Palladium-Catalyzed β-C-H Arylation of Alkyl Carboxamides with Sterically Hindered Aryl Iodides Using ortho-Sulfinyl Aniline Auxiliaries

Article abstract of DOI:10.1021/acscatal.6b03661

We disclose a pair of ortho-sulfinylaniline auxiliaries for palladium-catalyzed β-C-H arylation of alkyl carboxamides. Together, these auxiliaries offer a means to effect efficient β-methyl and methylene C-H bond arylation with sterically hindered aryl iodides. ortho-Methylsulfinylaniline (MSOA) enables efficient β-methyl C-H arylation of propanamide substrates with aryl iodides bearing various ortho-substituents including alkyl groups. ortho-Tosylsulfinylaniline (TSOA) enables β-methylene C-H arylation with ortho-substituted aryl iodides. Both amide-linked MSOA and TSOA auxiliaries can be easily removed to give ester products under relatively mild conditions.

Full text of DOI:10.1021/acscatal.6b03661

Subscriber access provided by HACETTEPE UNIVERSITESI KUTUPHANESI
Article
Palladium-Catalyzed #-C-H Arylation of Alkyl Carboxamides with
Sterically Hindered Aryl Iodides Using Ortho-Sulfinyl Aniline Auxiliaries
Delong Mu, Fang Gao, Gong Chen, and Gang He
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03661 • Publication Date (Web): 23 Jan 2017
Downloaded from http://pubs.acs.org on January 23, 2017
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
Palladium-Catalyzed β-C−H Arylation of Alkyl Carbox-
amides with Sterically Hindered Aryl Iodides Using Ortho-
Sulfinyl Aniline Auxiliaries
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
Delong Mu,a Fang Gao,a Gong Chen*a,b,c and Gang He*a,b
aState Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
bCollaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China.
cDepartment of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
ABSTRACT: We disclose a pair of ortho-sulfinylaniline auxiliaries for palladium-catalyzed β-C-H arylation of alkyl carboxamides. Together,
these auxiliaries offer a means to effect efficient β-methyl and methylene C–H bond arylation with sterically hindered aryl iodides. Ortho-
methylsulfinylaniline (MSOA) enables efficient β-methyl C-H arylation of propanamide substrates with aryl iodides bearing various ortho-
substituents including alkyl groups. Ortho-tosylsulfinylaniline (TSOA) enables β-methylene C-H arylation with ortho-substituted aryl iodides.
Both amide-linked MSOA and TSOA auxiliaries can be easily removed to give ester products under relatively mild conditions.
KEYWORDS: sp3 C-H arylation, methylene C-H, hindered aryl iodide, palladium, sulfinylaniline auxiliary
Metal-catalyzed directing group-facilitated C(sp3)-H
A) Ortho-substituted aryl coupling partners for C-H arylation
arylation reactions have been greatly advanced over the past dec-
X
ade.1 Among these reactions, palladium-catalyzed β-C-H arylation
Ro
of alkyl carboxamides equipped with amide–linked auxiliary groups
has enjoyed the most success, offering increasingly useful methods
for the synthesis of β-aryl alkylcarboxamides.2 However, despite
metal-coordinating groups
e.g. OMe, F, CO2Me
non-coordinating groups
e.g. alkyl
vs
these developments, significant limitations on substrate scope must
be overcome to achieve broad application of this reaction strategy.
