Nucleophilic Difluoromethylenation of Ketones Using Diethyl (Difluoro(trimethylsilyl)methyl)phosphonate Mediated by 18-Crown-6 Ether/KOAc

Article abstract of DOI:10.1021/acs.joc.6b01457

We report a general difluoromethylenation of various types of ketones using diethyl (difluoro(trimethylsilyl)methyl)phosphonate mediated by the combination of 18-crown-6 and KOAc. It provides facile access to structurally diverse β-hydroxy-α,α-difluorophosphonates as interesting targets for medicinal research.

Full text of DOI:10.1021/acs.joc.6b01457

Article
pubs.acs.org/joc
Nucleophilic Difluoromethylenation of Ketones Using Diethyl
(Difluoro(trimethylsilyl)methyl)phosphonate Mediated by 18-
Crown‑6 Ether/KOAc
Yu-Hui Wang,† Zhong-Yan Cao,† and Jian Zhou*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 N. Zhongshan Road, Shanghai 200062, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: We report a general difluoromethylenation of
various types of ketones using diethyl (difluoro(trimethylsilyl)-
methyl)phosphonate mediated by the combination of 18-crown-6
and KOAc. It provides facile access to structurally diverse β-
hydroxy-α,α-difluorophosphonates as interesting targets for
medicinal research.
pounds. A common method is the use of strong bases such as
LDA to deprotonate diethyl (difluoromethyl)phosphonate to
react with aldehydes or ketones,4d,5 which are usually carried
out at low reaction temperature. To make the reaction
conditions milder, the use of diethyl (difluoro(trimethylsilyl)-
methyl)phosphonate 5 as a carbanion equivalent becomes
popular.6 For example, Obayashi and Kondo reported the use
of a catalytic amount of CsF to mediate the reaction of carbonyl
compounds and 5.6a The use of tetrabutylammonium fluoride
(TBAF) to promote the reaction of 5 and aldehydes was also
tried, albeit with moderate to good yield.7a−d Beier also found
the tetrabutylammonium difluorotriphenylsilicate (TBAT) as
an efficient initiator for the reaction of 5 with various
aldehydes.7e In addition to fluorides, oxygen-based Lewis
basic promoter was also effective, as evidenced by Shibata
and Toru’s finding that 1,2-bis(diphenylphosphino)ethane/
Cu(OAc)2 mediated the reaction of p-nitrobenzaldehyde and 5
well.7f However, despite these impressive advances in
difluoromethylenation of aldehydes using 5,6,7 the correspond-
ing processes using ketone substrates are undeveloped in terms
of substrate scope and catalyst systems. To our knowledge, only
two reports mentioned preliminary results during the
corresponding research using aldehydes. Kondo et al. found
that CsF could promote the reaction of 5 with two substituted
acetophenones as well.6a They also observed that, in the
presence of 2 mol % CsF, the reaction of 5 and p-
NO2C6H4COMe afforded the desired adduct in only 38%
yield, along with rearrangement product in 27% yield. Beier et
al. found that the reaction of 5 with acetone worked well in the
presence of TBAT, but no more ketone substrates were tried.7e
Owing to the importance of tertiary alcohols in drug
INTRODUCTION
■
The selective incorporation of a difluoroalkyl group has become
a routine and effective approach to modulate the biological
activities of organic molecules in drug design.1,2 In this scenario,
the difluorophosphonate unit has drawn special attention due
to its potential as an analogue of biologically important
phosphate esters and application in new drug development.3 In
particular, β-hydroxy-α,α-difluorophosphonate is a prominent
structural motif that occurs in bioactive compounds.4 As shown
in Scheme 1, compound 1, the analogue of sphingomyelin,
Scheme 1. Representative Bioactive Compounds
inhibits tumor necrosis factor (TNF)-α-induced cell death of
PC-12 neurons at a low concentration of 0.1 μM.4a
Difluoroketophosphonate 2 is able to reduce infarct size in
the rat model of ischemia reperfusion injury.4b Farnesyl
transferase inhibitor 3, with a difluoromethylene group at the
α-position of the phosphonate group, shows a 15-fold increase
in inhibition over the nonfluorinated analogue 4.4c Therefore, it
is highly desirable to develop new methods to prepare β-
hydroxy-α,α-difluoromethylphosphonates.
In this context, a straightforward method is the addition of
(diethylphosphinyl)difluoromethyl carbanion to carbonyl com-
Received: June 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01457
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Table 1. Optimization of Conditions
a
entry
Lewis base
solvent
time (h)
yield (%)
1
2
3
4
5
KOAc
DMF
THF
12
0.5
20
7
57
86
62
56
55
90
90
62
87
58
LB7 + KOAc
LB7 + K2CO3
LB7 + K3PO4
LB7 + KOBut
LB7 + KOAc
LB7 + KOAc
LB7 + KOAc
LB7 + KOAc
THF
THF
THF
16
3.5
0.5
4.0
1.0
2.0
b
6
toluene
MeCN
CH2Cl2
THF
b
7
b
8
c
9
d
10
LB7 + KOAc
THF
a
b
c
d
Isolated yield. 1.0 equiv of KOAc used. 1.5 equiv of 5 used. 1.2 equiv of 5 used.
development,8 those featuring a difluoromethylphosphate
moiety are interesting targets for medicinal research. Therefore,
it is highly desirable to develop efficient methods for the
difluoromethylenation of various ketone substrates using
reagent 5 for the diverse synthesis of β-hydroxy-α,α-
difluorophosphonates.
compounds,7f,15 we first tried using KOAc to promote the
reaction carried out in DMF. The desired product 7a was
obtained in 57% yield after 12 h (entry 1). Considering that the
role of DMF as the solvent was possibly to increase the
solubility of KOAc, suppress ion-pairing, and make the acetate
anion naked and more nucleophilic, we tried using 18-crown-6
LB7 in combination with KOAc to mediate this reaction,
because Liotta et al. had reported that the nucleophilicity of
KOAc could be greatly enhanced in the presence of crown
ether.16 As expected, although either 18-crown-6 LB7 or KOAc
alone was unable to mediate this reaction when performed in
THF at room temperature, the combination of both allowed
the reaction to complete within half an hour, affording the
desired product 7a in 86% isolated yield (entry 2). Based on
this result, we further examined the performance of other
potassium salts or bases, in combination with 18-crown-6
(entries 3−5), but KOAc still proved to be the best in terms of
reactivity and yield of hydroxyoxindole 7a. Next, the solvent
effects were examined by using 18-crown-6 LB7/KOAc as the
promoter (entries 6−8). When using DCM, MeCN, or toluene
as the solvent, the reaction proceeded very slowly; 1.0 equiv of
KOAc in combination with 10 mol % of 18-crown-6 was
required to secure excellent yield of hydroxyoxindole 7a, and
no turnover was observed if only 10 mol % KOAc was used.
Possibly, the regeneration of acetate from the resulting
alkoxides and AcOTMS in THF was facilitated.17 Furthermore,
it was possible to reduce the amount of reagent 5 from 2.5
equiv to 1.5 equiv, while product 7a was still obtained in 87%
yield (entry 9). But further decreasing the amount of reagent 5
to 1.2 equiv resulted in significantly lower yield of product 7a
(entry 10).
RESULTS AND DISCUSSION
■
With our efforts in selective fluoroalkylation,9 we have found
that tertiary or secondary amine based chiral catalysts could
activate fluorinated enol silyl ethers to react with activated
ketones, ketimines, or Michael acceptors.10 Based on these
results, we wish to use Lewis base promoters other than
fluorides to activate difluoro(trimethylsilyl)methylphosphonate
5 for the nucleophilic addition reaction of different ketones, to
avoid possible rearrangement reaction caused by fluorides.
Herein, we wish to report that the combination of 18-crown-6
and KOAc (10 mol %, each) is found to be powerful for the
nucleophilic addition of reagent 5 with a broad scope of
ketones.
We began our research with the evaluation of various types of
Lewis bases11 in the reaction of 5 and N-methylisatin 6a, owing
to our interests in oxindole chemistry.12 It is worth mentioning
that 3-hydroxyoxindoles widely occur in natural products,
drugs, and bioactive compounds,13 and those with a C3
(diethylphosphinyl)difluoromethylene group are interesting for
medicinal research, but the synthesis of which is unknown. Our
screenings revealed that the choice of a suitable Lewis base
played a key role in reaction development. As shown in Table 1,
nitrogen-based Lewis bases LB1 and LB2, phosphine oxide LB3,
and nitrogen oxides LB4 and LB5, along with phosphorane LB6,
which we found to be a highly active promoter for ketone
cyanosilylation using TMSCN,14 all failed to mediate the
desired reaction.
To check whether these conditions could be extended to
other ketone substrates, we further examined the reaction of 5
and acetophenone 8a. To our delight, the reaction in THF
mediated by the combination of KOAc and 18-crown-6 could
finish within 1 h as well, giving product 9a in 68% yield. GC−
Inspired by literature reports on the use of acetates in DMF
to facilitate the addition of trimethylsilyl reagents to carbonyl
B
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Scheme 2. Control Experiments by Using DMF as Solvent
MS and TLC analysis of reaction mixture also revealed the
formation of trimethyl((1-phenylvinyl)oxy)silane I as the
byproduct. On the other hand, the use of n-Bu4NOAc in
THF resulted in only 27% yield for 9a, along with a large
amount of I by TLC analysis. KOAc, LiOAc, and n-Bu4NOAc
in DMF could also mediate this reaction even without 18-
crown-6 (Scheme 2), a condition that Mukaiyama et al.
developed for trifluoromethylation of carbonyl compounds
using TMSCF3.15a,b It was found that n-Bu4NOAc and LiOAc
promoted the reaction slowly, giving 9a in 54% and 45% yield,
respectively. The use of 10 mol % KOAc enabled the reaction
to finish within 1 h, giving product 9a in 64% yield, comparable
to that obtained by our method. In all the cases, I was detected
by both GC−MS and TLC analysis. It is worth mentioning that
although our method involves the use of 18-crown-6, it allows
the reactions to be performed in THF, which can be removed
by rotary evaporation after the reaction finishes, and then the
residue was directly subjected for column chromatography
purification. In contrast, the use of DMF as the solvent obviates
the use of 18-crown-6, but requires an extraction procedure to
remove DMF.
was deprotonated during the reaction course, which in turn
decreased the electrophilicity of the ketone carbonyl group.
