Synthesis of Conformationally Constrained Esters and Amines by Pd-Catalyzed α-Arylation of Hindered Substrates

Article abstract of DOI:10.1021/acscatal.6b00943

The α-arylation of sterically hindered silyl ketene acetals (SKAs) with sterically hindered aryl bromides occurs efficiently using Pd[P(t-Bu)₃]₂ as the optimal catalyst and ZnF₂ as a promoter. Less sensitive P(t-Bu)_3<

Full text of DOI:10.1021/acscatal.6b00943

Subscriber access provided by UOW Library
Article
Synthesis of Conformationally Constrained Esters and
Amines by Pd-Catalyzed #-Arylation of Hindered Substrates
Anthony Martin, Jean-Pierre Vors, and Olivier Baudoin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00943 • Publication Date (Web): 13 May 2016
Downloaded from http://pubs.acs.org on May 17, 2016
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.
ACS Catalysis 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 6
ACS Catalysis
1
2
3
4
5
6
7
8
9
Synthesis of Conformationally Constrained Esters and Amines by
PdꢀCatalyzed αꢀArylation of Hindered Substrates
Anthony Martin,† JeanꢀPierre Vors,‡ and Olivier Baudoin*,†,§
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
†Université Claude Bernard Lyon 1, CNRS UMR 5246 ꢀ Institut de Chimie et Biochimie Moléculaires et Supramoléculaires,
CPE Lyon, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France.
§Current address: Department of Chemistry, University of Basel, St. JohannsꢀRing 19, CHꢀ4056 Basel, Switzerland.
‡Bayer SAS, 14 Impasse Pierre Baizet, 69263 Lyon Cedex 09, France.
ABSTRACT: The αꢀarylation of sterically hindered silyl ketene acetals (SKAs) with sterically hindered aryl bromides occurs
efficiently using Pd[P(tꢀBu)3]2 as the optimal catalyst and ZnF2 as a promoter. Less sensitive P(tꢀBu)3ꢀbased catalysts could be also
employed, but showed a lower activity. The reaction showed broad scope with regard to both coupling partners, including heteroarꢀ
yl bromides and cyclic SKAs. It also proved scalable to multigram quantities, which allowed to further transform the ester group
and to access conformationally constrained benzylꢀ and phenethylamines, highly soughtꢀafter building blocks for the synthesis of
new agrochemicals.
Keywords: arylation; C–C coupling; palladium; esters; amines.
Benzylamines and phenethylamines are widespread strucꢀ
tural motifs in pharmaceuticals and agrochemicals. In particuꢀ
lar, benzylamines can be found in all classes of active agroꢀ
chemical ingredients (Scheme 1).1 The introduction of substitꢀ
uents at both the benzylic (R1) and the ortho (R2) positions of
these systems is highly desirable, because it would allow to
restrict conformational freedom by virtue of the minimization
of allylic 1,3ꢀstrains (see 1a),2 and hence to possibly enhance
the binding to their cellular target.3 Additional beneficial efꢀ
fects on the physicochemical properties can be also expected
due to increased lipophilicity and metabolic stability.4 Howevꢀ
er, the synthesis of such very sterically hindered benzylꢀ and
phenethylamines 1 by the current available methods is a sigꢀ
nificant challenge.5
We envisaged that amines 1 could be obtained from the
common ester precursor 2 via hydrolysis followed by Curtius
rearrangement or reductive amination, respectively. In turn,
one could consider building the very bulky ester 2 by Pd0ꢀ
catalyzed αꢀarylation of an enolate equivalent of carboxylic
ester 4 with aryl bromide 3. This crossꢀcoupling reaction is a
wellꢀestablished method to construct a variety of arylated
esters and carbonyl compounds.6 However, the developed
methods have been very rarely tested against steric hindrance
on both coupling partners.7ꢀ8 To the best of our knowledge, the
most sterically encumbered partners employed so far feature a
cyclohexyl group on the ester (R1,R1 = –(CH2)2ꢀCHMeꢀ
(CH2)2–) and a methyl group as R2, with a yield of only 37%.8b
Herein, we report an operationally simple and efficient method
which allows to couple a variety of sterically hindered esters
and (hetero)aryl bromides, by using stable silyl ketene acetals
as ester enolate equivalents and commercially available cataꢀ
lysts.
