Iridium-Catalyzed ortho-C(sp2)-H Amidation of Benzaldehydes with Organic Azides

Article abstract of DOI:10.1021/acs.joc.7b00531

An iridium-catalyzed ortho-C(sp²)-H amidation reaction of benzaldehydes with organic azides has been developed. A catalytic amount of 3,5-di(trifluoromethyl)aniline was used to promote the Ir-catalyzed directed C-H amination reaction through a transient aldimine intermediate. This reaction tolerates a broad scope of benzaldehyde substrates and works well with a range of aryl- and alkylsulfonyl azides.

Full text of DOI:10.1021/acs.joc.7b00531

Subscriber access provided by UNIV OF NEW ENGLAND
Note
Iridium-Catalyzed Ortho-C(sp2)–H Amidation
of Benzaldehydes with Organic Azides
Delong Mu, Xinmou Wang, Gong Chen, and Gang He
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 06 Apr 2017
Downloaded from http://pubs.acs.org on April 6, 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.
The Journal of Organic Chemistry 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 20
The Journal of Organic Chemistry
1
Iridium-Catalyzed Ortho-C(sp2)–H Amidation of Benzaldehydes with Organic Azides
2
3
Delong Mu, a,b Xinmou Wang, a,b Gong Chen*,a,b,c and Gang He*,a,b
4
5
6
7
8
9
10
11
a State Key Laboratory and Institute of ElementoꢀOrganic Chemistry, Nankai University, Tianjin
300071, China.
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, Chiꢀ
na.
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
c Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802,
United States.
CHO
Ar
CHO
Ar
RSO2−N3
H
H
N
R
S
[Cp∗IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
O O
3,5-di(trifluoromethyl)aniline (10 mol%)
DCE, 80 oC, air, 12 h
Abstract
An iridiumꢀcatalyzed orthoꢀC(sp2)–H amidation reaction of benzaldehydes with organic azides
has been developed. A catalytic amount of 3,5ꢀdi(trifluoromethyl)aniline was used to promote the Irꢀ
catalyzed directed CꢀH amination reaction through a transient aldimine intermediate. This reaction tolꢀ
erates a broad scope of benzaldehyde substrates and works well with a range of arylꢀ and alkylsulfonyl
azides.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
5
6
7
8
9
Orthoꢀaminobenzaldehydes are useful building blocks for the synthesis of natural products,
pharmaceuticals, and organic materials.1 Reactions based on metalꢀcatalyzed coupling of prefunctionalꢀ
ized arenes with amine partners, such as BuchwaldꢀHartwig amination, have provided powerful methꢀ
ods to form the C(sp2)–N bond of orthoꢀaminobenzaldehydes.2 Over the past several years, metalꢀ
catalyzed directing groupꢀcontrolled orthoꢀC(sp2)–H amination of arenes with organic azides, pioneered
by Chang and others, has come to offer an efficient alternative for appending ortho amide or sulfonaꢀ
mide groups.3ꢀ6 A range of functional groups including imine, ketone, ester, carboxylic acid and amide
have successfully facilitated the desired orthoꢀC(sp2)–H amination reactions under various metal cataꢀ
lyzed reaction manifolds (Scheme 1A). However, the direct orthoꢀCꢀH amination of benzaldehydes is
still challenging, probably due to the relatively weak coordinating ability and instability of the aldehyde
group.7,8 Recently, Shi reported an iridiumꢀcatalyzed orthoꢀC(sp2)–H amidation reaction of benzaldeꢀ
hydes with arylsulfonyl azides using preformed imines or subꢀstoichiometric amounts of aniline derivaꢀ
tives as transient directing groups (Scheme 1B).9 Herein, we report an efficient and broadly applicable
protocol for the synthesis of 2ꢀsulfonylaminobenzaldehydes via the Irꢀcatalyzed orthoꢀC(sp2)–H amiꢀ
dation of benzaldehydes with arylꢀ and alkylsulfonyl azides using a catalytic amount of 3,5ꢀ
di(trifluoromethyl)aniline (Scheme 1C). 10ꢀ15
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) Metal-catalyzed DG-controlled ortho-C(sp2)−H amination with azide
DG
Ar
DG
Ar
DG:
imine
amide, ester
carboxylic acid
R−N3
NHR
H
cat: Rh, Ru, Ir, Cu
B) Ir-catalyzed ortho-C(sp2)−H amidation of benzaldehyde
RSO2−N3
1.
[Cp∗IrCl2]2 (2 mol%)
AgPF6 (12 mol%)
3-trifluoromethylaniline
(40 mol%)
CHO
Ar
CHO
Ar
H
N
S
H
R
DCE, 100 oC, air, 24 h
O
O
2. aq. HCl (2 M), rt
C) This work:
RSO2−N3
[Cp∗IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
3,5-di(trifluoromethyl)aniline
(10 mol%)
CHO
Ar
CHO
Ar
H
H
N
R
S
O
O
DCE, 80 oC, air, 12 h
Scheme 1. Metalꢀcatalyzed orthoꢀC(sp2)ꢀH amination of arenes with organic azide
2
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
We commenced our study by evaluating catalytic amine promoters for the reaction of 2ꢀ
1
2
methylbenzaldehyde 1 with pꢀtoluenesulfonyl azide 2 under reported Irꢀcatalyzed amidation conditions,
with 2.5 mol% of [Cp*IrCl2]2 catalyst and 10 mol% of AgNTf2 in dichloroethane (DCE) solvent (Table
1).5e The desired CꢀH amidated product 3 was obtained in 19% NMR yield in the absence of any amine
additive. We were pleased to see that the addition of 10 mol% of aniline derivative significantly imꢀ
proved the CꢀH amidation reaction. In comparison, the use of aliphatic amines and amino acid derivaꢀ
tives gave less than 20% yield of 3 (see Supporting Information for details). In general, electron defiꢀ
cient anilines (e.g. L4, and L5) gave much better results than electron rich ones (e.g. L2, L3). Orthoꢀ
substituted anilines were less effective than paraꢀsubstituted ones (see L5 vs L7). 3,5ꢀ
di(trifluoromethyl)aniline L8 stood out among the aniline derivatives tested, providing product 3 in 90%
isolated yield. As shown in Table 2, a number of optimizations were necessary to achieve efficient or-
thoꢀCꢀH amination of 1 with L8. We found that AgNTf2 was the best chloride scavenger for generating
the active cationic iridium species (entry 2ꢀ5). Chlorobenzene and DCE were the best solvents; other
solvents tested gave significantly lower yield (entries 6ꢀ10). Other metal catalysts tested showed little
reactivity (entries 11ꢀ14).
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
CHO
[Cp∗IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
L (10 mol%)
CHO
H
NHTs
TsN3
(2.0 equiv)
2
+
3
DCE, Air, 80 oC, 12 ha
1
NH2
NH2
NH2
NH2
CF3
NH2
NH2
NONE
CF3
Me
OMe
NO2
19%
NH2
L1, 80% L2, 44%
L3, 36%
L4, 90%
L5, 86% L6, 89%
NH2
NH2
NH2
NH2
NH2
F
F
F
CF3
F
F
F
OH
N
F3C
CF3
F
F
CF3
F
L7, 67%
L8, 96% (90%)b
L9, 40% L10, 30% L11, 42% L12, 11%
Table 1. Evaluation of aniline promoters for orthoꢀCꢀH amidation of 2ꢀmethylbenzaldehyde 1 with pꢀ
1
toluenesulfonyl azide 2. a) Yields are based on HꢀNMR analysis on a 0.2 mmol scale using 1,1,2,2ꢀ
tetrachloroethane as internal standard. b) Isolated yield.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
CHO
[Cp∗IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
L8 (10 mol%)
CHO
H
NHTs
1
TsN3
(2 equiv)
2
+
2
3
4
3
DCE, Air, 80 oC, 12 ha
1
standard conditions
5
6
7
8
entry variation from the “standard condiꢀ Yield
tions”
(%)b
1
None
96
(90)c
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
2
AgSbF6 instead of AgNTf2
AgPF6 instead of AgNTf2
AgBF4 instead of AgNTf2
Ag2CO3 instead of AgNTf2
Dioxane instead of DCE
MeCN instead of DCE
87
79
63
<5
<5
<5
<5
10
86
ND
ND
5
3
4
5
6
7
8
tAmylOH instead of DCE
Toluene instead of DCE
Chlorobenzene instead of DCE
IrCl3 instead of [Cp*IrCl2]2
Pd(OAc)2 instead of [Cp*IrCl2]2
[Cp*RhCl2]2 instead of [Cp*IrCl2]2
[Ru(pꢀcymene)Cl2]2
9
10
11
12
13
14
<5
instead of [Cp*IrCl2]2
Table 2. Optimization of amidation reaction conditions. a) All the reactions were run on a 0.2 mmol
scale at 0.1 M concentration. b) NMR yield using 1,1,2,2ꢀtetrachloroethane as internal standard. c) Isoꢀ
lated yield. See Supporting Information for more evaluation conditions.
