A general, mild and efficient palladium-catalyzed 2,2,2-trifluoroethoxylation of activated aryl bromides and bromo-chalcones: Bromo-chalcones a new coupling partner in cross-coupling reaction

Article abstract of DOI:10.1016/j.tet.2015.08.071

An efficient protocol for Pd-catalyzed 2,2,2-trifluoroethoxylation of activated aryl bromides and bromo-chalcones has been developed. We unveil a fascinating insight into the Pd-catalyzed C-O cross-coupling reaction. Pd/tBuXPhos (L1) ligand system facilitates the C-O cross-coupling reaction between 2,2,2-trifluoroethanol and activated aryl bromides at both higher (115 °C) and lower temperatures (40 °C). Unprecedentedly, this catalyst system facilitates the C-O cross-coupling reaction in short span of reaction times, generally 5-25 min (at 115 °C). The structurally simple analogue of tBuXPhos ligand so called JohnPhos (L2) ligand is also facilitated the C-O bond formation with activated aryl bromides and bromo-chalcones. Interestingly, under the optimal conditions (L1), methanol is also coupled rapidly with activated aryl bromides. These catalyst systems (L1 and L2) fail to couple electron rich aryl bromides with 2,2,2-trifluoroethanol, thus these catalyst systems allow the reductive elimination through an electronic pathway of reductive elimination. The unusual reactivity of 2,2,2-trifluoroethanol in Pd-catalyzed C-O cross-coupling reaction makes that the chemistry of fluorinated molecules is unique than that of non-fluorinated analogues. The bromo-chalcones can be used as a new coupling partner in the cross-coupling reaction.

Full text of DOI:10.1016/j.tet.2015.08.071

Tetrahedron 71 (2015) 8307e8314
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A general, mild and efficient palladium-catalyzed
2,2,2-trifluoroethoxylation of activated aryl bromides and
bromo-chalcones: bromo-chalcones a new coupling partner in
cross-coupling reaction
, ,
,
*
T. M. Rangarajan a y, Kavita Devi b, Ayushee c, Ashok K. Prasad d, Rishi Pal Singh a
*
a Department of Chemistry, Sri Venkateswara College, University of Delhi, New Delhi, India
b Fluoroorganic Laboratory, Centre for Fire, Explosive and Environment Safety, DRDO, Delhi, India
c Department of Chemistry, Sri Guru Teg Bahadur Khalsa College, University of Delhi, India
d Department of Chemistry, University of Delhi, Delhi, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2015
Received in revised form 27 August 2015
Accepted 28 August 2015
Available online 1 September 2015
An efficient protocol for Pd-catalyzed 2,2,2-trifluoroethoxylation of activated aryl bromides and bromo-
chalcones has been developed. We unveil a fascinating insight into the Pd-catalyzed CeO cross-coupling
reaction. Pd/tBuXPhos (L1) ligand system facilitates the CeO cross-coupling reaction between 2,2,2-
trifluoroethanol and activated aryl bromides at both higher (115 ꢀC) and lower temperatures (40 ꢀC). Un-
precedentedly, this catalyst system facilitates the CeO cross-coupling reaction in short span of reaction
times, generally 5e25 min (at 115 ꢀC). The structurally simple analogue of tBuXPhos ligand so called John-
Phos (L2) ligand is also facilitated the CeO bond formation with activated aryl bromides and bromo-
chalcones. Interestingly, under the optimal conditions (L1), methanol is also coupled rapidly with acti-
vated aryl bromides. These catalyst systems (L1 and L2) fail to couple electron rich aryl bromides with 2,2,2-
trifluoroethanol, thus these catalyst systems allow the reductive elimination through an electronic pathway
of reductiveelimination. The unusual reactivity of 2,2,2-trifluoroethanol in Pd-catalyzed CeO cross-coupling
reaction makes thatthe chemistryof fluorinated molecules is unique than thatof non-fluorinated analogues.
The bromo-chalcones can be used as a new coupling partner in the cross-coupling reaction.
Keywords:
Pd-catalyzed C‒O coupling
Activated aryl bromides
Bromo-chalcones
Synthetic methods
2,2,2-Trifluoroethoxylation
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Dialkylbiaryl phosphine ligands, one of the important class of
phosphine ligands, developed by Buchwald group,3aee are excellent
In the past two decades, organic chemists have often been
buoyed by unimaginable reactions catalyzed by ‘heroic nature’ of
transition-metals that translated the classical way of thinking or-
ganic chemistry into more advanced level in all aspects of organic
synthesis.1 Transition-metal catalysts have now become an in-
dispensable ‘toolkit’ for organic chemists to do a startling chemis-
tries, especially, Pd and Cu catalyzed cross-coupling reactions play
a vital role in the modern organic synthesis.1n,2 The transition-
metal chemistries have become more popular and successful for
even difficult substrates or nucleophiles after the advent of various
structural derivatives of phosphours, and nitrogen based ligands.3
supporting or auxiliary ligands in Pd-catalyzed cross-coupling re-
actions for not only to couple CeC, CeN, CeO bonds etc.,3e,4 but also
to couple CeF, C‒CF3, C‒SCF3 bonds etc.5 Recently, it has been
demonstrated that the dialkylbiaryl phosphine ligand (BrettPhos)
has the property of altering the mechanistic pathway of reductive
elimination from nucleophile to nucleophile.6
It is important to note that the influence of fluorine on Pd-
catalyzed CeO bond formation has also been observed in our re-
cent studies. The catalytic activity of Pd/BrettPhos catalyst system
was entirely different for fluorinated and non-fluorinated alcohols.
This catalyst system could be coupled the fluorinated alcohols,
1H,1H-perfluoroalcohols, even up to C-9 carbon chain length6a al-
beit fluoroalcohols are week nucleophiles, whereas the catalytic
activity of Pd/BrettPhos system has dramatically dropped and fi-
nally become inactive when the chain length of the simple alkyl
alcohols (non-fluorinated alcohols) increases.6b Thus, the fluori-
nated molecules behave uniquely or differently with the non-
* Corresponding authors. E-mail addresses: rangarajan93150@gmail.com (T.M.
Rangarajan), rpsingh54@gmail.com (R. Pal Singh).
y
Present address: Center for Process Research and Innovations (CPRI), Dr. Reddy’s
Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad
500 046, Telangana, India.
http://dx.doi.org/10.1016/j.tet.2015.08.071
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

8308
T.M. Rangarajan et al. / Tetrahedron 71 (2015) 8307e8314
fluorinated analogues in both physico-chemical and biological
properties.
complete conversion even in short reaction time. Next, the effect of
Pd-sources on the reaction was examined using optimized base,
Cs2CO3. Among the Pd-sources, such as Pd(OAc)2 (entry 7), Pd(PPh3)4
(entry 8), and Pd(PPh3)2Cl2 (entry 9) with 0.5 mol %, only Pd(OAc)2
gave the desired product in almost same yield (84%) with complete
conversion as in the case of [Pd2(dba)3], but the reaction time was
relatively toolong, 9.0 h. The otherPd-sources, such asPd(PPh3)4, and
Pd(PPh3)2Cl2 also gave the desired product in moderate yields (70%)
with almost complete conversion for over about 22 h. As a result,
[Pd2(dba)3]/tBuXPhos ligand (L1) system and Cs2CO3 effected the
reaction efficiently in short reaction time at 85 ꢀC. This result reveals
that the rate and activity of the catalytic cycle depends solely on the
Pd-source for a given ligand and reaction conditions.
We further reduced the catalyst loading of [Pd2(dba)3] from
0.5 mol % to 0.25 mol % and finally to 0.1 mol %. At reduced catalyst
loading, 0.25 mol % (entry 10), no catalytic activity was reduced
with respect of yield, and conversion. At low catalyst loading
0.1 mol % (entry 11), the efficiency of catalytic system was dropped
considerably and the product obtained was only 67% over 22 h.