The scope of ketones other than isatins also worked well
under these conditions (Table 3). Acetophenone 8a and its
Table 3. Substrate Scope of Aryl Ketones
In light of the above screenings, the substrate scope was
evaluated by running the reaction in THF, in the presence of
18-crown-6 and KOAc (10 mol %, each), using 1.5 equiv of
reagent 5. To our delight, isatins 6a−i with different
substituents at the C5 or C7 position, no matter whether
electron withdrawing or donating, were viable substrates under
these conditions, giving the desired product 7a−i in 83−98%
yield (Table 2). However, a methyl or benzyl protecting group
on isatin was necessary, as unprotected isatin failed to react
with 5 under these conditions, possibly because its N−H bond
a
Isolated yield.
Table 2. Scope of Isatins
analogues 8b−g bearing a para electron-withdrawing group on
the phenyl ring readily afforded the desired products 9a−g in
good to high yield (entries 1−7). Nevertheless, the electron-
donating substituent retarded the reaction. For example, p-
methylphenyl methyl ketone 8h gave product 9h in only 39%
yield, because of the formation of the enol silyl ether from 8h
(entry 8). While o-chlorophenyl methyl ketone 8i yielded
product 9i in only 33% yield (entry 9), m-chlorophenyl methyl
ketone 8j provided product 9j in 77% yield (entry 10), showing
the negative effect of the ortho substituent of the phenyl ring on
the reactivity. Heteroaryl methyl ketones 8k,l also afforded the
desired products 9k,l in reasonable yield (entries 11 and 12).
Non-methyl ketones were also examined; while ethyl ketone
8m gave product 9m in moderate yield (entry 13), α-CF3 or
CF2H ketones provided the desired products 9n,o in good yield
(entries 14 and 15). 1-Tetralone afforded the desired product
9p in 56% yield (entry 16).
a
entry
isatin 6
7
time (h)
yield (%)
1
2
6a: R1 = H, R2 = Me
6b: R1 = 5-F, R2 = Me
6c: R1 = 5-Cl, R2 = Me
6d: R1 = 5-Br, R2 = Me
6e: R1 = 5-Me, R2 = Me
6f: R1 = 5-MeO, R2 = Me
6g: R1 = 7-Cl, R2 = Me
6h: R1 = 7-CF3, R2 = Me
6i: R1 = H, R2 = Bn
7a
7b
7c
7d
7e
7f
0.5
0.5
0.5
1.0
0.5
1.0
0.6
2.0
1.5
92
91
85
92
83
94
98
98
92
3
4
5
6
7
7g
7h
7i
8
9
10
6j: R1 = H, R2 = H
a
Isolated yield.
C
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The performance of other ketones and aldehydes was also
examined (Scheme 3). β,γ-Unsaturated α-ketoester or α,β-
side rearrangement reaction.6a This result justified the necessity
of using oxygen-based Lewis basic promoters.
The thus obtained products were very useful. For example,
when treated with NaH, adducts 7 readily convert to a 3-CF2H
3-hydroxyoxindole derivative via the transfer of the diethox-
yphosphoryl group, as shown by the synthesis of compound 7a
in 66% yield (Scheme 5). Notably, despite intensive studies
a
Scheme 3. Scope of Other Ketones and Aldehydes
Scheme 5. Product Elaboration
into the synthesis of quaternary 3-hydroxyoxindole derivatives,
methods to fluoroalkyl substituted ones are still limited.18 In
addition, other adducts such as 9a and 11 were known to be
able to undergo similar reaction under basic conditions.19
CONCLUSION
■
We have developed a general difluoromethylenation of
carbonyl compounds with diethyl difluoro(trimethylsilyl)-
methylphosphonate promoted by the combination of 18-
crown-6 ether and KOAc. In particular, the use of oxygen-based
Lewis basic promoters avoids a possible rearrangement reaction
that may take place when using fluoride promoters. The broad
substrate scope and the cheap and easily available promoters,
along with the mild reaction conditions, makes our method
very attractive for the synthesis of β-hydroxy-α,α-difluorome-
thylphosphates in great structural diversity, which are valuable
targets for medicinal research. The development of an
enantioselective version of this reaction is now in progress in
our laboratory.
a
All reactions were run on a 0.4 mmol scale. Isolated yield is given.
unsaturated ketones underwent aldol reaction selectively, as
shown by the synthesis of tertiary alcohols 9q−t in good to
high yield. With an alkene, alkynyl, or diene moiety as a
synthetic handle, these adducts could be further elaborated.
Aliphatic ketones were also viable substrates, as exemplified by
the synthesis of products 9u and 9v in 76% and 56% yield,
respectively. Furthermore, cyclic fluorinated ketone derived
product 9w was obtained in good yield as well. This method
was also workable for the difluoromethylenation of both aryl
and aliphatic aldehydes, as shown by the synthesis of adducts
11a−d in good to high yield.
Notably, under the above established conditions, we did not
detect side products resulting from the rearrangement of
phosphonates into phosphates, or the formation of 1,1-
difluoroalkenes via HWE-type elimination. However, when
trying to release alcohols 9q−w and 11 after the reaction
completed, to simplify the purification by column chromatog-
raphy, we found the use of tetrabutylammonium fluoride
(TBAF) to remove the TMS group led to side rearrangement
reaction, as shown by the synthesis of product 12 from
ketoester 8q in 74% yield (Scheme 4). However, the use of a
solution of HCl in MeOH to remove the TMS group did not
afford rearrangement products. This was in agreement with a
literature report that the use of a fluoride to promote the
ketone difluoromethylenation using reagent 5 might lead to
EXPERIMENTAL SECTION
■
General Information. Reactions were monitored by thin layer
chromatography using UV light or KMnO4 to visualize the course of
reaction. Purification of reaction products was carried out by flash
chromatography on silica gel. 300, 400, or 500 MHz NMR
spectrometers were used for all structural NMR data. Chemical shifts
for H and 13C NMR spectra were reported in ppm from CDCl3 or
1
acetone-d6 with the solvent resonance as the internal standard.
Chemical shifts for 19F NMR spectra were recorded under 1H
decoupling conditions and were reported in ppm with the PhCF3 as
the internal standard. Chemical shifts for 31P NMR spectra were
1
recorded under H decoupling conditions and were reported in ppm
with 85% H3PO4 as the external standard. HRMS measurements were
obtained on a TOF analyzer. All reactions were carried out under an
atmosphere of nitrogen unless otherwise noted. Anhydrous CH2Cl2
and MeCN were prepared by first distillation over P2O5 and then from
CaH2. Anhydrous THF and toluene were prepared by distillation over
sodium−benzophenone ketyl prior to use. Reagent 5 was prepared
using literature procedures.6
The abbreviation of AB is used to designate chemical shift
multiplicities for classical aromatic AB system in 1H NMR and
classical AB system of CF2 adjacent to a chiral carbon in 19F NMR
(under 1H decoupling conditions). In most cases, there is a
phosphonate group adjacent to a CF2 group, and each peak in the
AB system is further split by the P atom, resulting in an ABd pattern.
General Procedure for the Difluoromethylation of Reagent
5 with Isatins 6a−j. To a 10 mL Schlenk tube were added KOAc
(3.9 mg, 10 mol %), 18-crown-6 (10.6 mg, 10 mol %), and anhydrous
THF (1.5 mL), followed by the addition of reagent 5 (156.2 mg, 1.5
equiv) and isatins 6a−j (0.40 mmol). After the mixture was stirred at
Scheme 4. Side Rearrangement Reaction Using TBAF To
Remove the TMS Group
D
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room temperature until almost full conversion of isatins by TLC
analysis, a solution of p-TsOH in MeOH (1 M, 1 mL) was added to
the reaction mixture. The mixture was stirred at room temperature for
1 h, and then was concentrated and directly subjected to column
chromatography (DCM:acetone = 10:1) to afford the desired product
7a−i.
δ 5.33 (dd, J1 = 104.2 Hz, J2 = 90.4 Hz); IR (neat) 3314, 1712, 1610,
1493, 1270, 1162, 1070, 1008; MS (EI) 427 (M+, 30), 429 ([M + 2]+,
30), 275 (100), 273 (97), 245 (71), 247 (70), 240 (31), 242 (30);
HRMS (EI) exact mass calcd for C14H1779BrF2NO5P [M+] 426.9996,
found 426.9998.
Diethyl (difluoro(3-hydroxy-1,5-dimethyl-2-oxoindolin-3-
yl)methyl)phosphonate (7e): pale yellow solid; 120.5 mg, isolated
Note: The weighing of 18-crown-6 and KOAc is conducted in a
glovebox to avoid the absorption of moisture, which has a detrimental
effect on the reaction.
1
yield 83%; mp 116−118 °C; H NMR (300 MHz, CDCl3) δ 7.39 (s,
1H), 7.20 (AB, J = 8.1 Hz, 1H), 6.73 (AB, J = 7.8 Hz, 1H), 4.85 (s, br,
1H), 4.32−4.16 (m, 4H), 3.18 (s, 3H), 2.34 (s, 3H), 1.33 (t, J = 7.2
Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, acetone-d6) δ
172.5−172.4 (m), 143.6, 132.6, 132.0, 128.1, 125.5 (d, J = 2.4 Hz),
119.0 (td, J1 = 272.8 Hz, J2 = 204.6 Hz), 109.2, 77.2 (q, J = 20.4 Hz),
65.2 (d, J = 6.7 Hz), 65.0 (d, J = 6.6 Hz), 26.5, 21.0, 16.5 (d, J = 6.7
Hz), 16.4 (d, J = 6.2 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ
−117.18 (ABd, J1 = 309.4 Hz, J2 = 90.8 Hz), −119.68 (ABd, J1 = 309.4
Hz, J2 = 104.9 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 5.71
(dd, J1 = 105.3 Hz, J2 = 91.4 Hz); IR (neat) 3227, 1732, 1618, 1504,
1236, 1166, 1079, 1012; MS (EI) 363 (M+, 27), 209 (100), 181 (62),
176 (46), 191 (31), 210 (30), 207 (26), 182 (14); HRMS (EI) exact
mass calcd for C15H20F2NO5P [M+] 363.1047, found 363.1051.
