Synthesis of phosphorocyanidates via phosphorochloridates

Article abstract of DOI:10.1080/10426500307856

Dialkyl phosphorocyanidates (2) were obtained from dialkyl phosphorochloridates (1) in high yield (80-86%) at room temperature in methyl cyanide. Reaction between diethyl phosphorochloridate and potassium cyanide was greatly influenced by the solvents use

Full text of DOI:10.1080/10426500307856

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Phosphorocyanidates via
Phosphorochloridates
Enxue Shi a & Chengxin Pei a
a Beijing Insititute of Pharmceutic Chemistry , Beijing, China
Published online: 27 Oct 2010.
To cite this article: Enxue Shi & Chengxin Pei (2003) Synthesis of Phosphorocyanidates via Phosphorochloridates, Phosphorus,
Sulfur, and Silicon and the Related Elements, 178:5, 1093-1099, DOI: 10.1080/10426500307856
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:1093–1099
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DOI: 10.1080/10426500390208938
SYNTHESIS OF PHOSPHOROCYANIDATES VIA
PHOSPHOROCHLORIDATES
Enxue Shi and Chengxin Pei
Beijing Insititute of Pharmceutic Chemistry, Beijing, China
(Received September 3, 2002; accepted October 31, 2002)
Dialkyl phosphorocyanidates (2) were obtained from dialkyl phospho-
rochloridates (1) in high yield (80–86%) at room temperature in methyl
cyanide. Reaction between diethyl phosphorochloridate and potassium
cyanide was greatly influenced by the solvents used. Tetraethyl py-
rophosphate also was found to react with potassium cyanide to give
diethyl phosphorocyanidate in methyl cyanide.
Keywords: Dialkyl phosphorochloridates; dialkyl phosphorocyanides;
tetraealkyl pyrophosphates
The commonly known utility of diethyl phosphorocyanidate (DEPC)
as a versatile coupling and phosphorylating reagent had stimulated
considerable interest in peptide and organic synthesis over the last
decades.1 2 Recently derivatives of phosphorocyanidates also have been
used as starting materials for the synthesis of the famous herbicide
Roundup.3
The first reported synthesis of DEPC employed a reaction between
cyanogen iodide and triethyl phosphite,4 a variation of this was the
use of cyanogen bromide.5 An alternative approach reported by Tong6
employed the reaction of diethyl phosphite and sodium cyanide using
carbon tetrachloride as solvent, but Das7 failed to repeat this procedure;
so did we. On the other hand, phosphrochlridates were stated to be un-
10
reactive to sodium cyanide when used directly.4 All of the attempts7
to obtain phosphorocyanidates from phosphorochloridates had low
yields (18–46%). Das7 thought the reaction between dialkyl phos-
phorochloridates and cyanide in benzene involved the intermediacy
of tetraalkyl pyrophosphates when catalytic sodium hydroxide was
We express our sincere thanks to Dr. J. H. Xiao for his keen interest and encourage-
ment.
Address correspondence to Enxue Shi, Beijing Institute of Pharmaceutical Chemi-
stry, Beijing, P.R. China 102205. E-mail: shienxue@yahoo.com.cn
1093

1094
E. Shi and C. Pei
used. Diflurophosphorocyanidate F2P(O)CN also was prepared by nu-
cleophilic cleavage of pyrophosphonyl tetrafluoride F2P(O)OP(O)F2 by
Roesky.11 But Lennon3 got a mixture of (EtO)(KO)P(O)CN (47.5%),
(EtO)2(KO)P(O) (47.5%), and (EtO)3PO (5%) when using tetraethyl
pyrophosphate and potassium cyanide as starting material reacting
overnight in DMF at 50 C.
Here we report a new method for the synthesis dialkyl phos-
phorocyanidates (2) via dialkyl phosphorochloridates (1) under mild
conditions.
RESULTS AND DISCUSSION
Since the reaction between diethyl phosphorochloridate (DEPCl) and
KCN is a kind of two-phase reaction, it should be influenced greatly by
the solvents used. But some polar aprotic solvents such as CH3CN,
DMF, and DMSO have been said to suppress the reaction in basic
conditions.7 However, the GC analysis of the course of the reaction
between DEPCl and KCN in eight kinds of different aprotic solvents
under different conditions gave unexpected results (Table I).
TABLE I Reactions Between DEPCl and KCN in Different Solvents
No.
Solvent
ET(30) (kcal/mol)
Condition
Time (h)
Yielda (%)
1
2
3
4
5e
6
CH3OH
CH3CN
DMSO
DMF
CH3COCH3
ClCH2CH2Cl
55.5
46.0
45.0
43.8
42.2
41.9
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
3
3
3
3
3
0b
>90
0c
0d
>90
0
5
Reflux
r.t
3
5
10
>90
0
50–60
7
8
CHCl3
THF
39.1
37.4
Reflux
Reflux
cat.NaOH f
10
10
10
10
10
0
0
0
0
0
NO NaOH
The same to 5
The same to 5
The same to 5
9
10
11
1,4-dioxane
C6H6
CCl4
36.0
34.5
32.5
aRatio in GC.
bOnly (EtO)2P(O)OCH3 detected.
cOnly (EtO)3PO detected.
dThe final product was the mixture of (EtO)3PO (30%) and TEPP (70%).
eThe final product is 3.
f 0.1eq. NaOH.
r.t. = room temperature.

