Palladium-Catalyzed Arylation of Fluoroalkylamines

Article abstract of DOI:10.1021/jacs.5b02512

We report the synthesis of fluorinated anilines by palladium-catalyzed coupling of fluoroalkylamines with aryl bromides and aryl chlorides. The products of these reactions are valuable because anilines typically require the presence of an electron-withdrawing substituent on nitrogen to suppress aerobic or metabolic oxidation, and the fluoroalkyl groups have steric properties and polarity distinct from those of more common electron-withdrawing amide and sulfonamide units. The fluoroalkylaniline products are unstable under typical conditions for C-N coupling reactions (heat and strong base). However, the reactions conducted with the weaker base KOPh, which has rarely been used in cross-coupling to form C-N bonds, occurred in high yield in the presence of a catalyst derived from commercially available AdBippyPhos and [Pd(allyl)Cl]₂. Under these conditions, the reactions occur with low catalyst loadings (<0.50 mol % for most substrates) and tolerate the presence of various functional groups that react with the strong bases that are typically used in Pd-catalyzed C-N cross-coupling reactions of aryl halides. The resting state of the catalyst is the phenoxide complex, (BippyPhosPd(Ar)OPh); due to the electron-withdrawing property of the fluoroalkyl substituent, the turnover-limiting step of the reaction is reductive elimination to form the C-N bond.

Full text of DOI:10.1021/jacs.5b02512

Subscriber access provided by NEW YORK UNIV
Article
Palladium-Catalyzed Arylation of Fluoroalkylamines
Andrew T. Brusoe, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b02512 • Publication Date (Web): 12 Jun 2015
Downloaded from http://pubs.acs.org on June 15, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Palladium-Catalyzed Arylation of Fluoroalkylamines
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Andrew T. Brusoe and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
Supporting Information Placeholder
Aniline derivatives containing fluoroalkyl groups should pos-
ABSTRACT: We report the synthesis of fluorinated anilines by
palladium-catalyzed coupling of fluoroalkylamines with aryl
bromides and aryl chlorides. The products of these reactions are
valuable because anilines typically require the presence of an
electron withdrawing substituent on nitrogen to suppress aerobic
or metabolic oxidation, and the fluoroalkyl groups have distinct
steric properties and polarity from more common electron-
withdrawing amide and sulfonamide units. The fluoroalkylaniline
products are unstable under typical conditions for C-N coupling
reactions (heat and strong base). However, the reactions conduct-
ed with the weaker base KOPh, which has rarely been used in
cross-coupling to form C-N bonds, occurred in high yield in the
presence of a catalyst derived from commercially available Ad-
BippyPhos and [Pd(allyl)Cl]2. Under these conditions, the reac-
tions occur with low catalyst loadings (<0.50 mol% for most sub-
strates) and tolerate the presence of various functional groups that
react with the strong bases that are typically used in Pd-catalyzed
C-N cross coupling reactions of aryl halides. The resting state of
the catalyst is the phenoxide complex, (BippyPhosPd(Ar)OPh);
due to the electron-withdrawing property of the fluoroalkyl sub-
stituent, the turn-over limiting step of the reaction is reductive
elimination to form the C-N bond.
sess electronic properties that would mitigate oxidation. Con-
sistent with this assertion, fluoroalkylanilines have been shown to
be more stable toward P450 mediated oxidation than alkyl anilines
lacking fluorine atoms.12 While sharing the electronic properties
of the sulfonyl and carbonyl derivatives, the solubility properties,
intermolecular interactions, and steric properties of fluoroalkyl
anilines are distinct from those of sulfonyl and carbonyl deriva-
tives.
Figure 1. Historically important aniline derivatives and recently
patented fluorinated amine derivatives
Int roduction
The ability of fluorine atoms to change the electronic properties
of neighboring atoms has led to scattered examples of medi-
cines,13–17 agrochemicals,18 and dyes19,20 containing fluoroalkyl
aniline groups (Figure 1), but these aniline derivatives have not
been widely studied. One reason for the uncommon use of β-
fluoroalkyl anilines in these applications is that the methods to
prepare such substructures are limited, particularly from the aryl
halide synthetic intermediates commonly generated in medicinal
chemistry. The two most commonly used methods for the prepa-
ration of β-fluorinated anilines (e.g. N-trifluoroethyl aniline) are
the reductive amination of trifluoroacetaldehyde21 with the corre-
sponding aniline derivative and SNAr reactions.22 However, re-
ductive aminations form the N-alkyl bond, rather than the N-aryl
bond, and SNAr reactions require strongly electron-deficient
arenes and have been shown to occur slowly with the weakly
nucleophilic β−fluorinated amines.23 Additionally, aryl halides
can be coupled with trifluoroacetamide but the scope of this trans-
formation is limited and requires an additional step to generate a
fluorinated aniline.24–26
Molecules containing aniline and aniline derivatives are com-
mon in the pharmaceutical, agrochemical, and pigment indus-
tries.1 For example, an acetamide is found in the highest grossing
prescription drug of all time (Lipitor)2 and the most commonly
administered over-the-counter pain drug (Tylenol).3 In addition,
many of the most widely applied herbicides (e.g. Metolachlor)4,
as well as common pigment chromophores (e.g. Mauveine A)5,6
,
are aniline derivatives (Figure 1). Because of these important
applications, numerous classical and modern methods for the
preparation of anilines have been reported.7
Aniline derivatives containing electron-withdrawing substitu-
ents are more valuable than the parent anilines in medicinal chem-
istry because anilines are prone to oxidation.1 For example, N-
alkyl anilines are susceptible to aerobic or metabolic degradation
to the corresponding aniline via oxidation by cytochrome P4508,
and the parent anilines are usually oxidized further to N-aryl hy-
droxylamines that generate carcinogenic arenium ions.9–11 Thus,
anilines derivatives, such as sulfonamides, amides, ureas, or car-
bamates, possessing electron-withdrawing groups are the deriva-
tives most commonly contained in pharmaceuticals and agro-
chemicals.
