2
698
H. K. Gupta et al. / Tetrahedron Letters 50 (2009) 2697–2699
Table 1
Fluorination of substrates with different fluoride sources
0
31
1
Entry
R
R
Fluoride ion source
P{ H} NMR d (ppm)
JP–F (Hz)
TBAF(tert-BuOH)
4
TBAFꢁxH
Time (min)
2
O
KF
Time (min)
5c
Yielda,b (%)
Yieldb (%)
Time (min)
Yieldb (%)
i
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
C
C
3
H
H
7
NEt
NPr
NPr
2
88
92
87
88
91
92
94
90
90
93
87
85
91
87
85
5
5
5
5
5
5
5
5
5
5
5
5
10
10
10
78
74
70
77
71
76
77
64
65
64
65
69
74
72
69
45
45
45
45
45
35
37
42
39
42
34
45
70
70
67
64
68
65
58
62
44.82
44.87
43.72
41.79
41.82
18.30
20.70
30.40
28.15
31.80
30.67
32.43
ꢀ8.23
ꢀ8.25
ꢀ10.2
992.14
982.25
972.16
996.24
987.17
943.19
946.23
1071.50
1046.30
1067.50
1069.00
1085.70
975.24
970.14
969.16
i
c
3
7
2
2
5
c
C
C
C
NEt
NPr
CH
CH
C
3
H
7
5
c
2
H
5
H
5
2
NEt
NPr
NEt
NPr
2
5
c
2
2
5
c
2
5
45
45
c
2
2
5
n
c
3
O C
3
H
7
5
120
120
130
130
100
180
210
240
i
c
3
O C
3
H
H
H
7
5
c
1
1
1
1
1
1
2
H
H
5
7
OC
2
5
5
c
C
3
OC
O C
3
7
5
i
i
c
C
H
3 7
3
H
7
5
d
OCH
OC
O C
3
OCH
3
10
10
10
d
2
H
5
OC
O C
2
H
H
5
i
i
d
3
H
7
3
7
The NMR and GC–MS data compared well with authentic samples.
a
by 31P{ H} NMR prior to isolation.
1
1
00% conversion was observed for the reaction with TBAF(tert-BuOH)
4
b
c
The yields depicted for the reactions with the reagent TBAF(tert-BuOH)
These reactions were found to be almost instantaneous with TBAF(tert-BuOH)4.
These reactions occurred at 70 °C within 10 min.
4
represent isolated yields and NMR yields for the TBAFꢁxH
2
O and KF.
d
As revealed in Table 1, all the phosphorus(V) chlorides reacted
smoothly in short reaction times to produce the corresponding
phosphorus(V) fluorides in very good yields. In addition, scale up
of the procedure (0.1–10 mmol) did not show any significant
change in the isolated yield for the phosphorus(V) fluorides. De-
spite all the reactants showing complete conversion with the pro-
posed reagent, as observed by P{ H} NMR spectroscopy, the
isolated yield was found to be lower. This can be attributed to
the loss of the product during the work-up procedures. Neverthe-
less the isolated yields obtained from the proposed reagents were
higher than those obtained from the other two reagents. The
important advantage of this reaction is the completion of reaction
within 5 min at room temperature for N,N-dialkyl-P-alkyl phos-
phonamidic chlorides and O-alkyl alkylphosphonochloridates and
10 min for chlorophosphates at 70 °C.
In conclusion, we have developed a rapid, efficient and conve-
nient synthesis of a variety of phosphorus(V) fluorides from the
corresponding chlorides utilizing a new and efficient source of
fluoride ion under mild conditions. Moreover, the procedure offers
several advantages including excellent yield, clean reaction, opera-
tionally simple and high conversion, which makes it a useful and
attractive process for the synthesis of phosphorus(V) fluorides.
More importantly, this reaction can be carried out as and when re-
quired, yielding pure products. This minimizes the risk of exposure
of these potent AChE inhibitors to the personnel.
O
P
O
P
F
TBAF(tert-BuOH)4, MeCN
r.t
R
R'
R
R'
Cl
Scheme 1. Synthesis of N,N-dialkyl-P-alkyl phosphonamidic fluorides, O-alkyl alkyl
phosphonofluoridates and O,O -dialkyl fluorophosphates from their corresponding
chloro compounds.
