Solvent-Free Michaelis-Arbuzov Rearrangement under Flow Conditions

Article abstract of DOI:10.1021/acs.joc.8b03053

The first solvent- and catalyst-free procedure for the Michaelis-Arbuzov reaction under flow conditions was developed. A variety of alkylphosphonic esters could be obtained using this protocol starting from the corresponding trialkyl phosphites and even catalytic amounts of alkyl halides with very short reaction times (8.33-50 min) and excellent conversions. In general, this protocol works effectively when the alkyl halide is used in catalytic amounts as low as 5-10% only if it concerns the synthesis of homo alkylphosphonates. One equivalent and an excess of alkyl halides should be used in the reaction with alkyl phosphite if the alkyl group of the selected substrates differ. Thus, it provides a sustainable, fast alternative to the existing methods for the preparation of alkylphosphonates. The isolation of the reaction products is straightforward due to the lack of solvents and a high purity of the obtained products (conv ≥ 99%), and notably, in the catalytic procedures there are only traces of alkyl halides formed after the reaction is complete. The reactions conducted using a glass microreactor chip with an internal volume of 250 μL allow the production of 1.6-1.95 g of organophosphorus esters per hour.

Full text of DOI:10.1021/acs.joc.8b03053

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Article
The Solvent-free Michaelis-Arbuzov Rearrangement under Flow Conditions
Aleksandra Jasiak, Gra#yna Mielniczak, Krzysztof Owsianik,
Marek Koprowski, Dorota Krasowska, and Jozef Drabowicz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03053 • Publication Date (Web): 30 Jan 2019
Downloaded from http://pubs.acs.org on February 3, 2019
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The Solvent-free Michaelis-Arbuzov Rearrangement under Flow Conditions
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Aleksandra Jasiak,*† Grażyna Mielniczak,† Krzysztof Owsianik,† Marek Koprowski,† Dorota
Krasowska† and Józef Drabowicz*†,‡
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†Division of Organic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,
Sienkiewicza 112, 90-363 Łódź, Poland
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‡Institute of Chemistry, Health and Food Sciences, The Faculty of Mathematics and Natural Sciences, Jan
Długosz University in Częstochowa, Armii Krajowej 13/15, Częstochowa 42-201, Poland
*Corresponding Authors: E-mail: draj@cbmm.lodz.pl (J. Drabowicz) E-mail: ajasiak@cbmm.lodz.pl (A. Jasiak)
Abstract: The first solvent- and catalyst–free procedure for the Michaelis- Arbuzov reaction under flow
conditions was developed. A variety of alkylphosphonic esters could be obtained using this protocol
starting from the corresponding trialkyl phosphites and even catalytic amounts of alkyl halides with
very short reaction times (8.33 – 50 min.) and excellent conversions. In general, this protocol works
effectively when the alkyl halide is used in catalytic amounts as low as 5% to 10% only if it concerns
the synthesis of homo alkylphosphonates. One equivalent and an excess of alkyl halides should be
used in the reaction with alkyl phosphite if alkyl group of the selected substrates differ. Thus, it
provides a sustainable, fast alternative to the existing methods for the preparation of
alkylphosphonates. The isolation of the reaction products is straightforward due to the lack of solvents,
a high purity of the obtained products (conv. ≥ 99%), and notably, in the catalytic procedures there are
only traces of alkyl halides formed after the reaction is complete. The reactions conducted using a
glass microreactor chip with an internal volume of 250 µl allow the production of 1.6 – 1.95 g
organophosphorus esters per hour.
Introduction
Alkyl phosphonates can be considered as one of the basic families of organophosphorus compounds
that have found a broad spectrum of useful applications in the areas of industrial, agricultural and
medicinal chemistry.1 Their importance stems from their diverse biological activity, as well as their
utility as synthetic intermediates2 especially in the synthesis of other organophosphorus esters and
amides including also biologically active molecules.3 The Michaelis-Arbuzov (M-A) rearrangement,
also known as the Arbuzov reaction relies on a double SN2 reaction between an alkyl halide and a
trialkyl phosphite (Scheme 1) and is one of the most versatile methods for the preparation of
phosphonates, phosphinates and phosphine oxides starting from the corresponding tricoordinated
precursors.4
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R1O
O
R2
:
R1O
OR1
R1O
O
R2
R2
X
P
P
OR1
R1
X
P
+
R1
OR1
OR1
X
7
8
9
Scheme 1. The SN2 Arbuzov reaction mechanism.