Scheme 1. Access to Sterically Hindered Primary Amines
via PdꢀCatalyzed αꢀArylation of Esters
Pd0-catalyzed
R1 R1
R1 R1
α-arylation
At the onset of our studies, we tried to optimize the coupling
of in situꢀgenerated metal (Li, Na, or K) enolates of methyl
isobutyrate 4a with 1ꢀbromoꢀ2ꢀisopropylbenzene 3a (Scheme
2). Despite extensive efforts, the highest achieved yield was
only 40% under the shown conditions employing the lithium
enolate of 4a and P(tꢀBu)3 as the ligand.7d
R1
NH2
Br
( )n
CO2Me
R1
CO2Me
R2
R2
R2
1
2
3
4
e. g.:
1,3
A
strain
F3C
Cl Cl
H
N
Cl
Scheme 2. Optimized Coupling of Metal Enolates
N
O
Cl
O
O
HN
HN
Fluopicolide
fungicide
1,3
O
A
strain
N
1a
n = 0; R1 = Me; R2 = i-Pr
Cl
N
CHF2
(minimized structure)a
Flupyradiflurone
insecticide
Cumyluron
herbicide
a B3LYP, 6ꢀ31G*.
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 6
Based on previous observations,9 we ascribed this lack of
Other reaction promoters were tested, including fluorides
1
efficiency to catalyst deactivation by the amine (Cy2NH in
Scheme 2), which is generated in stoichiometric amounts
during the enolate formation. Hence, we turned to the coupling
of silyl ketene acetal (SKA) 5a, a commercially available,
stable and practical enolate equivalent which allows to perꢀ
form the αꢀarylation reaction under amineꢀfree conditions.7eꢀf,10
A careful optimization of the coupling of SKA 5a with aryl
bromide 3a was thus conducted (Table 1). Under conditions
close to those reported by Hartwig and coꢀworkers,7eꢀf i. e.
with P(tꢀBu)3 as the ligand and ZnF2 as a Lewis acid promoter
in DMF at 90 °C, the desired coupling product was obtained in
65% GC yield, thereby validating the choice of 5a as a superiꢀ
or enolate equivalent (entry 1). Gratifyingly, the wellꢀdefined
Pd0L2 complex significantly improved the yield (entry 2). The
amount of SKA 5a was varied, and 1.6 equiv proved the best
compromise, although a decent yield (74%) was obtained at 1
equiv (entry 2, note). The amount of ZnF2 could be also deꢀ
creased, but a longer reaction time was required to reach full
conversion (entry 3). Besides, a reaction temperature of 90 °C
proved to be optimal (entries 2, 4).
and zinc salts. The yield with KF or CsF (entry 5) was lower,
due to the competitive desilylation of 5a to give ester 4a, as
observed by GCMS. On the other hand, with ZnCl2 the conꢀ
version and yield were low (entry 6). Interestingly, the more
economical LiCl could be also employed instead of ZnF2,
albeit with a lower yield (entry 7). These results further conꢀ
firm that ZnF2 plays a unique role as a Lewisꢀacidic promoter
in the αꢀarylation of SKAs. Next, different precatalysts were
tested. The airꢀstable phosphonium tetrafluoroborate, P(tꢀ
Bu)3•HBF4,11 could be employed instead of the free phosphine
in combination with Pd2dba3 (entry 8, compare to entry 1),
however a coꢀcatalytic amount of a base such as K2CO3 was
required. Indeed ZnF2 does not seem to be sufficiently basic to
fully deprotonate the phosphonium in situ (entry 8, note).