Metal-catalyzed C-N coupling reactions could provide a gen-
eral method for preparing fluorinated anilines and would enable
chemists to evaluate these substructures as part of studies on
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 11
structure-activity relationships by conducting reactions on the
1
2
3
4
5
6
7
8
same aryl halide intermediate as would be used to introduce other
substituents from nitrogen, oxygen or carbon nucleophiles.27
However, general conditions for cross couplings of aryl halides
with fluorinated amines have not been reported. Buchwald report-
ed a single cross coupling of trifluoroethylamine (with 5-
bromoindazole), and this reaction occurred in moderate yield
(65%).28 In fact, the authors of this work concluded that trifluoro-
ethylamine hydrochloride inhibited cross couplings under the
standard conditions developed for the amination of het-
eroarenes.29 Thus, the requirements for achieving the coupling
with fluoroalkylanilines are distinct from those for coupling of
alkylamines or anilines, presumably due to the strong electron-
withdrawing effect of the trifluoromethyl group.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We report a generally applicable coupling of aryl bromides and
chlorides with primary amines containing fluorine β-to nitrogen.
The reaction occurs with a wide substrate scope, under mild con-
ditions, and with inexpensive reagents, precatalysts, and ligand.
One key to developing this process was revealing that strong base
leads to decomposition of the product and, therefore, identifying a
base that is sufficiently weak to avoid decomposition of the cou-
pled product but sufficiently strong to induce formation of the
arylpalladium amido intermediate. A second unusual feature of
the reaction is the resting state; the major palladium complex in
the reaction is an adduct with the phenoxide base. A third unusual
feature is the rate-limiting step. The electron-withdrawing proper-
ty of the fluoroalkyl group retards reductive elimination to form
the C-N bond, and kinetic studies indicate that this step has the
highest energy transition state, even though the reaction is con-
ducted with a palladium catalyst containing a class of ligand that
typically leads to fast reductive elimination.
Figure 2. a) Initial conditions for the coupling of trifluoroethyla-
mine with aryl bromides. b) Identification of bases that do not
cause decomposition of β-fluoroalkylanilines as determined by
19F NMR spectroscopy. The DMSO or THF pKa values are
shown for the conjugate acids of the soluble bases.
Heating an isolated fluoroalkylaniline in the presence of NaOt-
Bu showed that NaOtBu induces the decomposition of the product
under the reaction conditions. Therefore, the stability of 1 was
tested in the presence of various bases at 100 °C for 6 h in diox-
ane to determine which bases do not induce decomposition of 1.
Strong bases, such as LiHMDS, NaOtBu, and KOtBu, caused
complete decomposition of the product 1, whereas weaker inor-
ganic bases and KOPh caused only minimal decomposition of 1
(Figure 2b). Although we have not identified the decomposition
products, alkoxymethyl anilines have been shown to undergo
strong-base-mediated decomposition.30
Results and Discussion
Reaction Development. Due to the similar basicity of trifluo-
roethylamine and aniline, we hypothesized that trifluoroethyla-
mine would couple with aryl halides under conditions reported for
the coupling of aniline with aryl halides.29 To test this hypothesis,
trifluoroethylamine was allowed to react with 4-n-butyl bromo-
benzene in the presence of a Josiphos-ligated catalyst that couples
anilines with aryl halides with broad scope under mild condi-
tions.29 This reaction produced 1 in 81% yield after 15 hours
(Figure 2a). However, the yields of reactions of more electron-
rich or o-substituted aryl halides under these conditions reached a
maximum value (50%-73%, determined by 19F NMR spectrosco-
py) within an hour and decreased at longer reaction times. This
decrease in yield over time implied that the trifluoroethylaniline
products are unstable under the reaction conditions.
When coupling reactions were conducted in the presence of
these weaker bases, the yields of 1 were lower than 10% with a
Josiphos-ligated catalyst. Therefore, we sought combinations of
palladium precursors and ligands that would catalyze the reaction
under conditions with the weaker bases. Generally, the coupling
reactions of amines with aryl halides catalyzed by bisphosphine-
ligated Pd complexes require strong bases, whereas coupling reac-
tions catalyzed by monophosphine-ligated Pd complexes can be
conducted with weaker bases. It has been proposed that weaker
bases can be used because the amine binds more readily to an
LPd(Ar)(X) containing a monophosphine than to an L2Pd(Ar)(X)
complex containing
a
bisphosphine.31 The pKa of mono-
phosphine ligated LPd(Ar)(X)(amine) complexes are calculated
to be between 8 and 10 in H2O32 and can be deprotonated by weak
base.
Based on this information, we evaluated catalysts containing
monophosphine ligands in the presence of weak bases for the
coupling of aryl halides with fluorinated amines. Results are
summarized in Table 1. The combination of [Pd(allyl)Cl]2, Ad-
BippyPhos, and KOPh catalyzed the coupling of 4-n-butyl bro-
mobenzene with trifluoroethylamine in high yield using just 0.10
mol % catalyst. Under these conditions, no diarylamine or diaryl
ether products were observed. Phenoxides are not typical bases
for Pd-catalyzed C-N coupling reactions but have been used in
selected cases previously.32–35
Although the coupling of amines with aryl halides catalyzed by
complexes of AdBippyPhos has not previously been reported,
Singer at Pfizer published such couplings catalyzed by complexes
2
ACS Paragon Plus Environment

Page 3 of 11
Journal of the American Chemical Society
quire stronger bases, the test reaction conducted with the catalyst
Table 1. Effect of changing various reaction conditions for the
coupling of trifluoroethylamine with 4-n-butyl bromobenzene.
1
2
3
containing a hindered Josiphos ligand that is highly reactive for
coupling of primary amines with NaO-t-Bu base did not produce
any product under these conditions (Entry 4).
4
5
6
7
8
9
The effect of other reaction parameters on yield was evaluated
by allowing trifluoroethylamine to react with 4-n-butyl bromo-
benzene in the presence of a catalyst generated in situ from
[Pd(allyl)Cl]2 and AdBippyPhos. When the catalyst was generat-
ed from a 1:1 or 1:2 ratio of Pd to ligand the yields were nearly
identical (93% vs 99%). However, full conversion of the substrate
was typically achieved with lower loadings of the catalyst when a
1:2 ratio of Pd to ligand was used. For example, the reaction of
trifluoroethylamine with 3-chloropyridine to produce 14 occurred
to full conversion with a catalyst loading of 0.400 mol % when
generated from a 1:1 ratio of Pd to ligand, whereas the same reac-
tion required 0.250 mol % of catalyst to occur to completion with
a 1:2 ratio of Pd to ligand. Rigorously dry and air free conditions
are not required to obtain high yields of products. The model
reaction assembled in air and run with wet dioxane afforded 1 in
94% yield. A reaction conducted with sodium phenoxide, which
is fully soluble in dioxane under the reaction conditions, occurred
in the same yield as the reaction conducted with potassium phe-
noxide (Entry 10).41 Although KOPh is not available from com-
mon chemical suppliers, reactions conducted with this base gen-
erated and used in situ from phenol and KOtBu occurred in the
same yield as those initiated with isolated KOPh (Entry 11).
