Nucleophilic 1,1-Difluoroethylation with Fluorinated Phosphonium Salt

Article abstract of DOI:10.1021/acs.joc.6b02723

The fluorinated phosphonium salt (Ph₃P⁺CF₂CH₃ BF₄^-) was shown to act as a nucleophilic 1,1-difluoroethylation agent to enable difluoroethylation of aldehydes and imines.

Full text of DOI:10.1021/acs.joc.6b02723

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Brief Communication
Nucleophilic 1,1-difluoroethylation with fluorinated phosphonium salt
Zuyong Deng, Can Liu, Xian-Liang Zeng, Jin-Hong Lin, and Ji-Chang Xiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02723 • Publication Date (Web): 03 Dec 2016
Downloaded from http://pubs.acs.org on December 4, 2016
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Nucleophilic 1,1-difluoroethylation with fluorinated phosphonium salt
a
ab
a
a
a
Zuyong Deng, Can Liu, XianꢀLiang Zeng, JinꢀHong Lin, * and JiꢀChang Xiao *
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a.
Key Laboratory of Organofluorine Chemistry, Shanghai Institute Of Organic
Chmistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
3
45 Lingling Road, Shanghai 200032, China.
E-mail: jlin@sioc.ac.cn,
jchxiao@sioc.ac.cn ; Fax: +86-21-6416-6128; Tel: +86-21-5492-5340.
b
School of Chemistry and Chemical Engineering, University of South China,
Hengyang 421001, P. R. China
+
-
The fluorinated phosphonium salt (Ph P CF CH BF ) was shown to act as
3
2
3
4
a nucleophilic 1,1-difluoroethylation agent to enable difluoroethylation of
aldehydes and imines.
2 3
The 1,1ꢀdifluoroethyl group (CF CH ) has proved to be a valuable
pharmacophore, as it is not only an isostere of a methoxy group, but may also
1
improve the bioactivity of the target molecules. Consequently, significant
efforts have been directed towards the exploration of general methods for the
incorporation of this functionality. The traditional methods such as
deoxyfluorination of carbonyl compounds suffer from harsh reaction conditions
2
and a narrow substrate scope. CꢀH fluorination is an operationally simple
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approach for the installation of CF
2
CH
3
moiety, and fluorination of terminal
4
alkynes can also smoothly construct the CF
2
CH
3
group. Direct
difluoroethylation may serve as an efficient alternative to the fluorination
strategies, but the studies in this area remains largely unexplored. Baran and
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coꢀworkers disclosed that sodium difluoroethylsulfinate (CH
3
2 2
CF SO Na) could
5
be successfully applied to radical difluoroethylation reactions. Although
3 2
CH CF Br was found to be able to undergo difluoroethylation with aryl
3 2
Grignard agents catalyzed by cobalt complex, the high volatility of CH CF Br
6
results in operational inconveniences. Recently, it was found that TMSCF CH
2
3
7
was an effective nucleophilic difluoroethylation agent, but this agent is volatile
and its synthesis requires a multiꢀstep procedure. Therefore, the development of
mild protocols for 1,1ꢀdifluoroethylation is still highly desirable.
Phosphonium salts have played an increasingly important role in a variety
of research areas. The positively charged phosphorus increases the acidity of
the adjacent CꢀH bond due to an inductive effect, and can readily interact with a
counter anion because of Coulombic interaction. Therefore, phosphonium salts
8
9
have been widely used as ylide precursors, phaseꢀtransfer catalysts,
10
Lewisꢀacid catalysts, and so on. Apparently, these successful applications of
phosphonium salts arise from the high electrophilicity of the cation. From this
high electrophilicity it may be inferred that the cation or a substituent on the
cation cannot act as a nucleophile to construct CꢀC bond. However, we recently
discovered that a substituent on the phosphorus can be turned into a
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nucleophile, a process which was developed as a synthetic tool to carry out
11
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arylation and difluoromethylation reactions. The unprecedented findings
opened up new perspectives for the chemistry of phosphonium salts, and
prompted us to develop their applications further. We found that
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+
ꢀ
1
,1ꢀdifluoroethyl phosphonium salt (Ph
3 2 3 4
P CF CH BF ) can be used as a
nucleophilic difluoroethylation agent to enable difluoroethylation of aldehydes
13
and imines. The preliminary results are described herein.
+
ꢀ
Phosphonium salt
2
1
(Ph
3 2 3 4
P CF CH BF ) could be readily prepared from
ethyl phosphonium salt
by a stepwise fluorination process (Scheme 1). Salt
2
is shelfꢀstable and could be purified simply by washing with organic solvents,
allowing for its easy access.
Scheme 1. The preparation of 1,1ꢀdifluoroethyl phosphonium salt
2
With a reliable approach for the synthesis of salt
of difluoroethylation of aldehyde 3a with salt was conducted as shown in
Table 1. As it has been previously shown that Cs CO was a suitable promoter
2 3
for the nucleophilic reactions with phosphonium salts, the effect of Cs CO
2 established, optimization
2
2
3
1
1ꢀ12
was firstly examined in our initial attempts at this difluoroethylation conversion.
To our delight, the product was given by using THF as the solvent albeit in a
low yield (Table 1, entry 1). A brief survey of the reaction solvents (Table 1,
entries 2ꢀ6) revealed that a higher yield could be obtained in DMF (entry 6).
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Interestingly, the slow addition of a solution of salt
2 instead of adding the
agent in one portion significantly increased the yield to 90% (entry 7 vs. entry
11ꢀ12
6), which was similar to our previous observations.
A series of other
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promoters were also screened, but no better results were obtained (Table 1,
entries 8ꢀ11 vs. 7). Increasing the reaction scale did not lead to a decrease in the
yield (Table 1, entry 12 vs. 7).
a
Table 1. Screening reaction conditions
b
Entry
solvent
THF
promoter
4a, yield (%)
1
2
3
4
5
6
Cs
Cs
2
2
CO
CO
3
3
3
3
3
3
28
4
Cyclohexane
Toluene
EtOAc
Cs CO
0
2
Cs
Cs
Cs
Cs
2
2
2
2
CO
CO
CO
CO
23
8
3
CH CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
56
90
49
31
17
43
90
c
7
3
c
8
K CO
2 3
c
9
AcOCs
PhCO
CsF
Cs CO
c
10
2
K
c,d
1
1
c,e
1
2
2
3
a
b
Conditions: 3a (0.2 mmol), salt 2 (0.4 mmol) and promoter (2.5 equiv) in solvent at rt for 2 h;
19
c
Determined by F NMR by using PhCF
3
as an internal standard; A solution of salt 2 in DMF (1
d
mL) was added slowly into the solution of 3a and promoter in DMF (1 mL) in 30 min; 5 equiv of
e
CsF was used; The reaction scale was increased to 0.5 mmol (substrate 3a).
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With the optimized reaction conditions in hand (Table 1, entry 7)，we then
investigate the substrate scope for the nucleophilic difluoroethylation of carbonyls
with salt 2. As shown in Scheme 2, the examination of electronic effects showed that
neither the electronꢀdonating groups nor the electronꢀwithdrawing groups had side
effects for the conversion of aryl aldehydes (4a-4m). The transformation was
moderately sensitive to steric effects, as evidenced by the moderate yield of 4e.