Firstly, in comparison with the widely reported arylation reactions
of β-methyl C-H bonds, the arylation of unactivated methylene C-
H bonds are considerably more difficult and this transformation is
only available to substrates bearing small subset of auxiliary
groups.3,4 Secondly, while the use of sterically unhindered para- or
meta-substituted aryl coupling partners is common, the incorpora-
tion of ortho-substituted aryl groups presents a significant challenge
(Scheme 1A). Using established methods, the amenable ortho sub-
stituents of aryl coupling partners are mostly limited to groups with
metal-coordination ability, e.g. OMe, F, and ester.5 Successful cou-
pling reactions with aryl reactants bearing non-coordinating ortho-
substituents have only been sporadically reported for primary
C(sp3)-H bonds;6 efficient arylation of unactivated secondary
C(sp3)-H bonds with ortho-alkyl aryl partners has not been real-
ized. Herein, we report the development of a pair of new ortho-
sulfinylaniline auxiliaries for Pd-catalyzed β-C(sp3)-H arylation of
alkylcarboxamides with a broad range of sterically hindered aryl
iodides (Scheme 1B).7
B) This work
O
H
Ar−I (3 equiv)
O
Ro
N
R2
Pd(OAc)2 (10 mol%)
Ag2CO3 (2.5 equiv)
H
N
R2
R1
S
H
O
R
R1
S
O
R
KF (3 equiv) or PivOH (1 equiv)
HFIP, 110 oC, Ar, 24 h
(Me, Tol)
Ro : alkyl & others
Scheme 1. Pd-catalyzed β-C(sp3)-H arylation of alkyl carboxamides
with aryl iodides
pseudodipeptide intermediate.8 Subsequently, we demonstrated
the utility of this PE auxiliary with the synthesis of various β-aryl-α-
amino acids bearing ortho-substituted aryl side chains via β-methyl
C-H arylation of phthaloyl alanine precursor 1 (Scheme 2A).9
While the reaction of 1 with 2-methoxylphenyl iodide 3 proceeded
in good yield, the yield of the reaction with 2-iodotoluene 4
dropped substantially, and when 2-isopropylphenyl iodide 5 was
evaluated, no arylated product 10 was detected. Furthermore, the
β-methyl C-H arylation of conformationally more flexible PE-
coupled propanamide 11 with 3 gave notably decreased yield (13,
Scheme 2B), and β-methylene C-H arylation of PE-coupled bu-
tanamide 12 with 4 did not form any product 16. Clearly, aryl io-
dide substrates bearing non-coordinating ortho-alkyl substituents,
In the course of our recent total synthesis of hibispeptin
A, we discovered that the 2-pyridylethylamine (PE) directing
group enabled a challenging Pd-catalyzed arylation of the γ-methyl
C-H bond of phthaloyl isoleucine with a sterically hindered ortho-
benzyloxy aryl iodide, allowing us to prepare a key Calkyl-Caryl linked
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 6
A) PE-directed β-C−H arylation of 1
Table 1. β-C-H arylation of propanamide 31 with 4
I
I
1
2
3
4
5
6
7
8
3
5
2
4
MeO
I
(PE)
O
O
I
PhthN
PhthN
Ar
PE
N
N
H
H
N
entry
reagents (equiv)
solvent
t
yield
(%)a
<5
H
(3 equiv)
1
(oC)
110
110
6 (60%, with 2)a
8 (72%, with 3)
9 (17%, with 4)
10 (0%, with 5)
Pd(OAc)2 (10 mol%)
Ag2CO3 (1.5 equiv)
PhCl, 100 oC, Ar, 24 h
1
2
Ag2CO3 (2.5)
Ag2CO3 (2.5), K2CO3 (2.5)
tAmylOH
tAmylOH/
H2O (4/1)
CH3CN
DCE
TFE
tBuOH (F9)b
HFIP
HFIP
HFIP
HFIP
HFIP
<5
9
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ag2CO3 (2.5)
Ag2CO3 (2.5)
Ag2CO3 (2.5)
Ag2CO3 (2.5)
Ag2CO3 (2.5)
AgOAc (2.5)
Ag2CO3 (2.5), K2CO3 (2.5)
K2CO3 (2.5)
Ag2CO3 (2.5), KF (3.0)
Ag2CO3 (2.5), KF (3.0)
AgF (2.5)
Ag2CO3 (2.5), PivOH (1.0)
Ag2CO3 (2.5), (BnO)2PO2H (0.2)
Ag2CO3 (2.5), KF (3.0), PivOH
(1.0)
110
110
110
110
110
110
110
110
<5
<5
55
59
58
34
53
<5
B) Aux-directed β-C−H arylation of propanamides and butanamides
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
Ar
O
O
Ar-I (3 equiv)
Pd(OAc)2 (10 mol%)
H
Aux
Aux
R
N
N
R
H
H
13 (R: H, 45%)
14 (R: Me, 36%)
with 3
Ag2CO3 (1.5 equiv)
PhCl, 100 oC, Ar, 24 h
11 (R: H)
12 (R: Me)
Aux: PE
15 (R: H, 24%)
16 (R: Me, 0%)
with 4
110 74(71)c
19 (R: H, 54%)
20 (R: Me, 55%)
HFIP
HFIP
HFIP
HFIP
130
110
110
110
110
54
59
35
56
49
with 3
with 4
with 5
K2CO3 (2.5 equiv)
PivOH (0.2 equiv)
tAmylOH/H2O (4/1)
110 oC, Ar, 24 hb
N
H
N
21 (R: H, 45%)
22 (R: Me, 10%)
Aux: AQ
17 (R: H)
18 (R: Me)
23 (R: H, 40%)
24 (R: Me, <3%)
HFIP
a) Yields are based on 1H-NMR analysis on a 0.2 mmol scale using 1, 1,
2, 2-tetrachloroethane as internal standard; b) perfluoro-t-butanol; c)
Isolated yield. No β-di-arylated product was formed under the condi-
tions tested above.