Nevertheless, the wellꢀdefined Pd0L2 complex was more effiꢀ
cient than the in situ mixture (compare to entry 2). Other wellꢀ
defined P(tꢀBu)3ꢀcontaining precatalysts were assessed, startꢀ
ing with the commercially available [PdBrP(tꢀBu)3]2 dimer
(entry 9).12,7e The reaction was slow at 90 °C (entry 9, note),
but could be performed at 110 °C with a similar efficiency to
the Pd0L2 complex. However, the Pd0 monomer and the PdI
dimer are both airꢀsensitive, and thus we looked for a more
stable PdII precatalyst which could be employed out of the
gloveꢀbox. The recently introduced, commercially available
palladacycle precatalyst 613 provided a satisfying solution in
combination with coꢀcatalytic NEt3 to favor the generation of
the active Pd0L species by reductive elimination (entry 10).14
However, among all tested precatalysts, Pd[P(tꢀBu)3]2 clearly
remained the most active. Gratifyingly, the catalyst loading
could be lowered to 1 mol% without affecting the reaction
efficiency (entries 11ꢀ12).
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
Table 1. Optimization of the Coupling of Silyl Ketene Aceꢀ
tal 5a with Aryl Bromide 3a
Entry
1
Pd catalyst
(mol%)
Promoter
(equiv)
Temp.
(°C)
t
GC
Yield
(%)a
(h)
To further compare the various P(tꢀBu)3ꢀcontaining cataꢀ
lysts, the kinetic profiles of three representative examples
were determined at 90 °C (Figure 1).15 The Pd0L2 complex (2
mol%) clearly showed the highest conversion of aryl bromide
3a into product 2a (blue lines).
Pd2dba3 (5)/
P(tꢀBu)3 (10)
ZnF2 (1)
ZnF2 (1)
90
2
65
2
3
Pd[P(tꢀBu)3]2 (10)
Pd[P(tꢀBu)3]2 (10)
90
90
2
92b (86)
90
ZnF2
(0.5)
15
4
5
6
7
8
Pd[P(tꢀBu)3]2 (10)
Pd[P(tꢀBu)3]2 (10)
Pd[P(tꢀBu)3]2 (10)
Pd[P(tꢀBu)3]2 (10)
ZnF2 (1)
CsF (1)c
ZnCl2 (1)
LiCl (1)
ZnF2 (1)
70
90
90
90
90
2
16
15
15
15
2
<5
32
79 (66)
63
Pd2dba3 (5)/
P(tꢀBu)3•HBF4 (10)/
K2CO3 (10)d
9
[PdBrP(tꢀBu)3]2 (5)
6 (4)/NEt3 (4)f
ZnF2 (1)
ZnF2 (1)
ZnF2 (1)
ZnF2 (1)
110e
110g
90
2
91 (84)
76 (72)
95 (89)
100 (91)
10
11
12
15
7
Pd[P(tꢀBu)3]2 (5)
Pd[P(tꢀBu)3]2 (1)
90
7
a Determined by GCMS using tetradecane as the internal standꢀ
Figure 1. Kinetic profiles for the formation of 2a from 3a and 5a
with various P(tꢀBu)3ꢀbased catalysts. All reactions were perꢀ
formed in DMF at 90 °C at the same reactant concentrations and
at 2 mol% Pd. Solid lines: GC yield of 2a; dashed lines: GC yield
of 3a. Blue lines: Pd[P(tꢀBu)3]2 (2 mol%); green lines: Pd2dba3 (1
b
ard. Yield of the isolated product in parentheses. Yield with 1.0
c
d
equiv 5a: 74%. Yield with KF: 32%. Yield without K2CO3:
41%. e Yield at 90 °C: 65%. f Yield without NEt3: 47%. g Yield at
90 °C: 57%.
mol%)/ P(tꢀBu)3 (4 mol%); red lines: palladacycle
6 (2
mol%)/NEt3 (2 mol%).
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
Scheme 3. Scope and Limitations of the αꢀArylation of Hindered SKAs with Hindered (Hetero)aryl Bromides
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
a Reaction performed at 110 °C. b From the pyridyl chloride instead of the bromide.
The Pd2dba3/L combination using the same amount of Pd (2
mol%) and ligand (4 mol%) showed a faster and complete
conversion of 3a (red lines), but the yield of 2a plateaued at
ca. 65% with concomitant formation of cumene, indicating
that protodebromination competes with the arylation pathway.