With the optimized conditions in hand, we next explored the substrate scope of benzaldehydes
with pꢀtoluenesulfonyl azide 2 (Scheme 2). The amidation of benzaldehydes carrying either electron doꢀ
nating or withdrawing groups proceeded well under the standard conditions (see 5, 8). A variety of funcꢀ
tional groups including esters, ethers, and halides were tolerated. For metaꢀsubstituted benzaldehydes,
CꢀH amidation took place selectively at the less sterically hindered position (see 5ꢀ7). The reactions of
1ꢀnaphthaldehyde and 2ꢀnaphthaldehyde gave products 10 and 11, respectively, in good yield and with
excellent selectivity. The amidation of paraꢀsubstituted benzaldehydes proceeds with lower conversion
(see 12) for reasons that are not clear. Reactions of heteroarenes gave notably lower yield (see 13). As
seen in compounds 14ꢀ19, the reaction of 2ꢀmethylbenzaldehyde with various arylꢀ or alkylsulfonyl azꢀ
ides also proceeded smoothly. Furthermore, the reaction of 2ꢀmethylbenzaldehyde with 4ꢀnitrobenzoyl
azide gave amidation product 20 in good yield under modified conditions.
4
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
[Cp∗IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
L8 (10 mol%)
CHO
Ar
CHO
H
1
2
3
4
N
R
R-N3
(2 equiv)
+
Ar
DCE, Air, 80 oC, 12 ha
CHO
CHO
5
R'
6
7
8
9
4a,
4b,
4c,
4d,
4e,
4f,
NHTs
NHTs
R' = F, 98%
R' = Cl, 92%
R' = Br, 89%
R' = I,
R' = OMe,
R' = CO2Me,86%
83%
81%
NHTs
F3C
5, 86%
CHO
CHO
CHO
CHO
MeO
NHTs
NHTs
NHTs
10
11
Ph
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
OMe
Br
6, 89%
F
8, 63%
7, 69%
9, 83%
CHO
CHO
CHO
NHTs
CHO
NHTs
11, 75% (X-ray)
NHTs
NHTs
S
Br
12, 41%b
10, 65%
13, 20%c
CHO
H
14a,
14b,
14c,
14d,
14e,
14f,
R = o-F, 92%
R = o-Cl, 88%
R = o-Br, 89%
R = o-CF3,
R = m-NO2,
R = p-Br,
94%
83%d
74%
N
S
R
O
O
CHO
H
CHO
CHO
H
H
N
N
N
S
O
S
O O
S
O
O
O
O
17, 87%
15, 87%
16, 90%
NO2
CHO
H
CHO
H
CHO
H
N
N
N
S
S
Ph
O
O
O
O
20, 65%e
18, 83%
19, 65%
Scheme 2. Substrate scope of Irꢀcatalyzed orthoꢀCꢀH amination of benzaldehydes with organic azides.
a) Isolated yield on a 0.2 mmol scale. b) [Cp*IrCl2]2 (5.0 mol%), L8 (20 mol%), AgNTf2 (20 mol%), 90
oC. c) [Cp*IrCl2]2 (5.0 mol%), L8 (20 mol%), AgNTf2 (20 mol%), 110 oC. d) 100 oC. e) [Cp*IrCl2]2 (5.0
mol%), L8 (20 mol%), AgNTf2 (20 mol%). See the Xꢀray structure of compound 4e, 4f, and 11 in Supꢀ
porting Information (Figure S1ꢀFigure S3).
We carried out experiments to investigate the unique effectiveness of 3,5ꢀ
di(trifluoromethyl)aniline in this Irꢀcatalyzed orthoꢀCꢀH amidation reaction. As shown in Scheme 3A,
aldimine 21 was the major product of a competitive condensation reaction with equal amount of 2ꢀ
o
methylbenzaldehyde, 4ꢀmethoxylaniline (L3), and 3,5ꢀdi(trifluoromethyl)aniline (L8) in DCE at 80 C.
Aldimine 21 and 22 were then separately subjected to the standard Irꢀcatalyzed CꢀH amidation reaction
conditions with 2 (Scheme 3B). The reaction of 22 gave 85% of 24 along with 14% of 3 in 2 hours. In
comparison, the amidation of 21 gave 27% of 23 and a trace amount of 3 in 2 hours. After 12 hours, 83%
yield of 23 and 12% yield of 3 was obtained, while 72% yield of 24 and 22% yield of 3 was obtained
from the parallel reaction of 22. These results suggest that aldimine 22 is slower to form than 21, but is
more reactive to Irꢀcatalyzed orthoꢀCꢀH amidation.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
A) Formation of aldimine
OMe
H
1
2
N
3
4
5
6
L3 (0.2 mmol)
L8 (0.2 mmol)
21, 88%
CHO
+
CF3
1
DCE, 80 oC, 12 h
(0.2 mmol)
H
7
N
CF3
8
9
22, 10%
B) C-H amidation of preformed aldimines
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
2 (2 equiv)
OMe
H
[Cp∗IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
H
O
N
+
21
DCE, Air, 80 oC, 12 h
NHTs
NHTs
3
23
2 h: 27%
12 h: 83%
<5%
12%
CF3
2 (2 equiv)
[Cp∗IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
H
22
N
CF3
+
3
DCE, Air, 80 oC, 12 h
NHTs
24
2 h: 85%
12 h: 72%
14%
22%
Scheme 3. Mechanistic studies. NMR yield on a 0.2 mmol scale using 1,1,2,2ꢀtetrachloroethane as inꢀ
ternal standard
A) Gram-scale reaction
[Cp∗IrCl2]2 (2.5 mol%)
CHO
CHO
AgNTf2 (10 mol%)
L8 (10 mol%)
H
N
Ts-N3
(2 equiv)
Ts
+
DCE, Air, 80 oC, 12 h
25
(6 mmol)
2
26, 79% (1.37 g)
B) Transformations of 26
1)
O
OO
N
O
N
PPh3 (10 mol%)
MeCN, Ar,
80 oC, 12 h
O
Ts
N
N
O
O
27, 82%
28, 89%
[Cp∗RhCl2]2
(2.5 mol%)
Ag2CO3, DCE
Ar, 120 oC, 18 h
2) 1 N HCl,
rt, 5 min
CHO
NHTs
O
O
26
N
OMe
H
O
[Cp∗RhCl2]2
(2.5 mol%)
CsOAc, DCE
Ar, 100 oC, 14 h
CuCl (5 mol%)
Cu(OTf)2 (5 mol%)
DMAP, MeCN
Ar, 80 oC, 12 h
O
N
OMe
N
Ts
N
30, 53%
29, 72%
Ts
Scheme 4. Synthetic applications
6
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
In order to demonstrate the applicability of this amidation reaction, a large scale reaction and
1
2
3
4
5
6
7
8
9
post transformations of the amidated product were carried out. As shown in Scheme 4A, Irꢀcatalyzed
orthoꢀCꢀH amidation of 25 gave 26 in 79% yield on a 6 mmol scale. As shown in Scheme 4B, comꢀ
pound 26 were successfully transformed to a wide variety of Nꢀheterocyclic products including spiroꢀ
ketone 2716a, quinoline 2816b, indoline 2916c, and hydroquinolone 3016d in good yield following reported
procedures.
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
In summary, we have developed a new protocol for the Irꢀcatalyzed orthoꢀCꢀH amidation of
benzaldehydes with organic azides using a catalytic amount of 3,5ꢀdi(trifluoromethyl)aniline promoter.
3,5ꢀdi(trifluoromethyl)aniline facilitates the Irꢀcatalyzed directed CꢀH amination reaction through forꢀ
mation of a transient aldimine intermediate. This protocol tolerates a broad scope of both benzaldehydes
and sulfonyl azides, and offers a convenient method for the synthesis of various 2ꢀsulfonylaminoꢀ
benzaldehydes.
EXPERIMENTAL SECTION
General Method and Materials. All commercial materials were used as received unless otherwise noted.
TLC were performed on silica gel Huanghai HSGF254 plates and visualization of the developed chroꢀ
matogram was performed by fluorescence quenching (λmax = 254 nm). Flash chromatography was perꢀ
formed using Silica gel (200ꢀ300 mesh) purchased from Qingdao Haiyang Chemical Co., China.
