Copper-catalysed difluoroalkylation of aromatic aldehydes via a decarboxylation/aldol reaction

Article abstract of DOI:10.1039/c7ob01739a

A copper-catalysed tandem decarboxylation/aldol reaction of simple aromatic aldehydes with 2,2-difluoro-3-oxo-3-arylpropanoic acid has been developed under mild conditions. This method provides a new route for the direct one-pot synthesis of difluorinated aldols in moderate to good yields from simple substrates.

Full text of DOI:10.1039/c7ob01739a

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Copper-catalysed difluoroalkylation of aromatic
aldehydes via decarboxylation/aldol reaction
Cite this: DOI: 10.1039/x0xx00000x
JinꢀWei Yuan, ShuaiꢀNan Liu, WenꢀPeng Mai*
Received 00th January 2012,
Accepted 00th January 2012
Copperꢀcatalysed a tandem decarboxylation/aldol reaction of simple aromatic
aldehydes with 2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀarylpropanoic acid has been developed under
mild conditions. This method provides a new route for the direct oneꢀpot synthesis
of difluorinated aldols in moderate to good yields from simple substrates.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
ꢀonium difluorotriphenylsilicate as the catalyst at ꢀ40 ºC (Scheme 1,
eq. 2).5b Very recently, Sasaki also reported a La(OTf)3ꢀcatalyzed
Organic compounds containing a fluorine atom often show unique
bioactivities in medicinal chemistry or excellent properties in
material science.1 It is well known that many pharmaceuticals have
the effectiveness due to their possessing some fluorine atoms.2
Therefore, various organic fluorinated compounds have been
developed for application in these areas. For example, the
preparation of α,αꢀdifluoroꢀβꢀhydroxy ketones has been received
considerable attention due to their potency serving as renin
inhibitors.3 Recently, Colby and coꢀworkers reported the in vivo
studies of difluoromethyl ketones as γꢀAminobutyric acid (GABA)
agonists, in which, structureꢀactivity investigations indicated that
replacing the fluorines of the difluoromethyl ketone with hydrogens
resulted in an inactive analogue (Fig 1).4 However, the simple
synthetic routes of difluoromethyl ketone scaffold remain very rare.5
In 2013, Wolf et al developed copperꢀcatalyzed bond scission of
pentafluorobutaneꢀ1,3ꢀdiones and then reacted with aldehydes to
produce α,αꢀdifluoroꢀβꢀhydroxy ketones (Scheme 1, eq. 1).5a In 2016,
Leclerc reported a Brook/Elimination/Aldol reaction sequence for
oneꢀpot preparation of difluoromethyl ketones using tetrabutylamm
aldol reaction between difluoroenol OꢀBoc esters and carbonyl
compounds to construct α,αꢀdifluoroꢀβꢀhydroxy ketones (Scheme 1,
eq. 3).5c Even so, the formation of α,αꢀdifluoroꢀβꢀhydroxy ketones
from difluoroenolates and aldehydes is still complicated due to the
precursor of the difluoroenolate should be prepared via multiꢀsteps
under ꢀ78 ºC using LDA or nꢀBuLi and the Ruppert–Prakash reagent
(TMSCF3) is highly dependent in this transformation.5ꢀ6 Herein, as a
part of our efforts on decarboxylative reactions,7 we wish to report a
copperꢀcatalysed novel tandem decarboxylation/aldol reaction
toward the difluoromethyl ketone scaffold using 2,2ꢀdifluoroꢀ3ꢀoxoꢀ
3ꢀarylpropanoic acid as substrates which could be prepared easily
based on Zhang’s or Song’s works.8
Fig. 1 The GABA agonist α,αꢀdifluoroꢀβꢀhydroxy ketone.
a School of Chemical Engineering And Environment, Henan University
of Technology, Lianhua Street, Zhengzhou 450001, China. E-mail:
maiwp@yahoo.com. Fax: +86-371-67756715; Tel: +86-371-67756718
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
Scheme 1 The synthesis of α,αꢀdifluoroꢀβꢀhydroxy ketones.