Diethyl (difluoro(3-hydroxy-5-methoxy-1-methyl-2-oxoin-
dolin-3-yl)methyl)phosphonate (7f): pink solid; 142.5 mg, isolated
Diethyl (difluoro(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-
methyl)phosphonate (7a): white solid; 128.4 mg, isolated yield
92%; mp 111−113 °C; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 7.5
Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.84 (d, J =
7.8 Hz, 1H), 4.85 (s, br, 1H), 4.33−4.13 (m, 4H), 3.20 (s, 3H), 1.33
(t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz,
acetone-d6) δ 172.5−172.4 (m), 145.9, 131.8, 127.3, 125.4 (d, J = 2.6
Hz), 123.2, 118.9 (td, J1 = 272.9 Hz, J2 = 204.8 Hz), 109.4, 77.1 (q, J =
21.3 Hz), 65.2 (d, J = 6.6 Hz), 65.0 (d, J = 6.6 Hz), 26.5, 16.5 (d, J =
5.8 Hz), 16.4 (d, J = 5.8 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ
−116.66 (ABd, J1 = 309.1 Hz, J2 = 91.4 Hz), −118.93 (ABd, J1 = 309.4
Hz, J2 = 104.3 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 5.75
(dd, J1 = 105.0 Hz, J2 = 91.9 Hz); IR (neat) 3280, 1729, 1614, 1470,
1367, 1256, 1067, 1013; MS (EI) 349 (M+, 33), 162 (100), 161 (51),
132 (43), 195 (38), 188 (30), 160 (16), 196 (14); HRMS (EI) exact
mass calcd for C14H18F2NO5P [M+] 349.0891, found 349.0889.
Diethyl (difluoro(5-fluoro-3-hydroxy-1-methyl-2-oxoindo-
lin-3-yl)methyl)phosphonate (7b): yellow solid; 133.6 mg, isolated
yield 91%; mp 116−118 °C; 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J
= 8.0 Hz, 1H), 7.14−7.09 (m, 1H), 6.77 (dd, J1 = 8.4 Hz, J2 = 4.0 Hz,
1H), 5.00 (s, br, 1H), 4.34−4.21 (m, 4H), 3.19 (s, 3H), 1.35 (t, J = 7.2
Hz, 3H), 1.32 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ
172.1, 159.7 (d, J = 239.7 Hz), 142.0, 127.1 (d, J = 8.4 Hz), 118.8 (td,
J1 = 273.5 Hz, J2 = 205.6 Hz), 117.9 (d, J = 23.6 Hz), 115.2 (d, J = 25.9
Hz), 110.4 (d, J = 8.0 Hz), 77.2 (q, J = 21.0 Hz), 65.4 (d, J = 6.6 Hz),
65.2 (d, J = 6.7 Hz), 26.7, 16.5 (d, J = 5.6 Hz), 16.4 (d, J = 5.8 Hz); 19F
NMR (282 MHz, CDCl3, PhCF3) δ −117.35 (ABd, J1 = 310.1 Hz, J2 =
90.0 Hz, 1F), −119.07(s, 1F), −119.88 (ABd, J1 = 310.1 Hz, J2 = 104.1
Hz, 1F); 31P NMR (162 MHz, CDCl3, 85% H3PO4) δ 5.36 (dd, J1 =
104.2 Hz, J2 = 89.9 Hz); IR (neat) 3323, 1710, 1624, 1499, 1373,
1268, 1125, 1007; MS (EI) 367 (M+, 19), 213 (100), 185 (71), 180
(34), 214 (23), 186 (18), 145 (15), 109 (15); HRMS (EI) exact mass
calcd for C14H17F3NO5P [M+] 367.0796, found 367.0794.
1
yield 94%; mp 113−114 °C; H NMR (300 MHz, CDCl3) δ 7.20 (s,
1H), 6.93 (ABd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.75 (AB, J = 8.7 Hz,
1H), 4.90 (s, br, 1H), 4.32−4.22 (m, 4H), 3.80 (s, 3H), 3.17 (s, 3H),
1.34 (t, J = 6.9 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (126
MHz, acetone-d6) δ 172.2, 156.9, 139.2, 126.6, 119.0 (td, J1 = 273.2
Hz, J2 = 204.9 Hz), 116.2, 114.7, 109.9, 77.5 (q, J = 19.9 Hz), 65.2 (d, J
= 6.7 Hz), 65.1 (d, J = 6.6 Hz), 56.2, 26.6, 16.5 (d, J = 5.8 Hz), 16.4 (d,
J = 6.0 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ −117.20 (ABd, J1
= 309.6 Hz, J2 = 90.8 Hz), −119.71 (ABd, J1 = 309.8 Hz, J2 = 104.6
Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 5.86 (dd, J1 = 105.1
Hz, J2 = 91.4 Hz); IR (neat) 3326, 1714, 1504, 1476, 1271, 1073,
1045, 1012; MS (EI) 379 (M+, 65), 197 (100), 192 (78), 225 (54),
207 (40), 226 (36), 198 (23), 182 (20); HRMS (EI) exact mass calcd
for C15H20F2NO6P [M+] 379.0996, found 379.0999.
Diethyl ((7-chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-
difluoromethyl)phosphonate (7g): pale yellow solid; 150.1 mg,
1
isolated yield 98%; mp 89−90 °C; H NMR (300 MHz, CDCl3) δ
7.47 (d, J = 7.5 Hz, 1H), 7.33 (dd, J1 = 8.1 Hz, J2 = 1.2 Hz, 1H), 7.03
(t, J = 7.8 Hz, 1H), 4.97 (s, br, 1H), 4.35−4.19 (m, 4H), 3.56 (s, 3H),
1.34 (t, J = 6.9 Hz, 3H), 1.32 (t, J = 6.9 Hz, 3H); 13C NMR (126
MHz, acetone-d6) δ 172.8−172.8 (m), 141.6, 133.9, 128.5, 126.3,
124.5, 118.6 (td, J1 = 273.4 Hz, J2 = 205.0 Hz), 115.8, 76.5 (q, J = 20.9
Hz), 65.4 (d, J = 6.6 Hz), 65.2 (d, J = 6.7 Hz), 30.0, 16.5 (d, J = 5.5
Hz), 16.4 (d, J = 5.5 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ
−117.24 (ABd, J1 = 309.8 Hz, J2 = 90.0 Hz), −120.03 (ABd, J1 = 309.4
Hz, J2 = 104.6 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 5.68
(dd, J1 = 105.3 Hz, J2 = 90.4 Hz); IR (neat) 3312, 1730, 1610, 1466,
1258, 1168, 1072, 1015; MS (EI) 383 (M+, 10), 229 (100), 201 (67),
231 (35), 203 (23), 196 (22), 230 (19), 232 (19); HRMS (EI) exact
mass calcd for C14H1735ClF2NO5P [M+] 383.0501, found 383.0500.
Diethyl (difluoro(3-hydroxy-1-methyl-2-oxo-7-
(trifluoromethyl)indolin-3-yl)methyl)phosphonate (7h): yellow
Diethyl ((5-chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-
difluoromethyl)phosphonate (7c): white solid; 130.2 mg, isolated
1
yield 85%; mp 137−139 °C; H NMR (400 MHz, CDCl3) δ 7.55 (s,
1H), 7.38 (ABd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.77 (AB, J = 8.4 Hz,
1H), 5.00 (s, br, 1H), 4.32−4.19 (m, 4H), 3.19 (s, 3H), 1.36 (t, J = 6.8
Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ
171.9 (d, J = 3.1 Hz), 144.7, 131.6, 127.9, 127.5, 127.3, 118.7 (td, J1 =
273.7 Hz, J2 = 205.7 Hz), 110.9, 76.9 (q, J = 20.6 Hz), 65.4 (d, J = 6.7
Hz), 65.1 (d, J = 6.8 Hz), 26.7, 16.5 (d, J = 6.5 Hz), 16.4 (d, J = 6.6
Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ −117.38 (ABd, J1 =
310.1 Hz, J2 = 90.0 Hz), −119.84 (ABd, J1 = 309.9 Hz, J2 = 103.8 Hz);
31P NMR (162 MHz, CDCl3, 85% H3PO4) δ 5.51 (dd, J1 = 104.2 Hz,
J2 = 89.7 Hz); IR (neat) 3314, 1713, 1612, 1494, 1466, 1270, 1075,
1008; MS (EI) 383 (M+, 24), 385 ([M + 2]+, 8) 229 (100), 201 (75),
231 (37), 196 (34), 207 (29), 203 (26); HRMS (EI) exact mass calcd
for C14H1735ClF2NO5P [M+] 383.0501, found 383.0503.
1
solid; 163.5 mg, isolated yield 98%; mp 93−95 °C; H NMR (300
MHz, CDCl3) δ 7.76−7.68 (m, 2H), 7.22−7.17 (m, 1H), 5.05 (s, br,
1H), 4.33−4.22 (m, 4H), 3.40 (q, J = 2.1 Hz, 3H), 1.34 (t, J = 6.6 Hz,
3H), 1.32 (t, J = 6.6 Hz, 3H); 13C NMR (126 MHz, acetone-d6) δ
173.4−173.4 (m), 143.8, 131.3, 129.4 (q, J = 6.0 Hz), 128.4, 124.6 (q,
J = 271.4 Hz), 123.2, 118.6 (td, J1 = 273.7 Hz, J2 = 205.4 Hz), 112.8
(q, J = 33.1 Hz), 75.3 (q, J = 21.0 Hz), 65.5 (d, J = 6.7 Hz), 65.2 (d, J
= 6.8 Hz), 29.4 (q, J = 6.6 Hz), 16.5 (d, J = 5.7 Hz), 16.4 (d, J = 5.7
Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ −52.95 (s, 3F), −117.36
(ABd, J1 = 309.9 Hz, J2 = 89.4 Hz, 1F), −120.19 (ABd, J1 = 309.4 Hz,
J2 = 104.3 Hz, 1F); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 5.56
(dd, J1 = 104.9 Hz, J2 = 90.2 Hz); IR (neat) 3236, 1738, 1599, 1460,
1260, 1174, 1080, 1018; MS (EI) 417 (M+, 9), 263 (100), 235 (63),
215 (28), 264 (20), 230 (17), 195 (14), 236 (14); HRMS (EI) exact
mass calcd for C15H17F5NO5P [M+] 417.0765, found 417.0766.