Heteroaryl aldehydes were also well tolerated and could be converted smoothly into
the expected products in good yields (4n–4p). Enolizable aldehyde was found to be
inert towards difluoroethylation under these reaction conditions (4q). For the
conversion of ketone, the yield was decreased dramatically (4r). Due to the lower
reactivity of aliphatic aldehyde and ketone, the corresponding difluoroethylation
products (4q-4r) were obtained in very low yields. The attempts to increase their
yields by reoptimizing the reaction conditions such as increasing the loading of
reagent or elevating the reaction temperature were not successful.
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Scheme 2. Substrate scope for the difluoroethylation of carbonyls. Isolated yields;
The yields were determined by F NMR.
a
19
The successful conversion of aryl aldehydes encouraged us to examine the
difluoroethylation of imines. Compared with aldehydes, NꢀTs imines exhibited
lower reactivity and only moderate yields were obtained (Scheme 3). The
substrates containing electronꢀdonating groups could be well converted (6a-6f).
Although it may be expected that the aryl substrates containing
electronꢀwithdrawing group might be well transformed due to their higher
electrophilicity, the difluoroethylation of 4ꢀcyano phenyl imine gave the desired
product only in a very low yield (6g). That should be partially because the
substrate would readily undergo hydrolysis with cesium carbonate under these
reaction conditions.
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Scheme 3. Substrate scope for the difluoroethylation of imines. Isolated yields.
The yield was determined by F NMR.
a
19
On the basis of above results and our previous studies towards
11ꢀ12
nucleophilic reactions with phosphonium salts,
the difluoroethylation
CO at
(Scheme 4). Since the attack of a nucleophile at the
conversion is proposed to occur through initial attack of Cs
2
3
phosphonium salt
2
positively charged phosphorus would usually be along the axial direction and
the subsequent pseudorotation would place the electronegative substituent in
14
the other axial position, the trigonal bipyramidal phosphorus species Int
would be readily generated from this nucleophilic addition process.
Intermediate Int is highly reactive and its decarboxylation would occur rapidly,
3 2
giving Ph PO and resulting in the cleavage of PꢀCF bond. The bond breaking
may proceed concurrently with the nucleophilic addition of CH CF group to
3
2
the substrate. Hydrolysis gives the final product. Considering that cyano group
(in 4m in Scheme 2) was compatible with the reaction conditions, we believe
ꢀ
2
that the free CH
3
CF
ion may not be produced. The proposed mechanism was
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further supported by the almost full conversion of salt
2
into Ph
CF
H and CH
formed via the nucleophilic attack of CH CF moiety in Int at proton or CO2,
3
PO detected by
31
ꢀ
P NMR spectroscopy, the observation of CH
3
2 3 2 2
H and CH CF CO
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ꢀ
determined by F NMR spectroscopy. CH
3
CF
2
3 2 2
CF CO should be
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Scheme 4. Proposed reaction mechanism
Conclusions
In summary, we have disclosed that 1,1ꢀdifluoroethyl phosphonium salt
+
ꢀ
(
3 2 3 4
Ph P CF CH BF ) can be successfully applied to 1,1ꢀdifluoroethylation of
aldehydes and imines under mild conditions. This phosphonium salt is shelf
stable and easy to access, and therefore is reasonably expected to become an
efficient 1,1ꢀdifluoroethylation agent. This work offers new opportunities to
explore valuable applications of phosphonium salts in the chemistry of CꢀC
bond construction. The strategy for nucleophilic fluoroalkylation with
phosphonium salts may find synthetic utility in other research areas.
Experimental Section
All solvents were obtained from commercial available and were extra dry grade.
All glassware used was dried in a 120°C oven and cooled in a desiccator before use.
High resolution mass data were recorded on a high resolution mass spectrometer in
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the EI or ESI mode. H, F, P and C NMR spectra were recorded on a 400 MHz
1
13
NMR or 500 MHz NMR spectrometer. H NMR and C NMR chemical shifts were
19
determined relative to internal (CH
3 4
) Si (TMS) at δ 0.0 ppm. F NMR chemical shifts
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3
1
were determined relative to internal CFCl at 0.0 ppm. P NMR chemical shifts were
3
3 4
determined relative to internal H PO at 0.0 ppm.
The procedure for the synthesis of 1,1-difluoroethyl phosphonium salt:
1) The synthesis of ethyl phosphonium salt 1：
(
Under N
2
3
atmosphere, the mixture of Ph P (8.5 g, 33 mmol), EtBr (3.3 g, 30 mmol)
o
and pꢀxylene (20 mL) was stirred at 110 C for 3 h. The mixture was cooled to room
temperature. After filtration, the residue was washed with dry Et
dried under reduced pressure to afford the pure product.
2
O (60 mL) and then
15
1
Ethyl triphenylphosphonium bromide (1) : 7.1g, 63% yield, white solid. H NMR
(
3
400 MHz, CDCl ) δ 7.82 ꢀ 7.72 (m, 9H), 7.65 (td, J = 8.1, 3.5 Hz, 6H), 3.84 ꢀ 3.74
3
1
(
m, 2H), 1.34 (dt, J = 20.1, 7.4 Hz, 3H). P NMR (162 MHz, CDCl
3
) δ 26.28 (s, 1P).
(
2) The synthesis of 1ꢀfluoroethyl phosphonium salt 1’：
Under argon atmosphere, into the mixture of 1 (3.9 g, 10 mmol) and THF (16 mL)
o
at 0 C was added the solution of BuLi (2.5 M, 11 mmol) in hexane (4.4 mL)
dropwise via a syringe for 30 min. Upon the completion of addition, the resulting
mixture was warmed to room temperature and was further stirred for 30 min to give
+
ꢀ
the phosphonium ylide (Ph
bath before use.
3
P CH Me). The solution of this ylide was stored in ice
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Under
argon
atmosphere,
into
the
solution
of
NFSI
o
(
Nꢀfluoroꢀdibenzeneꢀsulfonimide) (10.6 g, 33 mmol) in THF (30 mL) at 0 C was
added slowly the solution of the phosphonium ylide in 30 min. Upon the completion
of addition, the resulting mixture was warmed to room temperature and was further
stirred for 30 min. The reaction mixture was then poured into the aqueous solution of
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HBF
phase was concentrated to afford a viscous liquid. Enough Et
into the liquid to precipitate the crude product, which was contaminated by NFSI, salt
4
(1 M, 100 mL), and extracted with CH
2
Cl
2
(50 mL X 6). The combined organic
2
O (500 mL) was added
1
and salt 2. After filtration, the solid was dissolved in CH Cl (20 mL) to give a
2 2
2
saturated solution. Enough Et O (500 mL) was added into the solution to precipitate
the product. The solid was collected by filtration. The dissolvingꢀprecipitate process
by CH
2
2
Cl
2
/Et
2
O was repeated once more to afford a solid. The solid was dissolved in
o
CH Cl
2
(about 20 mL) to give a saturated solution. The solutions was stirred at 80 C
and ethyl acetate (EA, 200 mL) was added slowly to precipitate the crude product.
