One-pot synthesis of 4,4-difluoro-3-oxo-2-(triphenylphosphoranylidene)-δ-lactones by Reformatsky reaction

Article abstract of DOI:10.1016/j.jfluchem.2009.07.018

In th presence of zinc and a catalytic amount of cuprous chloride, ethyl 4-bromo-4,4-difluoro-3-oxo-2-(triphenylphosphoranylidene)butanoate 1 reacted with carbonyl compounds to give the gem-difluoromethylenated 2-(triphenylphosphoranylidene)-δ-lactones 4

Full text of DOI:10.1016/j.jfluchem.2009.07.018

Journal of Fluorine Chemistry 130 (2009) 974–978
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
One-pot synthesis of 4,4-difluoro-3-oxo-2-(triphenylphosphoranylidene)-
lactones by Reformatsky reaction
d-
Xiang Fang a,b, Xueyan Yang a, Min Zhao a, Qingfeng Di a, Xiaoguang Wang a, Fanhong Wu a,b,
*
a Laboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, China
b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
A R T I C L E I N F O
A B S T R A C T
Article history:
In th presence of zinc and a catalytic amount of cuprous chloride, ethyl 4-bromo-4,4-difluoro-3-oxo-2-
(triphenylphosphoranylidene)butanoate reacted with carbonyl compounds to give the gem-
difluoromethylenated 2-(triphenylphosphoranylidene)-
Received 9 March 2009
Received in revised form 24 July 2009
Accepted 24 July 2009
1
d
-lactones 4 in moderate to high yields.
ß 2009 Elsevier B.V. All rights reserved.
Available online 3 August 2009
Keywords:
Reformatsky reaction
Zinc
Cuprous chloride
gem-Difluoromethylenated d-lactones
1. Introduction
employed in the synthesis of the lactones containing difluor-
omethylene moiety [7]. Although there are other synthetic
methods of difluoromethylene-lactones in the literatures [8,9],
the most advantageous and direct method is to utilize the
d
-Lactone is structural element commonly found in a large
number of natural products and biologically active compounds [1].
Introduction of fluorine atoms or fluorinated groups into lactone
can greatly change the biological activity which has attracted
many attentions in recent years. Among the fluorine-modified
compounds, gem-difluoromethylene moiety (CF2) has been proved
to be a key structural unit in many fluorinated compounds of
biological and pharmaceutical significance [2]. This group has been
suggested by Blackburn as an isopolar and isosteric substituent for
oxygen [3] and its utilization is one of the strategies for the
modification of biologically active compounds. For example, 20-
deoxy-20,20-difluorocytidine (gemcitabine) has been approved as a
drug for solid tumor treatment [4]. There are two kind methods to
introduce the difluoromethylene group, such as direct gem-
difluorination and difluoromethylenation. So far, the Refromatsky
reaction of halogeno-difluoromethylated compounds is the most
common approach in the construction of molecules derived from
Refromatsky reaction to prepare such kind of d-lactones [10,11].
In this paper, we wish to describe our results of the one-pot
reaction of ethyl 4-bromo-4,4-difluoro-3-oxo-2-(triphenylpho-
sphoranylidene)butanoate 1 with carbonyl compounds to give
the difluoromethylenated valerolactones.
2. Results and discussion
As shown in Scheme 1, ethyl 4-bromo-4,4-difluoro-3-oxo-2-
(triphenylphosphoranylidene)butanoate 1 was easily prepared by
the same procedure of Hamper [12] from the reaction of
bromodifluoroacetic anhydride [13] with readily available phos-
phonium salt in 85% yield.
When 1 was treated with benzaldehyde in the presence of acid-
washed zinc dust in diethyl ether [6] or THF at room temperature,
no reaction occurred (entries 1 and 2, Table 1). While the reaction
was conducted in refluxing THF, the addition product 3a was
formed and the difluoromethylenated valerolactone 4a was
obtained on a prolonged reaction time (entry 3, Table 1). The
effects of solvent, temperature, reaction time and the ratio of
cuprous chloride on the reaction of 1 with benzaldehyde 2a
(Scheme 2) were briefly investigated and the results are
summarized in Table 1. Some literatures have demonstrated that
zinc metal could be activated in situ by simple treatment with a
CF2-synthons [5,6]. The resultant
carbonyl compounds are valuable intermediates and can be
a,a-difluorinated b-hydroxy
* Corresponding author at: Laboratory for Advanced Material and Institute of Fine
Chemicals, School of Chemistry and Molecular Engineering, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Tel.: +86 21 64253530; fax: +86 21 64253074.
E-mail address: wfh@ecust.edu.cn (F. Wu).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.07.018

X. Fang et al. / Journal of Fluorine Chemistry 130 (2009) 974–978
975
Scheme 1.
Scheme 3.
Table 1
Optimization of reaction conditions for the Reformatsky reaction of
benzaldehyde (see Scheme 2).
1 with
Entry
CuCl (equiv.)
Slovent
Temperature
Time (h)
Results
a
1
2
0.3
–
Ether
THF
0 8C–r.t.
r.t.