[Cp*IrCl2]2 (> 94%) was purchased from TCI. AgNTf2 (99.3%) was purchased from Boka Chemical
Co., China. DCE (> 99.5%) was purchased from TCI, other solvents were purchased from J&K. Organꢀ
ic azides were prepared according to the literature method.17 NMR spectra were recorded on Bruker
AVANCE AV 400 instruments and all NMR experiments were reported in units, parts per million
(ppm), using residual solvent peaks as internal reference. Multiplicities are recorded as: s = singlet, d =
doublet, t = triplet, dd = doublet of doublets, m = multiplet. High resolution ESI mass experiments were
operated on a Waters Xevo G2ꢀXs QTof instrument. IR spectra were recorded on a Bruker Tensor 27
instrument and are reported in wavenumbers (cmꢀ1). Xꢀray crystallography was recorded on Rigaku 007
Saturn 70 or Bruker SMART APEX CCD instruments.
General procedure of ortho amidation of benzaldehydes with organic azides. To a 12 mL glass vial was
added benzaldehyde (0.2 mmol, 1.0 equiv), organic azide (0.4 mmol, 2.0 equiv), [Cp*IrCl2]2 (4.0 mg,
0.005 mmol, 2.5 mol%), AgNTf2 (7.8 mg, 0.02 mmol, 10 mol%) and L8 (4.6 mg, 0.02 mmol, 10 mol%)
at room temperature. DCE (2 mL) was then added and the vial was sealed with PTFE cap. The mixture
o
was stirred at 80 C for 12 hours. After been cooled to room temperature, the reaction mixture was diꢀ
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
luted with EtOAc (3 mL), and filtered through a pad of celite. The filtrate was concentrated in vacuo,
and the resulting residue was purified by flash column chromatography on silica gel to give the amidatꢀ
ed product.
1
2
3
4
5
6
7
8
9
2-Tolylsulfonylamino-6-methyl-benzaldehyde (3).8b Yellow solid, Rf = 0.3 (Hexanes/EtOAc = 4/1).
1
Yield: 52.0 mg, 90%. H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H), 10.32 (s, 1H), 7.75 (d, J = 8.1 Hz,
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
2H), 7.51 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 7.4 Hz, 1H),
2.59 (s, 3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.1, 144.2, 143.8, 140.9, 136.5, 136.1,
129.8, 127.3, 125.8, 119.4, 116.1, 21.6, 19.0.
2-Tolylsulfonylamino-6-fluoro-benzaldehyde (4a).8b Yellow solid, Rf = 0.6 (Hexanes/EtOAc = 4/1).
1
Yield: 57.3 mg, 98%. H NMR (400 MHz, CDCl3) δ 11.09 (s, 1H), 10.26 (s, 1H), 7.78 (d, J = 8.1 Hz,
2H), 7.51ꢀ7.44 (m, 2H), 7.27 (d, J = 7.9 Hz, 2H), 6.79ꢀ6.74 (m, 1H), 2.38 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 190.4 (d, J = 12.2 Hz), 166.0 (d, J = 260.6 Hz), 144.6, 141.4 (d, J = 20.2 Hz), 137.8 (d, J =
11.7 Hz), 136.1, 129.9, 127.4, 113.3 (d, J = 3.6 Hz), 110.8 (d, J = 9.4 Hz), 109.5 (d, J = 21.0 Hz), 21.6.
2-Tolylsulfonylamino-6-chloro-benzaldehyde (4b).9 Pale yellow solid, Rf = 0.7 (Hexanes/EtOAc = 4/1).
1
Yield: 57.0 mg, 92%. H NMR (400 MHz, CDCl3) δ 11.35 (s, 1H), 10.44 (s, 1H), 7.77 (d, J = 8.2 Hz,
2H), 7.61 (d, J = 8.5 Hz, 1H), 7.40 (t, J = 8.3 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 7.9 Hz, 1H),
2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.8, 144.6, 142.3, 140.4, 136.5, 136.2, 130.0, 127.4,
124.6, 117.6, 116.6, 21.6.
2-Tolylsulfonylamino-6-bromo-benzaldehyde (4c).9 Yellow solid, Rf = 0.6 (Hexanes/EtOAc = 4/1).
1
Yield: 63.2 mg, 89%. H NMR (400 MHz, CDCl3) δ 11.37 (s, 1H), 10.34 (s, 1H), 7.76 (d, J = 8.0 Hz,
13
2H), 7.65 (d, J = 6.6 Hz, 1H), 7.30ꢀ7.25 (m, 4H), 2.38 (s, 3H); C NMR (101 MHz, CDCl3) δ 196.3,
144.6, 142.3, 136.5, 136.1, 130.1, 130.0, 128.1, 127.3, 118.3, 117.4, 21.6.
2-Tolylsulfonylamino-6-iodo-benzaldehyde (4d).9 Brown solid, Rf = 0.6 (Hexanes/EtOAc = 4/1). Yield:
1
66.9 mg, 83%. H NMR (400 MHz, CDCl3) δ 11.38 (s, 1H), 10.06 (s, 1H), 7.76 (d, J = 8.3 Hz, 2H),
7.69 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.09 (t, J = 8.2 Hz, 1H), 2.38
13
(s, 3H); C NMR (101 MHz, CDCl3) δ 201.1, 144.6, 141.7, 136.5, 136.2, 135.4, 130.0, 127.4, 119.2,
118.5, 105.0, 21.7.
2-Tolylsulfonylamino-6-methoxy-benzaldehyde (4e).8b Pale yellow solid, Rf = 0.3 (Hexanes/EtOAc =
1
4/1). Yield: 49.4 mg, 81%. H NMR (400 MHz, CDCl3) δ 11.53 (s, 1H), 10.36 (s, 1H), 7.76 (d, J = 8.1
Hz, 2H), 7.39 (t, J = 8.4 Hz, 1H), 7.24ꢀ7.18 (m, 3H), 6.55 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 2.36 (s, 3H);
8
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
13C NMR (101 MHz, CDCl3) δ 193.0, 163.4, 144.2, 141.6, 137.6, 136.5, 129.8, 127.3, 110.9, 109.5,
105.1, 56.0, 21.6.
1
2
3
4
5
2-Tolylsulfonylamino-6-methoxycarbonyl-benzaldehyde (4f).9 Pale yellow solid, Rf = 0.3 (Hexꢀ
6
7
1
anes/EtOAc = 4/1). Yield: 57.6 mg, 86%. H NMR (400 MHz, CDCl3) δ 11.14 (s, 1H), 10.29 (s, 1H),
8
9
7.89 (d, J = 7.3 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.56ꢀ7.51 (m, 2H), 7.24 (d, J = 7.9 Hz, 2H), 3.94 (s,
3H), 2.37 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.6, 166.4, 144.5, 140.4, 136.2, 135.7, 134.7, 129.9,
127.3, 125.1, 122.3, 121.1, 53.3, 21.7.
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
2-Tolylsulfonylamino-5-trifluoromethyl-benzaldehyde (5). Pale yellow solid, mp 137ꢀ139 C, Rf = 0.6
1
(Hexanes/EtOAc = 4/1). Yield: 59.0 mg, 86%. H NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 9.90 (s,
1H), 7.87 (s, 1H), 7.82ꢀ7.79 (m, 3H), 7.72 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 194.2, 145.0, 142.8, 135.9, 133.1 (q, J = 3.4 Hz), 132.3 (q, J = 3.3 Hz),
130.1, 127.3, 124.9 (q, J = 34.1 Hz), 123.3 (q, J = 272.7 Hz), 121.0, 117.5, 21.6; HRMS calcd for
C15H13F3NO3S [M+H+]: 344.0563, found: 344.0565; IR (KBr) 3167, 2856, 2755, 2360, 2341, 1680,
1623, 1588, 1508, 1442, 1398, 1163, 874 cmꢀ1.
o
2-Tolylsulfonylamino-5-phenyl-benzaldehyde (6). Brown solid, mp 112ꢀ114 C, Rf = 0.6 (Hexꢀ
1
anes/EtOAc = 4/1). Yield: 62.5 mg, 89%. H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 9.89 (s, 1H),
7.81ꢀ7.71 (m, 5H), 7.51 (d, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.1 Hz, 1H), 7.25 (d, J
13
= 7.9 Hz, 2H), 2.36 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.2, 144.4, 139.0, 138.7, 136.5, 136.2,
134.5, 134.3, 129.9, 129.2, 128.0, 127.4, 126.7, 122.3, 118.4, 21.7; HRMS calcd for C20H17NNaO3S
[M+Na+]: 374.0821, found: 374.0825; IR (KBr) 3210, 2958, 2869, 2360, 2341, 1670, 1653, 1507,
1486,1382, 1158, 869 cmꢀ1.
