Dialkylation of diethyl ethoxycarbonylmethylphosphonate under microwave and solventless conditions

Article abstract of DOI:10.1002/hc.21142

To further broaden the methods for the heterogeneous phase alkylation of CH acidic compounds, the dialkylation of diethyl ethoxycarbonylmethylphosphonate was studied in the presence of Cs₂CO₃ under microwave and solvent-free conditio

Full text of DOI:10.1002/hc.21142

Heteroatom Chemistry
Volume 25, Number 2, 2014
Dialkylation of Diethyl
Ethoxycarbonylmethylphosphonate under
Microwave and Solventless Conditions
Alajos Gru¨n,1 Zso´fia Blastik,1 La´szlo´ Drahos,2 and Gyo¨rgy Keglevich1
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521, Budapest, Hungary
2Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1525, Budapest, Hungary
Received 6 September 2013; revised 17 December 2013
known [1,2]. A more developed version is the dialky-
ABSTRACT: To further broaden the methods for the
lation under the conditions of phase-transfer catal-
heterogeneous phase alkylation of CH acidic com-
ysis (PTC). The few examples described in the liter-
pounds, the dialkylation of diethyl ethoxycarbonyl-
ature comprise liquid–liquid (L–L) and solid–liquid
methylphosphonate was studied in the presence of
(S–L) accomplishments. In the L–L two-phase alky-
Cs2CO3 under microwave and solvent-free conditions.
lations, aqueous sodium hydroxide was the base and
It was found that after repeating the alkylations by
dichloromethane [3] or chloroform [4], the solvent.
the addition of newer portions of the alkylating agent
The S–L alkylations applied K2CO3 base in toluene
and the base on a few occasions, the dialkylation was
[5], acetonitrile [6], or dimethylformamide [7] as
quite efficient. Even dialkyl derivatives with different
the reaction medium. In the above cases, quaternary
alkyl groups could be synthesized. The presence of a
ammonium salts (Bu4NX and triethylbenzylammo-
phase-transfer catalyst was harmful, as prevented the
nium chloride, i.e., TEBAC) or 18-crown-6 served as
ꢀC
formation of the dialkyl products. 2014 Wiley Pe-
the catalyst. The “homo” dialkylated products were
isolated in yields of 68%–96%.
riodicals, Inc. Heteroatom Chem. 25:107–113, 2014;
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.21142
Regarding the dialkylation of P-functionalized
CH acidic compounds, mostly, ethoxycarbonyl-
methylphosphonate was the starting material. It was
dialkylated in two steps, applying potassium in xy-
lene [8], or in benzene [9]. Using different alkyl
halides, the yields were variable (54%–75%). It was
also an option to use sodium hydride as the base in
tetrahydrofuran [10, 11] or in 1,2-dimethoxyethane
[12]. In most cases, the mixtures of the mono- and di-
alkylated products were formed. Only one example
is known for phase-transfer catalyzed dialkylation,
which is the dialkylation of ethyl cyanomethylphos-
phonate with methyl and ethyl iodide, as well as
allyl and benzyl halides in the presence of TEBAC
and aqueous NaOH to afford the dialkylphospho-
nate derivatives in yields of 46%–88% [13].
INTRODUCTION
The dialkylation of simple CH acidic compounds by
the classical method of generating the anion with
sodium ethylate in ethanol and reacting it with an
alkyl halide followed by the repetition of this proce-
dure with the same or another alkyl halide is well
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
The combination of PTC [14] with microwave
(MW) [15–17] may offer additional advantages [18].
Contract grant number: OTKA No K83118.
ꢀC
2014 Wiley Periodicals, Inc.
107

108 Gru¨n et al.
MW
T, 3 h
Cs2CO3 (2 equiv.)
O
O
O
O
O
O
P(OEt)2
OEt
P(OEt)2
P(OEt)2
Et
Et
+
Et
+
EtI
No solvent
C
C
OEt
C
OEt
(1.2–5 equiv.)
1
2a
3a
SCHEME 1 The ethylation of ethoxycarbonylmethylphosphonate.
