Efficient and 'green' microwave-assisted synthesis of haloalkylphosphonates via the Michaelis-Arbuzov reaction

Article abstract of DOI:10.1039/c0gc00509f

This paper deals with a novel, efficient and environmentally friendly synthesis of dialkyl haloalkylphosphonates via a microwave-assisted Michaelis-Arbuzov reaction. The approach is solventless, requires only one equivalent of each of the starting compounds, and provides high yields of pure products from which the impurities are easy to remove. The process has been optimised for batch and flow reactors and is especially profitable for the production of key intermediates in synthesis of Ethephon or acyclic nucleoside phosphonates such as adefovir, tenofovir, and cidofovir. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00509f

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PAPER
Efficient and ‘green’ microwave-assisted synthesis of haloalkylphosphonates
via the Michaelis–Arbuzov reaction†
ˇ
Petr Jansa, Anton´ın Holy´, Martin Dracˇinsky´, Ondrˇej Baszczynˇski, Michal Cesnek and Zlatko Janeba*
Received 1st September 2010, Accepted 5th January 2011
DOI: 10.1039/c0gc00509f
This paper deals with a novel, efficient and environmentally friendly synthesis of dialkyl
haloalkylphosphonates via a microwave-assisted Michaelis–Arbuzov reaction. The approach is
solventless, requires only one equivalent of each of the starting compounds, and provides high
yields of pure products from which the impurities are easy to remove. The process has been
optimised for batch and flow reactors and is especially profitable for the production of key
intermediates in synthesis of Ethephon or acyclic nucleoside phosphonates such as adefovir,
tenofovir, and cidofovir.
plant growth regulator.16,17 Ethephon was first synthesised in
Introduction
1946,18 and its enormous commercial importance is demon-
Phosphonates represent a class of stable organophosphorus
strated by the fact that 290 tons of Ethephon were used in 2005
compounds containing a single carbon-phosphorus (C–P) bond,
in California alone.19
which makes them resistant to chemical and enzymatic hydrol-
Ethephon is usually prepared by an acid hydrolysis of
ysis, thermal decomposition,1 and photolysis.2 A phosphonate
motif is present in biomolecules which can act as inhibitors of
bis(2-chloroethyl) 2-chloroethylphosphonate20 prepared by an
isomerisation of tris(2-chloroethyl) phosphite via the M–A
certain biosynthetic pathways and can be degraded only by some
reaction.21 It has been demonstrated that the isomerisation
prokaryotic microorganisms.3 The high chemical stability of
produces low yields (~55%) and the subsequent hydrolysis does
phosphonates, together with their resistance to biodegradation,
not go to completion,22 yielding Ethephon contaminated with
makes this class of compounds of particular interest for the drug
2-chloroethyl 2-chloroethylphosphonate.22 In an attempt to re-
design. This approach is particularly attractive considering that
place bis(2-chloroethyl) 2-chloroethylphosphonate, diisopropyl
phosphonic acids derivatives can be conveniently synthesised by
2-chloroethylphosphonate was prepared from triisopropyl phos-
the Michaelis–Arbuzov (M–A) reaction, discovered at the end
phite and 1,2-dichloroethane by the M–A procedure.22,23 How-
of the 19th century.4
ever, the observed yield was only 54%. The reaction was slightly
improved by the use of 1-bromo-2-chloroethane,22,23 but this
Synthetic phosphonates are now widely used as herbicides,5
stimulants of the latex production of Hevea brasiliensis,5b
reaction is not ideal for the commercial application since the
pesticides,6 detergents,7 chelating agents for di- and trivalent
yield of the M–A reaction varies with the bromochloroalkane
metals ions,8 agents that inhibit crystal growth and scale
used.24
formation,9 reagents for Wittig–Horner reactions,10 hybrid
Dialkyl tosyloxymethylphosphonate is a cornerstone in
organic-inorganic supports and catalysts,11 antiviral agents,12
the chemistry of methylphosphonates.12b Its analogue, dialkyl
agents with antitumor activity13 or as chemical weapons of
iodomethylphosphonate, is not used so often since its prepa-
mass destruction (the V-series of nerve agents).14 The latest
ration is more problematic compared to the tosyl congener.25
achievements in the structure-based design of phosphonate
It was prepared in 47% yield by the classical M–A reaction of
inhibitors have been summarised and reviewed.15
One of the most important compounds of this class is 2-
triisopropyl phosphite with methylene diiodide,25 however our
numerous attempts to reproduce this experiment afforded much
chloroethylphosphonic acid (Ethephon), the most widely used
lower yields (3–17%).
