applied in a 15-fold quantity, and with the exception of the
volatile MeOH, they were used at 160–190 ◦C. The experimental data are listed in Table 3. One can
see that in reaction with MeOH at 120 ◦C for 3 h and at 140 ◦C for 2 h, a conversion average of 91%
was attained (Table 3/Entries 1 and 2). Alcoholysis with nPrOH and iPrOH at 180 ◦C took place in
conversions of 97% and 89%, after reaction times of 1 h and 2 h, respectively (Table 3/Entries 3 and 4).
n
◦
Regarding BuOH, quantitative conversions could be observed at parameter sets of 160 C/2.25 h
and 180 ◦C/40 min (Table 3/Entries 5 and 6). The transesterifications of ethyl phosphinate 2a with
iBuOH, PentOH, PentOH, 3-PentOH and BnOH were complete at 160 C/2.25 h, 180 C/40 min,
190 ◦C/40 min, 190 ◦C/45 min, and 180 ◦C/1 h, respectively (Table 3/Entries 7–11). Phosphinates 2b
2j were obtained in yields of 74–91% after flash column chromatography. One may conclude that the
n
i
◦
◦
–g,
–
l
uncatalyzed transesterifications of H-phosphinate 2a requires harsh conditions, but can be performed
efficiently under MW irradiation.
Table 3. Transesterification of ethyl-phenyl-H-phosphinate (2a) in a batch MW reactor.
Entry
R
T (◦C)
t (min) Conversion * (%) Yield (%)
Product
1
2
3
4
5
6
7
8
9
Me
Me
120
140
180
180
160
180
160
180
190
190
180
180
120
60
120
135
40
135
40
40
93
89
97
79
74
83
74
90
89
85
91
88
80
90
2j
2j
nPr
2b
2c
2d
2d
2e
2f
2g
2k
2l
iPr
89
nBu
nBu
iBu
100
100
100
100
100
95
nPent
iPent
3-Pent
Bn
10
11
45
60
100
* On the basis of relative 31P-NMR integrals.
In the next phase, we tried to elaborate the continuous flow transesterification of ethyl phosphinate
2a with nBuOH applied in a 15-fold excess quantity. As can be seen from Table 4, at 180 or 200 ◦C, the
alcoholysis remained incomplete (as characterized by conversions of 53–84%) no matter if the flow rate
was 0.25 or 0.15 mL/min (Table 4/Entries 1–4). At 220 ◦C, the conversions were 81% (0.25 mL/min) and
94% (0.15 mL/min) (Table 4/Entries 5 and 6). The optimum parameter set for a quantitative reaction
involved a temperature of 225 ◦C and a flow rate of 0.15 mL/min (Table 4/Entry 7). In this case, the yield
of butyl phosphinate 2d was 85%. Adopting these parameters to the transesterification of phosphinate
2a with iBuOH, nPentOH and iPentOH, the corresponding esters 2e
–g were obtained in complete
conversions, and in high yields of 82–89%.

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Table 4. Transesterification of 2a with n-butanol in a flow MW reactor in a concentration of 0.1 g/mL.
Conversion a,b (%)
Entry
R
T (◦C) V (mL/min)
1
2
3
4
5
6
7
8
9
nBu (d)
nBu (d)
nBu (d)
nBu (d)
nBu (d)
nBu (d)
nBu (d)
iBu (e)
180
180
200
200
220
220
225
225
220
220
0.25
0.15
0.25
0.15
0.25
0.15
0.15
0.15
0.15
0.15
53
62
71
84
81
94
100 c
100 d
100 e
100 f
nPent (f)
iPent (g)
10
a
On the basis of relative 31P-NMR integrals; b After reaching the steady state; c Yield of 2d: 85%; d Yield of 2e: 84%;
Yield of 2f: 82%; f Yield of 2g: 89%; c–f After an operation of 1 h.
e
2.3. MW-Assisted Transesterification of Dibenzyl Phosphite (3)
Keglevich and co-workers have investigated the MW-assisted transesterifications (alcoholyses) of
dialkyl phosphites [27,28]. These kinds of reactions take place in two steps resulting first in a phosphite
with two different alkyl groups, and in the second step the fully transesterified dialkyl phosphite.