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Several review articles on this rearrangement have been published,5 including reviews of the M-A
reaction of phosphorohalidites5c and Arbuzov rearrangements using haloacetylenes as a method for
synthesizing alkynyl phosphonates and other important organophosphorus compounds.5d From a
synthetic point of view the conventional Arbuzov reaction has several disadvantages. First of all, the
reaction requires high temperature for an extended period of time. Secondly, extended periods of
heating at higher temperatures led to the isolation of unexpected products. In addition one equivalent
of alkyl halide is formed in the reaction, which can react with the phosphite under the reaction
conditions to give an undesirable side-product, leading to the reduced yield. Considering these
limitations it should be noted that more and more alternative and green methods described in the
literature6 involve microwaves irradiations,7,8 microwaves irradiations with metallic Lewis acid,9
catalysis with either metal salts10 or the application of a non-metallic Lewis acid.11 An alcohol-version
of M-A reaction is achieved by an iodide-catalyzed C–P(O) formation reaction of a wide range of
alcohols with phosphites, phosphonites, and phosphinites.12 In light of the comments given above it
would still be useful to develop alternative approaches to the M-A rearrangement. Therefore, we
decided to be the first in examining the Arbuzov reaction under flow condition in order to develop a
practical, fast and industrially relevant, procedure for the synthesis of homo and mixed
alkylphosphonates (Scheme 2).6,13
Microreactor chip
:
O
R1O
OR1
R2
X
P
P
R2
+
R1O
OR1
+
R1
X
OR1
0.05-1.5 equiv.
conv. 90 - 99%
T = 50-150 oC
2
1
4
3
tres = 8.33-50 min.
Scheme 2. Continuous flow, solvent-free Michaelis-Arbuzov reaction.
We expected that with the flow solventless process one can avoid wasteful work-up operation as
products are isolated by simple evaporation traces of the alkyl halide, and the scale-up should be
effortless. Moreover, because of the small internal volume, as well rapid heat transfer associated with
the microreactor chip and the effective removal of heat generated in the exothermic reaction, the flow
process offers the utmost scale-independent safety level.14
Results and Discussion
In an effort to develop a facile and fast method for Arbuzov reaction, we started with the studies on the
optimization of this transformation under flow conditions. All reactions were performed solventless in a
microreactor (Syrris Asia 120) with an internal volume of 250 µl. In the first series of experiments, the
optimal conditions for the Arbuzov reaction between both phosphite 1 and alkyl halide 2 having the
same alkyl groups (R1 = R2) were elaborated. Residence time (tres), temperature, and stoichiometric
ratio were optimized evaluating the conversion by 1H and 31P NMR (Table 1 and 2).
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Table 1. Optimization of the solvent-free Arbuzov rearrangement between
trimetyl phosphite 1a and catalytic amount of methyl iodide 2a.
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8
9
MeI (2a)
(0.02-0.1 equiv.)
O
P
:
MeO
OMe
P
MeO
OMe
tres, T, neat
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OMe
Me
1a
3a
[a]
Entry
2a
(equiv.)
T (°C)
tres
Conversion[b] (%)
(min.)
25
1
2
3
4
5
6
7
8
9
0.02
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
100
50
66
5
25
60
25
9
70
25
20
49
83
≥99
97
80
80
25
90
25
100
100
100
8.33
5
batch,
7h[c]
[a] tres– residence time. [b] estimated on the basis of 1H and 31P NMR. [c] reaction
time.
To evaluate the optimal amount of halogen, residence time and temperature, the reaction of trimethyl
phosphite (1a) with methyl iodide (2a) was chosen as the model reaction. As shown in Table 1 (entry
1), the reaction with 0.02 equiv. of methyl iodide (2a) at 100 °C was initially carried out. Unfortunately,
the expected dimethyl methylphosphonate (3a) was obtained only in good conversion (66%) after
residence time of 25 minutes. From this experiment, it was clear that 0.02 equiv. of alkyl halide 2a was
insufficient, and we employed in the next attempts a quantity of 5 mol % of methyl iodide. Next, we
screened the temperature of the reaction as it was reasonable to examine how this reaction rate
depends on the temperature at constant residence time (Table 1, entries 2-7). At the temperatures in
the range 50-80 °C (Table 1, entries 2-5) the reaction proceeded with 5% or more conversion.
Increase in the reaction temperature up to 90 °C allow the conversion to raise to 83% maintaining a
residence time of 25 minutes (Table 1, entry 6). Excellent conversion (≥ 99%) and short residence
time (8.33 min.) was obtained for a ratio of 2a/1a of 0.05 at 100 °C (Table 1, entry 7). To our delight,
these results confirm the excellent heat transfer into reaction mixture using the flow system during this
rearrangement. Raising the temperature in the microchip by 20 degrees (from 80 °C to 100 °C)
increased the conversion of the reaction by 50 percent (Figure 1).
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40
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0
83
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2
3
4
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49
20
9
5
7
8
9
50
60
70
80
90
100
Temperature (°C)
Figure 1. Conversion of trimethyl phosphite 1a versus temperature under flow conditions and tres = 25
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min. (Table 1, entry 2-7).
Furthermore, to make the conditions even more cost-effective and less time-consuming, we decided to
decrease a residence time to as low as 5 minutes to give 97% conversion of 2a (Table 1, entry 8). The
same reaction carried out under batch conditions at 100°C required higher amounts of methyl iodide
(0.1 equiv.), a much longer time (7h) and gave the product in only 80% conversion (Table 1, entry 9).
Vaporization of the reagents into the headspace of the batch system decreases the concentration in
solution, therefore, reactions with low-boiling point reagents such as MeI consistently proceed more
efficiently in pressurized flow reactors.14 Process scale-up has been demonstrated to be facile and
rapid while the quantities of alkyl halide are strongly reduced. As a result it allows for the safe
production of 11.74 g of dimethyl methylphosphonate (3a) in 6 hours.