In the last decade, several attempts to accelerate the M–
A reaction by microwave irradiation were published, mostly
Institute of Organic Chemistry and Biochemistry, Academy of Sciences
using monoiodo- or monobromoalkyl derivatives as starting
material.26 To the best of our knowledge, there have been no
examples of analogous reactions starting with dichloro- or
diiodoalkanes. Only one paper deals with the application of
microwaves to the M–A reaction of dibromoalkyl derivatives
of the Czech Republic, Flemingovo na´m. 2, Prague, Czech Republic,
CZ-166 10. E-mail: janeba@uochb.cas.cz; Fax: +420 220183560;
Tel: +420 220183143
† Electronic supplementary information (ESI) available: Experimental
procedures, elemental analysis, boiling points, 1H NMR, 13C NMR, MS
and GC-MS analyses. See DOI: 10.1039/c0gc00509f
882 | Green Chem., 2011, 13, 882–888
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Table 1 The optimisation of the reaction of 1,2-dichloroethane (A) with triisopropyl phosphite (B)
Composition of the reaction mixture GC-MS (%)
Entry
Time (min)
Temp. (◦C)
Ratio A : B
B
C
D
1
E
Commentsa
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
80
80
80
80
80
80
80
80
130
150
130
150
180
200
180
200
210
200
180
200
200
200
190
190
190
180
190
190
190
190
190
190
190
190
190
190
190
190
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
10 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
3 : 1
2 : 1
1 : 1
1.2 : 1
98.7
98.6
96.0
98.2
93.0
85.2
97.3
95.5
8.6
15.5
78.1
81.2
0.0
0.0
19.5
0.0
98.9
44.2
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
1.3
1.4
4.0
1.8
3.1
3.5
2.7
4.5
28.7
20.4
21.9
18.8
3.2
5.0
1.3
3.3
1.1
1.4
2.2
2.3
3.3
3.5
23.7
3.7
5.9
8.6
10.8
12.8
14.3
2.9
0.0
0.0
0.0
0.0
3.9
11.4
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.5
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.5
1.3
2.4
2.3
a
a
a,b
a,b
a
a
a,b
a,b
a
0.0
9
15.5
10.1
0.0
46.7
54.0
0.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
a
a,b
a,b
c
0.0
0.0
13.4
13.9
5.3
12.0
0.0
1.9
10.3
8.5
0.0
0.3
73.9
0.6
13.0
22.0
11.2
13.5
15.8
15.7
83.4
81.1
73.9
84.8
0.0
52.6
87.5
89.2
8.8
d
c
e
80
c,f
c
160
160
160
160
160
160
160
160
160
160
160
160
190
c
c
0.0
87.9
85.3
0.0
82.9
15.3
0.0
1.4
0.1
4.4
0.0
c,g
c,h
c,i
c,j
c,k
c,l
a
10.9
2.4
12.8
65.8
69.5
76.1
72.3
63.1
79.1
a
a
c
For the general conditions, see the ESI† (the optimisation of the reaction of 1,2-dichloroethane with triisopropyl phosphite).a Comments: a (under
air), b (+20 eq. of toluene), c (5¥ argon-purged – see the experimental part), d (5¥ argon-purged, then opened for air and then closed), e (Entry 15
after the reaction was opened for air and then closed and treated for another 80 min.), f (+1 eq. of toluene), g (+10 eq. of xylene), h (+10 eq. of THF),
i (+10 eq. of pyridine), j (+10 eq. of diglyme), k (+10 eq. of CH3CN), l (+10 eq. of DMF). For an explanation of B, C, D, 1 and F, see Scheme 1.
under reflux,27 and obviously, such reaction conditions cannot
be used generally.