27 (R: H, 48%)
28 (R: Me, 5%)
Ag2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
tAmylOH/H2O (4/1)
110 oC, Ar, 24 hb
with 3
with 4
N
H
S
Aux: TA
29 (R: H, 25%)
30 (R: Me, 5%)
25 (R: H)
26 (R: Me)
33 (R: H, 65%)
34 (R: Me, 0%)
with 3
(HFIP)16 solvent at 110 oC. However, MSOA-directed β-
methylene C-H arylation of substrate 32 was unsuccessful (see 34,
36 and 38).
N
H
S
O
Ag2CO3 (2.5 equiv)
HFIP, 110 oC
Ar, 24 h
35 (R: H, 56%)
36 (R: Me, 0%)
with 4
with 5
Aux: MSOA
31 (R: H)
32 (R: Me)
37 (R: H, 52%)
38 (R: Me, 0%)
As seen in Table 1, choice of solvent is critical in the reaction of
31 with 4 (entries 1-7). The reaction performed best in fluorinated
alcohols such as trifluoroethanol (TFE), perfluoro-t-butanol and
HFIP.17 We chose HFIP solvent for further reaction optimization
due to its relatively lower cost. The use of Ag additive is also re-
quired (entry 10 vs 7). Interestingly, the addition of 3 equiv of KF
can further improve the reaction, giving 35 in 71% isolated yield
(entry 11).18
Scheme 2. Comparative studies of different amine-based auxiliaries for
β-C(sp3)-H arylation with aryl iodides. Isolated yields on a 0.2 mmol
scale. a) A β-diarylated side product 7 was obtained in 16% yield. No
substantial amount of β-diarylated products (< 3%) were detected for
the other reactions listed in this Scheme. b) These conditions were
optimized for the best results for reaction with 4. See supporting in-
formation for more results under other reactions conditions.
The substrate scope of MSOA-directed β-C(sp3)-H
arylation was then investigated under the optimized conditions A
(Scheme 3). β-Methyl C-H arylation of 31 with both 2-ethyl and 2-
isopropylphenyl iodides gave the desired products in good yields
(39, 37). However, arylation with 2-t-butylphenyl iodide did not
give any product 40. Aryl iodides bearing coordinating groups such
as MeO, CO2Me and F at the ortho position were well tolerated
(33, 42, 44). 2-Methyl-6-nitrophenyl iodide also reacted with 31 to
give 43 in good yield. As seen in 46 and 47, β-methylene C-H aryla-
tion of butanamide gave little product under conditions A. Interest-
ingly, replacing KF used in conditions A with 1 equiv of PivOH
(conditions B, entry 14 in Table 1) gave improved yield. However,
MSOA-directed β-methylene C-H arylation of many other sub-
strates still failed to proceed under either conditions A and B (see
34, 36, 48).
even as small as a methyl group, cannot be efficiently coupled via
PE-directed Pd-catalyzed C(sp3)-H arylation.
To address this substrate scope limitation, we then exam-
ined the performance of two other well-studied aniline-based bi-
dentate auxiliary groups. The 8-aminoquinoline (AQ) and 2-
(methylthio)aniline (TA) auxiliaries were first introduced by Dau-
gulis for Pd-catalyzed C-H arylation with aryl iodides (Scheme
2B).10 The reactions of aminoquinoline (AQ)-coupled propana-
mide 17 and butanamide 18 with 3 provided higher yield than the
corresponding PE-directed reactions under optimized conditions
(19 vs 13, 20 vs 14). However, the yield of arylation with ortho-
alkyl substituted aryl iodides 4 and 5 was poor (see 21-24). The 2-
(methylthio)aniline auxiliary exhibited comparable reactivity to PE
under the optimized conditions (see 27-30). Inspired by recent
reports on sulfoxide-based directing groups for Pd-catalyzed
C(sp2)-H functionalization,11-14 we synthesized 2-methylsulfinyl
aniline (MSOA) containing 3115 and subjected it to C(sp3)-H ary-
lation with our panel of ortho substituted aryl iodides. To our de-
light, propanamide 31 gave promising results (see 33, 35 and 37)
in the presence of Ag2CO3 additive in hexafluoroisopropanol