The crude product was collected by filtration. This dissolvingꢀprecipitate process by
31
CH
NMR. The product was then dissolved in CH
dried over anhydrous MgSO . After filtration, the solvent was removed by
concentration to give the pure product as a white solid (64%).
ꢀFluoroethyl triphenylphosphonium tetrafluoroborate (1’): 2.67 g. 64% yield, white
2
Cl
2
/EA was repeated for 3ꢀ4 times until the product was pure detected by
P
2
Cl
2
(80 mL), and the solution was then
4
1
o
1
solid. M.P.: 155 ꢀ 156 C. H NMR (400 MHz, CDCl ) δ 7.83 (td, J = 7.2, 1.6 Hz, 3H), 7.78 ꢀ 7.67
3
19
(
m, 12H), 6.98 ꢀ 6.78 (m, 1H), 1.91 ꢀ 1.72 (m, 3H). F NMR (376 MHz, CDCl
3
) δ ꢀ152.89 (s, 1F),
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1
ꢀ
152.95 (s, 3F), ꢀ193.71 (ddq, J = 69.6, 43.7, 25.9 Hz, 1F). P NMR (162 MHz, CDCl ) δ 22.28
3
1
3
1
(
3
d, J = 69.6 Hz, 1P). C{ H} NMR (101 MHz, CDCl ) δ 136.0 (d, J = 2.4 Hz), 134.2 (d, J = 9.7
Hz), 130.8 (d, J = 12.7 Hz), 114.7 (d, J = 84.2 Hz), 86.1 (dd, J = 191.7, 64.5 Hz), 16.4 (d, J = 21.1
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Hz). IR(KBr): 3066, 2967, 1587, 1486, 1382, 1320, 1283, 1193, 1168, 1113, 1060, 997, 887, 754,
ꢀ1
+
ꢀ +
7
28, 711, 690, 541, 526, 498 cm . HRMS (ESI): calcd. for [C20
H
19FP] [M ꢀ BF
4
] 309.1203,
found 309.1203.
(
3)The synthesis of 1,1ꢀdifluoroethyl phosphonium salt 2：
Under argon atmosphere, into the mixture of salt 1’ (3.96 g, 10 mmol) and THF
o
(40 mL) at ꢀ78 C was added dropwise the solution of KHMDS [Potassium
bis(trimethylsilyl)amide] (1.0 M, 15 mmol) in THF (15 mL) via a syringe for 30 min.
o
Upon the completion of addition, the resulting mixture was further stirred at 0 C until
the solid disappeared (about 20 min) to give the fluorinated phosphonium ylide
+
ꢀ
(
3
Ph P CF Me). The solution of this ylide was unstable and needed to be stored at ꢀ78
o
C before use.
Under argon atmosphere, into the solution of NFSI (14.2 g, 45 mmol) in THF (40
o
mL) at 0 C was added the solution of the fluorinated ylide slowly in 30 min. Upon
the completion of addition, the resulting mixture was warmed to room temperature
and was further stirred for 10 min. The reaction mixture was then poured into the
aqueous solution of HBF
combined organic phase was concentrated to afford a viscous liquid. Enough Et
500 mL) was added into the liquid to precipitate the crude product, which was
4 2 2
(200 mL), and extracted with CH Cl (50 mL X 6). The
2
O
(
contaminated by NFSI and salt 1’. After filtration under air atmosphere, the solid was
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dissolved in CH
2
Cl
2
2
(about 20 mL) to give a saturated solution. Enough Et O (500
mL) was added into the solution to precipitate the product. The solid was collected by
filtration under air atmosphere. The dissolvingꢀprecipitate process by CH Cl /Et
was repeated once more to afford a solid. The solid was dissolved in CH Cl (about
2
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2
O
0
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0
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9
0
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2
o
2
0 mL) to give a saturated solution. The solutions was stirred at 80 C and EA (200
mL) was added slowly to precipitate the crude product. The crude product was
2 2
collected by filtration. This dissolvingꢀprecipitate process by CH Cl /EA was repeated
31
for 3ꢀ4 times until the product was pure detected by P NMR. The product was then
dissolved in CH Cl (100 mL), and the solution was then dried over anhydrous
2
2
MgSO
product as a white solid (3.0 g, 72%).
,1ꢀdifluoroethyl triphenylphosphonium tetrafluoroborate (2): 3.0 g, 72% yield,
4
. After filtration, the solvent was removed by concentration to give the pure
1
o
1
white solid. M.P.: 153 ꢀ 154 C. H NMR (400 MHz, CDCl
3
) δ 7.93 (t, J = 7.3 Hz,
19
3
H), 7.84 ꢀ 7.70 (m, 12H), 2.19 [td, J = 21.8 (CH ꢀCF ), 9.7 Hz, 3H]. F NMR (376
3
2
31
3
MHz, CDCl ) δ ꢀ86.85 (dq, J = 95.8, 21.8 Hz, 2F), ꢀ153.27 (s, 1F), ꢀ153.33 (s, 3F). P
13
1
NMR (162 MHz, CDCl
CDCl ) δ 136.9 (d, J = 3.2 Hz), 134.6 (d, J = 10.3 Hz), 131.3 (d, J = 13.1 Hz), 124.0
td, J = 270.4, 92.4 Hz), 112.3 (d, J = 83.5 Hz), 22.7 (dt, J = 36.2, 18.1 Hz). IR(KBr):
3069, 1587, 1485, 1441, 1389, 1284, 1142, 1109, 1055, 997, 936, 899, 753, 729, 689,
3
) δ 25.15 (t, J = 95.8 Hz, 1P). C{ H} NMR (126 MHz,
3
(
ꢀ1
+
ꢀ +
5
44, 526, 494 cm . HRMS (ESI): calcd. For [C20
18 2 4
H F P] [M ꢀ BF ] 327.1105,
found 327.1105.
General procedure for 1,1-difluoroethylation of aldehydes and imines
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In a glove box, into a 25 mL Schlenk tube were added substrate (0.5 mmol),
2 3
Cs CO (407.3 mg, 1.25 mmol) and DMF (1 mL). The tube was sealed and then taken
out from the glove box. Into this mixture under argon atmosphere at room temperature,
the solution of 2 (414 mg, 1.0 mmol) in DMF (2.0 mL) was added dropwise via a
syringe for 30 min. Upon the completion of addition, the resulting mixture was further
stirred at the same temperature for 10 minutes. The reaction was quenched by 3 N
HCl (0.5 mL). The resulting mixture was diluted with water (40 mL) and extracted
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59
60
2 4
with DCM (4 × 40 mL). The combined organic phase was dried over Na SO . After
filtration, the solvent was removed by concentration, and the residue was subjected to
column chromatography (ethyl acetate and petroleum ether as the eluent) to afford the
pure product.
1
ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ2,2ꢀdifluoropropanꢀ1ꢀol (4a): 106.3 mg, 86% yield, white
o
1
solid. M.P.: 89 ꢀ90 C. H NMR (400 MHz, CDCl
3
) δ 7.63 ꢀ 7.58 (m, 4H), 7.52 (d, J =
8
.0 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 4.91 (td, J = 9.5, 3.8
19
Hz, 1H), 2.48 (d, J = 3.8 Hz, 1H), 1.58 (t, J = 18.8 Hz, 3H). F NMR (376 MHz,
CDCl ) δ ꢀ100.66 ((ABq)qd, δAB = 267.0 Hz, JAB = 241.9 Hz, J = 18.8, 9.5 Hz, 2F).
