N-heterocyclic carbene-catalyzed fluorinated silyl-Reformatsky reaction of aldehydes with difluoro (trimethylsilyl) acetate

Article abstract of DOI:10.1016/j.tet.2017.06.027

N-Heterocyclic carbenes (NHCs) have been employed as highly efficient organocatalysts for fluorinated silyl-Reformatsky reaction of carbonyl compounds. In the presence of 5–10 mol % NHC A, various aldehydes and 2,2,2–trifluoroacetophenone reacted with difluoro (trimethylsilyl) acetate to produce β–hydroxy gem–difluoro esters in 20–96% yields.

Full text of DOI:10.1016/j.tet.2017.06.027

Accepted Manuscript
N-heterocyclic carbene-catalyzed fluorinated silyl-Reformatsky reaction of aldehydes
with difluoro (trimethylsilyl) acetate
Ying Wang, Fen Xing, Cheng-Zhi Gu, Wen-Juan Li, Lin He, Bin Dai, Guang-Fen Du
PII:
S0040-4020(17)30646-4
10.1016/j.tet.2017.06.027
TET 28792
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 April 2017
Revised Date: 12 June 2017
Accepted Date: 14 June 2017
Please cite this article as: Wang Y, Xing F, Gu C-Z, Li W-J, He L, Dai B, Du G-F, N-heterocyclic
carbene-catalyzed fluorinated silyl-Reformatsky reaction of aldehydes with difluoro (trimethylsilyl)
acetate, Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.027.
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ACCEPTED MANUSCRIPT
Graphical Abstract
N-heterocyclic carbene-catalyzed fluorinated silyl-Reformatsky reaction of aldehydes and difluoro
(trimethylsilyl) acetate.

ACCEPTED MANUSCRIPT
N-heterocyclic carbene-catalyzed fluorinated silyl-Reformatsky
reaction of aldehydes with difluoro (trimethylsilyl) acetate
Ying Wang,a† Fen Xing,a† Cheng-Zhi Gu,a Wen-Juan Li,a* Lin He,a Bin
Dai,a Guang-Fen Du a*
a
Key Laboratory for Green Processing of Chemical Engineering of
Xinjiang Bingtuan, School of Chemistry and Chemical Engineering,
Shihezi University, Shihezi, Xinjiang Uygur Autonomous Region, P. R.
China, 832000, P. R. China, Fax: (+86) 993-2057270; E-mail:
lwj_tea@shzu.edu.cn; duguangfen@shzu.edu.cn
Abstract: N-Heterocyclic carbenes (NHCs) have been employed as
highly efficient organocatalysts for fluorinated silyl-Reformatsky reaction
of carbonyl compounds. In the presence of 5-10 mol % NHC A, various
aldehydes and 2,2,2–trifluoroacetophenone reacted with difluoro
(trimethylsilyl) acetate to produce β–hydroxy gem–difluoro esters in
20–96% yields.
Keywords: N-Heterocyclic carbene; difluoro (trimethylsilyl) acetate;
β–hydroxy gem–difluoro ester; silyl-Reformatsky reaction
1. Introduction
Fluorinated compounds have found a wide range of applications in
pharmaceuticals, agrochemicals and medical chemistry.1 Owing to the
special properties of fluorine, the incorporation of fluorine atoms or
fluorinated moieties into bioactive compounds has become a routine
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strategy in new drug discovery. Among various fluorinated molecules,
β–hydroxy gem–difluoro esters are particularly interesting with respect to
the synthesis of bioactive compounds.2 In the past decades, considerable
efforts have been directed towards the development of efficient methods
for the introduction of gem–difluoromethylene group into organic
molecules.3 Several fluorinating reagents such as DAST, BAST4 and
NBS-HF-amine complexes5 can react with ketones to construct
gem–difluoromethylene unit, but with very limited substrate scope.
Mukaiyama aldol reaction6 and Reformatsky reaction7 can introduce
gem–difluoromethylene into carbonyl compounds. However, the unstable
fluorinated silicon enolate, harsh reaction conditions for the preparation
of active organozinc reagents and the use of stoichiometric amounts of
transition-metal additives restrict the applications of these methods.
Therefore, the development of efficient and mild protocol for the
incorporation of CF2 group into carbonyl compounds is still highly
desirable.
Recently, Song reported8 that N–heterocyclic carbenes (NHCs) can be
utilized
as
highly
efficient
organocatalysts9
to
mediate
trifluoromethylation reaction between TMSCF3 and aldehydes. But
unfortunately, this protocol is not suitable for difluoromethylation
reaction between TMSCF2H and carbonyl compounds.10 We recently
found that NHCs can catalyze silyl–Reformatsky reaction between
2

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α–trimethyl silylcarbonyl compounds and aldehydes.11 Based on this
study, we envisioned that NHCs could be utilized to mediate fluorinated
silyl–Reformatsky reaction of difluoro (trimethylsilyl) acetate,12 which
would provide an organocatalytic approach for nucleophilic
difluoromethylenation of carbonyl compounds. Herein, we would like to
report this result.
2. Results and discussion
Our
research
started
with
the
reaction
of
2,2–difluoro–2–trimethylsilyl acetate 1a13 and p–chlorobenzaldehyde. In
the presence of 5 mol% NHC A,14 the reaction smoothly proceeded in
CH3CN to furnish 3a in 55% yield (Table 1, entry 1). With this fruitful
result in hand, other common NHCs were surveyed for the reaction.
NHCs generated from imidazolium can promote the reaction in moderate
yields, while NHC derived from saturated imidazolinium showed
relatively low reactivity (Table 1, entries 2-5). Both thiazolium and
triazolium salts derived NHCs cannot promote the addition (Table 1,
entries 6-8). A brief screening of reaction media indicated that the high
polar DMF can afford the desired product in excellent yield (Table 1,
entries 9-14). However, reduction catalyst loading to 1 mol% led to
dramatic decrease of the reaction yield (Table 1, entry 15).
Table 1 Optimization of reaction conditions a
3