Under the optimized reaction conditions, 0.25 mol % of [Pd2(dba)3],
0.625 mol % of tBuXPhos, and 1.5 equiv of Cs2CO3 in toluene, the
reaction was carried out at higher temperature, 115 ꢀC. Surprisingly,
the reaction was completed in 8.0 min (entry 12) without appre-
ciable change in the yield of the product. At the same time, the
reaction at low temperature, 45 ꢀC (entry 13), using 0.5 mol % of
[Pd2(dba)3] afforded the desired product of about 89% yield over
19 h. At very low temperature, 20 ꢀC (entry 14), the catalytic system
was ineffective and did not give the product at all.
Having the bizarre behavior of fluorine and its astonishing results
that emerged from the experiments, the fluorine chemistry has been
burgeoned as a special topic of interest among the chemists for more
than three decades.7 A remarkable growth in fluorine chemistry has
been realized as the chemists practiced to do polishing the physico-
chemical properties of organic molecules with fluorine, leading to
widespread applications in various field of applications.8
Herein, we report a general, mild and efficient Pd-catalyzed CeO
bond-forming reaction of activated aryl bromides and bromo-
chalcones9 with 2,2,2-trifluoroethanol. We also report the excep-
tional reactivity of 2,2,2-trifluoroethanol in CeO bond-forming re-
action and the ligands property in reductive elimination mechanism.
2. Results and discussion
2.1. Optimization of reaction conditions
InFurtheranceofourpreviousstudies, wewerepleased to explore
the ligands property in reductive elimination and effect of fluorine on
CeO bond formation by a pair of structurally related ligands, tBuX-
Phos (L1) and JohnPhos (L2). We started the optimization of 2,2,2-
trifluoroethoxylation with 4-bromoacetophenone, as a model sub-
strate, using tBuXPhos ligand (L1) under different experimental
conditions in an unique solvent, toluene. The results of optimization
are given in Table 1. The model reaction was carried out in the pres-
ence of 0.5 mol % [Pd2(dba)3] (dba¼dibenzylideneacetone), 1.25 mol
% of tBuXPhos ligand (L1) in toluene at 85 ꢀC by varying the bases,
such as tBuONa, K3PO4, KOH, Et3N, K2CO3 and Cs2CO3. The bases, such
as tBuONa, KOH and Cs2CO3 (entries 1, 3, and 6) effected the reaction
with complete conversions and the yields are about 36%, 57% and87%
respectively within short reaction times of about 25 min. Other bases
such as K3PO4 and K2CO3 (entries 2, and 5) also effected the reaction
in almost the same reaction times (9.0 h) and yields (60%) with
complete conversions. The organic base, Et3N (entry 4), failed to give
even a trace of product for over an 8.0 h reaction time. Of the bases
used only Cs2CO3 effected the transformation in good yield with
Under the optimized reaction conditions, the model reaction
was carried out with 0.5 mol % of [Pd2(dba)3] and JohnPhos ligand10
(L2) (in place of tBuXPhos), the desired product was obtained in
excellent yield of about 93% with complete conversion in 50 min
(Table 2).
Table 2
Optimization of the reaction conditions with JohnPhos ligand (L2)a
Entry
Pd source
Pd. (mol %)
Time (h)
Conv. (%)b
Yield (%)c
Table 1
1
2
3
4
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
0.5
1.0
0.25
0.5
0.83
8.0
1.0
16
100
100
100
90
93
78
77
49d
Optimization of the reaction conditionsa
a
4-Bromoacetophenone (1.0 mmol), 2,2,2-trifluoroethanol (2.0 mmol), base
(1.5 mmol), JohnPhos L2 (2.5 mol % w.r.t. Pd sources), toluene (1.5 ml), temperature
85 ꢀC.
Entry Pd source
Pd. (mol %) Base
Time (h) Conv. (%)b Yield (%)c
b
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
tBuONa
K3PO4
KOH
0.42
9.0
100
100
100
ND
36
62
57
NR
60
87
84
73
68
87
67
83d
89e
NRf
Based on starting material recovered.
Isolated yield.
Reaction temperature 40 ꢀC.
c
d
0.33
8.0
Et3N
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8.5
0.33
9.0
100
100
100
97
From these results it is clear that the rate and activity of the
catalytic cycle rely on the structure of ligands for a given Pd-source
and reaction conditions. Then the use of Pd(OAc)2 in the reaction,
the desired product was obtained in about 78% yield over 8.0 h.
When the catalyst loading, [Pd2(dba)3], was reduced from 0.5 mol %
to 0.25 mol %, the yield of the product was also reduced to 77%. The
reaction at low temperature, 40 ꢀC, over 16 h was not successful
with JohnPhos ligand (L2).
23
9
Pd(PPh3)2Cl2 0.5
22
0.40
24
100
100
98
10
11
12
13
14
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
0.25
0.1
0.25
0.5
0.25
0.133
19.0
20
100
100
ND
NDenot determined. NReno reaction.
a
4-Bromoacetophenone (1.0 mmol), 2,2,2-trifluoroethanol (2.0 mmol), base
(1.5 mmol), tBuXPhos L1 (2.5 mol % w.r.t. Pd sources), toluene (1.5 ml), reaction
temperature 85 ꢀC.
2.2. Ligands property in reductive elimination pathway
b
Based on starting material recovered.
c
Isolated yield.
Next, we examined the property of tBuXPhos and JohnPhos li-
gands in steric pathway of reductive elimination6a by 2,2,2-
trifluoroethoxylation with two different electron-rich aryl bromides.
d
Temperature, 115 ꢀC.
e
Temperature, 45 ꢀC and reaction time not optimized.
f
Temperature 20 ꢀC.

T.M. Rangarajan et al. / Tetrahedron 71 (2015) 8307e8314
8309
Table 5
We carried out the CeO bond-forming reaction between 2,2,2-
Pd-catalyzed coupling of activated aryl bromides with 2,2,2-trifluoroethanola
trifluoroethanol and 1-bromo-4-tbutylbenzene under optimized
reaction conditions with different Pd-sources of high catalyst
loadings (2.0 mol %) and ligands (L1 and L2). Both the ligands with
Pd-sources, such as Pd(OAc)2, [(allylPdCl)2] and [Pd2(dba)3], did not
give the desired product at all (Table 3). However, we carried out
the same reaction with 4-bromoanisole even under reported ex-
perimental conditions,4a,11a the reaction was unsuccessful (Table 4).
However, the tBuXPhos ligand was successful in the Pd-catalyzed
methoxylation and deuteriomethoxylation of (het.)aryl halides of
different electronic nature.4a,11a,b These experiments suggest that
the phosphine ligand possesses the property of altering the
mechanistic pathway of reductive elimination from nucleophile to
nucleophile as reported in our recent publications.6
Entry
Product
Pd (mol %)/L
Time (h)
Yield (%)b
1
2
[0.25]/L1
[0.5]/L2
0.133d
0.83c
83
93
Table 3
3
4
5
[0.25]/L1
[0.25]/L1
[0.5]/L2
0.133d
22e
77
70
69
2,2,2-Trifluoroethoxylation of 1-bromo-4-tbutylbenzene under optimized reaction
conditionsa
1.0c
6
7
8
[0.25]/L1
[0.25]/L1
[0.5]/L2
0.30d
17f
74
65
78
Entry
Pd source
Pd. (mol %)
Time (h)
Yield (%)
1.5c
1
2
3
4
5
Pd(OAc)2
[(AllylPdCl)2]
Pd2(dba)3
Pd2(dba)3
[(AllylPdCl)2]
2.0
2.0
2.0
2.0
2.0
17
17
16
17
17
NR
NR
9
[0.5]/L2
1.0c
73
NR
NRb
NRb
10
11
12
[0.25]/L1
[0.25]/L1
[0.5]/L2
0.28d
25e
82
76
86
NReno reaction.