3
1
3
1
C{ H} NMR (101 MHz, CDCl
3
) δ 141.6 (s), 140.6 (s), 135.6 (s), 128.9 (s), 127.7
(
s), 127.5 (s), 127.2 (s, Hz), 127.1 (s), 123.4 (t, J = 243.1 Hz), 75.6 (t, J = 28.6 Hz),
18.9 (t, J = 26.3 Hz). IR(KBr): 3612, 3457, 2922, 1489, 1449, 1394, 1232, 1186,
ꢀ1
1
126, 1058, 964, 924, 845, 802, 759, 738, 692, 610, 592, 524, 497 cm . HRMS (EI):
+
calcd. for [C15
H
14OF
2
] [M ] 248.1007, found 248.1008.
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1
ꢀ([1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ2,2ꢀdifluoropropanꢀ1ꢀol (4b): 93.4 mg, 78% yield, colorless
o
1
oil. M.P.: 49 ꢀ 50 C. H NMR (400 MHz, CDCl
3
) δ 7.72 (d, J = 7.4 Hz, 1H), 7.45 ꢀ
7
1
.33 (m, 5H), 7.30 (d, J = 7.3 Hz, 2H), 7.25 (d, J = 7.4 Hz, 1H), 4.96 (dd, J = 11.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
0.2 Hz, 1H), 2.13 (br, 1H), 1.42 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl ) δ
3
13
1
ꢀ
101.67 ((ABq)qd, δAB = 609.2 Hz, JAB = 244.3 Hz, J = 18.8, 10.2 Hz, 2F). C{ H}
NMR (101 MHz, CDCl ) δ 142.8 (s), 140.8 (s), 134.5 (s), 130.3 (s), 129.4 (s), 128.5
s), 128.3 (s), 127.9 (s), 127.5 (s), 127.4 (s), 123.3 (t, J = 244.0 Hz), 71.8 (t, J = 27.2
Hz), 20.4 (t, J = 26.4 Hz). IR(KBr): 3430, 3060, 3026, 2930, 1597, 1480, 1439, 1389,
3
(
1
6
285, 1236, 1184, 1129, 1110, 1057, 1047, 1009, 925, 878, 850, 775, 755, 704, 658,
ꢀ1
+
2
12, 592, 573, 537 cm . HRMS (EI): calcd. for [C15H14OF ] [M ] 248.1007, found
248.1012.
2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)propanꢀ1ꢀol (4c): 82.4 mg, 75% yield, colorless oil.
1
3
H NMR (400 MHz, CDCl ) δ 7.35 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 4.78
19
(t, J = 9.6 Hz, 1H), 3.80 (s, 3H), 2.44 (br, 1H), 1.49 (t, J = 18.9 Hz, 3H). F NMR
13
1
(376 MHz, CDCl
3
) δ ꢀ101.11 (qd, J = 18.9, 9.6 Hz, 2F). C{ H} NMR (101 MHz,
CDCl ) δ 159.8 (s), 128.9 (s), 128.5 (s), 123.4 (t, J = 242.9 Hz), 113.8 (s), 75.4 (t, J =
3
2
8.8 Hz), 55.3 (s), 18.9 (t, J = 26.4 Hz). IR(KBr): 3462, 3005, 2920, 2841, 1614,
1587, 1516, 1465, 1444, 1391, 1305, 1251, 1177, 1127, 1068, 1032, 963, 924, 859,
ꢀ1
8
39, 802, 789, 774, 645, 628, 616, 571, 520 cm . HRMS (EI): calcd. for [C H O F ]
10 12 2 2
+
[
M ] 202.0800, found 202. 0807.
2
,2ꢀdifluoroꢀ1ꢀ(2ꢀmethoxyphenyl)propanꢀ1ꢀol (4d): 71.0 mg, 60% yield, colorless oil.
1
3
H NMR (400 MHz, CDCl ) δ 7.40 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 6.98
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(
t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 5.13 (td, J = 11.1, 6.7 Hz, 1H), 3.85 (s,
1
9
3
3
H), 3.26 (d, J = 6.7 Hz, 1H), 1.57 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl )
δ ꢀ102.51 ((ABq) qd, δAB = 364.5 Hz, JAB = 241.8 Hz, J = 18.9, 11.1 Hz, 2F)).
10
11
12
13
14
15
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17
18
19
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 157.3 (s), 129.7 (s), 129.2 (s), 124.9 (s), 123.4 (t,
3
J = 244.1 Hz), 120.9 (s), 111.1 (s), 75.4 (t, J = 28.8 Hz), 55.6 (s), 20.0 (t, J = 26.4
Hz). IR(KBr): 3444, 3006, 2945, 2841, 1603, 1589, 1494, 1465, 1441, 1390, 1289,
1
245, 1185, 1128, 1050, 1026, 962, 924, 853, 814, 785, 757, 734, 658, 608, 581, 566,
ꢀ1
+
5
12 2 2
06 cm . HRMS (EI): calcd. for [C10H O F ] [M ] 202.0800, found 202.0800.
2
,2ꢀdifluoroꢀ1ꢀmesitylpropanꢀ1ꢀol (4e): 68.8 mg, 63% yield, white solid. M.P.: 49 ꢀ 50
o
1
C. H NMR (400 MHz, CDCl
3
) δ 6.86 (s, 2H), 5.31 (td, J = 11.3, 4.6 Hz, 1H), 2.43
19
(s, 6H), 2.28 (d, J = 4.6 Hz, 1H), 2.25 (s, 3H), 1.68 (t, J = 18.9 Hz, 3H). F NMR
(376 MHz, CDCl
3
) δ ꢀ98.31 ((ABq)qd, δAB = 614.4 Hz, JAB = 245.4 Hz, J = 18.9, 11.3
) δ 137.8 (s), 129.6 (s) , 124.40 (s), 124.39
13
1
Hz, 2F). C{ H} NMR (101 MHz, CDCl
3
(t, J = 243.4 Hz), 73.7 (dd, J = 30.0, 28.1 Hz), 21.3 (t, J = 3.3 Hz), 21.0 (s), 20.7 (s).
IR(KBr): 3462, 3004, 2925, 1611, 1576, 1450, 1387, 1232, 1186, 1124, 1068, 1022,
ꢀ1
954, 938, 917, 853, 821, 791, 727, 645, 635, 587, 522 cm . HRMS (EI): calcd. for
+
[
C
12
H
16OF
2
] [M ] 214.1164, found 214.1163.