Table 2. Optimization of the solvent-free Arbuzov reaction between trialkyl phosphites 1b, c and alkyl
halides 2b, c, f with the same alkyl substituents.
R X
0.05-0.15 equiv.
O
:
RO
OR
P
R
P
R X
+
RO
OR
tres, T, neat
OR
2b R = Et, X = I
2c R = Bn, X = Br
2f R = Et, X = Br
1b R = Et
1c R = Bn
3b R = Et
3c R = Bn
Entry
1
2
2
T (°C)
tres [a] (min.)
Prod. 3
Conversion[b]
(%)
(equiv.)
1
2
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
(EtO)3P (1b)
EtI (2b)
EtI (2b)
EtI (2b)
EtI (2b)
EtI (2b)
EtI (2b)
EtI (2b)
EtBr (2f)
EtBr (2f)
EtI (2b)
0.05
0.1
100
100
100
150
150
150
150
150
150
150
150
25
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3c
<5
<5
5
25
3
0.15
0.05
0.1
25
4
25
74
83
95
≥99
<5
<5
40
90
5
25
6
0.15
0.1
25
7
50
8
0.05
1
25
9
25
batch, 12h[c]
25
10
11
0.1
(PhCH2O)3P
PhCH2Br
0.1
(1c)
(2c)
12
13
(PhCH2O)3P
PhCH2Br
0.1
0.1
140
140
50
3c
3c
90
69
(1c)
(2c)
(PhCH2O)3P
PhCH2Br
batch, 7h[c]
(1c)
(2c)
[a] tres - residence time. [b] estimated on the basis of 1H and 31P NMR. [c] reaction time.
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In the next series of experiments, the effective conditions found in previous screening tests (Table 1,
entry 7), were applied for the reactions of triethyl phosphite (1b) with ethyl iodide (2b). Despite of the
using the optimal conditions found for (MeO)3P 1a and MeI 2a (100 °C, tres = 25 min., 0.05 equiv. 2a,
Table 1), in the case of (EtO)3P 1b and EtI 2b only traces of the product 3b were observed (Table 2,
entry 1). In the next attempt the use of 0.1, then 0.15 equiv. of ethyl iodide (2b) was found to be
inefficient in the increasing of a conversion (Table 2, entries 2 and 3). Hence, it was necessary to raise
the reaction temperature up to 150 °C to obtain a better result. The yield of 3b at this temperature was
improved up to 74% in the presence of 0.05 equiv. of EtI for 25 min. of residence time (Table 2, entry
4). When a higher amount of alkyl halide 2b (0.1 equiv.) was used, 83% conversion was observed at
the same tres and temperature (Table 2, entry 5). With marginally higher equivalents of ethyl iodide
(0.15 equiv.) the conversion of phosphite 1b to phosphonate 3b was very high (95%) in only during 25
minutes residence time (Table 2, entry 6). Interestingly, further studies have shown that the reaction at
longer residence time - 50 minutes, temperature 150 °C and slightly lower amounts of EtI (0.1 equiv.)
allowed the synthesis of 3b to proceed in excellent conversion ≥ 99% (Table 2, entry 7). The
comparison of the reactivity of trimetyl phosphite 1a toward MeI 2a and triethyl phosphite 1b toward
EtI 2b indicates that the later phosphite was much less reactive. Trimetyl phosphite gave >99% of
conversion at 100 °C, tres = 8.33 min. and 5% equiv. of 2a (Table 1, Entry 7) whereas triethyl phosphite
1b required higher temperature (150 °C), longer residence time (50 min.) and 10% equiv. of 2b (Table
2, Entry 7) to achieve the same result.
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Other alkyl halides such as EtBr were also tested, but the product 3b was formed in trace amounts
only, even in the presence of one equivalent of EtBr (Table 2, entries 8 and 9). To complete our
studies, the batch process was carried out in a similar way. As a result, 40% conversion was
accomplished in the reaction conducted at 150 °C for 12 hrs (Table 2, entry 10). Subsequently,
tribenzyl phosphite (1c), obtained according to the described literature procedure,15 was used to
examine the Arbuzov reaction with PhCH2Br (2c), in two runs at temperatures 140 °C or 150 °C and
residence times 50 or 25 minutes, respectively. The observed conversions for both experiments (90%)
(Table 2, entries 11, 12), were much better than under batch conditions after 7 hours at 140 °C (Table
2, entry 13). Using larger amounts of benzyl bromide 2c or shortening or elongation of reaction time
did not result in the enhancements of the conversion.
In the next series of experiments flow conditions for the reaction, between the phosphites and alkyl
halides with different alkyl substituents R1 and R2 were optimized. To examine the scope and
limitations of the microreactor-assisted reaction, several representative alkyl halides varying by the
length of hydrocarbon chain 2a, b, d, e were tested in the reaction with triethyl phosphite (1b) or
triisopropyl phosphite (1d) under flow conditions to afford the corresponding phosphonates 3d-h and
3b (Table 3).