To further improve the directing ability of ortho-sulfinyl
aniline auxiliary, we then examined various analogs of MSOA. We
were pleased to find that ortho-tolylsulfinyl aniline (TSOA) gave
notably improved results (Scheme 4). The β-methyl C-H arylation
of TSOA-coupled propanamide with various ortho alkyl substituted
aryl iodides gave good yields. As seen in 59, the arylation reactions
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
Ar-I (3 equiv)
Pd(OAc)2 (10 mol%)
Ag2CO3 (2.5 equiv), KF (3 equiv)
HFIP, 110 oC, Ar, 24 h
[conditions A]
Ar-I (3 equiv)
Pd(OAc)2 (10 mol%)
1
2
3
4
5
6
7
8
H
O
Ag2CO3 (2.5 equiv), KF (3 equiv)
HFIP, 110 oC, Ar, 24 h
H
O
Ar
O
Ar
O
O
N
R
MSOA
TSOA
TSOA
[conditions A for 1o C−H]
H
N
N
R
R
N
H
R
R'
S
H
H
O
R'
S
R'
R'
KF replaced with PivOH (1 equiv)
KF replaced with PivOH (1 equiv)
O
[conditions B]
(TSOA)
(MSOA)
[conditions B for 2o C−H]
O
O
O
O
O
TSOA
MSOA
TSOA
MSOA
MSOA
N
H
N
H
N
H
N
H
N
H
N
H
9
50, 65% [A]
51, 69% [A]
37, 62% [A]
52, <3% [A or B]
39, 60% [A]
40, <3% [A or B]
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
O
O
O
O
O
O
TSOA
N
TSOA
TSOA
MSOA
MSOA
MSOA
N
H
N
H
MeO2C
N
N
OMe
N
H
OMe
MeO2C
H
H
H
53, 76% [A]
54, 62% [A]
55, 69% [A]
33, 70% [A]
42, 68% [A]
41, 53% [A]
OMe
O
Br
F
O
O
O
O
O
MSOA
TSOA
MSOA
MSOA
TSOA
TSOA
N
H
N
H
N
N
H
F
N
H
N
H
H
N
NO2
NO2
O
Br
58, 55% [A]a
44, 73% [A]
43, 52% [A]
56, 70% [A]
57, 75% [A]
45, 63% [A]
O
O
O
O
O
MSOA
TSOA
TSOA
MSOA
MSOA
TSOA
N
H
N
H
N
H
N
H
OMe
N
H
MeO2C
N
H
47, <3% [A]
44% [B]
MeO
34, <3%
[A or B]
46, <5% [A]
47% [B]
59, 68% [A]
60, 75% [A]
61, 65% [A]
O
O
O
O
O
O
MSOA
PhthN
MSOA
MSOA
TSOA
TSOA
TSOA
N
H
N
H
N
H
N
N
N
H
OMe
MeO2C
H
H
MeO
63
<5% [A]
62
<5% [A]
64
MeO2C
49, <3% [A or B]
MeO
<5% [A]
64% (dr= 1.4:1) [B]
O
36, <3% [A or B]
48, <3% [A or B]
63% (dr= 1.2:1) [B]
80% (dr= 1.1:1) [B]
Scheme 3. Substrate scope of Pd-catalyzed MSOA-directed β-C(sp3)-
H arylation. Isolated yield on a 0.2 mmol scale.
O
O
O
TSOA
TSOA
TSOA
N
H
N
H
N
H
MeO2C
OMe
MeO2C
with 2-isopropylphenyl iodide 5 proceeded with selectivity for β-
methyl over methylene C-H bond functionalization. In the absence
of reactive β-methyl groups, the TSOA directing group enables β-
methylene C-H arylation with aryl iodides carrying coordinating
groups such as MeO, F, CO2Me, and ketones at the ortho position
under conditions B (see 62-70). However, β-methylene C-H aryla-
tions with ortho-alkyl aryl iodides gave lower yield. Nevertheless, an
18% yield of product 71, represents a notable improvement relative
to the results obtained from existing methylene C-H arylation sys-
tems (see 71 vs 24 in Scheme 2).
65, 66% (dr= 1.1:1) [B]
67, 61% (dr= 1.7:1) [B]
66, 64% (dr= 1.5:1) [B]
O
O
O
TSOA
O
TSOA
TSOA
N
N
F
N
NO2
H
H
H
70, 40% (dr= 1.2:1) [B]
69, <3% [A or B]
68, 70% (dr= 1.2:1) [B]
O
O
O
TSOA
PhthN
TSOA
TSOA
N
H
N
N
H
H
*
We have performed some preliminary mechanistic stud-
ies. As shown in Scheme 5A, both ortho-sulfonylaniline (74) and
para-sulfinyl aniline (75) auxiliaries failed to deliver arylated prod-
uct under the standard reaction conditions, suggesting the ortho-
sulfinyl group of aniline is critical to exert the directing ability. We
speculate that the higher yields of arylated product obtained using
ortho-sulfinyl auxiliary 31 as compared to ortho-thiomethyl aniline
25 results from stabilization of the auxiliary-catalyst complex via a π
backbonding interaction.19-21 A small kinetic isotope effect (KIE)
value (KH/KD ~ 1.2) was observed via the parallel β-methyl C-H
arylation of 76 and 77 with 4 under the conditions A, suggesting
that C-H palladation is not the turnover limiting step (Scheme 5B).