2,2ꢀdifluoroꢀ1ꢀ(naphthalenꢀ2ꢀyl)propanꢀ1ꢀol (4f): 86.6 mg, 78% yield, white solid.
o
1
M.P.: 53 – 54 C. H NMR (400 MHz, CDCl ) δ 7.91 (s, 1H), 7.88 ꢀ 7.81 (m, 3H),
3
7
.54 (d, J = 8.6 Hz, 1H), 7.52 ꢀ 7.46 (m, 2H), 5.02 (td, J = 9.5, 3.7 Hz, 1H), 2.55 (d, J
19
=
3.7 Hz, 1H), 1.52 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl ) δ ꢀ100.18 ꢀ
3
13
1
3
ꢀ100.41 (m, 2F). C{ H} NMR (101 MHz, CDCl ) δ 134.2 (s), 133.5 (s), 133.0 (s),
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8
28.2(s), 128.1 (s), 127.7 (s), 126.7 (s), 126.5 (s), 126.4 (s), 124.8 (s), 123.5 (t, J =
43.3 Hz), 75.9 (t, J = 28.8 Hz), 19.0 (t, J = 26.3 Hz). IR(KBr): 3442, 3059, 3007,
923, 1602, 1509, 1442, 1391, 1365, 1271, 1236, 1190, 1123, 1067, 963, 927, 886,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
61, 824, 805, 758, 744, 654, 564, 545, 501, 480 cm . HRMS (EI): calcd. for
+
[
C
13
H12OF
2
] [M ] 222.0851, found 222.0861.
1
2
,2ꢀdifluoroꢀ1ꢀ(4ꢀfluorophenyl)propanꢀ1ꢀol (4g): 79.6 mg, 82% yield, colorless oil. H
NMR (400 MHz, CDCl
3
) δ 7.41 (dd, J = 8.3, 5.6 Hz, 2H), 7.05 (t, J = 8.3 Hz, 2H),
19
4
.82 (t, J = 9.6 Hz, 1H), 2.14 (s, 1H), 1.48 (t, J = 18.9 Hz, 3H). F NMR (376 MHz,
CDCl ) δ ꢀ100.93 ((ABq)qd, δ = 219.1 Hz, JAB = 247.8 Hz, J = 18.9, 9.6 Hz, 2F),
3
AB
13
1
ꢀ113.35 – ꢀ113.47 (m, 1F). C{ H} NMR (101 MHz, CDCl
3
) δ 162.9 (d, J = 247.1
Hz), 132.4 (s), 129.0 (d, J = 8.2 Hz), 123.2 (t, J = 243.0 Hz), 115.3 (d, J = 21.6 Hz),
5.1 (t, J = 29.2 Hz), 18.7 (t, J = 26.3 Hz). IR(KBr): 3442, 2992, 1607, 1514, 1393,
7
ꢀ1
+
1228, 1129, 1068, 927, 844, 804, 562 cm . HRMS (EI): calcd. for [C
9 9 3
H OF ] [M ]
1
90.0600, found 190.0607.
1ꢀ(3ꢀchlorophenyl)ꢀ2,2ꢀdifluoropropanꢀ1ꢀol (4h): 83.8 mg, 81% yield, colorless oil.
1
3
H NMR (400 MHz, CDCl ) δ 7.45 (s, 1H), 7.35 ꢀ 7.25 (m, 3H), 4.81 (t, J = 9.2 Hz,
19
1H), 2.37 (br, 1H), 1.49 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl
3
) δ ꢀ100.42
13
1
((ABq)qd, δAB = 356.60 Hz, JAB = 249.1 Hz, J = 18.9, 9.2 Hz, 2F). C{ H} NMR
(101 MHz, CDCl ) δ 138.6 (d, J = 4.3 Hz), 134.4 (s), 129.6 (s), 128.8 (s), 127.4 (s),
3
1
25.5 (s), 123.1 (t, J = 242.7 Hz), 75.0 (dd, J = 28.7, 29.8 Hz), 18.7 (t, J = 26.2 Hz).
IR(KBr): 3589, 3437, 3071, 3007, 2923, 1600, 1576, 1475, 1432 , 1392, 1288, 1234,
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188, 1129, 1102, 1063, 964, 929, 819, 803, 776, 728, 707, 692, 656, 595, 514, 480
ꢀ1
+
9 9 2
cm . HRMS (EI): calcd. for [C H ClOF ] [M ] 206.0305, found 206.0309.
1
1
ꢀ(4ꢀbromophenyl)ꢀ2,2ꢀdifluoropropanꢀ1ꢀol (4i): 95.4 mg, 76% yield, colorless oil. H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (400 MHz, CDCl ) δ 7.50 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.81 (t,
3
19
J = 9.4 Hz, 1H), 2.47 (s, 1H), 1.48 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl
3
)
13
1
δ ꢀ100.65 ((ABq)qd, δAB = 333.9 Hz, JAB = 246.8 Hz, J = 18.9, 9.4 Hz, 2F). C{ H}
NMR (101 MHz, CDCl ) δ 135.6 (dd, J = 1.3, 4.4 Hz), 131.5 (s), 128.9 (t, J = 1.4
3
Hz), 123.1 (t, J = 244.0 Hz), 122.8 (s), 75.1 (dd, J = 28.4, 29.9 Hz), 18.6 (t, J = 26.3
Hz). IR(KBr): 3589, 3435, 3006, 2924, 2853, 1595, 1488, 1392, 1234, 1187, 1128,
ꢀ1
1074, 1012, 964, 927, 849, 836, 794, 779, 634, 622, 599, 564, 551, 502 cm . HRMS
+
(
EI): calcd. for [C H BrOF ] [M ] 249.9799, found 249.9804.
9
9
2
2,2ꢀdifluoroꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)propanꢀ1ꢀol (4j): 82.6 mg, 68% yield,
1
colorless oil. H NMR (400 MHz, CDCl
3
) δ 7.62 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.2
19
Hz, 2H), 4.90 (t, J = 9.2 Hz, 1H), 2.68 (br, 1H), 1.48 (t, J = 18.9 Hz, 3H). F NMR
376 MHz, CDCl ) δ ꢀ62.75 (s, 3F), ꢀ100.32 ((ABq)qd, δAB = 522.3 Hz, JAB = 250.3
Hz, J = 18.9, 9.2 Hz, 2F). C{ H} NMR (101 MHz, CDCl ) δ 140.5 (s), 130.9 (q, J =
(
3
13
1
3
3
2.5 Hz), 127.6 (s), 125.2 (q, J = 3.8 Hz), 124.0 (q, J = 273.4 Hz), 123.0 (t, J = 243.4
Hz), 75.1 (t, J = 29.4 Hz), 18.6 (t, J = 26.2 Hz). IR(KBr): 3608, 3447, 2924, 2361,
2
8
2
341, 1622, 1420, 1394, 1327, 1234, 1167, 1126, 1068, 1019, 956, 929, 851, 788,
ꢀ1
+
04, 766, 734, 679, 623, 609, 501 cm . HRMS (EI): calcd. for [C10
9 5
H OF ] [M ]
40.0568, found 240.0570.