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Table 3. Selective Michaelis-Arbuzov reaction between phosphites 1b, d and alkyl iodides 2a, b, d,
e, under flow.
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9
O
- R1-I
O
R1O
OR1
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P
R2
R2-I
R1O
OR1
P
+
+
P
R1
R1O
OR1
tres, T, neat
OR1
(0.05-1.5 equiv.)
2a R2 = Me
3d R1 = Et, R2 = Me
3e R1 = i-Pr, R2 = Me
3f R1 = i-Pr, R2 = Et
3g R1 = i-Pr, R2 = n-Pr
3h R1 = i-Pr, R2 = n-Bu
1b R1 = Et
3b R1 = Et
1d R1 = i-Pr
2b R2 = Et
2d R2 = n-Pr
2e R2 = n-Bu
[a]
Entry
R1 (1)
Et (1b)
Et (1b)
R2 (2)
Me (2a)
Me (2a)
2
T
tres
3
Conversion[b] Productivity
(equiv.) (°C) (min.)
(%)
(g/h)
1
2
0.05
100
25
3d/3b
28
-
5/23[c]
0.10
150
25
3d/3b
80
-
10/70[c]
3
4
Et (1b)
i-Pr (1d)
i-Pr (1d)
i-Pr (1d)
i-Pr (1d)
i-Pr (1d)
i-Pr (1d)
i-Pr (1d)
Me (2a)
Me (2a)
Et (2b)
1
1
100
100
100
150
150
150
150
150
8.33
8.33
25
3d
3e
3f
≥99
≥99
25
1.9
1.6
-
5
1
6
Et (2b)
1
25
3f
94
-
7
Et (2b)
1.5
1
8.33
25
3f
≥99
77
1.7
-
8
n-Pr (2d)
n-Pr (2d)
n-Bu (2e)
3g
3g
3h
9
1.5
1.5
8.33
8.33
≥99
≥99
1.95
1.8
10
[a] tres - residence time. [b] determined by H and 31P NMR of crude reaction mixtures. [c] ratio
determined by 31P NMR of crude reaction mixtures.
1
The optimization of the reaction conditions included the screening the residence time, flow rate,
reactor temperature and the ratio of reagents, allowed to reach a good selectivity. For these
experiments, it was obvious that the reactions at high temperature are preferable, hence a pressure
regulator set to 3.5 barg was used. The reaction course was monitored by H and 31P NMR as a
1
function of residence times. Initially, the reaction of triethyl phosphite (1b) with highly reactive methyl
iodide (2a) (0.05 equiv.) was carried out. Two flow reactions were performed for 25 minutes of
residence time at 100 °C or 150 °C affording the mixture of phosphites 3d (5% yield, entry 1, 10%
yield, entry 2) and 3b while the latter was a major one obtained in 23% yield (Table 3, entry 1) and 70
% yield (Table 3, entry 2). In order to prevent the formation of the side products 3b, an equimolar
amount or an excess of alkyl halides 2 were used. A quantitative conversion was observed when 1
equiv. of methyl iodide was used (Table 3, entry 3). Moreover, the residence time of this reaction could
be limited to 8.33 minutes allowing to obtain 1.9 g of the corresponding product 3d in 1 hour (Table 3,
entry 3). Similarly, within the short residence time of 8.33 min. the mixture of triisopropyl phosphite
(1d) and methyl iodide was flowed at 100 °C with an excellent conversion (≥99%) (Table 3, entry 4).
However, the replacement of MeI with less reactive EtI resulted in a lower conversion of 25% at 100
°C but 94% at 150 °C (Table 3, entries 5 and 6, Figure 2). Increase in the quantities of EtI used for
reaction to 1.5 equiv. at 150 °C resulted in the formation of diisopropyl ethylphosphonate (3f)
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exclusively (Table 3, entry 7). This straightforward continuous flow process, allows the production of
1.7 g of the desired product within 1 hour.
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94
100
84
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59
60
80
56
60
40
25
20
0
100
120
140
150
Temperature (°C)
Figure 2. The conversion of triisopropyl phosphite (1d) vs. temperature with 1 equiv. EtI and tres
=
25min. under flow conditions.
When n-propyl (2d) and n-butyl halides (2e) were reacted with triisopropyl phosphite (1d), the
optimized flow conditions again allowed the isolation of corresponding products 3g-3h (Table 3,
entries 8-10). As shown in entry 8, the use of 1 equiv. of n-PrI at 150 °C resulted in the conversion of
the triisopropyl phosphite (1d) being limited to 77%. However, excellent conversion (≥99%) was
obtained while using 1.5 molar equivalent of 2d to be reacted with phosphite 1d in a short residence
time of 8.33 minutes (Table 3, entry 9). When the microreactor ran for 1 hour 1.95 g of the only one
product 3g was isolated. Similarly, a longer carbon chain alkyl halide – n-Bu (2e) also reacted
efficiently with 1d to give the desired phosphonate 3h quantitatively (Table 3, entry 10). Finally, the
phosphonates 3b,d-h were easy purified by immediate vacuum evaporation of the traces of alkyl
halides.