Diethyl ((5-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-
difluoromethyl)phosphonate (7d): pale yellow solid; 157.1 mg,
1
isolated yield 92%; mp 125−127 °C; H NMR (400 MHz, CDCl3) δ
7.63 (s, 1H), 7.48 (ABd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.70 (AB, J =
8.4 Hz, 1H), 5.22 (s, br, 1H), 4.24−4.10 (m, 4H), 3.13 (s, 3H), 1.28
(t, J = 7.2 Hz, 3H), 1.24 (t, J = 6.8 Hz, 3H); 13C NMR (126 MHz,
acetone-d6) δ 171.8 (d, J = 4.2 Hz), 145.2, 134.6, 130.2, 127.7 (d, J =
2.8 Hz), 118.8 (td, J1 = 273.3 Hz, J2 = 205.2 Hz), 115.1, 111.4, 76.9 (q,
J = 20.7 Hz), 65.4 (d, J = 6.7 Hz), 65.2 (d, J = 6.7 Hz), 26.6, 16.5 (d, J
= 6.0 Hz), 16.4 (d, J = 6.0 Hz); 19F NMR (282 MHz, CDCl3, PhCF3)
δ −117.40 (ABd, J1 = 309.9 Hz, J2 = 90.0 Hz), −119.79 (ABd, J1 =
309.9 Hz, J2 = 103.8 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4)
E
DOI: 10.1021/acs.joc.6b01457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Diethyl ((1-benzyl-3-hydroxy-2-oxoindolin-3-yl)-
difluoromethyl)phosphonate (7i): white solid; 156.4 mg, isolated
yield 92%; mp 108−110 °C; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J
= 7.2 Hz, 1H), 7.30−7.22 (m, 6H), 7.06 (td, J1 = 7.6 Hz, J2 = 0.4 Hz,
1H), 6.66 (d, J = 8.0 Hz, 1H), 5.20 (s, br, 1H), 5.00 (AB, J = 16.0 Hz,
1H), 4.74 (AB, J = 16.0 Hz, 1H), 4.32−4.18 (m, 4H), 1.31 (t, J = 7.2
Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, acetone-d6) δ
172.8 (d, J = 4.0 Hz), 145.0, 136.8, 131.6, 129.4, 128.3, 128.2, 127.5,
125.6, 123.4, 118.9 (td, J1 = 272.4 Hz, J2 = 204.6 Hz), 110.3, 77.2 (q, J
= 19.5 Hz), 65.3 (d, J = 6.7 Hz), 65.1 (d, J = 6.7 Hz), 44.2, 16.5 (d, J =
5.7 Hz), 16.4 (d, J = 5.8 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ
−116.51 (ABd, J1 = 310.8 Hz, J2 = 90.0 Hz), −119.77 (ABd, J1 = 310.8
Hz, J2 = 105.2 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 5.86
(dd, J1 = 106.0 Hz, J2 = 90.4 Hz); IR (neat) 3306, 1712, 1613, 1469,
1370, 1287, 1156, 1019; MS (EI) 425 (M+, 8), 91 (100), 271 (96),
272 (19), 243 (14), 253 (12), 109 (10), 65 (10); HRMS (EI) exact
mass calcd for C20H22F2NO5P [M+] 425.1204, found 425.1206.
General Procedure for the Difluoromethylation of Reagent
5 with Ketones 8a−p. To a 10 mL Schlenk tube were added KOAc
(3.9 mg, 10 mol %), 18-crown-6 (10.6 mg, 10 mol %), and anhydrous
THF (1.5 mL), followed by the addition of reagent 5 (156.2 mg, 1.5
equiv) and aryl ketones 8a−p (0.40 mmol). After the mixture was
stirred at room temperature until almost full conversion of aryl ketones
8a−p by TLC analysis, the resultant was concentrated and directly
subjected to column chromatography (petroleum ether:EtOAc = 10:1)
to afford the desired product 9a−p.
Diethyl (2-(4-bromophenyl)-1,1-difluoro-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9d): yellow oil; 137.4 mg, isolated
yield 75%; H NMR (300 MHz, CDCl3) δ 7.47 (AB, J = 8.7 Hz,
1
2H), 7.39 (AB, J = 8.7 Hz, 2H), 4.22−4.02 (m, 4H), 1.92 (s, 3H), 1.31
(t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.14 (s, 9H); 13C NMR
(101 MHz, acetone-d6) δ 141.3−141.3 (m), 131.4, 130.6, 122.6, 120.1
(ddd, J1 = 274.3 Hz, J2 = 271.9 Hz, J3 = 205.5 Hz), 79.7 (td, J1 = 24.2
Hz, J2 = 14.8 Hz), 64.6 (d, J = 6.9 Hz), 64.4 (d, J = 6.8 Hz), 23.4 (t, J =
3.3 Hz), 16.7 (d, J = 5.9 Hz), 16.6 (d, J = 5.6 Hz), 2.2; 19F NMR (282
MHz, CDCl3, PhCF3) δ −115.02 (d, J = 105.2 Hz); 31P NMR (122
MHz, CDCl3, 85% H3PO4) δ 6.30 (t, J = 105.5 Hz); IR (neat) 2962,
1253, 1162, 1135, 1009, 977, 840, 754; MS (ESI) 483 (M + 2 + Na+);
HRMS (EI) exact mass calcd for C16H2679BrF2O4PSi [M+] 458.0489,
found 458.0481.
Diethyl (2-(4-cyanophenyl)-1,1-difluoro-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9e): yellow oil; 92.3 mg, isolated yield
1
57%; H NMR (300 MHz, CDCl3) δ 7.65 (s, 4H), 4.23−4.04 (m,
4H), 1.94 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 6.9 Hz, 3H),
0.16 (s, 9H); 13C NMR (101 MHz, acetone-d6) δ 147.4−147.3 (m),
132.2, 129.5, 120.1 (td, J1 = 273.9 Hz, J2 = 206.1 Hz), 119.2, 112.6,
80.0 (td, J1 = 23.7 Hz, J2 = 14.5 Hz), 64.8 (d, J = 7.0 Hz), 64.6 (d, J =
6.8 Hz), 23.4 (t, J = 3.3 Hz), 16.7 (d, J = 5.8 Hz), 16.6 (d, J = 5.6 Hz),
2.2; 19F NMR (282 MHz, CDCl3, PhCF3) δ −114.83 (d, J = 12.7 Hz),
−115.20 (d, J = 13.0 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4)
δ 5.76 (t, J = 104.6 Hz); IR (neat) 2967, 2230, 1254, 1164, 1135, 1052,
1017, 978; HRMS (ESI) exact mass calcd for C17H26F2NO4PSiNa [M
+ Na]+ 428.1235, found 428.1224.
Note: The weighing of 18-crown-6 and KOAc is conducted in a
glovebox to avoid the absorption of moisture, which has a detrimental
effect on the reaction.
Diethyl (1,1-difluoro-2-(4-(trifluoromethyl)phenyl)-2-
((trimethylsilyl)oxy)propyl)phosphonate (9f): yellow oil; 134.4
1
mg, isolated yield 75%; H NMR (300 MHz, CDCl3) δ 7.65 (AB, J =
Diethyl (1,1-difluoro-2-phenyl-2-((trimethylsilyl)oxy)-
propyl)phosphonate (9a): yellow oil; 103.4 mg, isolated yield
8.4 Hz, 2H), 7.61 (AB, J = 8.7 Hz, 2H), 4.23−4.01 (m, 4H), 1.96 (d, J
= 1.8 Hz, 3H), 1.30 (t, J = 6.9 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 0.16
(s, 9H); 13C NMR (101 MHz, acetone-d6) δ 146.5, 130.4 (q, J = 32.3
Hz), 129.3, 125.3 (q, J = 272.3 Hz), 125.3 (q, J = 3.8 Hz), 120.2 (td, J1
= 273.2 Hz, J2 = 206.1 Hz), 79.9 (td, J1 = 23.1 Hz, J2 = 14.7 Hz), 64.8
(d, J = 7.1 Hz), 64.6 (d, J = 6.8 Hz), 23.5 (t, J = 3.1 Hz), 16.7 (d, J =
5.8 Hz), 16.6 (d, J = 5.6 Hz), 2.2; 19F NMR (282 MHz, CDCl3,
PhCF3) δ −114.83 (d, J = 5.9 Hz), −115.20 (d, J = 6.2 Hz); 31P NMR
(122 MHz, CDCl3, 85% H3PO4) δ 6.09 (t, J = 105.2 Hz); IR (neat)
2963, 1327, 1254, 1164, 1110, 1015, 978, 842; HRMS (ESI) exact
mass calcd for C17H26F5O4PSiNa [M + Na]+ 471.1156, found
471.1149.
Diethyl (1,1-difluoro-2-(4-nitrophenyl)-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9g):6a yellow oil; 105.5 mg, isolated
yield 62%; 1H NMR (300 MHz, CDCl3) δ 8.21 (AB, J = 9.0 Hz, 2H),
7.71 (AB, J = 9.0 Hz, 2H), 4.22−4.10 (m, 4H), 1.97 (s, 3H), 1.32 (t, J
= 7.5 Hz, 3H), 1.26 (t, J = 6.9 Hz, 3H), 0.18 (s, 9H); 13C NMR (101
MHz, acetone-d6) δ 149.3−149.3 (m), 148.6, 129.9, 123.4, 120.1 (td,
J1 = 273.4 Hz, J2 = 206.14 Hz), 80.0 (td, J1 = 23.6 Hz, J2 = 14.5 Hz),
64.8 (d, J = 7.0 Hz), 64.7 (d, J = 6.8 Hz), 23.5 (t, J = 3.2 Hz), 16.7 (d, J
= 5.8 Hz), 16.6 (d, J = 5.6 Hz), 2.2; 19F NMR (282 MHz, CDCl3,
PhCF3) δ −114.81 (ABd, J1 = 302.6 Hz, J2 = 103.8 Hz), −115.12
(ABd, J1 = 302.7 Hz, J2 = 103.8 Hz); 31P NMR (122 MHz, CDCl3,
85% H3PO4) δ 5.84 (t, J = 104.3 Hz); IR (neat) 2963, 1522, 1349,
1254, 1164, 1136, 1052, 1014.
1
68%; H NMR (300 MHz, CDCl3) δ 7.54−7.52 (m, 2H), 7.38−7.30
(m, 3H), 4.24−3.97 (m, 4H), 1.95 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H),
1.22 (t, J = 7.2 Hz, 3H), 0.14 (s, 9H); 13C NMR (101 MHz, acetone-
d6) δ 141.8 (dd, J1 = 4.4 Hz, J2 = 2.1 Hz), 128.7, 128.5, 128.3, 120.4
(ddd, J1 = 274.7 Hz, J2 = 271.0 Hz, J3 = 205.1 Hz), 79.9 (ddd, J1 = 24.4
Hz, J2 = 22.1 Hz, J3 = 14.8 Hz), 64.5 (d, J = 7.0 Hz), 64.3 (d, J = 6.7
Hz), 23.6 (t, J = 3.2 Hz), 16.7 (d, J = 6.0 Hz), 16.6 (d, J = 5.6 Hz), 2.3;
19F NMR (282 MHz, CDCl3, PhCF3) δ −114.54 (d, J = 5.4 Hz),
−114.91 (d, J = 5.1 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ
6.59 (t, J = 106.3 Hz); IR (neat) 2961, 1447, 1252, 1134, 1024, 977,
840, 755; HRMS (ESI) exact mass calcd for C16H27F2O4PSiNa [M +
Na]+ 403.1282, found 403.1276.