2
18
40
10
16
40
40
40
27
27
–
a
–
3
–
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
3a and 4a
1 and 3a
4
0.3
0.3
0.3
0.3
1
THF
Scheme 4.
5
THF
1, 3a and 4a
4a, 45%c
4a, 66%
6
THFb
THF
7
8
THF
4a, 67%
9
0.3
0.3
Dioxane
Toluene
4a, 66%
4a, 48%c
10
a
Addition product 3a or 4a was not detected.
THF was not dried.
b
c
Byproduct HCF2COC(PPh3)CO2Et was isolated.
Scheme 5.
Table 2
Reactions of 1 with aldehydes or ketones.
catalytic amount of copper (I) chloride (0.3 equiv.) in refluxing
dioxane, affording 4 in good yields (Scheme 3). Various sub-
stituents on the phenyl ring, either electron-withdrawing or
electron-donating groups, such as cyano, chloro, bromo, methyl,
methoxy, etc., could be tolerated and had little effect on the yields
except for p-nitrobenzaldehyde which gave no product under
various conditions [15]. Under similar conditions, the reaction also
Entry
2
R1
R2
Product 4
Yield (%)a
1
2
2a
Ph
H
4a
4b
4c
4d
4e
4f
66
56
63
80
64
70
–
2b
2c
2d
2e
2f
4-CH3C6H4
4-OCH3C6H4
4-BrC6H4
4-ClC6H4
2-ClC6H4
4-NO2C6H4
4-CNC6H4
(CH3)2CH
PhCH5CH
CH25CH
Ph
H
3
H
4
H
5
H
6
H
proceeded with
a,b-unsaturated aldehydes, such as acrolein and
7
2g
2h
2i
H
4g
4h
4i
cinnamaldehyde in moderate yields (entries 10 and 11, Table 2).
Shen reported that fluorinated (dicarbonylmethylene) triphe-
nylphosphoranes were stable and unreactive toward aldehydes or
ketones due to the strong electron-withdrawing effect of the two
carbonyl groups, but they reacted with a variety of Grignard
8
H
85
75
47
31
56b
54b
9
H
10
11
12
13
2j
H
4j
2k
2l
H
4k
4l
CH3
CH3
2m
4-CH3C6H4
4m
reagents and lithium reagents to give corresponding
a,b-
a
Isolated yields based on 1.
b
unsaturated esters through the protonation and elimination of
triphenylphosphine oxide [16,17]. We conducted the reaction of 4
with excess amount of benzaldehyde, no reaction occurred.
Unfortunately, the reaction of 4 with n-butyl lithium also failed
10–20% of HCF2COC(PPh3)CO2Et was isolated.
small quantity of cuprous chloride [14]. From the results shown in
entries 3 and 7 in our experiments, 0.3 equiv. of cuprous chloride
could really accelerate the formation of difluoromethylenated
valerolactone 4a. However, increasing the ratio of CuCl could not
improve the yield efficiently (entry 8, Table 1). When 1 reacted
with 2a in the presence of zinc dust (3.0 equiv.) and cuprous
chloride (0.3 equiv.) in refluxing anhydrous dioxane for 27 h, the
expected difluoromethylenated valerolactone 4a was obtained in
one-pot in 66% yield (entry 9, Table 1). The yields were decreased
in wet THF and toluene due to the formation of byproduct
HCF2COC(PPh3)CO2Et (entries 6 and 10, Table 1).
With the optimized reaction conditions in hand, we further
investigated the Reformatsky reactions of 1 with a variety of
aromatic aldehydes (entries 1–8, Table 2), aliphatic alkyl aldehydes
(entry 9, Table 2) and aromatic ketones (entries 12 and 13, Table 2)
in the presence of both acid-washed zinc dust (3 equiv.) and a
to give
a
,
b
-unsaturated lactone while the lactone ring of 4 was
-carbonyl of
decomposed. Meanwhile we failed to reduce the
b
lactone 4 when NaBH4 or NaBH4 with Lewis acids were used as
reducing agents (Scheme 4). And 4 was decomposed if LiAlH4 was
used.
It was reported that the Reformatsky reactions of halodifluor-
oacetate with aldimines and chiral 1,3-oxazolidines usually gave
difluorinated b-lactams [18–21]. However, the similar reactions of
4-bromo-4,4-difluoroacetoacetate with aldimines and ketimines
were reported to give complicated results [22]. We found that the
Reformatsky-imine addition reaction of 1 with a series of aromatic
aldimines provided the correspondent amines 6 in low yields and
the
d-lactams were not detected under the above reaction
conditions (Scheme 5), possibly due to the weak of reactivity of
Scheme 2.

976
X. Fang et al. / Journal of Fluorine Chemistry 130 (2009) 974–978
q, J = 7.2 Hz), 0.88 (3H, t, J = 7.2 Hz). 19F NMR (CDCl3, 470 MHz)
d
Table 3
Reactions of 1 with aldimines.