1.5c
a
1-Bromo-4-tbutylbenzene (0.61 mmol), 2,2,2-trifluoroethanol (2.0 equiv),
Cs2CO3 (1.5 equiv), tBuXPhos L1 (4.4 mol %), toluene (2.5 ml), temperature 85 ꢀC.
a
Aryl bromides (1.0 mmol), 2,2,2-trifluoroethanol (1.5 mmol), Cs2CO3 (1.5 mmol),
ligands, L1 & L2 (2.5 mol % w.r.t Pd catalyst), toluene (1.5 ml), Ar atm.
b
JohnPhos L2 (4.4 mol %).
b
Isolated yield.
c
Temperature 85 ꢀC.
Table 4
d
Temperature 115 ꢀC.
2,2,2-Trifluoroethoxylation of 4-bromoanisole under reported experimental
conditions
e
Temperature 40 ꢀC.
f
Temperature 60 ꢀC.
Entry
Pd source
Pd. (mol %)/L
Time [h]
Yield [%]
Ref.
substrates, such as 4-bromobenzonitrile, 4-bromobenzaldehyde, 1-
bromo-4-nitrobenzene and 4-bromobenzophenone gave the de-
sired products 2, 3, 4, and 5 in moderate to good yields in relatively
long reaction times (entries 5, 8, 9 and 12).
1a
2b
3a
4b
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
3.0/L1
1.0/L1
3.0/L2
1.0/L2
17
17
17
17
NR
NR
NR
NR
11a
4a
11a
4a
Finally, under optimized reaction conditions, we carried out the
CeO bond formation between activated aryl bromides with non-
fluorinated alcohols, methanol and ethanol, to discern the prop-
erty of the Pd/ligand catalyst systems and effect of fluorinated
molecules in the CeO cross-coupling reaction. More surprisingly,
the coupling of methanol with activated aryl bromides,4a,11 by Pd/
tBuXPhos catalyst system, was completed in few minutes with
moderate to good yields (Table 6). The desired products 6, 8, 9, and
10 were obtained in few minutes with the yields are about 79%,
85%, 86%, and 90% respectively, whereas the coupling of 2,2,2-
NReno reaction.
a
Reported reaction conditions: 4-bromoanisole (0.56 mmol), 2,2,2-
trifluoroethanol (0.75 ml), Cs2CO3 (1.5 equiv), L1 or L2, (6.0 mol %), toluene
(0.75 ml), temperature 85 ꢀC.
b
4-bromoanisole (0.56 mmol), 2,2,2-trifluoroethanol (5.0 equiv), tBuONa
(1.5 equiv), L1 or L2, (4.0 mol %), 1,4-dioxane, (1.5 ml), temperature 85 ꢀC.
2.3. Rapid CeO bond formation of activated aryl bromides
We also explored the reactions to other activated aryl bromides
using both the ligands (L1 and L2). The results are summarized in
Table 5. The ligand (L1) showed the highest catalytic activity with
[Pd2(dba)3]. This is the first example of tBuXPhos ligand (L1) that
facilitates the CeO bond formation at lower temperature, which has
not yet been reported.4a,11a,b It is appealing that at a high temperature
(115 ꢀC), the Pd/tBuXPhos ligand (L1) system gave the desired
products 2, 3, and 5 in few minutes (rapid reductive elimination)12 by
the reaction of 2,2,2-trifluoroethanol with corresponding aryl bro-
mides (entries 3, 6 and 10). At lower temperature (40 ꢀC), Pd/tBuX-
Phos ligand (L1) system gave the desired products 2, 3, and 5 with
slightly lower in yields (entries 4, 7 and 11) when compared with
those at high temperature (115 ꢀC). The ligand (L2) afforded the de-
sired product 1 in excellent yield, 93%, with 0.5 mol % catalyst loading
and short reaction time (50 min) at 85 ꢀC (entry 1). While with other
trifluoroethanol,
CF3-substituted
methanol,
with
4-bro
moacetophenone, (Table 1, entry 6) under identical conditions,
gave the desired product in relatively longer reaction time, 20 min.
This result suggests that the sensitivity of the reaction by the Pd/
tBuXPhos ligand catalyst system relies more on the nucleophilic
character of the alcohols than acidity of the alcohols.6b It is also
necessary to emphasize that S. Peruncheralathan11a and G. L. Tol-
nai11b methods (Scheme 1) consisting of methoxylation and deu-
teriomethoxylation of activated aryl bromides by Pd/tBuXPhos
catalyst system with high catalyst loading, large excess of alcohol,
and relatively longer reaction time over against the present
method. However, the reported methods were successful with
deactivated and hetero aryl halides but the present method is un-
successful with deactivated aryl bromides (Tables 3 and 4). This
result reveals that the slight change in the reaction conditions may

8310
T.M. Rangarajan et al. / Tetrahedron 71 (2015) 8307e8314
chalcone).6 Under similar reaction conditions, we explored the
2,2,2-trifluoroethoxylation of various bromo-chalcones, due to the
fluorinated organic compounds and chalcones have received
greater interest in medicinal and applied chemistry. The results are
summarized in Table 7. Both the ligands, such as tBuXPhos (L1), and
JohnPhos (L2), were effective towards the coupling of 2,2,2-
triflluoroethanol with (E)-1-substituted-3-(4-bromophenyl)-prop-
2-en-1-ones, bearing substituents, such as (E)-1-phenyl-, (E)-1-(p-
tolyl)-, (E)-1-(4-fluorophenyl)-, (E)-1-(naphthalen-1-yl)-, and (E)-
1-(2-methoxyphenyl)- gave the desired 2,2,2-trifluoroethoxylated
products 11, 12, 15, 21, and 22 respectively in moderate to excel-
lent yields. Similarly, (E)-3-substituted-1-(4-bromophenyl)prop-2-
en-1-ones, such as (E)-3-(p-tolyl)-, (E)-3-(3,4,5-trimethoxyphenyl)-,
(E)-3-(4-fluorophenyl)-, (E)-3-(4-(benzyloxy)phenyl)-, (E)-3-(fu-
ran-2-yl)-, (E)-3-(3-nitrophenyl)-, and (E)-3-(2,5-dimethoxy
phenyl)- gave the 2,2,2-trifluoroethoxylated products 13, 14, 16,
17, 19, 20, and 23 respectively in fair to good yields. The chalcone of
(E)-1,3-bis(4-bromophenyl)prop-2-en-1-one, proceeded 2,2,2-
trifluoro-ethoxylation smoothly at both the positions gave (E)-
1,3-bis(4 -(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one 18 in 84%
yield with L1. 3-Bromosubstituted chalcone, (E)-3-(p-tolyl)-1-(3-
bromophenyl)prop-2-en-1-one did not give any coupling product
24 with 2,2,2-trifluoroethanol.
