An efficient and general route to the synthesis of diethyl α,α-bromofluorophosphonates

Article abstract of DOI:10.1016/j.jfluchem.2011.06.016

An efficient and general two-step halogenation procedure to prepare diethyl α,α-bromofluorophosphonates was described, which included bromination by PPh₃, 2,3-dichloro-5,6-dicyanobenzquinone (DDQ) and n-Bu₄NBr, and electrophilic fluo

Full text of DOI:10.1016/j.jfluchem.2011.06.016

Journal of Fluorine Chemistry 132 (2011) 636–640
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short Communication
An efficient and general route to the synthesis of
diethyl -bromofluorophosphonates
a,a
*
Jian-Ping Fu, Yan-Hong He, Jun Zhong, Yang Yang, Xiang Deng, Zhi Guan
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
A R T I C L E I N F O
A B S T R A C T
An efficient and general two-step halogenation procedure to prepare diethyl
Article history:
a,a-bromofluoropho-
Received 12 April 2011
Received in revised form 13 June 2011
Accepted 16 June 2011
Available online 23 June 2011
sphonates was described, which included bromination by PPh3, 2,3-dichloro-5,6-dicyanobenzquinone
(DDQ) and n-Bu4NBr, and electrophilic fluorination by N-fluorobisbenzenesulfonimide (NFSI). Both
aromatic and aliphatic
a
,a
-bromofluorophosphonates could be prepared by this method.
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Bromination
Fluorination
Diethyl
Diethyl
a
-bromophosphonate
-bromofluorophosphonate
a,
a
1. Introduction
tases (PTPs) based on our reports on the synthesis of diethyl
chlorofluorophosphonates recently [6].
a,a-
Since many of the most important biochemicals are organo-
phosphates, including DNA and RNA as well as many cofactors
that are essential for life, the organophosphorus chemistry has
In this paper, we describe the synthesis of a series of diethyl
a,a-bromofluorophosphonates. The starting materials 1 were
prepared by the Pudovik reaction starting from corresponding
aldehydes and diethyl phosphate easily. Followed by a two-step
been rapidly developed recently [1]. In particular,
a-mono-
halogenated [2] and -dihalogenated phosphonates [3] have
a
,
a
halogenation procedure (Scheme 1), the target products, a,a-
been designed as phosphate mimics used as metabolite probes,
anticancer drugs, and enzyme inhibitors due to their structural
and electronic similarities to the parent phosphate groups. In
fact, fluorine as the optimum substitution atom of phosphate
bromofluorophosphonates, could be prepared in reasonable yields.
This method was applicable for the synthesis of both aromatic and
aliphatic
a,a-bromofluorophosphonates.
mimics, the synthesis strategies of
a-monofluoro- and a,a-
2. Results and discussion
difluoroalkylphosphonates, including nucleophilic [4] and elec-
trophilic fluorination [5], have been reported a lot. However, the
attention which is paid to the synthesis of phosphonates bearing
The starting materials,
a-hydroxyphosphonates 1, were
obtained in excellent yields from corresponding aldehydes and
diethyl phosphate with sodium ethoxide as catalyst [7]. The
following step was nucleophilic bromination. In our initial
investigation, we adopted the procedure of PPh3/Br2/pyridine in
CH3CN according to the literature [8]. To our disappointment, the
procedures did not proceed as smoothly as expected. The yields
were low (40–56%) (Scheme 2). The plausible explanation was
that the secondary hydroxyl possessed larger steric hindrance.
Thus, it was difficult for nucleophilic reagent PPh3Br2 to approach.
In other words, the bromination with PPh3Br2 was practically
dependent on the structure. The above results prompted us to try
another reported method using PPh3/DDQ/n-Bu4NBr in CH2Cl2 [9]
two different halogen substituents in the
phosphorus atom is limited. -Bromobenzylphosphonates have
been demonstrated to be better enzyme inhibitors compared to
-chlorobenzylphosphonates and -flurobenzylphosphonates
[6]. Since the bromine atom is a better leaving group than
chlorine and fluorine atoms, -bromofluorophosphonates may
be more effective inhibitors. Therefore, it is necessary to explore
a efficient method for the preparation of -bromofluoropho-
a-position to the
a
a
a
a,a
a,a
sphonate to enrich probe library of protein tyrosine phospha-
to obtain
a-bromophosphonates. In order to improve the
conversion rates, the reaction was refluxed at 40 8C, and it
* Corresponding author. Tel.: +86 23 68254091; fax: +86 23 68254091.
E-mail address: guanzhi@swu.edu.cn (Z. Guan).
worked well (Scheme 2). As shown in Table 1, various types of
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.016

J.-P. Fu et al. / Journal of Fluorine Chemistry 132 (2011) 636–640
637
O
O
O
O
R
P(OEt)2
R
P(OEt)2
R
R
P(OEt)2
O
+
PH(OEt)2
OH
Br
F
Br
R = aryl or alkyl
Scheme 1. Strategy for the preparation of
a,
a-bromofluorophosphonates.
PPh3Br2, Pyridine
diethyl
a-bromophosphonates 2 were obtained in good to
excellent yields (82–93%).
Having achieved an efficient synthesis of
nates, we proceeded with the synthesis of
sphonates by treating a solution of the respective compound 2 in
dry THF with excess sodium hexamethyldisilazide (NaHMDS) and
CH2Cl2, -20ºC to r.t.