ꢀ55.89 (2F, s). 13C NMR (CDCl3, 125.8 MHz)
d
177.6 (2JCF = 20 Hz),
166.4 (2JCP = 13 Hz), 134.0 (3JCP = 10 Hz), 133.1, 129.6
Entry
5
R1
R2
Product
Yield (%)a,b
1
(3JCP = 13 Hz), 125.0 (1JCP = 94 Hz), 116.0 (CF2, JCF = 318 Hz,
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
Ph
6a
6b
6c
6d
6e
6f
30
23
–
3JCP = 14 Hz), 68.7 (1JCP = 111 Hz), 60.7, 14.3. EI-MS (m/z) 506
(M++2, 2), 504 (M+, 2), 461 (3), 459 (3), 375 (100), 347 (9), 262 (44),
183 (37). IR (cmꢀ1, KBr) 1689, 1586, 1569, 690. HRMS calcd for
4-ClC6H4
2-OCH3C6H4
4-CNC6H4
Ph
Ph
Ph
Ph
25
15
–
4-OCH3C6H4
2-ClC6H4
4-CF3C6H4
C24H20BrF2O3P: 504.0302, found 504.0301.
Ph
5g
Ph
6g
–
4.2. Reformatsky addition reactions of 1 with aldehydes and ketones;
typical procedure
a
Isolated yields of pure compounds based on 1.
b
Most product was HCF2COC(PPh3)CO2Et.
A
solution of benzaldehyde (117 mg, 1.1 mmol) and 1
the corresponding aldimines. Most of the reactant 1 was reduced to
HCF2COC(PPh3)CO2Et. No addition products were either detected
(entries 3 and 6, Table 3) because of the much lower reactivities of
sterically bulky 5c and 5f.
(505 mg, 1 mmol) in anhydrous dioxane (1 mL) was added
dropwise to a heterogeneous solution of acid-washed zinc dust
(196 mg, 3.0 mmol) and CuCl (30 mg, 0.3 mmol) in anhydrous
dioxane (2 mL). The reaction mixture was stirred under reflux
for 27 h. Then saturated NH4Cl (5 mL) was added. Excess zinc
was removed by suction filtration and washed with EtOAc
(10 mL). The organic layer was separated. The aqueous layer was
extracted with EtOAc (3 ꢁ 10 mL), the organic layers were
combined and washed with water, brine, then dried over
Na2SO4. After evaporation of the solvents, the residue was
chromatographed on silica gel eluting with PE-EtOAc, 3:1 to give
4a (321 mg) in 66% yield.
3. Conclusions
In summary, we have described an efficient one-pot synthesis
of 4,4-difluoro-3-oxo-2-(triphenylphosphoranylidene)-d-valero-
lactones by the Reformatsky reactions of ethyl 4-bromo-4,4-
difluoro-3-oxo-2-(triphenylphosphoranylidene)butanoate 1 with
carbonyl compounds in the presence of zinc and a catalytic amount
of cuprous chloride. The preparation of ethyl 4,4-difluoro-3-oxo-2-
4.2.1. 5-Phenyl-4,4-difluoro-3-oxo-2-(triphenylphosphoranylidene)-
(triphenylphosphoranylidene)-5-aminopentanoates
6
by the
d
-valerolactone (4a)
White spumy solid, mp 81–82 8C. 1H NMR (CDCl3, 500 MHz)
Reformatsky-imine addition reactions of with aldimines
promoted by zinc-cuprous chloride was also resulted.
1
d
7.72–7.62 (8H, m), 7.56–7.51 (8H, m), 7.42–7.39 (4H, m), 5.60 (1H,
dd, J = 18 Hz, J = 7 Hz). 19F NMR (CDCl3, 470 MHz)
d
ꢀ122.8 (1F, dd,
4. Experimental
JF–F = 282 Hz, JF–H = 17 Hz), ꢀ123.5 (1F, d, JF–F = 282 Hz). 13C NMR
All melting points were uncorrected. IR spectra were measured
on a Nicolet Magna IR-550 spectrometer using potassium bromide
pellet. High resolution mass spectra were carried out on a Finnigan
GC-MS-4021 spectrometer. 1H NMR (500 MHz) and 13C NMR
(125.8 MHz) spectra were recorded on a Bruker AC-500 spectro-
meter with Me4Si as internal standard. 19F NMR spectra were
obtained on Bruker AC-500 (470 MHz) spectrometer in CDCl3 with
CFCl3 as external standard, downfield shifts being designated as
(CDCl3, 125.8 MHz)
d
179.6, 166.7 (2JCP = 11 Hz), 134.5
(3JCP = 10 Hz), 133.8, 129.7 (3JCP = 13 Hz), 128.9, 128.8, 123.1
(1JCP = 93 Hz), 109.6 (CF2, 1JCF = 254 Hz, 3JCP = 14 Hz), 69.6
(1JCP = 111 Hz). EI-MS (m/z) 486 (M+, 25), 349 (34), 301 (100),
183 (15). IR (cmꢀ1, KBr) 1690, 1628, 691. HRMS calcd for
C29H21F2O3P: 486.1196, found 486.1197.