The outcome of the reaction depended on the temperature, and on the molar ratio of the reactants.
It was not easy to achieve selectivity. At the same time, it is known that the benzyl phosphonates may
undergo easy substitution of the BnO group [29]. For this, alcoholysis of dibenzyl phosphite (3) seemed
to be an appropriate model. Simple C1–C4 alkyl alcohols were used as reactants in 25 equivalent
quantities in the temperature range of 80–130 ◦C under MW irradiation. Experimental data can be
found in Table 5. In reaction with MeOH, irradiation at 80 ◦C for 3 h or at 120 ◦C for 0.5 h led to similar
results, to a mixture containing 26/26% starting phosphite 3, 57/54% of the intermediate 4a, and 17/20%
of the fully transesterified phosphite 5a (Table 5/Entries 1 and 3). Running the alcoholysis at 100 ◦C for
2 h or at 120 ◦C for 1.5 h, dimethyl ester 5a predominated in 56/70% (Table 5/Entries 2 and 4). After a
2.5 h heating the diester (5a) was present in a maximum quantity of 87% (Table 5/Entry 5). Using EtOH,
the course of alcoholysis towards diethyl phosphite was somewhat slower than that with MeOH
(Table 5/Entries 6, 9 and 10 vs. 1, 2 and 3, respectively). After an irradiation at 120 ◦C for 1 h, the ratio
of products 3b
A comparison was made at 100 ◦C/0.5 h to see the effect of 20% of [bmim][PF6] as an additive. In the
absence of the IL, the starting dibenzyl phosphite ( ) was the main component (65%), while performing
the alcoholysis in the presence of the additive, the diethyl ester ( ) predominated (58%) (Table 5/Entries
, 4b and 5b was 9:51:40, that after 4 h was shifted to 0:11:89 (Table 5/Entries 11 and 12).
3
5
7 and 8). In the presence of iPrOH as the agent, the consecutive transformation was slower at 100 and
120 ◦C (Table 5/Entries 13 and 14). There was need for a 5 h irradiation at 130 ◦C to compensate the
effect of steric hindrance (Table 5/Entries 15 and 16). In reaction with nBuOH, almost similar results
were obtained as with EtOH (Table 5/Entries 17, 18 and 20 vs. 9, 10 and 12). A comparative thermal
experiment at 100 ◦C for 2 h took place in a lower conversion of 73% (Table 5/Entry 17/ footnote “d”).
It is recalled that the conversion of the MW variation was 92% (Table 5/Entry 17). While the relative
quantity of the intermediate (4d) was almost the same (59/61%), that of dibutyl phosphite (5d) was 14%
(∆) and 31% (MW).
It is noteworthy that the valuable H-phosphonates with different alkyl groups could be obtained
in a maximum proportion of 57% (4a), 68% (4b), 60% (4c) and 61% (4d) covered by entries 1, 10, 13 and
17, respectively (Table 5). Isolated yields of the BnO–RO phosphonates 4a–d fell in the range of 47–59%.

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Table 5. Alcoholysis of dibenzyl phosphite (3) in a batch MW reactor.
Composition a (%)
T (◦C)
t (h)
Yield (%)
Entry
R
Product
4a
3
26
6
4
57
38
5
17
56
3 b
2
1
2
80
100
49
–
3
120
0.5
26
54
20
47
4a
Me
4
5
6
120
120
80
1.5
2.5 b
3 b
3
0
49
27
13
50
70
87
1
–
72
–
7
8
100
100
0.5
0.5 c
65
6
33
36
2
–
–
58
Et
9
100
120
120
120
100
120
2
0.5
1
11
23
9
0
35
4
64
68
51
11
60
33
25
9
40
89
5
59
58
–
75
51
–
4b
4b
10
11
12
13
14
4 b
2
4c
3 b
63
iPr
Bu
15
130
2.5
2
46
52
–
16
17
18
130
100 d
120
5
2
0.5
0
8
22
5
61
54
95
31
24
80
52
–
4d
19
20
120
120
1.5
4
0
0
29
6
71
94
–
82
a
On the basis of relative 31P-NMR integrals. DMSO-d6 was used to ensure better separation of the signals; b No
change of further irradiation; c In the presence of 20% [bmim]PF6; d The comparative thermal experiment led to a
composition of 27% (3), 59% (4d), 14% (5d); the shaded percentage values refer to the maximum ratios.