Since triethyl phosphite treated with methyl iodide is able to undergo a facile a continuous flow
Arbuzov rearrangement, it was of our interest to compare its reactivity toward the less reactive n-
propyl iodide. The selected results from this study are summarized in Table 4.
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Table 4. The competitive Arbuzov reaction of phosphite 1b with
n-propyl iodide (2d) and ethyl iodide.
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7
8
9
O
P
O
P
:
EtO OEt
-EtI
P
n-PrI
+
+
EtO
n-
OEt
EtO
OEt
tres = 25 min.
T = 150oC
OEt
1b
Et
3b
Pr
3i
2d
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Entry
2d (equiv.)
Ratio[a] 3i/3b
55/45
Conversion[b] (%)
1
2
3
4
5
6
7
1
1.5
2
≥99
≥99
≥99
≥99
≥99
≥99
≥99
67/33
72/28
3
77/23
5
84/16
8
92/8
10
100/0
[a] Ratios were determined by 31P NMR of crude reaction
mixtures. [b] determined by H and 31P NMR of crude reaction
1
mixtures.
Due to the small difference in the reactivity of the alkyl halides EtI and n-PrI, both phosphonates 3i and
3b in the 55/45 ratio were formed as shown by NMR spectroscopy. All reactions of triethyl phosphite
(1b) with n-propyl iodide (2d) in molar ratios ranging from 1:1 to 1:5, proceeded in 25 minutes of
residence time, at 150 °C to give the desired phosphonate 3i being in a majority, indicating that a large
excess of alkyl halide should be added (Table 4, entry 1-5). Similar ratio of the products was obtained
when 5 equiv. of 2d and microwave irradiation (1100 W) for 5 min. were applied.16 An increase of n-
propyl halide 2d amount to 10 molar equiv. allowed to receive the product 3i exclusively (Table 4,
entry 7).
Conclusions
In summary, we have developed the first highly efficient, continuous flow Michaelis-Arbuzov
rearrangement, performed without solvents, which enable the scalable synthesis of the
organophosphorus esters. We have shown that trialkyl phosphites 1a-d react with different alkyl
halides 2a-e with formation of the corresponding phosphonates 3a-i in excellent conversions (up to
≥99%), high selectivity and short residence times (8.33-50 min.). In the case of homoalkylated
reagents, catalytic amounts of halides were sufficient to achieve complete conversions. Upscaling the
reaction resulted in a productivity of 1.6-1.95 g/h of esters. In the cases where catalytic amount of alkyl
halides are sufficient to quantitative conversion, the reaction becomes industrially relevant. This
method could provide a very convenient alternative to the existing procedures of Michaelis-Arbuzov
rearrangement.
Experimental Section
All trialkyl phosphites and alkyl halides are commercially available. Liquid reagents were used in neat
form and, if necessary, distilled prior to use. The continuous flow reactions were performed using a
fully automated microreactor Asia 120 System (Syrris) (Table 5) fitted with a glass microreactor chip of
250 µl internal volume and 1 x 100 µl, and 1 x 50 µl syringes (ILS).
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The reactions were performed at temperatures up to 150 °C using Asia Heater. The use of 3.5 barg
pressure at microreactor chip permitted lower boiling point reagents for high-temperature reaction.
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To prevent the formation of gas bubbles in the microreactor chip during reactions at high
temperatures, pressure of 3.5 barg was used because the temperatures of the reactions in most cases
exceeded the boiling points of alkyl halides (MeX and EtX, X = Br, I) at standard conditions.
Barg refers to a gauge pressure, a relative pressure when the reference is atmospheric pressure (1
bar). The microreactor was rinsed with acetone before use and allowed to dry. Subsequently, the
microreactor was filled with the mixture of trialkyl phosphite and alkyl halide using flow rate of 200-250
µl min-1 for 5 min. Finally, a mixture of reagents was pumped through the microreactor with a flow rate
corresponding to an applied ratio and a residence time. After a steady state period (8.33-50 min.
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depending on the flow rate, total volume of 250 µl), a sample was collected to be analysed by 1H, 31
P
NMR. Excess of alkyl halide was evaporated using a vacuum evaporator for 1-2 min., and the crude
product was analysed by 1H, 31P NMR again. The 1H and 31P NMR spectra of all obtained
phosphonates 3 are consistent with the data reported in the literature.
Synthetic procedures
All reagents were purchased from Sigma-Aldrich and were used as received, if necessary, distilled
prior to use. Tribenzyl phosphite (1c) was prepared according to the described literature procedure. 1H
and 31P NMR spectra were acquired on commercial instruments (Bruker Avance 200 MHz, Bruker
Avance III 500 MHz). Reaction mixtures were introduced into the fully automated microreactor Asia
120 system (Syrris) fitted with a glass microreactor chip of 250 µl internal volume and 1 x 100 µl, and 1
x 50 µl syringes (ILS). The reactions were performed at temperatures up to 150 °C using Asia Heater.
A microreactor chip pressure of 3.5 barg was used in order to keep all reagents in liquid phase at
elevated temperatures.