This behavior may be imputed to the known inhibitory effect
of dba.9,16 The combination of palladacycle 6 and NEt3 showed
the lowest activity (green lines), with incomplete (ca. 80%)
conversion of 3a and <40% yield of arylated product. This
behavior can be ascribed to both competitive protodebrominaꢀ
tion and catalyst deactivation due to the lack of extra stabilizꢀ
ing ligand. As can be seen in Table 1 (entry 10), precatalyst 6
requires a higher temperature (110 °C) and loading (4 mol%)
to furnish a good yield of product. Overall, the activity of
Pd[P(tꢀBu)3]2 at lower temperature and catalyst loading could
not be surpassed by the considered alternatives. This complex
seems to be the most efficient in delivering the active species
that catalyzes the arylation reaction, presumably the monoliꢀ
gated species Pd[P(tꢀBu)3].17
(Scheme 3a). High yields were achieved for substrates bearing
a single alkyl (including cyclopropyl) or phenyl orthoꢀ
substituent (2aꢀe). A limitation was found for compounds
bearing one tꢀbutyl group (2f) or two ortho methyl groups
(2g), presumably due to the excessive allylic strain disfavoring
C–C reductive elimination (see computed structure in Scheme
1). The formation of 2g was accompanied by the correspondꢀ
ing βꢀarylated isomer 7g (R3 = R4 = Me), arising from Pd
migration at the terminal carbon. Similar α/β mixtures were
obtained with electronꢀwithdrawing substituents (CF3, Cl,
OCF3), in line with our previous studies showing that such
electronicallyꢀbiased substituents favor Pd migration and longꢀ
range arylation.9,18 Nevertheless, αꢀarylated products 2gꢀj
could all be separated from their β isomers by preparative
HPLC and isolated in low to moderate yield (11ꢀ51%), deꢀ
pending on the α/β selectivity. Finally, we were very interestꢀ
ed in the introduction of an electronꢀdonating ortho nitrogen
substituent that would both give minimal βꢀarylation product
and constitute a convenient precursor for the free amino group.
Whereas the free aniline itself and the acetanilide did not
provide any arylation product, the corresponding benzaldimine
was found to be an excellent surrogate, which provided prodꢀ
uct 2k in 78% yield and complete α selectivity.
The scope of the αꢀarylation process was then examined
under optimized conditions at 2 mol% catalyst loading
(Scheme 3). First, various ortho substituents (R3, R4) on the
aryl bromide were examined in combination with SKA 5a
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 6
The reaction of pyridyl bromides, relevant to the synthesis reduction to the primary alcohol (11), followed by conversion
1
of active agrochemical ingredients (see examples in Scheme
1), was next investigated (Scheme 3b). When the pyridine
nitrogen atom was located in ortho position to the bromine
atom in 3, the αꢀheteroarylated product was exclusively obꢀ
tained, with no observable β isomer. This results contrasts
with the selectivity observed with phenyl rings (compare 2l
with 2h, 2p with 2i, 2q with 2j). The αꢀcoupled products 2l
and 2pꢀr bearing one ortho electronꢀwithdrawing substituent
were obtained in moderate to good yields (41ꢀ84%). In conꢀ
trast, when the nitrogen atom of the pyridine ring was located
in meta position to the bromine atom, the β isomer (7nꢀo) was
exclusively obtained. In this case, the increased β selectivity
compared to the corresponding benzene ring (2h/7h 14:86)
can be imputed to the increased electronꢀdeficiency of the
pyridine ring which disfavors αꢀreductive elimination, in line
with previous mechanistic data.9 In contrast, for 2ꢀ
bromopyridines, the total α selectivity might originate in the
formation of pyridylꢀbridged Pd dimers,19 which would block
βꢀH elimination and therefore would shut down the βꢀ
arylation pathway. Importantly, the reaction of SKA 5a with
2,3ꢀdichloroꢀ5ꢀtrifluoromethylpyridine, relevant to the syntheꢀ
sis of Fluopicolide analogues (Scheme 1), furnished comꢀ
pound 2s in 89% yield, in a completely siteꢀselective manner.