4.2.2. 5-p-Tolyl-4,4-difluoro-3-oxo-2-(triphenylphosphoranylidene)-
negative. All chemical shifts (
d
) are expressed in ppm, coupling
d
-valerolactone (4b)
constants (J) are given in Hz. Anhydrous THF was dried and freshly
distilled from sodium wire. All other reagents were purified before
use according to the standard methods.
White solid, mp 217–219 8C. 1H NMR (CDCl3, 500 MHz)
d 7.60–
7.30 (17H, m), 7.08 (2H, d, J = 7.9 Hz), 5.48 (1H, dd, J = 16 Hz,
J = 9 Hz), 2.23 (3H, s). 19F NMR (CDCl3, 470 MHz)
d
ꢀ122.7 (1F, dd,
JF–F = 277 Hz, JF–H = 14 Hz), ꢀ123.4 (1F, d, JF–F = 277 Hz). 13C NMR
4.1. Procedure for the preparation of ethyl 4-bromo-4,4-difluoro-3-
oxo-2-(triphenylphosphoranylidene)butanoate
(CDCl3, 125.8 MHz) d
179.4 (2JCF = 13 Hz), 166.5 (2JCP = 11 Hz),
139.5, 134.3 (3JCP = 10 Hz), 133.6, 129.5 (3JCP = 13 Hz), 129.0, 128.5,
122.9 (1JCP = 93 Hz), 109.6 (CF2, JCF = 254 Hz, JCP = 14 Hz), 69.5
(1JCP = 111 Hz), 21.7. EI-MS (m/z) 500 (M+, 13), 349 (14), 301 (100),
183 (12). IR (cmꢀ1, KBr) 1690, 1628, 691. HRMS calcd for
1
3
A slurry of (carbethoxymethyl)-triphenylphosphonium bro-
mide (21.5 g, 50 mmol) in 100 mL of anhydrous THF was cooled in
an ice-water bath and treated with triethylamine (15 mL,
110 mmol). After being stirred for 30 min, the mixture was treated
dropwise with bromodifluoroacetic anhydride (18.25 g, 55 mmol)
and allowed to stir for 2 h. The mixture was filtered, the
precipitates were washed three times with cold THF, and the
filtrate was concentrated in vacuum to afford a yellow oily residue.
C
30H23F2O3P: 500.1353, found 500.1353.
4.2.3. 5-(4-Methoxyphenyl)-4,4-difluoro-3-oxo-2-
(triphenylphosphoranylidene)- -valerolactone (4c)
White spumy solid, mp 199–201 8C. 1H NMR (CDCl3, 500 MHz)
7.80–7.42 (17H, m), 6.91 (2H, d, J = 8.7 Hz), 5.56 (1H, dd,
J = 17.6 Hz, J = 7.5 Hz), 3.77 (3H, s). 19F NMR (CDCl3, 470 MHz)
ꢀ122.0 (1F, dd, JF–F = 277 Hz, JF–H = 14 Hz), ꢀ122.6 (1F, d, JF–
F = 277 Hz). 13C NMR (CDCl3, 125.8 MHz) 179.6 (2JCF = 25 Hz,
163.1, 160.9, 134.3
d
d
Trituration of the residue with 60 mL of water afforded
a
d
crystalline product, which was collected, washed with water,
and dried in vacuum to afford 21.5 g (85%) of a cream colored solid.
An analytical sample of 1, a white needle solid, was obtained by
recrystallization from methanol–water.
d
2JCP = 5 Hz),
166.7
(2JCP = 11 Hz),
(3JCP = 10.4 Hz), 133.7, 131.4, 130.1, 129.7, 129.6 (3JCP = 13 Hz),
127.5, 123.9, 122.9 (1JCP = 93 Hz), 114.2, 109.7 (CF2, JCF = 253 Hz,
1
4.1.1. Ethyl 4-bromo-4,4-difluoro-3-oxo-2-
3JCP = 14 Hz), 102.2, 69.5 (1JCP = 111 Hz), 55.8. EI-MS (m/z) 516 (M+,
8), 472 (11), 301 (100), 183 (11). IR (cmꢀ1, KBr) 1698, 1625, 1584,
1256, 1177, 1077, 690. HRMS calcd for C30H23F2O4P: 516.1302,
found 516.1301.
