BrettPhos ligand supported palladium-catalyzed C-O bond formation through an electronic pathway of reductive elimination: Fluoroalkoxylation of activated aryl halides

Article abstract of DOI:10.1002/chem.201404121

We report an unprecedented BrettPhos ligand supported Pd-catalyzed C-O bond-forming reaction of activated aryl halides with primary fluoroalkyl alcohols. We demonstrate that the Phosphine ligand (BrettPhos) possesses the property of altering the mechanistic pathway of reductive elimination from nucleophile to nucleophile. The Pd/BrettPhos catalyst system facilitates the reductive elimination of the oxygen nucleophile through an electronic pathway.

Full text of DOI:10.1002/chem.201404121

DOI: 10.1002/chem.201404121
Communication
&
Organic Synthesis
BrettPhos Ligand Supported Palladium-Catalyzed CÀO Bond
Formation through an Electronic Pathway of Reductive
Elimination: Fluoroalkoxylation of Activated Aryl Halides
T. M. Rangarajan,[a, c] Rajendra Singh,*[b] Raju Brahma,[b] Kavita Devi,[b] Rishi Pal Singh,[a]
R. P. Singh,*[b] and Ashok K. Prasad[c]
gies have been shown ingress in almost all aspects of chemical
syntheses.[3,4] In recent years, aryl fluoroalkyl ethers (Scheme 1)
Abstract: We report an unprecedented BrettPhos ligand
have also been paid as much attention as other fluorinated or-
supported Pd-catalyzed CÀO bond-forming reaction of ac-
ganic compounds in pharmaceuticals,[5] PET imaging,[1b,6] hair
tivated aryl halides with primary fluoroalkyl alcohols. We
dye ingredients,[7a] pesticides,[7b] liquid-crystal display applica-
tions,[7c] fluorous chemistry,[7d] etc. Transition-metal-catalyzed
sesses the property of altering the mechanistic pathway
demonstrate that the Phosphine ligand (BrettPhos) pos-
CÀO cross-coupling methodologies have become an efficient
of reductive elimination from nucleophile to nucleophile.
and alternative tool over traditional methods, such as William-
son ether synthesis, the Ullmann reaction, and alkylation of
phenols, as these methods involve harsh reaction conditions,
low functional-group tolerance, and carcinogenic reagents.[8]
The Pd/BrettPhos catalyst system facilitates the reductive
elimination of the oxygen nucleophile through an elec-
tronic pathway.
The chemistry of fluorine has been an inviting subject for
chemists for more than three decades because of fluorine’s ex-
cellent and even bizarre physical and chemical properties. In
fact, fluorinated organic compounds have found pervasive ap-
plications in medicinal,[1a] molecular imaging,[1b] agrochemi-
cals,[1c] and material sciences.[1d–f] Therefore, the incorporation
of the fluorine atom and fluorine-containing functional groups
into organic molecules has recently received a spectacular
growth of interest among chemists.[2,3]
Recently, transition-metal-catalyzed cross-coupling reactions
(particularly Pd and Cu) have become a splendid tool not only
to couple CÀC, CÀN, CÀO bonds etc.,[4] but also CÀF, CÀCF3,
CÀOCF3, CÀCF3, and CÀSCF3 bonds. Thanks to the success of
fluorination reactions under mild reaction conditions, coupling
reactions involving fluorine chemistry have reached an ad-
vanced level in all branches of chemistry.[3] By popular
demand, transition-metal-catalyzed cross-coupling methodolo-
Scheme 1. Selected examples of aryl fluoroalkyl ether containing com-
pounds in various fields.
Various structural derivatives of phosphine ligated transition-
metal-catalyzed cross-coupling methodologies offer a wide
scope in the organic synthesis, were initially developed by
Buchwald[9,10d,e,12c] and Hartwig groups,[10,12c] and subsequent
contributions have been made by Beller[9b,c,10c,11,12c] and oth-
ers[9b,c,10d,e,12] over last few decades. The electron-rich counter-
part of the X-Phos ligand, the so-called electron-rich, relatively
bulky BrettPhos ligand (L1) (Scheme 2), developed by the
Buchwald group,[9f,13a] is one of the most effective supporting
ligands that has promisingly facilitated several cross-coupling
reactions,[3c,13,14] depicted in Scheme 3.