40-56% yield
O
O
a
-bromophospho-
a,a-bromofluoropho-
R
P(OEt)2
R
P(OEt)2
OH
Br
PPh3, DDQ, Bu4NBr
NFSI. Namely,
a-bromophosphonates was deprotonated by
1
2
CH2Cl2, reflux
82-93% yield
NaHMDS (1.5 equiv) in THF at À78 8C for 1 h under an inert
atmosphere, followed by treatment with NFSI (1.3 equiv) at
À78 8C to À30 8C (Scheme 3). Fortunately, this procedure worked
Scheme 2. Preparation of diethyl
a-bromophosphonates 2.
well, and both
a,a-bromofluoroalkylphosphonates and a,a-
bromofluorobenzylphosphonates (Entries 3a–h, Table 2) were
obtained in reasonable to good yields (46–92%). Their structure
was unequivocally confirmed by 13C NMR and 19F NMR
spectroscopy (Table 2).
These compounds were stable at À20 8C for at least half a year
and for at least one month without solvent at room temperature. It
can be seen from Table 2 that an array of electron-withdrawing
substituents on aromatic ring could be tolerated. This was because
electron-withdrawing groups decreased electron density of the
aromatic ring, which enhanced the stability of intermediate
phosphonate carbanions. However, inferior results were displayed
when the substrates 2 with electron-donating groups on aromatic
O
O
NaHMDS, NFSI
R
P(OEt)2
R
P(OEt)2
-78ºC to -30ºC
43-92% yield
Br
F
Br
3
2
Scheme 3. Preparation of diethyl
a,a-bromofluorophosphonates 3.
the aromatic ring, which made it difficult to form intermediate
phosphonate carbanions during the reaction process, and these
electron-donating groups had stronger influence when they were at
the 2- and 4-positionsof aromaticrings than at 3-position.In addition,
ring were employed. When some
a-bromophosphonates (R = 4-
MeC6H4, 2-, 3- and 4-MeOC6H4) were used for the synthesis of
a,a-
bromofluorophosphonates, only 3f (R = 3-MeOC6H4) was obtainable
in alow yield of 43%(Entry3f, Table 2). We reasoned thattheelectron-
donating group might contribute to an increased electron density of
the reaction was also applicable to a-bromophosphonates with
aliphatic substituents. Moderate yields were obtained for 3 g (R = Et)
and 3 h (R = n-Pr) (Entries 3g and h, Table 2).
Table 1
Spectroscopic data of diethyl
a-bromophosphonates 2.
Entry
R
1H NMR(
d
, ppm, J, Hz)
13C NMR(
d
, ppm, J, Hz)
Yielda
(%)
2
1
2a
2b
2c
2d
2e
2f
4-NO2C6H4-
3-NO2C6H4-
2-NO2C6H4-
4-CNC6H4-
3-CNC6H4-
3-MeOC6H4-
Et-
4.91 (d, JPH = 13.9)
39.6 (d, JPC = 156.2)
93
91
92
90
88
93
82
85
2
1
4.93 (d, JPH = 13.6)
39.6 (d, JPC = 157.1)
2
1
6.00 (d, JPH = 14.8)
34.0 (d, JPC = 157.3)
2
1
4.87 (d, JPH = 13.7)
40.3 (d, JPC = 156.5)
2
1
4.81 (d, JPH = 13.5)
39.7 (d, JPC = 157.3)
2
1
4.81 (d, JPH = 12.9)
41.4 (d, JPC = 158.0)
2
1
2g
2h
3.74 (dt, JPH = 12.9)
44.0 (d, JPC = 156.8)
2
1
n-Pr-
3.79 (dt, JPH = 10.2)
41.9 (d, JPC = 157.1)
a
Isolated yields.
Table 2
Spectroscopic data of diethyl
a,
a-bromofluorophosphonates 3.
Entry
R
13C NMR(
d
, ppm, J, Hz)
19F NMR(
d
, ppm, J, Hz)
Yielda
(%)
1
1
2
3a
3b
3c
3d
3e
3f
4-NO2C6H4-
98.3 (dd, JPC = 188.1, JFC = 267.9)
À129.0 (d, JPF = 80.4 Hz)
87
92
81
82
87
43
54
46
1
1
2
3-NO2C6H4-
2-NO2C6H4-
4-CNC6H4-
3-CNC6H4-
3-MeOC6H4-
Et-
98.3 (dd, JPC = 189.8, JFC = 267.3)
À128.9 (d, JPF =82.3 Hz)
1
1
2
97.4 (dd, JPC = 189.0, JFC = 268.9)
À128.9 (d, JPF =82.1 Hz)
1
1
2
98.5 (dd, JPC = 190.0, JFC = 267.8)
À129.6 (d, JPF =80.7 Hz)
1
1
2
98.5 (dd, JPC = 189.7, JFC = 267.6)
À129.6 (d, JPF =80.7 Hz)
1
1
2
99.4 (dd, JPC = 189.5, JFC = 267.1)
À127.4 (d, JPF =82.6 Hz)
1
1
2
3g
3h
104.5 (dd, JPC = 189.5, JFC = 265.3)
À124.6 (ddd, JPF = 84.6 Hz)
1
1
2
n-Pr-
104.6 (dd, JPC = 189.9, JFC = 265.4)
À122.9 (ddd, JPF = 84.6 Hz)
a
Isolated yields.

638
J.-P. Fu et al. / Journal of Fluorine Chemistry 132 (2011) 636–640
3. Conclusions
4.2.4. Diethyl
a-hydroxy-4-cyanobenzylphosphonate (1d) [6]
Yellowish solid, mp 78–80 8C. 1H NMR (300 MHz, CDCl3):
d
A new methodology for the synthesis of
sphonates is developed from the corresponding
a
,
a
-bromofluoropho-
-hydroxypho-
sphonates via nucleophilic bromination and then electrophilic
fluorination. Both aromatic and aliphatic -bromofluoropho-
1.23–1.30 ppm (m, 6H, CH3), 4.04–4.13 ppm (m, 4H, OCH2),
5.12 ppm (d, JPH = 12.2 Hz, 1H, CHOH), 7.61 ppm (d, J = 8.7 Hz,
2H, Ar-H), 7.65 ppm (d, J = 8.5 Hz, 2H, Ar-H); 13C NMR (75 MHz,
2
a
3
3
a
,
a
CDCl3): d 16.4 ppm (d, JPC = 2.6 Hz), 16.5 ppm (d, JPC = 2.4 Hz),
sphonates could be obtained by this method. These compounds
are potential non-peptidyl inhibitors of PTPs. Study of asymmet-
ric fluorination and biological activity of the products are in
progress.