o
2-Tolylsulfonylamino-4-fluoro-5-methyl-benzaldehyde (7). Pale yellow solid, mp 143ꢀ145 C, Rf = 0.4
1
(Hexanes/EtOAc = 4/1). Yield: 42.5 mg, 69%. H NMR (400 MHz, CDCl3) δ 10.87 (s, 1H), 9.73 (s,
1H), 7.76 (d, J = 8.0 Hz, 2H), 7.43ꢀ7.36 (m, 2H), 7.26 (d, J = 8.1 Hz, 2H), 2.38 (s, 3H), 2.22 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 193.8, 165.5 (d, J = 258.2 Hz), 144.5, 140.2 (d, J = 12.8 Hz), 139.5 (d, J =
9.0 Hz), 136.1, 130.0, 127.3, 120.3 (d, J = 19.0 Hz), 118.6, 105.2 (d, J = 29.1 Hz), 21.6, 13.8 (d, J = 2.8
Hz); HRMS calcd for C15H14FNNaO3S [M+Na+]: 330.0571, found: 330.0575; IR (KBr) 3126, 2926,
2864, 2360, 2341, 1668, 1653, 1583, 1507, 1405, 1320, 1157, 845 cmꢀ1.
o
2-Tolylsulfonylamino-4,6-dimethoxy-benzaldehyde (8). White solid, mp 200ꢀ201 C, Rf = 0.4 (Hexꢀ
1
anes/EtOAc = 4/1). Yield: 42.3 mg, 63%. H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 10.16 (s, 1H),
7.77 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 6.77 (s, 1H), 6.02 (s, 1H), 3.82 (s, 6H), 2.38 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 191.0, 167.0, 164.9, 144.2, 144.1, 136.7, 129.9, 127.5, 105.8, 94.0, 92.9,
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
56.0, 55.9, 21.7; HRMS calcd for C16H18NO5S [M+H+]: 336.0900, found: 336.0903; IR (KBr) 3060,
2983, 2892, 2360, 2341, 1652, 1614, 1576, 1494, 1432, 1396, 1341, 1283, 1155, 843 cmꢀ1.
1
2
3
4
5
o
2-Tolylsulfonylamino-4-bromo-6-methyl-benzaldehyde (9). Yellow solid, mp 183ꢀ185 C, Rf = 0.3
6
7
1
(Hexanes/EtOAc = 4/1). Yield: 61.4 mg, 83%. H NMR (400 MHz, CDCl3) δ 11.47 (s, 1H), 10.26 (s,
8
9
1H), 7.76 (d, J = 7.9 Hz, 2H), 7.72 (s, 1H). 7.27 (d, J = 7.8 Hz, 2H), 7.01 (s, 1H), 2.56 (s, 3H), 2.38 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 193.3, 145.1, 144.5, 141.7, 136.2, 131.3, 130.0, 128.7, 127.4,
119.0, 117.9, 21.7, 18.9; HRMS calcd for C15H15BrNO3S [M+H+]: 367.9951, found: 367.9949; IR
(KBr) 3051, 2902, 2803, 2360, 2341, 1654, 1586, 1559, 1488, 1416, 1372, 1162, 868 cmꢀ1.
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
2-Tolylsulfonylamino-1-naphthaldehyde (10).9 Yellow solid, Rf = 0.6 (Hexanes/EtOAc = 4/1). Yield:
1
42.3 mg, 65%. H NMR (400 MHz, CDCl3) δ 12.16 (s, 1H), 10.88 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H),
7.96ꢀ7.90 (m, 2H), 7.80 (t, J = 7.6 Hz, 3H), 7.61 (t, J = 7.0 Hz, 1H), 7.46 (t, J = 7.0 Hz, 1H), 7.23 (d, J =
7.3 Hz, 2H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 192.4, 144.4, 141.6, 137.7, 136.6, 133.6,
129.9, 129.51, 129.46, 129.36, 127.3, 125.5, 119.7, 116.8, 112.8, 21.6.
3-Tolylsulfonylamino-2-naphthaldehyde (11). Yellow solid, mp 157ꢀ159 oC, Rf = 0.2 (Hexanes/EtOAc =
4/1). Yield: 49.1 mg, 75%. 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 9.93 (s, 1H), 8.10 (s, 1H), 8.00
(s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 3H), 7.60 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz,
13
1H), 7.17 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.0, 144.1, 140.4, 136.5,
136.3, 134.6, 130.7, 129.7, 129.2, 128.9, 127.6, 127.3, 126.2, 122.9, 115.8, 21.6; HRMS calcd for
C18H15NNaO3S [M+Na+]: 348.0665, found: 348.0670; IR (KBr) 3203, 2844, 2759, 2360, 2342, 1668,
1597, 1558, 1508, 1473, 1404, 1375, 1156, 870 cmꢀ1.
2-Tolylsulfonylamino-4-bromo-benzaldehyde (12).8b To a 12 mL glass vial was added 4ꢀbromoꢀ
benzaldehyde (37.0 mg, 0.2 mmol, 1.0 equiv), pꢀtoluenesulfonyl azide 2 (78.9 mg, 0.4 mmol, 2.0
equiv), [Cp*IrCl2]2 (8.0 mg, 0.01 mmol, 5 mol%), AgNTf2 (15.6 mg, 0.04 mmol, 20 mol%) and L8 (9.2
mg, 0.04 mmol, 20 mol%) at room temperature. DCE (2 mL) was then added and the vial was sealed
o
with PTFE cap. The mixture was stirred at 90 C for 12 hours. After been cooled to room temperature,
the reaction mixture was diluted with EtOAc (3 mL), and filtered through a pad of celite. The filtrate
was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on
silica gel to give compound 12 in 41% yield (29.1 mg). Pale yellow solid, Rf = 0.3 (Hexanes/EtOAc =
1
4/1). H NMR (400 MHz, CDCl3) δ 10.84 (s, 1H), 9.78 (s, 1H), 7.89 (s, 1H), 7.79 (d, J = 7.0 Hz, 2H),
13
7.43 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 6.7 Hz, 3H), 2.39 (s, 3H); C NMR (101 MHz, CDCl3) δ 194.2,
144.7, 141.0, 137.1, 136.2, 131.6, 130.1, 127.4, 126.4, 120.9, 120.5, 21.7.
10
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
3-Tolylsulfonylamino-thiophene-2-carbaldehyde (13).8b To a 12 mL glass vial was added thiopheneꢀ2ꢀ
carbaldehyde (22.4 mg, 0.2 mmol, 1.0 equiv), pꢀtoluenesulfonyl azide 2 (78.9 mg, 0.4 mmol, 2.0 equiv),
[Cp*IrCl2]2 (8.0 mg, 0.01 mmol, 5 mol%), AgNTf2 (15.6 mg, 0.04 mmol, 20 mol%) and L8 (9.2 mg,
0.04 mmol, 20 mol%) at room temperature. DCE (2 mL) was then added and the vial was sealed with
1
2
3
4
5
6
7
8
o
PTFE cap. The mixture was stirred at 110 C for 12 hours. After been cooled to room temperature, the
9
reaction mixture was diluted with EtOAc (3 mL), and filtered through a pad of celite. The filtrate was
concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica
gel to give compound 13 in 20% yield (11.2 mg). Pale yellow solid, Rf = 0.3 (Hexanes/EtOAc = 4/1). 1H
NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 9.60 (s, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 5.3 Hz,
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
13
1H), 7.43 (d, J = 5.3 Hz, 1H), 7.28ꢀ7.26 (m, 2H), 2.39 (s, 3H); C NMR (101 MHz, CDCl3) δ 184.0,
144.6, 143.8, 136.5, 136.4, 130.0, 127.2, 121.0, 120.7, 21.7.
o
2-(2-Fluorobenzenesulfonyl)-amino-6-methyl-benzaldehyde (14a). Brown solid, mp 132ꢀ135 C, Rf =
1
0.3 (Hexanes/EtOAc = 4/1). Yield: 54.2 mg, 92%. H NMR (400 MHz, CDCl3) δ 11.79 (s, 1H), 10.39
(s, 1H), 7.99 (t, J = 7.0 Hz, 1H), 7.55 (d, J = 5.2 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.34ꢀ7.25 (m, 2H),
13
7.12 (t, J = 9.1 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 2.62 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.9,
158.9 (d, J = 258.2 Hz), 143.9, 140.2, 136.1, 135.8 (d, J = 8.5 Hz), 130.9, 127.2 (d, J = 13.2 Hz), 126.0,
124.4 (d, J = 3.9 Hz), 119.2, 117.4 (d, J = 20.9 Hz), 115.3, 19.0; HRMS calcd for C14H13FNO3S
[M+H+]: 294.0595, found: 294.0596; IR (KBr) 3089, 2925, 2786, 2360, 2341, 1664, 1599, 1579, 1488,
1385, 1157, 763 cmꢀ1.
