Phase-transfer catalyzed pseudohalogenation of phosphorochloridates

Article abstract of DOI:10.1081/SCC-200050359

Pseudohalogenation of phosphorochloridates by sodium pseudohalides with different phase transfer catalysts and solvents was optimized. Dialkyl and diaryl phosphorazidates phosphorocyanidates, and phosphor(isotniocyanidate)s were prepared in good yields from phosphorochloridates under two kinds of mild phase-transfer catalyzed conditions respectively.

Full text of DOI:10.1081/SCC-200050359

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Phase‐Transfer Catalyzed Pseudohalogenation
of Phosphorochloridates
Enxue Shi a & Chengxin Pei a
a Beijing Institute of Pharmaceutical Chemistry, Beijing, P. R China
Published online: 20 Aug 2006.
To cite this article: Enxue Shi & Chengxin Pei (2005) Phase‐Transfer Catalyzed Pseudohalogenation of
Phosphorochloridates, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:5, 669-673, DOI: 10.1081/SCC-200050359
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Synthetic Communicationsw, 35: 669–673, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050359
Phase-Transfer Catalyzed
Pseudohalogenation of Phosphorochloridates
Enxue Shi and Chengxin Pei
Beijing Institute of Pharmaceutical Chemistry, Beijing, P. R China
Abstract: Pseudohalogenation of phosphorochloridates by sodium pseudohalides with
different phase transfer catalysts and solvents was optimized. Dialkyl and diaryl phos-
phorazidates phosphorocyanidates, and phosphor(isothiocyanidate)s were prepared in
good yields from phosphorochloridates under two kinds of mild phase-transfer
catalyzed conditions respectively.
Keywords: Pseudohalogenation, pseudohalophosphates, pseudohalides, phosphoro-
chloridates, phase transfer catalyst
Azide, cyanide, and thiocyanide are the most known and versatile pseudo-
halides in organic chemistry. The corresponding pseudohalophosphates are
widely used reagents for organic synthesis.[1] Replacement of a phosphorus-
bound chlorine by pseudohalides using a variety of experimental procedures
is by far the most common way to prepare phosphorazidates,[2] phosphoro-
cyanidates,[3] and phosphor(isothiocyanidate)s.[4] However, some reported
methods suffer from disadvantages such as high temperature, long reaction
times, or the need for special reagents, which are probably due to the low
reactivities between organic compounds and inorganic ions.
On the other hand, phase-transfer catalysts (PTC) have shown great
performance in many kinds of reactions in last decades. With the exception
Received in Poland 20 October 2004
Address correspondence to Enxue Shi, Beijing Institute of Pharmaceutical
Chemistry, Beijing 102205, P. R China. Fax: þ86-10-69767099. E-mail: shienxue@
yahoo.com

670
E. Shi and C. Pei
of the early reports in cyanation[5a] and azidation[5b] of carboxylic chloride, we
have recently reported a successful cyanation of dialkyl phosphorochloridates
by potassium cyanide under phase transfer catalyzed conditions.[6] Herein are
our further investigations about pseudohalogenation, including azidation,
cyanation, and thiocyanation of both dialkyl and diaryl phosphorochloridates.
In order to optimize the reaction conditions, azidation of diethyl phos-
phorochloridate (DEPCl) was selected. Results of the influence of different
solvents and phase-transfer catalysts to the reaction are shown in Table 1.
When quaternary ammonium salts, including tetramethylammonium
chloride (TMACl), tetrabutylammonium bromide (TBAB), tetrabutylammo-
nium iodide (TBAI), were used as catalysts, a small quantity of water was
found to be vitally important to proceed or accelerate the reaction;
otherwise azidation of DEPCl became much slower or even impossible.
This is similar to former reports[8] that an increasing number of carbon
atoms around the central nitrogen atom of the ammonium catalysts increase
their lipophilicity, enabling the transfer of azide ion into the organic layer,
thus facilitating the reaction. All aprotic solvents that are immiscible with
water are capable of conducting the reaction, especially when TBAB is
used. But different from the conventional reports,[9] the apparent extraction
constants (AEC) of solvents showed no obvious regular effects on the
reaction rate. In addition, it should be emphasized that little hydrolysis of
DEPCl was detected by 31P-NMR in the aqueous-organic reaction system.
However, when 18-crown-6 was used, no matter whether water was
added or not, azidation was completed within half an hour in ethyl acetate
or in 1,2-dichloroethane. Addition of catalytic amount of water leads to
formation of side products such as tetraethyl pyrophosphate as evidenced by
gas chromatography-mass spectrometry (GC-MS). This may be explained
by the generally known difference between activity of quaternary
ammonium salts and crown ethers as catalysts.[8]
Table 1. Azidation of DEPCl by NaN3 with different PTC and solvents
Yield of 2a (%)b with different catalysts
Entry
Solvent
chloroform
AECa TMAClc TBABc TBAIc 18-crown-6d
1
2
3
4
100
92
3
10
5
97
100
100
100
64
76
20/22
89/68
25/20
97/98
1,2-dichloroethane
dichloromethane
ethyl acetate
88
16
100
100
34
aApparent extraction constant (AEC).[7]
bConversion of DEPCl to 2a calculated from GC after 30 min.
c10% water added.
dNo water added/10% water added.