We have developed a universal approach for the preparation
of various haloalkylphosphonates. To avoid the problem of
volatility of dichloroalkanes used in the M–A reaction, a closed-
vessel mode was the logical option for such a procedure. The
Scheme 1 The synthesis of diisopropyl 2-chloroethylphosphonate (1)
general problems with the reactivity of the reagents and by-
by the reaction of 1,2-dichloroethane (A) with triisopropyl phosphite
product formation were effectively solved by means of accurate
(B), where diisopropyl phosphonate (C), triisopropyl phosphate (D)
temperature control.
and tetraisopropyl ethane-1,2-diyldiphosphonate (E) are formed as by-
products.
Results and discussion
both reaction time (80 min) and reaction temperature leads to
1. The reaction of 1,2-dichloroethane with triisopropyl
phosphite
a higher consumption of the starting material B (at 200 ◦C
◦
15.5% of B is remaining, entry 10 and at 210 C 9.1% of B is
At first, the reaction of 1,2-dichloroethane with triisopropyl
phosphite leading to an Ethephon intermediate 1 (Scheme 1),
was chosen as a test case. The overall optimisation of this
reaction is shown in Table 1. First of all, we have focused on
the effect of the reaction temperature (ReT) at constant reaction
time (20 min, entries 1, 2, 5 and 6).
remaining, entry 9), but simultaneously, the product formation
decreased (54.0% of 1, entry 10 and only 46.7% of 1, entry
9). In addition, formation of by-products was observed and
especially the elimination reaction (by-product C) is accelerated
by higher temperatures. The elimination was not observed at
180 ◦C. It should be noted that compound C can be formed
by a hydrolysis of starting compound B if the reagents are not
completely dry. The oxidation reaction (by-product D) is also
accelerated by higher temperatures (entries 9 and 10), but it can
be easily suppressed by removal of oxygen from the reaction
No product was detected in the reactions carried out at 130 ◦C
and 150 ◦C (entries 1 and 2). Some product was formed during
reactions at 180 ◦C (3.9% of 1, entry 5) and 200 ◦C (11.4%
of 1, 200 ◦C, entry 6). We have found that the increase of
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mixture (only 3.2% of D, entry 13, as compared to 20.4% of D,
entry 10). Even a short contact of the well argon-purged reaction
mixture with air leads to the increase of D formation (only 3.2%
of D, entry 13, as compared to 5.0% of D, entry 14).
To suppress elimination, the reaction temperature was de-
creased. Then however, the reaction requires a longer reaction
time (19.5% of B is remaining, 190 ◦C, 80 min, entry 15). When
the experiment (entry 15) was treated for another 80 min, total
conversion was observed (entry 16). The amount of the by-
products was significantly reduced and the yield of product
increased when the experiment was run for 160 min (87.5% of 1,
190 ◦C, entry 19, as compared to 83.4% of 1, 200 ◦C, entry 13).
Further reaction temperature decrease resulted in an extremely
slow reaction (44.2% of B is remaining, 180 ◦C, 160 min, entry
18). Thus, all subsequent experiments were conducted at 190 ◦C.
Subsequently, the effect of the A : B ratio on the reaction yield
was scrutinised. An increase of the A : B ratio leads to only
slightly higher yields (89.2%, A : B = 10 : 1, entry 20 and 87.5%,
A : B = 4 : 1, entry 19). Interestingly, lowering the A : B ratio also
leads to only slightly lower yields as well (76.1% of 1, A : B =
3 : 1, entry 27; 72.3% of 1, A : B = 2 : 1, entry 28 and 63.1% of 1,
A : B = 1 : 1, entry 29). The reaction yield was further improved
by purging the reaction mixture with dry inert gas (A : B ratio
1.2 : 1, entry 30, 79.1% of 1; the slight excess (1.2 equiv.) of
volatile A is used to compensate its loss during argon-purging).