2-(2-Chlorobenzenesulfonyl)-amino-6-methyl-benzaldehyde (14b). Pale yellow solid, mp 138ꢀ140 oC, Rf
= 0.4 (Hexanes/EtOAc = 4/1). Yield: 54.5 mg, 88%. 1H NMR (400 MHz, CDCl3) δ 11.97 (s, 1H), 10.39
(s, 1H), 8.22 (d, J = 7.5 Hz, 1H), 7.50ꢀ7.47 (m, 1H), 7.44ꢀ7.40 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.28 (t,
13
J = 8.0 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 2.62 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.8, 144.0,
140.1, 136.4, 136.1, 134.4, 132.2, 132.1, 132.1, 127.0, 125.7, 118.9, 114.6, 19.1; HRMS calcd for
C14H13ClNO3S [M+H+]: 310.0299, found: 310.0300; IR (KBr) 3090, 2902, 2361, 2341, 1666, 1599,
1577, 1489, 1472, 1386, 1162, 758 cmꢀ1.
o
2-(2-Bromobenzenesulfonyl)-amino-6-methyl-benzaldehyde (14c). Pale yellow solid, mp 158ꢀ160 C, Rf
= 0.3 (Hexanes/EtOAc = 4/1). Yield: 63.0 mg, 89%. 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 10.40
(s, 1H), 8.28 (dd, J = 7.8, 1.3 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.41ꢀ7.37 (m,
1H), 7.34 (d, J = 8.4 Hz, 1H), 7.30ꢀ7.26 (m, 1H), 6.84 (d, J = 7.3 Hz, 1H), 2.63 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 193.7, 144.0, 140.2, 138.3, 136.1, 135.7, 134.4, 132.4, 127.6, 125.6, 120.5, 118.9,
114.6, 19.2; HRMS calcd for C14H13BrNO3S [M+H+]: 353.9794, found: 353.9792; IR (KBr) 3091,
2360, 1652, 1598, 1575, 1558, 1471, 1448, 1380, 1165, 732 cmꢀ1.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
2-(2-Trifluoromethylbenzenesulfonyl)-amino-6-methyl-benzaldehyde (14d). Pale yellow solid, mp 121ꢀ
123 oC, Rf = 0.4 (Hexanes/EtOAc = 4/1). Yield: 64.5 mg, 94%. 1H NMR (400 MHz, CDCl3) δ 11.83 (s,
1H), 10.38 (s, 1H), 8.31ꢀ8.29 (m, 1H), 7.86ꢀ7.84 (m, 1H), 7.70ꢀ7.68 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H),
1
2
3
4
5
6
13
7.33 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 2.62 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.9,
7
8
9
144.1, 140.2, 137.9, 136.2, 133.4, 132.4, 131.9, 128.9, 128.8 (q, J = 6.2 Hz), 128.1 (q, J = 33.3 Hz),
125.9, 122.7 (q, J = 275.4 Hz), 119.1, 114.9, 19.1; HRMS calcd for C15H12F3NNaO3S [M+Na+]:
366.0382, found: 366.0388; IR (KBr) 3118, 2920, 2360, 1636, 1597, 1576, 1507, 1456, 1388, 1168, 770
cmꢀ1.
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
2-(3-Nitrobenzenesulfonyl)-amino-6-methyl-benzaldehyde (14e). To a 12 mL glass vial was added 2ꢀ
methylbenzaldehyde 1 (24.0 mg, 0.2 mmol, 1.0 equiv), 3ꢀnitrobenzenesulfonyl azide (91.3 mg, 0.4
mmol, 2.0 equiv), [Cp*IrCl2]2 (4.0 mg, 0.005 mmol, 2.5 mol%), AgNTf2 (7.8 mg, 0.02 mmol, 10 mol%)
and L8 (4.6 mg, 0.02 mmol, 10 mol%) at room temperature. DCE (2 mL) was then added and the vial
o
was sealed with PTFE cap. The mixture was stirred at 100 C for 12 hours. After been cooled to room
temperature, the reaction mixture was diluted with EtOAc (3 mL), and filtered through a pad of celite.
The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromaꢀ
tography on silica gel to give compound 14e in 83% yield (53.2 mg). Brown solid, mp 157ꢀ159 oC, Rf =
1
0.2 (Hexanes/EtOAc = 4/1). H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 10.34 (s, 1H), 8.69 (s, 1H),
8.38 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.42
(t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 2.61 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.3, 148.3,
144.3, 141.7, 140.0, 136.5, 132.8, 130.8, 127.8, 126.9, 122.6, 119.8, 116.4, 19.1; HRMS calcd for
C14H13N2O5S [M+H+]: 321.0540, found: 321.0537; IR (KBr) 3084, 2360, 1646, 1602, 1576, 1472,
1457, 1385, 1169, 791, 733 cmꢀ1.
2-(4-Bromobenzenesulfonyl)-amino-6-methyl-benzaldehyde (14f). Brown solid, mp 158ꢀ160 oC, Rf = 0.5
1
(Hexanes/EtOAc = 4/1). Yield: 52.7 mg, 74%. H NMR (400 MHz, CDCl3) δ 11.44 (s, 1H), 10.32 (s,
1H), 7.72 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H),
6.89 (d, J = 7.5 Hz, 1H), 2.60 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.2, 144.0, 140.4, 138.6, 136.2,
132.5, 128.9, 128.3, 126.3, 119.6, 116.3, 19.0; HRMS calcd for C14H13BrNO3S [M+H+]: 353.9794,
found: 353.9789; IR (KBr) 3093, 2903, 2360, 1645, 1598, 1575, 1470, 1456, 1390, 1168, 863 cmꢀ1.
2-Methylsulfonyl-amino-6-methyl-benzaldehyde (15).8b Yellow solid, Rf = 0.5 (Hexanes/EtOAc = 4/1).
1
Yield: 37.3 mg, 87%. H NMR (400 MHz, CDCl3) δ 11.18 (s, 1H), 10.41 (s, 1H), 7.55 (d, J = 8.4 Hz,
13
1H), 7.46 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 3.07 (s, 3H), 2.67 (s, 3H); C NMR (101 MHz,
CDCl3) δ 201.7, 144.2, 141.2, 136.5, 125.9, 119.2, 115.4, 40.3, 19.1.
12
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
o
2-Propanylsulfonyl-amino-6-methyl-benzaldehyde (16). Brown solid, mp 57ꢀ59 C, Rf = 0.6 (Hexꢀ
1
2
3
1
anes/EtOAc = 4/1). Yield: 43.4 mg, 90%. H NMR (400 MHz, CDCl3) δ 11.14 (s, 1H), 10.41 (s, 1H),
7.58 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 3.14ꢀ3.11 (m, 2H), 2.67 (s,
4
5
6
13
3H), 1.85ꢀ1.75 (m, 2H), 0.99 (t, J = 7.5 Hz, 3H); C NMR (101 MHz, CDCl3) δ 194.1, 144.2, 141.4,
7
8
9
136.5, 125.6, 119.0, 115.3, 54.0, 19.2, 17.3, 12.9; HRMS calcd for C11H16NO3S [M+H+]: 242.0845,
found: 242.0848; IR (KBr) 3117, 2972, 2876, 2360, 1652, 1600, 1576, 1507, 1457,1375 cmꢀ1.
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
2-(1-Naphthylsulfonyl)-amino-6-methyl-benzaldehyde (17). Pale yellow solid, mp 167ꢀ169 C, Rf = 0.3
1
(Hexanes/EtOAc = 4/1). Yield: 56.5 mg, 87%. H NMR (400 MHz, CDCl3) δ 11.92 (s, 1H), 10.25 (s,
1H), 8.69 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.1 Hz,
1H), 7.69 (t, J = 7.6 Hz, 1H), 7.58ꢀ7.49 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.75
(d, J = 7.3 Hz, 1H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.0, 143.8, 140.8, 136.1, 135.0,
134.2, 134.0, 130.5, 129.1, 128.7, 127.9, 127.1, 125.4, 124.2, 123.9, 118.8, 115.1, 18.9; HRMS calcd
for C18H15NNaO3S [M+Na+]: 348.0665, found: 348.0670; IR (KBr) 3057, 2915, 2342, 1646, 1601,
1577, 1506, 1468, 1376, 1159 cmꢀ1.
o
2-Isopropanylsulfonyl-amino-6-methyl-benzaldehyde (18). Brown solid, mp 78ꢀ80 C, Rf = 0.3 (Hexꢀ
1
anes/EtOAc = 4/1). Yield: 40.0 mg, 83%. H NMR (400 MHz, CDCl3) δ 11.08 (s, 1H), 10.41 (s, 1H),
7.65 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 3.37ꢀ3.30 (m, 1H), 2.66 (s,
3H), 1.36 (d, J = 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 194.1, 144.1, 141.9, 136.5, 125.5, 119.0,
115.6, 53.3, 19.2, 16.5; HRMS calcd for C11H16NO3S [M+H+]: 242.0845, found: 242.0843; IR (KBr)
3099, 2979, 2936, 2360, 1636, 1600, 1576, 1507, 1456, 1380, 1142 cmꢀ1.