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OH
F
O
O
TMS
CO2Et
1) NHC
+
OEt
F
Cl
Cl
2) HCl
F
F
2a
1a
3a
Ar
R
N
N
X
N
N
R
Ar
A
B1: R = 2,4,6-Me3C6H2, X = Cl
Ar = 2,6-(i-Pr)2C6H3
B2:
R = Cy, X = BF4
B3: R = t-Bu, X = BF4
R
Ar
N
X
S
N
Cl
N
N
N
Cl
Ph
N
Ar
HO
C
D1: R = Bn, X = Cl
E
D2
Ar = 2,6-(i-Pr)2C6H3
: R = Me, X = I
Entry
1
Conditions
5 mol% A, CH3CN
Time (h)
12
Yield b (%)
55
2
3
4
5
6
7
8
9
5 mol% B1, DBU, CH3CN
5 mol% B2, DBU, CH3CN
5 mol% B3, DBU, CH3CN
5 mol% C, DBU, CH3CN
5 mol% D1, DBU, CH3CN
5 mol% D2, DBU, CH3CN
5 mol% E, DBU, CH3CN
5 mol% A, toluene
12
12
12
12
12
12
12
24
56
53
55
39
< 10
< 10
< 10
15
10
11
12
13
14
15
5 mol% A, CH2Cl2
5 mol% A, CHCl3
5 mol% A, Et2O
5 mol% A, THF
5 mol% A, DMF
1 mol% A, DMF
24
24
24
24
12
24
13
16
22
26
95
65
[a] Reaction conditions: 1.5 equiv of 1a, 0.3 mol/L of 2a, room temperature. [b] Isolated
yield.
With the optimal reaction conditions in hand (Table 1, entry 14), the
scope of aldehydes was next examined and the results were summarized
in Table 2. A wide range of aldehydes performed the reaction very well.
Aromatic aldehydes with electron-withdrawing groups gave higher yields
than those with electron-neutral or donating groups (Table 2, entries 1-8),
while different positions of the substituents had no obvious effects on the
4

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reaction (Table 2, entries 9-15). Both heliotropin and naphthaldehydes
were proved to be suitable substrates, producing the corresponding
products in excellent yields (Table 2, entries 16-18). Heteroaromatic
aldehydes such as furfural and 2–thienyl aldehyde reacted with silylated
reagent 1a smoothly, affording the desired products in 67% and 68%
yield, respectively (Table 2, entries 19 and 20). Gratifyingly, when
trans–cinnamaldehyde was used for the reaction, the desired product 3u
can be obtained in 77% yield (Table 2, entry 21). Notably, aliphatic
aldehydes, such as cyclohexanecarboxaldehyde and phenylpropyl
aldehyde were also proved to be competent reactants, producing the
desired product in 58% and 40% yield, respectively (Table 2, entries 22
and 23). Intriguingly, 2,2,2–trifluoroacetophenone can participate in the
reaction well, producing 3x in moderate yield (Table 2, entry 24). More
interestingly, the reaction can be conducted on gram-scale and high yield
maintained
(Table
2,
entry
25).
However,
when
2,2–difluoro–2–trimethylsilyl acetate 1b was used instead of 1a, the
desired product was only isolated in 20% yield (Table 2, entry 26).
Table 2 Evaluation of substrates scope a
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Entry
1
R
Time (h)
12
Product
Yield b (%)
95
3a
3b
3c
3d
3e
3f
2
3
12
15
12
6
92
96
96
94
77
80
71
68
4
5
6c
7
24
24
24
24
3g
3h
3i
8
9c
10c
11c
12c
13c
14c
15c
24
15
15
15
6
71
80
79
83
82
72
3j
3k
3l
NO2
3m
3n
3o
6
16c
17
15
12
85
90
3p
3q
6

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18c
19
20
21
22
23
24
15
15
12
15
13
87
67
68
77
58
40
3r
3s
O
S
3t
3u
3v
3w
24
15
45
3x
25d
26e
12
12
85
20
3a
3y
[a] Reaction conditions: 5 mol% of NHC A, 1.5 equiv of 1a, 0.3 mol/L of
2, room temperature. [b] Isolated yield. [c] Using 10 mol% of NHC A. [d]
mol% of NHC A, 1 (7.5 mmol), 2a (5.0 mmol), room temperature.
Using 1b instead of 1a.
5
[e]
Based on the pioneering work of NHC–mediated nucleophilic
addition reactions of silicon-based nucleophiles, a plausible mechanism is
proposed as depicted in Scheme 1. NHC attacks the silicon atom of
TMSCF2COOEt to form a reactive hexavalent species I in DMF, which
can initiate the following addition with aldehyde to produce intermediate
II. The oxy anion attacks TMS group to form trimethylsilyl ether III, and
after acidic work-up affords the final product.
7