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3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
,2ꢀdifluoroꢀ1ꢀ(3ꢀ(trifluoromethyl)phenyl)propanꢀ1ꢀol (4k): 88.5 mg, 73% yield,
1
colorless oil. H NMR (400 MHz, CDCl
3
) δ 7.72 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7
1
.61 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 4.91 (t, J = 9.0 Hz, 1H), 2.40 (br,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
H), 1.49 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl ) δ ꢀ62.71 (s, 3F), ꢀ100.47
3
1
3
1
(
(ABq)qd, δAB = 532.2 Hz, JAB = 248.4 Hz, J = 18.9, 9.0 Hz, 2F). C{ H} NMR (101
MHz, CDCl ) δ 137.6 (d, J = 4.6 Hz), 130.8 (q, J = 32.5 Hz), 130.7 (s), 128.8 (s),
25.5 (q, J = 3.7 Hz), 124.1 (q, J = 3.8 Hz), 124.0 (q, J = 272.4 Hz), 123.0 (t, J =
3
1
2
3
8
44.4 Hz), 75.1 (dd, J = 30.1, 29.0 Hz), 18.6 (t, J = 26.2 Hz). IR(KBr): 3603, 3439,
011, 2923, 1619, 1494, 1451, 1394, 1330, 1234, 1167, 1127, 1075, 1003, 965, 928,
ꢀ1
13, 193, 758, 704, 683, 654, 613, 613, 590, 555, 506 cm . HRMS (EI): calcd. for
+
[C10
H
9
OF
5
] [M ] 240.0568, found 240.0578.
2,2ꢀdifluoroꢀ1ꢀ(2ꢀ(trifluoromethyl)phenyl)propanꢀ1ꢀol (4l): 98.1 mg, 81% yield,
1
colorless oil. H NMR (400 MHz, CDCl
3
) δ 7.86 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8
Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 5.25 (t, J = 10.5 Hz, 1H),
19
2
.18 (br, 1H), 1.57 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl
3
) δ ꢀ57.21 (t, J =
13
1
4.0 Hz, 3F), ꢀ101.00 ꢀ ꢀ102.05 (m, 1F), ꢀ102.59 ꢀ ꢀ103.73 (m, 1F). C{ H} NMR (101
MHz, CDCl
128.9 (s), 125.8 (q, J = 5.8 Hz), 124.1 (q, J = 274.5 Hz), 122.5 (t, J = 244.5 Hz), 70.8
tq, J = 27.5, 2.6 Hz), 20.6 (t, J = 26.4 Hz). IR(KBr): 3604, 3433, 3011, 1894, 1609,
3
) δ 135.6 (s), 132.2 (s), 129.5 (t, J = 2.9 Hz), 128.9 (q, J = 30.1 Hz),
(
1
588, 1457, 1392, 1313, 1235, 1167, 1123, 1070, 1054, 1035, 964, 931, 855, 817,
ꢀ1
+
7
71, 750, 677, 678, 613, 599 cm . HRMS (EI): calcd. for [C H OF ] [M ] 240.0568,
10 9 5
found 240.0576.
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ꢀ(2,2ꢀdifluoroꢀ1ꢀhydroxypropyl)benzonitrile (4m): 66.0 mg, 69% yield, yellow oil.
1
3
H NMR (400 MHz, CDCl ) δ 7.75 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8
Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 4.86 (t, J = 9.1 Hz, 1H), 3.14 (br, 1H), 1.48 (t, J =
10
11
12
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
9
1
8.9 Hz, 3H). F NMR (376 MHz, CDCl ) δ ꢀ98.56 ꢀ ꢀ99.48 (m, 1F), ꢀ101.04 ꢀ
3
13
1
ꢀ
101.99 (m, 1F). C{ H} NMR (101 MHz, CDCl
3
) δ 138.5 (s), 132.2 (s), 131.9 (s),
1
1
1
31.0 (s), 129.1 (s), 122.9 (t, J = 243.6 Hz), 118.6 (s), 112.3 (s), 74.5 (t, J = 29.9 Hz),
8.7 (t, J = 26.1 Hz). IR(KBr): 3453, 3007, 2234, 1585, 1484, 1438, 1391, 1275,
ꢀ1
259, 1235, 1190, 1141, 1066, 966, 927, 787, 750, 692, 613, 588, 538 cm . HRMS
+
(
EI): calcd. for [C H ONF ] [M ] 197.0647, found 197.0654.
10
9
2
2
,2ꢀdifluoroꢀ1ꢀ(quinolinꢀ3ꢀyl)propanꢀ1ꢀol (4n): 82.6 mg, 77% yield, white solid.
o
1
M.P.: 126 – 127 C. H NMR (400 MHz, CDCl
3
) δ 8.92 (s, 1H), 8.27 (s, 1H), 8.10 (d,
J = 8.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.56 (t, J = 7.6 Hz,
19
1H), 5.08 (t, J = 9.2 Hz, 1H), 3.49 (br, 1H), 1.57 (t, J = 18.9 Hz, 3H). F NMR (376
MHz, CDCl ) δ ꢀ100.30 ((ABq)qd, δ = 747.1 Hz, JAB = 251.2 Hz,, J = 18.9, 9.2 Hz,
3
AB
13
1
2F). C{ H} NMR (101 MHz, CDCl
3
) δ 149.5 (s), 147.4 (s), 135.4 (s), 130.8 (s),
1
30.1 (s), 128.4 (s), 128.1 (s), 127.6 (s), 127.1 (s), 123.3 (t, J = 243.4 Hz), 73.5 (t, J =
30.3 Hz), 19.0 (t, J = 26.2 Hz). IR(KBr): 3061, 2958, 1991, 1652, 1595, 1391, 1260,
ꢀ1
1
238, 1187, 1123, 1091, 1014, 964, 919, 818, 775, 758, 616, 593, 550 cm . HRMS
+
(EI): calcd. for [C H NOF ] [M ] 223.0803, found 223.0811.
12
11
2
1
ꢀ(benzo[b]thiophenꢀ2ꢀyl)ꢀ2,2ꢀdifluoropropanꢀ1ꢀol (4o): 90.9 mg, 82% yield, yellow
o
1
solid. M.P.: 65 – 66 C. H NMR (400 MHz, CDCl
3
) δ 7.82 (d, J = 8.3 Hz, 1H), 7.75
(
dd, J = 6.5, 2.5 Hz, 1H), 7.40 ꢀ 7.29 (m, 3H), 5.16 (t, J = 9.1 Hz, 1H), 2.60 (br, 1H),
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3
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5
5
5
5
5
5
6
1
9
1
3
1
2
3
8
2
.63 (t, J = 18.9 Hz, 3H). F NMR (376 MHz, CDCl
3
) δ ꢀ100.59 ((ABq)qd, δAB
=
1
3
1
49.4 Hz, JAB = 249.9 Hz, J = 18.9, 9.1 Hz, 2F). C{ H} NMR (101 MHz, CDCl
3
) δ
40.0 (s), 139.8 (s), 139.2 (s), 124.7 (s), 124.5 (s), 123.8 (s), 123.2 (s), 122.8 (t, J =
44.3 Hz), 122.4 (s), 73.0 (t, J = 30.6 Hz), 19.0 (t, J = 25.9 Hz). IR(KBr): 3430, 3059,
000,5, 2924, 1458, 1437, 1391, 1334, 1308, 1260, 1234, 1186, 1126, 1046, 927, 862,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
+
39, 804, 747, 726, 632, 609, 562 cm . HRMS (EI): calcd. for [C11
2
H10OSF ] [M ]
28.0415, found 228.0421.
1ꢀ(benzofuranꢀ2ꢀyl)ꢀ2,2ꢀdifluoropropanꢀ1ꢀol (4p): 81.4 mg, 76% yield, colorless oil.