2-Benzylsulfonyl-amino-6-methyl-benzaldehyde (19). Brown oil, Rf = 0.5 (Hexanes/EtOAc = 4/1).
1
Yield: 37.6 mg, 65%. H NMR (400 MHz, CDCl3) δ 11.04 (s, 1H), 10.27 (s, 1H), 7.50 (d, J = 8.4 Hz,
1H), 7.39 (t, J = 8.0 Hz, 1H), 7.33ꢀ7.25 (m, 3H), 7.18 (d, J = 7.0 Hz, 2H), 6.92 (d, J = 7.4 Hz, 1H), 4.41
13
(s, 2H), 2.64 (s, 3H); C NMR (101 MHz, CDCl3) δ 193.6, 143.9, 141.5, 136.3, 130.7, 129.1, 128.8,
128.2, 125.7, 119.0, 115.5, 58.7, 19.1; HRMS calcd for C15H15NNaO3S [M+Na+]: 312.0665, found:
312.0670; IR (KBr) 3066, 2917, 2360, 1652, 1576, 1540, 1507, 1488, 1362, 1154, 763, 693 cmꢀ1.
2-(4-Nitrobenzoyl)-amino-6-methyl-benzaldehyde (20). To a 12 mL glass vial was added 2ꢀ
methylbenzaldehyde 1 (24.0 mg, 0.2 mmol, 1.0 equiv), pꢀnitrobenzoyl azide (76.8 mg, 0.4 mmol, 2.0
equiv), [Cp*IrCl2]2 (8.0 mg, 0.01 mmol, 5 mol%), AgNTf2 (15.6 mg, 0.04 mmol, 20 mol%) and L8 (9.2
mg, 0.04 mmol, 20 mol%) at room temperature. DCE (2 mL) was then added and the vial was sealed
o
with PTFE cap. The mixture was stirred at 80 C for 12 hours. After been cooled to room temperature,
the reaction mixture was diluted with EtOAc (3 mL), and filtered through a pad of celite. The filtrate
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on
1
2
3
4
5
6
o
silica gel to give compound 20 in 62% yield (35.3 mg). Yellow solid, mp 212ꢀ214 C, Rf = 0.5 (Hexꢀ
anes/EtOAc = 4/1). 1H NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 10.54 (s, 1H), 8.79 (d, J = 8.5 Hz, 1H),
8.38 (d, J = 8.8 Hz, 2H), 8.24 (d, J = 8.8 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 2.74
7
8
9
13
(s, 3H); C NMR (101 MHz, CDCl3) δ 195.2, 164.1, 150.1, 143.8, 141.6, 140.3, 137.0, 128.9, 126.9,
124.2, 119.9, 118.8, 19.3; HRMS calcd for C15H13N2O4 [M+H+]: 285.0870, found: 285.0870; IR (KBr)
3108, 2923, 2793, 2360, 1653, 1609, 1576, 1508, 1458, 1396, 1197, 802 cmꢀ1.
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
(E)-N-(4-methoxyphenyl)-1-(o-tolyl)methanimine (21). To a solution of 2ꢀmethylbenzaldehyde 1 (1.20
g, 10 mmol, 1.0 equiv) and 4ꢀmethoxyaniline L3 (1.23 g, 10 mmol, 1.0 equiv) in DCM (20 mL) was
added MgSO4 (2.4 g). The mixture was stirred at room temperature overnight, then filtered through a
pad of celite. The filtrate was concentrated in vacuo, and the residue was purified by flash column
o
chromatography on silica gel to afford compound 21 as yellow solid (mp 56ꢀ57 C, Rf = 0.6, Hexꢀ
1
anes/EtOAc = 10/1) in 98% yield (2.2 g). H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.06 (d, J = 7.6
Hz, 1H), 7.34ꢀ7.26 (m, 2H), 7.21 (dd, J = 7.2, 5.0 Hz, 3H), 6.92 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 2.56
13
(s, 3H); C NMR (101 MHz, CDCl3) δ 158.3, 157.2, 145.6, 138.4, 134.4, 131.0, 130.8, 127.6, 126.4,
122.3, 114.5, 55.6, 19.5; HRMS calcd for C15H16NO [M+H+]: 226.1226, found: 226.1223; IR (KBr)
1652, 1616, 1558, 1506, 1456, 1436, 1246, 856 cmꢀ1.
(E)-N-(3,5-bis(trifluoromethyl)phenyl)-1-(o-tolyl)methanimine (22). To
a
solution of 2ꢀ
methylbenzaldehyde 1 (1.0 g, 8.3 mmol, 1.0 equiv) in toluene (5 mL) was added L8 (1.91 g, 8.3 mmol,
1.0 equiv) and 4ꢀmethylbenzenesulfonic acid (30 mg, 0.17 mmol, 2 mol%). The mixture was stirred at
110 oC for 12 h. After been cooled to room temperature, the reaction mixture was diluted with hexanes
(20 mL), and filtered through a pad of celite. The filtrate was concentrated in vacuo, the crude residue
was recrystallized with hexanes/DCM (50/1) to afford the compound 22 as colorless solid (mp 52ꢀ53 oC,
Rf = 0.8, Hexanes/EtOAc = 10/1) in 89% yield (2.4 g). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.04
(dd, J = 7.8, 1.2 Hz, 1H), 7.72 (s, 1H), 7.58 (s, 2H), 7.43ꢀ7.37 (m, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.26 (d,
13
J = 7.6 Hz, 1H), 2.62 (s, 3H); C NMR (101 MHz, CDCl3) δ 162.1, 154.1, 139.5, 133.4, 133.2, 132.9,
132.5, 132.2, 131.5, 128.8, 126.7, 123.4 (q, J = 273.9 Hz), 121.2, 119.1 (m), 19.7; HRMS calcd for
C16H12F6N [M+H+]: 332.0868, found: 332.0873; IR (KBr) 1634, 1576, 1540, 1507, 1457, 1376, 760 cmꢀ
1
.
Competitive reaction for aldimine formation. A mixture of 2ꢀmethylbenzaldehyde 1 (24.0 mg, 0.2
mmol, 1.0 equiv), L3 (24.6 mg, 0.2 mmol, 1.0 equiv), and L8 (45.8 mg, 0.2 mmol, 1.0 equiv) in DCE (2
mL) was heated at 80 oC for 12 h. After been cooled to room temperature, the reaction mixture was diꢀ
luted with EtOAc (3 mL), and filtered through a pad of celite. The filtrate was concentrated in vacuo,
14
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
and the crude residue was dissolved in 1 mL of deuterated chloroform for HꢀNMR analysis. 1,1,2,2ꢀ
1
2
3
4
5
tetrachloroethane (33.6 mg, 0.2 mmol, 1.0 equiv, a singlet peak around 5.92 ppm was set as 1.00) was
1
added as an internal standard. By analysis of crude HꢀNMR, 88% of compound 21 and 10% of comꢀ
pound 22 were formed.
6
7
8
9
Competitive reaction for CꢀH amidation. Compound 21 and 22 (0.2 mmol, 1.0 equiv) were applied into
the standard amidation conditions for 2 hour and 12 hour respectively. After been cooled to room temꢀ
perature, the reaction mixture was diluted with EtOAc (3 mL), and filtered through a pad of celite. The
filtrate was concentrated in vacuo, the resulting crude residue was dissolved in 1 mL of deuterated chloꢀ
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
1
roform for HꢀNMR analysis. 1,1,2,2ꢀtetrachloroethane (33.6 mg, 0.2 mmol, 1.0 equiv, a singlet peak
around 5.92 ppm was set as 1.00 ) was added as internal standard.
(E)-N-(2-(((4-methoxyphenyl)imino)methyl)-3-methylphenyl)-4-methylbenzenesulfonamide (23). Yellow
o
1
solid, mp 158ꢀ160 C, Rf = 0.1 (Hexanes/EtOAc = 10/1). H NMR (400 MHz, CDCl3) δ 13.78 (s, 1H),
8.91 (s, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 8.3 Hz, 1H), 7.35ꢀ7.31 (m, 2H), 7.23 (d, J = 8.0 Hz,
13
3H), 7.02 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 7.4 Hz, 1H), 3.91 (s, 3H), 2.54 (s, 3H), 2.39 (s, 3H); C
NMR (101 MHz, CDCl3) δ 159.2, 156.9, 143.5, 142.3, 140.4, 140.1, 137.4, 132.0, 129.6, 127.3, 125.4,
122.6, 119.1, 116.7, 114.8, 55.7, 21.6, 20.1; HRMS calcd for C22H23N2O3S [M+H+]: 395.1424, found:
395.1421; IR (KBr) 2959, 2311, 1575, 1506, 1456, 1253, 1161, 808 cmꢀ1.