Regarding the conditions (T and t) needed to reach complete conversions (disappearance of the
starting material (3) from the mixture, and predominant appearance of the fully transesterified product
(5)) (see entries 5, 12, 16 and 20 of Table 5), the order of reactivity of the alcohols was the following:
MeOH > BuOH ~ EtOH > iPrOH.
It is worth noting that dibenzyl phosphite (3) is significantly more reactive in transeserifications than
ethyl phenyl-H-phosphinate 2a. The enhanced reactivity of dibenzyl phosphite (
3
) in transesterification
prompted us to try the reaction with nBuOH at room temperature. The data summarized in Table 6 and
Figure 3. showed that the consecutive transesterification took place slowly: after 18 days, there was
54% of the starting phosphite (
derivative 5d (Table 6/Entry 7). The final “equilibrium” concentration was attained after 38 days,
when the mixture comprised 16% of the starting material ( ), 67% of the Bu-Bn ester (4d) and only 17%
3) together with 44% of the “mixed” ester 4d, and 2% of the dibutyl
3
of the dibutyl ester (5d) (Table 6/Entry 10). This experiment was found reproducible. It is assumed that
the application of a larger excess of BuOH would result in the shift of the equilibrium toward esters 4d
and 5d. However, it is worth noting that the composition of the above “equilibrium” mixture with 67%
of the benzyl-butyl ester (4d) is favorable, as it is a valuable intermediate.

Molecules 2020, 25, 719
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Table 6. Alcoholysis of dibenzyl phosphite (3) at room temperature.
BuO
O
BnO
BuO
O
H
BnO
BnO
O
H
25 °C
P
P
P
+
BuOH
(25 equiv.)
BuO
H
4d
5d
3
Composition * (%)
Entry
t (days)
3
4d
5d
1
2
3
4
5
6
7
8
9
1
3
5
98
89
84
82
71
64
54
36
25
2
0
0
0
2
1
1
2
7
13
11
16
20
28
35
44
57
62
7
10
14
18
24
31
10
38
16
67
17
* On the basis of relative 31P NMR integrals. DMSO-d6 was used to ensure better separation of the signals.
Figure 3. Alcoholysis of dibenzyl phosphite (3) with butanol at room temperature.
The next step was to try the continuous flow method. The transesterification of dibenzyl phosphite
(3
) with MeOH at 110 ◦C applying a flow rate of 0.25 mL/min led to a mixture containing 24% of the
starting◦material (
3
), 52% of the “mixed” ester (4a) and 24% of dimethyl phosphite (5a) (Table 7/Entry 1).
), 44% (4a) and 39% (5a) (Table 7/Entry 2). Operation at a
4a and 5a) in relative
At 120 C, the composition was 17% (
lower rate of 0.15 mL/min and at 135 ◦C provided the three components (3a
3
,
quantities of 5%, 23% and 72%, respectively (Table 7/Entry 3). EtOH displayed somewhat lower
reactivity, and under the previous two sets of parameters, mixtures containing 28% of 3b, 48% of
4b, 24% of 5b, and 7% of 3b, 27% of 4b and 66% of 5b, respectively, were obtained (Table 7/Entries 4
and 7). The use of parameter sets of 0.15 mL/min at 120 ◦C and 0.25 mL/min at 135 ◦C resulted in
a comparative outcomes of 20/17% of 3b, 40/36% of 4b and 40/47% of 5b (Table 7/Entries 5 and 6).