Results and discussion
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DOI: 10.1039/C7OB01739A
Table 1 Optimization of reaction conditionsa
unexpected product α,αꢀdifluoroꢀβꢀhydroxy ketone (3ab) was
isolated in 28% yield (Table 1, entry 1). Changing the ligand
from L2 to L5, the best result was achieved when 1,10ꢀ
phenanthroline (L3) as ligand using Cu(OAc)2 as catalyst in
DMSO (Table 1, entry 3). Using L3 as ligand, other Cu salts such
as CuCl, CuBr and CuI showed better catalytic effect than
Cu(OAc)2 under the same conditions (Table 1, entries 6ꢀ8). 71%
isolated yield was obtained when CuI was explored as the
catalyst (Table 1, entry 8). On the contrary, CuO or Cu2O serving
as catalyst displayed no effect in this transfromation (Table 1,
entries 9ꢀ10). Further screening of solvents revealed that the
solvents were also crucial for this reaction. No desired product
was found when the reaction proceeded in toluene (table 1, entry
14) and only 39% product 3ab was obtained when performing
the reaction in dioxane (Table 1, entry 13). Diglyme or CH3CN
as the solvent, the reaction gave the desired product in moderate
yields (Table 1, entries 12 and 15). However, reaction conducted
with CuI as the catalys and L3 ligand formed the desired product
in 76% yield in DME (Table 1, entry 11).
OH
O
O
O
Catalyst
Ligand
COOH
H
+
F
F
F
F
Solvent/T
I
I
1a
2b
3ab
N
N
N
N
N
N
1
4
2
3
N
H
N
COOH
H
N
H
5
Entry
Catalyst (equiv.)
Cu(OAc)2(0.1)
Cu(OAc)2(0.1)
Cu(OAc)2(0.1)
Cu(OAc)2(0.1)
Ligand(equiv.)
L1 (0.1)
Yieldb(%)
Solvent/T(ºC)
DMSO/80
DMSO/80
DMSO/80
DMSO/80
1
2
3
4
28
37
L2 (0.1)
L3 (0.1)
50
L4 (0.1)
trace
5
6
Cu(OAc)2(0.1)
CuCl(0.1)
CuBr(0.1)
CuI(0.1)
CuO(0.1)
Cu2O(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.1)
CuI(0.05)
CuI(0.05)
CuI(0.05)
CuI(0.05)
ꢀ
L5 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.1)
L3 (0.05)
L3 (0.05)
L3 (0.05)
-
DMSO/80
DMSO/80
DMSO/80
DMSO/80
DMSO/80
DMSO/80
DME/80
trace
63
Table 2 Reaction of aromatic aldehydes with different 2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀ
arylpropanoic acid a,b
7
60
8
71
9
0
10
11
12
13
14
15
16
17
18
19c
20d
0
76
Diglyme/80
Dioxane/80
Toluene/80
CH3CN/80
DME/80
71
O
OH
O
OH
O
OH
39
F
F
F
F
F F
trace
65
S
I
CN
3ab, 78%
OH
3ac, 70%
3ad, 65%
O
O
OH
O
OH
78
NO2
F
F
O
F
F
F F
DME/50
39
Br
3ag, 82%
3ae, 82%
OH
O
3af
, 85%
DME/28
trace
30
O
O
OH
O
OH Cl
O
DME/80
F
F
F
F
N
F F
L3 (0.05)
DME/80
trace
Cl
3ah, 90%
OH
3ai, 50%
OH
3aj, 89%
O
O
a
O
OH
Reaction conditions: 1a (1.0 mmol), 2b (1.5 mmol), catalyst (0.05 or 0.1
Cl
F
F
F
F
F
F
equiv), Ligand (0.05 or 0.1 equiv), K2CO3 (2.0 equiv), solvent (5 mL) in 50
under N2 for 10 h. b Isolated yield. c under air
O
Br
F
3ka, 74%
OH
3la, 75%
OH
3ma, 66%
OH
mL roundꢀbottom flask at 80
℃
O
O
O
and without Ligand. d Without catalyst.