[a] T. M. Rangarajan, Dr. R. P. Singh
Department of Chemistry
Sri Venkateswara College, University of Delhi
New Delhi (India)
[b] Dr. R. Singh, Dr. R. Brahma, K. Devi, Dr. R. P. Singh
Fluoroorganic Laboratory
Centre for Fire, Explosive and Environment Safety
DRDO, Delhi (India)
E-mail: rajendra@cfees.drdo.in
rajcfees@gmail.com
This catalytic system offered coupling products even with
weak nucleophiles, such as a FÀ anoin,[14b] trifluoromethyl
anion,[14c] and trifluoromethylthio anion.[3c] However, this Pd/
BrettPhos catalytic system, albeit it involves an oxidative addi-
tion step, failed to give CÀO coupling reactions with relatively
weak nucleophiles, such as ethyl acetohydroximate,[14e] metha-
[c] T. M. Rangarajan, Prof. Dr. A. K. Prasad
Department of Chemistry
University of Delhi
Delhi (India)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404121.
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and deactivated aryl bromides
were also conducted under the
same reaction conditions with
another nucleophile (phenyl bor-
onic acid) to ensure the Brett-
Phos ligand (phosphine ligand)
possesses the property of alter-
ing the mechanistic pathway of
reductive elimination from nu-
cleophile to nucleophile (de-
pending on the nature of the
nucleophile). To the best of our
knowledge, this is the first exam-
Scheme 2. Structures of the biarylphosphine ligands used for screening purposes.
ple of
a Pd/BrettPhos ligand
system that clearly separates the
steric and electronic pathway of
reductive elimination from nu-
cleophile to nucleophile by facili-
tating the CÀO bond formation
through a pure electronic-assist-
ed reductive elimination path-
way and CÀC bond formation
through a steric and/or electron-
ic pathway of reductive elimina-
tion.
A growing interest in aryl fluo-
roalkyl ethers in both academia
and industry (Scheme 1) and
a lack of efficient methodologies
available for the synthesis of aryl
fluoroalkyl ethers[6,7,15,16] have
really kindled or interest in de-
veloping an efficient protocol for
the fluoroalkoxylation of aryl hal-
ides with wide substrate scope.
In fact, our study with the li-
gands available at hand was nar-
rowed down by the substrate
scope of the reaction. Thankfully,
we were able to discern a ligand
that possesses the ability of al-
tering the mechanistic pathway
of reductive elimination from nu-
Scheme 3. Examples of BrettPhos ligand supported palladium-catalyzed cross-coupling reactions.
nol,[14f] and phenol[14g] (Scheme 3). To the best of our knowl-
edge, the discrepancy observed in catalyzing the cross-cou-
pling reactions by a given catalytic system (Pd/BrettPhos
system, Scheme 3) from nucleophile to nucleophile is yet to be
accounted for. In this Communication, we disentangled the
aforementioned discrepancy associated with Pd/BrettPhos
ligand system by an intermolecular CÀO bond-forming reac-
tion of primary fluoroalkyl alcohols with aryl bromides. Aryl
chlorides were also effectively coupled by this catalytic system.
We investigated the coupling reaction of 2,2,2-trifluoroethanol
with electronically different aryl bromides to understand the
properties of the ligands in deciding the mechanistic pathway
(electronic or steric) of the reductive elimination step under
optimized reaction conditions. Coupling reactions of activated
cleophile to nucleophile in cross-coupling reactions.
To begin with, we investigated 2,2,2-trifluoroethoxylation of
p-bromoanisole with 2,2,2-trifluoroethanol in the presence of
0.5 mol%
of
[Pd2(dba)3]
(dba=dibenzylideneacetone),
1.25 mol% of commercially available BrettPhos ligand (L1), and
a strong base, NaH, in toluene at 858C over 24 h. After this
time, no coupling product was observed. Fortunately, we con-
ducted the same reaction with p-bromoacetophenone as the
substrate based on an inkling from mechanistic studies carried
out by Buchwald and Hartwig groups.[17] Surprisingly, the reac-
tion gave the desired product 2a in about 31% yield and 51%
conversion over 24 h. Thenceforth p-bromoacetophenone
became a model substrate for further optimization of the reac-
tion conditions. The complete optimization of the reaction
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conditions are given in the Sup-
porting Information (Table S1).