Dimethyl methylphosphonate (3a)
A mixture of trimethyl phosphite (1.0 equiv.) and methyl iodide (0.05 equiv.) was continuously pumped
through the microreactor with a flow rate of 30 µl/min. Reaction progress was monitored by 1H and 31
P
NMR as a function of residence times. After 8.33 min. of residence time the quantitative amount of the
desired product 3a was observed. After collecting the crude reaction mixture, the remaining excess of
alkyl halide was removed under reduced pressure on a vacuum evaporator in 1 minute to give a
1
colorless liquid (1.95 g/h; ≥ 99% yield). H NMR (81 MHz, CDCl3) δ (ppm)= 3.74 (d, 6H, J=11.1 Hz),
1.43 (d, 3H, J=17.5 Hz); 31P NMR (200 MHz, CDCl3) δ (ppm)= 32.03; 13C NMR (50 MHz, CDCl3) δ
(ppm) = 7.77 (d, 1JPC = 144.0 Hz, P(O)CH3), 50.21 (d, 2JPC = 6.2 Hz, P(O)OCH3). 1H and 31P NMR data
were consistent with those previously reported.16
Diethyl ethylphosphonate (3b)
A mixture of triethyl phosphite (1.0 equiv.) and ethyl iodide (0.1 equiv.) was continuously pumped
through the microreactor with a flow rate of 5 µl/min. Reaction progress was monitored by 1H and 31
P
NMR as a function of residence times. After 50 min. of residence time the quantitative amount of the
desired product 3b was observed. After collecting the right fraction, the remaining excess of alkyl
halide was removed under reduced pressure on a vacuum evaporator in 1 minute to give a colorless
liquid (0.27 g/h; ≥ 99% yield).1H NMR (200 MHz, CDCl3) δ (ppm) = 4.05 (m, 4H), 1.72 (m, 2H), 1.28 (t,
6H, J = 7.1 Hz), 1.12 (dt, 3H, J = 20.3, 7.4 Hz); 31P NMR (81 MHz, CDCl3) δ (ppm) = 33.8; 13C NMR
2
3
(50 MHz, CDCl3) δ (ppm) = 5.03 (d, JPC = 6.8 Hz, P(O)CH2CH3), 14.94 (d, JPC = 5.9 Hz,
1
3
1
2xP(O)OCH2CH3), 17.25 (d, JPC = 142.7 Hz, P(O)CH2), 59,87 (d, JPC = 6.5 Hz, 2xP(O)OCH2). H
and 31P NMR data were consistent with those previously reported.17
Dibenzyl benzylphosphonate (3c)
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A mixture of tribenzyl phosphite (1.0 equiv.) and benzyl bromide (0.1 equiv.) were continuously
pumped through the microreactor with a flow rate of 10 µl/min. Reaction progress was monitored by 1H
and 31P NMR as a function of residence times. After 25 min. of residence time the quantitative amount
of the desired product 3c was observed. After collecting the desired fraction, the remaining excess of
alkyl halide was removed under reduced pressure on a vacuum evaporator in 2 minutes to give a
1
colorless oil (0.32 g/h; 90% yield). H NMR (200 MHz, CDCl3) δ (ppm) = 7.39-7.25 (m, 15H), 4.89 (d,
4H, J = 8.3 Hz), 3.16 (d, 2H, J = 21.73 Hz); 31P NMR (81 MHz, CDCl3) δ (ppm) = 27.60; 13C NMR (50
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1
2
MHz, CDCl3) δ (ppm) = 32.76 (d, JPC = 137.6 Hz, P(O)CH2, CH2), 66.34 (d, JPC = 6.7 Hz,
5
2xP(O)OCH2, CH2), 125.73 (d, JPC = 3.5 Hz, p-PhCH2P(O), CH), 126.68 (s, 4x o-PhCH2OP(O), CH),
127.10 (s, 2x p-PhCH2OP(O), CH), 127.29 (s, 4x m-PhCH2OP(O), CH), 127.33 (d, JPC = 3.9 Hz, m-
4
3
2
PhCH2P(O), CH), 128.65 (d, JPC = 6.6 Hz, o-PhCH2P(O), CH), 129.97 (d, JPC = 9.1 Hz, ipso-
PhCH2P(O), >C<), 135.10 (d, JPC = 5.8 Hz, 2x ipso-PhCH2O, >C<). H and 31P NMR data were
3
1
consistent with those previously reported.18
Diethyl methylphosphonate (3d)
A mixture of triethylphosphite (1.0 equiv.) and methyl iodide (1.0 equiv.) was continuously pumped
through the microreactor with a flow rate of 30 µl/min. Reaction progress was monitored by 1H and 31
P
NMR as a function of residence times. After 8.33 min. of residence time the quantitative amount of the
desired product 3d was observed. After collecting the desired fraction, the remaining excess of alkyl
halide was removed under reduced pressure on a vacuum evaporator in 1 minute to give a colorless
oily product (1.9 g/h; ≥ 99% yield).1H NMR (200 MHz, CDCl3) δ (ppm) = 4.16 – 3.95 (m, 4H), 1.44 (d,