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Scheme 1 Proposed Mechanism
3. Conclusions
In conclusion, an NHC-catalyzed fluorinated silyl-Reformatsky reaction
between carbonyl compounds and difluoro (trimethylsilyl) acetate has
been described. The mild reaction conditions, simple procedure and high
yields provide an efficient approach for the synthesis of β–hydroxy
gem–difluoro esters.
4. Experimental section
4.1 General methods
Unless otherwise indicated, all reactions were conducted under nitrogen
atmosphere in oven-dried glassware with magnetic stirring bar. Column
chromatograph was performed with silica gel (200~300 mesh) and
1
13
analytical TLC on silica gel 60-F254. H NMR (400 MHz, CDCl3), C
19
NMR (100 MHz, CDCl3), F NMR (376 MHz, CDCl3) spectra were
recorded on a Bruker-DMX 400 spectrometer in CDCl3, with
tetramethylsilane as an internal standard and reported in ppm (δ).
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N-heterocyclic carbenes A and B1 were prepared according to literature
procedure.14 Silylated reagents 1 were prepared according to literature
procedure.13 All other chemicals were obtained from commercial supplies
and used as received. Anhydrous THF and Et2O, were distilled from
sodium and benzophenone. DMF, CH2Cl2 and CH3CN were distilled
from calcium hydride. CHCl3 was distilled from phosphorus pentoxide.
Petroleum ether, where used, has a boiling range of 30 - 60 oC.
4.2 General procedure for the preparation of β–hydroxyl
gem–difluoro esters
To a solution of IPr (NHC A, 6.0 mg, 0.015 mmol) in CH3CN (1.0 mL)
was added aldehyde (2, 0.3 mmol) and silylated reagent (1a, 0.45mmol,
88.2 mg). Subsequently the reaction solution was stirred at room
temperature until full consume of the starting aldehyde indicated by TLC,
1.0 mL 1.0 N HCl was added at this moment and the mixture was
continuously stirred for 0.5 h, then the mixture was extracted by ethyl
acetate (3×10 mL). The combined organic phase was washed with
saturated sodium bicarbonate and H2O, dried by anhydrous Na2SO4, and
concentrated under vacuum. The crude product was purified through flash
column chromatography (silica gel, PE/EtOAc) to give the desired
products.
4.2.1 Ethyl 3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropanoate (3a)15
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Light yellow liquid; IR (KBr film): 1754, 1598, 1374, 1312, 1189, 1107,
1
1018, 1014, 852, 830, 778, 744, 672 cm-1; H NMR (400 MHz,
Chloroform-d) δ 7.46 – 7.36 (m, 4H), 5.17 (dd, J = 15.3, 7.6 Hz, 1H),
4.33 (q, J = 7.1 Hz, 2H), 2.80 (s, 1H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, Chloroform-d) δ 163.4 (dd, J = 32.2, 30.6 Hz), 135.2, 132.9,
129.1 (t, J = 1.3 Hz), 128.7, 113.5 (dd, J = 259.7, 254.6 Hz), 73.1 (dd, J =
19
28.2, 24.6 Hz), 63.3, 13.9; F NMR (376 MHz, Chloroform-d) δ -113.3
(d, J = 264.2 Hz), -120.5 (d, J = 264.2 Hz); GC-MS (EI): m/z 264.0 (M+).
4.2.2 Ethyl 2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropanoate (3b)16
Light yellow liquid, IR (KBr film): 3488, 2991, 2943, 1754, 1650, 1511,
1447, 1397, 1375, 1312, 1225, 1189, 1101, 1069, 1014, 944, 853, 795,
781, 740, 729, 694, 636 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.52
– 7.38 (m, 2H), 7.14 – 7.05 (m, 2H), 5.17 (dd, J = 15.3, 7.8 Hz, 1H), 4.32
(q, J = 7.1 Hz, 2H), 2.99 (s, 1H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (101
MHz, Chloroform-d) δ 163.5 (dd, J = 32.3, 30.8 Hz), 163.2 (d, J = 248.0
Hz), 130.3 (d, J = 2.6 Hz), 129.6 (dt, J = 8.4, 1.3 Hz), 115.4 (d, J = 21.9
Hz), 113.6 (dd, J = 259.7, 254.5 Hz), 73.1 (dd, J = 27.9, 24.5 Hz), 63.3,
19
13.8; F NMR (376 MHz, Chloroform-d) δ -113.6 (d, J = 262.7 Hz),
-120.5 (d, J = 263.0 Hz); GC-MS (EI): m/z 248.0 (M+).
4.2.3 Ethyl 3-(4-bromophenyl)-2,2-difluoro-3-hydroxypropanoate (3c)7d
Light yellow liquid, IR (KBr film): 3502, 2989, 2964, 1914, 1769, 1593,
1490, 1464, 1393, 1371, 1344, 1308, 1289, 1267, 1205, 1182, 1118, 1050,
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1008, 865, 833, 787, 772, 734, 701, 657, 627 cm-1; 1H NMR (400 MHz,
Chloroform-d) δ 7.59 – 7.50 (m, 2H), 7.38 – 7.30 (m, 2H), 5.15 (dd, J =
15.4, 7.6 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.98 (s, 1H), 1.32 (t, J = 7.2
Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.4 (dd, J = 32.4, 30.7
Hz), 133.4 (d, J = 1.9 Hz), 131.6, 129.4 (t, J = 1.1 Hz), 123.4, 113.4 (dd,
19
J = 258.7, 253.6 Hz), 73.1 (dd, J = 28.0, 24.5 Hz), 63.3, 13.9; F NMR
(376 MHz, Chloroform-d) δ -113.1 (d, J = 263.7 Hz), -120.6 (d, J = 263.7
Hz); GC-MS (EI): m/z 307.9 (M+).
4.2.4 Ethyl 3-(4-cyanophenyl)-2,2-difluoro-3-hydroxypropanoate (3d)7d
Light yellow liquid, IR (KBr film): 1755, 1611, 1505, 1399, 1374, 1299,
1190, 1105, 1070, 1019, 855, 883, 782, 687 cm-1; 1H NMR (400 MHz,
Chloroform-d) δ 7.80 – 7.67 (m, 2H), 7.66 – 7.55 (m, 2H), 5.27 (dd, J =
15.6, 6.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.10 (s, 1H), 1.34 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.1 (dd, J = 32.1, 30.9
Hz), 139.6 (dd, J = 1.3, 0.7 Hz), 132.1, 128.5 (t, J = 1.4 Hz), 118.4, 113.2
(dd, J = 261.2, 254.9 Hz), 113.0, 73.0 (dd, J = 28.3, 24.6 Hz), 63.5, 13.9;
19F NMR (376 MHz, Chloroform-d) δ -112.0 (d, J = 267.7 Hz), -120.7 (d,
J = 267.5 Hz); GC-MS (EI): m/z 255.0 (M+).
4.2.5 Ethyl 2,2-difluoro-3-hydroxy-3-(4-nitrophenyl)propanoate (3e)
Light yellow liquid, IR (KBr film): 3502, 3078, 2916, 2848, 1758, 1608,
1522, 1495, 1464, 1448, 1372, 1352, 1448, 1372, 1352, 1308, 1201, 1177,
1118, 1061, 1014, 996, 866, 850, 829, 796, 745, 726, 691, 655 cm-1; 1H
11