In agreement with expectation, iPrOH was found to be the less reactive alcohol. Setting a flow rate of

Molecules 2020, 25, 719
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0.25 mL/min at 120 ◦C, the composition of the reaction mixture was 49% of 3c, 48% of 4c and 3% of 5c
(Table 7/Entry 8). In order to achieve a more complete conversion, a temperature of 145 ◦C and a rate
of 0.15 mL/min were applied (Table 7/Entry 9). The results with nBuOH were again rather similar to
those obtained with EtOH (Table 7/Entries 10 and 11 vs. entries 4 and 7). The experiments providing
the phosphites with different alkoxy groups 4a–d are of importance, as the “mixed” phosphites may be
used as valuable intermediates in the reactions outlined in the Introduction. Optical resolution may
lead to enantiomer-enriched forms of the >P(O)H species. The best runs are marked by entries 1, 4,
8 and 10 of Table 7. The proportions of 47–52% allowed isolated yields of 39–44% for the “mixed”
esters 4a–d. A comparative thermal transesterification of dibenzyl ester 3 with butanol at 120 ◦C and
at a flow rate of 0.25 mL/min led to a composition of 49% of starting material 3, 47% of benzyl-butyl
ester 4d, and 4% of dibutyl ester 5d, suggesting that on conventional heating, the efficiency is lower
(compare footnote “d” of Table 7 with Entry 10).
Table 7. Continuous flow MW-assisted alcoholysis of dibenzyl phosphite.
Composition a,b (%)
T (◦C)
Yield c (%)
Entry
V (mL/min)
R
Product
4a
3
4
5
1
2
3
0.25
0.25
0.15
110
120
135
24
17
5
52
44
23
24
39
72
44
–
–
Me
4
5
6
7
0.25
0.15
0.25
0.15
120
120
135
135
28
20
17
7
48
40
36
27
24
40
47
66
41
–
–
4b
Et
–
8
9
0.25
0.15
120
145
49
18
48
36
3
46
39
–
4c
iPr
Bu
120 d
135
10
11
0.25
0.15
30
8
47
34
23
58
40
–
4d
a
On the basis of relative 31P-NMR integrals. DMSO-d6 was used to ensure better separation of the signals; b After
reaching the steady state; c After an operation of 30 or 45 min belonging to 0.25 mL/min and 0.15 mL/min, respectively;
d
Comparative thermal experiment at 120 ◦C after a steady state operation led to a composition of 49% (
3), 47% (4d),
4% (5d).
As a novel trial, the pre-reacted mixture of dibenzyl phosphite (
comprising 55% of dibenzyl phosphite, 41% of the “mixed” ester (4d) and 4% of dibutyl phosphite (5d
was re-fed into the flow reactor at 120 ◦C applying 0.25 mL/min. The final mixture contained 8% of the
starting material ( ), as well as 23% and 69% of esters 4d and 5d, respectively. Hence, the product ratio
3
) and BuOH (26 ◦C, 18 days)
)
3
could be shifted towards the fully transesterified product 5d.
3. Materials and Methods
3.1. General Information
The MW-assisted reactions were carried out in a Discover (300 W) focused MW reactor
(CEM Microwave Ltd. Buckingham, UK) equipped with a stirrer and a pressure controller applying
irradiation. The reaction temperature was monitored by an external IR sensor located at the bottom of
the cavity.

Molecules 2020, 25, 719
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The continuous flow reactions were performed in a system using a CEM® Discover (300 W) focused
MW reactor equipped with a CEM® 10-mL Flow Cell Accessory continuous flow unit (irradiated
volume 7 mL). The material flow was ensured by a 305 HPLC pump (Gilson Inc., Middleton, WI, USA)
while the pressure of 250 psi (17.2 bar) was maintained by an HPLC backpressure regulator. Teflon®
tubes with an outside diameter of 3.175 mm and an inside diameter of 1.575 mm were used. All of
the accessories applied were compatible with a regular HPLC system. The reaction temperature was
monitored by an external IR sensor.
The 31P-, 13C- and 1H-NMR spectra were obtained in CDCl3 or DMSO-d6 solution on an AV-300
or DRX-500 spectrometer (Bruker AXS GmBH, Karlsruhe, Germany) operating at 121.5, 75.5 and 300 or
202, 126 and 500 MHz, respectively. The 31P-NMR chemical shifts are referred to H3PO4, while the 13
C
and 1H chemical shifts to TMS. The couplings are given in Hz. The exact mass measurements were
performed using an 6545 QTOF mass spectrometer (Agilent Technologies, Santa Clara, CA, USA) in high
resolution, positive electrospray mode.The reagents and solvents were purchased from Sigma-Aldrich
Ltd. (St. Louis, MO, USA), and were used as received without further purification.