(triphenylphosphoranylidene)butanoate (1)
White needle solid, mp 121–122 8C. 1H NMR (CDCl3, 500 MHz)
d
7.72–7.65 (6H, m), 7.61–7.57 (3H, m), 7.52–7.47 (6H, m), 3.80 (2H,

X. Fang et al. / Journal of Fluorine Chemistry 130 (2009) 974–978
977
4.2.4. 5-(4-Bromophenyl)-4,4-difluoro-3-oxo-2-
(triphenylphosphoranylidene)- -valerolactone (4d)
White spumy solid, mp 86–87 8C. 1H NMR (CDCl3, 500 MHz)
7.73–7.62 (9H, m), 7.56–7.51 (8H, m), 7.45 (2H, d, J = 8.4 Hz), 5.58
4.2.9. (E)-4,4-Difluoro-5-styryl-3-oxo-2-
(triphenylphosphoranylidene)- -valerolactone (4j)
White spumy solid, mp 69–71 8C. 1H NMR (CDCl3, 500 MHz)
7.74–7.27 (20H, m), 6.96 (1H, d, J = 16 Hz), 6.40 (1H, dd, J = 16 Hz,
J = 5.8 Hz), 5.24 (1H, dt, J = 16.6 Hz, J = 5 Hz). 19F NMR (CDCl3,
d
d
d
d
(1H, dd, J = 21 Hz, J = 3.4 Hz). 19F NMR (CDCl3, 470 MHz)
d
ꢀ122.6
(1F, dd, JF–F = 277 Hz, JF–H = 19 Hz), ꢀ123.8 (1F, d, JF–F = 277 Hz). 13
C
470 MHz)
d
ꢀ119.9 (1F, d, JF–F = 277 Hz), ꢀ124.5 (1F, dd, JF–
NMR (CDCl3, 125.8 MHz)
d
179.2 (2JCF = 29 Hz), 166.4
F = 277 Hz, JF–H = 14 Hz). 13C NMR (CDCl3, 125.8 MHz)
d
179.3
(2JCP = 11 Hz), 134.5 (3JCP = 10 Hz), 133.9, 132.1, 131.1, 130.5,
129.8 (3JCP = 13 Hz), 124.1, 122.9 (1JCP = 93 Hz), 109.6 (CF2,
(2JCF = 25 Hz), 166.3 (2JCP = 11 Hz), 136.8, 134.5 (3JCP = 10.3 Hz),
133.8, 129.7 (3JCP = 13 Hz), 129.4, 129.2, 127.6, 123.1 (1JCP = 93 Hz),
119.4, 110.1 (CF2, 1JCF = 253 Hz, 3JCP = 17 Hz), 69.8 (1JCP = 111.5 Hz).
1JCF = 254 Hz, JCP = 14 Hz), 69.8 (1JCP = 111 Hz). EI-MS (m/z) 566
3
(M++2, 11), 564 (M+, 11), 349 (16), 301 (100), 183 (10). IR (cmꢀ1
,
EI-MS (m/z) 512 (M+, 3), 375 (100), 301 (33), 183 (11). IR (cmꢀ1
,
KBr) 1691, 1629, 1075, 691. HRMS calcd for C29H20BrF2O3P:
564.0302, found 564.0303.
KBr) 1689, 1626, 691. HRMS calcd for C31H23F2O3P: 512.1353,
found 512.1353.
4.2.5. 5-(4-Chlorophenyl)-4,4-difluoro-3-oxo-2-
4.2.10. 4,4-Difluoro-5-vinyl-3-oxo-2-(triphenylphosphoranylidene)-
(triphenylphosphoranylidene)-
White solid, mp 190–191 8C. 1H NMR (CDCl3, 500 MHz)
7.47 (17H, m), 7.34 (2H, d, J = 8.3 Hz), 5.59 (1H, d, J = 21 Hz). 19F
d
-valerolactone (4e)
d
-valerolactone (4k)
d
7.71–
White spumy solid, mp 158–159 8C. 1H NMR (CDCl3, 500 MHz)
7.69–7.47 (15H, m), 6.08–6.00 (1H, m), 5.66 (1H, d, J = 17.3 Hz),
d
NMR (CDCl3, 470 MHz)
d
ꢀ122.5 (1F, dd, JF–F = 282 Hz, JF–
5.52 (1H, d, J = 10.7 Hz), 5.03 (1H, dt, J = 18 Hz, J = 5 Hz). 19F NMR
H = 23.5 Hz), ꢀ123.7 (1F, d, JF–F = 277 Hz). 13C NMR (CDCl3,
(CDCl3, 470 MHz)
F = 277 Hz, JF–H = 14 Hz). 13C NMR (CDCl3, 125.8 MHz)
(2JCF = 25 Hz, 2JCP = 5 Hz), (2JCP = 11 Hz),
165.5
(3JCP = 10.4 Hz), 133.1, 129.0 (3JCP = 13 Hz), 127.8, 122.3
(1JCP = 93 Hz), 121.7, 109.1 (CF2, JCF = 268 Hz, JCP = 14 Hz), 69.0
(1JCP = 111.6 Hz). EI-MS (m/z) 436 (M+, 18), 349 (55), 301 (100), 183
(20). IR (cmꢀ1, KBr) 1689, 1622, 688. HRMS calcd for C25H19F2O3P:
436.1040, found 436.1040.
d
ꢀ120.1 (1F, d, JF–F = 277 Hz), ꢀ123.5 (1F, dd, JF–
125.8 MHz)
d
179.1 (2JCF = 20 Hz), 166.2 (2JCP = 11 Hz), 135.7,
d
178.3
133.7
134.3 (3JCP = 10.3 Hz), 133.8, 130.5, 130.1, 129.7 (3JCP = 13 Hz),
1
3
129.0, 122.7 (1JCP = 93 Hz), 109.4 (CF2, JCF = 253 Hz, JCP = 17 Hz),
69.7 (1JCP = 111 Hz). EI-MS (m/z) 522 (M++2, 7), 520 (M+, 17), 301
(100), 183 (11). IR (cmꢀ1, KBr) 1703, 1621, 1078, 687. HRMS calcd
for C29H20ClF2O3P: 520.0807, found 520.0808.