Entry
Deviation from Standard Conditions
tBuBrettPhos instead of AdBippyPhos
tBuXPhos instead of AdBippyPhos
JackiePhos instead of AdBippyPhos
CyPFtBu instead of AdBippyPhos
Yielda
88%
10%
10%
0%
1
2
3
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
6
7
8
9
tBuBippyPhos instead of AdBippyPhos
CyBippyPhos instead of AdBippyPhos
1:1 Metal to Ligand Ratio instead of 1:2
NaOtBu instead of KOPh
100%
20%
93%
43%
94%
Assembled on bench top with wet solvents in a
vial, not in a glove box with dried solvents
10
11
NaOPh instead of KOPh
100%
100%
1.10 equiv of phenol, 1.05 equiv of KOtBu or
NaOtBu instead of isolated KOPh
Scope of the Arylation of Fluoroalkylamines. Figure 3 sum-
marizes the scope of the reaction of trifluoroethylamine with a
variety of aryl and heteroaryl bromides and chlorides under the
conditions shown in Table 1. The minimum amount of catalyst
required for each reaction to reach full conversion is reported.
Electron-neutral (1), electron-rich (2 - 4), and electron-poor aryl
halides (5 - 10) reacted to form the corresponding trifluoroethyl-
aniline in good isolated yields within 6 h. The reactions of aryl
halides possessing ortho substituents also occurred to form prod-
ucts 10–12 in high yield, but required higher catalyst loadings
than reactions of less-hindered substrates. In addition, the cou-
pling of 2,6-dimethyl-chlorobenzene occurred in good yield with
0.750 mol % catalyst;the reactions catalyzed by the system gener-
ated from CyBippyPhos as the ligand occurred in higher yield
than those containing AdBippyPhos as ligand. Although the iso-
lated yield of 13 is moderate because the compound is volatile,
the reaction occurs in 92% yield, as determined by 19F NMR
spectroscopy.
aYield determined by 19F NMR spectroscopy
of BippyPhos.36,37 Stradiotto and coworkers recently reported the
scope of C-N coupling reactions catalyzed by palladium com-
plexes of tBuBippyPhos and showed that this system catalyzes the
coupling of a wide variety of aryl halides and amines with low
catalyst loadings.38 Researchers at Abbot reported that palladium
complexes of BippyPhos catalyze the N-arylation of ureas.39 Fi-
nally, Beller has shown that the combination of palladium and
AdBippyPhos catalyzes the etherification of aryl halides with
primary alcohols.40 Other BippyPhos derivatives, all of which are
commercially available and readily synthesized, form complexes
that catalyze this transformation (Table 1). The reaction of trifluo-
roethylamine with 4-n-butyl bromobenzene catalyzed by the
complex generated from [Pd(allyl)Cl]2 and tBuBippyPhos formed
the product in same yield as the system derived from AdBip-
pyPhos. However, we found the yields and conversions for reac-
tions of aryl halides other than 4-n-butyl bromobenzene were
typically higher for reactions conducted with AdBippyPhos than
for those conducted with tBuBippyPhos. Catalysts generated from
both ligands were selective for C-N bond formation; side products
from etherification with the phenoxide base and hydrodehalo-
genation were generally not observed. The analogous reaction
conducted with CyBippyPhos as the ligand occurred in much
lower yield, but the reactions of highly hindered substrates oc-
curred in high yield when catalyzed by the complex containing
this ligand (vide infra). While tBuBrettPhos generates a system
that catalyzes the reaction in high yield, other monophosphine
ligands, such as tBuXPhos (Entry 2) or JackiePhos (Entry 3) did
not generate a catalyst that produces the product in greater than
10% yield. Consistent with prior observations that aryl halide
aminations catalyzed by complexes ligated by bisphosphines re-
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 11
halides containing acidic N-H bonds, such as 5-bromo-indole, did
not react to form trifluoroethylanilines under these conditions.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Scope of the reaction of substrates containing function-
al groups that are sensitive to base or nucleophiles (shown in
blue).
The reactions of aryl halides containing functional groups that
are sensitive to strong base and nucleophiles are shown in Figure
4. Unprotected acetophenones (24 and 25), free alcohols (26),
acetamides (27), methyl cinnamate esters (28), and non-enolizable
aldehydes (29) all were tolerated under the standard reaction con-
ditions. Although competing reactions of these functional groups
were not observed in most cases, small amounts of side products
were observed in the reactions to form 26 and 29. However, high
yields of these products were obtained by simply increasing the
number of equivalents of amine.
The combination of high functional group compatibility and the
tolerance of basic functional groups should allow this reaction to
occur with a wide range of medicinally relevant compounds. For
example, the coupling of Etoricoxib with trifluoroaniline occurred
with low loadings of the catalyst without undergoing side reac-
tions. It is likely that the low nucleophilicity and basicity of both
KOPh and trifluoroethylamine, as well as the low solubility of
KOPh in dioxane, create the high functional group compatibility.
Scheme 1. Fluoroalkylamination of Etoricoxib
To determine the scope of the fluoroalkylamines that undergo
this coupling process we evaluated our conditions for the coupling
of three fluorinated amines that would form fluorinated anilines
with various properties (Figure 5). Coupling with difluoroethyla-
mine (pKa conjugate acid = 7.1)42 would generate an aniline that
should be less prone to oxidation than a typical aniline, while
possessing two hydrogen bond donors (N-H and the C-H of
CF2H).43 The coupling of pentafluoropropylamine (pKa conjugate
acid = 5.7)44 was also conducted because perfluoroethyl groups
have been shown to alter lipophilicity and would further suppress
alkyl aniline oxidation. Finally, the coupling of β,β-
difluorophenethylamine (pKa conjugate acid = 6.8)45 was evalu-
ated because phenethylamine moieties are present in many bio-
logically active compounds. Both difluoroethylamine and pen-
tafluoropropylamine are commercially available; difluorophene-
4
Figure 3. Scope of the fluoroalkyklamination of aryl halides.