63.3 ppm (d, 2JPC = 7.6 Hz), 63.9 ppm (d, 2JPC = 7.1 Hz), 70.2 ppm (d,
1JPC = 157.8 Hz), 111.7, 118.8, 127.7, 132.0, 142.5 ppm.
4.2.5. Diethyl
a-hydroxy-3-cyanobenzylphosphonate (1e) [6]
White solid, mp 84–86 8C. 1H NMR (300 MHz, CDCl3):
d
1.24–
4. Experimental
1.32 ppm (m, 6H, CH3), 4.08–4.15 ppm (m, 4H, OCH2), 5.08 ppm (d,
2JPH = 11.1 Hz, 1H, CHOH), 7.48 ppm (t, J = 7.7 Hz, 1H, Ar-H),
7.61 ppm (d, J = 7.4 Hz, 1H, Ar-H), 7.73 ppm (d, J = 7.6 Hz, 1H,
4.1. General methods
Ar-H), 7.83 ppm (s, 1H, Ar-H); 13C NMR (75 MHz, CDCl3):
d
All reactions were carried out under an atmosphere of dry
argon. THF was freshly distilled from sodiumbenzophenone ketyl.
1H NMR (300 MHz), 13C NMR (75 MHz) and 19F NMR (282 MHz)
spectra were recorded on a Bruker AV-300. TMS (1H), CDCl3
were used as internal standards and CFCl3
external standard. Chemical shifts ( ) are reported in ppm and
16.1 ppm (d, 3JPC = 1.6 Hz), 16.2 ppm (d, 3JPC = 1.4 Hz), 63.1 ppm (d,
2JPC = 7.5 Hz), 63.5 ppm (d, 2JPC = 7.2 Hz), 69.3 ppm (d,
1JPC = 161.2 Hz), 111.9, 118.5, 128.7, 130.4, 131.3, 139.0 ppm.
(
13C)
(
19F) was used as
4.2.6. Diethyl
a
-hydroxy-3-methoxybenzylphosphonate (1f) [6]
1.24 ppm (t,
d
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
coupling constants (J) in Hz. High-resolution mass spectrometry
(HRMS) spectra were recorded on a high resolution ESI-FTICR mass
spectrometry (Varian 7.0 T).
J = 7.0 Hz, 3H, CH3), 1.28 ppm (t, J = 7.0 Hz, 3H, CH3), 3.82 ppm (s,
3H, OCH3), 3.95–4.11 ppm (m, 4H, OCH2), 5.01 ppm (d,
2JPH = 10.8 Hz, 1H, CHOH), 6.86 ppm (d, J = 8.1 Hz, 1H, Ar-H),
7.07 ppm (s, 2H, Ar-H), 7.30 ppm (d, J = 8.1 Hz, 1H, Ar-H); 13C NMR
3
4.2. Typical procedurefor the preparationof
a-hydroxyphosphonates 1
(75 MHz, CDCl3):
d
16.3 ppm (d, JPC = 1.4 Hz), 16.4 ppm (d,
3JPC = 1.6 Hz), 55.2 ppm, 63.0 ppm (d, JPC = 7.3 Hz), 63.4 ppm (d,
2JPC = 7.0 Hz), 70.6 ppm (d, JPC = 158.6 Hz), 112.4, 113.8, 119.5,
2
1
To a solution of sodium ethoxide (0.765 g, 11.25 mmol) in
CH2Cl2 (10 ml) was added diethyl phosphite (1.05 ml, 7.6 mmol)
via syringe at À35 8C under argon. The reaction was stirred for
30 min. and a solution of 4-nitrobenzaldehyde (1 g, 6.62 mmol) in
CH2Cl2 (5 ml) was added. The mixture was stirred for 3–5 h. The
reaction was quenched with 0.1 N HC1 and the resulting solution
was extracted with ethyl acetate. The organic layer was dried with
MgSO4 and the solvents were removed in vacuo. The crude
material was purified via flash column chromatography to yield 1a
as white solid (1.81 g, 95% yield).
129.1, 138.5, 159.5 ppm.
4.2.7. Diethyl
a-hydroxyethylphosphonate (1g) [6]
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
1.08 ppm (t,
J = 7.4 Hz, 3H, CH2CH3), 1.34 ppm (t, J = 7.0 Hz, 6H, OCH2CH3),
2
1.71–1.86 ppm (m, 2H, CH2CH3), 3.77 ppm (dd, JPH = 9.9 Hz,
J = 5.8 Hz, 1H, CHOH), 4.12–4.22 ppm (m, 4H, OCH2).
4.2.8. Diethyl
a-hydroxypropylphosphonate (1h) [6]
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
0.95 ppm (t,
4.2.1. Diethyl
a
-hydroxy-4-nitrobenzylphosphonate (1a) [6]
J = 6.8 Hz, 3H, CH2CH3), 1.34 ppm (t, J = 7.0 Hz, 6H, OCH2CH3),
1.45–1.74 ppm (m, 4H, CH2CH2), 3.87 ppm (t, JPH = 4.9 Hz, 1H,
2
White solid, mp 86–88 8C. 1H NMR (300 MHz, CDCl3):
d
1.24–
1.32 ppm (m, 6H, CH3), 4.05–4.18 ppm (m, 4H, OCH2), 5.18 ppm (d,
CHOH), 4.13–4.22 ppm (m, 4H, OCH2).