1
3
4.2.6. 5-(2-Chlorophenyl)-4,4-difluoro-3-oxo-2-
(triphenylphosphoranylidene)-
White spumy solid, mp 104–105 8C. 1H NMR (CDCl3, 500 MHz)
7.82–7.52 (17H, m), 7.43–7.31 (2H, m), 6.22 (1H, d, J = 23.7 Hz). 19
d
-valerolactone (4f)
4.2.11. 5-Methyl-5-phenyl-4,4-difluoro-3-oxo-2-
d
F
(triphenylphosphoranylidene)-
d-valerolactone (4l)
White solid, mp 200–202 8C. 1H NMR (CDCl3, 500 MHz)
d 7.69–
ꢀ114.8 (1F,
NMR(CDCl3,470 MHz)
d
ꢀ121.5(1F,dd,JF–F = 282 Hz,JF–H = 23.5 Hz),
7.37 (20H, m), 1.84 (3H, s). 19F NMR (CDCl3, 470 MHz)
d
ꢀ126.0 (1F, d, JF–F = 277 Hz). 13C NMR (CDCl3, 125.8 MHz)
d
179.3
d, JF–F = 268 Hz), ꢀ124.0 (1F, d, JF–F = 272 Hz). 13C NMR (CDCl3,
(2JCF = 25 Hz), 166.6 (2JCP = 11 Hz), 134.4 (3JCP = 10.4 Hz), 133.7,
131.3, 131.0, 129.9, 129.6 (3JCP = 13 Hz), 127.3, 122.8 (1JCP = 93 Hz),
109.8(CF2, 1JCF = 253 Hz, 3JCP = 17 Hz), 69.4(1JCP = 111 Hz).EI-MS(m/
125.8 MHz)
d
179.0 (2JCF = 25 Hz, JCP = 5 Hz), 165.9 (2JCP = 11 Hz),
2
140.4, 134.2 (3JCP = 10 Hz), 133.5, 129.5 (3JCP = 12.6 Hz), 129.1,
126.4, 122.9 (1JCP = 93 Hz), 109.2 (CF2, JCF = 244 Hz, JCP = 12 Hz),
69.5 (1JCP = 114 Hz), 22.9. EI-MS (m/z) 500 (M+, 20), 349 (28), 301
(100), 183 (12). IR (cmꢀ1, KBr) 1687, 1628, 689. HRMS calcd for
1
3
z) 522 (M++2, 1), 520 (M+, 3), 485 (100), 301 (90), 183 (11). IR (cmꢀ1
KBr) 3062, 2984, 1695, 1633, 1043, 691. HRMS calcd for
29H20ClF2O3P: 520.0807, found 520.0807.
,
C
C30H23F2O3P: 500.1353, found 500.1353.
4.2.7. 4-(3,3-Difluoro-4,6-dioxo-3-
4.2.12. 5-Methyl-5-p-tolyl-4,4-difluoro-3-oxo-2-
(triphenylphosphoranylidene)- -valerolactone (4m)
White solid, mp 215–217 8C. 1H NMR (CDCl3, 500 MHz)
7.30 (17H, m), 7.13 (2H, d, J = 8 Hz), 2.33 (3H, s), 1.75 (3H, s). 19F
NMR (CDCl3, 470 MHz)
ꢀ115.2 (1F, d, JF–F = 268 Hz), ꢀ124.0 (1F,
d, JF–F = 268 Hz). 13C NMR (CDCl3, 125.8 MHz) 177.6 (2JCF = 25 Hz,
2JCP = 5 Hz), 164.5 (2JCP = 11 Hz), 136.9, 135.8, 132.7 (3JCP = 10 Hz),
128.1, 127.8 (3JCP = 12.8 Hz), 124.9, 121.5 (1JCP = 93.5 Hz), 110.5
(CF2, 1JCF = 255 Hz, 3JCP = 14 Hz), 67.7 (1JCP = 114 Hz), 21.3, 20.1. EI-
MS (m/z) 514 (M+, 17), 349 (13), 301 (100), 183 (10). IR (cmꢀ1, KBr)
1686, 1625, 690. HRMS calcd for C31H25F2O3P: 514.1509, found
514.1510.
(triphenylphoranylidene)tetrahydro-2H-pyran-2-yl)benzonitrile
(4 h)
d
d
7.61–
White spumy solid, mp 218–219 8C. 1H NMR (CDCl3, 500 MHz)
d
7.72–7.51 (19H, m), 5.65 (1H, d, J = 23 Hz). 19F NMR (CDCl3,
d
470 MHz)
d
ꢀ121.0 (1F, dd, JF–F = 277 Hz, JF–H = 23.5 Hz), ꢀ123.2
d
(1F, d, JF–F = 282 Hz). 13C NMR (CDCl3, 125.8 MHz)
d
178.8
(2JCF = 25 Hz), 165.9 (2JCP = 11 Hz), 137.1, 134.4 (3JCP = 10.3 Hz),
133.9, 132.6, 129.7 (3JCP = 13 Hz), 129.4, 122.6 (1JCP = 93 Hz), 119.0,
113.7, 109.2 (CF2, JCF = 251 Hz, JCP = 14 Hz), 69.8 (1JCP = 111 Hz).