F
F
F F
F
F
NC
Cl
Cl
3ca, 47%
OH OCH3
3ga, 85%
OH
3na, 87%
OH
O
O
At the beginning, based on our assumption, copper catalyzed direct
αꢀarylation of α,αꢀdifluoroketone acid with aryl iodide via
decarboxylation process was investigated.9 Unfortunately, no
coupling product was found using 2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀ
phenylpropanoic acid (1a) and 4ꢀiodobenzaldehyde (2b) as the
substrates. Another CꢀC bond formation through aldol reaction was
observed unexpectedly. Thus, we simply continue to use the two
substrates for the optimal conditions of the “unexpected reaction”.
Firstly, the reaction was performed in the presence of 10 %
Cu(OAc)2 and 10 % 2,2'ꢀbipyridine in DMSO at 80 ºC. The
O
Cl
F
F
F
F
F
F
I
3ob, 65%
OH
3lm, 74%
OH
3mo
, 55%
O
OH
O
O
F
F
F
F
F F
R
3ap, trace
3aq, 0
3ar, trace, R = OCH3
3as, trace, R = N(CH3)2
a
Reaction conditions: 1 (1.0 mmol), aromatic aldehydes (1.5 mmol), CuI
, 10 h. b Isolated yield.
(0.05 mmol), Phen (0.05 mmol ), DME (5 mL), 80
℃
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB01739A
occur and no product was obtained (Table 2, 3ap and 3aq). The
reason for this result is not clear at present. Moreover, the aryl
aldehydes which have strong electronꢀdonating groups at paraꢀ
position were not tolerated under the current conditions (Table 2,
3ar and 3as). It could be due to the decrease of the formyl
group’s electrophilicity in 4ꢀmethoxybenzaldehyde (2r) and 4ꢀ
(dimethylamino)benzaldehyde (2s).
Reducing the amount of the catalyst system did not delay the
reaction (Table 1, entry 16). Nevertheless, the temperature
influenced the results of this transformation obviously, no
reaction occur at room temperature (Table 1, entries 17ꢀ18). The
reaction did not occur in the absence of CuI at all or produced
low yield without ligand, it displayed that both of the catalyst
and ligand were important for the transformation (Table 1,
entries 19ꢀ20).
After investigating the reaction conditions, the substrates
testing were carried out subsequently. As shown in Table 2,
various aromatic aldehydes reacted with 2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀ
phenylpropanoic acid (1a), the decarboxylation/aldolꢀadduct
products were isolated in moderate to good yields. 1a with
aromatic aldehydes such as methyl 4ꢀformylbenzoate and 3ꢀ
nitrobenzaldehyde, the α,αꢀdifluoroꢀβꢀhydroxy ketones were
obtained in 82% and 85% yield respectively (Table 2, 3ae and
3af). Even in the presence of copper salt, aromatic aldehydes
containing halides (I, Br, Cl) could take part in this
Radical trapping experiment was subsequently performed in
order to understand the mechanism of copper catalysed
decarboxylation/aldol reaction (Scheme 2, a). The desired
product 3ab was still obtained in 71% yield when the radical
scavenger 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) was
added. This result displayed the decarboxylation process is not
through radical route. Moreover, classic radical decarboxylative
process catalysed by AgNO3 was not effective in this
transformation (Scheme 2, b). Stoichiometric metalꢀmediate
Reformatsky reaction of bromodifluoromethyl ketone with 4ꢀ
iodobenzaldehyde (2b) could gave the desired product in low
yield using a known procedure (Scheme 2, c).10 But the same
reaction did not occur under the current catalytic conditions
(Scheme 2, d). This result demonstrates the current protocol is a
Reformatskyꢀtype reaction of catalytic version using 2,2ꢀ
difluoroꢀ3ꢀoxoꢀ3ꢀarylpropanoic acid as substrate. In addition,
decarboxylic reaction of 1a could occur in the presence of
catalytic copper iodide which provided some evidence of the
formation of enolate anion (Scheme 2, e).
transformation
smoothly
without
dehalogenation.