Finally, the solvent effect was studied. The M–A reaction
is usually performed without a solvent or the corresponding
dihaloalkane can serve as a solvent. However, for some special
applications (solid starting material, scale-up) the use of solvent
could be beneficial.
The presence of toluene showed the total suppression of the
MW-assisted M–A reaction (0% of 1, entries 7, 8, 11 and 12).
The negative effect of toluene is so strong that even 1 equiv.
of toluene fully suppresses the reaction (73.9% of 1, entry 15,
compared to 0% of 1, entry 17). A number of other solvents
were scrutinised to study their effect on the reaction progress
(xylene, entry 21; THF, entry 22; pyridine, entry 23; diglyme,
entry 24; CH3CN, entry 25; DMF, entry 26). The MW-assisted
M–A reaction works well in either CH3CN (65.8% of 1, entry 25)
or DMF (69.5% of 1, entry 26). The reaction is faster in DMF
but less of by-products C and D are formed in CH3CN. Thus,
CH3CN was selected as the solvent for the further scale-up of
the M–A reactions using a continuous MW-reactor. Entries 19
and 30 were repeated on a preparative scale and diisopropyl 2-
chloroethylphosphonate (1) was isolated in 83% resp. 74% yield
(see ESI†, procedure 1.1 and 1.2).
Scheme
2
The synthesis of diisopropyl 2-(2-chloroethoxy)ethyl-
phosphonate (2) by the reaction of 2,2¢-dichlorodiethyl ether (F) with
triisopropyl phosphite (B), where diisopropyl phosphonate (C) and
triisopropyl phosphate (D) are formed as by-products.
(73%) as compared to 81% yield in procedure 2.1. A higher
proportion of the elimination reaction during the scale-up can
be explained by the higher actual MW power which is used to
reach the same temperature of larger reaction mixture volumes.
Finally, the applicability of the continuous flow MW reactor
was studied (Table 2, see the ESI†, procedure 2.3). The reaction
temperature of the experiments was elevated gradually from 120
to 210 ◦C in 10 ◦C increments every time after 45 min intervals. A
significant acceleration of the product formation starts at 170 ◦C
and the reaction proceeds well at temperatures ≥180 ◦C. This is
in agreement with the results obtained from the discontinuous
MW reactor (preparative yield of 70%). The slightly lower ReT
(180 ◦C) in the flow reactor as compared to discontinuous
reactor (190 ◦C) can be explained by the different technique
of the ReT measurement (IR sensor in the batch reactor versus
internal probe in the flow reactor).
3. The reaction of 1,2-dibromoethane with triisopropyl
phosphite
Next, the MW-assisted M–A reaction of dibromoalkanes was
studied. 1,2-Dibromoethane (G) was chosen to compare its
reactivity to that of the previously studied 1,2-dichloroethane
(A). Analogously, the reaction (Scheme 3) was carried out at
various temperatures and reaction times (Table 3).
◦
The reaction at lower temperature (130 C) required longer
reaction time and the starting compound B was completely
consumed after 120 min (entry 4, Table 3). The reaction time
is cut to 30 min at 150 ◦C with only a slightly higher content of
by-products C and D (entry 5, Table 3). Eventually, the reaction
is complete after 10 min at 170 ◦C with almost the same yield as
in the previous runs (88.7% from GC-MS, entry 6). The isolated
Table 2 The optimisation of the reaction of 2,2¢-dichlorodiethyl ether
(F) with triisopropyl phosphite (B) in a continuous MW reactor
Composition of the reaction
mixture GC-MS (%)
Sample
Temp. (◦C)
B
C
D
2
2. The reaction of 2,2¢-dichlorodiethyl ether with triisopropyl
phosphite
1
2
3
4
5
6
7
8
9
120
140
150
160
170
180
190
200
210
91.0
88.0
83.4
78.9
64.6
38.6
19.2
11.2
0.0
3.7
3.1
4.5
5.4
7.3
9.2
11.6
12.8
15.5
1.5
1.6
1.9
2.4
2.3
2.3
2.6
2.2
2.4
3.8
7.3
The above optimised reaction conditions (via entry 30, Table
1) were used to study the reaction of 2,2¢-dichlorodiethyl ether
with triisopropyl phosphite (Scheme 2). The desired product 2
was obtained in a high preparative yield (81%, see the ESI†,
procedure 2.1).