Pseudohalogenation of Phosphorochloridates
671
Similar to DEPCl, azidation, cyanation, and thiocyanation of both diiso-
butyl and diphenyl phosphorochloridates by pseudohalides gives satisfactory
results under similar conditions. Moreover, phosphorothiocyanidates formed
initially, there were isomerized completely into phosphor(isothiocyanatidate)s
at elevated temperatures during distillation.
Thus, the commonly not-easy-to-achieve pseudohalogenation of phosphoro-
chloridates can be accomplished very smoothly and rapidly in good yield under
TBAB or 18-crown-6 catalyzed conditions respectively (Scheme 1).
Synthesis of diethyl, diisobutyl, and diphenyl phosphorazidates, phospho-
rocyanidates, and phosphor(isothiocyanidate)s 2a–i under the two kinds of
PTC conditions are shown in Table 2.
In summary, the presented PTC methodology in pseudohalogenation of
phosphorochloridates shows at least the following advantages over the
conventional procedures: (a) no requirement for anhydrous solvents; (b)
improved reaction rates; (c) milder reaction conditions; (d) increased yields
through the suppression of side reactions. More importantly, the PTC method-
ology also exhibits a prosperous potential to be applied to phosphorylating
or/and other necleophilic substitution reactions.
EXPERIMENTAL
The GC-MS was recorded on a Varian CP-3800 spectrometer and a Finnigan
Mat TSQ70 spectrometer, The infrared (IR) on a Bio-Rad FTS185 spectrometer,
p-nuclear magnetic resonance (P-NMR) on a Varian UNITY500 spectrometer.
Diethyl phosphorochloridate,[10a] diisobutyl phosphorochloridate,[10a]
and diphenyl phosphorochloridate[10b] were prepared according to the
known procedures.
Pseudohalogenation of Phosphorochloridates: (General procedure)
(I): To the solution of phosphorochloridate (20 mmol) and tetrabutyl
ammonium bromide (2 mmol) in dichloromethane (20 mL), pseudohalide
Scheme 1.

Table 2. Synthesis and spectroscopies of pseudohalophosphates 2a–i
Yield (%)
IR (cm21
)
Products
R
X
I
II
b.p. (8C/mm)
31P-NMR (ppm)
n(P5O)
nX
MS m/z (%)
2a
2b
2c
2d
2e
2f
Et
Et
N3
85
81
72
75
81
74
66
73
77
78
84
79
84
88
72
74
78
78
68–69/2.0
54–55/0.7
49–51/0.3
79–80/0.1
86–88/1.0
84–85/0.1
137–139/0.2
128–130/0.4
144–146/0.2
20.30
2 20.60
2 18.00
2 0.23
2 19.60
2 17.52
2 9.73
1269.1
1305.9
1276.1
1270.9
1306.8
1286.9
1289.1
1322.0
1300.7
2163.2
2209.5
2004.9
2163.0
2208.9
2004.0
2171.9
2210.9
1986.9
180 (M þ 1, 6)
164 (M þ 1, 4)
196 (M þ 1, 3)
236 (M þ 1, 2)
220 (M þ 1, 2)
252 (M þ 1, 2)
276 (M þ 1, 14)
259 (M, 75)
CN
NCS
N3
Et
i-Bu
i-Bu
i-Bu
Ph
CN
NCS
N3
2g
2h
2i
Ph
Ph
CN
NCS
2 29.20
2 27.71
292 (M þ 1, 7)
(I) NaX, Bu4NBr/CH2Cl2/H2O; (II) NaX, 18-crown-6/EtOAc.

Pseudohalogenation of Phosphorochloridates
673
(30 mmol) in water (2 mL) was dropped at room temperature. The mixture was
then stirred for 20–30 min. After filtration, the filtrate was dried by anhydrous
MgSO4 for 24 h and concentrated in vacuo and distillation gave the corre-
sponding product.
(II): To the solution of phosphorochloridate (20 mmol) and 18-crown-6
(2 mmol) in ethyl acetate (20 mL), pseudohalide (30 mmol) was added at
room temperature. The mixture was then stirred for 20–30 min. After fil-
tration, the filtrate was concentrated in vacuo and distillation gave the corre-
sponding product.
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