This was the case also within a few alkylations of
CH acidic compounds [19, 20]. Recently, we have
studied the effect of MW and PTC on the alkylation
of a variety of CH acidic compounds in detail [21].
We found that diethyl malonate, ethyl acetoacetate,
and ethyl cianoacetate could be alkylated efficiently
under MW and solvent-free conditions in the pres-
ence of K2CO3 and in the absence of a phase-transfer
catalyst [22, 23]. It means that MW irradiation sub-
stituted the catalyst. A similar situation was experi-
enced for the ethylation of tetraethyl methylenebis-
phosphonate using Cs2CO3 [24], for the alkylation of
ethoxycarbonylmethylphosphonate [25], and for the
alkylation of diethyl cyanomethylphosphonate [26].
Tetraphenylmethylene(bisphosphine oxide), which
is a hindered model, underwent alkylations in the
presence of 5% of TEBAC in acetonitrile solution
using Cs2CO3 [26].
ter a reaction time of 2 h. The monoethylated prod-
uct (2a) predominated over the diethyl species (3a)
formed in 83% and 6%, respectively (Table 1, entry
1). Remaining at 120◦C, but using 3 equiv. of ethyl
iodide and 2 equiv. of Cs2CO3, the ratio of products
2a and 3a was 58:42 after 3 h (Table 1, entry 2).
The increase of the temperature to 140◦C had prac-
tically no effect on the product ratio (Table 1, entry
3). Returning to 120◦C, but measuring in 5 equiv.
of ethyl iodide resulted in a slight increase in the
proportion of the diethylated product (3a) that was
found 48% (Table 1, entry 4). One can see that vary-
ing the different parameters, a maximum amount of
only approximately 48% of the diethyl species (3a)
can be attained.
Hence, in the next experiments, a multistep ap-
proach was followed as shown in Scheme 2 and
Table 2. The first step was performed as shown
by the experiment specified by Table 1, entry 1.
The reaction mixture was then diluted with ethyl
acetate, and the solid components were removed
by filtration. The filtrate was concentrated and re-
acted further with a second portion (2 equiv.) of
ethyl iodide in the presence of 1.5 equiv. of Cs2CO3
at 120◦C for 2 h. After the second ethylation, the
ratio of the monoethyl and diethyl product (3a)
was 41%–59% (Table 2, entry 1, step 2). Repeat-
ing the procedure twice, the proportion of the di-
ethyl compound (3a) was, in order, 91% and 98%
(Table 2, entry 1, steps 3 and 4). Column chromatog-
raphy afforded the final product (3a) in a yield of
64%.
Then, the procedure elaborated was applied for
the preparation of the dipropyl product 3b (Table 2,
entries 2 and 3). Applying propyl bromide and propyl
iodide, the proportion of the dipropyl species (3b)
was 61% and 70%, respectively, after the fourth alky-
lation (Table 2, entry 2, step 4 and Table 2, entry 3,
step 4). Chromatography furnished product 3b in
29/41% yields.
The dibutylation was also performed (Table 2,
entries 4 and 5). The final outcome was more
modest with butyl bromide than with butyl iodide;
in the fourth step, product 3c was obtained in 36%
and 76%, respectively (Table 2, entry 4, step 4 and
Table 2, entry 5, step 4). The preparative yield of
In this paper, we wished to extend our study
to the dialkylation of a P O-functionalized CH
acidic compound, that is, diethyl ethoxycarbonyl-
methylphosphonate, investigating the role of the
MW and PTC techniques.
RESULTS AND DISCUSSION
First, we wished to study how the outcome of
the ethylations of ethoxycarbonylmethylphospho-
nate (1) may be influenced by the molar ratios and
the temperature (Scheme 1, Table 1). Working at
120◦C in the presence of 1.2 equiv. of ethyl iodide
and 1 equiv. of Cs2CO3, the conversion was 89% af-
TABLE 1 The Alkylation of Ethoxycarbonylmethylphospho-
nate (1) under Different Conditions
Product Ratio (%)a
Entry
EtI (equivalent)
T (◦C)
2a
3a
Other
c
1
2
3
4
1.2
3
3
120b
120
140
120
83
58
60
52
6
42
40
48
5
aOn the basis GC.
bCs2CO3: 1 equivalent; reaction time: 2 h.
cStarting material (1): 11%.