The product ratios were determined on the basis of relative 31P-NMR intensities. Representative
examples are shown in the Supplementary Materials for the cases marked by Table 2/Entries 5 and 11,
Table 3/Entry 7 and Table 5/Entry 13.
3.2. General Procedure for the Batch Esterificaton of Phenyl-H-Phosphinic Acid (1)
A mixture of phosphinic acid 1 (0.10 g, 0.70 mmol) and 15 equivalents of the alcohol (0.60 mL of
ethanol, 0.79 mL of n-propanol, 0.80 mL of isopropanol, 0.96 mL of n-butanol, 1.0 mL of isobutanol,
1.14 mL of n-pentanol, 0.14 mL of i-pentanol, 1.65 mL of n-octanol, 1.64 mL of 2-ethylhexanol) was
measured into a sealed tube in the presence or absence of 13.6 µL (0.07 mmol) of [bmim][PF6],
and irradiated in a CEM MW reactor at first with a power of 200–300 W, and after the set temperature
was attained, it was maintained by an automatic regulation using 80–150 W. The values for the
temperature and pressure together with the times are shown in Table 1. Then, 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 give phosphinates
GC. Identification data of the phosphinates 2a–i can be found in Table 8.
2
as oils in a purity of
≥
98% according to
Table 8. 31P-NMR and HRMS data for phosphinates 2.
Product
R
δ (CDCl3)
P
δ [lit]
P
[M + H]+
[M + H]+
requires
Formula
found
2a
2b
2c
2d
2e
2f
2g
2h
2i
Et
nPr
24.7
24.8
22.5
24.9
24.9
25.6
27.7
25.1
25.1
25.7 [30]
24.9 [20]
22.3 [20]
25.3 [30]
25.0 [20]
25.7 [23]
25.7 [23]
25.0 [23]
25.2 [23]
171.0569
185.0725
185.0726
199.0881
199.0881
213.1037
213.1042
255.1517
255.1516
171.0575
C8H11O2P
C9H13O2P
C9H13O2P
C10H15O2P
C10H15O2P
C11H18O2P
C11H18O2P
C14H24O2P
C14H24O2P
185.0731
185.0731
199.0888
199.0888
213.1044
213.1044
255.1514
255.1514
iPr
nBu
iBu
nPent
iPent
nOct
iOct
3.3. General Procedure for the Continuous Flow Direct Esterification of Phenyl-H-Phosphinic Acid (1)
A mixture of phosphinic acid (10.0 g, 70.4 mmol) and 100 mL of an alcohol (2.8 mol of ethanol,
1
2.1 mol of n-propanol, 2.1 mol of isopropanol, 1.1 mol of n-butanol, 1.1 mol of i-butanol, 0.92 mol of
n-pentanol, 0.92 mol of i-pentanol, 0.64 mol of n-octanol, 0.64 mol of 2-ethylhexanol) was homogenized
◦
by stirring for 5 min at 25 C in the presence or absence of 3.5 mmol (0.68 mL) of [bmim][PF6].
The reactor was flushed with 20 mL of the mixture with a flow rate of 10 mL/min at 25 ◦C and 17 bar.
Then, the flow rate was set to the desired value (see Table 2), and the flow cell was irradiated with a
power of 200–300 W for a few minutes, until the desired temperature was reached. After this, the power

Molecules 2020, 25, 719
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was controlled automatically (by 80–150 W) to maintain the value set. The operation was regarded
steady state after an unstationary phase of 45–70 min as suggested by 31P- NMR analysis. After a 45 min
or 75 min period of steady state operation belonging to 0.25 mL/min and 0.15 mL/min, respectively,
the collected sample was concentrated 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
2 as oils in a purity of ≥98% according to GC.