Unless otherwise stated, the yields refer to isolated material from
reactions with 0.5 mmol of aryl or heteroaryl halide. aYield meas-
ured by 1H NMR spectroscopy. bThe pyridinium hydrochloride
salt was used with 2.05 equiv KOPh. cConducted with 0.35 mmol
of aryl halide.
The reactions of a variety of heteroaryl halides were also eval-
uated under these conditions, including those of 2-, 3-, and 4-
halopyridines, pyrimidines, quinoxalines, thiophenes, indoles, and
benzothiazoles. These reactions generally occurred in the pres-
ence of low loadings of catalyst to form heteroaryl trifluoroethyl
anilines 14 – 23 in high yield. However, other 5-membered het-
eroaryl halides, such as N-trityl-4-chloro-pyrazole, and heteroaryl
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
thylamine was prepared in two steps from ethyl difluoro-
phenylacetate.
rides. This result suggests that the side products are not formed by
1
2
3
an SNAr process, but are likely formed via the palladium catalyst,
presumably by direct reductive elimination of the palladium rest-
ing state.
The selectivity for amination over etherification was improved
by reducing the reaction temperature (80 °C instead of 100 °C),
using a slightly less-hindered ligand (tBuBippyPhos instead of
AdBippyPhos), and by increasing the number of equivalents of
amine (from 2.0 to 3.0). These modified conditions afforded
higher yields from reactions of aryl halides containing strongly
electron-withdrawing groups. The SFC traces of products isolated
from reactions of enantiopure trifluoroisopropylamine do not
contain a signal at the retention time corresponding to the minor
enantiomer.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Fluoroalkyl anilines derived from difluoroethyl-, pen-
tafluoropropyl-, and β-β-difluorophenethylamine. All yields are
isolated yields of 0.50 or 0.35 mmol reactions.
These fluoroalkylamines were allowed to react with a set of ar-
yl halides that contain different electronic and steric properties
(Figure 5, electron-rich, electron-deficient, heteroaromatic, and o-
substituted). These amines reacted under our standard conditions
to form the coupled products in good yields. Like the couplings of
trifluoroethylamine, these reactions occurred in high yields with
catalyst loadings of just 0.100 – 0.600 mol %. The reactions of
difluoroethylamine and pentafluoropropyl amine required two
equivalents of amine, presumably due to the low boiling point of
these amines (68 °C and 50 °C, respectively). However, reactions
of difluorophenethylamine occurred to full conversion of the aryl
halide with just 1.1 equiv of amine.
Branched fluorinated amines and secondary fluorinated amines
could react to form fluoroalkyl anilines that cannot be readily
prepared via reductive amination or alkylation. Therefore, the
coupling of additional fluorinated amines were conducted under
our standard reaction conditions. Reactions of trifluoroisopropyl-
amine with the same subset of aryl halides used to generate the
products in (see Figures 5 and 6a), occurred to high conversion
but variable yield. In contrast to the reactions of primary un-
branched fluoroalkylamines (e.g., trifluoroethylamine), reactions
of trifluoroisoropylamine formed products from etherification of
the aryl halide in certain cases. These side-products were formed
in greater than 10% yield from the reactions of aryl halides con-
taining electron-withdrawing (p-cyano in 43) or ortho (o-methyl
in 45) substituents, presumably because these substituents accel-
erate direct reductive elimination from the phenoxide resting state
54 (vide infra). The selectivity between etherification and amina-
tion was the same for reactions of aryl bromides and aryl chlo-
Figure 6. Fluoroalkyl anilines derived from trifluoroisoporpyla-
mine and 2-(trifluoromethyl)pyrrolidine. Reactions were conduct-
ed on 0.300 mmol scale; yields of products obtained from aryl
chlorides are isolated yields, whereas yields of reactions of aryl
a
bromides were determined by 19F NMR spectroscopy. Reaction
conducted with tBuBippyPhos as the ligand and with 3.00 equiv
of amine.
These conditions do not lead to the coupling of the same set of
aryl halides with 2-(trifluoromethyl)pyrrolidine; instead, such
couplings occur with the catalyst containing CyBippyPhos as
ligand and with NaOtBu as base (Figure 6b) at 65 °C.46 Although
reactions of representative ortho-substituted aryl halides or het-
eroaryl halides occur in moderate yield, reactions of representa-
tive electron-rich and electron-deficient aryl halides occur in good
yield. The GC traces of products isolated from reactions of enan-
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
tiopure 2-(trifluoromethyl)pyrrolidine do not contain a signal at
the retention time corresponding to the minor enantiomer. Finally,
we investigated reactions of more highly fluorinated amines;
sion, the 31P NMR spectrum contained two singlets in a 1:1 ratio.
1
2
3
4
5
6
7
8
One singlet at 2.6 ppm corresponds to free tBuBippyPhos,
whereas the second singlet at 38.4 ppm corresponds to the resting
state of the palladium. The 19F NMR spectrum of the same reac-
tion contained resonances for 4-fluorochlorobenzene (-117.53
ppm), 4-fluoro-N-trifluoroethylaniline (53, -128.90 ppm), trifluo-
roethylamine (-76.68 ppm), and a new signal at -122.25 ppm.
This signal at -122.25 ppm was tentatively assigned to an arylpal-
ladium complex because the integration of this signal indicated
that the fluoroaryl group was present in the same concentration as
the palladium in the reaction. Furthermore, when the same reac-
tion was conducted with potassium 4-fluorophenoxide as the base,
an additional resonance at -134.09 ppm was present in the 19F
NMR spectrum. The intensity of this resonance was the same as
that of the resonance at -122.25 ppm (attributed to an arylpalladi-
um species). No 19F NMR signals that could be attributed to a Pd
amido complex were observed. The 31P NMR spectrum of an
identical reaction conducted with 4-fluorobromobenzene was the
same as the 31P spectrum of the reaction conducted with 4-
fluorochlorobenzene. This observation indicates that the resting
state lacks a halide ligand because the 31P NMR chemical shifts of
an aryl palladium chloride complex and an aryl palladium bro-
mide complex should be distinct from each other.
however,
couplings
of
hexafluoroisopropylamine
or
bis(trifluoroethyl)amine did not produce anilines under either set
of conditions.