Heteroatom Chemistry DOI 10.1002/hc

Dialkylation of Diethyl Ethoxycarbonylmethylphosphonate under Microwave Conditions 109
1) MW
120°C, 2 h
RX (1.2 equiv.), Cs2CO3 (1 equiv.)
No solvent
O
O
O
O
O
O
P(OEt)2
OEt
P(OEt)2
P(OEt)2
R
R
R
+
2–4) MW
C
C
OEt
C
OEt
120°C, 2 h
RX (2 equiv.), Cs2CO3 (1.5 equiv.)
No solvent
1
2
3
R = Et (a), Pr (b), Bu (c)
RX = EtI, PrBr, PrI, BuBr, BuI
SCHEME 2 The alkylation/dialkylation of ethoxycarbonylmethylphosphonate.
dibutyl compound 3c was 48% in respect of the last
experiment.
It can be seen that the four-step procedure is
suitable to “enrich” the content of the dialkyl ethoxy-
carbonylmethylphosphonate (3a–c) to an extent of
70%–98%.
The three products (3a–c) were characterized by
31P, 13C, and 1H nuclear magnetic resonance (NMR),
as well as high-resolution mass spectrometry (HR-
MS).
Comparative thermal experiments were also car-
ried out for the four-step alkylation with propyl io-
dide. It can be seen that after the fourth step, the
proportion of the dialkylated product (3b) was some-
what lower and, at the same time, that of the by-
products was somewhat higher as compared with
the MW variation (Table 2, entries 6 vs. 3 in respect
of step 4).
In the next part of our work, we investigated
the effect of a phase-transfer catalyst, such as
TEBAC or tetrabutylammonium bromide (TBAB)
(Scheme 3, Table 3). Using 10% of TEBAC, the rel-
ative proportion of the monoethyl product (2a) de-
creased from 83% to 75%, while that of the start-
ing material (1) and diethyl product (3a) remained
almost unchanged (11/8% and 6/7%, respectively).
A total of 10% of unidentified by-products also ap-
peared in the mixture (Table 2, entry 1, step 1 vs.
Table 3, entry 1, step 1). After the second ethylation,
the ratio of 2a and 3a was 62:21 (Table 3, entry 1,
TABLE 2 MW-Assisted Dialkylation of Ethoxycarbonylmethylphosphonate 1 by a Four-Step Alkylation Fashion
Composition (%)a
Entry
1
Step
RX
EtI
EtI
EtI
EtI
Equivalent
Cs2CO3 (equivalent)
1
2
3
Other
Yield of 3 (%)
64 (3a)
1
2
3
4
1.2
2
2
1
11
–
–
83 (2a)
41 (2a)
9 (2a)
6 (3a)
59 (3a)
91 (3a)
98 (3a)
1.5
1.5
1.5
2
–
2 (2a)
2
1
2
3
4
PrBr
PrBr
PrBr
PrBr
1.2
2
2
1
10
–
–
81 (2b)
62 (2b)
41 (2b)
29 (2b)
4 (3b)
33 (3b)
51 (3b)
61 (3b)
5
5
8
29 (3b)
41 (3b)
1.5
1.5
1.5
2
–
10
3
1
2
3
4
PrI
PrI
PrI
PrI
1.2
2
2
1
12
–
–
77 (2b)
64 (2b)
32 (2b)
16 (2b)
3 (3b)
27 (3b)
55 (3b)
70 (3b)
8
9
13
14
1.5
1.5
1.5
2
–
4
1
2
3
4
BuBr
BuBr
BuBr
BuBr
1.2
2
2
1
14
–
–
79 (2c)
73 (2c)
66 (2c)
55 (2c)
3 (3c)
19 (3c)
26 (3c)
36 (3c)
4
8
8
9
1.5
1.5
1.5
2
–
5
1
2
3
4
BuI
BuI
BuI
BuI
1.2
2
2
1
14
–
–
77 (2c)
67 (2c)
29 (2c)
13 (2c)
5 (3c)
27 (3c)
62 (3c)
76 (3c)
4
6
9
48 (3c)
1.5
1.5
1.5
2
–
11
6b
1
2
3
4
PrI
PrI
PrI
PrI
1.2
2
2
1
12
–
–
72 (2b)
62 (2b)
28 (2b)
17 (2b)
3 (3b)
20 (3b)
49 (3b)
59 (3b)
13
18
23
24
1.5
1.5
1.5
2
–
aOn the basis GC.
bComparative thermal experiments.