The
corresponding products were obtained in moderate yields (Table
2, 3ab, 3ag and 3aj). We further examined heteroaromatic
aldehydes, for furanꢀ2ꢀcarbaldehyde, the desired product was
obtained in 90% (Table 2, 3ah), for 4ꢀpyridinecarboxaldehyde,
only 50% product was obtained (Table 2, 3ai). Then the scope of
2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀarylpropanoic acid was also tested. Both
electronꢀwithdrawing groups (CN, F, Br) and electronꢀdonating
groups (CH3O, CH3) on the phenyl ring of the substrate 1 were
well tolerated in the decarboxylatio/aldol processes. CN and F on
the paraꢀposition of the phenyl ring of the substrate 1, produced
the corresponding products in 47% and 65% respectively (Table
2, 3ca and 3ob). At the same position, Cl and Br group did not
influence the reactivity and the desired products were obtained in
high yields (Table 2, 3ga and 3na). 2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀ
arylpropanoic acid with electronꢀdonating groups (CH3O, CH3)
underwent efficient decarboxylation to provide the expected
products in 75% yield (Table 2, 3ka and 3la). Nevertheless, for
alphatic aldehyde (2p) or acetophenone (2q), the reaction did not
Scheme 3 Proposed mechanism for the reaction
Based on the previous works on the synthesis of α,αꢀdifluoroꢀβꢀ
hydroxy
decarboxylation/aldol
ketones,5
a
primary
mechanism
for
the
reaction
of
2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀ
phenylpropanoic acid 1a with 4ꢀiodobenzaldehyde 2b has been
proposed (Scheme 3). At first, by the assistance of Cu(I) catalyst, the
intermediate A was formed through decarboxylation. After ketoꢀenol
tautomerism, the intermediates B or C were formed. Then, the
nucleophilic addition of the intermediate B or C to aromatic
aldehyde 2b, leads to the product 3ab.
Conclusions
Scheme 2 Control experiments
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DOI: 10.1039/C7OB01739A
In summary, we have developed a practical method for the 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H), 5.44 (dt, J = 20.0, 4.0 Hz, 1H),
synthesis of α,αꢀdifluoroꢀβꢀhydroxy ketones owning biological 3.92 (s, 3H), 3.33 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
activity via catalytic decarboxylation/aldol reaction using 2,2ꢀ δ 190.63 (t, JC-F = 29.0 Hz), 139.66, 134.81, 132.16, 130.32, 130.26,
difluoroꢀ3ꢀoxoꢀ3ꢀarylpropanoic acids as substrates which can be 129.46, 128.75, 128.19, 115.42 (t, JC-F = 256 Hz), 72.86 (dd, JC-F
=
easily prepared in some simple steps. The novel method is 28, 23 Hz), 52.23; 19F NMR (CDCl3, 376 MHz): δ ꢀ103.67 (d, J =
catalysed by simple copper salt and used cheap ligand under mild 297.04 Hz), ꢀ116.06 (d, J = 297.04 Hz).
conditions. Comparing with the previous methods, the substrates
used in this reaction are moistureꢀ and airꢀstable, moreover, the (3af). Colorless liquid (known compound), H NMR (CDCl3, 400
reaction does not need low temperature (stabilizing enol anion) MHz) δ 8.42 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz,
2,2-difluoro-3-hydroxy-3-(3-nitrophenyl)-1-phenylpropan-1-one
1
or high temperature (decarboxylation＞150℃).
2H), 7.88 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.60 (t, J =
8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H), 5.55 (dt, J = 20.0, 4.0 Hz, 1H),
3.39 (d, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 190.34 (t,
JC-F = 29.0 Hz), 136.76, 135.12, 134.26, 131.78, 130.36, 129.19,
Experimental section
General experimental procedure for the synthesis of 3
To a mixture of 2,2ꢀdifluoroꢀ3ꢀoxoꢀ3ꢀarylpropanoic acids
1
(1.0 128.86, 123.88, 123.35, 114.90 (t, JC-F = 256 Hz), 72.17 (dd, JC-F =
mmol) and aromatic aldehydes
9.5 mg), 1,10ꢀphenanthroline (5.0 mmol, 9.0 mg) was added Hz), ꢀ117.33 (d, J = 300.80 Hz).