Table 6
Pd-catalyzed coupling of activated aryl bromides with alkyl alcoholsa
Entry
Product
R
L
Time (h)
Yield (%)b
1
2
6, Me
7, Et
L1
L1
0.12
21
79
28
3
8, Me
9, Me
L1
0.083
85
4
5
L1
L2
0.12
17
86
40
6
10, Me
L1
0.42
90
a
Aryl bromides (1.0 mmol), methanol (3.0 mmol) or ethanol (1.5 mmol), Cs2CO3
(1.5 mmol), [Pd2(dba)3] (0.5 mol %), ligands L1 & L2 (1.25 mol %), toluene (1.5 ml), Ar
atm.
b
Isolated yield.
lead to a profound effect on the catalytic activity and mechanism of
reductive elimination. When the non-fluorinated alcohol, ethanol,
used for the coupling of 4-bromoacetophenone under identical
conditions, the reaction gave the desired product 7 in 28% yield and
95% conversion over 21 h. Moreover, the coupling of 4-
bromobenzophenone with methanol by Pd/JohnPhos catalyst sys-
tem, gave the desired products 9 in about 40% yield with the con-
version of 60% over 17 h. However, these catalyst systems could
able to couple 2,2,2-trifluoroethanol successfully with activated
aryl bromides. This result implies that the fluorinated alcohols
cannot be treated as non-fluorinated alcohols.7 This is the first
example of rapid palladium-catalyzed CeO bond formation of ac-
tivated aryl bromides with weak nucleophilic alcohols, reported as
yet.4a,10,11,13 As a result, the rapid CeO bond formation strongly
suggests that the property of the ligand that allows to occur re-
ductive elimination through an electronic pathway of reductive
3. Conclusions
In summary, we have devised an efficient methodology to
couple 2,2,2-trifluoroethanol and methanol with activated aryl
bromides in short reaction times. This methodology may be useful
in the radio-labeling of 13C or 18F radionucleides into organic
molecules for PET imaging purpose. These ligand catalyst systems
possess a property of allowing the reductive elimination only
through an electronic pathway thus these catalyst system could
couple 2,2,2-trifluoroethanol with activated aryl bromides and
failed to couple 2,2,2-trifluoroethanol with deactivated aryl bro-
mides. We have demonstrated an exceptional reactivity of 2,2,2-
trifluoroethanol in Pd-chemistry that suggests the chemistry of
non-fluorinated molecules cannot be simply translated into that of
fluorinated molecules. We found that the sensitivity of the reaction
by the Pd/tBuXPhos (L1) ligand catalyst system relies more on the
nucleophilic character of alcohol. On the other hand, the reverse is
true for the Pd/JohnPhos (L2) ligand catalyst system as it failed to
couple alkyl alcohols. We also found that slight change in the re-
action conditions leads to a profound effects on the reactivity and
mechanism of reductive elimination. We have extended the utility
of the catalyst system to bromo-chalcones, under identical condi-
tions, as a new coupling partner in the cross-coupling reaction.
elimination, which proceeds through
Meisenheimer-type transition state by an electron withdrawing
group at p-position of the Pd-bound aryl group.
a resonance stabilized
4. Experimental
Scheme 1. Pd-catalyzed methoxylation/deuteriomethoxylation of activated aryl bro-
mides by Pd/tBuXPhos.
4.1. General considerations
All biaryl phosphine ligands, [Pd2(dba)3], Pd(OAc)2, [(p-
2.4. Bromo-chalcones a new coupling partner in the cross-
coupling reaction
allylPdCl)2], Pd(PPh3)4, Pd(PPh)2Cl2, 2,2,2-trifluoroethanol, 4-
bromobenzophenone and K3PO4 were purchased from Sigmae
Aldrich and Sterm Chemicals. Dry anhydrous toluene and Cs2CO3
were purchased from Spectrochem Pvt. Ltd., India and purged with
nitrogen after every use. All other aryl bromides and other common
reagents were used as received from Spectrochem Pvt. Ltd., India.
Chalcones were prepared by base (KOH) catalyzed condensation
reaction, reported elsewhere in the literature, of acetophenones
with aldehydes. Products were purified by flash chromatography
on silica gel (230e400 mesh). Reactions were monitored by thin
layer chromatography (TLC) on pre-coated silica gel (Merck silica
gel 60, F254) plates and visualized under UV light.
Based on few examples given in the previous publications,6 we
are delighted to introduce bromo-chalcones as a new coupling
partner in the CeO cross-coupling reactions with 2,2,2-
trifluoroethanol.9 We also intended to demonstrate that those Pd/
L catalyst systems, facilitate the CeO bond-forming reaction only
with activated aryl halides through an electronic pathway of re-
ductive elimination, can also be used in the CeO bond-forming
reaction with relatively high molecular weight compounds (mac-
romolecules) having extended resonance conjugation (bromo-

T.M. Rangarajan et al. / Tetrahedron 71 (2015) 8307e8314
8311
Table 7
Palladium-catalyzed 2,2,2-trifluoroethoxylation of bromo-chalconesa,b
(L1, 72%, 2.5 h)
(L2, 78%, 16 hb,d
(L2, 94%, 17 hb,d
)
(L1, 73%, 4.0 h)
)
(L1, 85%, 1.5 h)
(L1, 77%, 17 hd)
(L1, 81%, 17 hd)
(L1, 81%, 1.5 h)
(L1, 74%, 16 hd)
(L1, 84%, 17 hc,d
)
(L2, 78%, 16 hb,d
)
(L1, 76%, 17 hd)
(L2, 66%, 17 hb,d
(L2, 66%, 17 hb,d
)
(L1, 43%, 16 hd)
)
(L1, 51%, 17 hd)
Bromo-chalcones (1.0 mmol), 2,2,2-trifluoroethanol (1.5 mmol), Cs2CO3 (1.5 mmol), Pd2(dba)3 (0.25 mol%), tBuXPhos (L1)
(L1, 0%, 16 h)
a
b
(0.625 mol%), toluene (3.0 ml), Ar atm. Bromo-chalcones (1.0 mmol), 2,2,2-trifluoroethanol (1.5 mmol), Cs2CO3 (1.5 mmol),
Pd2(dba)3 (0.5 mol%), JohnPhos (L2) (1.25 mol%), toluene (3.0 ml), Ar atm. c Dibromo-chalcone (1.0 mmol), 2,2,2-trifluoroethanol
d
(3.0 mmol), Cs2CO3 (3.0 mmol), Pd2(dba)3 (0.5 mol%), tBuXPhos (L1) (1.25 mol%), toluene (3.0 ml), Ar atm. Isolated yield;
reaction time not optimized.
4.2. Analytical methods
gun under vacuum. The R.B. flask was allowed to cool under argon
atmosphere. Activated aryl bromides or bromo-chalcones,
[Pd2(dba)3] and ligands (L1 or L2) were added in quick succes-
sion. The flask was then flushed with argon repeatedly for three
times. To this, 1.5 ml or 3.0 ml of anhydrous toluene was added via
syringe and again the flask was flushed with argon for three times.
2,2,2-Trifluoroethanol was added to the reaction mixture via sy-
ringe and the flask was placed in a pre-heated oil bath at a tem-
perature mentioned in the tables. The reaction mixture was stirred
vigorously until completion of the reaction as indicated by TLC
analysis. The reaction mixture was allowed to cool to room tem-
perature and passed through a short silica (230e400 mesh size)
column eluted with chloroform under N2 pressure. The solvent
removal under reduced pressure afforded the desired compounds
with sufficient purity as a yellow oil or solid. If necessary, the
compound was further purified by column chromatography on
silica gel using 2% ethyl acetate in hexane as eluent.
NMR data were obtained on Jeol 400 MHz spectrometers. All
compounds were characterized by 1H, 13C, 19F NMR (399.78 MHz,
100.5 MHz, 376.17 MHz respectively), IR, and HRMS. Copies of 1H,
13C and 19F NMR spectra can be found at the end of the
Supplementary data. All 1H and 13C chemical shifts are reported in
parts per million (ppm) and were measured relative to TMS or
residual deuterated CDCl3 as solvent. 19F NMR signals are reported
in ppm unit and were referenced to CFCl3 as external reference.
FTIR spectra were recorded on PerkineElmer model RXI using KBr
disc. HRMS (ESI) measurements were performed on Thermo Sci-
entific Orbitrap Elite Hybrid Ion Trap-Orbitrap Mass Spectrometer.
Yields referred to isolated compounds.