Derivatization of the Coupled Products. As noted earlier in
this paper, the fluorinated anilines produced by coupling of triflu-
oroethylamine with aryl halides are unstable in the presence of
strong base at 100 °C (Figure 2). Thus, it was unclear if the fluor-
inated anilines would undergo decomposition in further transfor-
mations, such as a second arylation, acetylation, or alkylation that
would be conducted under basic conditions. To address this issue,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
we tested the room temperature coupling of
1 with 4-
bromoanisole in the presence of a catalyst for the coupling of
diarylamines with aryl halides and 1.2 equiv of NaOtBu (Equa-
tion 1). This reaction produced diaryl fluoroalkylamine 51 in
quantitative yield. This result indicates that decomposition of
fluorinated anilines in the presence of strong base does not occur
rapidly at room temperature. While a full evaluation of the reac-
tions of fluorinated anilines is beyond the scope of this paper, this
result indicates that the fluoroalkylanilines produced in this work
can undergo subsequent transformations that require strong base
when conducted at or near room temperature.
Collectively, these data suggest that the catalyst resting state is
[(tBuBippyPhos)Pd(Ar)(OPh)]. To test this hypothesis, we al-
lowed [Pd(allyl)Cl]2, tBuBippyPhos, 4-fluoro-chlorobenzene, and
potassium phenoxide to react at room temperature in THF. Filtra-
tion, partial removal of the solvent, and the addition of pentane
produced a yellow solid. The 31P NMR spectrum of this yellow
solid contained a single resonance that matched the 31P spectrum
of the catalyst resting state.
The structure of the catalyst resting state was unambiguously
shown by X-ray diffraction to be [(tBuBippyPhos)Pd(Ar)(OPh)]
(54, Figure 7). The complex contains a dative bond between Pd
and the bipyrazole backbone, which has been reported for the
tBuBippyPhos complex of PdCl2,47 and for other Pd complexes
containing bulky biaryl phosphine ligands.48–51 This complex is
stable in air in the absence of excess phenoxide, which is con-
sistent with the ability to conduct the amination without rigorous
exclusion of air.
Mechanistic Studies of the Coupling of Aryl Halides with
Fluoroalkylamines. Typical conditions for the Pd-catalyzed cou-
pling reactions to form C-N bonds include strong alkoxide or
amide bases, rather than the phenoxide base in the reactions re-
ported here. The fluorinated amines that undergo coupling under
these conditions are less basic than the non-fluorinated aliphatic
amines that are typically coupled with aryl halides. Therefore, we
studied the mechanism of the amination of fluoroalkylamines
under the catalytic reaction conditions we developed (Scheme 2)
to determine the effect of the low basicity and solubility of potas-
sium phenoxide and low nucleophilicity of the amine on the reac-
tion. Although higher TON are observed when the reaction is
conducted with the catalyst generated from AdBippyPhos as the
ligand than with the catalyst generated from tBuBippyPhos,
mechanistic studies were conducted with tBuBippyPhos as the
ligand because multigram quantities can be readily prepared from
inexpensive materials.
Scheme 2. Model reaction for mechanistic studies
Identification of the Catalyst Resting State. The reaction of 4-
fluorochlorobenzene (52) with trifluoroethylamine catalyzed by
the combination of 2.5 mol % of [Pd(allyl)Cl]2 and 10 mol % of
tBuBippyPhos was conducted in an NMR tube and was monitored
by 19F and 31P NMR spectroscopy (Scheme 2). At 50% conver-
Figure 7. Catalyst resting state 54 structure shown with 50%
thermal ellipsoid. Hydrogen atoms are omitted for clarity. Select-
ed bond lengths (Å) and angles (°) of 45: C1-Pd1 = 2.429(2);
6
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
C33-Pd1 = 1.992(2); O1-Pd1 = 2.0447(14); P1-Pd1 = 2.2658(6);
N3-C1-Pd1 = 103.74(12)
dium halide complex, conversion of the arylpalladium halide
1
2
3
4
5
6
7
8
complex to an arylpalladium fluoroalkylamido species, and reduc-
tive elimination to form Pd(0) and the C-N bond in the fluoroal-
kylamido product. However, the first mechanism (Figure 8a)
involves turnover-limiting reductive elimination, whereas the
second mechanism involves turnover-limiting formation of a pal-
ladium amido complex (Figure 8b). These two mechanisms can
be distinguished by additional kinetic experiments. If reductive
elimination were turnover limiting, then formation of the palladi-
um-amido complex would be reversible. In this scenario (Figure
8a), the amination reaction would be inverse 1st order in phenol
because it is generated as a stoichiometric by-product during the
ligand exchange.
Reaction Kinetics. To assess the connection between this com-
plex and the steps of the catalytic cycle, we determined the rate
law for the reaction (Scheme 2). To increase the solubility of the
base, potassium 4-nBu-phenoxide was used in place of KOPh.
The 31P NMR spectrum of a reaction conducted with 4-nBu-
phenoxide was the same as that conducted with KOPh. This result
indicates that the change in base does not cause a change in the
catalyst resting state.