1
H NMR (400 MHz, CDCl ) δ 7.56 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.30
3
(t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.82 (s, 1H), 4.97 (t, J = 9.4 Hz, 1H), 2.56
19
(
br, 1H), 1.71 (t, J = 18.8 Hz, 3H). F NMR (376 MHz, CDCl ) δ ꢀ99.89 ꢀ ꢀ100.84
3
1
3
1
(m, 1F), ꢀ100.95 ꢀ ꢀ101.88 (m, 1F). C{ H} NMR (101 MHz, CDCl
3
) δ 154.9 (s),
1
52.3 (s), 127.7 (s), 124.9 (s), 123.2 (s), 122.2 (t, J = 244.4 Hz), 121.4 (s), 111.5 (s),
106.1 (s), 70.9 (t, J = 31.0 Hz), 19.7 (t, J = 26.0 Hz). IR(KBr): 3428, 2992, 1476,
ꢀ1
1
454, 1393, 1238, 1138, 1061, 1009, 931, 885, 805, 751 cm . HRMS (EI): calcd. for
+
[C H O F ] [M ] 212.0643, found 212.0644.
1
1
10
2 2
Nꢀ(1ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ2,2ꢀdifluoropropyl)ꢀ4ꢀmethylbenzenesulfonamide
(6a):
130.6 mg, 66% yield, white solid. M.P.: 188 ꢀ 189 C. H NMR (400 MHz, CDCl ) δ
.52 ꢀ 7.31 (m, 9H), 7.12 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 5.27 (d, J = 8.5
o
1
3
7
1
9
Hz, 1H), 4.59 (td, J = 13.3, 8.5 Hz,, 1H), 2.27 (s, 3H), 1.61 (t, J = 18.7 Hz, 3H). F
13
1
NMR (376 MHz, CDCl ) δ ꢀ98.35 ꢀ ꢀ101.08 (m, 2F). C{ H} NMR (101 MHz,
3
CDCl
3
) δ 143.4 (s), 141.4 (s), 140.3 (s), 137.2 (s), 133.1 (s), 129.3 (s), 128.8 (s), 128.6
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(
s), 127.6 (s), 127.1 (s), 127.0 (s), 122.3 (t, J = 245.8 Hz), 62.1 (t, J = 26.8 Hz), 21.7
t, J = 26.4 Hz), 21.4 (s). IR(KBr): 3278, 3035, 2972, 2925, 1920, 1600, 1568, 1489,
(
1
8
451, 1410, 1389, 1306, 1236, 1192, 1151, 1118, 1083, 1021, 1006, 963, 949, 911,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ1
64, 853, 812, 763, 739, 696, 670, 611571, 552, 544, 511 cm . HRMS (ESI): calcd.
+
for [C22
H
22
O
2
NSF
2
] [M + H ] 402.1333, found 402.1334.
Nꢀ(2,2ꢀdifluoroꢀ1ꢀ(pꢀtolyl)propyl)ꢀ4ꢀmethylbenzenesulfonamide (6b): 93.2 mg, 55%
o
1
yield, white solid. M.P.: 196 ꢀ 197 C. H NMR (400 MHz, CDCl
3
) δ 7.49 (d, J = 8.2
Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H),
5
1
.24 (d, J = 8.0 Hz, 1H), 4.49 (td, J = 13.0, 8.0 Hz, 1H), 2.32 (s, 3H), 2.26 (s, 3H),
19
.54 (t, J = 18.7 Hz, 3H). F NMR (376 MHz, CDCl
3
) δ ꢀ99.71 ((ABq)qd, δAB
=
13
1
613.7 Hz, JAB = 244.3 Hz, J = 18.7, 13.0 Hz, 2F). C{ H} NMR (101 MHz, CDCl
3
) δ
1
43.3 (s), 138.4 (s), 137.3 (s), 131.3 (s), 129.3 (s), 129.1 (s), 128.0 (s), 127.1 (s),
122.3 (t, J = 245.0 Hz), 62.1 (dd, J = 25.6, 27.4 Hz), 21.6 (t, J = 26.3 Hz), 21.4 (s),
1.1 (s). IR(KBr): 3269, 3041, 3008, 2981, 1922, 1741, 1598, 1519, 1496, 1455,
2
1389, 1331, 1308, 1287, 1236, 1213, 1194, 1165, 1128, 1090, 1025, 961, 937, 911,
ꢀ1
8
46, 813, 802, 781, 721, 705, 670, 645, 627, 582, 559, 545 cm . HRMS (ESI): calcd.
+
for [C17
H
20
O
2
NSF
2
] [M + H ] 340.1177, found 340.1177.
Nꢀ(2,2ꢀdifluoroꢀ1ꢀ(4ꢀmethoxyphenyl)propyl)ꢀ4ꢀmethylbenzenesulfonamide (6c): 96.0
o
1
mg, 54% yield, white solid. M.P.: 156 ꢀ 157 C. H NMR (400 MHz, CDCl ) δ 7.49
3
(
d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.6
Hz, 2H), 5.32 (d, J = 8.8 Hz, 1H), 4.49 (td, J = 12.6, 8.8 Hz, 1H), 3.74 (s, 3H), 2.32
19
(
s, 3H), 1.54 (t, J = 18.6 Hz, 3H). F NMR (376 MHz, CDCl
3
) δ ꢀ99.84 ((ABq)qd,
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5
5
5
5
5
6
1
3
1
δ
AB = 618.3 Hz, JAB = 246.6 Hz, J = 18.6, 12.6 Hz, 2F). C{ H} NMR (101 MHz,
CDCl ) δ 159.6 (s), 143.2 (s), 137.3 (s), 129.31 (s), 129.28 (s), 127.0 (s), 126.4 (s),
22.4 (t, J = 243.9 Hz), 113.8 (s), 61.8 (dd, J = 25.8, 27.9 Hz), 55.2 (s), 21.5 (t, J =
3
1
2
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6.3 Hz), 21.4 (s). IR(KBr): 3279, 3066, 3010, 2978, 2939, 2844, 1616, 1599, 1585,
519, 1496, 1457, 1390, 1323, 1320, 1285, 1259, 1233, 1198, 1185, 1164, 1128,
090, 1035, 956, 940, 912, 868, 845, 812, 727, 705, 670, 642, 626, 580, 559, 547
ꢀ
1
+
cm . HRMS (ESI): calcd. for [C17
20 3 2
H O NSF ] [M + H ] 356.1126, found 356.1126.
Nꢀ(2,2ꢀdifluoroꢀ1ꢀmesitylpropyl)ꢀ4ꢀmethylbenzenesulfonamide (6d): 92.1 mg, 50%
o
1
yield, white solid. M.P.: 160 ꢀ 161 C. H NMR (400 MHz, CDCl ) δ 7.41 (d, J = 8.3
3
Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.73 (s, 1H), 6.56 (s, 1H), 5.31 (d, J = 9.2 Hz, 1H),
5.24 ꢀ 5.06 (m, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 2.17 (s, 6H), 1.63 (t, J = 18.7 Hz, 3H).
19
F NMR (376 MHz, CDCl
3
) δ ꢀ93.22 ꢀ ꢀ94.16 (m, 1F), ꢀ94.43 ꢀ ꢀ95.35 (m, 1F).