The bases K3PO4 and Cs2CO3 ef-
fected the coupling reaction
Table 1. Palladium-catalyzed 2,2,2-trifluoroethoxylation of aryl bromides and chlorides.[a,b]
with
complete
conversion.
Indeed, Cs2CO3 gave the desired
product with 85% yield in
2.25 h. It has also been observed
that when catalyst loading is re-
duced from 0.5 to 0.1 mol%, the
catalytic activity has also been
reduced. The higher catalyst
loading and higher temperature
gave the desired product in
short reaction times of 1.5 and
0.75 h, respectively, without al-
tering the yield of the product.
No other palladium sources,
Entry Substrate X, R
Product
Pd [mol%] Time [h] Yield [%][c]
Cl, 4-COCH3;
1
0.5
7.0
73
F=0.33; R=0.17[d]
Br, 4-CHO;
2
0.5
0.5
6.0
72
70
F=0.33; R=0.09
3
Cl, p-CHO
17[e]
Br, 4-CN;
F=0.51; R=0.15
4
0.5
2.0
92
such
as
Pd(OAc)2
and
Br, 4-COOEt;
F=0.34; R=0.11
Cl, 4-COOEt
[Pd(PPh3)4], were as effective as
[Pd2(dba)3]. Finally, we examined
the commercially available li-
gands (Scheme 2) XPhos (L2),
Me4-tBuXPhos (L3), SPhos (L4),
and DavePhos (L5); however,
these ligands could not facilitate
the reaction as effectively as
BrettPhos ligand (L1). It is im-
portant to note that all the li-
gands with palladium catalyst
could not effectively couple the
nucleophile even with strong
activated aryl or heteroaryl hal-
ides.[18]
5
6
1.0
1.0
6.0
63
60
17[e]
Br, 4-OMe;
F=0.29; R=À0.56
7
8
1.0
0.5
24
12
NR
NR
Br, 4-F;
F=0.45; R=À0.39
Br, 4-NO2;
F=0.65; R=0.13
Cl, 4-NO2
9
1.0
1.0
2.0
2.0
89
87
10
With the optimized reaction
conditions in hand, we further
explored the coupling reaction
of 2,2,2-trifluoroethanol with
aryl bromides of a different elec-
tronic nature in order to under-
stand the ligand’s properties in
the Pd-catalyzed coupling reac-
tions. Also, we extended the
scope of the reaction to activat-
ed aryl chlorides and the results
are presented in Table 1. Aryl
bromides bearing electron-with-
Br, 3-NO2;
F=0.65; R=0.13
11
12
13
1.0
1.0
1.0
12
24
20
NR
Br, 2-NO2, 4-Br; Br,
R=À0.22; NO2, R=0.13
28
Br, 2-Br, 4-NO2
trace
14
15
Br, 2-NO2, 4-NO2
Cl, 2-NO2, 4-NO2
0.5
0.5
1.75
1.0
92
74
drawing
functional
groups
(EWG), such as ÀCHO, ÀCN,
ÀCOOEt, and ÀNO2 at the p-po-
sition gave the coupling prod-
ucts with 2,2,2-trifluoroethanol
in moderate to excellent yield
(Table 1, entries 2, 4, 5, and 9).