9
The kinetics were determined by measuring initial rates with
the ratios of reagents close to that of the preparative reactions and
the isolated resting state as the catalyst. Due to the low boiling
point of trifluoroethylamine (BP = 35 °C), the rates were meas-
ured at 50 °C, instead of the 100 °C temperature of the preparative
reactions. The reaction progress was followed by the formation of
fluoroalkylaniline 53 by 19F NMR spectroscopy; this approach
was appropriate because the mass balance of the reaction with
respect to the limiting reagent (aryl halide 52) was >98%. The
reaction was conducted with 0.667 mol % of an equimolar
amount of the phenoxide complex 54 and tBuBippyPhos as cata-
lyst, aryl halide 52 as limiting reagent, 1.05 equiv 4-n-Bu-PhOK,
and 2.00 equiv trifluoroethylamine in dioxane.52 The amination
reaction was found to be 0th order in 1-chloro-4-fluorobenzene
and tBuBippyPhos; it was found to be 1st order in trifluoroethyl-
amine and in palladium phenoxide complex 54. A nearly zero, but
small positive dependence on the concentration of potassium 4-
nBu-phenoxide was also found; an explanation for this depend-
ence is presented below.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Determination of the order of the reaction in phenol is com-
plex because phenol forms strong hydrogen-bond adducts with
phenoxide.53 These hydrogen bond adducts reduce the concentra-
tion of free phenol. Therefore we monitored the initial rates of
stoichiometric reactions of the palladium phenoxide 54 with tri-
fluoroethylamine in the presence of varied concentrations of phe-
nol (eq 2) in the absence of phenoxide base. Analysis of the initial
rates (Figure 9) showed that the reaction of 54 with trifluoroethyl-
amine is inverse 1st order in phenol. This result implies that the
conversion of the phenoxide to the arylamine and Pd(0) species
occurs by reversible proton exchange between the amine and the
phenoxide complex, followed by irreversible reductive elimina-
tion to form the arylamine product.
Figure 9. Plot of 1/Initial Rate versus the concentration of phe-
nol used to determine the reaction order in phenol.
The inverse order observed for phenol and the formation of
strong hydrogen bonds between potassium phenoxides and phe-
nols provides a plausible explanation for the observed partial
order in potassium 4-nBu-phenoxide. Excess 4-nBu-phenoxide
reduces the concentration of the phenol byproduct because the
phenoxide hydrogen bonds to the phenol. Therefore the concen-
tration of free phenol is higher in reactions conducted with lower
concentrations of 4-nBu-phenoxide than in reactions conducted
with higher concentrations of the phenoxide, and reactions con-
ducted with higher concentrations of 4-nBu-phenoxide occur
faster than reactions conducted with lower concentrations of the
phenoxide.
Figure 8. Two mechanisms consistent with the observed rest-
ing state and reaction kinetics.
Two mechanisms that fit the kinetic data are shown in Figure 8.
Both mechanisms include oxidative addition to form an arylpalla-
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
To determine the relative reactivity of different amines under
ally direct view of the formation of the amido complex. The ami-
1
2
3
4
5
6
7
8
these conditions, we conducted a reaction containing three distinct
nitrogen nucleophiles: n-butylamine, p-toluidine, and pen-
tafluoropropylamine (eq 3) in the presence of 1.0 mol % catalyst.
This coupling occurred to full conversion in just 30 min at 65 °C.
Products arising from the couplings of p-toluidine and n-
butylamine were formed in 55% and 44% yield, respectively; the
product from coupling of pentafluoropropylamine was not ob-
served under these conditions. The formation of products from the
aryl and alylamine over the fluoroalkylamine could be due to
faster formation of the alkylamido or anilido complex relative to
the formation of a fluoroalkylamido complex or from faster re-
ductive elimination from the alkylamido or anilido complexes
than from the fluoroalkylamido complex. Although we have not
studied the origin of the observed selectivity, this result clearly
demonstrates that the weak basicity of fluorinated amines dramat-
ically changes the rate at which they react in C-N coupling reac-
tions. Furthermore, this experiment demonstrates that the combi-
nation of this catalyst and phenoxide base is suitable for the cou-
pling of alkylamines and arylamines, although we have not yet
studied the scope of reactions with this base in depth.
do complex has been proposed to form in cross-coupling reactions
by coordination of the amine, followed by deprotonation of the
bound amine by the base, or by formation of an alkoxide com-
plex, followed by proton transfer to convert the alkoxide complex
to an amido complex.58 For reactions catalyzed by complexes of
monophosphine complexes, the most commonly proposed mech-
anism is that involving coordination of the amine and deprotona-
tion.59,60
Numerous groups have reported the preparation of arylpalladi-
um-amine complexes ligated by monophosphines and have shown
that addition of amide or alkoxide base to these complexes results
in the formation of anilines by reductive elimination from an ar-
ylpalladium amido intermediates.59,61,62 These data imply that the
reactions of alkylamines catalyzed by complexes of bulky mono-
phosphines occurs by coordination of the amine and deprotona-
tion by base.63 For this reason, the direct observation of a phenox-
ide complex bound by a monophosphine as the resting state was
unexpected. Assuming the proposed mechanism for formation of
an alkylamido complex from the previous work is valid, the dif-
ference in mechanism for the reaction of alkylamines in the prior
studies and the fluoroalkylamines in the current studies likely
results from the large difference in Lewis basicity of the two types
of amines or the different properties of phenoxide bases relative
to tert-alkoxide bases. Indeed, the prior observation of an alkoxo
complex during cross coupling to form amines catalyzed by com-
plexes of bisphosphines was made on the reaction of an arylamine
mediated by NaOtBu, not an alkylamine.64,65
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Mechanistic Conclusions. Our mechanistic data are consistent
with the pathway shown in Figure 8a. Oxidative addition of the
aryl halide occurs to the palladium(0) species ligated by tBuBip-
pyPhos to generate a tBuBippyPhos(Ar)X complex. This complex
reacts with phenoxide to generate the catalyst resting state, phe-
noxide complex 54. Complex 54 reacts reversibly with trifluoro-
ethylamine to form an amido complex. The transition state with
the highest energy is that for reductive elimination.
Conclusion
In summary, we have developed conditions for the coupling of
primary fluoroalkylamines with aryl bromides and aryl chlorides.
The reaction occurs in high yield and can be conducted with low
catalyst loadings for most substrates. The observed instability of
the products toward strong bases led to the development of condi-
tions in which weaker bases are used to promote the coupling
reaction. Moreover, the combination of the low nucleophilicity of
the amine and the low basicity of KOPh allows the reaction to
occur in the presence of functional groups that are typically not
tolerated by C-N coupling reactions. We anticipate that the prod-
ucts will have useful applications in pharmaceutical and agro-
chemical industries.