Dimethoxyethane (DME) (5.0 mL). The mixture was stirred at 80 3-(4-bromophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-1-
2
(1.5 mmol) and CuI (5% mmol, 28, 23 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ103.80 (d, J = 300.80
1
ºC under N2 for 10 hours. After completion of the reaction as one (3ag). White solid (known compound), H NMR (CDCl3, 400
indicated by TLC, the solvent was evaporated under reduced MHz) δ 8.07 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.47ꢀ
pressure. The residue was diluted with EtOAc (20 mL), washed 7.54 (m, 4H), 7.39 (d, J = 8.0 Hz, 2H), 5.37 (dt, J = 20.0, 4.0 Hz,
with saturated brine and NaHCO3, and then dried over anhydrous 1H), 3.39 (d, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
MgSO4. Evaporation of the solvent followed by purification on 190.68 (t, JC-F = 32.0 Hz), 134.84, 133.64, 132.11, 131.46, 130.30,
silica gel provided the corresponding product 3.
130.26, 129.83, 128.76, 115.11 (t, JC-F = 266 Hz), 72.67 (dd, JC-F =
28, 23 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ103.87 (d, J = 297.04
Hz), ꢀ117.11 (d, J = 297.04 Hz).
2,2-difluoro-3-hydroxy-3-(4-iodophenyl)-1-phenylpropan-1-
1
one (3ab). White solid, H NMR (CDCl3, 400 MHz): δ 8.08 (d, J =
2,2-difluoro-3-(furan-2-yl)-3-hydroxy-1-phenylpropan-1-one
8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (3ah). Pale yellow liquid (known compound), 1H NMR (CDCl3, 400
(t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 5.38 (dd, J = 20.0, 4.0 MHz) δ 8.07 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.47 (t, J =
Hz, 1H), 3.14 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 190.68 (t, JC-F 8.0 Hz, 2H), 7.42 (s, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.43 (dd, J =
= 32.0 Hz), 137.42, 134.84, 134.31, 132.11, 130.30, 130.00, 128.76, 16.0, 4.0 Hz, 1H), 3.28 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
115.26 (t, JC-F = 256 Hz), 95.08, 72.75 (dd, JC-F = 28, 23 Hz); 19F 190.02 (t, JC-F = 29.0 Hz), 148.41, 143.29, 134.68, 130.20, 130.17,
NMR (CDCl3, 376 MHz): δ ꢀ103.83 (d, J = 297.04 Hz), ꢀ116.34 (d, J 128.74, 115.52 (t, JC-F = 256 Hz), 110.71, 110.20, 68.15 (dd, JC-F
=
= 297.04 Hz); HRMS: cacld for C15H11F2IO2 [M+H]+ 387.9772; 25.0 Hz, 4.0 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ105.90 (d, J =
found 387.9766.
289.52 Hz), ꢀ113.58 (d, J = 289.52 Hz).
4-(2,2-difluoro-1-hydroxy-3-oxo-3-phenylpropyl)benzonitrile
2,2-difluoro-3-hydroxy-1-phenyl-3-(pyridin-4-yl)propan-1-one
1
(3ac). White solid, 1H NMR (CDCl3, 400 MHz) δ 8.07 (d, J = 8.0 Hz, (3ai). White solid, H NMR (CDCl3, 400 MHz) δ 8.48 (s, 2H), 8.10
2H), 7.28 (q, J = 8.0 Hz, 5H), 7.49 (t, J = 8.0 Hz, 2H), 5.47 (dd, J = (d, J = 8.0 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 4H),
20.0, 4.0 Hz, 1H), 3.49 (s, 1H); 13C NMR (CDCl3 100 MHz) δ 5.41 (dd, J = 20.0, 4.0 Hz, 1H) 13C NMR (CDCl3, 100 MHz) δ
;
190.68 (t, JC-F = 32.0 Hz), 140.04, 135.00, 131.95, 130.31, 130.28, 190.68 (JC-F = 32.0 Hz), 148.95, 145.58, 134.63, 132.54, 130.25,
128.95, 128.81, 118.54, 115.33 (t, JC-F = 256 Hz), 112.70, 72.42 (dd, 128.70, 123.28, 115.90 (t, JC-F = 266 Hz), 71.57 (dd, JC-F = 28, 23
JC-F = 28, 23 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ103.28 (d, J = Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ103.36 (d, J = 289.52 Hz), ꢀ
+
297.04 Hz), ꢀ116.16 (d, J = 297.04 Hz); HRMS: calcd for 116.10 (d, J = 289.52 Hz); HRMS: calcd for C14H12F2NO2 [M+H]
C16H12F2NO2 [M+H]+ 288.0836; found 288.0839.