This siteꢀselectivity, which was also observed for 2p, can be
inferred to the more electronꢀdeficient character of the 2ꢀ
position vs. the 3ꢀposition of the pyridine, favoring the initial
oxidative addition to Pd0. Of note, control experiments, conꢀ
ducted for 2ꢀhalopyridine substrates without Pd catalyst,
showed no coupling product, thereby excluding any contribuꢀ
to the corresponding azide and Staudinger reduction.
2
3
4
5
6
7
8
9
In conclusion, the arylation of sterically hindered esters and
aryl bromides has been realized by employing silyl ketene
acetals as stable and convenient enolate surrogates, Pd[P(tꢀ
Bu)3]2 as the optimal catalyst and ZnF2 as a promoter. Less
sensitive catalysts could be also employed, but showed a reꢀ
duced activity. The reaction showed broad scope with regard
to both coupling partners, proved to be scalable, and the ester
group could be further transformed to access very bulky benꢀ
zylꢀ and phenethylamines, which are valuable new building
blocks for the synthesis of agrochemicals with potentially
improved properties.
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
Scheme 4. Scaleꢀup and PostꢀFunctionalizationa
tion
of
SNAr
mechanism.
Finally,
an
orthoꢀ
methylbromopyrrazole could be coupled successfully and
selectively to 5a (product 2t), thereby demonstrating the feasiꢀ
bility of αꢀheteroarylation beyond pyridine.
a
Reaction conditions: (a) Pd[P(tꢀBu)3]2 (5 mol%), ZnF2 (1
equiv), DMF, 110 °C, 15 h. (b) KOH (20 equiv),
THF/MeOH/H2O 1:1:1, ꢀW (150 °C), 30 min (75%). (c)
(EtO)2P(O)N3 (1.04 equiv), NEt3 (1.15 equiv), toluene, ꢀW (110
°C), 45 min, then 37% aq. HCl, THF, 20 °C, 15 h (83%). (d)
(COCl)2 (1.1 equiv), DMF (5 mol%), CH2Cl2, 20 °C, 15 h, then
28% aq. NH4OH, THF, 20 °C, 2 h. (e) LiAlH4 (5 equiv), THF, 25
°C, 15 h (96%). (f) PPh3 (1.2 equiv), iꢀPrO2CN=NCO2iꢀPr (1.2
equiv), (EtO)2P(O)N3 (1.2 equiv), THF, 25 °C, 15 h then PPh3
(1.3 equiv), 60 °C, 4 h, then H2O, 80 °C, 1 h (68%).
The scope with regard to the SKA coupling partner was also
examined, in combination with aryl bromide 3a (Scheme 3c).
SKAs were conveniently prepared in a standard fashion from
the corresponding methyl ester 4 upon deprotonation by LDA
and reaction with TMSCl, and were found to be stable for
several weeks under moistureꢀfree conditions. Both acyclic
(2u) and cyclic (2wꢀz) SKAs, including a Bocꢀprotected piperꢀ
idine (2z), were coupled successfully. Interestingly, cyclobutyl
compound 5w predominantly exists as the Oꢀenolate (OꢀSi/Cꢀ
Si 9:1) whereas its cyclopropyl analogue 5v exclusively occurs
as the Cꢀenolate. The lack of reactivity of 5v vs. 5w can be
ascribed to the use of ZnF2, which is suitable to promote the
reaction of SKAs but not of organosilanes, for which a better
fluoride source would likely be required.20ꢀ21
ASSOCIATED CONTENT
Supporting Information.
Full characterization of all new compounds, detailed experimental
procedures, copies of NMR spectra for target molecules. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Finally, the crossꢀcoupling of aryl bromide 3d and SKA 5y
was chosen for scaleꢀup studies, which allowed to obtain mulꢀ
tigram quantities of arylated ester 2aa in 89% yield (Scheme
4). In this case, using 5 mol% catalyst and heating to 110 °c
proved necessary to achieve full conversion. The ester group
in 2aa could then be further transformed to provide useful
building blocks for the synthesis of potential new agrochemiꢀ
cals (see Scheme 1). It was first converted to benzylamine 9
by hydrolysis to the carboxylic acid (8) and Curtius rearꢀ
rangement, both steps requiring microwave irradiation due to
steric hindrance. Primary amide 10 was also obtained from the
same carboxylic acid intermediate 8 upon formation of the
acid chloride and reaction of the latter with aqueous ammonia.