(E)-N-(2-(((3,5-bis(trifluoromethyl)phenyl)imino)methyl)-3-methylphenyl)-4-methylbenzenesulfonamide
(24). Pale yellow solid, mp 162ꢀ164 oC, Rf = 0.1 (Hexanes/EtOAc = 10/1). 1H NMR (400 MHz, CDCl3)
δ 12.57 (s, 1H), 8.81 (s, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.55 (s, 3H), 7.31 (t, J = 7.9 Hz,
1H), 7.23 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 7.3 Hz, 1H), 2.53 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 162.7, 151.5, 144.0, 141.7, 140.4, 137.2, 133.8, 133.1 (q, J = 34.0 Hz), 129.8, 127.3, 125.8,
123.2 (q, J = 274.0 Hz), 121.5, 120.2 (m), 118.6, 117.3, 21.6, 20.2; HRMS calcd for C23H19F6N2O2S
[M+H+]: 501.1066, found: 501.1063; IR (KBr) 3079, 2930, 1598, 1571, 1468, 1376, 1152, 784 cmꢀ1.
2-Tolylsulfonyl-amino-5-methyl-benzaldehyde (26). To
a
250 mL flask were added 3ꢀ
methylbenzaldehyde 25 (0.72 g, 6 mmol, 1.0 equiv), pꢀtoluenesulfonyl azide (TsN3) 2 (2.37 g, 12 mmol,
2.0 equiv), [Cp*IrCl2]2 (119.5 mg, 0.15 mmol, 2.5 mol%), AgNTf2 (232.8 mg, 0.6 mmol, 10 mol%) and
L8 (137.4 mg, 0.06 mmol, 10 mol%) at room temperature. DCE (60 mL) was then added under air atꢀ
mosphere and the mixture was stirred at 80 oC for 12 h. After been cooled to room temperature, the reacꢀ
tion mixture was diluted with EtOAc (100 mL), and filtered through a pad of celite. The filtrate was
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford
o
compound 26 as pale yellow solid (mp 107ꢀ109 C, Rf = 0.3, Hexanes/EtOAc = 4/1) in 79% yield
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
(1.37g). 1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 9.76 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.59 (d, J =
8.4 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 2.35 (s, 3H), 2.32 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 195.2, 144.1, 137.4, 136.7, 136.4, 133.0, 129.8, 127.3, 122.1, 118.2,
21.6, 20.4; HRMS calcd for C15H16NO3S [M+H+]: 290.0845, found: 290.0846; IR (KBr) 3131, 2924,
2856, 2361, 2341, 1664, 1585, 1497, 1405, 1308, 1154, 901 cmꢀ1.
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
1',5-dimethyl-1-[(4-methylphenyl)sulfonyl]-Spiro-[2H-indole-2,3'-pyrrolidine]-2',3,5'(1H)-trione
(27).16a Compound 26 (57.9 mg, 0.2 mmol, 1.0 equiv), NꢀMethyl maleimide (44 mg, 0.4 mmol, 2.0
equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 2.5 mol%), Ag2CO3 (55.2 mg, 0.2 mmol, 1.0 equiv) and
DCE (2 mL) were added to a 12 mL glass vial at room temperature. The vial was purged with argon for
1 min and then sealed with PTFE cap. The reaction mixture was stirred at 120 °C for 18 h. After been
cooled to room temperature, the solvent was removed under reduced pressure and the residue was puriꢀ
fied by flash column chromatography on silica gel to afford the compound 27 as pale yellow liquid (Rf =
1
0.3, Hexanes/EtOAc = 4/1) in 82% yield (65.3 mg). H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz,
2H), 7.50 (s, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 3H), 3.49 (d, J = 17.8 Hz, 1H), 3.16 (s,
13
3H), 3.11 (d, J = 17.8 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H); C NMR (101 MHz, CDCl3) δ 192.8, 173.1,
170.9, 151.5, 145.7, 139.6, 135.6, 134.3, 130.2, 128.2, 125.4, 121.4, 113.8, 73.9, 39.2, 26.1, 21.8, 20.7.
3-acetyl-6-methyl-quinoline (28). Compound 26 (57.9 mg, 0.2 mmol, 1.0 equiv), acetylacetylene (20.4
mg, 0.3 mmol, 1.5 equiv), PPh3 (5.2 mg, 0.02 mmol, 10 mol%), and MeCN (1 mL) were added to a 12
mL glass vial at room temperature. The vial was purged with argon for 1 min and then sealed with
PTFE cap. The reaction mixture was stirred at 80 °C for 12 h. After been cooled to room temperature,
1M aqueous solution of HCl (1 mL) was added, and the mixture was stirred for 5 min before quenched
with aqueous NaHCO3 (1 mL). The mixture was extracted with EtOAc for three times and the combined
organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by
o
flash column chromatography on silica gel to afford compound 28 as yellow solid (mp 83ꢀ85 C, Rf =
0.3, Hexanes/EtOAc = 4/1) in 89% yield (33.1 mg). 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.58 (s,
1H), 8.01 (d, J = 8.3 Hz, 1H), 7.66ꢀ7.62 (m, 2H), 2.70 (s, 3H), 2.54 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 196.9, 148.4, 148.3, 137.7, 136.8, 134.5, 129.1, 128.2, 26.9, 21.6; HRMS calcd for C12H12NO
[M+H+]: 186.0913, found: 186.0915; IR (KBr) 1574, 1419 cmꢀ1.
(Z)-2-(2-methoxyethylidene)-5-methyl-3-(piperidin-1-yl)-1-tosylindoline (29). Compound 26 (57.9 mg,
0.2 mmol, 1.0 equiv), piperidine (17.0 mg, 0.2 mmol, 1.0 equiv), 3ꢀmethoxypropꢀ1ꢀyne (21.0 mg, 0.3
mmol, 1.5 equiv), CuCl (1.0 mg, 0.01 mmol, 5 mol%), Cu(OTf)2 (3.6 mg, 0.01 mmol, 5 mol%), DMAP
(24.4 mg, 0.2 mmol, 1.0 equiv), and MeCN (2 mL) were added to a 12 mL glass vial at room temperaꢀ
ture. The vial was purged with argon for 1 min and then sealed with PTFE cap. The reaction mixture
16
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
was stirred at 80 °C for 12 h. After been cooled to room temperature, the solvent was removed under
reduced pressure and the residue was purified by flash column chromatography on silica gel to afford
1
2
3
4
1
compound 29 as yellow oil (Rf = 0.6, Hexanes/EtOAc = 10/1) in 72% yield (61.4 mg). H NMR (400
5
MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.08ꢀ7.05 (m, 3H), 6.95 (s, 1H), 5.86ꢀ
5.82 (m, 1H), 4.54ꢀ4.48 (m, 1H), 4.44ꢀ4.39 (m, 1H), 3.81 (s, 1H), 3.36 (s, 3H), 2.58ꢀ2.54 (m, 2H), 2.36ꢀ
2.32 (m, 5H), 2.30 (s, 3H), 1.44ꢀ1.42 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 144.2, 140.5, 139.8,
135.4, 134.1, 133.6, 129.2, 129.0, 128.0, 125.8, 121.3, 119.7, 70.1, 68.5, 58.2, 50.4, 26.8, 24.6, 21.7,
21.4; HRMS calcd for C24H31N2O3S [M+H+]: 427.2050, found: 427.2053; IR (KBr) 1575, 1437, 1364,
1171, 816 cmꢀ1.
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
2,3-dihydro-2,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-4(1H)-Quinolinone (30).16d Compound 26 (57.9
mg, 0.2 mmol, 1.0 equiv), allyl methyl carbonate (69.6 mg, 0.6 mmol, 3.0 equiv), [Cp*RhCl2]2 (3.1 mg,
0.005 mmol, 2.5 mol%), CsOAc (57.6 mg, 0.3 mmol, 1.5 equiv), and DCE (2 mL) were added to a 12
mL glass vial at room temperature. The vial was purged with argon for 1 min and then sealed with
PTFE cap. The reaction mixture was stirred at 100 °C for 14 h. After been cooled to room temperature,
the reaction mixture was diluted with EtOAc (2 mL), and filtered through a pad of celite. The filtrate
was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on
silica gel to afford compound 30 as yellow solid (Rf = 0.2, Hexanes/EtOAc = 4/1) in 53% yield (35.1
mg). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.72 (s, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.42
(d, J = 7.9 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 4.87ꢀ4.84 (m, 1H), 2.41ꢀ2.29 (m, 7H), 2.18 (d, J = 17.8 Hz,
1H), 1.27 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 192.9, 144.4, 137.3, 136.7, 136.0, 135.8,
130.1, 127.2, 126.97, 126.62, 125.3, 51.9, 41.9, 21.7, 20.9, 19.8.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
XXXXX.