) δ 143.2 (s), 137.8 (s), 137.7 (s), 137.0 (s), 136.3
1
3
1
C{ H} NMR (101 MHz, CDCl
3
(
s), 131.4 (s), 129.3 (s), 129.1 (s), 127.7 (d, J = 2.4 Hz), 126.6 (s), 123.4 (t, J = 245.1
Hz), 58.4 (dd, J = 29.5, 26.0 Hz), 22.2 (t, J = 26.9 Hz), 21.4 (s), 21.2 (s), 21.1 (t, J =
.9 Hz), 20.7 (s). IR(KBr): 3335, 2971, 1613, 1600, 1577, 1498, 1441, 1386, 1336,
5
1289, 1230, 1189, 1168, 1148, 1084, 1028, 971, 948, 919, 903, 857, 835, 819, 805,
ꢀ1
7
26, 707, 670, 629, 595, 573, 549 cm . HRMS (ESI): calcd. for [C19
H
24
O
2
NSF
2
] [M
+
+ H ] 368.1490, found 368.1490.
Nꢀ(2,2ꢀdifluoroꢀ1ꢀphenylpropyl)ꢀ4ꢀmethylbenzenesulfonamide (6e): 88.3 mg, 54%
o
1
3
yield, white solid. M.P.: 175 ꢀ 176 C. H NMR (400 MHz, CDCl ) δ 7.49 (d, J = 8.3
Hz, 2H), 7.24 ꢀ 7.14 (m, 3H), 7.08 ꢀ 7.04 (m, 4H), 5.24 (d, J = 8.9 Hz, 1H), 4.64 ꢀ
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.44 (m, 1H), 2.31 (s, 3H), 1.56 (t, J = 18.7 Hz, 3H). F NMR (376 MHz, CDCl ) δ
13
1
ꢀ
99.84 ((Abq)qd, δAB = 522.9 Hz, JAB = 244.8 Hz, J = 18.7, 13.5 Hz, 2F). C{ H}
NMR (101 MHz, CDCl ) δ 143.3 (s), 137.2 (s), 134.3 (d, J = 2.7 Hz), 129.3 (s), 128.5
s), 128.4 (s), 128.1 (s), 127.0 (s), 122.3 (t, J = 245.0 Hz), 62.3 (dd, J = 27.7, 25.4
Hz), 21.6 (t, J = 26.4 Hz), 21.4 (s). IR(KBr): 3266, 3069, 3013, 2974, 1600, 1497,
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
1
9
459, 1448, 1389, 1332, 1309, 1269, 1234, 1190, 1166, 1127, 1095, 1070, 936, 953,
ꢀ1
11, 861, 831, 813, 752, 703, 676, 643, 580, 558, 548 cm . HRMS (ESI): calcd. For
+
[
C
16
H
18
O
2
NSF
2
] [M + H ] 326.1020, found 326.1021.
Nꢀ(2,2ꢀdifluoroꢀ1ꢀ(naphthalenꢀ2ꢀyl)propyl)ꢀ4ꢀmethylbenzenesulfonamide (6f): 74.2
o
1
mg, 39% yield, white solid. M.P.: 134 ꢀ 135 C. H NMR (400 MHz, CDCl
7.72 (m, 1H), 7.67 ꢀ 7.61 (m, 2H), 7.49 ꢀ 7.38 (m, 5H), 7.20 (d, J = 8.4 Hz, 1H), 6.86
d, J = 8.0 Hz, 2H), 5.41 (d, J = 6.5 Hz, 1H), 4.74 ꢀ 4.63 (m, 1H), 2.09 (s, 3H), 1.61 (t,
3
) δ 7.78 ꢀ
(
1
9
3
J = 18.7 Hz, 3H). F NMR (376 MHz, CDCl ) δ ꢀ99.42 ((ABq)qd, δAB = 516.3 Hz,
13
1
JAB = 244.6 Hz, J = 18.7, 13.0 Hz, 2F). C{ H} NMR (101 MHz, CDCl ) δ 143.3 (s),
3
137.0 (s), 133.0 (s), 132.8 (s), 131.3 (s), 129.1 (s), 128.4 (s), 128.2 (s), 128.0 (s),
1
27.5 (s), 127.0 (s), 126.5 (s), 126.3 (s), 125.0 (s), 122.4 (t, J = 245.7 Hz), 62.6 (dd, J
= 27.9, 25.7 Hz), 21.7 (t, J = 26.2 Hz), 21.2 (s). IR(KBr): 3273, 3062, 3007, 2953,
921, 1594, 1511, 1492, 1452, 1432, 1395, 1335, 1308, 1270, 1247, 1202, 1165,
1126, 1086, 1040, 1017, 975, 936, 910, 866, 816, 806, 781, 766, 752, 705, 670, 603,
1
ꢀ1
+
5
64, 543 cm . HRMS (ESI): calcd. for [C20 NSF
H
20
O
2
2
] [M + H ] 376.1177, found
376.1175. Elem. Anal. Calcd for C20 NSF : C, 63.98; H, 5.10; N, 3.73; F, 10.12;
H
19
O
2
2
S, 8.54; found C, 63.60; H, 5.13; N, 3.54; F, 10.34; S, 8.59.
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Nꢀ(1ꢀ(4ꢀcyanophenyl)ꢀ2,2ꢀdifluoropropyl)ꢀ4ꢀmethylbenzenesulfonamide (6g): 16%
19
yield determined by F NMR. In order to isolate this product to get the full
characterization data, the reaction scale was increased (1.25 mmol of substrate). 54.6
0
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9
0
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0
o
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mg, 12%; White solid. M.P.: 152 ꢀ 153 C; H NMR (400 MHz, CDCl ) δ 7.53 (d, J =
3
8
2
1
.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz,
H), 6.11 (d, J = 9.2 Hz, 1H), 4.63 (dt, J = 15.1, 9.2 Hz, 1H), 2.36 (s, 3H), 1.61 (t, J =
1
9
13
8.3 Hz, 3H). F NMR (376 MHz, CDCl
) δ 144.0 (s), 139.3 (d, J = 1.7 Hz), 136.7 (s), 132.0 (s), 129.5 (s), 129.1
s), 126.9 (s), 121.8 (t, J = 249.7 Hz), 118.2 (s), 112.3 (s), 61.8 (dd, J = 29.6, 25.8
Hz), 21.47 (t, J = 26.2 Hz), 21.44 (s). IR (neat) ν = 3271, 1418, 1330, 1235, 1184,
3
) δ ꢀ97.74 ꢀ ꢀ100.50 (m, 2F). C NMR (101
MHz, CDCl
3
(
ꢀ1
ꢀ
1164, 1089, 911, 668, 585 cm ; HRMS (ESI) Calcd for C17
15 2 2 2
H O N F S [MꢀH] :
3
49.0822, Found: 349.0828.
Acknowledgements
We thank National Basic Research Program of China (2015CB931900,
012CBA01200), the National Natural Science Foundation (21421002,
1472222, 21502214, 21672242), the Chinese Academy of Sciences
2
2
(XDA02020105, XDA02020106), and the Science and Technology
Commission of Shanghai Municipality (15DZ1200102, 14ZR1448800) for
financial support.
1
19
31
13
Supporting Information: Copies of H, F, P and C NMR spectra of
products.
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