264.0836; found 264.0838.
2,2-difluoro-3-hydroxy-3-(4-(methylthio)phenyl)-1-phenylpro-
3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxy-1-phenylpropan-
pan-1-one (3ad). Yellow solid, 1H NMR (CDCl3, 400 MHz) δ 8.06 1-one (3aj). White solid, H NMR (CDCl3, 400 MHz) δ 8.11 (d, J =
(d, J = 8.0 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 8.0 Hz, 2H), 7.63ꢀ7.68 (m, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.42 (s, 1H),
7.40 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.35 (dt, J = 20.0, 7.34 (d, J = 8.0 Hz, 1H), 5.96 (dd, J = 20.0, 4.0 Hz, 1H), 3.18 (d, J =
4.0 Hz, 1H), 3.01 (s, 1H), 2.49 (s, 3H); 13C NMR (CDCl3, 100 MHz) 4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 190.45 (t, JC-F = 29.0
δ 190.88 (t, JC-F = 32.0 Hz), 139.75, 134.64, 132.38, 131.35, 130.26, Hz), 135.47, 134.94, 134.65, 131.84, 131.45, 131.09, 130.35, 129.17,
1
128.69, 128.55, 126.14, 115.68 (t, JC-F = 256 Hz), 72.96 (dd, JC-F
=
128.81, 127.39, 115.50 (t, JC-F = 265 Hz), 68.52 (dd, JC-F = 29, 22
28, 23 Hz), 15.58; 19F NMR (CDCl3, 376 MHz): δ ꢀ104.34 (d, J = Hz). 19F NMR (CDCl3, 376MHz): δ ꢀ103.19 (d, J = 300.80 Hz), ꢀ
289.52 Hz), ꢀ116.10 (d, J = 289.52 Hz); HRMS: calcd for 117.56 (d, J = 300.80 Hz); HRMS: calcd for C15H11Cl2F2O2 [M+H] +
C16H15F2O2S [M+H]+ 309.0761; found 309.0770.
331.0104; found 331.0106.
Methyl-4-(2,2-difluoro-1-hydroxy-3-oxo-3-phenylpropyl)-
2,2-difluoro-3-hydroxy-1-(4-methoxyphenyl)-3-phenylpropan-
1
benzoate (3ae). White solid (known compound), H NMR (CDCl3, 1-one (3ka). White solid (known compound), 1H NMR (CDCl3, 400
400 MHz) δ 8.04ꢀ8.07 (m, 4H), 7.64 (t, J = 8.0 Hz, 1H), 7.57 (d, J = MHz) δ 8.07 (d, J = 8.0 Hz, 2H), 7.49ꢀ7.50 (m, 2H), 7.34ꢀ7.40
4 | J. Name., 2012, 00, 1-3
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Journal Name
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View Article OPnAliPneER
DOI: 10.1039/C7OB01739A
(m,3H), 6.91 (d, J = 12.0 Hz, 2H), 5.36 (dt, J = 20.0, 4.0 Hz, 1H), 4.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 188.82 (t, JC-F = 32.0 Hz),
3.87 (s, 3H), 3.22 (d, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 167.99 (d, JC-F = 257 Hz), 137.45, 134.21, 133.36, 129.97, 128.51,
δ 189.13 (t, JC-F = 29.0 Hz), 164.81, 134.85, 133.00, 132.96, 132.93, 116.25 (d, JC-F = 23 Hz), 115.33 (t, JC-F = 260 Hz), 95.41, 72.69 (dd,
128.17, 125.17, 115.86 (t, JC-F = 263 Hz), 114.02, 73.40 (dd, JC-F
=
JC-F = 28, 23 Hz); 19F NMR (CDCl3, 376MHz): δ ꢀ101.01, ꢀ103.63
28.0 Hz, 23.0 Hz), 55.60; 19F NMR (CDCl3, 376MHz): δ ꢀ103.68 (d, (d, J = 297.04 Hz), ꢀ116.19 (d, J = 297.04 Hz); HRMS: calcd for
J = 293.28 Hz), ꢀ115.50 (d, J = 293.28 Hz).