Synthesis of Phosphorocyanidates via Phosphorochloridates
1095
Whether heated to reflux or added to catalytic sodium hydroxide, DE-
PCl was unreactive with KCN in THF, 1,4-dioxane, benzene, or carbon
tetrachloride. However, in those more polar solvents such as chloro-
form, 1,2-dichloroethane, acetone, and methyl cyanide (except DMSO
and DMF), the reaction was accomplished more smoothly in the order
of experiential polarity parameter ET(30). Larger solubility of KCN and
more ABCP+ O formed in the equilibrium ABCP=O↔ABCP+ O in
more polar solvents12 probably led to the regular changes in different
solvents in Table I. In the protic solvent of methanol, (EtO)2P(O)OCH3
was the only formed product due to the well-known reaction between
DEPCl and CH3OH. However, the negative results in DMSO and DMF
suggested that some factors superior to the polarity of solvents severely
affected the reaction.
In light of the above experiments, methyl cyanide seemed to be a
good solvent to synthesize dialkyl phosphorocyanidates (2) from dialkyl
phosphorochloridates (1) in the following procedure (Scheme 1).
SCHEME 1
Compounds 2a–2g were prepared in high yield at room temperature
(Table II). Diphenyl phosphorocyanidate (2h) also was prepared in the
same procedure, yield 47%. But dimethyl phosphorochloridate seemed
unreactive to KCN under the same conditions.
Dialkyl phosphorocyanidates 2a–2g all showed sharp bands of
1
medium intensity at ca. 2208–2210 cm 1, but no 2085 cm bands of
the isomeric isocyanidates that Das reported.7 The 31P-NMR spectra
(Table III) of 2a–2g revealed that the chemical shift of 2c and 2f de-
creased 1–2 ppm mainly because of the changes of polarities among
P OR bonds.13
It should be mentioned that DEPC was found to change completely
into acetone cyanohydrin O-phosphate (3) when using acetone as sol-
vent. And when a mixture of equal mole of DEPCl, KCN in acetone was
stirred at room temperature for 10 h, pure (3) was obtained in 91% yield.
TABLE II Dialkyl Phosphorocyanidates 2a–2g
No.
2a
2b
2c
2d
2e
2f
2g
R
C2H5
81
nC3H7
86
iC3H7
86
nC4H9
80
iC4H9
82
sC4H9
82
nC5H11
83
Yield (%)

1096
E. Shi and C. Pei
TABLE III 31P-NMR of Dialkyl Phosphorocyanidates 2a–2g (in CDCl3)
No.
2a
2b
2c
2d
2e
2f
2g
(ppm)
20.583
19.872
23.366
19.904
19.591
22.117
19.913
GC analysis of the course of the reaction suggested a possible mecha-
nism shown in Scheme 2, probably involving Me2C(OK)CN formed by
acetone and KCN.
SCHEME 2
During the preparation of DEPC from DEPCl, another interesting
phenomenon similar to what Lennon3 reported was that when using
tetraethyl pyrophosphate (TEPP) as starting material was found:
When undertaken at high temperature, such as refluxing, DEPCl first
went into DEPC, which then mainly changed into EtOPO(CN)OK
(
=
19.7) and CH3CH2CN after about 10 h. The same side reactions
P
also were observed among other dialkyl phosphorochloridates. A
possible mechanism of this kind of side reaction may be expressed as in
Scheme 3.
SCHEME 3
Studies also were undertaken on the course of the reaction between
TEPP and KCN in methyl cyanide at room temperature. As expected,
TEPP facilely reacted with potassium cyanide to give DEPC (Table IV),
but only in about 50% yield probably because of the equilibrium between
TEPP and (EtO)2P(O)(OK) as shown in Scheme 4.
SCHEME 4
It also was observed that TEPP and DEPC in the mixture both
changed into EtOPO(CN)OK when heated to reflux between 8–10 h.