Diethyl (1,1-difluoro-2-(4-fluorophenyl)-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9b): yellow oil; 117.8 mg, isolated
1
yield 74%; H NMR (300 MHz, CDCl3) δ 7.52−7.47 (m, 2H), 7.03
(t, J = 8.7 Hz, 2H), 4.25−4.01 (m, 4H), 1.94 (s, 3H), 1.32 (t, J = 7.2
Hz, 3H), 1.24 (t, J = 6.9 Hz, 3H), 0.13 (s, 9H); 13C NMR (101 MHz,
acetone-d6) δ 163.4 (d, J = 245.8 Hz), 138.0 (d, J = 2.2 Hz), 130.4 (d, J
= 8.4 Hz), 120.3 (td, J1 = 274.3 Hz, J2 = 205.3 Hz), 115.0 (d, J = 21.5
Hz), 79.6 (ddd, J1 = 24.3 Hz, J2 = 22.4 Hz, J3 = 15.0 Hz), 64.6 (d, J =
7.0 Hz), 64.4 (d, J = 6.8 Hz), 23.6 (t, J = 3.2 Hz), 16.7 (d, J = 5.8 Hz),
16.6 (d, J = 5.6 Hz), 2.2; 19F NMR (282 MHz, CDCl3, PhCF3) δ
−114.81 (d, J = 1.7 Hz), −115.18 (d, J = 2.0 Hz); 31P NMR (122
MHz, CDCl3, 85% H3PO4) δ 6.44 (t, J = 105.9 Hz); IR (neat) 2962,
1509, 1253, 1157, 1016, 977, 840, 756; HRMS (ESI) exact mass calcd
for C16H26F3O4PSiNa [M + Na]+ 421.1188, found 421.1179.
Diethyl (1,1-difluoro-2-(p-tolyl)-2-((trimethylsilyl)oxy)-
propyl)phosphonate (9h): yellow oil; 61.5 mg, isolated yield 39%;
1H NMR (300 MHz, CDCl3) δ 7.40 (AB, J = 8.1 Hz, 2H), 7.15 (AB, J
Diethyl (2-(4-chlorophenyl)-1,1-difluoro-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9c): yellow oil; 137.4 mg, isolated yield
83%; 1H NMR (300 MHz, CDCl3) δ 7.45 (AB, J = 8.7 Hz, 2H), 7.32
(AB, J = 8.7 Hz, 2H), 4.24−4.02 (m, 4H), 1.93 (s, 3H), 1.32 (t, J = 7.2
Hz, 3H), 1.24 (t, J = 6.9 Hz, 3H), 0.14 (s, 9H); 13C NMR (101 MHz,
acetone-d6) δ 140.9−140.9 (m), 134.4, 130.4, 128.4, 120.2 (td, J1 =
274.2 Hz, J2 = 205.5 Hz), 79.7 (td, J1 = 24.1 Hz, J2 = 14.8 Hz), 64.7 (d,
J = 7.0 Hz), 64.5 (d, J = 6.7 Hz), 23.5 (t, J = 3.3 Hz), 16.7 (d, J = 5.8
Hz), 16.6 (d, J = 5.6 Hz), 2.2; 19F NMR (282 MHz, CDCl3, PhCF3) δ
−115.00 (d, J = 105.2 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4)
δ 6.34 (t, J = 105.8 Hz); IR (neat) 2962, 1492, 1399, 1253, 1162, 1135,
1013, 977; HRMS (ESI) exact mass calcd for C16H2735ClF2O4PSi [M
+ H]+ 415.1069, found 415.1067.
= 8.1 Hz, 2H), 4.25−3.99 (m, 4H), 2.34 (s, 3H), 1.94 (s, 3H), 1.32 (t,
J = 7.2 Hz, 3H), 1.23 (t, J = 6.9 Hz, 3H), 0.13 (s, 9H); 13C NMR (101
MHz, acetone-d6) δ 138.9 (dd, J1 = 4.5 Hz, J2 = 2.3 Hz), 138.2, 129.0,
128.5, 120.4 (ddd, J1 = 274.7 Hz, J2 = 270.7 Hz, J3 = 204.9 Hz), 79.8
(ddd, J1 = 24.5 Hz, J2 = 21.9 Hz, J3 = 14.8 Hz), 64.55 (d, J = 7.1 Hz),
64.3 (d, J = 6.8 Hz), 23.6 (t, J = 3.1 Hz), 21.0, 16.7 (d, J = 6.0 Hz),
16.6 (d, J = 5.6 Hz), 2.3; 19F NMR (282 MHz, CDCl3, PhCF3) δ
−114.40 (ABd, J1 = 301.2 Hz, J2 = 106.3 Hz), −114.86 (ABd, J1 =
301.2 Hz, J2 = 106.0 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4)
δ 6.68 (t, J = 106.4 Hz); IR (neat) 2959, 1252, 1160, 1134, 1020, 976,
864, 841; HRMS (ESI) exact mass calcd for C17H29F2O4PSiNa [M +
Na]+ 417.1439, found 417.1435.
F
DOI: 10.1021/acs.joc.6b01457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Diethyl (2-(2-chlorophenyl)-1,1-difluoro-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9i): yellow oil; 54.6 mg, isolated yield
33%; H NMR (300 MHz, CDCl3) δ 7.73−7.69 (m, 1H), 7.39−7.36
1299, 1266, 1252, 1167, 1088, 1013; HRMS (ESI) exact mass calcd for
C17H2935ClF2O4PSi [M + H]+ 429.1224, found 429.1226.
1
Diethyl (1,1,3,3,3-pentafluoro-2-phenyl-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9n): yellow oil; 116.3 mg, isolated
yield 67%; 1H NMR (300 MHz, CDCl3) δ 7.71−7.69 (m, 2H),
7.42−7.39 (m, 3H), 4.23−3.97 (m, 2H), 3.90−3.69 (m, 2H), 1.27 (t, J
= 6.9 Hz, 3H), 1.08 (t, J = 6.9 Hz, 3H), 0.30 (s, 9H); 13C NMR (101
MHz, acetone-d6) δ 133.8 (d, J = 4.7 Hz), 130.3, 128.8, 128.5, 124.7
(qd, J1 = 292.0 Hz, J2 = 11.8 Hz), 119.3 (td, J1 = 280.5 Hz, J2 = 212.3
Hz), 81.8−81.4 (m), 65.1 (d, J = 6.8 Hz), 64.6 (d, J = 7.1 Hz), 16.6 (d,
J = 5.4 Hz), 16.3 (d, J = 5.6 Hz), 1.7; 19F NMR (282 MHz, CDCl3,
PhCF3) δ −68.78 (ddd, J1 = 15.0 Hz, J2 = 10.6 Hz, J3 = 4.6 Hz, 3F),
−110.60 (ABdq, J1 = 311.0 Hz, J2 = 97.9 Hz, J3 = 10.6 Hz, 1F),
−114.41 (ABdq, J1 = 313.9 Hz, J2 = 106.6 Hz, J3 = 14.4 Hz, 1F); the
ABdq is used to show that the CF2 group in compound 9n is first split
by P atom and then by the CF3 group; 31P NMR (122 MHz, CDCl3,
85% H3PO4) δ 3.99 (t, J = 100.8 Hz); IR (neat) 2984, 1254, 1184,
1018, 935, 846, 758, 711; MS (ESI) 457 (M+Na+); HRMS (EI) exact
mass calcd for C16H24F5O4PSi [M+] 434.1102, found 434.1100.
Diethyl (1,1,3,3-tetrafluoro-2-phenyl-2-((trimethylsilyl)oxy)-
propyl)phosphonate (9o): red oil; 121.5 mg, isolated yield 73%; 1H
NMR (300 MHz, CDCl3) δ 7.64−7.61 (m, 2H), 7.40−7.36 (m, 3H),
6.68 (dd, J1 = 54.6 Hz, J2 = 53.4 Hz, 1H), 4.20−4.02 (m, 4H), 1.27 (t,
J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.21 (d, J = 0.6 Hz, 9H); 13C
NMR (101 MHz, acetone-d6) δ 134.3, 129.7, 129.0, 128.5, 119.0 (td,
J1 = 276.2 Hz, J2 = 206.6 Hz), 115.6 (td, J1 = 252.3 Hz, J2 = 2.6 Hz),
81.6 (td, J1 = 22.0 Hz, J2 = 15.2 Hz), 65.2 (d, J = 2.4 Hz), 65.1 (d, J =
2.9 Hz), 16.6 (d, J = 5.8 Hz), 16.5 (d, J = 5.6 Hz), 1.9 (d, J = 2.0 Hz);
19F NMR (282 MHz, CDCl3, PhCF3) δ −113.65 to −113.73 (m, 1F),
(m, 1H), 7.28−7.22 (m, 2H), 4.29−4.11 (m, 4H), 2.20 (s, 3H), 1.34
(t, J = 7.2 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H), 0.15 (s, 9H); 13C NMR
(101 MHz, acetone-d6) δ 138.5 (dd, J1 = 5.8 Hz, J2 = 2.3 Hz), 134.1,
132.8, 132.8, 130.6, 127.1, 121.2 (ddd, J1 = 277.0 Hz, J2 = 271.0 Hz, J3
= 204.9 Hz), 81.3 (ddd, J1 = 27.1 Hz, J2 = 22.0 Hz, J3 = 15.0 Hz),
64.9−64.8 (m), 64.6 (d, J = 6.0 Hz), 25.0 (t, J = 3.1 Hz), 16.7 (d, J =
6.5 Hz), 16.7 (d, J = 6.0 Hz), 2.1; 19F NMR (282 MHz, CDCl3,
PhCF3) δ −111.98 (ABd, J1 = 301.6 Hz, J2 = 104.9 Hz), −113.10
(ABd, J1 = 301.5 Hz, J2 = 104.0 Hz) ; 31P NMR (122 MHz, CDCl3,
85% H3PO4) δ 6.09 (t, J = 105.2 Hz); IR (neat) 2964, 1428, 1252,
1138, 1023, 977, 840, 747; HRMS (ESI) exact mass calcd for
C16H2635ClF2O4PSiNa [M + Na]+ 437.0892, found 437.0897.