3H, J = 17.4 Hz), 1.29 (t, 6H, J = 7.1 Hz); 31P NMR (81 MHz, CDCl3) δ (ppm) = 30.61; 13C NMR (50
MHz, CDCl3) δ (ppm) = 9.35 (d, 1JPC = 144.2 Hz, P(O)CH3), 14.64 (d, 3JPC = 6.1 Hz, 2xP(O)OCH2CH3),
2
1
59.61 (d, JPC = 6.1 Hz, 2xP(O)CH2). H and 31P NMR data were consistent with those previously
reported.16
Diisopropyl methylphosphonate (3e)
A mixture of triisopropyl phosphite (1.0 equiv.) and methyl iodide (1.0 equiv.) was continuously
pumped through the microreactor with a flow rate of 30 µl/min. The reaction progress was monitored
by 1H and 31P NMR as a function of residence times. After 8.33 min. of residence time the quantitative
amount of the desired product 3e was observed. After collecting the reaction mixture, the remaining
excess of alkyl halide was removed under reduced pressure on a vacuum evaporator in 1 minute to
give a product as colorless oily liquid (1.6 g/h; ≥ 99% yield). 1H NMR (200 MHz, CDCl3) δ (ppm) = 4.78
– 4.55 (m, 2H), 1.42 (d, 3H, J = 17.7 Hz), 1.29 (d, 12H, J = 6.56 Hz); 31P NMR (81 MHz, CDCl3) δ
1
(ppm) = 28.57; 13C NMR (50 MHz, CDCl3) δ (ppm) = 11.40 (d, JPC = 145.3 Hz, P(O)CH3), 22.64 (d,
3
2
1
22.64 (d, JPC = 3.4 Hz, 2xP(O)OCH(CH3)2), 68.54 (d, JPC = 6.2 Hz, 2xP(O)OCH). H and 31P NMR
data were consistent with those previously reported.19,20
Diisopropyl ethylphosphonate (3f)
A mixture of triisopropyl phosphite (1.0 equiv.) and ethyl iodide (1.5 equiv.) was continuously pumped
through the microreactor with a flow rate of 30 µl/min. The reaction progress was monitored by 1H and
31P NMR as a function of residence times. After 8.33 min. of residence time the quantitative amount of
the desired product 3f was observed. After collecting the reaction mixture, the remaining excess of
alkyl halide was removed under reduced pressure on a vacuum evaporator to give a colorless oily
product (1.7 g/h; ≥ 99% yield). 1H NMR (200 MHz, CDCl3) δ (ppm) = 4.75 – 4.55 (m, 2H), 1.80 – 1.54
(m, 2H), 1.28 (d, 2H, J = 6.1 Hz), 1.21 – 0.99 (m, 3H); 31P NMR (81 MHz, CDCl3) δ (ppm) = 31.75; 13
NMR (125 MHz, CDCl3) δ (ppm) = 6.71 (d, JPC = 6.9 Hz, P(O)CH2CH3), 19.99 (d, JPC = 143.8 Hz,
C
2
1
3
2
1
P(O)CH2), 24.03 (d, JPC = 4.1 Hz, 2xP(O)OCH(CH3)2), 69.80 (d, JPC = 6.6 Hz, 2xP(O)OCH). H and
31P NMR data were consistent with those previously reported21,22 and those predicted NMR data
calculated using Advance Chemistry Development, Inc. (ACD/Labs) Software V11.01.
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Diisopropyl n-propylphosphonate (3g)
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A mixture of triisopropyl phosphite (1.0 equiv.) and n-propyl iodide (1.5 equiv.) was continuously
pumped through the microreactor with a flow rate of 30 µl/min. Reaction progress was monitored by 1H
and 31P NMR as a function of residence times. After 8.33 min. of residence time the quantitative
amount of the desired product 3f was observed. After collecting the right fraction, the remaining
excess of alkyl halide was removed under reduced pressure on a vacuum evaporator in 1 minutes to
give a colorless oily product (1.95 g/h; ≥ 99% yield) 1H NMR (200 MHz, CDCl3) δ (ppm) = 4.76 – 4.53
(m, 2H), 1.76 – 1.46 (m, 2H), 1.28 (d, 2H, J = 6.05 Hz), 0.98 (t, 3H, J = 7.2 Hz); 31P NMR (81 MHz,
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CDCl3) δ (ppm) = 30.41; 13C NMR (50 MHz, CDCl3) δ (ppm) = 14.02 (d, JPC = 18.1 Hz,
P(O)CH2CH2CH3), 14.97 (d, 2JPC = 5.3 Hz, P(O)CH2CH2), 22.75 (d, 3JPC = 4.1 Hz, 2xP(O)OCH(CH3)2),
27.72 (d, 1JPC = 141.5 Hz, P(O)CH2), 68.42 (d, 2JPC = 6.6 Hz, 2xP(O)OCH). 1H and 31P NMR data were
consistent with those previously reported.16
Diisopropyl n-butylphosphonate (3h)
A mixture of triisopropylphosphite (1.0 equiv.) and n-butyl iodide (1.5 equiv.) was continuously pumped
through the microreactor with a flow rate of 30 µl/min. Reaction progress was monitored by 1H and 31
P