We have scrutinised the scale-up procedure again (see the
ESI†, procedure2.2) and it was found that the optimised reaction
conditions can be applied generally. The desired product 2
(Scheme 2), was obtained in a slightly lower preparative yield
10.2
13.4
25.8
50.0
66.5
73.9
82.0
For the general conditions, see the ESI† (procedure 2.3). F:B loaded in
a 1.2 : 1 ratio. For an explanation of B, C, D and 2, see Scheme 2.
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Table 3 The optimisation of the reaction of 1,2-dibromoethane (G)
with triisopropyl phosphite (B)
5. The reaction of diiodomethane with triisopropyl phosphite
To compare the reactivity of dihalomethanes in the M–A
reaction, the reaction of diiodomethane (J) with triisopropyl
phosphite (B) (Scheme 5) was studied and optimised (Table 4,
see the ESI†, procedure 5.1).
Composition of the
reaction mixture GC-MS (%)
Entry Temp. (◦C) Time (min)
B
C
D
3
E
1
2
3
4
5
6
130
130
130
130
150
170
30
60
90
120
30
10
41.5
9.7
2.5
0.0
0.7
0.0
2.6
2.1
2.9
2.7
4.0
4.4
2.0
2.5
3.3
3.8
4.9
4.4
53.4 0.4
83.8 2.0
89.0 2.3
90.5 3.1
87.3 3.0
88.7 2.5
For the general conditions, see the ESI† (procedure 3). G:B loaded in a
1.2 : 1 ratio. For an explanation of B, C, D, 3 and E, see Scheme 3.
Scheme 5 The synthesis of diisopropyl iodomethylphosphonate (5)
by the reaction of diiodomethane (J) with triisopropyl phosphite (B),
where diisopropyl phosphonate (C), triisopropyl phosphate (D) and
tetraisopropyl ethane-1,2-diyldiphosphonate (K) are formed as by-
products.
Analogously, the reactions of diiodomethane (J) with triiso-
propyl phosphite (B) were carried out at various temperatures
(80 ◦C, 90 ◦C, 100 ◦C) and reaction times (Table 4). It was found
that the reaction works well at 90 ◦C (73.5% of 5, entry 2) and
that the formation of the undesired bisphosphonate K can be
controlled by the maximum power output of the MW reactor.
While 5.3% of the by-product K was formed at max. power of
300 W (entry 2), only 1.9% of K was formed at max. power of
50 W (entry 3).
Fig. 1 demonstrates the thermal shock which leads to the
overheating of the reaction mixture during the M–A reaction
(30 ◦C jump, 30 W – model reaction, Scheme 5). The enormous
increase in the temperature leads to production of higher amount
of the corresponding bisphosphonate K, as well as higher
amount of the elimination by-product C. Moreover, the reaction
mixture is not ideally homogenous owing to the high difference
in the densities of the starting compounds. It was found that a
small amount of the desired product (5) added to the reaction
mixture helped to homogenise the reaction mixture and the
thermal shock was totally suppressed (Fig. 2).
Scheme 3 The synthesis of diisopropyl 2-bromoethylphosphonate (3)
by the reaction of 1,2-dibromoethane (G) with triisopropyl phosphite
(B), where diisopropyl phosphonate (C), triisopropyl phosphate (D)
and tetraisopropyl ethane-1,2-diyldiphosphonate (E) are formed as by-
products.
yield of product 3 was high (84%, see the ESI†, procedure 3)
although it was contaminated (<3%) with the corresponding
bisphosphonate (E).