Finally, phenethylamine 12 was synthesized from 2aa by
*Eꢀmail: olivier.baudoin@unibas.ch
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Bayer CropScience AG for financial support.
REFERENCES
(1) (a) Fungicide Resistance Action Committee, Mode of Action
Poster. http://www.frac.info/publications (accessed May 8, 2016). (b)
Herbicide Resistance Action Committee, Mode of Action Poster.
http://www.hracglobal.com (accessed May 8, 2016). (c) Insecticide
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
Resistance Action Committee, Mode of Action Poster.
http://www.iracꢀonline.org (accessed May 8, 2016).
(2) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841ꢀ1860.
(3) Fang, Z.; Song, Y.; Zhan, P.; Zhang, Q.; Liu, X. Future Med.
Chem. 2014, 6, 885ꢀ901.
(10) (a) Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T.
J. Org. Chem. 1991, 56, 261ꢀ263. (b) Galarini, R.; Musco, A.; Pontelꢀ
lini, R.; Santi, R. J. Mol. Catal. 1992, 72, L11ꢀL13. (c) Sakamoto, T. ;
Kondo, Y. ; Masumoto, K. ; Yamanaka, H. Heterocycles 1993, 36,
2509ꢀ2512. (d) Sakamoto, T. ; Kondo, Y. ; Masumoto, K. ; Yamanaꢀ
ka, H. J. Chem. Soc. Perkin Trans. 1 1994, 235ꢀ236. (e) Agnelli, F. ;
Sulikowski, G. A. Tetrahedron Lett. 1998, 39, 8807ꢀ8810. (f) Huang,
Z. ; Liu, Z. ; Zhou, J. J. Am. Chem. Soc. 2011, 133, 15882ꢀ15885.
1
2
3
4
5
6
7
8
(4) Wanka, L.; Iqbal, K.; Schreiner, P. R. Chem. Rev. 2013, 113,
3516ꢀ3604.
(5) For recent efforts to synthesize hindered Nꢀarylamines: (a)
RuizꢀCastillo, P.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2015, 137, 3085ꢀ3092. (b) Park, N. H.; Vinogradova, E. V.;
Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2015, 54, 8259ꢀ
8262. (c) Gui, J.; Pan, C.ꢀM. Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.;
Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.;
Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S. Science
2015, 348, 886ꢀ891.
(11) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295ꢀ4298
(12) Vilar, R. ; Mingos, D. M. P. ; Cardin, C. J. Dalton Trans.
1996, 4313ꢀ4314
.
.
9
(13) (a) Bruno, N. C. ; Niljianskul, N. ; Buchwald, S. L. J. Org.
Chem. 2014, 79, 4161ꢀ4166. (b) Friis, S. D. ; Skrydstrup, T. ; Buchꢀ
wald, S. L. Org. Lett. 2014, 16, 4296ꢀ4299.
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
(14) For a recent review on aminobiphenyl precatalysts : Bruneau,
A. ; Roche, M. ; Alami, M. ; Messaoudi, S. ACS Catal. 2015, 5, 1386ꢀ
1396.
(15) See the Supporting Information for separate curves showing
data points.
(16) (a) Amatore, C.; Jutand, A.; Khalil, F.; M’Barki, M. A.; Motꢀ
tier, L. Organometallics 1993, 12, 3168ꢀ3178; for a review: (b) Fairꢀ
lamb, I. J. S. Org. Biomol. Chem. 2008, 6, 3645ꢀ3656.
(17) Christmann, U.; Vilar, R. Angew. Chem. Int. Ed. 2005, 44,
366ꢀ374.
(18) For the βꢀarylation of ester lithium enolates: (a) Renaudat, A.;
JeanꢀGérard, L.; Jazzar, R.; Kefalidis, C. E.; Clot, E.; Baudoin, O.