We obtained palladacycle intermediate 79 from the reaction of
stoichiometric amounts of pivalamide 78 and Pd(OAc)2 in acetoni-
MeO
MeO2C
73, 66% (dr= 1:1) [B]
O
71, 18% (dr= 1.1:1) [B]b
72, 73% (dr= 3:1) [B]
Scheme 4. Substrates scope of Pd-catalyzed TSOA-directed β-C(sp3)-
H arylation. Isolated yields on a 0.2 mmol scale. a) t-Amyl-OH was
used instead of HFIP. b) 120 oC.
added to compound 79, arylated product 80 was formed in moder-
ate yield (Scheme 5D). Based on these results, we propose that the
catalytic cycle of ortho-sulfinylaniline-directed C-H arylation fea-
tures a sequence of C−H palladation, oxidative addition with aryl
iodide, and reductive elimination.
As shown in Scheme 6A, enantioenriched TSOA* 83 was
prepared following a known procedure.12h TSOA*-directed β-C-H
arylation of 84 with methyl 4-iodobenzoate proceeded with mod-
erate diastereoselectivity (dr = 3:1) under the general conditions
B.23 The TSOA group of 85 was removed by treatment with HCl in
1
trile. Palladacycle 79 was characterized by H-NMR and IR spec-
troscopy (Scheme 5C).22 When 2-isopropyl-iodobenzene 5 was
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 6
A) Evaluation of different S-substituted aniline auxiliaries
A) Enantioenriched TSOA
4 (3 equiv)
Pd(OAc)2 (10 mol%)
Ag2CO3 (2.5 equiv)
KF (3 equiv)
1
2
3
4
5
6
7
8
1. iPrMgCl (3 equiv)
THF, -78 o
C
O
O
H
2.
Aux
iPr
N
Aux
H
O
N
S
HFIP, 110 oC, Ar, 24 h
H
O
O
H2N
O
S
82
*
S
Ph
Cl
O
Aux:
(Boc)2N
81
N
N
H
N
H
S
O
H
Et3N, THF, rt
3. TFA/DCM, rt
82% over 3 steps
I
83 TSOA*
O
S
N
H
S
99% ee
O
29, <3%
75, NO
35, 71%
74, NO
I
O
9
O
H
TSOA
B) KIE
N
TSOA*
CO2Me
(3 equiv)
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
H
O
4 (3 equiv)
N
H
Pd(OAc)2 (10 mol%)
H3C
TSOA
*
(D) (D)
N
Ph
O
Ag2CO3 (2.5 equiv), KF (3 equiv)
HFIP, 110 oC, Ar, 40 min
H
H
H
conditions B
76
CO2Me
TSOA
84 (49%, 97% ee)
vs
N
H
85, 76%, dr = 3:1
O
KIE ~ 1.2
D3C
TSOA
B) Removal of TSOA and MSOA
N
H
77
O
O
TSOA
C) Palladacycle intermediate
OMe
N
H
HCl/MeOH (10 equiv)
MeOH, 100 oC, 12 h
O
O
Pd(OAc)2
CH3CN, 90 o
N
N
H
S
O
O
CO2Me
CO2Me
C
S
Pd
85
86, 82%
O
NCCH3
~90%
O
79
78
MSOA
N
characterized by
NMR and IR
HCl/MeOH (10 equiv)
MeOH, 100 oC, 12h
OMe
H
D) Arylation of 79
O
35
87, 75%
TSOA
HFIP, 110 oC
Ar, 12 h
I
N
H
Scheme 6. Application of enantioenriched TSOA auxiliary.
+
79
5
ACKNOWLEDGMENT
(3 equiv)
80, 40%
We gratefully thank the State Key Laboratory of Elemento-Organic
Chemistry at Nankai University and Natural Science Foundation of
China (21502098, 21421062) for financial support of this work.
Scheme 5. Mechanism studies.
o
MeOH at 100 C to give the corresponding methyl ester 86 in ex-
cellent yield (Scheme 6B). The MSOA group of 35 can also be
removed under the same conditions to give ester 87 in good yield.
REFERENCES
1
For selected reviews on metal-catalyzed C(sp3)–H functionaliza-
tion: (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer J.; Bau-
doin, O. Chem. Eur. J. 2010, 16, 2654-2672. (b) Li, H.; Li, B.-J.; Shi,
Z.-J. Catal. Sci. Technol. 2011, 1, 191-206. (c) Hartwig, J. F. Chem.
Soc. Rev. 2011, 40, 1992-2002. (d) Roizen, J. L.; Harvey, M. E.; Du
Bois, J. Acc. Chem. Res. 2012, 45, 911-922. (e) Huang, Z.; Dong, G.