Diethyl (2-(3-chlorophenyl)-1,1-difluoro-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9j): yellow oil; 127.5 mg, isolated yield
1
77%; H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.42−7.40 (m,
1H), 7.29−7.27 (m, 2H), 4.25−4.02 (m, 4H), 1.93 (s, 3H), 1.32 (t, J =
7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.16 (s, 9H); 13C NMR (101
MHz, acetone-d6) δ 114.4−144.4 (m), 134.0, 130.1, 128.8, 128.6,
127.0, 120.1 (td, J1 = 272.2 Hz, J2 = 205.7 Hz), 79.7 (td, J1 = 22.6 Hz,
J2 = 14.8 Hz), 64.7 (d, J = 7.1 Hz), 64.5 (d, J = 6.8 Hz), 23.5 (t, J = 3.2
Hz), 16.7 (d, J = 5.8 Hz), 16.6 (d, J = 5.6 Hz), 2.2; 19F NMR (282
MHz, CDCl3, PhCF3) δ −114.85 (d, J = 105.2 Hz); 31P NMR (122
MHz, CDCl3, 85% H3PO4) δ 6.26 (t, J = 105.8 Hz); IR (neat) 2960,
1573, 1267, 1253, 1163, 1137, 1023, 978; HRMS (ESI) exact mass
calcd for C16H2735ClF2O4PSi [M + H]+ 415.1067, found 415.1070.
Diethyl (1,1-difluoro-2-(pyridin-2-yl)-2-((trimethylsilyl)oxy)-
propyl)phosphonate (9k): yellow oil; 106.7 mg, isolated yield
−114.00 to −114.09 (m, 1F), −123.87 (ABt, J1 = 290.5 Hz, J2 = 12.4
Hz, 1F), −126.87 (ABt, J1 = 290.7 Hz, J2 = 9.6 Hz, 1F); the ABt is
used to show that the CF2 group in compound 9o is split by the CF2H
group; 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 5.19 (t, J = 101.6
Hz); IR (neat) 2984, 1253, 1138, 1120, 1018, 983, 872, 843; MS (ESI)
439 (M+Na+); HRMS (EI) exact mass calcd for C16H25F4O4PSi [M+]
416.1196, found 416.1201.
1
70%; H NMR (300 MHz, CDCl3) δ 8.60−8.59 (m, 1H), 7.76−7.68
(m, 2H), 7.24−7.20 (m, 1H), 4.26−4.08 (m, 4H), 2.01 (t, J = 1.8 Hz,
3H), 1.31 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 6.9 Hz, 3H), 0.14 (s, 9H);
13C NMR (101 MHz, acetone-d6) δ 160.5 (dd, J1 = 5.4 Hz, J2 = 2.5
Hz), 148.8, 136.6, 123.9, 123.7, 120.6 (ddd, J1 = 274.7 Hz, J2 = 272.3
Hz, J3 = 206.3 Hz), 81.4 (dd, J1 = 23.6 Hz, J2 = 21.5 Hz, J3 = 14.4 Hz),
64.6 (d, J = 7.0 Hz), 64.4 (d, J = 6.8 Hz), 22.7 (t, J = 3.1 Hz), 16.7 (d, J
= 6.0 Hz), 16.6 (d, J = 5.6 Hz), 2.3; 19F NMR (282 MHz, CDCl3,
PhCF3) δ −114.66 (ABd, J1 = 303.3 Hz, J2 = 104.9 Hz), −115.06
(ABd, J1 = 303.0 Hz, J2 = 105.5 Hz); 31P NMR (122 MHz, CDCl3,
85% H3PO4) δ 6.40 (t, J = 105.8 Hz); IR (neat) 2959, 1588, 1433,
1253, 1167, 1139, 1016, 978; HRMS (ESI) exact mass calcd for
C15H26F2NO4PSiNa [M + Na]+ 404.1235, found 404.1215.
Diethyl (difluoro(1-((trimethylsilyl)oxy)-1,2,3,4-tetrahydro-
naphthalen-1-yl)methyl)phosphonate (9p): yellow oil; 90.9 mg,
1
isolated yield 56%; H NMR (300 MHz, CDCl3) δ 7.70−7.68 (m,
1H), 7.24−7.15 (m, 2H), 7.10−7.08 (m, 1H), 4.32−4.00 (m, 4H),
2.90−2.76 (m, 3H), 2.03−2.00 (m, 2H), 1.84−1.78 (m, 1H), 1.38 (t, J
= 7.2 Hz, 3H), 1.27 (t, J = 6.9 Hz, 3H), −0.02 (s, 9H); 13C NMR (101
MHz, acetone-d6) δ 139.9, 135.8 (dd, J1 = 5.2 Hz, J2 = 2.0 Hz), 130.8
(dd, J1 = 4.7 Hz, J2 = 2.0 Hz), 129.4, 129.0, 126.0, 120.6 (ddd, J1 =
276.7 Hz, J2 = 270.5 Hz, J3 = 203.5 Hz), 77.6 (ddd, J1 = 23.7 Hz, J2 =
18.5 Hz, J3 = 16.7 Hz), 64.7 (dd, J = 7.0 Hz, J = 1.2 Hz), 64.3 (d, J =
6.6 Hz), 34.4 (d, J = 3.3 Hz), 19.9, 19.8, 16.8 (d, J = 5.8 Hz), 16.6 (d, J
= 5.6 Hz), 2.1; 19F NMR (282 MHz, CDCl3, PhCF3) δ −118.72 (ABd,
J1 = 304.6 Hz, J2 = 105.5 Hz), −112.12 (ABd, J1 = 304.4 Hz, J2 = 106.6
Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 7.07 (t, J = 106.9
Hz); IR (neat) 2959, 1251, 1142, 1017, 978, 884, 839, 741; HRMS
(ESI) exact mass calcd for C18H29F2O4PSiNa [M + Na]+ 429.1439,
found 429.1436.
Diethyl (1,1-difluoro-2-(thiophen-2-yl)-2-((trimethylsilyl)-
oxy)propyl)phosphonate (9l): yellow oil; 77.2 mg, isolated yield
1
50%; H NMR (300 MHz, CDCl3) δ 7.30−7.28 (m, 1H), 7.06−7.05
(m, 1H), 7.00−6.97 (m, 1H), 4.28−4.04 (m, 4H), 1.98 (d, J = 1.8 Hz,
3H), 1.34 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 6.9 Hz, 3H), 0.15 (s, 9H);
13C NMR (101 MHz, acetone-d6) δ 141.4 (dd, J1 = 5.2 Hz, J2 = 2.3
Hz), 127.3, 127.1, 127.0, 119.7 (ddd, J1 = 275.5 Hz, J2 = 271.0 Hz, J3 =
205.0 Hz), 78.9 (ddd, J1 = 25.4 Hz, J2 = 22.1 Hz, J3 = 16.6 Hz), 64.8
(d, J = 7.1 Hz), 64.5 (d, J = 6.7 Hz), 24.6 (t, J = 3.0 Hz), 16.7 (d, J =
5.8 Hz), 16.6 (d, J = 5.6 Hz), 2.0; 19F NMR (282 MHz, CDCl3,
PhCF3) δ −114.77 (ABd, J1 = 301.7 Hz, J2 = 100.4 Hz), −114.77
(ABd, J1 = 300.5 Hz, J2 = 104.6 Hz); 31P NMR (122 MHz, CDCl3,
85% H3PO4) δ 5.96 (t, J = 105.3 Hz); IR (neat) 2966, 1267, 1252,
1158, 1130, 1023, 973, 841; HRMS (ESI) exact mass calcd for
C14H25F2O4PSSiNa [M + Na]+ 409.0846, found 409.0847.
Diethyl (2-(4-chlorophenyl)-1,1-difluoro-2-((trimethylsilyl)-
oxy)butyl)phosphonate (9m): yellow oil; 78.7 mg, isolated yield
46%; 1H NMR (300 MHz, CDCl3) δ 7.48 (AB, J = 8.4 Hz, 2H), 7.30
(AB, J = 7.8 Hz, 2H), 4.04−3.80 (m, 4H), 2.43−2.33 (m, 1H), 2.19−
2.07 (m, 1H), 1.16 (q, J = 7.2 Hz, 6H), 0.70 (t, J = 7.2 Hz, 3H), 0.26
(s, 9H); 13C NMR (101 MHz, acetone-d6) δ 138.4, 134.1, 130.6,
128.4, 120.9 (td, J1 = 274.0 Hz, J2 = 205.1 Hz), 83.4 (td, J1 = 20.9 Hz,
J2 = 16.6 Hz), 64.5 (d, J = 7.3 Hz), 64.4 (d, J = 7.1 Hz), 26.6 (d, J = 2.4
Hz), 16.5 (d, J = 3.8 Hz), 16.4 (d, J = 4.0 Hz), 7.8, 2.4; 19F NMR (282
MHz, CDCl3, PhCF3) δ −113.04 (ABd, J1 = 300.0 Hz, J2 = 104.0 Hz),
−115.68 (ABd, J1 = 299.9 Hz, J2 = 104.9 Hz); 31P NMR (122 MHz,
CDCl3, 85% H3PO4) δ 5.72 (t, J = 104.8 Hz); IR (neat) 2981, 1491,
General Procedure for the Difluoromethylation of Reagent
5 with Ketones 8q−w and Aldehydes 10a−d. To a 10 mL
Schlenk tube were added KOAc (3.9 mg, 10 mol %), 18-crown-6 (10.6
mg, 10 mol %), and anhydrous THF (1.5 mL), followed by the
addition of reagent 5 (156.2 mg, 1.5 equiv) and ketones 8q−w (0.40
mmol) (or aldehydes 10a−d, 0.40 mmol). After the mixture was
stirred at room temperature until almost full conversion of 8 or 10 by
TLC analysis, a solution of concentrated HCl in MeOH (2 M, 1 mL)
was added to the reaction mixture. The mixture was stirred at room
temperature for 1 h, and then was concentrated and directly subjected
to column chromatography (petroleum ether:EtOAc = 4:1) to afford
the desired product 9q−w, 11a−d.
Note: The weighing of 18-crown-6 and KOAc is conducted in a
glovebox to avoid the absorption of moisture, which has a detrimental
effect on the reaction.
(E)-Methyl 2-((diethoxyphosphoryl)difluoromethyl)-2-hy-
droxy-4-phenylbut-3-enoate (9q): yellow oil; 90.7 mg, isolated
G
DOI: 10.1021/acs.joc.6b01457
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
yield 60%; H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 6.9 Hz, 2H),
NMR (282 MHz, CDCl3, PhCF3) δ −118.10 (ABd, J1 = 303.8 Hz, J2 =
108.3 Hz), −118.85 (ABd, J1 = 302.3 Hz, J2 = 104.9 Hz); 31P NMR
(122 MHz, CDCl3, 85% H3PO4) δ 7.79 (t, J = 105.5 Hz); IR (neat)
3386, 2986, 1254, 1098, 1016, 796, 750, 700; MS (ESI) 359 (M+Na+);
HRMS (EI) exact mass calcd for C15H23F2O4P [M+] 336.1302, found
336.1307.