2JPH = 12.2 Hz, 1H, CHOH), 7.68 ppm (d, J = 7.6 Hz, 2H, Ar-H),
8.23 ppm (d, J = 8.3 Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3):
d
4.3. Typical procedure for the preparation of
from -hydroxyphosphonates 1
a-bromophosphonates 2
16.3 ppm (d, 3JPC = 5.6 Hz), 63.2 ppm (d, 2JPC = 7.6 Hz), 63.9 ppm (d,
a
1
2JPC = 7.2 Hz), 69.9 ppm (d, JPC = 158.4 Hz), 123.1, 127.6, 144.5,
147.3 ppm.
To a stirring mixture of DDQ (0.908 g, 4 mmol) and PPh3
(1.048 g, 4 mmol) in dry CH2Cl2 (10 mL) was added n-Bu4NBr
(1.288 g, 4 mmol) at room temperature. Then 1a (0.648 g, 2 mmol)
was added to the reaction mixture. The reaction was refluxed at
40 8C. The reaction mixture was turned dark red. After 8 h, the
reaction mixture was washed with saturated Na2CO3 solution
(3 mL Â 20 mL). The organic layer was separated and dried over
anhydrous Na2SO4 and filtered. Evaporation of the solvent afforded
a crude product that was purified by column chromatography on
silica gel using hexane/ethyl acetate (3:1) as an eluent to afford 2a
as a yellow oily compound (0.653 g, 93% yield).
4.2.2. Diethyl
a-hydroxy-3-nitrobenzylphosphonate (1b) [6]
White solid, mp 88–90 8C. 1H NMR (300 MHz, CDCl3):
d
1.25–
1.33 ppm (m, 6H, CH3), 4.04-4.19 ppm (m, 4H, OCH2), 5.18 ppm
2
(dd, JPH = 11.3 Hz, J = 5.6 Hz, 1H, CHOH), 5.47 ppm (br, 1H, OH),
7.53 ppm (t, J = 7.9 Hz, 1H, Ar-H), 7.82 ppm (d, J = 7.5 Hz, 1H, Ar-H),
8.17 ppm (d, J = 8.0 Hz, 1H, Ar-H), 8.42 ppm (s, 1H, Ar-H); 13C NMR
3
(75 MHz, CDCl3):
d
16.0 ppm (d, JPC = 5.7 Hz), 63.1 ppm (d,
2JPC = 7.5 Hz), 63.6 ppm (d, 2JPC = 7.2 Hz), 69.3 ppm (d,
1JPC = 161.0 Hz), 121.7, 122.4, 128.7, 132.9, 139.5, 147.8 ppm.
4.2.3. Diethyl
a
-hydroxy-2-nitrobenzylphosphonate (1c) [6]
4.3.1. Diethyl
a
-bromo-4-nitrobenzylphosphonate (2a) [9]
1.22 ppm (t, J = 7.0 Hz,
Yellowish solid, mp 127–129 8C. 1H NMR (300 MHz, CDCl3):
d
Yellow oil. 1H NMR (300 MHz, CDCl3):
d
1.20 ppm (t, J = 7.0 Hz, 3H, CH3), 1.28 ppm (t, J = 7.0 Hz, 3H, CH3),
4.06–4.15 ppm (m, 4H, OCH2), 6.26 ppm (d, JPH = 14.2 Hz, 1H,
3H, CH3), 1.35 ppm (t, J = 7.0 Hz, 3H, CH3), 3.95–4.16 ppm (m, 2H,
OCH2), 4.21–4.30 ppm (m, 2H, OCH2), 4.91 ppm (d, JPH = 13.9 Hz,
2
2
CHOH), 7.46 ppm (t, J = 7.8 Hz, 1H, Ar-H), 7.69 ppm (t, J = 7.5 Hz,
1H, Ar-H), 8.00 ppm (d, J = 8.0 Hz, 2H, Ar-H); 13C NMR (75 MHz,
1H, CHBr), 7.74 ppm (d, J = 8.5 Hz, 2H, Ar-H), 8.22 ppm (d,
J = 8.6 Hz, 2H, Ar-H). 13C NMR (75 MHz, CDCl3):
d 16.1 ppm (dd,
3
2
CDCl3):
d
16.2 ppm (d, JPC = 8.7 Hz), 63.2 ppm (d, JPC = 7.5 Hz),
3JPC = 1.8 Hz, 5.6 Hz), 16.3 ppm (dd, 3JPC = 1.9 Hz, 5.6 Hz), 39.6 ppm
(d, 1JPC = 156.2 Hz), 64.1 ppm (dd, 2JPC = 2 Hz, 7 Hz), 64.6 ppm (dd,
2JPC = 2 Hz, 7 Hz), 123.6, 130.4, 141.9, 147.8 ppm.
2
1
64.1 ppm (d, JPC = 7.0 Hz), 65.5 ppm (d, JPC = 159.4 Hz), 124.6,
128.3, 128.9, 133.1, 133.2, 147.5 ppm.