Tetrahedron Lett. 2014, 55, 5869-5889. (f) Chen, Z.; Wang, B.;
Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2,
1107-1295. (g) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2016, 55, 10578-10599.
In summary, ortho-sulfinyl aniline-based auxiliaries
MSOA and TSOA are uniquely effective at facilitating palladium-
catalyzed β-C-H arylation of alkyl carboxamides with sterically
hindered aryl iodides. The structurally simpler MSOA auxiliary
enables efficient β-methyl C-H arylation of propanamide with aryl
iodides carrying various ortho-substituents including those bearing
ortho alkyl groups. The TSOA auxiliary enables more challenging β-
methylene C-H arylation with various ortho-substituted aryl io-
dides. We suspect that π acidity of sulfoxides may contribute to the
directing ability of these auxiliaries. Both MSOA and TSOA auxilia-
ries can be easily removed under relatively mild acidic conditions.
We are investigating the use of these auxiliaries in other Pd-
catalyzed C-H functionalization reactions.
2
For selected reviews on Pd-catalyzed C(sp3)–H arylation: (a)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2009, 48, 5094-5115. (b) Daugulis, O.; Do, H.-Q.; Shabashov,
D. Acc. Chem. Res. 2009, 42, 1074-1086. (c) Ackermann, L.; Vicen-
te, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792-9826. (d)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147-1169. (e)
Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902-4911. (f) Rouquet, G.;
Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726-11743. (g)
Yang, X.; Shan, G.; Wang, L.; Rao, Y. Tetrahedron Lett. 2016, 57,
819-836. (h) He, G.; Wang, B.; Nack, W. A.; Chen, G. Acc. Chem.
Res. 2016, 49, 635-645.
ASSOCIATED CONTENT
Supporting Information
Additional experimental procedures and spectroscopic data for all new
compounds are supplied. This material is available free of charge via
the Internet at http://pubs.acs.org.
3
For selected examples of Pd-catalyzed methylene C(sp3)-H aryla-
tion of acyclic alkyl carboxamides: (a) Reddy, B. V. S.; Reddy, L. R.;
Corey, E. J. Org. Lett. 2006, 8, 3391-3394. (b) Feng, Y.; Chen, G.
Angew. Chem., Int. Ed. 2010, 49, 958-961. (c) Feng, Y.; Wang, Y.;
Landgraf, B.; Liu S.; Chen, G. Org. Lett. 2010, 12, 3414-3417. (d)
Wasa, M.; Chan, K. S. L.; Zhang, X.-G.; He, J.; Miura, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2012, 134, 18570-18572. (e) Pan, F.; Shen, P.-X.;
Zhang, L.-S.; Wang, X.; Shi, Z.-J. Org. Lett. 2013, 15, 4758-4761. (f)
Zhang, Q.; Yin, X.-S.; Zhao, S.; Fang, S.-L.; Shi, B.-F. Chem. Com-
mun. 2014, 50, 8353-8355. (g) Wei, Y.; Tang, H.; Cong, X.; Rao, B.;
AUTHOR INFORMATION
Corresponding Author
hegang@nankai.edu.cn, gongchen@nankai.edu.cn,
guc11@psu.edu
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
Wu, C.; Zeng, X. Org. Lett. 2014, 16, 2248-2251. (h) Gou, Q.;
M.; Urbano, A. Chem. Commun. 2009, 45, 6129-6144. (b) Sipos,
G.; Drinkel, E. E.; Dorta, R. Chem. Soc. Rev. 2015, 44, 3834-3860.
(c) Trost, B. M.; Rao, M. Angew. Chem., Int. Ed. 2015, 54, 5026-
5043.
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
Zhang, Z.-F.; Liu, Z.-C.; Qin, J. J. Org. Chem. 2015, 80, 3176-3186.
(i) Chen, G.; Gong, W.; Zhuang, Z.; S.Andrä, M.; Chen, Y.-Q.;
Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Science 2016,
353, 1023-1027.
14 For selected examples of sulfoxide ligands for Pd-catalyzed C-H
functionalization reactions: (a) Chen, M. S.; White, M. C. J. Am.
Chem. Soc. 2004, 126, 1346-1347. (b) Covell, D. J.; White, M. C.
Angew. Chem., Int. Ed. 2008, 47, 6448-6451. (c) Yamaguchi, K.;
Hondo, H.; Yamaguchi, J.; Itami. K. Chem. Sci. 2013, 4, 3753-3757.
(d) Kondo, H.; Yu, F.; Yamaguchi, J.; Liu, G.; Itami. K. Org. Lett.
2014, 16, 4212-4215.