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NMR (400 MHz, Chloroform-d) δ 8.31 – 8.18 (m, 2H), 7.75 – 7.62 (m,
2H), 5.34 (dd, J = 15.6, 6.7 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.38 (s,
13
1H), 1.34 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, Chloroform-d) δ
163.2 (dd, J = 32.3, 30.6 Hz), 148.4, 141.5, 128.7 (t, J = 1.3 Hz), 123.4,
113.2 (dd, J = 261.9, 256.0 Hz), 72.8 (dd, J = 28.5, 24.3 Hz), 63.6, 13.9;
19F NMR (376 MHz, Chloroform-d) δ -111.7 (d, J = 266.5 Hz), -120.7 (d,
J = 266.8 Hz); GC-MS (EI): m/z 275.0 (M+). HRMS (ESI) m/z calcd for
C11H12F2NO5 [M+H]+ 276.0678, found 276.0676.
4.2.6 Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate (3f)16
Light yellow liquid, IR (KBr film): 3502, 2988, 2964, 2900, 1755, 1496,
1455, 1394, 1375, 1318, 1191, 1065, 1027, 922, 856, 836, 802, 782, 742,
718, 698, 629 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.49 – 7.38 (m,
5H), 5.17 (dd, J = 15.5, 8.0 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.85 (s,
1H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ
163.6 (dd, J = 32.3, 30.8 Hz), 134.5 (d, J = 2.1 Hz), 129.2, 128.4, 127.7,
113.8 (dd, J = 259.4, 254.2 Hz), 73.8 (dd, J = 27.7, 24.4 Hz), 63.2, 13.8;
19F NMR (376 MHz, Chloroform-d) δ -113.8 (d, J = 261.6 Hz), -120.4 (d,
J = 261.6 Hz); GC-MS (EI): m/z 230.0 (M+).
4.2.7 Ethyl 2,2-difluoro-3-hydroxy-3-(p-tolyl)propanoate (3g)16
Light yellow liquid, IR (KBr film): 2988, 2957, 1756, 1653, 1616, 1558,
1516, 1447, 1394, 1374, 1316, 1190, 1104, 1069, 1043, 1020, 856, 828,
1
774, 723, 696, 622 cm-1; H NMR (400 MHz, Chloroform-d) δ 7.39 –
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7.30 (m, 2H), 7.25 – 7.16 (m, 2H), 5.14 (dd, J = 15.6, 8.1 Hz, 1H), 4.32
(q, J = 7.2 Hz, 2H), 2.78 (s, 1H), 2.39 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H);
13C NMR (101 MHz, Chloroform-d) δ 163.6 (dd, J = 32.5, 31.4 Hz),
139.2, 131.5 (d, J = 2.1 Hz), 129.2, 127.6 (t, J = 1.1 Hz), 113.8 (dd, J =
258.4, 252.9 Hz), 73.7 (dd, J = 27.8, 24.4 Hz), 63.1, 21.2, 13.8; 19F NMR
(376 MHz, Chloroform-d) δ -113.9 (d, J = 261.0 Hz), -120.5 (d, J = 261.0
Hz); GC-MS (EI): m/z 244.0 (M+).
4.2.8 Ethyl 2,2-difluoro-3-hydroxy-3-(4-methoxyphenyl)propanoate
(3h)17
Light yellow liquid, IR (KBr film): 3675, 3502, 2988, 2961, 1755, 1612,
1586, 1514, 1465, 1395, 1374, 1305, 1249, 1176, 1066, 1028, 835, 786,
1
740, 697, 637, 603 cm-1; H NMR (400 MHz, Chloroform-d) δ 7.40 –
7.34 (m, 2H), 6.95 – 6.89 (m, 2H), 5.11 (dd, J = 15.4, 8.3 Hz, 1H), 4.31
(q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.90 (s, 1H), 1.31 (t, J = 7.2 Hz, 3H);
13C NMR (101 MHz, Chloroform-d) δ 163.7 (dd, J = 32.6, 30.9 Hz),
160.3, 129.1 (t, J = 1.1 Hz), 126.6 (d, J = 2.2 Hz), 113.9, 113.8 (dd, J =
259.6, 253.5 Hz), 73.4 (dd, J = 27.8, 24.4 Hz), 63.1, 55.3, 13.9; 19F NMR
(376 MHz, Chloroform-d) δ -114.2 (d, J = 260.5 Hz), -120.5 (d, J = 260.4
Hz); GC-MS (EI): m/z 260.0 (M+).
4.2.9 Ethyl 2,2-difluoro-3-hydroxy-3-(2-methoxyphenyl)propanoate (3i)
Light yellow liquid, IR (KBr film): 3502, 2998, 2964, 1757, 1603, 1589,
1493, 1464, 1441, 1394, 1374, 1310, 1288, 1245, 1184, 1118, 1066, 1044,
13