The yields were calculated on the basis of the molar quantity of the ester [m(
2
)/Mw(
] obtained after purification, taking into
c( ), where V:
2), where m(2):
weight of ester , Mw( ): molecular weight of ester
2
2
2
consideration the molar quantity of the phosphinic acid fed in during the given time [V·
t
·
1
the flow rate (0.15 mL/min or 0.25 mL/min), t: time of stationary operation (45 min or 75 min) and c(
molar concentration of acid 1 (0.65 mmol/mL)]
1):
Realization of the recirculation: the reaction mixture obtained from 10.0 g (70.4 mmol) of phosphinic
1 and 100 mL (2.8 mol) of ethanol in the presence of 0.68 mL (3.5 mmol) of [bmim][PF6] as shown
acid
above in the general procedure (and marked by Table 2/Entry 12) was placed in the container of the
starting mixture, and after a flush with 20 mL of the mixture with a flow rate of 10 mL/min at 25 ◦C
and 17 bar, and after setting a flow rate of 0.15 mL/min, the temperature was adjusted to 160 ◦C exactly
as described above for the first run. The product was collected after getting in the stationary operation
phase (Table 2/footnote “e”).
3.4. General Procedure for the Batch Transesterification of Ethyl-H-Phenylphosphinate (2a)
A mixture of ethyl-H-phenylphosphinate (2a, 0.10 g, 0.58 mmol) and 15 equivalents of an alcohol
(0.36 mL of methanol, 0.66 mL of n-propanol, 0.70 mL of isopropanol, 0.81 mL of n-butanol, 0.81 mL
of i-butanol, 0.96 mL of n-pentanol, 0.96 mL of i-pentanol, 0.95 mL of 3-pentanol, 0.92 mL of benzyl
alcohol) was measured in a sealed tube and irradiated in the MW reactor at first with a power of
80–300 W, and after the set temperature was attained, it was maintained by an automatic regulation
using 50–150 W. The temperatures and the times are shown in Table 3. Then, 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
2 as oils in a purity of ~98% according
to GC.
3.5. General Procedure for the Continuous Flow Transesterification of Ethyl-H-Phenylphosphinate (2a)
A mixture of ethyl-H-phenylphosphinate (2a, 10.0 g, 58.8 mmol) and 100 mL of an alcohol (1.1 mol
of n-butanol, 1.1 mol of i-butanol, 0.92 mol of n-pentanol and 0.92 mol of i-pentanol) was homogenized
by stirring for 5 min at 25 ◦C. The reactor was flushed with 20 mL of the mixture with a flow rate
◦
of 10 mL/min at 25 C and 17 bar. Then, the flow rate was set to the desired value (see Table 4),
and the system irradiated as described above under point 3 (300 W/150–200 W). The operation
was regarded steady state on the basis of the 31P-NMR analyses. In the preparative experiments,
the solutions containing esters 2d
fraction was removed under reduced pressure, and the residue so obtained purified by flash column
chromatography using silica gel and ethyl acetate as the eluant to provide phosphinates 2d as oils in
a purity of ~98% according to GC. The yield of 2d was calculated similarly as shown for that of 2a
–g were collected for 1 h. Excess of the alcohol of the collected
–
g
–g
–i
above [(m(2)/Mw(2)/ V·t·c(2a), where V: 0.15 mL/min, t: 1 h, c(2a): 0.54 mmol/mL.
3.6. General Procedure for the Batch Transesterification of Dibenzyl Phosphite
A mixture of dibenzyl phosphite (0.11 mL, 0.50 mmol) and 12.5 mmol of an alcohol (0.51 mL of
methanol or 0.73 mL of ethanol or 0.96 mL of isopropanol or 1.1 mL of butanol) was heated in a sealed
tube in the MW reactor (at first with a power of 60–80 W, then, in the maintainance phase by 30–50 W)
at the temperatures and for the times shown in Table 5. The volatile components were removed under
vacuum, and the residual oil was analyzed by 31P-NMR spectroscopy. The crude mixture was purified
by column chromatography using hexane–ethyl acetate 6:4 (for 4a–c) or hexane–acetone 8:2 (for 4d)

Molecules 2020, 25, 719
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as the eluent. The phosphites 4a
>99% purities.