It is unusual for Pd-catalyzed couplings of an aryl halide with
an amine catalyzed by a complex containing a monophosphine
ligand to occur with reductive elimination as the turnover-limiting
step. Two prior studies, one on the coupling of benzophenone
hydrazone54 and one on the coupling of ammonia55 with aryl hal-
ides implied that reductive elimination was the turn-over limiting
step. However, these studies were conducted with palladium cata-
lysts ligated by the bisphosphines BINAP and Josiphos, respec-
tively. Thus, our mechanistic experiments reveal an unusual case
in which aryl halide amination catalyzed by palladium ligated by
a monophosphine occurs with reductive elimination as the turno-
ver-limiting step. The reaction of the fluoroalkylamines in the
current also constitute an unusual case in which the coupling of an
aryl halide with an aliphatic amine occurs by a mechanism in-
volving turnover limiting reductive elimination. The unusual
turnover-limiting step is likely the result of the strongly electron-
withdrawing property of the trifluoroethyl group. Reductive elim-
ination from palladium amido complexes derived from electron
rich amines (e.g. iBuNH2) has been shown to be faster than reduc-
tive elimination from palladium amido complexes derived from
less electron rich amines (PhNH2).56 Indeed, the only other case
of reductive elimination as the slow step in a C-N coupling reac-
tion of an aliphatic amine catalyzed by a monophosphine ligated
palladium complex was recently reported, although the authors
concede they cannot exclude formation of the amido complex as
the turnover limiting step.57
The reaction occurs with several unusual mechanistic features.
First, the catalyst resting state is the phenoxide complex
[(tBuBippyPhos)Pd(Ar)(OPh)] (54). The observation of this com-
plex is the first evidence that a monophosphine ligated arylpalla-
dium phenoxide or alkoxide complex can be an intermediate in
the coupling process. Second, the turnover-limiting step for the
reaction is reductive elimination. The kinetic data provide rare
evidence that reductive elimination to form a C-N bond can be
rate-limiting during cross-coupling reactions to form amines cata-
lyzed by complexes of the commonly used bulky monophos-
phines. These unusual features result from the selection of a base,
rarely used in cross coupling, that enabled reactions to form prod-
ucts valuable for medicinal chemistry, agrochemistry, and coordi-
nation chemistry, from a class of amine that is unexplored for
cross-coupling reactions.
ASSOCIATED CONTENT
Supporting Information
The resting state of the catalyst in the current study is also
unique for a coupling to form an arylamine and allows an unusu-
8
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
NMR spectra (1H, 13C, 19F, 31P), HRMS, and IR spectra of all
(22) Francotte, P.; Goffin, E.; Fraikin, P.; Lestage, P.; Van Heugen, J.-
C.; Gillotin, F.; Danober, L.; Thomas, J.-Y.; Chiap, P.; Caignard, D.-H.;
Pirotte, B.; de Tullio, P. J. Med. Chem. 2010, 53, 1700.
(23) Ormazábal-Toledo, R.; Contreras, R.; Tapia, R. A.; Campodónico,
P. R. Org. Biomol. Chem. 2013, 11, 2302.
1
2
3
reaction products are include in the supporting information. “This
material is available free of charge via the Internet at
http://pubs.acs.org.”
4
5
6
7
8
9
(24) Wiedemann, S. H.; Ellman, J. A.; Bergman, R. G. J. Org. Chem.
2006, 71, 1969.
(25) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 13001.
(26) Tao, C.-Z.; Li, J.; Fu, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett.
2008, 49, 70.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jhartwig@berkeley.edu.
(27) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(28) Henderson, J. L.; Buchwald, S. L. Org. Lett. 2010, 12, 4442.
(29) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(30) Barluenga, J.; Bayón, A. M.; Asensio, G. J. Chem. Soc. Chem.
Commun. 1983, 19, 1109.
(31) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359.
(32) Hoi, K. H.; Organ, M. G. Chem. Eur. J. 2012, 18, 804.
(33) Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 12905.
(34) Shekhar, S.; Hartwig, J. F. Organometallics 2007, 26, 340.
(35) Schulte II, J.; Tweedie, S. Synlett 2007, 2331.
(36) Singer, R. A.; Doré, M.; Sieser, J. E.; Berliner, M. A. Tetrahedron
Lett. 2006, 47, 3727.
(37) Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org. Process Res. Dev.
2008, 12, 480.
(38) Crawford, S. M.; Lavery, C. B.; Stradiotto, M. Chem. Eur. J. 2013,
19, 16760.
(39) Kotecki, B. J.; Fernando, D. P.; Haight, A. R.; Lukin, K. A. Org.
Lett. 2009, 11, 947.
(40) Gowrisankar, S.; Sergeev, A. G.; Anbarasan, P.; Spannenberg, A.;
Neumann, H.; Beller, M. J. Am. Chem. Soc. 2010, 132, 11592.
(41) Sodium phenoxide is commercially available but some samples
from some commercial suppliers contain impurities that inhibit the cou-
pling reaction. For example, a reaction containing anhydrous NaOPh from
a new bottle purchased from MP Biomedicals did not produce any prod-
uct, whereas a similar reaction wherein NaOPh generated from phenol and
NaH produced 1 in quantitative yeild. See the supporting information for
more details.
(42) Love, P.; Cohen, R. B.; Taft, R. W. J. Am. Chem. Soc. 1968, 90,
2455.
(43) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
(44) Podol’skii, A. V.; German, L. S.; Knunyants, I. L. Bull. Acad. Sci.
USSR Div. Chem. Sci. 1967, 16, 1092.
(45) Molloy, Bryan B.; Fuller, Ray W. In Biochemistry Involving Car-
bon-Fluorine Bonds; ACS Symposium Series; AMERICAN CHEMICAL
SOCIETY, 1976; Vol. 28, pp 77–98.
(46) A coupling of an aryl chloride with (trifluoromethyl)pyrrolidine
was reported while this manuscript was under revision. Park, N. H.;
Vinogradova, E. V.; Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed.
2015, 10.1002/anie.201502626.
(47) Lavery, C. B.; Rotta-Loria, N. L.; McDonald, R.; Stradiotto, M.
Adv. Synth. Catal. 2013, 355, 981.
(48) Christmann, U.; Pantazis, D. A.; Benet-Buchholz, J.; McGrady, J.
E.; Maseras, F.; Vilar, R. J. Am. Chem. Soc. 2006, 128, 6376.
(49) Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Organometallics
2007, 26, 2183.
Notes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A provisional patent based on this worked has been filed.
ACKNOWLEDGMENT
We thank the Dow Chemical company and the NIH (GM-55382
and Shared Instrumentation Grant S10-RR027172) for funding.