J.-P. Fu et al. / Journal of Fluorine Chemistry 132 (2011) 636–640
639
4.3.2. Diethyl
a
-bromo-3-nitrobenzylphosphonate (2b) [9]
1.24 ppm (t, J = 7.0 Hz,
4.3.8. Diethyl
a
-bromopropylbenzylphosphonate (2h) [8]
0.92 ppm (t,
Yellow oil. 1H NMR (300 MHz, CDCl3):
d
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
3H, CH3), 1.35 ppm (t, J = 7.0 Hz, 3H, CH3), 4.00–4.13 ppm (m, 2H,
OCH2), 4.14–4.30 ppm (m, 2H, OCH2), 4.93 ppm (d, JPH = 13.6 Hz,
1H, CHBr), 7.56 ppm (t, J = 8.0 Hz, 1H, Ar-H), 7.95 ppm (d, J = 7.7 Hz,
1H, Ar-H), 8.20 ppm (d, J = 8.0 Hz, 1H, Ar-H), 8.39 ppm (s, 1H, Ar-
J = 7.3 Hz, 3H, CH2CH3), 1.34 ppm (t, J = 7.1 Hz, 6H, OCH2CH3),
1.39–1.49 ppm (m, 1H, CH2CH3), 1.61–1.76 ppm (m, 1H, CH2CH3),
1.81–1.94 ppm (m, 1H, CH2CHBr), 1.96–2.09 ppm (m, 1H,
2
2
CH2CHBr), 3.79 ppm (dt, JPH = 10.2 Hz, J = 3.3 Hz, CHBr), 4.13–
3
H). 13C NMR (75 MHz, CDCl3):
d
16.2 ppm (d, JPC = 5.8 Hz),
2.26 ppm (m, 4H, OCH2CH3). 13C NMR (75 MHz, CDCl3):
d 12.94,
16.3 ppm (d, 3JPC = 5.8 Hz), 39.6 ppm (d, 1JPC = 157.1 Hz),
64.2 ppm (d, JPC = 7.0 Hz), 64.5 ppm (d, JPC = 7.0 Hz), 124.7,
16.3 ppm (d, JPC = 5.8 Hz), 20.8 ppm (d, JPC = 12.8 Hz), 34.1 ppm,
41.9 ppm (d, 1JPC = 157.1), 63.3 ppm (d, 2JPC = 6.8 Hz), 63.6 ppm (d,
2JPC = 7.0 Hz).
3
3
2
2
124.3, 129.6, 135.4, 136.9, 148.0 ppm.
4.3.3. Diethyl
a
-bromo-2-nitrobenzylphosphonate (2c) [9]
1.15 ppm (t,
4.4. Typical procedure for the preparation of
a,a-
Yellowish oil. 1H NMR (300 MHz, CDCl3):
d
bromofluorophosphonates 3 from -bromophosphonates 2
a
J = 7.0 Hz, 3H, CH3), 1.35 ppm (t, J = 7.0 Hz, 3H, CH3), 3.92–
4.09 ppm (m, 2H, OCH2), 4.23–4.33 ppm (m, 2H, OCH2),
6.00 ppm (d, JPH = 14.8, 1H, CHBr), 7.49 ppm (t, J = 7.7 Hz, 1H,
Ar-H), 7.66 ppm (t, J = 7.5 Hz, 1H, Ar-H), 7.91 ppm (d, J = 8.1 Hz, 1H,
Ar-H), 8.17 ppm (d, J = 7.9 Hz, 1H, Ar-H). 13C NMR (75 MHz, CDCl3):
To a solution of a-bromophosphonate 2a (0.31 g, 0.88 mmol)
2
in dry THF (10 ml) at À78 8C was added a solution of NaHMDS
(0.66 ml, 2.0 M in THF, 1.32 mmol) over a period of 10 min under
an atmosphere of dry argon. The resulting dark red solution was
stirred for 1 h at À78 8C. A solution of NFSI (0.36 g, 1.15 mmol) in
dry THF (5 ml) was added over a period of 10 min and the
resulting solution stirred at À78 8C for 2 h. The solution was
allowed to warm to À30 8C and a precipitate formed and
quenched with 0.01 M hydrochloric acid. Volatiles were re-
moved under reduced pressure and the residue extracted with
CH2Cl2. The organic layers were combined and concentrated by
rotary evaporation. The crude material was purified via flash
column chromatography of silica gel to yield 3a as yellow oil
(0.28 g, 87% yield).
3
3
d
16.0 ppm (d, JPC = 5.7 Hz), 16.3 ppm (d, JPC = 5.8 Hz), 34.0 ppm
1
2
(d, JPC = 157.3 Hz), 64.0 ppm (d, JPC = 7.1 Hz), 64.7 ppm (d,
2JPC = 7.1 Hz), 124.7, 129.4, 129.5, 133.2, 133.3, 148.1 ppm.
4.3.4. Diethyl
a
-bromo-4-cyanobenzylphosphonate (2d) [9]
1.20 ppm (t,
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
J = 6.0 Hz, 3H, CH3), 1.35 ppm (t, J = 6.0 Hz, 3H, CH3), 3.96–
4.14 ppm (m, 2H, OCH2), 4.22–4.27 ppm (m, 2H, OCH2),
2
4.87 ppm (d, JPH = 13.7, 1H, CHBr), 7.67 ppm (s, 4H, Ar-H). 13C
3
NMR (75 MHz, CDCl3):
d
16.0 ppm (d, JPC = 5.7 Hz), 16.5 ppm (d,
3JPC = 5.7 Hz), 40.3 ppm (d, 1JPC = 156.5 Hz), 64.3 ppm (d,
2JPC = 6.9 Hz), 64.7 ppm (d, JPC = 7.1 Hz), 112.8, 118.3, 130.4,
4.4.1. Diethy
a
,
a
-bromofluoro-4-nitrobenzylphosphonate (3a)
1.22 ppm (t, J = 7.0 Hz, 3H,
2
132.4, 140.1 ppm. HRMS for C12H15BrNO3PH [M+H]+: calculated
332.0051; found 332.0047.