Synthesis of Phosphorocyanidates via Phosphorochloridates
1097
TABLE IV Reaction Between TEPP and Potassium Cyanidea
Time (h)
Yield (%)
0
0
2
36
4
52
6
45
8
42
10
0
a0–8 h, r.t.; 8–10 h, refluxing.
To sum up, in proper polar aprotic solvents such as methyl cyanide,
dialkyl phosporochloridates, and tetraalkyl pyrophosphates, both xxx
and xxx can react with potassium cyanide to yield dialkyl phosphoro-
cyanidates under mild conditions. But phosphorochloridates seems to
be a better choice not only because of the high yield (80–86%) in
preparing phosphorocyanidates but also the convenience as starting
material.
EXPERIMENTAL
Boiling points are uncorrected. Solvents were purified by standard
methods. Dialkyl phosphorochloridates were prepared according to
Steinberg.14 GC were recorded on a Varian 3700 spectrometer, IR on a
Bio-Rad FTS185 spectrometer, 31P-NMR on a Varian UNITY500 spec-
trometer using 85% H3PO4 as external reference, MS on a Finnigan
Mat TSQ70 spectrometer.
Dialkyl Phosphorocyanidate 2a–2g
To a 50 ml flask, anhydrous methyl cyanide (20 ml), potassium
cyanide (0.4 mmol), and dialkyl phosphorochloridate (0.2 mmol) was
added. The mixture was stirred vigorously at room temperature for 3 h,
then filtered. After the solvent was removed, the residue was distilled
under reduced pressure.
Diethyl phosphorocyanidate 2a. Yield 81%; b.p. 54–55 (0.7 mm);
IR 2209.5 ( N), 1305.9 ( O); 31P-NMR (CDCl3)
=
20.583 ppm;
C
P
MS m/z(%) 164(M + 1, 4) 148(2) 136(30) 134(12) 120(35) 108(100) 91(5)
83(10) 65(5) 55(35) 45(14).
Dipropyl phosphorocyanidate 2b. Yield 86%; b.p. 76–78 (1.0 mm); IR
2209.2 ( N), 1300.1 ( O); 31P-NMR (CDCl3)
=
19.872 ppm; MS
C
P
m/z(%) 192(M + 1, 4) 162(2) 150(3) 134(5) 121(6) 108(100) 83(11) 69(3)
55(5) 43(32) 41(22) 27(6).
Diisopropyl phosphorocyanidate 2c. Yield 86%; b.p. 50–51 (0.2 mm);
IR 2208.4 ( N), 1297.3 ( O); 31P-NMR (CDCl3) = 23.366 ppm; MS
C
P

1098
E. Shi and C. Pei
m/z(%) 192(M + 1, 3) 176(4) 150(12) 134(95) 108(100) 81(4) 69(22) 59(3)
43(28) 41(22).
Dibutyl phosphorocyanidate 2d. Yield 80%; b.p. 92–94 (0.8 mm); IR
2208.8 ( N), 1299.4 ( O); 31P-NMR (CDCl3)
m/z(%) 220(M + 1, 5) 164(15) 134(5) 108(100) 83(10) 57(40) 41(58).
=
19.904 ppm; MS
C
P
Diisobutyl phosphorocyanidate 2e. Yield 82%; b.p. 86–88 (1.0 mm);
IR 2208.9 ( N), 1306.8 ( O); 31P-NMR (CDCl3) = 19.591 ppm; MS
C
P
m/z(%) 220(M + 1, 2) 164(8) 148(7) 136(3) 121(12) 108(55) 96(4) 83(5)
57(100) 41(98).
Disecbutyl phosphorocyanidate 2f. Yield 81%; b.p. 68–69 (0.3 mm);
IR 2208.0 ( N), 1299.4 ( O); 31P-NMR (CDCl3)
=
22.117 ppm;
C
P
MS m/z(%) 220(M + 1, 2) 190(4) 164(16) 148(18) 134(72) 108(100) 97(6)
83(43) 70(4) 57(32) 41(50) 29(60).
Diamyl phosphorocyanidate 2g. Yield 83%; b.p. 130–131 (1.2 mm);
IR 2208.7 ( N), 1305.1 ( O); 31P-NMR (CDCl3)
=
19.913 ppm;
C
P
MS m/z(%) 248(M + 1, 2) 178(11) 148(5) 108(64) 96(5) 83(10) 71(100)
55(26) 43(50) 29(10).
Diphneyl phosphorocyanidate 2h. Yield 47%; b.p. 128–130 (0.4 mm);
IR 2210.9 ( N), 1321.9 ( O); 31P-NMR (CDCl3)
=
29.159 ppm;
C
P
MS m/z(%) 259(M + 1, 75) 166(5) 140(100) 119(25) 94(90) 77(45) 65(22)
51(21).
Acetone Cyanohydrin O-phosphate (3)
To a 50 ml flask, 1.73 g diethyl phosphorochloridate (0.1 mmol),
1.3 g potassium cyanide (0.2 mmol), and 10 ml anhydrous acetone
was added. The mixture was stirred vigorously at room temperature
for 10 h, then filtered. After acetone was removed, distillation gave
2.0 g acetone cyanohydrin O-phosphate (3), b.p. 86–88 (0.5 mm), yield
91%. IR 2242.8 ( N), 1278.3 ( O); 31P-NMR (CDCl3) = 4.732 ppm;
C
P
MS m/z(%) 222(M + 1, 6) 194(5) 179(7) 167(20) 155(21) 127(95) 99(100)
81(25) 68(22); 1H-NMR (CDCl3) 1.374(2t, 6H), 1.845(s, 6H), 4.177
(q, 4H).
Reaction Between Tetraethyl Pyrophosphate and
Potassium Cyanide
To a 50 ml flask, methyl cyanide (20 ml), potassium cyanide
(0.4 mmol), and tetraethyl pyrophosphate (0.2 mmol) was added. The
mixture was stirred vigorously at room temperature for 8 h, then heated
to reflux for 2 h. Samples for GC analysis were taken every 2 h during
the course of the reaction.

Synthesis of Phosphorocyanidates via Phosphorochloridates
1099
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