Heteroatom Chemistry DOI 10.1002/hc

110 Gru¨n et al.
O
O
O
P(OEt)2
P(OEt)2
Et
Et
Et
+
+
+
+
1) MW
120°C, 2 h
C
OEt
C
OEt
O
O
O
O
EtI (1.2 equiv.), M2CO3 (1 equiv.)
PTC (0.1 equiv.) No solvent
P(OEt)2
OEt
2a
3a
2) MW
120°C, 2 h
EtI (2 equiv.), M2CO3 (1.5 equiv.)
PTC (0.1 equiv.) No solvent
OEt
OEt
OEt
O
O
O
C
P
C
4
Et
P
C
Bn
Bn
P
C
Bn
OEt
OEt
OEt
OEt
OEt
OEt
1
Bn
O
O
M = K, Cs
5d
6
SCHEME 3 The ethylation of ethoxycarbonylmethylphosphonate in the presence of a phase transfer catalyst.
step 2), while in the absence of TEBAC, this ratio was
41:59 (Table 2, entry 1, step 2). Moreover, the pro-
portion of the by-products amounted to 17% when
TEBAC was used (Table 3, entry 1, step 2). It can
be concluded that the presence of the phase-transfer
catalyst disfavored the formation of the monoethyl
compound 2a in the first step and that of the di-
ethyl species 3a, to a higher extent, in the second
step. The by-products were identified as the benzyl,
benzyl–ethyl, and the dibenzyl compounds formu-
lated as 4, 5d, and 6, respectively. Their formation
suggested that TEBAC also took part in the reaction
as an alkylating agent. Quaternary onium salts may
act, or may be used as alkylating agents [27]. Struc-
ture of the C-benzyl by-products (4, 5d, and 6) was
supported by 31P NMR and HR-MS.
Finally, we aimed at the synthesis dialkylated
ethoxycarbonylmethylphosphonates with two differ-
ent alkyl groups. Our previous protocol was followed
as shown in Scheme 2 and Table 2, with the differ-
ence that in the first step, propyl iodide, butyl iodide,
or benzyl bromide was used, while, in all cases, ethyl
iodide was applied in the second, third, and fourth
alkylation steps (Scheme 4, Table 4). In all instances,
by-products up to 26% appeared in the mixtures.
Proportion of the ethyl–propyl product (5b) was 74%
after the fourth alkylation step, which was isolated in
a yield of 39% by column chromatography (Table 4,
entry 1, step 4). The ethyl–butyl and ethyl–benzyl
compounds (5c and 5d) were obtained in similar
proportions and yields (Table 4, entry 2 step 4 and
entry 3 step 3).
Carrying out the two-step ethylation in the pres-
ence of K2CO3 as the base, proportion of the diethyl
product (3a) was even lower (10%) and proportion of
the by-products was 20% (Table 3, entry 2, step 2). It
is confirmed that the presence of TEBAC as a phase-
transfer catalyst is harmful in the MW-assisted di-
ethylation of ethoxycarbonylmethylphosphonate 1.
However the use of 10% of TBAB did not pre-
vent so much the formation of the diethyl compound
(3a), as, in this case, after the second ethylation,
the proportion of 3a was 43% (Table 3, entry 3,
step 2).
5b, 5c, and 5d are new compounds that were
1
characterized by 31P, 13C, and H NMR, as well as
HR-MS.
It can be said that mixed dialkylated products
(5b–d) could also be prepared by the three- or four-
step MW-assisted, solvent-free alkylation.