White. 1H NMR (300 MHz, CDCl3):
d
CH3), 1.43 (t, J = 7.0 Hz, 3H, CH3), 3.97–4.18 ppm (m, 2H, OCH2),
4.39–4.45 ppm (m, 2H, OCH2), 7.87 ppm (d, J = 8.4 Hz, 2H, Ar-H),
4.3.5. Diethyl
a
-bromo-3-cyanobenzylphosphonate (2e)
1.16 ppm (t,
8.28 ppm (d, J = 8.5 Hz, 2H, Ar-H). 13C NMR (75 MHz, CDCl3):
d 16.2
Yellowish oil. 1H NMR (300 MHz, CDCl3):
d
(d, 3JPC = 5.6 Hz), 16.3 (d, 3JPC = 5.6 Hz), 65.4 ppm (d, 2JPC = 7.5 Hz),
66.4 ppm (d, 2JPC = 6.2 Hz), 98.3 ppm (dd, 1JPC = 188.1 Hz,
J = 7.1 Hz, 3H, CH3), 1.29 ppm (t, J = 6.0 Hz, 3H, CH3), 3.90–
4.11 ppm (m, 2H, OCH2), 4.14–4.24 ppm (m, 2H, OCH2), 4.81 (d,
2JPH = 13.5, 1H, CHBr), 7.43 ppm (t, J = 7.5 Hz, 1H, Ar-H), 7.57 ppm
(d, J = 7.7 Hz, 1H, Ar-H), 7.78 ppm (d, J = 8.4 Hz, 2H, Ar-H). 13C NMR
2
1JFC = 267.9 Hz), 123.4, 127.1, 143.6 ppm (d, JFC = 20.1 Hz),
148.5 ppm. 19F NMR (282 MHz, CDCl3):
d
À129.0 ppm (d,
2JPF = 80.4 Hz). HRMS for C11H14BrFNO5PNa [M+Na]+: calculated
3
(75 MHz, CDCl3):
d
16.2 ppm (d, JPC = 5.7 Hz), 16.3 ppm (d,
391.9669; found 391.9671.
3JPC = 5.8 Hz), 39.7 (d, JPC = 157.3 Hz), 64.1 ppm (d, JPC = 7.0 Hz),
64.5 ppm (d, 2JPC = 7.1 Hz), 112.8, 118.0, 129.5, 132.4, 132.9, 133.9,
136.5 ppm. HRMS for C12H15BrNO3PH [M+H]+: calculated
332.0051; found 332.0047.
1
2
4.4.2. Diethy
a
,
a
-bromofluoro-3-nitrobenzylphosphonate (3b)
1.25 ppm (t, J = 7.0 Hz,
Yellow oil. 1H NMR (300 MHz, CDCl3):
d
3H, CH3), 1.43 (t, J = 7.0 Hz, 3H, CH3), 4.03–4.22 ppm (m, 2H, OCH2),
4.36–4.45 ppm (m, 2H, OCH2), 7.64 ppm (t, J = 8 Hz, 1H, Ar-H),
8.06 ppm (d, J = 7.8 Hz, 1H, Ar-H), 8.28 ppm (d, J = 8.2 Hz, 1H, Ar-
H), 8.53 ppm (s, 1H, Ar-H). 13C NMR (75 MHz, CDCl3):
d 16.1 ppm
4.3.6. Diethyl
a
-bromo-3-methoxybenzylphosphonate (2f)
1.15 ppm (t,
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
3
3
J = 7.1 Hz, 3H, CH3), 1.32 ppm (t, J = 7.1 Hz, 3H, CH3), 3.80 ppm (s,
3H, OCH3), 3.82–3.93 ppm (m, 1H, OCH2), 3.98–4.11 ppm (m, 1H,
OCH2), 4.15–4.26 ppm (m, 2H, OCH2), 4.81 (d, 2JPH = 12.9 Hz, CHBr),
6.85 ppm (d, J = 8.1 Hz, 1H, Ar-H), 7.10 ppm (d, J = 9.0 Hz, 2H, Ar-
(d, JPC = 5.6 Hz), 16.3 ppm (d, JPC = 5.6 Hz), 65.5 ppm (d,
2JPC = 7.3 Hz), 66.3 ppm (d, 2JPC = 7.3 Hz), 98.3 ppm (dd,
1JPC = 189.8 Hz, JFC = 267.3 Hz), 120.9, 125.3, 129.3, 132.2,
139.3 ppm (d, JFC = 20.8 Hz), 147.9 ppm. 19F NMR (282 MHz,
1
2
H), 7.24 ppm (t, J = 7.9 Hz, 1H, Ar-H). 13C NMR (75 MHz, CDCl3):
d
CDCl3):
d
À128.9 ppm (d, 2JPF = 82.3 Hz). HRMS for
16.2 ppm (d, 3JPC = 5.9 Hz), 16.4 ppm (d, 3JPC = 5.9 Hz), 41.4 ppm (d,
C
11H14BrFNO5PNa [M+Na]+: calculated 391.9669; found 391.9667.
2
1JPC = 158.0 Hz), 55.3, 64.1 ppm (d, JPC = 4.6 Hz), 64.2 ppm (d,
2JPC = 4.7 Hz), 114.7, 115.0, 112.8, 129.6, 135.8, 159.5 ppm. HRMS
4.4.3. Diethy
a
,
a
-bromofluoro-2-nitrobenzylphosphonate (3c)
1.21 ppm (t, J = 7.0 Hz,
for C12H18BrO4PH [M+H]+: calculated 337.0204; found 337.0199.
Yellow oil. 1H NMR (300 MHz, CDCl3):
d
3H, CH3), 1.44 (t, J = 7.0 Hz, 3H, CH3), 4.00–4.16 ppm (m, 2H,
OCH2), 4.25–4.53 ppm (m, 2H, OCH2), 7.44 ppm (d, J = 7.1 Hz, 1H,
Ar-H), 7.51–7.61 ppm (m, 2H, Ar-H), 8.08 (d, J = 7.4 Hz, 1H, Ar-H).