15 Compound 31 was prepared in high yield via H2O2 oxidation of 25.
(see Supporting Information)
16 Use of HFIP solvent did not improve the AQ- or TA-directed C-H
arylation reactions listed in Scheme 2. See Supporting Information
for more details.
17 For a discussion on the use of fluorinated alcohols as solvents in
metal catalyzed C-H functionalization reactions, see: Wencel-
Delord, J.; Colobert, F. Org. Chem. Front. 2016, 3, 394-400.
18 Hameed, A.; Alharthy, R. D.; Iqbal, J.; Langer, P. Tetrahedron 2016,
72, 2763-2812.
19 For selected reviews on structure and bonding in metal sulfoxide
complexes see: (a) Davies, J. A. Adv. Inorg. Chem. Radiochem. 1981,
24, 115-187. (b) Calligaris, M.; Carugo, O. Coord. Chem. Rev. 1996,
153, 83-154. (c) Calligaris, M. Coord. Chem. Rev. 2004, 248, 351-
375.
20 For studies on π backbonding interactions between sulfoxide lig-
ands and Ru or Ir: (a) Stener, M.; Calligaris, M. J. Mol. Chem. (The-
ochem) 2000, 497, 91-104. (b) Evans, D. R.; Huang, M.; Seganish,
W. M.; Fettinger, J. C.; Williams, T. L. Inorg. Chem. Commun. 2003,
6, 462-465.
21 For a computational study of π backbonding interactions between
sulfoxide and Pd: Xu, Z.-G.; Gu, G.-B.; Liu, H.-Y. Chin. J. Inorg.
Chem. 2007, 23, 785-790. The results suggest that di-phenyl sulfox-
ide has a stronger π-backbonding interaction with Pd(II) than di-
hexyl sulfoxide.
22 We were unsuccessful in our attempts to obtain an X-ray structure
of 79. The IR spectrum of 79 indicates an increase in the SO
stretching frequency (~ 80 cm-1), compared to the IR spectrum of
78. The binding of sulfoxide ligands to a metal center through a sul-
fur atom typically causes a decrease in the S-O bond length and an
increase of its stretching frequencies in IR spectroscopy. For select-
ed studies on IR of palladium sulfoxide complex see: (a) Price, J. H.;
Williamson, A. N.; Schramm, R. F.; Wayland, B. B. Inorg. Chem.
1972, 11, 1280-1284. (b) Diao, T.; White, P.; Guzei, I.; Stahl, S. S.
Inorg. Chem. 2012, 51, 11898-11909. (c) Drinkel, E. E.; Wu, L.;
Linden, A.; Dorta, R. Organometallics 2014, 33, 627-636. (d) To-
kunoh, R.; Sodeoka, M.; Aoe, K.; Shibasaki, M. Tetrahedron Lett.
1995, 36, 8035-8038.
23 For examples of Pd-catalyzed stereoselective arylation of methylene
C(sp3)–H bonds using enantioenriched auxiliaries: (a) Chen, K.;
Li, Z.-W.; Shen, P.-X.; Zhao, H.-W.; Shi, Z.-J. Chem. Eur. J. 2015,
21, 7389-7393. (b) Kim, J.; Sim, M.; Kim, N.; Hong, S. Chem. Sci.
2015, 6, 3611-3616. (c) Ling, P.-X.; Fang, S.-L.; Yin, X.-S.; Chen,
K.; Sun, B.-Z.; Shi, B.-F. Chem. Eur. J. 2015, 21, 17503-17507.
4
For selected examples of Pd-catalyzed methylene C(sp3)-H aryla-
tion of cyclic alkyl carboxamides: (a) Wasa, M.; Engle, K. M.; Lin,
D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598-
19601. (b) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011,
133, 19076-19079. (c) Gutekunst, W. R.; Gianatassio, R.; Baran, P.
S. Angew. Chem., Int. Ed. 2012, 51, 7507-7510. (d) Parella, R.; Go-
palakrishnan, B.; Babu, S. A. J. Org. Chem. 2013, 78, 11911-11934.
(e) Parella, R.; Gopalakrishnan, B.; Babu, S. A. Org. Lett. 2013, 15,
3238-3241. (f) Gutekunst, W. R.; Baran, P. S. J. Org. Chem. 2014,
79, 2430-2452. (g) Ting, C. P.; Maimone, T. J. Angew. Chem., Int.
Ed. 2014, 53, 3115-3119. (h) Affron, D. P.; Davis, O. A.; Bull, J. A.
Org. Lett. 2014, 16, 4956-4959. (i) Parella, R.; Babu, S. A. J. Org.