The functional groups ÀOMe
(entry 7), ÀF (entry 8), and ÀPh
(not included in table) did not
16
17
Br, 2-COOEt
Cl, 2-NO2
1.0
1.0
23
16
NR
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transition state. Hence, the re-
ductive elimination fails through
Table 1. (Continued)
the
electronic
pathway
(Scheme 5, path i). This strongly
suggests that this catalytic
system facilitates the CÀO bond
formation by inner sphere nu-
cleophilic attack of fluoroalkox-
ide at the ipso-carbon atom of
the palladium-bound aryl group
via a Meisenheimer complex. In
general, electron-rich and -neu-
tral aryl bromides facilitate the
Entry Substrate X, R
Product
Pd [mol%] Time [h] Yield [%][c]
18
1.0
1.0
22
60[f]
Br, 4-COPh;
19
reductive
elimination
only
4.0
92
F=0.31; R=0.12
through a concerted, symmetric,
three-centered transition state,
whereas for activated aryl bro-
mides both the mechanisms
may possibly occur.[17a,b]
[a] Reaction conditions: ArX (1.0 mmol), 2,2,2-trifluoroethanol (1.5 mmol), Cs2CO3 (1.5 mmol), [Pd2(dba)3]
(0.5 mol%), BrettPhos (1.25 mol%), toluene (3.0 mL), Ar atm., 858C. [b] ArX (0.6111 mmol), 2,2,2-trifluoroethanol
(0.917 mmol), Cs2CO3 (0.917 mmol), [Pd2(dba)3] (1.0 mol%), BrettPhos (2.5 mol%), toluene (2.0 mL), Ar atm.,
858C. [c] Isolated yield. [d] Swan–Lapton’s field (F) and resonance (R) dual substituent constants for substituent
R. [e] Reaction time not optimized. NR=No Reaction. [f] 90% conversion.
However, it is ascertained that
the
Pd/BrettPhos
catalytic
system enables CÀO bond for-
mation only through the elec-
give any coupling products. The functional groups ÀCOCH3
(see Table S1 in the Supporting Information), ÀCN (entry 4),
and ÀNO2 (entry 9) gave the coupling products in very good
yields in short reaction times, whereas ÀCHO (entry 2) and
ÀCOOEt (entry 5) gave the desired products in moderate yield
with relatively long reaction time. This reaction trend can
easily be explained with the help of the resonance constant of
Swan–Lapton[19] field (F) and resonance (R) dual substituent pa-
rameters.[17a,b,20] The positive R values for the substituents indi-
cate the electron-withdrawing
tronic pathway of reductive elimination (Scheme 4, path i) as
this catalytic system hinders the steric pathway of reductive
elimination. This can further be demonstrated by the reaction
of 2,2,2-trifluoroethanol with 1-bromo-3-nitrobenzene (Table 1,
entry 11), 1,4-dibromo-2-nitrobenzene (entry 12), 1,2-dibromo-
4-nitrobenzene (entry 13), and 1-bromo-2,4-dinitrobenzene
(entry 14). Entry 11 did not give the coupling product at all
due to the m-NO2 group, which increases the electron density
at the ipso-carbon atom both by inductive and resonance ef-
extended p-resonance conjuga-
tion between the functional
group and the site of interest.
The negative R values for sub-
stituents indicate the electron-
releasing extended p-resonance
conjugation between the func-
tional group and the site of in-
terest. Therefore, EWG reduces
the electron density accumulat-
ed at the ipso-carbon atom of
the palladium-bound aryl group
by inner-sphere attack of fluo-
roalkoxide in the transition state
leading to a stabilization that fa-
cilitates the reductive elimina-
tion (Scheme 4, path i). In con-
trast, electron-releasing group
(ERG) increases the electron den-
sity at the ipso-carbon atom of
the palladium-bound aryl group,
which hinders the fluoroalkoxide
attack in the transition state,
Scheme 4. Plausible mechanistic pathway of CÀO reductive elimination of activated (I) aryl halides. EWG=elec-
leading to destabilization of the tron-withdrawing group.
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latter, on the other hand, offered
the desired product 2o in 92%
yield; this is a result of a R value
of 0.12, that is, extended reso-
nance stabilization.[23] Aryl chlor-
ides were also coupled with
2,2,2-trifluoroethanol under the
same reaction conditions but
the yields were comparably low
with aryl bromides in some in-
stances (entries 1 and 15). Other
aryl chlorides gave the desired
products in almost equal yield
with bromo analogues (entries 3,
6, and 10).
Furthermore, we were pleased
to carry out a few reactions both
of electron-rich and -poor aryl
bromides with phenyl boronic
acid[14a] (carbon nucleophile)
under the same reaction condi-
tions to explore the ligand’s role
in the reductive elimination step
with respect to the nucleophile.
Scheme 5. Plausible mechanistic pathway of CÀO reductive elimination of deactivated and neutral (II) aryl halides.