Diethyl (1,1-difluoro-2-hydroxy-2-methylpentyl)-
phosphonate (9v): pale yellow oil; 61.4 mg, isolated yield 56%;
1H NMR (300 MHz, CDCl3) δ 4.33−4.24 (m, 4H), 2.66 (s, br, 1H),
7.36−7.26 (m, 3H), 7.04 (AB, J = 15.6 Hz, 1H), 6.43 (AB, J = 15.9 Hz,
1H), 4.32−4.23 (m, 5H), 3.91 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H), 1.34
(t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ 170.4, 136.8,
134.1, 129.5, 129.1, 127.7, 123.3 (q, J = 3.4 Hz), 118.8 (td, J1 = 274.5
Hz, J2 = 206.6 Hz), 79.5 (td, J1 = 23.1 Hz, J2 = 14.1 Hz), 65.2, 65.1,
53.9, 16.6, 16.6 (d, J = 0.9 Hz); 19F NMR (282 MHz, CDCl3, PhCF3)
δ −113.13 (ABd, J1 = 306.8 Hz, J2 = 101.0 Hz), −115.78 (ABd, J1 =
306.5 Hz, J2 = 99.3 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ
5.89 (t, J = 100.6 Hz); IR (neat) 3318, 2986, 1743, 1439, 1256, 1163,
1014, 747; MS (EI) 378 (M+, 24), 131 (100), 191 (82), 319 (71), 161
(59), 188 (51), 132 (48), 245 (47); HRMS (EI) exact mass calcd for
C16H21F2O6P [M+] 378.1044, found 378.1050.
Diethyl (1,1-difluoro-2-hydroxy-2-methyl-4-phenylbut-3-yn-
1-yl)phosphonate (9r): yellow oil; 108.9 mg, isolated yield 82%; 1H
NMR (300 MHz, CDCl3) δ 7.47−7.44 (m, 2H), 7.33−7.31 (m, 3H),
4.39−4.25 (m, 5H), 1.70 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H), 1.30 (t, J =
7.2 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ 132.4, 129.8, 129.4,
122.9, 119.3 (td, J1 = 272.9 Hz, J2 = 203.4 Hz), 88.6 (d, J = 4.4 Hz),
86.2, 70.9 (td, J1 = 23.8 Hz, J2 = 17.2 Hz), 65.2 (d, J = 6.6 Hz), 65.1 (d,
J = 6.8 Hz), 24.2 (d, J = 1.6 Hz), 16.7 (d, J = 2.7 Hz), 16.6 (d, J = 2.8
Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ −114.30 (ABd, J1 =
295.1 Hz, J2 = 94.8 Hz), −120.99 (ABd, J1 = 295.0 Hz, J2 = 106.6 Hz);
31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 7.52 (dd, J1 = 107.4 Hz,
1.71−1.33 (m, 13H), 0.94 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 120.6 (td, J1 = 272.5 Hz, J2 = 201.5 Hz), 75.0 (td, J1 = 21.4
Hz, J2 = 14.1 Hz), 64.9 (t, J = 7.9 Hz), 37.5 (q, J = 2.3 Hz), 19.6 (d, J =
2.8 Hz), 16.3 (d, J = 5.6 Hz), 15.9, 14.5; 19F NMR (282 MHz, CDCl3,
PhCF3) δ −118.02 (ABd, J1 = 302.0 Hz, J2 = 106.0 Hz), −118.52
(ABd, J1 = 302.0 Hz, J2 = 105.2 Hz); 31P NMR (122 MHz, CDCl3,
85% H3PO4) δ 8.07 (t, J = 106.1 Hz); IR (neat) 3396, 2964, 1394,
1254, 1019, 979, 957, 796; HRMS (EI) exact mass calcd for
C10H21F2O4P [M+] 274.1146, found 274.1142.
Diethyl ((2,2-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-
inden-1-yl)difluoromethyl)phosphonate (9w): white solid; 84.4
mg, isolated yield 57%; mp 105−107 °C; 1H NMR (300 MHz,
CDCl3) δ 7.96−7.84 (m, 3H), 7.72−7.66 (m, 1H), 5.56 (s, br, 1H),
4.39−4.32 (m, 4H), 1.42 (t, J = 4.2 Hz, 3H), 1.39 (t, J = 4.2 Hz, 3H);
13C NMR (101 MHz, acetone-d6) δ 188.1 (t, J = 24.4 Hz), 146.6 (d, J
J2 = 95.4 Hz); IR (neat) 3331, 2987, 1490, 1444, 1254, 1014, 757, 692;
MS (EI) 332 (M+, 16), 161 (100), 132 (83), 178 (79), 188 (68), 145
(65), 133 (30), 160 (30); HRMS (EI) exact mass calcd for
C15H19F2O4P [M+] 332.0989, found 332.0994.
(E)-Diethyl (1,1-difluoro-2-hydroxy-2-methyl-4-phenylbut-3-
en-1-yl)phosphonate (9s): yellow oil; 116.2 mg, isolated yield 87%;
1H NMR (300 MHz, CDCl3) δ 7.41 (AB, J = 7.2 Hz, 2H), 7.32 (t, J =
7.2 Hz, 3H), 6.86 (AB, J = 16.2 Hz, 1H), 6.32 (ABd, J1 = 15.9 Hz, J2 =
1.8 Hz, 1H), 4.32 (quint, J = 6.9 Hz, 2H), 4.21−4.05 (m, 3H), 1.50 (s,
3H), 1.39 (t, J = 6.9 Hz, 3H), 1.21 (t, J = 6.9 Hz, 3H); 13C NMR (101
MHz, acetone-d6) δ 137.6, 131.2, 130.4 (d, J = 2.4 Hz), 129.4, 128.6,
127.5, 120.7 (td, J1 = 272.4 Hz, J2 = 203.3 Hz), 75.8 (td, J1 = 22.2 Hz,
J2 = 15.2 Hz), 65.1 (d, J = 6.6 Hz), 64.9 (d, J = 6.8 Hz), 22.3 (q, J = 2.9
Hz), 16.6 (d, J = 5.8 Hz), 16.6 (d, J = 5.8 Hz); 19F NMR (282 MHz,
CDCl3, PhCF3) δ −117.64 (ABd, J1 = 300.3 Hz, J2 = 96.7 Hz),
−120.63 (ABd, J1 = 300.5 Hz, J2 = 110.0 Hz); 31P NMR (122 MHz,
CDCl3, 85% H3PO4) δ 7.97 (dd, J1 = 110.4 Hz, J2 = 97.6 Hz); IR
(neat) 3375, 2987, 1448, 1394, 1370, 1254, 1164, 1015; MS (EI) 334
(M+, 6), 147 (100), 132 (22), 161 (21), 129 (13), 148 (11), 188 (10),
160 (8); HRMS (EI) exact mass calcd for C15H21F2O4P [M+]
334.1146, found 334.1147.
= 5.8 Hz), 138.0, 134.0 (t, J = 3.6 Hz), 132.8, 129.2, 124.8, 119.2 (td,
J1 = 275.0 Hz, J2 = 205.0 Hz), 115.9 (dd, J1 = 277.6 Hz, J2 = 258.9 Hz),
80.1−79.0 (m), 65.6 (d, J = 6.6 Hz), 65.4 (d, J = 6.9 Hz), 16.5 (d, J =
5.8 Hz), 16.4 (d, J = 5.8 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ
−109.94 (ABdd, J1 = 314.7 Hz, J2 = 88.3 Hz, J3 = 24.2 Hz, 1F),
−114.01 (ABdd, J1 = 314.6 Hz, J2 = 104.0 Hz, J3 = 5.9 Hz, 1F),
−116.18 (AB, J = 280.9 Hz, 1F), −124.32 (ABd, J1 = 280.9 Hz, J2 =
24.2 Hz, 1F); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 6.80 (dd,
J1 = 104.7 Hz, J2 = 88.3 Hz); IR (neat) 3212, 1742, 1276, 1199, 1139,
1101, 1070, 1015; MS (EI) 370 (M+, 4), 350 (100), 132 (92), 188
(86), 161 (72), 111 (51), 138 (39), 183 (36); HRMS (EI) exact mass
calcd for C14H15F4O5P [M+] 370.0593, found 370.0597.
Diethyl (2-(4-chlorophenyl)-1,1-difluoro-2-hydroxyethyl)-
phosphonate (11a):4d white solid; 110.4 mg, isolated yield 84%;
1
mp 97−98 °C; H NMR (300 MHz, CDCl3) δ 7.42 (AB, J = 8.7 Hz,
2H), 7.36 (AB, J = 8.7 Hz, 2H), 5.08 (dq, J1 = 20.4 Hz, J2 = 4.8 Hz,
1H), 4.27−4.23 (m, 4H), 3.88 (d, J = 4.8 Hz, 1H), 1.37 (t, J = 6.9 Hz,
3H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, acetone-d6) δ
136.4 (dd, J1 = 5.8 Hz, J2 = 2.8 Hz), 134.7, 130.9, 128.8, 119.4 (ddd, J1
= 272.5 Hz, J2 = 263.1 Hz, J3 = 207.9 Hz), 73.1 (ddd, J1 = 26.7 Hz, J2 =
21.4 Hz, J3 = 14.9 Hz), 65.2 (d, J = 6.4 Hz), 64.8 (d, J = 6.8 Hz), 16.6
(d, J = 5.7 Hz), 16.6 (d, J = 5.7 Hz); 19F NMR (282 MHz, CDCl3,
PhCF3) δ −114.19 (ABd, J1 = 304.7 Hz, J2 = 98.4 Hz), −125.10 (ABd,
J1 = 304.8 Hz, J2 = 104.6 Hz); 31P NMR (122 MHz, CDCl3, 85%
H3PO4) δ 7.30 (dd, J1 = 105.3 Hz, J2 = 99.1 Hz); IR (neat) 3310,
2976, 1490, 1398, 1247, 1172, 1084, 1014.
Diethyl ((3E,5E)-1,1-difluoro-2-hydroxy-2-methyl-6-phenyl-
hexa-3,5-dien-1-yl)phosphonate (9t): yellow oil; 113.8 mg,
1
isolated yield 79%; H NMR (300 MHz, CDCl3) δ 7.40 (AB, J =
7.2 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.22 (AB, J = 7.2 Hz, 1H), 6.79−
6.61 (m, 3H), 5.92 (AB, J = 15.0 Hz, 1H), 4.36−4.13 (m, 4H), 3.96
(br, 1H), 1.47 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H), 1.33 (t, J = 6.9 Hz,
3H); 13C NMR (101 MHz, acetone-d6) δ 138.1, 134.3 (d, J = 2.2 Hz),
134.1, 131.9, 129.5, 129.1, 128.5, 127.3, 120.7 (td, J1 = 272.4 Hz, J2 =
203.1 Hz), 75.6 (td, J1 = 22.2 Hz, J2 = 15.2 Hz), 65.0 (d, J = 8.7 Hz),
64.9 (d, J = 7.2 Hz), 22.4 (d, J = 2.8 Hz), 16.7 (d, J = 1.8 Hz), 16.6 (d,
J = 1.9 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ −117.48 (ABd, J1
= 300.0 Hz, J2 = 97.6 Hz), −120.14 (ABd, J1 = 300.3 Hz, J2 = 109.1
Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 7.82 (dd, J1 = 109.7
Hz, J2 = 98.2 Hz); IR (neat) 3347, 2982, 1451, 1392, 1254, 1232,
1174, 1012; MS (EI) 360 (M+, 8), 173 (100), 91 (56), 207 (14), 132
(14), 174 (13), 128 (11), 129 (11); HRMS (EI) exact mass calcd for
C17H23F2O4P [M+] 360.1302, found 360.1305.