4.3.7. Diethyl
a-bromoethylphosphonate (2g) [8]
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
1.10 ppm (t,
J = 7.2 Hz, 3H, CH2CH3), 1.32 ppm (t, J = 7.1 Hz, 6H, OCH2CH3),
1.80–1.94 ppm (m, 1H, CH2), 2.09-2.22 ppm (m, 1H, CH2), 3.74 (dt,
2JPH = 12.9 Hz, J = 3.3 Hz, 1H, CHBr), 4.13–4.25 ppm (m, 4H, OCH2).
13C NMR (75 MHz, CDCl3):
20.7, 25.9 ppm (dd, JPC = 1.9 Hz, J = 5.9 Hz), 44.0 ppm (d,
1JPC = 156.8 Hz), 63.5 ppm (d, 2JPC = 6.9 Hz), 63.8 ppm (d,
2JPC = 6.9 Hz).
13C NMR (75 MHz, CDCl3):
d
16.1 ppm (d, 3JPC = 5.6 Hz), 16.4 ppm
3
2
(d, JPC = 5.6 Hz), 65.7 ppm (d, JPC = 7.7 Hz), 66.9 ppm (d,
2JPC = 7.5 Hz), 97.4 ppm (dd, JPC = 189.0 Hz, JFC = 268.9 Hz),
1
1
d
12.4, 12.6, 16.3 ppm (d, 3JPC = 5.9 Hz),
123.5, 124.4, 129.1, 129.6, 130.6, 131.1 ppm. 19F NMR
3
2
(282 MHz, CDCl3):
d
À128.9 ppm (d, JPF = 82.1 Hz). HRMS
for C11H14BrFNO5PNa [M+Na]+: calculated 391.9669; found
391.9666.

640
J.-P. Fu et al. / Journal of Fluorine Chemistry 132 (2011) 636–640
2
4.4.4. Diethy
a
,
a
-bromofluoro-4-cyanobenzylphosphonate (3d)
1.19 ppm (t,
À124.6 ppm (ddd, JPF = 84.6 Hz). HRMS for C7H15BrFO3PH
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
[M+H]+: calculated 277.0004; found 277.0002.
J = 7.0 Hz, 3H, CH3), 1.39 ppm (t, J = 7.0 Hz, 3H, CH3), 3.91–
4.16 ppm (m, 2H, OCH2), 4.35–4.46 ppm (m, 2H, OCH2),
7.73 ppm (d, J = 7.1 Hz, 2H, Ar-H), 7.80 ppm (d, J = 8.0 Hz, 2H,
4.4.8. Diethy
a,a-bromofluoropropylphosphonate (3h)
Colourless oil. 1H NMR (300 MHz, CDCl3):
d 1.01 ppm (t,
3
Ar-H). 13C NMR (75 MHz, CDCl3):
d
16.3 ppm (d, JPC = 5.6 Hz),
J = 7.5 Hz, 3H, CH2CH3), 1.39 ppm (t, J = 7.0 Hz, 3H, OCH2CH3),
1.40 ppm (t, J = 7.0 Hz, 3H, OCH2CH3), 1.67–1.85 ppm (m, 2H,
CH2CH3), 2.11–2.37 ppm (m, 2H, CH2CH2), 4.23-4.44 ppm (m, 4H,
16.5 ppm (d, 3JPC = 5.6 Hz), 65.5 ppm (d, 2JPC = 7.2 Hz), 66.5 ppm (d,
2JPC = 7.2 Hz), 98.5 ppm (dd, 1JPC = 190.0 Hz, 1JFC = 267.8 Hz), 113.9,
3
118.1, 126.9 ppm (d, JFC = 9.0 Hz), 132.2, 142.2 ppm (d,
OCH2). 13C NMR (75 MHz, CDCl3):
d 13.5, 16.4, 17.3 ppm (d,
2JFC = 20.2 Hz). 19F NMR (282 MHz, CDCl3):
d
À129.6 ppm (d,
3JPC = 6.6 Hz), 40.4 ppm (d, 2JPC = 6.1 Hz), 41.8 ppm (d,
2JPC = 6.1 Hz), 64.6 ppm (d, 2JPC = 6.9 Hz), 65.4 ppm (d,
2JPF = 80.7 Hz). HRMS for C12H14BrFNO3PNa [M+Na]+: calculated
1
1
371.9771; found 371.9767.
2JPC = 7.1 Hz), 104.6 ppm (dd, JPC = 189.9 Hz, JFC = 265.4 Hz), 19F
NMR (282 MHz, CDCl3):
for C8H17BrFO3PH [M+H]+: calculated 291.0162; found 291.0157.
d
À122.9 ppm (ddd, 2JPF = 84.6 Hz). HRMS
4.4.5. Diethy
a
,
a
-bromofluoro-3-cyanobenzylphosphonate (3e)
1.17 ppm (t,
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
J = 7.0 Hz, 3H, CH3), 1.39 ppm (t, J = 7.0 Hz, 3H, CH3), 3.89–
4.03 ppm (m, 2H, OCH2), 4.34–4.45 ppm (m, 2H, OCH2),
Acknowledgements
7.70 ppm (d, J = 8.4 Hz, 2H, Ar-H), 7.80 ppm (d, J = 7.2 Hz, 2H,
Financial support from Natural Science Foundation Project of
CQ CSTC (2009BA5051) is gratefully acknowledged.