Chem. 2015, 80, 2339-2355. (j) Feng, R.; Wang, B.; Liu, Y.; Liu, Z.;
Zhang, Y. Eur. J. Org. Chem. 2015, 142-151. (k) Nack, W. A.; Wang,
B.; Wu, X.; Jiao, R.; He, G.; Chen, G. Org. Chem. Front. 2016, 3,
561-564. (l) Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford,
M. S. Nature 2016, 531, 220-224.
5
Examples of Pd-catalyzed arylation of unactivated C(sp3)–H bonds
with aryl iodides bearing ortho substituents: (a) Wasa, M.; Engle, K.
M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886-9887. (b) He, J.; Li,
S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.; Homes, A.; Yu,
J.-Q. Science 2014, 343, 1216-1220. (c) Chen, K.; Zhang, S.-Q.; Xu,
J.-W.; Hu, F.; Shi, B.-F. Chem. Commun. 2014, 50, 13924-13927. (d)
Liu, J.; Xie, Y.; Zeng, W.; Lin, D.; Deng, Y.; Lu, X. J. Org. Chem.
2015, 80, 4618-4626.
For rare examples of high-yielding Pd-catalyzed C–H arylation with
2-iodotoluene 4, see: (a) Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu,
J.-Q. J. Am. Chem. Soc. 2014, 136, 16940-16946. (b) Zhang, S.-K.;
Yang, X.-Y.; Zhao, X.-M.; Li, P.-X.; Niu, J.-L.; Song, M.-P. Organo-
metallics 2015, 34, 4331-4339.
During the preparation of this manuscript, a related Pd-catalyzed
asymmetric C(sp3)-H arylation of small cycloalkanes using sulfinyl
aniline auxiliaries was reported: Jerhaoui, S.; Chahdoura, F.; Rose,
C.; Djukic, J.; Wencel-Delord, J.; Colobert, F. Chem. Eur. J. 2016,
22, 17397-17406.
He, G.; Zhang, S.-Y.; Nack, W. A; Pearson, R.; Rabb-Lynch, J.;
Chen, G. Org. Lett. 2014, 16, 6488-6491.
6
7
8
9
Zhang, X.; He, G.; Chen, G. Org. Biomol. Chem. 2016, 14, 5511-
5515.
10 (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154-13155. (b) Shabashov, D.; Daugulis, O. J. Am.
Chem. Soc. 2010, 132, 3965-3972. (c) Tran, L. D.; Daugulis, O. An-
gew. Chem., Int. Ed. 2012, 51, 5188-5191.
11 For a recent review on sulfoxide-directed C-H functionalization:
Pulis, A. P.; Procter, D. J. Angew. Chem., Int. Ed. 2016, 55, 9842-
9860.
12 For selected examples of metal-catalyzed sulfoxide-directed C-H
functionalization: (a) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J.
Am. Chem. Soc. 2009, 131, 6932-6933. (b) Wesch, T.; Berthelot-
Bréhier, A.; Leroux, F. R.; Colobert, F. Org. Lett. 2013, 15, 2490-
2493. (c) Wesch, T.; Leroux, F. R.; Colobert, F. Adv. Synth. Catal.
2013, 355, 2139-2144. (d) Wang, B.; Shen, C.; Yao, J.; Yin, H.;
Zhang, Y. Org. Lett. 2014, 16, 46-49. (e) Wang, B.; Liu, Y.; Lin, C.;
Xu, Y.; Liu, Z.; Zhang, Y. Org. Lett. 2014, 16, 4574-4577. (f) No-
bushige, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2014, 16,
1188-1191. (g) Padala, K.; Jeganmohan, M. Chem. Commun. 2014,
50, 14573-14576. (h) Hazra, C. K.; Dherbassy, Q.; Wencel-Delord,
J.; Colobert, F. Angew. Chem., Int. Ed. 2014, 53, 13871-13875. (i)
Dherbassy, Q.; Schwertz, G.; Chessé, M.; Hazra, C. K.; Wencel-
Delord, J.; Colobert, F. Chem. Eur. J. 2016, 22, 1735-1743. (j) Col-
lins, B. S. L.; Kistemaker, J. C. M.; Otten, E.; Feringa, B. L. Nat.
Chem. 2016, 8, 860-866.
13 For selected reviews on chiral sulfoxide ligands in asymmetric catal-
ysis, see: (a) Carreño, M. C.; Hernández-Torres, G.; Ribagorda,
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
1
2
Table of Contents (TOC)
3
I
4
5
Ro
(3 equiv)
6
7
8
9
Pd(OAc)2 (10 mol%)
Ag2CO3 (2.5 equiv)
O
H
O
Ro
N
R2
N
R2
H
H
R1
S
KF (3 equiv)
R1
S
O
R
O
R
or PivOH (1 equiv)
HFIP, 110 oC, Ar, 24 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
(R: Me, Tol)
Ro : alkyl & others
ACS Paragon Plus Environment