NMR as a function of residence times. After 8.33 min. of residence time the quantitative amount of the
desired product 3f was observed. After collecting the desired fraction, the remaining excess of alkyl
halide was removed under reduced pressure on a vacuum evaporator in 1 minutes to give a colorless
1
oily product (1.8 g/h; ≥ 99% yield). H NMR (200 MHz, CDCl3) δ (ppm) = 4.76 – 4.55 (m, 2H), 1.76 –
1.36 (m, 6H), 1.28 (d, 12H, J = 6.03 Hz), 0.88 (t, 3H, J = 7.2 Hz); 31P NMR (81 MHz, CDCl3) δ (ppm) =
3
30.80; 13C NMR (125 MHz, CDCl3) δ (ppm) = 13.56 (s, P(O)CH2CH2CH2CH3), 23.71 (d, JPC = 18.0
3
2
Hz, P(O)CH2CH2CH2), 24.05 (d, JPC = 4.0 Hz, 2xP(O)OCH(CH3)2), 24.60 (d, JPC = 5.3 Hz,
P(O)CH2CH2), 26.67 (d, 1JPC = 141.6 Hz, P(O)CH2), 69.76 (d, 2JPC = 6.6 Hz, 2xP(O)OCH). 1H and 31
NMR data were consistent with those previously reported.16
P
Diethyl n-propylphosphonate (3i)
A mixture of triethylphosphite (1.0 equiv.) and n-propyl iodide (10 equiv.) was continuously pumped
through the microreactor with a flow rate of 10 µl/min. Reaction progress was monitored by 1H and 31
P
NMR as a function of residence times. After 25 min. of residence time the quantitative amount of the
desired product 3i was observed. After collecting the desired fraction, the remaining excess of alkyl
halide was removed under reduced pressure on a vacuum evaporator in 1 minute to give a colorless
product (0.56 g/h; ≥ 99% yield). 1H NMR (200 MHz, CDCl3) δ (ppm) = 4.20 – 3.95 (m, 4H), 1.70 – 1.49
(m, 4H), 1.29 (t, 6H, J = 7.0 Hz), 0.99 (m, 3H); 31P NMR (81 MHz, CDCl3) δ (ppm) = 32.49; 13C NMR
(125 MHz, CDCl3) δ (ppm) = 13.66 (d, 3JPC = 17.3 Hz, P(O)CH2CH2CH3, CH3), 14.54 (d, 2JPC = 5.2 Hz,
3
1
P(O)CH2CH2CH3, CH2), 14.86 (d, JPC = 6.0 Hz, 2xP(O)OCH2CH3, CH3), 26.10 (d, JPC = 140.3 Hz,
2
1
P(O)CH2CH2CH3, CH2), 59.68 (d, JPC = 6.5 Hz, 2xP(O)OCH2CH3, CH2). H and 31P NMR data were
consistent with those previously reported.23
Dimethyl methylphosphonate (3a) (batch)
A mixture of trimethyl phosphite 1a (2.0 g, 16 mmol) and methyl iodide 2a (0.22 g, 1.6 mmol) was
1
heated at 100 °C, in Schlenk tube under argon. After 7 h the conversion of 80% was detected by H
and 31P NMR.
Diethyl ethylphosphonate (3b) (batch)
A mixture of triethyl phosphite 1b (2.0 g, 12 mmol) and ethyl iodide 2b (0.19 g, 1.2 mmol) was placed
in Schlenk tube and heated at 150 °C under argon. After 12 h the conversion of 40% was confirmed
by 1H and 31P NMR.
Dibenzyl benzylphosphonate (3c) (batch)
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A mixture of tribenzyl phosphite 1c (1.65 g, 4.6 mmol) and benzyl bromide 2c (0.08 g, 0.46 mmol) was
placed in Schlenk tube and heated at 140 °C under argon. After 7 h the conversion of 69% was
confirmed by 1H and 31P NMR.
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Supporting Information
Supporting Information available. Segmental experiment data, 1H, 31P, and 13C NMR data for all compounds are
provided. The Supporting Information is available free of charge on the ACS Publications website at DOI: xxx
Author Information
Corresponding Author
*E-mail: draj@cbmm.lodz.pl (J. Drabowicz) E-mail: ajasiak@cbmm.lodz.pl (A. Jasiak)
ORCID
Aleksandra Jasiak: 0000-0003-1570-5372
Grażyna Mielniczak: 0000-0002-0408-9722
Krzysztof Owsianik: 0000-0002-9053-3315
Marek Koprowski: 0000-0003-0122-1326
Dorota Krasowska: 0000-0002-2361-6401
Józef Drabowicz: 0000-0002-4899-5970
Acknowledgments
The project was financed by the National Science Centre (NCN), Poland on the basis of the decision
number UMO-2014/15/B/ST5/05329. We would like to thank prof. P. Kiełbasiński for helpful comments
during the preparation of this manuscript, Mr David Chambers (Queen’s University Belfast) and Prof.
Charles J. M. Stirling FRS (University of Sheffield) for reading the final version.
References and Endnotes
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