In summary, a multistep MW-assisted, solvent-
and catalyst-free method was elaborated for the
synthesis of dialkyl ethoxycarbonylmethylphospho-
nates with identical or mixed alkyl groups. The prod-
ucts with two different alkyl groups are of special
importance. The method developed completes well
TABLE 3 Two-Step Ethylation of Ethoxycarbonylmethylphosphonate 1 under MW Conditions in the Presence of a Phase-
Transfer Catalyst
Composition (%)a
Entry
1
Step
PTC
M2CO3
Equivalent
1
2a
3a
Otherb
1
2
TEBAC
TEBAC
Cs2CO3
Cs2CO3
1
1.5
8
–
75
62
7
21
10
17
2
3
1
2
TEBAC
TEBAC
K2CO3
K2CO3
1
1.5
21
–
68
70
1
10
9
20
1
2
TBAB
TBAB
Cs2CO3
Cs2CO3
1
1.5
–
–
75
57
25
43
–
–
aOn the basis of GC.
bC-benzyl- product (4, 5d, and 6).
Heteroatom Chemistry DOI 10.1002/hc

Dialkylation of Diethyl Ethoxycarbonylmethylphosphonate under Microwave Conditions 111
1) MW
120°C, 2 h
O
O
O
O
O
O
RX (1.2 equiv.), Cs2CO3 (1 equiv.)
No solvent
P(OEt)2
OEt
P(OEt)2
P(OEt)2
R
R
+
2–4) MW
Et
C
C
OEt
C
OEt
120°C, 2 h
EtI (2 equiv.), Cs2CO3 (1.5 equiv.)
No solvent
1
2
5
R = Pr (b), Bu (c), Bn (d)
RX = PrI, BuI, BnBr
SCHEME 4
the earlier procedures and offers the advantage
of using an up-to-date approach comprising MW
irradiation without a solvent and phase-transfer
catalyst.
sium carbonate (0.65 g; 1.8 mmol) were measured
in a tube that was placed in the MW reactor and
was irradiated under pressure control at 50 W at
120◦C for 3 h. Then the mixture was taken up in
10 mL of ethyl acetate, the resulting suspension was
filtered, and the filtrate was concentrated in vac-
uum. The residue so obtained contained 52% of
the monoethyl compound (2a) and 48% of the di-
ethyl species (3a) according to gas chromatography
(GC).
EXPERIMENTAL
General
The 31P, 13C, and 1H NMR spectra were obtained
on a Bruker DRX-500 spectrometer (Bruker Corp.
Billerica, MA, USA) operating at 202.4, 125.7, and
500 MHz, respectively. Chemical shifts are down-
field relative to 85% H3PO4 or tetramethylsilane.
The couplings are given in Hz. Mass spectrome-
try was performed on a Q-TOF Premier mass spec-
trometer (Waters Corp., Milford, MA, USA) in pos-
itive electrospray mode. The MW-assisted reactions
were carried out in a CEM Discover MW reactor
(CEM, Microwave Technology Ltd., Buckingham,
UK) equipped with a pressure controller using ca.