EI-MS (m/z) 511 (M+, 39), 301 (100), 183 (13). IR (cmꢀ1, KBr) 2920,
2225, 1685, 1639, 691. HRMS calcd for C30H20F2NO3P: 511.1149,
found 511.1150.
1
3
4.3. Reformatsky imine addition reactions of 1 with aldimines;
4.2.8. 4,4-Difluoro-5-isopropyl-3-oxo-2-
typical procedure
(triphenylphosphoranylidene)-
White spumy solid, mp 59–60 8C. 1H NMR (CDCl3, 500 MHz)
7.68–7.46 (15H, m), 4.30 (1H, d, J = 27 Hz), 2.33 (1H, td, J = 13.3 Hz,
J = 6.6 Hz), 1.14 (6H, t, J = 6.8 Hz). 19F NMR (CDCl3, 470 MHz)
ꢀ120.1 (1F, d, JF–F = 277 Hz), ꢀ122.3 (1F, dd, JF–F = 282 Hz, JF–
d-valerolactone (4i)
d
A solution of benzylideneaniline (199 mg, 1.1 mmol) and 1
(505 mg, 1 mmol) in anhydrous dioxane (1 mL) was added
dropwise to a heterogeneous solution of acid-washed zinc dust
(196 mg, 3.0 mmol) and CuCl (30 mg, 0.3 mmol) in anhydrous
dioxane (2 mL). The reaction mixture was stirred under reflux for
27 h. Then saturated NH4Cl (5 mL) was added. Excess zinc was
removed by suction filtration and washed with EtOAc (10 mL). The
organic layer was separated. The aqueous layer was extracted with
EtOAc (3 ꢁ 10 mL), the organic layers were combined and washed
with water and brine, then dried over Na2SO4. After evaporation of
d
H = 24 Hz). 13C NMR (CDCl3, 125.8 MHz)
d
179.9 (2JCF = 25 Hz,
2JCP = 4.4 Hz), 168.0 (2JCP = 11 Hz), 134.3 (3JCP = 10.4 Hz), 133.7,
1
129.7 (3JCP = 13 Hz), 122.6 (1JCP = 93 Hz), 111.1 (CF2, JCF = 250 Hz,
3JCP = 7 Hz), 70.1 (1JCP = 111 Hz), 27.5, 19.8, 18.9. EI-MS (m/z) 452
(M+, 6), 410 (100), 301 (51), 183 (14). IR (cmꢀ1, KBr) 1686, 1622,
690. HRMS calcd for C26H23F2O3P: 452.1353, found 452.1353.

978
X. Fang et al. / Journal of Fluorine Chemistry 130 (2009) 974–978
the solvents, the residue was chromatographed on silica gel eluting
4.3.4. Ethyl 4,4-difluoro-5-(4-methoxyphenyl-amino)-3-oxo-2-
with PE-EtOAc (3:1) to give 6a (182 mg) in 30% yield.
(triphenylphosphoranylidene)-5-phenylpentanoate (6e)
White solid, mp 129–130 8C. 1H NMR (CDCl3, 500 MHz)
d 7.63–
4.3.1. Ethyl 4,4-difluoro-3-oxo-2-(triphenylphosphoranylidene)-5-
7.27 (21H, m), 6.76 (1H, d, J = 8.9 Hz), 6.63 (2H, d, J = 8.9 Hz), 5.71
(1H, d, J = 23 Hz), 5.38 (1H, s), 3.73 (3H, s), 3.61 (2H, q, J = 7.2 Hz),
phenyl-5-(phenyl-amino)pentanoate (6a)
White solid, mp 207–208 8C. 1H NMR (CDCl3, 500 MHz)
d
7.61–
0.74 (3H, t, J = 7.2 Hz). 19F NMR (CDCl3, 470 MHz)
d
ꢀ105.2 (1F, d,
7.27 (20H, m), 7.15(2H, t, J = 7.6 Hz), 6.71–6.67(3H, m), 5.72(1H, dd,
J = 16 Hz, J = 9 Hz), 3.73–3.69 (2H, m), 0.74 (3H, t, J = 7.2 Hz). 19F
JF–F = 244 Hz), ꢀ118.3 (1F, dd, JF–F = 244 Hz, JF–H = 24 Hz). 13C NMR
(CDCl3, 125.8 MHz)
d
183.6 (2JCF = 25 Hz), 167.0 (2JCP = 13 Hz),
NMR (CDCl3, 470 MHz)
d
ꢀ104.7 (1F, d, JF–F = 244 Hz), ꢀ118.2 (1F,
151.9, 140.7, 136.3, 133.1 (3JCP = 10 Hz), 132.0, 128.8 (3JCP = 13 Hz),
127.8, 125.3, 124.6, 114.6 (1JCP = 75 Hz), 108.7 (CF2, 1JCF = 318 Hz),
70.2 (1JCP = 109 Hz), 60.3 (2JCF = 23 Hz), 59.8, 59.1, 13.6. EI-MS (m/z)
637 (M+, 1), 375 (100), 183 (10). IR (cmꢀ1, KBr) 1671, 1590, 1105,
dd, JF–F = 244 Hz, JF–H = 24 Hz). 13C NMR (CDCl3, 125.8 MHz)
d
183.9
(2JCF = 25 Hz), 165.9 (2JCP = 13 Hz), 145.5, 135.1, 132.1 (3JCP = 10 Hz),
131.0, 128.2, 127.8 (3JCP = 13 Hz), 127.1, 126.8, 123.8 (1JCP = 94 Hz),
1
116.2, 116.4 (CF2, JCF = 318 Hz), 112.1, 69.8 (1JCP = 110 Hz), 58.8,
1045, 690. HRMS calcd for
637.2194.