C15H11F3IO2 [M+ H]+, 406.9756; found 406.9755.
2,2-difluoro-3-hydroxy-3-phenyl-1-(p-tolyl)propan-1-one (3la).
3-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-1-(p-tolyl)propan-1-
White solid (known compound), 1H NMR (CDCl3, 400 MHz) δ 8.00 one (3lm). Colorless thick liquid, H NMR (CDCl3, 400 MHz) δ
(d, J = 8.0 Hz, 2H), 7.52ꢀ7.53 (m, 2H), 7.42ꢀ7.43 (s, 3H), 7.31 (d, J 7.98 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H), 7.29ꢀ7.36 (m, 5H), 5.36 (d, J =
= 8.0 Hz, 2H), 5.42 (dd, J = 20.0, 4.0 Hz, 1H), 3.14 (s, 1H), 2.45 (s, 16.0 Hz, 1H), 3.23 (s, 1H), 2.42 (s 3H); 13C NMR (CDCl3, 100 MHz)
3H); 13C NMR (CDCl3, 100 MHz) δ 190.46 (t, J = 32.0 Hz), 145.99, δ 190.49 (t, JC-F = 30.0 Hz), 146.25, 136.74, 134.28, 130.48, 129.50,
134.76, 130.45 (t, J = 3.0 Hz), 129.81, 129.43, 128.99, 128.29, 129.45, 129.09, 128.35, 126.38, 115.33 (t, JC-F = 260 Hz), 72.66 (dd,
128.16, 115.76 (t, JC-F = 255 Hz), 73.37 (dd, JC-F = 28.0 Hz, 23.0 JC-F = 28, 23 Hz), 21.88; 19F NMR (CDCl3, 376 MHz): δ ꢀ103.44 (d,
Hz), 21.87; 19F NMR (CDCl3, 376MHz): δ ꢀ104.12 (d, J = 293.28 J = 297.04 Hz), ꢀ116.28 (d, J = 297.04 Hz); HRMS: calcd for
1
Hz), ꢀ115.92 (d, J = 293.28 Hz).
C16H14ClF2O2 [M+H]+, 311.0650; found 311.0657.
1-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-3-phenylpropan-1-
1-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-3-(2-methoxyphenyl)
1
1
one (3ma). Colorless thick liquid, H NMR (CDCl3, 400 MHz) δ propan-1-one (3mo). Colorless thick liquid, H NMR (CDCl3, 400
7.92 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.50 ((d, J = 8.0 MHz) δ 7.98 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz,
Hz, 1H), 7.42 (s, 2H), 7.38ꢀ7.40 (m, 4H), 5.37 (dd, J = 20.0, 4.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.39 (d, J =
1H), 3.01 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 189.95 (JC-F
=
8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.63
29.0 Hz), 134.95, 134.52, 134.44, 134.03, 130.14, 129.96, 129.22, (dd, J = 16.0, 8.0 Hz, 1H), 3.70 (s, 1H); 13C NMR (CDCl3, 100 MHz)
128.40, 128.28, 128.07, 115.76 (JC-F = 256 Hz), 73.30 (dd, JC-F = 28, δ 189.37 (t, JC-F = 28.0 Hz), 157.32, 134.81, 134.42, 134.06, 130.34,
23 Hz); 19F NMR (CDCl3, 376MHz): δ ꢀ104.69 (d, J = 289.52 Hz), ꢀ 130.06, 129.86, 129.59, 128.14, 122.57, 121.08, 116.76 (t, JC-F = 265
116.10 (d, J = 289.52 Hz); HRMS: calcd for C15H12ClF2O2 [M+H]+, Hz), 114.27, 70.37 (dd, JC-F = 28.0 Hz, 23.0 Hz), 55.35; 19F NMR
297.0494; found 297.0487.