50 W irradiation.
General Procedure for the Multiple-Step
Dialkylation of Diethyl
Ethoxycarbonylmethylphosphonate under MW
Conditions
First step: 0.20 g (0.89 mmol) of ethoxycarbonyl-
methylphosphonate 1, 1.1 mmol of alkyl halide
(ethyl iodide: 0.09 mL, n-propyl bromide: 0.10 mL, n-
propyl iodide: 0.10 mL, n-butyl bromide: 0.12 mL, n-
butyl iodide: 0.12 mL, benzyl chloride: 0.13 mL, and
benzyl bromide: 0.13 mL), and 0.32 g (0.89 mmol)
of Cs2CO3 were measured in a tube that was placed
in the MW reactor and was irradiated under pres-
sure control at 50 W at 120◦C for 2 h. Then the
mixture was taken up in 10 mL of ethyl acetate, the
resulting suspension was filtered, and the filtrate was
One-Step Diethylation of Diethyl
Ethoxycarbonylmethylphosphonate (1) under
MW Conditions (Table 1, entry 4)
Ethoxycarbonylmethylphosphonate 1, (0.20 g; 0.89
mmol), ethyl iodide (0.36 mL; 4.5 mmol), and ce-
TABLE 4 MW-Assisted Dialkylation of Ethoxycarbonylmethylphosphonate 1 in a Four-Step Fashion
Composition (%)a
Entry
1
Step
RX
PrI
EtI
EtI
EtI
Equivalent
Cs2CO3 (Equivalent)
1
2
5
Other
Yield of 5 (%)
39 (5b)
1
2
3
4
1.2
2
2
1
12
–
–
77 (2b)
37 (2b)
16 (2b)
1 (2b)
–
11
20
25
25
1.5
1.5
1.5
43 (5b)
59 (5b)
74 (5b)
2
–
2
3
1
2
3
4
1b
2
BuBr
EtI
EtI
1.2
2
2
1
14
–
–
79 (2c)
51 (2c)
25 (2c)
6 (2c)
–
7
23
25
23
36 (5c)
40 (5d)
1.5
1.5
1.5
26 (5c)
50 (5c)
71 (5c)
EtI
2
–
BnBr
EtI
EtI
1.2
2
2
1
1.5
1.5
–
–
–
75 (2d)
21 (2d)
–
–
25
26
26
53 (5d)
74 (5d)
3
aOn the basis of GC.
bPurified by column chromatography.
Heteroatom Chemistry DOI 10.1002/hc

112 Gru¨n et al.
concentrated in vacuum. The residue so obtained
was analyzed by GC.
The mixed alkyl products (5b–d) were also pre-
pared by the general procedure.
Next steps: According to the quantity of the prod-
uct of previous step, 2 equiv. alkyl halide (ethyl io-
dide, n-propyl bromide, n-propyl iodide, n-butyl bro-
mide, n-butyl iodide, and 1.5 equiv. Cs2CO3 were
measured in a tube that was irradiated as in the
previous case. Then the mixture was taken up in
10 mL of ethyl acetate, the resulting suspension was
filtered, and the filtrate was concentrated in vacuum.
The residue so obtained was analyzed by GC. The
residue of the last step was purified by column chro-
matography (hexane–ethyl acetate 6:4, silica gel) to
give the products as colorless oils (see Table 2).
Diethyl
1-ethyl-1-(ethoxycarbonyl)butylphos-
phonate (5b). Yield: 39%, 31P NMR (CDCl3) δ: 26.4;
13C NMR (CDCl3) δ: 9.3 (d, J = 7.4, OCH2CH3), 14.1
(s, CH2CH3), 14.6 (s, CH2CH2CH3), 16.4 (d, J = 5.9,
POCH2CH3), 17.9 (d, J = 7.4, CH2CH2CH3), 25.2
(d, J = 3.7, CCH2), 34.0 (d, J = 3.6, CCH2), 52.8 (d,
J = 133.6, PCC), 61.0 (s, OCH2), 62.3 (d, J = 7.2,
POCH2), 171.4 (d, J = 3.0, C O); 1H NMR (CDCl3) δ:
0.92 (t, 3H, J = 7.5, CH3), 0.98 (t, 3H, J = 7.4, CH3),
1.34–1.26 (m, 9H + 1H, CH2, CH3), 1.51–1.43 (m,
1H, CH2), 1.98–1.80 (m, 2H + 2H, CH2), 4.24–4.10
Diethyl
1-ethyl-1-(ethoxycarbonyl)propylphos-
(m, 6H, OCH2); HR-MS, (M + H)+
= 295.1673,
found
phonate (3a). Yield: 64%, 31P NMR (CDCl3) δ: 27.3;
13C NMR (CDCl3) δ: 9.3 (d, J = 7.5, CCH2CH3), 14.2
(s, OCH2CH3), 16.5 (d, J = 5.9, POCH2CH3), 24.8
(d, J = 3.6, CCH2CH3), 53.1 (d, J = 133.9, PCC),
61.1 (s, OCH2), 62.4 (d, J = 7.2, POCH2), 171.4 (d,
C13H28O5P requires 295.1674, (M + Na)+
=
found
317.1492, C13H27O5PNa requires 317.1494.