ERG=electron-releasing group+neutral.
fects.[17b] Moreover, entries 12 and 14 offered the coupling
products 2i and 2k in 28 and 92% yields, respectively. It is
clear that the former resists the reductive elimination through
the Br-atom from the p-position since the overall resonance
effect R is negative (R=À0.09) and the later readily offered
the coupling product even in low catalyst loading. On the
other hand, entry 13 gave traces of product 2j. These re-
sults suggest that both the electron-donating and steric
bulkiness of the Br atom increases the electron density at
the ipso-carbon atom of the palladium-bound aryl group
resist the reductive elimination by the electronic pathway.
In the case of ortho-substituted aryl halides, entry 16 failed
to couple, whereas entry 17 offered the desired product
2m 38% yield.[21] This may be attributed to steric over-
crowding of the {Ar-Pd(Ln)-OCH2Rf} complex system that
could force the aryl group and the substituents on the aryl
group out of the plane. Thus, they are probably no longer
in a co-planar or nearly co-planar conformation, which re-
sults in a considerable reduction in the extent of conjuga-
tion between the substituent and the aryl group that in-
creases electron-density at the ipso-carbon atom of the pal-
ladium-bound aryl group.[22] Thus, resonance stabilization
plays a vital role in the electronic pathway of reductive
elimination; this can be further confirmed by the reaction
of 2,2,2-trifluroethanol with (E)-1-(4-bromophenyl)-3-(furan-
2-yl)prop-2-en-1-one (entry 18) and 4-bromobenzophenone
(entry 19). The former gave the desired product 2n in 60%
yield with 90% conversion over 22 h. The poor yield and in-
complete conversion are due to the reduction of extended
electron-withdrawing resonance p-conjugation between the
carbonyl group and the palladium-bound aryl group by in-
creased extended resonance p-conjugation between the car-
bonyl group and the a,b-unsaturated furfurylidene group. The
The results are given in Table 2. Under the same reaction con-
ditions, phenyl boronic acid was successfully coupled with sub-
strates bearing a different electronic nature from activated to
deactivated aryl bromides affording the desired products (3a–
Table 2. Coupling of phenyl boronic acid with deactivated and activated aryl
bromides.[a,b]
3a (84%, 1.5 h)
3b (90%, 16 h[c])
3c (72%, 3.5 h) 3d (88%, 3 h)
[a] Reaction conditions: ArBr (1.0 mmol), phenyl boronic acid (1.5 mmol), Cs2CO3
(1.5 mmol), [Pd2(dba)3] (0.5 mol%), BrettPhos (1.25 mol%), toluene (2.0 mL), Ar
atm., 958C. [b] Yields are referred to isolated products. [c] Reaction time not op-
timized.
d) in good to very good yields (72–90%). This result strongly
suggests that this catalytic system now facilitates the CÀC
bond formation between aryl bromides and the carbon nucle-
ophile through a steric-assisted reductive elimination pathway
(Scheme 5, path ii). However, in this case, it is difficult to ascer-
tain the actual mechanistic pathway of reductive elimination
for activated aryl bromide since both the mechanistic path-
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ways of reductive elimination
are possible for activated aryl
substrates (Scheme 4).
Table 3. Palladium-catalyzed 1H,1H-perfluoroalkoxylation of activated aryl halides.[a]
Consequently, the phosphine
ligand (BrettPhos) possesses the
property of altering the mecha-
nistic pathway of reductive elim-
ination from nucleophile to nu-
cleophile. The Pd/BrettPhos
ligand system shows a preference
for the pure electronic pathway
of reductive elimination towards
the oxygen nucleophile, but
when it comes to the carbon nu-
cleophile, it prefers the steric or
steric and electronic pathway of
reductive elimination. More re-
cently, Z. Novak et al.[18b] studied
the screening of ligands with
two aryl chlorides with different
electronic properties, such as 4-
chloroacteophenone and 4-
chlorotoluene. It is interesting to
note that the Pd/XPhos catalytic
system facilitated the coupling
reaction between 4-chloroacteo-
phenone and sodium tetrameth-
oxyborate in 81% yield, whereas
this catalytic system failed to
couple the nucleophile with 4-
chlorotoluene.