(CDCl3, 376 MHz): δ ꢀ106.78 (d, J = 270.72 Hz), ꢀ114.67 (d, J =
1-(4-bromophenyl)-2,2-difluoro-3-hydroxy-3-phenylpropan-1-
270.72 Hz); HRMS: calcd for C16H13ClF2O3 [M+H]+, 326.0521;
1
one (3ga). White solid, H NMR (CDCl3, 400 MHz) δ 7.99 (d, J = found 326.0528.
8.0 Hz, 2H), 7.39ꢀ7.49 (m, 7H), 6.92ꢀ6.98 (m, 3H), 5.37 (dt, J = 20.0,
4.0 Hz, 1H), 2.97 (d, J = 4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) Acknowledgements
δ 189.95 (JC-F = 29.0 Hz), 141.35, 134.55, 131.65, 130.80, 129.16,
129.07, 128.38, 128.08, 115.83 (t, JC-F = 262 Hz), 73.35 (dd, JC-F
=
We gratefully acknowledge the National Natural Science
28, 23 Hz); 19F NMR (CDCl3, 376MHz): δ ꢀ104.48 (d, J = 293.28 Foundation of China No. 21302042 and the Department of Henan
Hz), ꢀ116.02 (d, J = 293.28 Hz); HRMS: calcd for C15H12BrF2O2 Province Natural Science and Technology Foundation
[M+H]+, 340.9989; found 340.9984.
(No. 172102210225), Natural Science Foundation in Henan
Province Department of Education (No. 17A150005), the
1-(4-chlorophenyl)-2,2-difluoro-3-hydroxy-3-phenylpropan-1-
1
one (3na). White solid (known compound), H NMR (CDCl3, 400 Program for Innovative Research Team from Zhengzhou (No.
MHz) δ 7.91 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.48 (s, 131PCXTD605) and Project of Youth Backbone Teachers of
2H), 7.39ꢀ7.41 (m, 3H), 5.37 (dt, J = 20.0, 4.0 Hz, 1H), 2.97 (d, J = Henan University of Technology (2016003).
4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 190.14 (t, JC-F = 32.0
Hz), 134.52, 132.08, 131.62, 131.20, 130.07, 129.18, 128.39, 128.08, Notes and references
115.70 (t, JC-F = 262 Hz), 73.33 (dd, JC-F = 28, 23 Hz); 19F NMR
(CDCl3, 376 MHz): δ ꢀ104.55 (d, J = 289.52 Hz), ꢀ116.09 (d, J =
289.52 Hz).
1
(a) S. Purser, P. R. Moore, S. Swallow, V. Gouveneur, Chem. Soc.
Rev., 2008, 37, 320; (b) J. Wang, M. SánchezꢀRoselló, J. L. Aceña,
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4-(2,2-difluoro-3-hydroxy-3-phenylpropanoyl)benzonitrile (3ca).
White solid, 1H NMR (CDCl3, 400 MHz) δ 8.07 (d, J = 8.0 Hz, 2H),
7.62 (t, J = 8.0 Hz, 1H), 7.48ꢀ7.50 (m, 3H), 7.39ꢀ7.40 (m, 3H), 5.40
(dd, J = 20.0, 4.0 Hz, 1H), 3.05 (s, 1H); 13C NMR (CDCl3, 100MHz)
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128.67, 128.32, 128.13, 118.30, 115.75 (t, JC-F = 265 Hz) 73.37 (dd,
JC-F = 28, 23 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ104.37 (d, J =
293.28 Hz), ꢀ116.04 (d, J = 293.28 Hz). HRMS: calcd for
C16H12F2NO2 [M+H]+ 288.0836; found 288.0836.
2
(a) H. A. Schenck, P. W. Lenkowski, I. ChoudhuryꢀMukherjee, S. H.
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1
propan-1-one (3ob). White solid, H NMR (CDCl3, 400 MHz) δ
8.09ꢀ8.12 (m, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H),
7.16 (d, J = 8.0 Hz, 2H), 5.33 (dt, J = 20.0, 4.0 Hz, 1H), 3.11 (d, J =
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J. Name., 2012, 00, 1-3 | 5

Organic & Biomolecular Chemistry
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