A.T.B. thanks Rebecca A. Green, Matthew A. Larsen, and Dr.
Patrick S. Fier for helpful conversations.
REFERENCES
(1) The Chemistry of Anilines; Rappoport, Z., Ed.; Wiley, 2007; Vol.
1.
(2) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ.
2010, 87, 1348.
(3) Schiødt, F. V.; Rochling, F. A.; Casey, D. L.; Lee, W. M. N. Engl.
J. Med. 1997, 337, 1112.
(4) Blaser, H.-U. Adv. Synth. Catal. 2002, 344, 17.
(5) Perkin, W. H. Proc. R. Soc. Lond. 1862, 12, 713.
(6) Sousa, M. M.; Melo, M. J.; Parola, A. J.; Morris, P. J. T.; Rzepa, H.
S.; de Melo, J. S. S. Chem. Eur. J. 2008, 14, 8507.
(7) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In
PATAI’S Chemistry of Functional Groups; John Wiley & Sons, Ltd, 2009.
(8) Guengerich, F. P. Chem. Res. Toxicol. 2001, 14, 611.
(9) Wiśniewska-Knypl, J. M.; Jablońska, J. K.; Piotrowski, J. K. Br. J.
Ind. Med. 1975, 32, 42.
(10) French, C. L.; Yaun, S.-S.; Baldwin, L. A.; Leonard, D. A.; Zhao,
X. Q.; Calabrese, E. J. J. Appl. Toxicol. 1995, 15, 167.
(11) Wu, X.; Kannan, S.; Sadagopa Ramanujam, V. M.-; Firoze Khan,
M. J. Toxicol. Environ. Health A 2005, 68, 657.
(12) Bhakta, M.; Hollenberg, P. F.; Wimalasena, K. Chem. Commun.
2005, No. 2, 265.
(13) Fauber, B. P.; de Leon Boenig, G.; Burton, B.; Eidenschenk, C.;
Everett, C.; Gobbi, A.; Hymowitz, S. G.; Johnson, A. R.; Liimatta, M.;
Lockey, P.; Norman, M.; Ouyang, W.; René, O.; Wong, H. Bioorg. Med.
Chem. Lett. 2013, 23, 6604.
(14) Phillips, B.; Cai, R.; Delaney, W.; Du, Z.; Ji, M.; Jin, H.; Lee, J.;
Li, J.; Niedziela-Majka, A.; Mish, M.; Pyun, H.-J.; Saugier, J.; Tirunagari,
N.; Wang, J.; Yang, H.; Wu, Q.; Sheng, C.; Zonte, C. J. Med. Chem. 2014,
57, 2161.
(15) Steinman, M.; Topliss, J. G.; Alekel, R.; Wong, Y.-S.; York, E. E.
J. Med. Chem. 1973, 16, 1354.
(16) Van Oeveren, A.; Pio, B. A.; Tegley, C. M.; Higuchi, R. I.; Wu,
M.; Jones, T. K.; Marschke, K. B.; Negro-Vilar, A.; Zhi, L. Bioorg. Med.
Chem. Lett. 2007, 17, 1523.
(17) Xue, F.; Li, H.; Delker, S. L.; Fang, J.; Martásek, P.; Roman, L. J.;
Poulos, T. L.; Silverman, R. B. J. Am. Chem. Soc. 2010, 132, 14229.
(18) Andersch, W.; Curtis, D.; Guan, S.; Guilhabert-Goya, M.; Royalty,
R. N.; Springer, B.; Thielert, W.; Zhu, H. US201422821, August 14,
2014.
(19) Hell, S.; Belov, V.; Mitronova, G.; Bossi, M.; Moneron, G.; Wurm,
C.; Jakobs, S.; Eggeling, C.; Bierwagen, J.; Meyer, L. US2012135459,
May 31, 2012.
(20) Metais, E.; Sabelle, S. US2006021157, February 2, 2006.
(21) Mimura, H.; Kawada, K.; Yamashita, T.; Sakamoto, T.; Kikugawa,
Y. J. Fluor. Chem. 2010, 131, 477.
(50) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
12003.
(51) Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M.
K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106.
(52) See Table S2 in the supporting information for the concentrations
of each reagent and the initial rates used to determine the orders in each
reagent.
(53) Bordwell, F. G.; McCallum, R. J.; Olmstead, W. N. J. Org. Chem.
1984, 49, 1424.
(54) Ferretti, A. C.; Mathew, J. S.; Ashworth, I.; Purdy, M.; Brennan,
C.; Blackmond, D. G. Adv. Synth. Catal. 2008, 350, 1007.
(55) Klinkenberg, J. L.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
11830.
(56) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936.
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
(57) Ruiz-Castillo, P.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2015, 137, 3085.
1
(58) Hartwig, J. Organotransition Metal Chemistry. From Bonding to
Catalysis; University Science Books: Sausalito, California, 2010.
(59) Louie, J.; Paul, F.; Hartwig, J. F. Organometallics 1996, 15, 2794.
(60) Driver, M. S.; Hartwig, J. F. Organometallics 1997, 16, 5706.
(61) Biscoe, M. R.; Barder, T. E.; Buchwald, S. L. Angew. Chem. Int.
Ed. 2007, 46, 7232.
2
3
4
5
6
7
(62) Tardiff, B. J.; McDonald, R.; Ferguson, M. J.; Stradiotto, M. J.
Org. Chem. 2011, 77, 1056.
(63) Sunesson, Y.; Limé, E.; Nilsson Lill, S. O.; Meadows, R. E.;
Norrby, P.-O. J. Org. Chem. 2014, 79, 11961.
(64) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
(65) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernández-Rivas, C. J.
Am. Chem. Soc. 1998, 120, 827.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
TOC GRAPHIC
cat. [Pd(allyl)Cl]2
cat. AdBippyPhos
H
X
H2N
N
R1
+
R1
CF2R2
R2 = H, F, CF3, Ph
1.05 equiv KOPh
Dioxane
CF2R2
100 °C
8
X = Cl or Br
9
Slow
Resting State
H2N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
via:
L
Pd OPh
Ar
PhOH
L
Pd
Ar
N
+
+
CF3
CF3
11
ACS Paragon Plus Environment