3
Ar-H). 13C NMR (75 MHz, CDCl3):
d
16.2 ppm (d, JPC = 5.6 Hz),
16.4 ppm (d, 3JPC = 5.6 Hz), 65.4 ppm (d, 2JPC = 7.3 Hz), 66.4 ppm (d,
2JPC = 7.3 Hz), 98.5 ppm (dd, 1JPC = 188.4 Hz, 1JFC = 267.8 Hz), 111.4,
Appendix A. Supplementary data
113.7, 117.9, 126.7, 132.1, 141.8 ppm. 19F NMR (282 MHz, CDCl3):
2
d
À129.6 ppm (d, JPF = 80.7 Hz). HRMS for C12H14BrFNO3PNa
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2011.06.016.
[M+Na]+: calculated 371.9771; found 371.9768.
4.4.6. Diethy
a
,
a
-bromofluoro-3-methoxycyanobenzylphosphonate
1.17 ppm (t, J = 7.0 Hz,
References
(3f)
Yellow oil. 1H NMR (300 MHz, CDCl3):
d
[1] J. Boutagy, R. Thomas, Chem. Rev. 74 (1974) 87–99.
[2] (a) S. Kumar, B. Zhou, F. Liang, W.Q. Wang, Z. Huang, Z.Y. Zhang, Proc. Natl. Acad.
Sci. U.S.A. 101 (2004) 7943–7948;
3H, CH3), 1.40 ppm (t, J = 7.0 Hz, 3H, CH3), 3.83 ppm (s, 3H, OCH3),
3.85–3.97 ppm (m, 1H, OCH2), 4.02–4.15 ppm (m, 1H, OCH2), 4.33–
4.43 ppm (m, 2H, OCH2), 6.92 ppm (d, J = 7.0 Hz, 1H, Ar-H), 7.26–
(b) W.P. Taylor, Z.Y. Zhang, T.S. Widlanski, Bioorg. Med. Chem. 4 (1996) 1515–1520;
(c) V. Pham, W. Zhang, V. Chen, T. Whitney, J. Yao, D. Froese, A.D. Friesen, J.M. Diakur,
W. Haque, J. Med. Chem. 46 (2003) 3680–3687.
7.35 ppm (m, 3H, Ar-H). 13C NMR (75 MHz, CDCl3):
d 16.2 ppm (d,
3
3JPC = 5.6 Hz), 16.4 ppm (d, JPC = 5.5 Hz), 55.4 ppm, 65.2 ppm (d,
[3] (a) K. Shen, Y.F. Keng, L. Wu, X.L. Guo, D.S. Lawrence, Z.Y. Zhang, J. Biol. Chem. 276
(2001) 47311–47319;
2JPC = 7.1 Hz), 65.9 ppm (d, 2JPC = 7.3 Hz), 99.4 ppm (dd,
1JPC = 189.5 Hz, JFC = 267.1 Hz), 111.2, 115.8, 118.2, 129.4, 137.9
1
(b) J.P. Sun, A.A. Fedorov, S.Y. Lee, X.L. Guo, K. Shen, D.S. Lawrence, S.C. Almo, Z.Y.
Zhang, J. Biol. Chem. 278 (2003) 12406–12414;
(c) S.Y. Lee, F. Liang, X.L. Guo, L. Xie, S.M. Cahill, M. Blumenstein, H. Yang, D.S.
Lawrence, Z.Y. Zhang, Angew. Chem. Int. Ed. 44 (2005) 4242–4244.
[4] (a) N.A. Caplan, C.I. Pogson, D.J. Hayes, G.M. Blackburn, J. Chem. Soc., Perkin Trans.
13 (2000) 421–437;
159.3 ppm. 19F NMR (282 MHz, CDCl3):
d
À127.4 ppm (d,
2JPF = 82.6 Hz). HRMS for C12H17BrFO4PNa [M+Na]+: calculated
376.9924; found 376.9923.
(b) F. Benayoud, D.J. deMendonca, C.A. Digits, G.A. Moniz, T.C. Sanders, G.B.
Hammond, J. Org. Chem. 61 (1996) 5159–5164.
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(b) Q. Wang, Z. Huang, C. Ramachandran, A.N. Dinaut, S.D. Taylor, Bioorg. Med.
Chem. Lett. 8 (1998) 345–350;
(c) Y. Xu, L. Qian, G.D. Prestwich, Org. Lett. 5 (2003) 2267–2270.
[6] (a) D. Wu, Y.H. He, R.C. Tang, Z. Guan, Synlett 13 (2009) 2180;
(b) Z. Guan, D. Wu, J.P. Fu, Y.H. He, Heteroat. Chem. 4 (2010) 250–255.
[7] M. Drescher, Y.F. Li, F. Hammerschmidt, Tetrahedron 51 (1995) 4933–4946.
[8] T. Gajda, Phosphorus, Sulfur Silicon Relat. Elem. 53 (1990) 327–331.
[9] H. Firouzabadi, N. Iranpoor, S. Sobhani, Tetrahedron 60 (2004) 203–210.
4.4.7. Diethy
a,a-bromofluoroethylphosphonate (3g)
Colourless oil. 1H NMR (300 MHz, CDCl3):
d
1.20 ppm (t,
J = 7.2 Hz, 3H, CH2CH3), 1.39–1.42 ppm (m, 6H, OCH2CH3), 2.30–
2.48 ppm (m, 2H, CH2), 4.23–4.41 ppm (m, 4H, OCH2). 13C NMR
3
(75 MHz, CDCl3):
d
8.18 ppm (d, JPC = 4.9 Hz), 16.3 ppm (d,
3JPC = 4.9 Hz), 33.2 ppm (d, 2JPC = 19.9 Hz), 64.6 ppm (d,
2JPC = 7.1 Hz), 65.3 ppm (d, 2JPC = 7.0 Hz), 104.5 ppm (dd,
1JPC = 189.5 Hz, JFC = 265.3 Hz). 19F NMR (282 MHz, CDCl3):
d
1