4. The reaction of dibromomethane with triisopropyl phosphite
The mixture of dibromomethane (H) and triisopropyl phosphite
(B) was treated at 150 ◦C for 30 min (Scheme 4), without further
optimisation and the desired diisopropyl bromomethylphospho-
nate (4) was isolated in 78% yield (see the ESI†, procedure 4).
Thus, the addition of 5 leads to the suppression of the by-
products’ formation (1.9% of K, 6.4% of C, entry 3 and 0% of
K, 0.7% of C, entry 4; Table 4) and to much higher product
formation (79.3% of 5, entry 3 and 87.4% of 5, entry 4; Table 4).
Scheme 4 The synthesis of diisopropyl bromomethylphosphonate (4)
by the reaction of dibromomethane (H) with triisopropyl phosphite (B).
Table 4 The optimisation of the reaction of diiodomethane (J) with triisopropyl phosphite (B)
Composition of the reaction mixture GC-MS (%)
Entry
Time (min)
Temp. (◦C)
Ratio J : B
B
C
D
5
K
Commentsa
1
2
3
4
5
6
7
8
9
15
80
90
90
90
90
100
90
90
90
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
4 : 1
2 : 1
1 : 1
1 : 1
93.8
4.9
5.7
9.6
2.3
0.0
0.5
6.7
0.2
0.6
8.9
6.4
0.7
1.2
2.2
1.6
2.7
3.1
1.5
7.4
6.7
2.3
4.1
2.1
3.2
3.4
3.6
4.1
0.0
5.3
1.9
0.0
0.0
0.2
0.1
0.1
0.3
a
120
120
120
150
60
180
180
200
73.5
79.3
87.4
92.4
95.5
94.6
87.1
92.8
a
a,b
a,b,c
a,b,c
a,b,c
a,b,c
a,b,c
a,b,c
For the general conditions, see the ESI† (procedure 5.1). For an explanation of B, C, D, 5 and K, see Scheme 5.a Comments: a (5¥ argon-purged – see
the ESI†), b (max. power = 50 W), c (+0.03 eq. of 5).
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Finally, the scale-up procedure of the MW-assisted M–A
reaction for potential industrial application was scrutinised and
optimised (Table 5, see the ESI†, procedure 5.2).
The optimum reaction temperature (120 ◦C) observed for the
scale-up ◦was about 20–30 ◦C higher than that of the small scales
(90–100 C). The difference can be caused by slightly different
temperature reading techniques (see the ESI†). Another increase
of the reaction temperature over 120 ◦C led again to higher by-
product formation and thus to a less pure product and lower
◦
yield (87.9% of 5, 120 C, entry 5, as compared to 84.5% of 5,
130 ◦C, Entry 6).
The higher by-product formation observed for scaled-up
reactions can be explained by the higher actual MW power
which is necessary to reach the same reaction temperature in
larger volumes. Therefore, the effect of the maximum power
output was also studied in detail. It was found that a decrease of
the maximum power output led to a higher yield of the desired
product (87.9% of 5, 100 W, entry 5, as compared to 85.4% of 5,
200 W, entry 3).
Fig. 1 The reaction temperature of the model reaction – the thermal
shock during the formation of (5) via entry 2, Table 4 with constant
power (30 W).
It was also found that addition of a small amount (0.03 eq.)
of the desired product into the reaction mixture improves the
yield (85.4% of 5, with addition, entry 3, compared to 70.5% of
5, without addition, entry 4). The desired product was isolated
from entry 5 in a high yield (80%, see the ESI†, procedure 5.2).
6. The reaction of 1,2-dichloroethane with triethyl phosphite
For comparison, the reaction of 1,2-dichloroethane (A) with
triethyl phosphite (L) was carried out under two different
reaction conditions (Scheme 6, Table 6).
Fig. 2 The reaction temperature of the model reaction – no thermal
shock during the formation of (5) after the addition of 0.03 eq. of (5)
into the reaction mixture. Entry 4, Table 4 with constant power (30 W).