4.3. General procedure for the palladium-catalyzed 2,2,2-
trifluoroethoxylation of activated aryl bromides and bromo-
chalcones
4.3.1. (E)-1-Phenyl-3-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-
one (11). The general procedure described above was followed to
get the title compound from (E)-3-(4-bromophenyl)-1-phenylprop-
An oven dried 5.0 ml two-neck round bottomed flask was
equipped with a magnetic stir bar, a rubber septum, condenser and
an argon balloon on the top of the condenser with the aid of an
adaptor. The flask was charged with Cs2CO3 and dried with hot air
2-en-1-one (287 mg, 1.0 mmol), 2,2,2-trifluoroethanol (110
mL,
1.52 mmol), Cs2CO3 (489 mg,1.5 mmol), Pd2(dba)3 (2.3 mg, 0.25 mol

8312
T.M. Rangarajan et al. / Tetrahedron 71 (2015) 8307e8314
%), tBuXPhos (L1) (2.6 mg, 0.625 mol %), with toluene as solvent
(3.0 ml) were heated at 90 ꢀC for 2.5 h. The crude reaction mixture
was filtered through a short silica (230e400 mesh) column using
chloroform to afford the title compound as a yellow solid (219 mg,
filtered through a short silica (230e400 mesh) column using
chloroform to afford the title compound as a yellow solid (304 mg,
77% yield): Mp: 114e118 ꢀC; 1H NMR (400 MHz, CDCl3)
d/ppm: 3.90
(s, 3H), 3.92 (s, 6H), 4.44 (q, 2H, 3J¼8.0 Hz), 6.86 (s, 2H), 7.04 (d, 2H,
72% yield): Mp: 110e113 ꢀC; 1H NMR (400 MHz, CDCl3)
d/ppm: 4.40
3J¼8.5 Hz) 7.39 (d, 1H, 3J¼15.4 Hz), 7.72 (d, 1H, 3J¼15.6 Hz), 8.05 (d,
(q, 2H, 3J¼8.0 Hz), 6.99 (d, 2H, 3J¼8.4 Hz), 7.45 (d,1H, 3J¼15.6 Hz) 7.51
2H, 3J¼8.6 Hz); 13C NMR (100 MHz, CDCl3)
d/ppm: 56.36, 61.14,
65.69 (q, JCeF¼36.35 Hz), 105.80, 114.72, 121.10, 130.51, 131.01,
(m, 2H), 7.59 (m,1H), 7.64 (d, 2H, 3J¼8.5 Hz), 7.78 (d,1H, 3J¼15.7 Hz),
2
8.02 (d, 2H, 3J¼7.7 Hz); 13C NMR (100 MHz, CDCl3)
d
/ppm: 65.60 (q,
132.90, 140.59, 144.92,153.64,160.81,188.78; 19F NMR (376.17 MHz,
2JCeF¼35.8 Hz),115.37,120.99,128.59,128.76,129.53,130.40,132.89,
CDCl3)
d
/ppm: ꢁ73.66 (t, 3J¼8.2 Hz); IR (KBr)
¼3006, 2976, 2949,
n
138.41, 144.06, 159.14, 190.58; 19F NMR (376.17 MHz, CDCl3)
d
/ppm:
2842, 1660, 1609, 1583, 1508, 1455, 1419, 1327, 1282, 1250, 1215,
1174,1151,1132,1071,1031, 996, 976, 870, 817, 672, 632 cmꢁ1; HRMS
(ESI) calcd for C20H19F3O5: [MþH]þ 397.1263, [MþNa]þ 419.1082;
found: 397.1253, 419.1072.
ꢁ73.75 (t, 3F, 3J¼8.7 Hz); IR (KBr)
¼3061, 2918, 2849, 1656, 1602,
n
1574, 1512, 1460, 1450, 1425, 1294, 1245, 1219, 1171, 1074, 1064, 1017,
976, 864, 825, 778, 721, 690 cmꢁ1; HRMS (ESI) calcd for C17H13F3O2:
[MþH]þ 307.0946, [MþNa]þ 329.0765; found: 307.0936, 329.0755.
4.3.5. (E)-1-(4-Fluorophenyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)
prop-2-en-1-one (15). The general procedure described above was
followed to get the title compound from (E)-3-(4-bromophenyl)-1-
(4-fluorophenyl)prop-2-en-1-one (305 mg, 1.0 mmol), 2,2,2-
4.3.2. (E)-1-(p-Tolyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-
1-one (12). The general procedure described above was followed to
get the title compound from (E)-3-(4-bromophenyl)-1-(p-tolyl)
prop-2-en-1-one (301 mg, 1.0 mmol), 2,2,2-trifluoroethanol
trifluoro-ethanol (110 mL, 1.52 mmol), Cs2CO3 (489 mg, 1.5 mmol),
(110
m
L, 1.52 mmol), Cs2CO3 (489 mg, 1.5 mmol), Pd2(dba)3
Pd2(dba)3 (2.3 mg, 0.25 mol %), tBuXPhos (L1) (2.6 mg, 0.625 mol %),
(4.6 mg, 0.5 mol %), JohnPhos (L2) (3.7 mg, 1.25 mol %), with toluene
as solvent (3.0 ml) were heated at 90 ꢀC for 17 h. The crude reaction
mixture was filtered through a short silica (230e400 mesh) column
using chloroform to afford the title compound as a yellow solid
with toluene as solvent (3.0 ml) were heated at 90 ꢀC for 1.5 h. The
crude reaction mixture was filtered through
a short silica
(230e400 mesh) column using chloroform to afford the title
compound as a yellow crystalline solid (275 mg, 85% yield): Mp:
(302 mg, 94% yield): Mp: 125e128 ꢀC; 1H NMR (400 MHz, CDCl3)
d/
129e132 ꢀC; 1H NMR (400 MHz, CDCl3)
d/ppm: 4.40 (q, 2H,
ppm: 2.44 (s, 3H), 4.40 (q, 2H, 3J¼8.0 Hz), 6.98 (d, 2H, 3J¼8.5 Hz),
3J¼8.0 Hz), 6.99 (d, 2H, 3J¼8.4 Hz), 7.18 (t, 2H, 3J¼8.4 Hz) 7.42 (d, 1H,
7.30 (d, 2H, 3J¼8.2 Hz) 7.45 (d, 1H, 3J¼15.6 Hz), 7.63 (d, 2H,
3J¼15.6 Hz), 7.63 (d, 2H, 3J¼8.4 Hz), 7.78 (d,1H, 3J¼15.7 Hz), 8.05 (m,
3J¼8.5 Hz), 7.77 (d, 1H, 3J¼15.6 Hz), 7.93 (d, 2H, 3J¼8.0 Hz); 13C NMR
2H); 13C NMR (100 MHz, CDCl3)
d
/ppm: 65.80 (q, JCeF¼35.9 Hz),
2
2
2
(100 MHz, CDCl3)
d
/ppm: 21.82, 65.81 (q, JCeF¼35.3 Hz), 115.37,
115.41, 115.89 (d, JCeF¼22.0 Hz), 120.50, 129.43, 130.44, 131.18 (d,
1
121.05, 128.75, 129.48, 129.69, 130.34, 135.84, 143.61, 143.76, 159.07,
3JCeF¼9.2 Hz), 134.74, 144.29, 159.24, 165.74 (d, JCeF¼255 Hz),
190.06; 19F NMR (376.17 MHz, CDCl3)
d
/ppm: ꢁ73.89 (t, 3F,
188.89; 19F NMR (376.17 MHz, CDCl3)
d
/ppm: ꢁ73.70, (t, 3F,
3J¼7.7 Hz); IR (KBr)
n
¼3059, 3037, 2945, 2920, 1662, 1601, 1579,
3J¼7.9 Hz), 105.52 (s, 1F); IR (KBr)
¼2955, 1667, 1613, 1580, 1513,
n
1512, 1459, 1423, 1341, 1290, 1246, 1222, 1177, 1154, 1082, 1034, 972,
862, 807, 666 cmꢁ1; HRMS (ESI) calcd for C18H15F3O2: [MþH]þ
321.1102, [MþNa]þ 343.0922; found: 321.1094, 343.0913.