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1
1025, 943, 856, 836, 801, 784, 754, 708, 627 cm-1; H NMR (400 MHz,
Chloroform-d) δ 7.42 – 7.32 (m, 2H), 7.07 – 6.91 (m, 2H), 5.36 (dd, J =
18.0, 7.5 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.34 (t, J = 7.2
Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.8 (dd, J = 32.9, 30.5
Hz), 157.9, 130.3, 129.9 (t, J = 1.2 Hz), 122.2 (d, J = 1.6 Hz), 121.0,
114.4 (dd, J = 259.4, 254.9 Hz), 111.3, 71.8 (dd, J = 28.4, 24.5 Hz), 63.0,
55.8, 13.9; 19F NMR (376 MHz, Chloroform-d) δ -112.9 (d, J = 256.2 Hz),
-121.5 (d, J = 256.1 Hz); GC-MS (EI): m/z 260.0 (M+); HRMS (ESI) m/z
calcd for C12H15F2O4 [M+H]+ 261.0932, found 261.0929.
4.2.10 Ethyl 2,2-difluoro-3-hydroxy-3-(3-methoxyphenyl)propanoate
(3j)18
Light yellow liquid, IR (KBr film): 3675, 3502, 2988, 2961, 1755, 1602,
1587, 1491, 1456, 1457, 1394, 1374, 1309, 1257, 1189, 1158, 1096, 1067,
1
1039, 927, 850, 767, 716, 696, 641 cm-1; H NMR (400 MHz,
Chloroform-d) δ 7.35 – 7.28 (m, 1H), 7.08 – 7.00 (m, 2H), 6.97 – 6.88 (m,
1H), 5.15 (dd, J = 14.2, 7.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.82 (s,
13
3H), 2.96 (s, 1H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (101 MHz,
Chloroform-d) δ 163.6 (dd, J = 32.6, 30.8 Hz), 159.6, 136.0 (d, J = 2.1
Hz), 129.4, 120.0 (t, J = 1.1 Hz), 114.9, 113.7 (dd, J = 259.9, 254.4 Hz),
113.1 (t, J = 1.2 Hz), 73.7 (dd, J = 27.8, 24.3 Hz), 63.2, 55.3, 13.8; 19F
NMR (376 MHz, Chloroform-d) δ -113.7 (d, J = 261.5 Hz), -120.4 (d, J =
261.5 Hz); GC-MS (EI): m/z 260.1 (M+).
14

ACCEPTED MANUSCRIPT
4.2.11 Ethyl 3-(3-chlorophenyl)-2,2-difluoro-3-hydroxypropanoate (3k)
Light yellow liquid, IR (KBr film): 1754, 1656, 1599, 1576, 1475, 1432,
1374, 1306, 1191, 1101, 1067, 1009, 900, 848, 772, 748, 692, 664 cm-1;
1H NMR (400 MHz, Chloroform-d) δ 7.51 – 7.44 (m, 1H), 7.41 – 7.30 (m,
3H), 5.16 (dd, J = 15.3, 7.5 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.23 (s,
1H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ
163.4 (dd, J = 33.0, 30.4 Hz), 136.5 (dd, J = 1.8, 0.6 Hz), 134.4, 129.7,
129.3, 127.9 (t, J = 1.2 Hz), 125.9 (t, J = 1.3 Hz), 113.5 (dd, J = 259.8,
256.2 Hz), 73.1 (dd, J = 28.0, 24.6 Hz), 63.4, 13.8; 19F NMR (376 MHz,
Chloroform-d) δ -113.0 (d, J = 263.6 Hz), -120.4 (d, J = 263.4 Hz);
GC-MS (EI): 263.9 (M+). HRMS (ESI) m/z calcd for C11H12ClF2O3
[M+H]+ 265.0437, found 265.0438.
4.2.12 Ethyl 2,2-difluoro-3-hydroxy-3-(2-nitrophenyl)propanoate (3l)19
Light brown liquid, IR (KBr film): 3568, 3003, 2954, 2840, 1743, 1716,
1600, 1586, 1528, 1492, 1463, 1437, 1352, 1290, 1243, 1119, 1080, 1053,
1
1025, 924, 853, 830, 796, 751, 691, 673 cm-1; H NMR (400 MHz,
Chloroform-d) δ 8.02 – 7.89 (m, 2H), 7.76 – 7.66 (m, 1H), 7.60 – 7.50 (m,
1H), 6.25 (dd, J = 15.3, 6.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.55 (s,
1H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ
163.1 (dd, J = 32.6, 30.8 Hz), 148.8, 133.3, 130.1 (t, J = 1.5 Hz), 129.8,
129.5 (d, J = 1.4 Hz), 124.7, 113.4 (dd, J = 260.7, 255.5 Hz), 67.7 (dd, J
15

ACCEPTED MANUSCRIPT
= 28.7, 23.6 Hz), 63.6, 13.8; 19F NMR (376 MHz, Chloroform-d) δ -111.8
(d, J = 266.2 Hz), -120.4 (d, J = 265.7 Hz); GC-MS (EI): 275.0 (M+).
4.2.13 Ethyl 2,2-difluoro-3-hydroxy-3-(3-nitrophenyl)propanoate (3m)
Light brown liquid, IR (KBr film): 1751, 1585, 1536, 1471, 1411, 1351,
1322, 1194, 1056, 930, 909, 858, 825, 726, 680, 671, 628 cm-1; 1H NMR
(400 MHz, Chloroform-d) δ 8.41 – 8.34 (m, 1H), 8.30 – 8.22 (m, 1H),
7.90 – 7.80 (m, 1H), 7.66 – 7.57 (m, 1H), 5.34 (dd, J = 15.4, 6.8 Hz, 1H),
4.37 (q, J = 7.6 Hz, 2H), 3.23 (s, 1H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, Chloroform-d) δ 163.1 (dd, J = 32.5, 30.8 Hz), 148.2, 136.6,
133.8 (t, J = 1.3 Hz), 129.4, 124.1, 122.8 (t, J = 1.3 Hz), 113.2 (dd, J =
261.4, 254.8 Hz), 72.7 (dd, J = 28.7, 24.7 Hz), 63.6, 13.9; 19F NMR (376
MHz, Chloroform-d) δ -111.9 (d, J = 267.7 Hz), -120.8 (d, J = 267.0 Hz);
GC-MS (EI): m/z 275.0 (M+); HRMS (ESI) m/z calcd for C11H11F2NO5
[M+H]+ 275.0605, found 275.0609.
4.2.14 Ethyl 3-(3-bromophenyl)-2,2-difluoro-3-hydroxypropanoate (3n)
Light yellow liquid, IR (KBr film): 3675, 3411, 2988, 2923, 2851, 1762,
1676, 1593, 1578, 1489, 1449, 1387, 1318, 1125, 1205, 1176, 1084, 1027,
1002, 973, 855, 753, 672, 645 cm-1; 1H NMR (400 MHz, Chloroform-d) δ
7.66 – 7.60 (m, 1H), 7.57 – 7.50 (m, 1H), 7.42 – 7.36 (m, 1H), 7.31 –
7.26 (m, 1H), 5.15 (dd, J = 15.3, 7.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H),
3.10 (s, 1H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d)
δ 163.4 (dd, J = 32.4, 31.0 Hz), 136.7, 132.3, 130.8 (t, J = 1.3 Hz), 129.9,
16