Detailed optimization of reaction conditions, crystal structure of compounds 4e, 4f, 11 and copy
of 1H and 13C NMR spectra of all new compounds (PDF)
Xꢀray crystallographic data of compounds 4e, 4f and 11 (CIF)
AUTHOR INFORMATION
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
Corresponding Author
1
2
3
4
hegang@nankai.edu.cn, gongchen@nankai.edu.cn, guc11@psu.edu
5
6
ACKNOWLEDGMENT
7
8
9
We gratefully thank the State Key Laboratory of ElementoꢀOrganic Chemistry at Nankai Universiꢀ
ty and Natural Science Foundation of China (21502098, 21421062) for financial support of this
work.
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
REFERENCES
(1) (a) Thummel, R. P. 2ꢀAminobenzaldehyde. e-EROS Encyclopedia of Reagents for Organic Synthesis
2001, DOI: 10.1002/047084289X.ra088. (b) Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian,
Z. Adv. Heterocycl. Chem. 2011, 102, 139.
(2) For selected reviews on BuchwaldꢀHartwig amination: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.ꢀF.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (b) RuizꢀCastillo, P.; Buchwald, S. L. Chem. Rev. 2016,
116, 12564. (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(3) For selected reviews on metal catalyzed C(sp2)–H amination with organic azides: (a) Shin, K.; Kim,
H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040. (b) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, DOI:
10.1021/acs.chemrev.6b00644.
(4) For a recent review on intermolecular C–H amination with organic azides: Intrieri, D.; Zardi, P.; Caꢀ
selli, A.; Gallo, E. Chem. Commun. 2014, 50, 11440.
(5) For Chang’s pioneering work on metalꢀcatalyzed C(sp2)–H amination with organic azides: (a) Kim,
J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134, 9110. (b)
Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904. (c) Shin, K.;
Baek, Y.; Chang, S. Angew. Chem., Int. Ed. 2013, 52, 8031. (d) Park, S. H.; Kwak, J.; Shin, K.; Ryu, J.;
Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136, 2492. (e) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang,
S. J. Am. Chem. Soc. 2013, 135, 12861. (f) Kim, J.; Chang, S. Angew. Chem., Int. Ed. 2014, 53, 2203.
(g) Hwang, H.; Kim, J.; Jeong, J.; Chang, S. J. Am. Chem. Soc. 2014, 136, 10770.
(6) For selected metal catalyzed C(sp2)–H amination reactions with organic azides developed by others:
(a) Tang, C.; Jiao, N. J. Am. Chem. Soc. 2012, 134, 18924. (b) Bhanuchandra, M.; Yadav, M. R.; Rit, R.
K.; Kuram, M. R.; Sahoo, A. K. Chem. Commun. 2013, 49, 5225. (c) Yu, D.ꢀG.; Suri, M.; Glorius, F. J.
18
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
Am. Chem. Soc. 2013, 135, 8802. (d) Thirunavukkarasu, V. S.; Raghuvanshi, K.; Ackermann, L. Org.
Lett. 2013, 15, 3286. (e) Pi, C.; Cui, X.; Wu, Y. J. Org. Chem. 2015, 80, 7333. (f) Becker, P.; Pirꢀ
werdjan, R.; Bolm, C. Angew. Chem., Int. Ed. 2015, 54, 15493.
1
2
3
4
5
6
7
8
9
(7) For selected examples of C(sp2)ꢀH functionalizations of benzaldehyde: (a) Gürbüz, N.; Özdemir, I.;
Çetinkaya, B. Tetrahedron Lett. 2005, 46, 2273. (b) Padala, K.; Jeganmohan, M. Org. Lett. 2012, 14,
1134. (c) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262. (d) Yang, F.; Rauch, K.; Kettelhoit, K.;
Ackermann, L. Angew. Chem., Int. Ed. 2014, 53, 11285. (e) Santhoshkumar, R.; Mannathan, S.; Cheng,
C.ꢀH. J. Am. Chem. Soc. 2015, 137, 16116.
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
(8) For aldimine directed C(sp2)–H amination of benzaldehydes with organic azides: (a) Lian, Y.;
Hummel, J. R.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 12548. A catalytic version
using 40 mol % of benzyl amine to form a directing group in situ was also reported in this manuscript.
(b) Li, Y.; Feng, Y.; Xu, L.; Wang, L.; Cui, X. Org. Lett. 2016, 18, 4924.
(9) Zhang, Y.ꢀF.; Wu, B.; Shi, Z.ꢀJ. Chem. – Eur. J. 2016, 22, 17808.
(10) For selected reviews on transient directing group facilitated CꢀH functionalization: Park, J. Y.;
Park, J.ꢀW.; Jun, C.ꢀH. Acc. Chem. Res. 2008, 41, 222.
(11) For Jun’s pioneering work on transient directing group facilitated CꢀH functionalization: (a) Jun,
C.ꢀH.; Lee, H.; Hong, J.ꢀB. J. Org. Chem. 1997, 62, 1200. (b) Jun, C.ꢀH.; Lee, H.; Park, J.ꢀB.; Lee, D.ꢀ
Y. Org. Lett. 1999, 1, 2161. (c) Jun, C.ꢀH.; Chung, K.ꢀY.; Hong, J.ꢀB. Org. Lett. 2001, 3, 785. (d) Lim,
S.ꢀG.; Lee, J. H.; Moon, C. W.; Hong, J.ꢀB.; Jun, C.ꢀH. Org. Lett. 2003, 5, 2759.
(12) (a) Wang, Z.; Reinus, B. J.; Dong, G. J. Am. Chem. Soc. 2012, 134, 13954. (b) Mo, F.; Dong, G.
Science, 2014, 345, 68. (c) Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.; Dong, G. Angew. Chem.,
Int. Ed. 2016, 55, 9084.
(13) (a) Chen, S.; Yu, J.; Jiang, Y.; Chen, F.; Cheng, J. Org. Lett. 2013, 15, 4754. (b) Tan, W. P.; Juꢀ
waini, N. A. B.; Seayad, J. Org. Lett. 2013, 15, 5166.
(14) (a) Zhang, F. L.; Hong, K.; Li, T.ꢀJ.; Park, H.; Yu, J.ꢀQ. Science, 2016, 351, 252. (b) Bisht, R.;
Chattopadhyay, B. J. Am. Chem. Soc. 2016, 138, 84. (c) Ma, F.; Lei, M.; Hu, L. Org. Lett. 2016, 18,
2708. (d) Yang, K.; Li, Q.; Liu, Y.; Li, G.; Ge, H. J. Am. Chem. Soc. 2016, 138, 12775. (e) Liu, Y.; Ge,
H. Nat. Chem. 2017, 9, 26. (f) Yada, A.; Liao, W.; Sato, Y.; Murakami, M. Angew. Chem., Int. Ed.
2017, 56, 1073.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
(15) During the preparation of this manuscript, a related Pdꢀcatalyzed C(sp2)–H arylation, chlorination,
bromination and Irꢀcatalyzed C(sp2)–H amidation of benzaldehydes was reported: Liu, X.ꢀH.; Park, H.;
Hu, J.ꢀ H.; Hu, Y.; Zhang, Q.ꢀL.; Wang, B.ꢀL.; Sun, B.; Yeung, K.ꢀS.; Zhang, F.ꢀL.; Yu, J.ꢀQ. J. Am.
Chem. Soc. 2017, 139, 888.
1
2
3
4
5
6
7
8
9
(16) (a) Zhang, T.; Qi, Z.; Zhang, X.; Wu, L.; Li, X. Chem. – Eur. J. 2014, 20, 3283. (b) Khong, S.;
Kwon, O. J. Org. Chem. 2012, 77, 8257. (c) Chernyak, D.; Chernyak, N.; Gevorgyan, V. Adv. Synth.
Catal. 2010, 352, 961. (d) Yang, T.; Zhang, T.; Yang, S.; Chen, S.; Li, X. Org. Biomol. Chem. 2014, 12,
4290.
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
(17) (a) Kang, T.; Kim,Y.; Lee, D.; Wang, Z.; Chang, S. J. Am. Chem. Soc. 2014, 136, 4141; (b) Xiao,
X.ꢀS.; Hou, C.; Zhang, Z.ꢀH.; Ke, Z.ꢀF.; Lan, J.ꢀY.; Jiang, H.ꢀF.; Zeng, W. Angew. Chem. Int. Ed. 2016,
55, 11897.
20
ACS Paragon Plus Environment