C38H34F2NO4P: 637.2194, found
58.4 (2JCF = 23 Hz), 12.5. EI-MS (m/z) 607 (M+, 4), 552 (40), 375 (100),
182 (48). IR (cmꢀ1, KBr) 3305, 1681, 1558, 1110, 691. HRMS calcd for
C37H32F2NO3P: 607.2088, found 607.2089.
Acknowledgement
4.3.2. Ethyl 5-(4-chlorophenyl)-4,4-difluoro-3-oxo-2-
The authors thank the National Natural Science Foundation of
China (NNSFC) (no. 20672034) for financial support.
(triphenylphosphoranylidene)-5-(phenyl-amino)pentanoate (6b)
White solid, mp 220–221 8C. 1H NMR (CDCl3, 500 MHz)
d 7.60–
References
7.24 (19H, m), 7.16 (2H, t, J = 7.8 Hz), 6.71 (1H, t, J = 7.3 Hz), 6.65
(2H, d, J = 8 Hz), 5.81 (1H, s), 5.71 (1H, d, J = 23 Hz), 3.72–3.65 (2H,
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m), 0.71 (3H, t, J = 7.1 Hz). 19F NMR (CDCl3, 470 MHz)
d
ꢀ104.9 (1F,
d, JF–F = 244 Hz), ꢀ118.0 (1F, dd, JF–F = 244 Hz, JF–H = 24 Hz). 13C
NMR (CDCl3, 125.8 MHz)
d
183.6 (2JCF = 25 Hz), 168.7
(2JCP = 13 Hz), 148.0, 136.5, 135.4, 134.8 (3JCP = 10 Hz), 133.8,
131.9, 131.0, 130.5 (3JCP = 13 Hz), 130.1, 126.4 (1JCP = 94 Hz),
119.2, 118.8 (CF2, JCF = 318 Hz), 114.8, 72.6 (1JCP = 109 Hz), 61.6,
1
60.7 (2JCF = 23 Hz), 15.2. EI-MS (m/z) 643 (M++2, 2), 641 (M+, 5), 586
(46), 375 (100), 183 (25). IR (cmꢀ1, KBr) 3314, 1673, 1560, 1104,
1050, 690. HRMS calcd for C37H31ClF2NO3P: 641.1698, found
641.1699.
4.3.3. Ethyl 5-(4-cyanophenyl)-4,4-difluoro-3-oxo-2-
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(triphenylphosphoranylidene)-5-(phenyl-amino)pentanoate (6d)
White solid, mp 241–242 8C. 1H NMR (CDCl3, 500 MHz)
d 7.63–
7.26 (19H, m), 7.1 (2H, t, J = 7.4 Hz), 6.66 (1H, t, J = 7.3 Hz), 6.53 (2H,
d, J = 7.7 Hz), 5.82 (1H, s), 5.70 (1H, d, J = 23 Hz), 3.61 (2H, q,
J = 7.1 Hz), 0.63 (3H, t, J = 7.1 Hz). 19F NMR (CDCl3, 470 MHz)
d
ꢀ104.4 (1F, d, JF–F = 249 Hz), ꢀ117.8 (1F, dd, JF–F = 249 Hz, JF–
H = 24 Hz). 13C NMR (CDCl3, 125.8 MHz)
d
182.2 (2JCF = 25 Hz),
166.0 (2JCP = 12 Hz), 144.9, 141.0, 132.1 (3JCP = 10 Hz), 130.9, 128.6,
127.8 (3JCP = 9.3 Hz), 123.7 (1JCP = 94 Hz), 117.9, 112.1, 110.8, 107.6
1
(CF2, JCF = 318 Hz), 69.6 (1JCP = 109 Hz), 58.9, 58.4 (2JCF = 28 Hz),
12.5. EI-MS (m/z) 632 (M+, 3), 577 (96), 375 (100). IR (cmꢀ1, KBr)
3310, 1669, 1563, 1103, 1047, 691. HRMS calcd for C38H31F2N2O3P:
632.2040, found 632.2017.