The elevation of the reaction temperature (100 ◦C, Entry 6)
reduced the reaction time (60 min) and gave the best yield of
product 5 (95.5%), but slightly more bisphosphonate K was
formed.
In addition, the effect of the J : B ratio on the yields of the
M–A reaction of diiodomethane was studied. It was shown
that decreasing the J : B ratio does not dramatically affect the
reaction yield (entries 7, 8 and 9; Table 4) but a longer reaction
time is required to reach full conversion in the case of an
equimolar ratio of the starting compounds (entry 9). Entry 9
was repeated on the preparative scale and the desired product
was obtained in 86% yield (see the ESI†, procedure 5.1).
Scheme 6 The synthesis of diethyl 2-chloroethylphosphonate (6) by
the reaction of 1,2-dichloroethane (A) with triethyl phosphite (L), where
diethyl phosphonate (M), triethyl phosphate (N), tetraethyl ethane-1,2-
diyldiphosphonate (O) and diethyl ethylphosphonate (P) are formed as
by-products.
While the reaction was slow at 170 ◦C (entry 1, Table 6),
the reaction at 190 ◦C was completed in 120 min (entry 2) and
the corresponding product 6 was formed in 77.3% yield. In this
experiment, diethyl ethylphosphonate (P) was formed in 15.5%
Table 5 The optimisation of the scale-up reaction of diiodomethane (J) with triisopropyl phosphite (B)
Composition of the reaction mixture GC-MS (%)
Entry
Max. power (W)
Temp. (◦C)
Ratio J : B
B
C
D
5
K
Commentsa
1
2
3
4
5
6
200
200
200
200
100
100
100
110
120
120
120
130
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
51.2
12.5
0.0
0.0
0.0
1.5
2.3
4.1
10.4
3.8
4.8
3.2
4.6
6.0
11.4
6.2
5.2
43.9
80.1
85.4
70.5
87.9
84.5
0.2
0.5
4.5
7.7
2.1
5.5
a,b
a,b
a,b
a
a,b
a,b
0.0
For the general conditions, see the ESI† (procedure 5.2). For an explanation of B, C, D, 5 and K, see Scheme 5.a Comments: a (5¥ argon-purged – see
the ESI†), b (+0.03 eq. of 5).
886 | Green Chem., 2011, 13, 882–888
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Table 6 The optimisation of the reaction of 1.2-dichloroethane (A) with triethyl phosphite (L)
Composition of the reaction mixture GC-MS (%)
Entry
Time (min)
Temp. (◦C)
Ratio A : L
L
M
N
6
O
P
1
2
60
120
170
190
4 : 1
4 : 1
85.1
0.0
0.0
1.0
0.3
2.9
14.1
77.3
0.5
3.3
0.3
15.5
For the general conditions, see the ESI† (procedure 6). For an explanation of A, L, M, N, 6, O and P, see Scheme 6.
yield. This new type of by-product P is formed by the M–A
reaction of triethyl phosphite with chloroethane formed during
the process. The by-product P was not detected in the case of
the M–A reaction with triisopropyl phosphite. This finding can
be explained by the fact that 2-chloropropane (formed from
triisopropyl phosphite) is a much worse substrate for the M–
A reaction than chloroethane (formed from triethyl phosphite).
Thus, the use of triisopropyl phosphite for the MW-assisted
M–A reaction is clearly preferable to use of triethyl phosphite.
Entry 1 was repeated on the preparative scale and diethyl 2-
chloroethylphosphonate (6) was isolated in 62% yield (see the
ESI†, procedure 6).
iodoethylphosphonate (8, Scheme 8). The compound 8 was
prepared in 88% yield by the Finkelstein reaction starting
from diisopropyl 2-chloroethylphosphonate (1) (see the ESI†,
procedure 8). This alternative to the M–A reaction was chosen
on account of the high price of 1,2-diiodoethane.
Scheme 8 The synthesis of diisopropyl 2-iodoethylphosphonate (8) by
the reaction of diisopropyl 2-chloroethylphosphonate (1) with sodium
iodide.