Angew. Chem. Int. Ed. 2010, 49, 7261ꢀ7265. (b) Aspin, S.; Goutierre,
A.ꢀS.; Larini, P.; Jazzar, R.; Baudoin, O. Angew. Chem. Int. Ed. 2012,
51, 10808ꢀ10811. (c) For the βꢀarylation of SKAs: (c) Aspin, A.;
LópezꢀSuárez, L.; Larini, P.; Goutierre, A.ꢀS.; Jazzar, R.; Baudoin, O.
Org. Lett. 2013, 15, 5056ꢀ5059.
(19) (a) Isobe, K.; Kai, E.; Nakamura, Y.; Nishimoto, K.; Miwa,
T.; Kawaguchi, S.; Kinoshita, K.; Nakatsu, K. J. Am. Chem. Soc.
1980, 102, 2475ꢀ2476. (b) Beeby, A.; Bettington, S.; Fairlamb, I. J.
S.; Goeta, A. E.; Kapdi, A. R.; Niemelä, E. H.; Thompson, A. L. New
J. Chem. 2004, 28, 600ꢀ605.
(20) Ge, S. ; Arlow, S. I. ; Mormino, M. G. ; Hartwig, J. F. J. Am.
Chem. Soc. 2014, 136, 14401ꢀ14404.
(21) For the αꢀarylation of cyclopropyl nitriles via lithium enoꢀ
lates : McCabe Dunn, J. M. ; Kuethe, J. T. ; Orr, R. K. ; Tudge, M. ;
Campeau, L.ꢀC. Org. Lett. 2014, 16, 6314ꢀ6317.
(6) Reviews: (a) Johansson, C. C. C.; Colacot, T. J. Angew. Chem.
Int. Ed. 2010, 49, 676ꢀ707. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010,
110, 1082ꢀ1146.
(7) For examples with steric hindrance on either the ester (R1 ≠ H)
or the aryl halide (R2 ≠ H) coupling partner: (a) Koch, K.; Melvin, L.
S., Jr.; Reiter, L. A.; Biggers, M. S.; Showell, H. J.; Griffiths, R. J.;
Pettipher, E. R.; Cheng, J. B.; Milici, A. J.; Breslow, R.; Conklyn, M.
J.; Smith, M. A.; Hackman, B. C.; Doherty, N. S.; Salter, E.; Farrell,
C. A.; Schulte, G. J. Med. Chem. 1994, 37, 3197ꢀ3199. (b) Moradi,
W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996ꢀ8002. (c)
Lee, S. Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
8410ꢀ8411. (d) Jørgensen, M., Lee, S.; Liu, X.; Wolkowski, J. P.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557ꢀ12565. (e) Hama,
T.; Liu, X. Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
11176ꢀ11177. (f) Liu, X. Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
5182ꢀ5191. (g) Shetty, R.; Moffett, K. K. Tetrahedron Lett. 2006, 47,
8021ꢀ8024. (h) Wang, Y.; Nair, R. Tetrahedron Lett. 2007, 48, 1191ꢀ
1193. (i) Hama, T. Hartwig, J. F. Org. Lett. 2008, 10, 1545ꢀ1548. (j)
Hama, T. Hartwig, J. F. Org. Lett. 2008, 10, 1549ꢀ1552. (k) Biscoe,
M. R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773ꢀ1775.
(8) For examples with steric hindrance on both the ester and the
aryl halide coupling partners (R1, R2 ≠ H): (a) Johnson, P. D.; Sohn,
J.ꢀH.; Rawal, V. H. J. Org. Chem. 2006, 71, 7899ꢀ7902. (b) Bercot, E.
A.; Caille, S.; Bostick, T. M.; Ranganathan, K.; Jensen, R.; Faul, M.
M. Org. Lett. 2008, 10, 5251ꢀ5254. (c) Hama, T.; Ge, S.; Hartwig, J.
F. J. Org. Chem. 2013, 78, 8250ꢀ8266.
(9) Larini, P.; Kefalidis, C. E.; Jazzar, R.; Renaudat, A.; Clot, E.;
Baudoin, O. Chem.–Eur. J. 2012, 18, 1932ꢀ1944.
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
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
6
ACS Paragon Plus Environment