1461, 1435, 1286, 1248, 1219, 1180, 1157, 1082, 1033, 974, 864, 827,
810, 667 cmꢁ1; HRMS (ESI) calcd for C17H12F4O2: [MþH]þ 325.0852,
[MþNa]þ 347.0671; found: 325.0843, 347.0662.
4.3.3. (E)-3-(p-Tolyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-
1-one (13). The general procedure described above was followed to
get the title compound from (E)-1-(4-bromophenyl)-3-(p-tolyl)
prop-2-en-1-one (301 mg, 1.0 mmol), 2,2,2-trifluoroethanol
4.3.6. (E)-3-(4-Fluorophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)
prop-2-en-1-one (16). The general procedure described above was
followed to get the title compound from (E)-1-(4-bromophenyl)-3-(4-
fluorophenyl)prop-2-en-1-one (305 mg, 1.0 mmol), 2,2,2-trifluoro-
(110
mL, 1.52 mmol), Cs2CO3 (489 mg, 1.5 mmol), Pd2(dba)3
ethanol (110 mL, 1.52 mmol), Cs2CO3 (489 mg, 1.5 mmol), Pd2(dba)3
(2.3 mg, 0.25 mol %), tBuXPhos (L1) (2.6 mg, 0.625 mol %), with
(2.3 mg, 0.25 mol %), tBuXPhos (L1) (2.6 mg, 0.625 mol %), with toluene
as solvent (3.0 ml) were heated at 90 ꢀC for 1.5 h. The crude reaction
mixture was filtered through a short silica (230e400 mesh) column
using chloroform to afford the title compound as a yellow solid
toluene as solvent (3.0 ml) were heated at 90 ꢀC for 4 h. The crude
reaction mixture was filtered through
a
short silica
(230e400 mesh) column using chloroform to afford the title
compound as a yellow crystalline solid (232 mg, 73% yield): Mp:
(262 mg, 81% yield): Mp: 112e115 ꢀC; 1H NMR (400 MHz, CDCl3)
d/
148e151 ꢀC; 1H NMR (400 MHz, CDCl3)
d
/ppm: 2.40 (s, 3H), 4.44 (q,
ppm: 4.44 (q, 2H, 3J¼8.0 Hz), 7.04 (d, 2H, 3J¼8.4 Hz), 7.12 (t, 2H,
2H, 3J¼7.9 Hz), 7.04 (d, 2H, 3J¼8.6 Hz), 7.23 (d, 2H, 3J¼7.7 Hz), 7.48
3J¼8.5Hz)7.45(d,1H,3J¼15.6Hz),7.64(m,2H),7.78(d,1H,3J¼15.7 Hz),
(d, 1H, 3J¼15.6 Hz), 7.55 (d, 2H, 3J¼7.8 Hz), 7.80 (d, 1H, 3J¼15.7 Hz),
8.06 (d, 2H, 3J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d/ppm: 65.71 (q,
8.06 (d, 2H, 3J¼8.6 Hz); 13C NMR (100 MHz, CDCl3)
d
/ppm: 21.68,
2JCeF¼36.9 Hz), 114.77, 116.30 (d, JCeF¼22 Hz), 121.47, 130.48 (d,
2
2
65.70 (q, JCeF¼37.2 Hz), 114.71, 120.75, 128.62, 129.87, 131.00,
3JCeF¼8.6 Hz), 131.03, 131.32, 132.79, 143.44, 160.90, 188.59; 19F NMR
132.30, 133.00, 141.26, 144.88, 160.77, 188.95; 19F NMR (376.17 MHz,
(376.17 MHz, CDCl3)
(KBr)
d
/ppm: ꢁ73.70 (t, 3F, 3J¼8.7 Hz), 108.98 (s, 1F); IR
CDCl3)
d
/ppm: ꢁ73.69 (t, 3J¼7.8 Hz); IR (KBr)
n¼3052, 2948, 1656,
n
¼3076, 2947, 2897,1612,1598,1510, 1460, 1418, 1341, 1286, 1251,
1606,1593,1510,1458,1416,1346,1309,1287,1257,1226,1176,1164,
1073, 1027, 977, 866, 813, 679 cmꢁ1; HRMS (ESI) calcd for
1223, 1175, 1160, 1077, 1037, 984, 842, 828, 842, 748, 683, 668 cmꢁ1
;
HRMS (ESI) calcd for C17H12F4O2: [MþH]þ 325.0852, [MþNa]þ
C
18H15F3O2: [MþH]þ 321.1102, [MþNa]þ 343.0922; found:
347.0671; found: 325.0843, 347.0661.
321.1094, 343.0912.
4.3.7. (E)-3-(4-(Benzyloxy)phenyl)-1-(4-(2,2,2-trifluoroethoxy)phe-
nyl)prop-2-en-1-one (17). The general procedure described above
was followed to get the title compound from (E)-3-(4-(benzyloxy)
phenyl)-1-(4-bromophenyl)prop-2-en-1-one (393 mg, 1.0 mmol),
4.3.4. (E)-1-(4-(2,2,2-Trifluoroethoxy)phenyl)-3-(3,4,5-
trimethoxyphenyl)prop-2-en-1-one (14). The general procedure
described above was followed to get the title compound from (E)-1-
(4-bromophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one
2,2,2-tri-fluoroethanol (110
mL, 1.52 mmol), Cs2CO3 (489 mg,
(377 mg, 1.0 mmol), 2,2,2-trifluoroethanol (110
m
L, 1.52 mmol),
1.5 mmol), Pd2(dba)3 (2.3 mg, 0.25 mol %), tBuXPhos (L1) (2.6 mg,
0.625 mol %), with toluene as solvent (3.0 ml) were heated at 90 ꢀC
for 17 h. The crude reaction mixture was filtered through a short
silica (230e400 mesh) column using chloroform to afford the title
Cs2CO3 (489 mg, 1.5 mmol), Pd2(dba)3 (2.3 mg, 0.25 mol %), tBuX-
Phos (L1) (2.6 mg, 0.625 mol %), with toluene as solvent (3.0 ml)
were heated at 90 ꢀC for 17 h. The crude reaction mixture was

T.M. Rangarajan et al. / Tetrahedron 71 (2015) 8307e8314
8313
compound as a yellow solid (334 mg, 81% yield): Mp: 140e143 ꢀC;
187.92; 19F NMR (376.17 MHz, CDCl3)
d
/ppm: ꢁ73.65 (t, 3F,
1H NMR (400 MHz, CDCl3)
d
/ppm: 4.44 (q, 2H, 3J¼8.0 Hz), 5.12 (s,
3J¼7.9 Hz); IR (KBr)
¼3092, 2918, 1664, 1607, 1579, 1529, 1513,
n
2H), 7.00e7.04 (m, 4H), 7.36e7.45 (m, 6H) 7.60 (d, 2H, 3J¼8.3 Hz),
7.79 (d, 1H, 3J¼15.6 Hz), 8.05 (d, 2H, 3J¼8.4 Hz); 13C NMR (100 MHz,
1440, 1353, 1308, 1254, 1223, 1185, 1154, 1118, 1073, 979, 871, 817,
803, 748, 730 cmꢁ1; HRMS (ESI) calcd for C17H12F3NO4: [MþH]þ
352.0797, [MþNa]þ 374.0616; found: 352.0787, 374.0605.