–
d
with different alkoxy groups were obtained as colorless oils in
3.7. General Procedure for the Continuous Flow Transesterification of Dibenzyl Phosphite
A mixture of dibenzyl phosphite (7.7 mL, 35 mmol) and 0.88 mol of an alcohol (35.6 mL of
methanol or 51.4 mL of ethanol or 67.8 mL of isopropanol or 80.5 mL of butanol) was homogenized
by stirring for 5 min at 25 ◦C. The reactor was flushed with 20 mL of the mixture with a flow rate of
10 mL/min at 25 ◦C and 17 bar. Then, the flow rate was set to the desired value (see Table 7), and the
flow cell was irradiated with a power of 60-100 W for a few minutes, until the desired temperature
was reached. After this, the power was controlled automatically (by 30–70 W) to maintain the value
set. The operation was regarded steady state on the basis of the 31P-NMR results. Development of
the steady state condition required ca. 45–80 min. The details can be seen in Table 7. The solutions
containing esters 4a
components of the collected fractions were removed in vacuum, and the crude mixture was purified
by column chromatography as above (see Section 3.6). Products 4a were obtained as colorless oils in
>99% purities. Yields were calculated on the basis of the isolated molar quantity of the product 4a as
compared to the molar quantity of dibenzyl phosphite (3) fed in during the stationary operation.
–d were collected until 30 min (0.25 mL/min) or 45 min (0.15 mL/min). The volatile
–
d
–
d
Realization of the experiment starting from a pre-reacted mixture: the pre-reacted mi◦xture of
dibenzyl phosphite (3, 7.1 mL, 32.0 mmol) and BuOH (73.2 mL, 0.80 mol) obtained at 26 C after
a 18 days stirring was fed in the MW reactor at 120 ◦C at a flow rate of 0.25 mL/min as the “fresh”
mixtures exactly as shown above to result in a mixture consisting 8% of 3, 23% of the ”mixed” ester 4d,
and 69% of the fully transesterified product 5d in the stationary phase.
3.8. Product Characterization Data
Benzyl methyl-H-phosphonate (4a). Yield: 0.50 g (44%); 31P-NMR (CDCl3)
δ
9.2; 13C-NMR (CDCl3)
52.1 (d, J = 5.9, OCH2 ), 67.5 (d, J = 5.6, OCH3 ), 128.1 (C2b), 128.8 (C3b and C4), 135.7 (d, J = 5.9, C1);
1H-NMR (CDCl3)
3.71 (d, J = 12.0, 3H, OCH3), 5.11 (d, J = 9.7, 2H, OCH2), 6.84 (d, J = 703.0, 1H, PH),
7.32–7.42 (m, 5H, ArH), a,bmay be reversed; [M + H]+ = 187.0528, C8H12O3P requires 187.0524.
δ
a
a
δ
Benzyl ethyl-H-phosphonate (4b). Yield: 0.36 g (41%); 31P-NMR (CDCl3)
8.6; δP 31] (CDCl3) 5.2;
13C-NMR (CDCl3)
16.4 (d, J = 6.3, CH3), 62.1 (d, J = 5.9, OCH2), 67.3 (d, J = 5.5, OCH2), 128.1 (C2*),
128.7 (C4), 128.8 (C3*) 135.8 (d, J = 6.0, C1), *may be reversed; 1H-NMR (CDCl3)
1.31 (t, J = 7.1, 3H,
CH3), 4.00–4.19 (m, 2H, OCH2CH3), 5.10 (d, J = 9.6, 2H, OCH2Ph), 6.86 (d, J = 700.0, 1H, PH), 7.30–7.42
δ
[
δ
δ
(m, 5H, ArH); δH [31] 1.31 (t, 3H, J = 7.0), 4.09 (qd, 2H, J1 = 7.0, J2 = 9.2), 5.10 (d, 2H, J = 9.6), 6.86 (d, 1H,
J = 698.9), 7.37 (m, 5H); [M + H]+ = 201.0685, C9H14O3P requires 201.0681.
Benzyl isopropyl-H-phosphonate (4c). Yield: 0.29 g (39%); 31P-NMR (CDCl3)
δ
6.2; 13C-NMR (CDCl3)
δ
24.0 (d, J = 4.8, CH3), 24.1 (d, J = 4.3, CH3), 67.2 (d, J = 5.5, OCH2a), 71.5 (d, J = 6.0, OCHa), 128.0 (C2b),
128.7 (C4), 128.8 (C3b) 135.9 (d, J = 6.3, C1), a,bmay be reversed; 1H-NMR (CDCl3)
δ 1.33 (m, 6H, OCH3),
4.65–4.82 (m, 1H, OCH), 5.10 (d, J = 9.3, 2H, OCH2), 6.89 (d, J = 697.1, 1H, PH), 7.31–7.43 (m, 5H, ArH);
[M + H]+ = 215.0838, C10H16O3P requires 215.0837.