ACCEPTED MANUSCRIPT
126.4 (t, J = 1.3 Hz), 122.5, 113.5 (dd, J = 259.9, 254.5 Hz), 73.0 (dd, J =
28.1, 24.7 Hz), 63.4, 13.8; 19F NMR (376 MHz, Chloroform-d) δ -113.0
(d, J = 263.5 Hz), -120.4 (d, J = 263.5 Hz); GC-MS (EI): m/z 307.9 (M+).
HRMS (ESI) m/z calcd for C11H12BrF2O3 [M+H]+ 308.9932, found
308.9934.
4.2.15 Ethyl 3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropanoate
(3o)
Light yellow liquid, IR (KBr film): 3675, 3502, 2988, 2959, 1754, 1590,
1563, 1563, 1534, 1473, 1376, 1309, 1184, 1108, 1070, 1042, 1010, 847,
830, 780, 741, 689, 659 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.66
– 7.55 (m, 1H), 7.46 – 7.40 (m, 1H), 7.38 – 7.31 (m, 1H), 5.73 (dd, J =
15.9, 6.5 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.02 (s, 1H), 1.36 (t, J = 7.2
Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.4 (dd, J = 32.5, 30.6
Hz), 135.7, 134.5, 131.2 (d, J = 1.5 Hz), 130.7 (dd, J = 2.1, 1.2 Hz),
129.3, 127.5, 113.5 (dd, J = 260.8, 255.3 Hz), 69.1 (dd, J = 28.9, 23.7
Hz), 63.5, 13.9; 19F NMR (376 MHz, Chloroform-d) δ -112.7 (d, J =
265.5 Hz), -120.9 (d, J = 265.6 Hz); GC-MS (EI): m/z 297.5 (M+).
HRMS (ESI) m/z calcd for C11H11Cl2F2O3 [M+H]+ 299.0047, found
299.0042.
4.2.16Ethyl3-(benzo[d][1,3]dioxol-5-yl)-2,2-difluoro-3-hydroxypropanoa
te (3p)7d
17

ACCEPTED MANUSCRIPT
Light yellow liquid; IR (KBr film): 3502, 2992, 2908, 1754, 1610, 1505,
1489, 1445, 1375, 1396, 1307, 1244, 1187, 1095, 1067, 1-34, 925, 853,
778, 711, 633 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.01 – 6.94 (m,
0H), 6.93 – 6.88 (m, 1H), 6.85 – 6.80 (m, 1H), 6.00 (s, 2H), 5.10 (dd, J =
15.2, 8.1 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.81 (s, 1H), 1.33 (t, J = 7.2
Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.5 (dd, J = 32.5, 30.8
Hz), 148.4, 147.9, 128.1 (t, J = 1.8 Hz), 121.7 (t, J = 1.1 Hz), 113.6 (dd, J
= 259.2, 253.9 Hz), 108.1, 108.0 (t, J = 1.5 Hz), 101.3, 73.6 (dd, J = 27.8,
24.3 Hz), 63.2, 13.9; 19F NMR (376 MHz, Chloroform-d) δ -114.1 (d, J =
261.5 Hz), -120.5 (d, J = 261.5 Hz); GC-MS (EI): 274.0(M+).
4.2.17
Ethyl
2,2-difluoro-3-hydroxy-3-(naphthalen-1-yl)propanoate
(3q)16
Light yellow liquid; IR (KBr film): 3523, 2988, 2958, 1755, 1635, 1653,
1598, 1558, 1540, 1514, 1471, 1446, 1395, 1374, 1306, 1193, 1170, 1080,
1
1066, 998, 953, 845, 787, 753, 718, 640, 625 cm-1; H NMR (400 MHz,
Chloroform-d) δ 8.17 – 8.08 (m, 1H), 7.95 – 7.87 (m, 2H), 7.85 – 7.77 (m,
1H), 7.61 – 7.49 (m, 3H), 6.08 (dd, J = 15.7, 7.0 Hz, 1H), 4.27 (q, J = 7.2
Hz, 2H), 2.95 (s, 1H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
Chloroform-d) δ 163.8 (dd, J = 32.7, 30.6 Hz), 133.6, 131.4, 130.7 (d, J =
1.6 Hz), 129.9, 128.9, 126.6, 126.2 (d, J = 1.5 Hz), 125.8, 125.2, 123.2
(dd, J = 2.4, 1.3 Hz), 114.3 (dd, J = 260.3, 254.3 Hz), 69.7 (dd, J = 28.5,
18