Diethyl
1-ethyl-1-(ethoxycarbonyl)pentylphos-
1
J = 3.1, C O); H NMR (CDCl3) δ: 0.98 (t, 6H, J =
phonate (5c). Yield: 36%, 31P NMR (CDCl3) δ: 26.4;
13C NMR (CDCl3) δ: 9.4 (d, J = 7.2, CCH2CH3),
13.9 (s, CH2CH2CH3), 14.1 (s, OCH2CH3), 16.5 (d,
J = 5.9, POCH2CH3), 23.3 (s, CH2), 25.2 (d, J =
3.7, CH2), 26.7 (d, J = 7.3, CCH2CH3), 31.5 (d, J =
3.6, CH2), 52.7 (d, J = 133.5, PCC), 61.1 (s, OCH2),
62.4 (d, J = 7.2, POCH2), 171.5 (d, J = 3.1, C O);
1H NMR (CDCl3) δ: 0.91 (t, 3H, J = 6.8, CH3),
0.99 (t, 3H, J = 7.4, CH3), 1.45–1.26 (m, 9H + 4H,
CH2, CH3), 2.17–1.82 (m, 4H, CH2), 4.24–4.10 (m,
7.4, CH3), 1.34–1.26 (m, 6H + 3H, CH3), 2.04–1.89
(m, 4H, CH2), 4.25–4.10 (m, 6H, CH2); HR-MS,
(M + H)+
= 281.1520, C12H25O5P requires
found
281.1518, (M + Na)+
= 303.1341, C12H24O5PNa
found
requires 303.1337.
Diethyl
1-propyl-1-(ethoxycarbonyl)butylphos-
phonate (3b). Yield: 41%, 31P NMR (CDCl3) δ: 27.1;
13C NMR (CDCl3) δ: 14.1 (s, OCH2CH3), 14.7 (s,
CH2CH2CH3), 16.5 (d, J = 5.9, POCH2CH3), 18.1
(d, J = 7.3, CH2), 34.5 (d, J = 3.7, CH2), 52.6 (d,
J = 133.4, PCC), 61.1 (s, OCH2), 62.4 (d, J = 7.2,
6H, OCH2); HR-MS, (M + H)+
= 309.1832,
found
C14H30O5P requires 309.1831, (M + Na)+
=
found
331.1654, C14H29O5PNa requires 331.1650.
1
POCH2), 171.5 (d, J = 3.1, C O); H NMR (CDCl3)
δ: 0.92 (t, 6H, J = 7.3, CH3), 1.34–1.26 (m, 9H +
2H, CH2, CH3), 1.51–1.37 (m, 2H, CH2), 1.94–1.76
(m, 4H, CH2), 4.24–4.10 (m, 6H, OCH2); HR-MS,
Diethyl
1-benzyl-1-(ethoxycarbonyl)propyl-
(M + H)+
= 309.1830, C14H30O5P requires
phosphonate (5d). Yield: 40%, 31P NMR (CDCl3)
δ: 25.5; 13C NMR (CDCl3) δ: 10.4 (d, J = 4.5,
CCH2CH3), 14.3 (s, COCH2CH3), 16.6 (d, J = 5.9,
POCH2CH3), 16.7 (d, J = 5.9, POCH2CH3), 25.8
(d, J = 3.4, CCH2CH3), 39.6 (d, J = 3.6, CCH2Ar),
54.4 (d, J = 134.9, PCC), 61.4 (s, COCH2), 62.5 (d,
J = 7.1, POCH2), 62.8 (d, J = 7.2, POCH2), 127.0
found
309.1831, (M + Na)+
= 331.1651, C14H29O5PNa
found
requires 331.1650.