Diethyl (1,1-difluoro-2-hydroxy-2-(4-methoxyphenyl)ethyl)-
phosphonate (11b):20 white solid; 118.0 mg, isolated yield 91%; mp
58−59 °C; 1H NMR (300 MHz, CDCl3) δ 7.40 (AB, J = 8.7 Hz, 2H),
6.91 (AB, J = 8.7 Hz, 2H), 5.06 (dq, J1 = 20.4 Hz, J2 = 4.5 Hz, 1H),
4.27−4.20 (m, 4H), 3.81 (s, 3H), 3.65−3.60 (m, 1H), 1.35 (t, J = 7.2
Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ
160.9, 130.4, 129.3 (dd, J1 = 5.9 Hz, J2 = 2.8 Hz), 119.6 (ddd, J1 =
272.6 Hz, J2 = 262.8 Hz, J3 = 207.4 Hz), 114.1, 73.4 (ddd, J = 26.8 Hz,
J = 21.1 Hz, J = 14.9 Hz), 65.0 (d, J = 6.4 Hz), 64.6 (d, J = 6.7 Hz),
55.5, 16.6 (d, J = 5.2 Hz), 16.6 (d, J = 5.2 Hz); 19F NMR (282 MHz,
CDCl3, PhCF3) δ −114.35 (ABd, J1 = 303.7 Hz, J2 = 99.8 Hz),
−124.80 (ABd, J1 = 303.7 Hz, J2 = 105.8 Hz); 31P NMR (122 MHz,
CDCl3, 85% H3PO4) δ 7.67 (dd, J1 = 106.0 Hz, J2 = 100.4 Hz); IR
(neat) 3316, 2985, 1611, 1511, 1246, 1170, 1085, 1012.
Diethyl (1,1-difluoro-2-hydroxy-2-methyl-4-phenylbutyl)-
phosphonate (9u): pale yellow solid; 102.2 mg, isolated yield
1
76%; mp 37−38 °C; H NMR (300 MHz, CDCl3) δ 7.31−7.29 (m,
Diethyl (2-cyclohexyl-1,1-difluoro-2-hydroxyethyl)-
phosphonate (11c): yellow oil; 60.0 mg, isolated yield 50%; 1H
NMR (300 MHz, CDCl3) δ 4.33−4.25 (m, 4H), 3.83−3.70 (m, 1H),
2.75 (d, J = 5.7 Hz, 1H), 1.95−1.58 (m, 6H), 1.41−1.17 (m, 11H);
13C NMR (126 MHz, acetone-d6) δ 121.8 (ddd, J1 = 270.3 Hz, J2 =
2H), 7.22−7.16 (m, 3H), 4.30 (sext, J = 7.2 Hz, 4H), 2.89−2.68 (m,
3H), 2.09−1.94 (m, 2H), 1.45 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H), 1.36
(t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ 143.4, 129.2,
126.6, 122.1 (td, J1 = 271.1 Hz, J2 = 202.4 Hz), 75.2 (td, J1 = 21.3 Hz,
J2 = 15.2 Hz), 64.8, 64.9, 38.3 (q, J = 2.9 Hz), 29.7, 20.6, 16.7, 16.6; 19
F
265.6 Hz, J3 = 207.3 Hz), 75.3−74.9 (m), 64.9 (d, J = 6.5 Hz), 64.6 (d,
H
DOI: 10.1021/acs.joc.6b01457
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The Journal of Organic Chemistry
Article
J = 6.8 Hz), 39.1−39.1 (m), 30.9−30.8 (m), 27.8, 27.0, 26.9, 26.7, 16.7
(d, J = 1.6 Hz), 16.6 (d, J = 1.7 Hz); 19F NMR (282 MHz, CDCl3,
PhCF3) δ −113.32 (ABd, J1 = 304.4 Hz, J2 = 102.1 Hz), −122.67
(ABd, J1 = 304.3 Hz, J2 = 106.6 Hz); 31P NMR (122 MHz, CDCl3,
85% H3PO4) δ 7.93 (dd, J1 = 107.2 Hz, J2 = 102.5 Hz); IR (neat)
3362, 2924, 2854, 1450, 1394, 1253, 1165, 1015; MS (ESI) 301 (M
+H+); HRMS (EI) exact mass calcd for C12H23F2O4P [M+] 300.1302,
found 300.1299.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01457.
■
S
1H, 19F, 31P, and 13C NMR spectra of new compounds
(PDF)
Diethyl (1,1-difluoro-2-hydroxy-4-phenylbutyl)-
AUTHOR INFORMATION
Corresponding Author
*E-mail: jzhou@chem.ecnu.edu.cn.
Notes
phosphonate (11d):4d yellow solid; 72.2 mg, isolated yield 56%;
■
1
mp 31−33 °C; H NMR (300 MHz, CDCl3) δ 7.32−7.20 (m, 5H),
4.28 (quint, J = 7.5 Hz, 4H), 4.02−3.89 (m, 1H), 2.98−2.90 (m, 2H),
2.78−2.70 (m, 1H), 2.04−1.94 (m, 2H), 1.37 (t, J = 6.9 Hz, 6H); 13C
NMR (101 MHz, acetone-d6) δ 142.5, 129.3, 129.2, 124.4, 120.7 (ddd,
J1 = 268.2 Hz, J2 = 265.2 Hz, J3 = 206.4 Hz), 71.1 (ddd, J1 = 24.4 Hz, J2
= 22.3 Hz, J3 = 15.2 Hz), 64.8 (d, J = 2.3 Hz), 64.7 (d, J = 2.4 Hz),
32.0, 16.7, 16.6; 19F NMR (282 MHz, CDCl3, PhCF3) δ −116.75
(ABd, J1 = 303.7 Hz, J2 = 101.2 Hz), −124.94 (ABd, J1 = 303.8 Hz, J2
= 104.9 Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ 7.66 (dd, J1
= 105.5 Hz, J2 = 102.0 Hz); IR (neat) 3365, 2985, 2932, 1251, 1164,
1015, 750, 700.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The financial support from NSFC (21472049) is appreciated.
■
REFERENCES
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Synthesis of Product 12 by Using TBAF To Remove TMS
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0.5 h, and then was concentrated and directly subjected to column
chromatography (petroleum ether:EtOAc = 4:1) to afford the
1
rearranged product 12 in 74% yield as yellow oil: H NMR (400
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MHz, CDCl3) δ 7.46−7.45 (m, 2H), 7.44−7.31 (m, 3H), 6.94 (AB, J
= 16.4 Hz, 1H), 6.48 (d, J = 16.4 Hz, 1H), 6.24 (t, J = 54.8 Hz, 1H),
4.25−4.13 (m, 4H), 3.91 (s, 3H), 1.37−1.31 (m, 6H); 13C NMR (126
MHz, acetone-d6) δ 167.4−167.3 (m), 136.8, 136.3, 129.7, 129.6,
127.8, 120.6−120.6 (m), 114.5 (td, J1 = 250.4 Hz, J2 = 7.7 Hz), 83.1
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16.3 (d, J = 4.3 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ −127.61
(AB, J = 284.0 Hz), −129.16 (AB, J = 284.0 Hz); 31P NMR (122
MHz, CDCl3, 85% H3PO4) δ −4.32 (s); IR (neat) 2986, 1722, 1441,
1218, 1164, 1025, 757, 698; MS (EI) 378 (M+, 9), 165 (100), 155
(60), 209 (58), 204 (45), 224 (39), 115 (38), 127 (36); HRMS (EI)
exact mass calcd for C16H21F2O6P [M+] 378.1044, found 378.1050.
Rearrangement Reaction of Product 7a. To a solution of 7a
(139.6 mg, 0.4 mmol) in 2.0 mL of anhydrous THF at room
temperature was added NaH (48 mg, 5 equiv, washed with anhydrous
hexane prior to use) in portions. After full conversion of 7a by TLC
analysis, water was added cautiously at −10 °C. The mixture was
extracted with ethyl acetate three times, and the combined organic
layers were dried over anhydrous Na2SO4. After concentration, the
crude material was purified by column chromatography (petroleum
ether:EtOAc = 4:1) to afford the rearrangement product 13 in 66%
yield as brown oil: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 7.5 Hz,
1H), 7.45 (t, J = 7.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.8
Hz, 1H), 6.06 (dd, J1 = 56.5 Hz, J2 = 54.3 Hz, 1H), 4.14 (quint, 2H),
3.96−3.86 (m, 2H), 3.24 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.21 (t, J =
7.2 Hz, 3H); 13C NMR (126 MHz, acetone-d6) δ 170.5 (d, J = 5.9
Hz), 146.7, 132.8, 127.4, 123.4, 121.6, 114.8 (ddd, J1 = 252.2 Hz, J2 =
243.0 Hz, J3 = 16.2 Hz), 110.0, 79.4 (ddd, J1 = 31.1 Hz, J2 = 22.4 Hz, J3
= 4.8 Hz), 64.9 (d, J = 6.2 Hz), 64.7 (d, J = 5.5 Hz), 26.8, 16.2 (d, J =
4.4 Hz), 16.1 (d, J = 4.8 Hz); 19F NMR (282 MHz, CDCl3, PhCF3) δ
−129.49 (ABd, J1 = 289.9 Hz, J2 = 4.5 Hz), −133.56 (AB, J = 290.3
Hz); 31P NMR (122 MHz, CDCl3, 85% H3PO4) δ −4.00 (d, J = 3.8
Hz); IR (neat) 2998, 1733, 1614, 1473, 1370, 1287, 1093, 1016; MS
(EI) 349 (M+, 24), 195 (100), 167 (53), 162 (45), 196 (24), 168 (15),
127 (12), 148 (9); HRMS (EI) exact mass calcd for C14H18F2NO5P
[M+] 349.0891, found 349.0893.
I
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