ACCEPTED MANUSCRIPT
24.3 Hz), 63.3, 13.8; 19F NMR (376 MHz, Chloroform-d) δ -112.2 (d, J =
260.3 Hz), -119.6 (d, J = 260.6 Hz); GC-MS (EI) 280.0 (M+).
4.2.18 Ethyl 2,2-difluoro-3-hydroxy-3-(naphthalen-2-yl)propanoate (3r)16
Light yellow liquid, IR (KBr film): 3484, 2988, 2940, 1753, 1596, 1572,
1474, 1429, 1397, 1308, 1189, 1089, 1099, 1070, 998, 855, 770, 742, 691,
668, 630 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.97 – 7.81 (m, 4H),
7.62 – 7.49 (m, 3H), 5.35 (dd, J = 15.4, 8.0 Hz, 1H), 4.31 (q, J = 7.1 Hz,
13
2H), 3.23 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H); C NMR (101 MHz,
Chloroform-d) δ 163.7 (dd, J = 32.5, 30.9 Hz), 133.7, 132.9, 132.0 (d, J =
2.2 Hz), 128.2, 128.2, 127.7, 127.5, 126.7, 126.4, 124.8 (t, J = 1.4 Hz),
114.0 (dd, J = 260.0, 253.6 Hz), 73.9 (dd, J = 27.9, 24.5 Hz), 63.2, 13.8;
19F NMR (376 MHz, Chloroform-d) δ -113.3 (d, J = 261.6 Hz), -120.0 (d,
J = 261.6 Hz); GC-MS (EI) 280.0 (M+).
4.2.19 Ethyl 2,2-difluoro-3-(furan-2-yl)-3-hydroxypropanoate (3s)16
Light yellow liquid; IR (KBr film): 3675, 3469, 2988, 2900, 1755, 1646,
1502, 1448, 1394, 1375, 1308, 1198, 1147, 1080, 1065, 1012, 944, 928,
886, 854, 789, 708, 645 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.47
(dd, J = 1.8, 0.8 Hz, 1H), 6.54 – 6.51 (m, 1H), 6.44 – 6.41 (m, 1H), 5.22
(dd, J = 14.6, 8.2 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.01 (s, 1H), 1.35 (t,
J = 7.1 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.0 (dd, J =
32.1, 30.8 Hz), 143.5, 113.0 (dd, J = 258.8, 255.7 Hz), 110.7, 110.1 (t, J
19
= 1.4 Hz), 68.3 (dd, J = 28.5, 25.8 Hz), 63.3, 13.9; F NMR (376 MHz,
19

ACCEPTED MANUSCRIPT
Chloroform-d) δ -114.5 (d, J = 262.9 Hz), -119.7 (d, J = 263.0 Hz);
GC-MS (EI): m/z 220.0 (M+).
4.2.20 Ethyl 2,2-difluoro-3-hydroxy-3-(thiophen-2-yl)propanoate (3t)16
Light yellow liquid; IR (KBr film): 3675, 2988, 2958, 1755, 1653, 1558,
1537, 1471, 1436, 1394, 1375, 1305, 1183, 1164, 1066, 1041, 854, 755,
1
742, 705, 644 cm-1; H NMR (400 MHz, Chloroform-d) δ 7.39 (dd, J =
5.1, 1.2 Hz, 1H), 7.22 – 7.15 (m, 1H), 7.05 (dd, J = 5.1, 3.6 Hz, 1H), 5.44
(dd, J = 14.8, 7.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.98 (s, 1H), 1.32 (t,
J = 7.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 163.3 (dd, J =
32.5, 30.8 Hz), 136.8 (d, J = 2.3 Hz), 127.5 (t, J = 1.2 Hz), 127.0, 126.9,
113.2 (dd, J = 259.6, 255.0 Hz), 70.3 (dd, J = 28.8, 25.5 Hz), 63.3, 13.8;
19F NMR (376 MHz, Chloroform-d) δ -114.0 (d, J = 261.7 Hz), -120.2 (d,
J = 261.7 Hz); GC-MS (EI): m/z 236.0 (M+).
4.2.21 Ethyl (E)-2,2-difluoro-3-hydroxy-5-phenylpent-4-enoate (3u)16
Light yellow liquid; IR (KBr film): 3467, 3028, 2940, 1754, 1654, 1578,
1491, 1456, 1437, 1394, 1374, 1309, 1257, 1189, 1158, 1096, 1067, 1039,
927, 850, 767, 716, 696, 641 cm-1; 1H NMR (400 MHz, Chloroform-d) δ
7.48 – 7.41 (m, 2H), 7.40 – 7.29 (m, 3H), 6.83 (d, J = 16.0 Hz, 1H), 6.26
(dd, J = 16.0, 6.7 Hz, 1H), 4.88 – 4.69 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H),
2.50 (s, 1H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, Chloroform-d)
δ 163.4 (dd, J = 32.2, 30.9 Hz), 135.9, 135.7, 128.7, 128.6, 126.9, 121.5
(dd, J = 3.5, 2.3 Hz), 113.9 (dd, J = 258.0, 255.6 Hz), 73.0 (dd, J = 27.9,
20

ACCEPTED MANUSCRIPT
25.2 Hz), 63.2, 14.0; 19F NMR (376 MHz, Chloroform-d) δ -114.2 (d, J =
263.6 Hz), -120.6 (d, J = 263.1 Hz); GC-MS (EI): m/z 256.1 (M+).
4.2.22 Ethyl 3-cyclohexyl-2,2-difluoro-3-hydroxypropanoate (3v)17,20
OH
O
Light yellow liquid; IR (KBr film): 3523, 2990, 2926,
2854, 1757, 1535, 1450, 1395, 1374, 1314, 1209,
O
F F
1181, 1093, 1062, 1041, 957, 924, 895, 855, 842, 781, 741, 715, 658 cm-1;
1H NMR (400 MHz, Chloroform-d) δ 4.37 (q, J = 7.1 Hz, 2H), 3.84 (dt, J
= 17.8, 6.7 Hz, 1H), 2.15 (s, 1H), 1.99 – 1.89 (m, 1H), 1.83 – 1.65 (m,
5H), 1.38 (t, J = 7.1 Hz, 3H), 1.32 – 1.11 (m, 5H); 13C NMR (101 MHz,
Chloroform-d) δ 163.9 (dd, J = 33.0, 31.0 Hz), 115.4 (dd, J = 258.3,
255.6 Hz), 75.2 (dd, J = 26.1, 23.8 Hz), 63.0, 38.2 (d, J = 1.5 Hz), 29.6
(dd, J = 2.3, 1.2 Hz), 27.3 (dd, J = 1.7, 0.9 Hz), 26.1, 26.0, 25.8, 13.9;19F
NMR (376 MHz, Chloroform-d) δ -111.6 (d, J = 263.5 Hz), -120.1 (d, J =
263.2 Hz); GC-MS (EI): m/z 236.0 (M+).
4.2.23 Ethyl 2,2-difluoro-3-hydroxy-5-phenylpentanoate (3w)20
Colorless liquid, IR (KBr film): 1755, 1603, 1486, 1454, 1373, 1307,
1
1307, 1216, 1172, 1067, 1030, 856, 781, 698, 654 cm-1; H NMR (400
MHz, Chloroform-d) δ 7.31 – 7.27 (m, 2H), 7.21 – 7.18 (m, 3H), 4.32 (dd,
J = 7.1, 14.2 Hz, 2H), 4.60-4.97 (m, 1H), 2.97-2.89 (m, 1H), 2.80-2.69
(m, 1H), 2.15(s, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
Chloroform-d) δ 163.5 (dd, J = 31.3, 33.3 Hz), 140.7, 128.5, 128.4ꢀ
126.2ꢀ 114.52 (dd, J = 255.5, 257.5 Hz), 70.9 (dd, J = 25.2, 27.2 Hz),
21