3
1
1
0
4
TBAF(tert-BuOH) and N,N-dipropyl-P-isopropyl phosphonamidic
chloride 11.25 mg (0.05 mmol) at room temperature in MeCN, the
reaction was monitored by 31P NMR and GC–MS. (Scheme 1).
Complete conversion of the N,N-dipropyl-P-isopropyl phospho-
namidic chloride to the corresponding fluoride was observed with-
in 5 min. Encouraged by this initial finding, we focused on the
reaction with various N,N-dialkyl-P-alkyl phosphonamidic chlo-
rides, bis(N,N-dialkyl)phosphoramidic chlorides, O-alkyl alkyl-
23
0
phosphonochloridates, and O,O -dialkyl chlorophosphates. The
reactions of the N,N-dialkyl-P-alkyl phosphonamidic chlorides
and O-alkyl alkylphosphonochloridates with the reagent afforded
the corresponding fluorides within 5 min in excellent yields (Table
, entries 1–12). The chlorophosphates were found to react com-
pletely in 10 min at 70 °C (Table 1, entries 13–15). It is noteworthy
that the use of TBAF(tert-BuOH) in slight excess is always advis-
1
4
able to ensure complete conversion. To establish the efficiency of
this reagent over commonly used KF and TBAF, comparison for
the fluorination of same substrates was also carried out. It was also
observed that when these substrates were subjected to fluorine ex-
References and notes
1.
(a) Wilson, B. W.; Walkar, C. R. Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 3194; (b)
Bartlett, P. A.; Lamdem, L. A. Bioorg. Chem. 1986, 14, 356.
change, using TBAFꢁxH
2
O and KF, the yields remain low with both
2. (a) Engel, R. Chem. Rev. 1977, 77, 349; (b) Kosolapoff, G. M.. In Organic
Phosphorus Compounds; Wiley Intertscience: New York, 1950; Vol. 6. pp 319–
these reagents. Whereas, with KF, the reaction resulted in lower
yields (65–75%) even after refluxing the reaction mixture for an ex-
tended period of up to 240 min in some cases. This can be attrib-
uted to the biphasic nature of the reactants. The reaction with
510.
3
4
.
.
(a) Camps, F.; Coll, J.; Fabrias, G.; Guerrero, A. Tetrahedron 1984, 40, 2871; (b)
De Frank, J. J. In Applications of Enzyme Biotechnology; Kelly, J. W., Baldwin, T. O.,
Eds.; Plenum: New York, 1991; pp 165–180.
(a) Sikder, A. K.; Ghosh, A. K.; Jaiswal, D. K. J. Pharm. Sci. 1993, 82, 258; (b)
Marjit, D. N.; Sharma, U. S. Indian J. Chem., Sect. A 1989, 28, 958; (c) Sikder, A. K.;
Pandey, K. S.; Jaiswal, D. K.; Dube, S. N.; Kumar, D.; Hussain, K.; Bhattacharya,
R.; Das Gupta, S. J. Pharm. Pharmacol. 1992, 44, 1038.
TBAFꢁxH
pyrophosphonamidates and pyrophosphoramidates. The proposed
reagent being remarkably less hygroscopic than TBAFꢁxH O, does
not lead to the formation of any hydrolytic products. On the other
O is a deliquescent solid, which leads to lower avail-
2
O resulted in lower yields with formation of undesired
2
5.
(a) Eyer, P. Toxicol. Rev. 2003, 22, 165; (b) Kim, T. H.; Oh, K. A.; Park, N. J.; Park,
N. S.; Kim, Y. J.; Yum, E. K.; Jung, Y. S. J. Appl. Biomed. 2006, 67; (c) Koelle, G. J.
Pharmacol. Exp. Ther. 1946, 88, 232.
hand TBAFꢁxH
2
ability of free fluoride ions and the formation hydrolytic degrada-
tion products can be attributed to the moisture present therein.
6. DeFrank, J. J. In Applications of Enzyme Biotechnology; Kelly, J. W., Baldwin, T. O.,
Eds.; Plenum: New York, 1991; pp 165–180.