Benzyl butyl-H-phosphonate (4d). Yield: 0.27 g (40%); 31P-NMR (CDCl3)
(CH3), 18.8 (CH3CH2), 32.4 (d, J = 6.2, OCH2CH2), 65.7 (d, J = 6.2, OCH2), 67.3 (d, J = 5.6, OCH2),
128.1 (C2*), 128.75 (C4), 128.80 (C3*), 135.8 (d, J = 6.0, C1), *may be reversed; 1H-NMR (CDCl3)
0.91
δ δ 13.6
7.9; 13C-NMR (CDCl3)
δ
(t, J = 7.4, 3H, CH3), 1.31–1.44 (m, 2H, CH2), 1.58-1.69 (m, 2H, CH2), 3.95–4.11 (m, 2H, OCH2CH2), 5.11
(d, J = 9.6, 2H, OCH2Ph), 6.87 (d, J = 699.4, 1H, PH), 7.32–7.43 (m, 5H, ArH); [M + H]+ = 229.0989,
C11H18O3P requires 229.0994.
NMR spectra of products 4a–d are shown in the Supplementary Materials.
The characterization data of the dialkyl phosphites 5 is summarized in Table 9.

Molecules 2020, 25, 719
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Table 9. 31P NMR and HRMS data for the known compounds 5a–d prepared.
Compound δ (CDCl3)
δ [lit]
P
[M + H]+
[M + H]+
requires
Formula
P
found
5a
5b
5c
8.6
7.8
1.8
8.6
8.5 [32]
7.9 [33]
1.9 [32]
8.4 [33]
111.0213
139.0527
167.0837
195.1149
111.0211
C2H8O3P
C4H12O3P
C6H16O3P
C8H20O3P
139.0524
167.0837
195.1150
5d
4. Conclusions
The microwave-assisted direct esterification of phenyl-H-phosphinic acid, transesterification of
the resulting alkyl phenyl-H-phosphinates, as well as that of dibenzyl phosphite was elaborated,
and then, after optimization of the parameters (temperature and flow rate), these transformations
were translated into continuous flow methods. While the direct esterifications were performed at
160–200 ◦C, the transesterifications of the ethyl phosphinate required somewhat higher temperatures
up to 225 ◦C. Dibenzyl phosphite was more reactive, and already took part in alcoholyses at 80–145 ◦C.
The esterifications and transesterifications proved to be more productive in the flow embodiment.
Regarding the esterifications, while the flow preparation may give ca. 0.75 g ester/30 min, the batch
method affords only ca. 0.10 g product after the same time. In the optimized cases, esters
obtained in yields above 75%. The two-step alcoholysis of dibenzyl phosphite involves an intermediate
with two different alkyl groups prepared in moderate yields that, among other uses, may be important
2 were
4
precursors for optically active reagents in the Hirao reaction or the Kabachnik–Fields condensation,
which will be further studied by us in future work.
Supplementary Materials: Representative examples for the calculation of the conversions in the esterifications
and transesterifications, as well as 31P-, 13C- and 1H-NMR spectra for the new alkyl, alkyl’ phosphites.
Author Contributions: N.Z.K, G.K. and R.H planned the experiments. N.Z.K. and R.H. carried out the
experimental work. G.K. managed the project and wrote the paper. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by the National Research, Development and Innovation Fund of Hungary in
the frame of the FIEK_16-1-2016-0007 (Higher Education and Industrial Cooperation Center) project and by the
National Research, Development and Innovation Office (K119202).
Acknowledgments: This project was supported by N.Z.K. is grateful for the János Bolyai Research Scholarship of
the Hungarian Academy of Sciences (BO/00130/19/7) and ÚNKP-19-4-BME-444 New National Excellence Program
of the Ministry of Human Capacities. R.H. is grateful for the support of the Gedeon Richter’s Talentum Foundation.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of all the compounds prepared are available from the authors.
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