Diethyl
1-butyl-1-(ethoxycarbonyl)pentylphos-
phonate (3c) [8]. Yield: 48%, 31P NMR (CDCl3)
δ: 26.4; 13C NMR (CDCl3) δ: 14.0 (s, CH3), 14.3
(s, OCH2CH3), 16.6 (d, J = 5.9, POCH2CH3), 23.4
(s, CH2), 26.9 (d, J = 7.0, CH2), 32.1 (d, J = 3.6,
CH2), 52.6 (d, J = 133.2, PCC), 61.2 (s, OCH2),
62.5 (d, J = 7.2, POCH2), 171.7 (d, J = 3.1, C O);
1H NMR (CDCl3) δ: 0.91 (t, 6H, J = 6.7, CH3),
1.46–1.23 (m, 9H + 8H, CH2, CH3), 1.92–1.82
(m, 4H, CH2), 4.24–4.09 (m, 6H, OCH2); HR-MS,
ꢁ
ꢁ
ꢁ
(s, C4 ), 128.2 (s, C2 )*, 130.7 (s, C3 )*, 136.6 (d,
ꢁ
J = 12.2, C1 ), 171.1 (d, J = 2.7, C O), *tentative
assignment; 1H NMR (CDCl3) δ: 1.07 (t, 3H, J = 7.5,
CH3), 1.34–1.25 (m, 9H, CH3), 1.88–1.71 (m, 2H,
CH2), 3.08 (dd, 1H, J1 = 13.6, J2 = 10.9, CH2Ar),
3.42 (dd, 1H, J1 = 13.6, J2 = 10.9, CH2Ar), 4.24–4.09
(m, 6H, OCH2), 7.27–7.16 (m, 5H, ArH); HR-MS,
(M + H)+
= 337.2142, C16H34O5P requires
(M + H)+
= 343.1670, C17H28O5P requires
found
found
337.2144, (M + Na)+
= 359.1964, C16H33O5PNa
343.1674, (M + Na)+
= 365.1491, C17H27O5PNa
found
found
requires 359.1963.
requires 365.1494.
Heteroatom Chemistry DOI 10.1002/hc

Dialkylation of Diethyl Ethoxycarbonylmethylphosphonate under Microwave Conditions 113
TABLE 5 Identification of the Minor Components (4, 5d, and 6) Formed in the Phase-Transfer Catalyzed Ethylation of
Ethoxycarbonylmethylphosphonate 1
Compound
δP (CDCl3)
δP [lit]
HR-MS, [M + H]+
Requires
found
4
5d
6
22.2
25.4
24.2
22.0 [25]
315.1365
343.1671
405.1832
315.1361
343.1674
405.1831
C15H24O5P
C17H28O5P
C
22H30O5P
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Two-Step Diethylation of Diethyl
Ethoxycarbonylmethylphosphonate under
MW-PTC Conditions (Table 3, entry 3)
First step: 0.20 g (0.89 mmol) of triethyl phospho-
noacetate (1), 0.09 mL (1.07 mmol) ethyl iodide
0.29 g (0.89 mmol) of cesium carbonate, and 0.03
g (0.09 mmol) of TBAB were measured in a tube
that was placed in the MW reactor and was irradi-
ated as above at 120◦C for 2 h. Then the mixture
was taken up in 10 mL of ethyl acetate, the resulting
suspension was filtered, and the filtrate was concen-
trated in vacuum. The residue contained 8% of the
starting material 1, 75% of the monoethylated prod-
uct, and 7% of the diethylated product (2a and 3a,
respectively) according to GC (Table 3, entry 1, step
1).
Second step: The residue of first step, 2 equiv. of
ethyl iodide, 1.5 equiv. of cesium carbonate, and 0.1
equiv. of TBAB were measured in a tube that was
placed in the MW reactor and was irradiated un-
der pressure control at 50 W at 120◦C for 2 h. Then
the mixture was taken up in 10 mL of ethyl acetate,
the resulting suspension was filtered, and the filtrate
was concentrated in vacuum. The residue contained
62% of the monoethyl compound (2a and 21% of
the diethyl species (3a) along with 17% of other
products (4, 5d, and 6) according to GC and gas
chromatography–mass spectrometry (Table 3, entry
1, step 2). The 31P NMR shifts and HR-MS data for
minor components 4, 5d, and 6 are shown in Table 5.
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Heteroatom Chemistry DOI 10.1002/hc