[a] Reaction conditions: ArX (0.6111 mmol, 1 equiv), 1H,1H-perifluoroalkanol (n=1, 0.917 mmol, 1.5 equiv; n=2,
0.4278 mmol, 0.7 equiv), Cs2CO3 (0.917 mmol, 1.5 equiv), [Pd2(dba)3] (1.0 mol%), BrettPhos (2.5 mol%), toluene
(2.0 mL), Ar atm., 858C, 3–17 h; isolated yields. [b] Reaction time not optimized. [c] 27% of starting material
was recovered. [d] 2% of starting material was recovered.
Table 4. Palladium-catalyzed 2-fluoroethoxylation of activated aryl bromides.[a]
Finally, we examined the reac-
tion of activated aryl halides
with commercially available
higher
fluorinated
alcohols
(Table 3) and 2-fluoroethanol
(Table 4) under optimized reac-
tion conditions. For higher fluo-
roalcohols, relatively more cata-
lyst loading (1.0 mol%) was re-
quired to achieve the reaction
successfully. The reactivity trend
of substrates with higher fluori-
nated alcohols are the same as
those with 2,2,2-trifluoroethanol.
[a] Reaction conditions: ArBr (1.0 mmol), 2-fluoroethanol (1.5 mmol), [Pd2(dba)3] (0.5 mol%), BrettPhos
(1.25 mol%), Cs2CO3 (1.5 mmol), toluene (3.0 mL), Ar atm., 858C, isolated yields. [b] [Pd2(dba)3] (1.0 mol%); con-
version: 93%.
Those substituents with higher resonance constant values (R)
such as cyano (4a, 4h and 4i), nitro (4c and 4 f), acetyl (4d),
and benzoyl (4g) at para-position were effectively coupled
with 1H,1H-perfluoropropanol, 1H,1H-perfluorobutanol, 1H,1H-
perfluorononanol, and 1H,1H,4H,4H-perfluorobutan-1,4-diol
(Table 3) in good to very good yields, whereas those substitu-
ents with lower resonance constant values (R), such as ester
(4b) and formyl (4e), gave products in moderate yields. These
data suggest that the extended electron-withdrawing reso-
nance p-conjugation is an important factor for the electronic
pathway of reductive elimination (Scheme 4, path i) via a Mei-
senheimer-type transition state. In all the reactions only
1.5 equivalents of fluoroalcohols were used.[15h]
It is also interesting to note that this catalytic system effec-
tively coupled the activated aryl bromides with 2-fluoroethanol
in short reaction times (Table 4) compared with 2,2,2-trifluoro-
ethanol (Table 1) and other higher fluorinated alcohols
(Table 3) except in the case of 1-bromo-4-nitrobenzene, which
offered the desired product 5e with 2-fluoroethanol in 3.5 h.
This is a relatively longer reaction time compared to those sub-
strates with 2,2,2-trifluoroethanol. All other aryl bromides gave
the desired products (5a–f) in very good to moderate yield
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(65–86%) but these yields were relatively lower when com-
pared to reactions with 2,2,2-trifluoroethanol.
Acknowledgements
In conclusion, we have disclosed a new insight into a phos-
phine ligand (BrettPhos) that possesses the property of altering
the mechanistic pathway of reductive elimination from nucleo-
phile to nucleophile. This Pd/BrettPhos catalytic system ena-
bled CÀO bond formation from the oxygen nucleophile by
a pure electronic pathway of reductive elimination via the Mei-
senheimer-type transition state, whereas CÀC bond formation
from the carbon nucleophile occurs by a steric or steric and
electronic pathway of reductive elimination. Other phosphine
ligands, such as XPhos (L2), Me4-tBuXPhos (L3), SPhos (L4), and
DavePhos (L5) did not catalyze the CÀO bond-forming reaction
even with activated substrate p-bromoacetophenone. More-
over, we have demonstrated a clear separation of the steric
and electronic pathway of reductive elimination with respect
to the nucleophiles for the first time. Further, utility of this cat-
alytic system in the CÀC cross-coupling reaction of aryl halides
in wide substrate scope with aryl/heteroaryl boronic acid is
under progress.