7. The MW heating of the reaction mixture containing
dibromomethane and tris(2-chloroethyl) phosphite
Finally, to prove the universal applicability of the MW-
assisted Michaelis–Arbuzov reaction, another MW instrument
was used. The above reaction was carried out in the MW-
syntheses instrument Type II (see the ESI†) according to the
procedures 1.1 and 5.1 and practically the same compositions of
the reaction mixtures were observed. The slightly longer reaction
times used to reach the same conversion can be explained by
the efficiency of MW heating. The MW-syntheses instrument
Type I issues focused MW heating, as compared to Type II with
unfocused MW heating. For the same maximum power output,
the real absorbed MW power is lower for Type II resulting in
longer reaction times.
Previous results indicated that the reactions using more reactive
bromoalkanes are initiated at lower temperature (130 ◦C)
compared to those using the chloroalkanes (180 ◦C). For
this reason, we have studied a reaction of dibromomethane
(H) with tris(2-chloroethyl) phosphite (Q) under the MW
conditions (Scheme 7). The optimised M–A reaction conditions
for the preparation of diisopropyl 2-bromoethylphosphonate (3)
and diisopropyl bromomethylphosphonate (4) were used and
the formation of bis(2-chloroethyl) 2-chloroethylphosphonate
(7) as the only product was observed. Bis(2-chloroethyl) 2-
chloroethylphosphonate (7) was isolated in 83% yield (see the
ESI†, procedure 7). This result indicates that under MW condi-
tions the intramolecular M–A reaction of phosphorus atom with
chloroethyl substituent is even faster than the intermolecular M–
A reaction with dibromomethane.
Conclusions
The selective formation of the desired dialkyl haloalkylphos-
phonates by the microwave-assisted M–A reactions of di-
haloalkanes can be reached very effectively by the accurate
control of the reaction temperature. The selective substitution
of only one halogen atom performed well at 180–190 ◦C for
dichloroalkanes, at 130–170 ◦C for dibromoalkanes, and at 90–
100 ◦C for diiodoalkanes. The problem of the reaction mixture
homogeneity was solved by the addition of a small amount
(0.03 eq.) of the desired product into the reaction mixture.
Surprisingly, the selectivity for the monosubstitution by M–
A reaction is also preserved in the case of dihaloalkanes with
five carbon atoms between the two halogen atoms, where the
steric effects cannot play a significant role. We can speculate
that this phenomenon is caused by much higher absorption of
microwave irradiation by dihaloalkanes compared to dialkyl
haloalkylphosphonates and/or by the different absorption by
the corresponding transition states formed during the M–A
reaction. Thus, under the MW-assisted conditions, the reactivity
of the halogen atom would be higher in dihaloalkanes compared
to dialkyl haloalkylphosphonates.
Scheme
7
The
formation
of
bis(2-chloroethyl)
2-
chloroethylphosphonate (7) by the MW heating of the reaction
mixture containing dibromomethane (H) and tris(2-chloroethyl)
phosphite (Q).
8. The preparation of diisopropyl 2-iodoethylphosphonate
To complete the series of 2-haloalkylphosphonates, an al-
ternative pathway was used to prepare diisopropyl 2-
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Watkins, A. Ray, R. Shibata, G. Birkus, T. Cihlar, S. Wu, B. Li, X.
Liu, I. N. Henne, G. H. I. Wolfgang, M. Desai, G. R. Rhodes, A.
Fridland, W. A. Lee, W. Plunkett, D. Vail, D. H. Thamm, R. Jeraj
and D. B. Tumas, Clin. Cancer Res., 2008, 14, 2824.
Acknowledgements
This study was performed as a part of Research Project Z4055
0506 of the Institute of Organic Chemistry and Biochemistry. It
was supported by the Grant Agency of the Academy of Sciences
of the Czech Republic through Project KJB400550903, by the
Centre of New Antivirals and Antineoplastics 1M0508, by the
Ministry of Education, Youth and Sports of the Czech Republic
and by the Gilead Sciences and IOCB Research Centre.
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