CDCl3)
d
/ppm: 65.68 (q, 2JCeF¼35.9 Hz), 70.26, 114.67, 115.44, 119.51,
127.63, 127.96, 128.34, 128.83, 130.38, 130.94, 133.08, 136.51, 144.61,
160.70, 160.98, 188.92; 19F NMR (376.17 MHz, CDCl3)
d
/ppm: ꢁ73.71
4.3.11. (E)-1-(Naphthalen-1-yl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)
prop-2-en-1-one (21). The general procedure described above was
followed to get the title compound from (E)-3-(4-bromophenyl)-1-
(naphthalen-1-yl)prop-2-en-1-one (337 mg, 1.0 mmol), 2,2,2-
(t, 3F, 3J¼7.9 Hz); IR (KBr)
¼3037, 2942, 1656, 1589, 1509, 1456,
n
1422, 1386, 1346, 1285, 1254, 1220, 1168, 1075, 1028, 1002, 970, 864,
814, 741, 695, 681, 666 cmꢁ1; HRMS (ESI) calcd for C24H19F3O3:
[MþH]þ 413.1365, [MþNa]þ 435.1184; found: 413.1357, 435.1177.
trifluoroethanol (110 mL, 1.52 mmol), Cs2CO3 (489 mg, 1.5 mmol),
Pd2(dba)3 (2.3 mg, 0.25 mol %), tBuXPhos (L1) (2.6 mg, 0.625 mol %),
4.3.8. (E)-1,3-Bis(4-(2,2,2-trifluoroethoxy)phenyl)prop-2-en-1-one
(18). The general procedure described above was followed to get the
title compound from (E)-1,3-bis(4-bromophenyl)prop-2-en-1-one
with toluene as solvent (3.0 ml) were heated at 90 ꢀC for 17 h. The
crude reaction mixture was filtered through
a short silica
(230e400 mesh) column using chloroform to afford the title com-
(366 mg, 1.0 mmol), 2,2,2-trifluoroethanol (220
mL, 3.0 mmol),
pound as a yellow solid (270 mg, 76% yield): Mp: 91e93 ꢀC; 1H NMR
Cs2CO3 (978 mg, 3.0 mmol), Pd2(dba)3 (4.6 mg, 0.5 mol %), tBuXPhos
(L1) (5.3 mg, 1.25 mol %), with toluene as solvent (3.0 ml) were
heated at 90 ꢀC for 17 h. The crude reaction mixture was filtered
through a short silica (230e400 mesh) column using chloroform to
afford the title compound as a yellow solid (340 mg, 84% yield): Mp:
(400 MHz, CDCl3)
d
/ppm: 4.39 (q, 2H, 3J¼8.0 Hz), 6.97 (d, 2H,
3J¼8.5 Hz), 7.22 (d, 1H, 3J¼16.0 Hz) 7.52e7.58 (m, 6H), 7.76 (d, 1H,
3J¼7.2 Hz), 7.91e7.93 (m, 1H), 8.00 (d,1H, 3J¼8.3 Hz), 8.30 (m,1H); 13
C
NMR (100 MHz, CDCl3)
d
/ppm: 65.74 (q, 2JCeF¼35.9Hz),115.37,124.66,
125.77, 126.12, 126.61, 127.13, 127.56, 128.59, 129.21, 130.46, 130.61,
132e136 ꢀC; 1H NMR (400 MHz, CDCl3)
d/ppm: 4.37e4.47 (m, 4H),
131.66, 133.97, 137.31, 145.22, 159.25, 195.87; 19F NMR (376.17 MHz,
6.98 (d, 2H, 3J¼8.5 Hz), 7.03 (d, 2H, 3J¼8.6 Hz) 7.44 (d, 1H,
CDCl3)
d
/ppm: ꢁ73.74 (t, 3F, 3J¼8.0 Hz); IR (KBr)
¼3049, 1662, 1588,
n
3J¼15.6 Hz), 7.63 (d, 2H, 3J¼8.5 Hz), 7.78 (d, 1H, 3J¼15.6 Hz), 8.05 (d,
1596,1575,1514,1463,1424,1290,1251,1172,1101,1073, 971, 866, 828,
799, 774 cmꢁ1; HRMS (ESI) calcd for C21H15F3O2: [MþH]þ 357.1102,
[MþNa]þ 379.0922; found: 357.1095, 379.0912.
2H, 3J¼8.6 Hz); 13C NMR (100 MHz, CDCl3)
d/ppm: 65.13e66.31 (m),
114.71, 115.36, 120.49, 129.52, 130.40, 130.99, 132.88, 143.86, 159.14,
160.81, 188.73; 19F NMR (376.17 MHz, CDCl3)
d/ppm:
ꢁ73.75eꢁ73.66 (m, 6F); IR (KBr)
n
¼3071, 2948, 2895, 1662, 1605,
4.3.12. (E)-1-(2-Methoxyphenyl)-3-(4-(2,2,2-trifluoroethoxy)phenyl)
prop-2-en-1-one (22). The general procedure described above was
followed to get the title compound from (E)-3-(4-bromophenyl)-1-
(2-methoxyphenyl)prop-2-en-1-one (317 mg, 1.0 mmol), 2,2,2-
1578, 1510, 1458, 1426, 1349, 1293, 1251, 1218, 1175, 1079, 1031, 971,
862, 821, 808, 663 cmꢁ1; HRMS (ESI) calcd for C19H14F6O3: [MþH]þ
405.0925, [MþNa]þ 427.0745; found: 405.0917, 427.0735.
trifluoroethanol (110 mL, 1.52 mmol), Cs2CO3 (489 mg, 1.52 mmol),
4.3.9. 3-(E)-(Furan-2-yl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)-2-
propen-1-one (19). The general procedure described above was
followed to get the title compound from (E)-1-(4-bromophenyl)-3-
(furan-2-yl)2-propen-1-one (277 mg, 1.0 mmol), 2,2,2-
Pd2(dba)3 (4.6 mg, 0.5 mol %), JohnPhos (L2) (3.7 mg, 1.25 mol %),
with toluene as solvent (3.0 ml) were heated at 90 ꢀC for 17 h. The
crude reaction mixture was filtered through
a short silica
(230e400 mesh) column using chloroform to afford the title
trifluoroethanol (110
m
L, 1.52 mmol), Cs2CO3 (489 mg, 1.5 mmol),
compound as a pale yellow solid (222 mg, 66% yield): Mp:
Pd2(dba)3 (2.3 mg, 0.25 mol %), tBuXPhos (L1) (2.6 mg, 0.625 mol %),
76e78 ꢀC; 1H NMR (400 MHz, CDCl3)
d/ppm: 3.86 (s, 3H), 4.35 (q,
with toluene as solvent (3.0 ml) were heated at 90 ꢀC for 16 h. The
2H, 3J¼8.1 Hz), 6.91e7.02 (m, 4H), 7.24 (d, 1H, 3J¼15.1 Hz), 7.41e7.46
crude reaction mixture was filtered through
(230e400 mesh) column using chloroform to afford the title
a
short silica
(m, 1H), 7.51e7.58 (m, 4H); 13C NMR (100 MHz, CDCl3)
d/ppm:
2
55.88, 65.77 (q, JCeF¼35.5 Hz), 111.75, 115.30, 120.87, 126.08,
compound as a yellow crystalline solid (219 mg, 74% yield): Mp:
129.45, 129.75, 130.29, 130.42, 132.95, 142.57, 158.17, 158.94, 193.10;
93e95 ꢀC (lit.6a 94.5e96.5); 1H NMR (400 MHz, CDCl3)
d/ppm: 4.43
19F NMR (376.17 MHz, CDCl3)
d
/ppm: ꢁ73.74 (t, 3F, 3J¼8.0 Hz); IR
(q, 2H, 3J¼8.0 Hz), 6.52 (m, 1H), 6.72 (d, 1H, 3J¼3.4 Hz) 7.02 (d, 2H,
(KBr)
n
¼3070, 3005, 2956, 2837, 1655, 1603, 1574, 1512, 1485, 1437,
3J¼8.5 Hz), 7.44 (d, 1H, 3J¼15.1 Hz), 7.53 (s, 1H), 7.59 (d, 1H,
1340, 1286, 1242, 1182, 1160, 1116, 1074, 1016, 968, 863, 829, 764,
752, 643 cmꢁ1; HRMS (ESI) calcd for C18H15F3O3: [MþH]þ 337.1052,
[MþNa]þ 359.0871; found: 337.1043, 359.0861.