Authors are grateful to Defense R & D Organization (DRDO) for
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 to USIC-University of Delhi and Director, INMAS, DRDO
for analytical supports. T.M.R, would like to express a deep
sense of gratitude to the Management of past employment
Shasun Research Centre (SRC) and Dr. M. Somasundaram (SRC)
and Dr. K. Karuppaian (SRC), Chennai, Tamil Nadu, India. We
thank Dr. A. Gubendran, Associate Professor, Department of
Chemistry, Saraswathi Narayanan College, Madurai, India for
helpful discussions.
Keywords: alcohols · BrettPhos · CÀO coupling · ethers ·
reductive elimination
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Experimental Section
General procedure for the BrettPhos ligand supported palla-
dium-catalyzed CÀO cross-coupling reaction
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S. L. Buchwald, Chem. Sci. 2011, 2, 27; g) Y. Monguchi, K. Sakai, K. Endo,
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cot, V. Snieckus, Angew. Chem. 2012, 124, 5150; Angew. Chem. Int. Ed.
2012, 51, 5062.
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 gun under vacuum. The R.B. flask was allowed to cool under an
argon atmosphere. [Pd2(dba)3] and BrettPhos ligand were added
successively. The flask was then flushed with argon repeatedly
three times. To this, anhydrous toluene (1.0 mL) was added by sy-
ringe and the mixture was stirred for five minutes at room temper-
ature. A solution of aryl halides and fluoroalcohols in toluene
(1.0 mL) was added to the flask by syringe. Additional toluene
(1.0 mL, for rinsing) was added to the reaction flask and the flask
was placed into a pre-heated oil bath at 85Æ28C. The reaction
mixture was stirred vigorously until completion as indicated by
TLC analysis. The reaction mixture was allowed to cool to room
temperature and passed through a short silica (230–400 mesh size)
column eluted with chloroform or directly with hexane/ethyl ace-
tate solvent mixture under N2 pressure. The solvent removal under
reduced pressure afforded the desired compounds as a yellow oily
liquid or yellow/colorless solid.
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General procedure for the BrettPhos ligand supported palla-
dium-catalyzed CÀC cross-coupling reaction
The same procedure was followed as in CÀO cross-coupling reac-
tion with a little modification. After the round-bottomed flask was
allowed to cool under an Ar atmosphere, phenyl boronic acid,
[Pd2(dba)3], BrettPhos, and aryl bromides were successively added.
To this mixture, anhydrous toluene (2.0 mL) was added in a single
addition and the flask was placed into a pre-heated oil bath at
958C. The reaction was left until completion, as judged by TLC
analysis. The reaction mixture was treated as above.
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[20] Buchwald et al. used the Hammett substituent constant (s) to account
for the electronic dependence of CÀO reductive elimination. Indeed,
the inductive and resonance effect of the substituents could not be ex-
plained by the s constant.
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[23] The corresponding aryl bromides of the product 2a–c and 2o showed
no product formation with 2,2,2-trifluoroethanol, even over 16 h reac-
tion under similar experimental conditions without the Pd/ligand cata-
lytic system (SNAr conditions). While the corresponding aryl bromides
of 2g offered 18% of desired product with 79% conversion over 16 h
(SNAr conditions).
Received: June 25, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Organic Synthesis
T. M. Rangarajan, R. Singh,* R. Brahma,
K. Devi, R. P. Singh, R. P. Singh,*
A. K. Prasad
&& – &&
BrettPhos Ligand Supported
Palladium-Catalyzed CÀO Bond
Formation through an Electronic
Pathway of Reductive Elimination:
Fluoroalkoxylation of Activated Aryl
Halides
CÀO coupling: A BrettPhos ligand sup-
ported Pd-catalyzed CÀO bond-forming
reaction of activated aryl halides with
primary fluoroalkyl alcohols is reported.
BrettPhos ligand (L1) can alter the
(see scheme; Rf =–(CF2)nCF3; R=elec-
tron-releasing groups (ERGs) at o-, m-
and p-positions, -neutral, and electron-
withdrawing groups at o- and m-posi-
tions; EWG=electron-withdrawing
group).
mechanistic pathway of reductive elimi-
nation from nucleophile to nucleophile
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