ACCEPTED MANUSCRIPT
63.1, 31.2, 30.75 – 30.70 (m), 13.9; 19F NMR (376 MHz, Chloroform-d) δ
-114.8 (d, J = 266.9 Hz), -121.8 (d, J = 266.9 Hz), -121.7 (dd, J = 3.7,
266.9 Hz ); GC-MS (EI): m/z 297.9 (M+).
4.2.24 Ethyl 2,2,4,4,4-pentafluoro-3-hydroxy-3-phenylbutanoate (3x)
Colorless liquid; IR (KBr film): 3575, 3467, 2988, 2923, 2851, 1731,
1647, 1447, 1393, 1374, 1317, 1251, 1198, 1075, 1026, 956, 891, 820,
796, 734, 662 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.80 – 7.71 (m,
2H), 7.50 – 7.42 (m, 3H), 4.28 (s, 1H), 4.23 (qd, J = 7.1, 1.4 Hz, 2H),
1.17 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, Chloroform-d) δ 162.4,
130.3 (d, J = 1.1 Hz), 130.0, 128.4, 127.0 (q, J = 2.0 Hz), 124.6, 121.7,
112.0 (t, J = 266.2 Hz), 64.0, 13.5; 19F NMR (376 MHz, Chloroform-d) δ
-74.1 (t, J = 10.2 Hz), -113.7 (dq, J = 19.9, 10.1 Hz). HRMS (ESI) m/z
calcd for C12H12F5O3 [M+H]+ 299.0701, found 299.0700.
4.2.25 Phenyl 3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropanoate
(3y)21
o
White solid; m.p. 92.1-93.2 C; IR (KBr film): 1733, 1637, 1492, 1289,
1067,
1015,
764,
749,687,571cm-1;1HNMR (400 MHz, Chloroform-d) δ 7.6 – 7.4 (m, 6H)
, 7.4 – 7.3 (m, 1H), 7.2– 7.1 (m, 2H), 5.3 (dd,J= 15.1, 7.8 Hz, 1H), 2.8 (s,
1H);13CNMR (101 MHz, Chloroform-d) δ 161.8 (dd,J= 33.5, 31.7 Hz),1
49.6 , 135.5 , 132.6 , 129.8 , 129.2 , 128.8 , 126.9 , 120.8 , 113.7 (dd,J= 2
60.4, 254.9 Hz), 73.4 (dd,J= 28.0, 24.5 Hz);19F NMR(376 MHz, Chlorof
22

ACCEPTED MANUSCRIPT
orm-d) δ -113.2 (d,J= 263.1 Hz), -119.9 (d,J= 263.1 Hz); GC-MS (EI):
m/z 311.9 (M+).
Acknowledgement
This work was supported by the National Natural Science Foundation of
China (No. 21262027) and and the Start-up Foundation of Shihezi
University (Nos. 2015ZRKX05 and RCZX201521).
Notes and references
ꢁ These authors contributed equally to this work.
Notes and references
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C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev., 2014,
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Reactivity, Applications, 2nd Edn; Wiley-VCH: Weinheim, 2013; (c) Ojima, I. J.
Org. Chem.
,
2013
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78, 6358; (d) Uneyama, K. J. Fluorine Chem. 2008
, 129, 550;
(e) J. Nie, H. C. Guo, D. Cahard and J. A. Ma, Chem. Rev., 2011
,
111, 455; (f)
Bégué, J. P.; Bonnet-Delpon, D. In Bioorganic and Medicinal Chemistry of
Fluorine, Wiley-VCH: Weinheim, 2008. (g) In Fluorine in Medicinal Chemistry
and Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell: Chichester, 2009. (h) In
Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects
to Clinical Applications; Gouverneur, V., Muller, K., Eds.; Imperial College Press:
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2. (a) Kirk, K. L. In Fluorine-Containing Amino-Acids Synthesis and Properties;
Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: New York, 1995; pp 343. (b) Jimenez,
O.; Bosch, M. P.; Guerrero, A. Synthesis 2000, 1917. (c) Evans, G. B.; Furneaux, R.
H.; Lewandowicz, A.; Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2003, 46, 3412. (d)
Hallinan, E. A.; Kramer, S. W.; Houdek, S. C.; Moore, W. M.; Jerome, G. M.;
23

ACCEPTED MANUSCRIPT
Spangler, D. P.; Stevens, A. M.; Shieh, H. S.; Manning, P. T.; Pitzele, B. S. Org.
Biomol. Chem. 2003, 1, 3527.
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Pannecoucke, X. Chem. Eur. J. 2014 20, 16830. (e) Liu, Y.-L.; Yu, J.-S.; Zhou, J.
Asian J. Org. Chem. 2013 , 194; (f) Hu, J.-B.; Zhang, W.; Wang, F. Chem.
Commun. 2009, 7465. (g) Ni, C.; Hu, M.; Hu, J.-B. Chem. Rev. 2015 115, 765.
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Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y.
Tetrahedron 1997, 53, 10271.
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Graphical Abstract
N-heterocyclic carbene-catalyzed fluorinated silyl-Reformatsky reaction of aldehydes and difluoro
(trimethylsilyl) acetate.
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