3J¼15.6 Hz), 8.06 (d, 2H, 3J¼8.5 Hz); 13C NMR (100 MHz, CDCl3)
d/
ppm: 65.68 (q, 2JCeF¼36.9 Hz), 112.83, 114.71, 116.37, 119.03, 123.22
1
(d, JCeF¼277.9 Hz), 130.62, 130.96, 132.85, 145.03, 151.84, 160.82,
188.16. The 1H and 13C NMR spectral data were in good agreement
with those previously reported compound.6a
4.3.13. (E)-3-(2,5-Dimethoxyphenyl)-1-(4-(2,2,2-trifluoroethoxy)
phenyl)prop-2-en-1-one (23). The general procedure described
above was followed to get the title compound from (E)-1-(4-
bromophenyl)-3-(2,5-dimethoxyphenyl)prop-2-en-1-one
4.3.10. (E)-3-(3-Nitrophenyl)-1-(4-(2,2,2-trifluoroethoxy)phenyl)
prop-2-en-1-one (20). The general procedure described above was
followed to get the title compound from (E)-1-(4-bromophenyl)-3-
(3-nitrophenyl)prop-2-en-1-one (332 mg, 1.0 mmol), 2,2,2-
(347 mg, 1.0 mmol), 2,2,2-trifluoroethanol (110
mL, 1.52 mmol),
Cs2CO3 (489 mg, 1.5 mmol), Pd2(dba)3 (2.3 mg, 0.25 mol %), tBuX-
Phos (L1) (2.6 mg, 0.625 mol %), with toluene as solvent (3.0 ml)
were heated at 90 ꢀC for 17 h. The crude reaction mixture was fil-
tered through a short silica (230e400 mesh) column using chlo-
roform to afford the title compound (fluorescent) as a yellow solid
trifluoroethanol (110 mL, 1.52 mmol), Cs2CO3 (489 mg, 1.5 mmol),
Pd2(dba)3 (2.3 mg, 0.25 mol %), tBuXPhos (L1) (2.6 mg, 0.625 mol %),
with toluene as solvent (3.0 ml) were heated at 90 ꢀC for 16 h. The
crude reaction mixture was filtered through
a
short silica
(188 mg, 51% yield): Mp: 97e99 ꢀC; 1H NMR (400 MHz, CDCl3)
d/
(230e400 mesh) column using chloroform to afford the title
ppm: 3.82 (s, 3H), 3.88 (s, 3H), 4.44 (q, 2H, 3J¼8.0 Hz), 6.88 (d, 1H,
3J¼9.0 Hz), 6.95 (dd, 1H, 3J¼9.0 Hz, 4J¼3.0 Hz), 7.03 (d, 2H,
3J¼8.7 Hz), 7.16 (d, 1H, 4J¼3.0 Hz), 7.57 (d, 1H, 3J¼15.8 Hz),
compound as a yellow solid (152 mg, 43% yield): Mp: 168e171 ꢀC;
1H NMR (400 MHz, CDCl3)
d
/ppm: 4.46 (q, 2H, 3J¼7.9 Hz), 7.07 (d,
2H, 3J¼8.6 Hz), 7.60e7.67 (m, 2H) 7.84 (d, 1H, 3J¼15.7 Hz), 7.92 (m,
8.04e8.09 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
/ppm: 55.97, 56.24,
1H), 8.10 (m, 2H), 8.26 (m, 1H), 8.52 (m, 1H); 13C NMR (100 MHz,
65.66 (q, JCeF¼35.9 Hz), 112.58, 113.98, 114.64, 117.26, 122.84,
2
2
CDCl3)
d
/ppm: 65.68 (q, JCeF¼35.9 Hz), 114.89, 122.37, 124.33,
124.62, 131.04, 133.07, 140.08, 153.45, 153.63, 160.67, 189.39; 19F
124.80, 130.22, 131.21, 132.24, 134.59, 136.80, 141.58, 148.87, 161.20,
NMR (376.17 MHz, CDCl3)
d
/ppm: ꢁ73.71 (t, 3F, 3J¼7.5 Hz); IR (KBr)

8314
T.M. Rangarajan et al. / Tetrahedron 71 (2015) 8307e8314
Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829; (f) Evano, G.; Blanchard, N.; Toumi,
n
¼3068, 2959, 2844, 1659, 1605, 1575, 1497, 1428, 1320, 1282, 1213,
M. Chem. Rev. 2008, 108, 3054; (g) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400.
1178, 1159, 1072, 1052, 1028, 983, 962, 835, 806, 750, 716, 670,
571 cmꢁ1; HRMS (ESI) calcd for C19H17F3O4: [MþH]þ 367.1157,
[MþNa]þ 389.0977; found: 367.1149, 389.0966.
3. (a) Ueda, S.; Ali, S.; Fors, B. P.; Buchwald, S. L. J. Org. Chem. 2012, 72, 2543; (b)
Salvi, L.; Davis, N. R.; Ali, S. Z.; Buchwald, S. L. Org. Lett. 2012, 14, 170; (c)
Hoshiya, N.; Buchwald, S. L. Adv. Synth. Catal. 2012, 354, 2031; (d) Lundgren, R.
J.; Stradiotto, M. Chem.dEur. J. 2012, 18, 9758; (e) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2011, 2, 27; (f) Bellina, F.; Rossi, R. Adv. Synth. Catal. 2010, 352, 1223;
(g) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240; (h)
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954; (i) Withbroe, G.
J.; Singer, R. A.; Sieser, J. E. Org. Process Res. Dev. 2008, 12, 480; (j) Harkal, S.;
Kumar, K.; Michalik, D.; Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.;
Monsees, A.; Beller, M. Tetrahedron Lett. 2005, 46, 3237; (k) Rataboul, F.; Zapf,
A.; Jackstell, R.; Harkel, S.; Riermeier, T.; Monsees, A.; Dingerdissen, U.; Beller,
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Acknowledgements
Authors are grateful to Defence R & D organization (DRDO) for
the financial assistance. Authors also acknowledge Principal, Sri
Venkateswara College, University of Delhi, and Director, CFEES,
DRDO for their encouraging support throughout this work. We
thank USIC-University of Delhi for NMR and other analytical sup-
port. We thank Dr. A. Gubendran, Associate Professor, Department
of Chemistry, Saraswathi Narayanan College, Madurai, India for
helpful discussions.
4. (a) Cheung, C. W.; Buchwald, S. L. Org. Lett. 2013, 15, 3998; (b) Maimone, T. J.;
Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 9990; (c) Bhayana, B.; Fors, B. P.;
Buchwald, S. L. Org. Lett. 2009, 11, 3954; (d) Surry, D. S.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 6338.
5. (a) Lee, H. G.; Milner, P. J.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 3792; (b)
Teverovskiy, G.; Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 7312;
(c) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L.
Science 2010, 328, 1679.
6. (a) Rangarajan, T. M.; Singh, R.; Brahma, R.; Devi, K.; Singh, R. P.; Singh, R. P.;
Prasad, A. K. Chem.dEur. J. 2014, 20, 14218; (b) Rangarajan, T. M.; Brahma, R.;
Ayushee; Prasad, A. K.; Verma, A. K.; Singh, R. P. Tetrahedron Lett. 2015, 56, 2234.
7. Cahard, D.; Bizet, V. Chem. Soc. Rev. 2014, 43, 135.
Supplementary data
Supplementary data (Proton, carbon, and fluorine NMR data for
compounds 11e23) associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2015.08.071.
8. (a) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-
Blackwell: Chichester, UK, 2009; (b) Tressaud, A.; Haufe, G. Fluorine and Health:
Molecular Imaging, Biomedical Materials and Pharmaceuticals, 1st ed.; Elsevier:
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