Visible Light-Induced Radical Rearrangement to Construct C-C Bonds via an Intramolecular Aryl Migration/Desulfonylation Process

Article abstract of DOI:10.1021/acs.joc.6b00735

A highly efficient intramolecular selective aryl migration/desulfonylation of 2-bromo-N-aryl-N-(arenesulfonyl)amide via visible light-induced photoredox catalysis has been accomplished. This approach allows for the construction of a variety of multisubstituted N,2-diarylacetamide under mild reaction conditions.

Full text of DOI:10.1021/acs.joc.6b00735

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Article
Visible Light-Induced Radical Rearrangement to Construct C-C
Bonds via Intramolecular Aryl Migration/Desulfonylation Process
Yuyuan Li, Bei Hu, Wuheng Dong, Xiaomin Xie, Jun Wan, and Zhaoguo Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00735 • Publication Date (Web): 28 Jun 2016
Downloaded from http://pubs.acs.org on June 28, 2016
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Visible Light-Induced Radical Rearrangement to Construct C-C
Bonds via Intramolecular Aryl Migration/Desulfonylation Process
8
Yuyuan Li,† Bei Hu,‡ Wuheng Dong,‡ Xiaomin Xie,‡ Jun Wan*† and Zhaoguo Zhang*‡
†Key Laboratory of Sensor Analysis of Tumor Marker, Ministry of Education, College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, China,
Fax: (+86)-532-8402-2617; phone: (+86)-532-8402-2617; E-mail: wanjundz@sohu.com
‡School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai, 200240, China
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Fax: (+86)-21-5474-8925; phone: (+86)-21-5474-8925; E-mail: zhaoguo@sjtu.edu.cn
ABSTRACT
A highly efficient intramolecular selective aryl migration/desulfonylation of 2-bromo-N-aryl-N-
(arenesulfonyl)amide via visible light-induced photoredox catalysis has been accomplished. This approach
allows for the construction of a variety of multi-substituted N,2-diarylacetamide under mild reaction conditions.
INTRODUCTION
Aryl migration reaction was considered as an efficient method to reconstruct complex compounds and had
been widely applied to the synthesis of natural products.1 Among them, the free radical aryl migrations can
occur between carbon and carbon radicals, carbon and heteroatom-centered radicals to reconstruct the bond of
C-X (X = C, Si, N). While in the early reports, poisonous radical initiator was usually used in the aryl migration
reactions,2-3 and a tremendous effort has been made to seek more efficient methods for this kind of reactions.
Recently, Zhu’s group reported an aryl migration reaction using 3 equivalents of dicumyl peroxide as radical
initiator under the temperature of 140 °C to give desired products in good yields.4 In addition, transition metal-
mediated reactions have also been applied to the field of aryl migration reactions. For example, Nevado’s
group has reported a copper-catalyzed aryl migration reaction by using Togni’s reagent5 to generate
trifluoromethyl radical species.6 Although some progress has been made, these transformations still suffered
the common drawbacks of harsh reaction conditions including high temperature, high catalyst loading, narrow
range of substrates and the use of poisonous or environment-unfriendly radical initiators.7 Therefore, it is
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profound and significant to develop mild and effective methodologies for aryl migration reactions.
In recent years, visible light photoredox catalysis has received widespread attention as a powerful tool in the
field of synthetic organic chemistry owing to its attractive features including mild reaction conditions,
excellent functional group tolerance and high reactivity.8-9 To the best of our knowledge, several groups have
reported intermolecular radical addition/1,2-aryl migration reaction via visible light-induced conditions.10
However，few examples of intramolecular aryl migration reactions under the visible light-mediated condition
have been reported until some works have been introduced by Xia’s group and Stephenson’s group. 11 Xia’s
group has reported a intermolecular radical addition/ 1,4-aryl shift/desulfonylation cascade reaction with a
trifluoromethyl radical involved as the key radical source (scheme 1a). On the other hand, Stephenson’s group
provided an efficient approach to achieve the benzylic difluoroethanol motif via an intramolecular radical
addition/1,4-aryl shift/desulfonylation process (scheme 1b). Besides that, the activation of C-X (X = Cl, Br, I)
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by visible-light participation has been widely reported in recent years and an efficient intramolecular
dearomative cyclization reaction occurred via C-Br bond fragmentation has been reported by our group.13
Therefore, We envisioned that 2-bromo-N-phenyl-N-(phenylsulfonyl)acetamide could generate α-carbonyl
radical under visible light catalysis, which may then undergo intramolecular ipso addition/elimination and
hydrogen abstraction followed by polar extrusion of SO2 leading to the desired product. Herein, we report a
visible light-induced intramolecular aryl migration/desulfonylation process for the synthesis of N,2-
diarylacetamide products under a mild reaction condition (scheme 1c).
Scheme 1. Reported the aryl migration reactions and our strategy
RESULTS AND DISCUSSION
We initiated our investigation by examining the reaction of 2-bromo-2-methyl-N-phenyl-N-
(phenylsulfonyl)propanamide (1a) with fac-Ir(ppy)3 (2 mol%) in DMF under a 23W household fluorescent
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lamp irradiation (Table 1, entry 1). Fortunately, the reaction occurred at room temperature, giving the desired
product (2a) with 26% yield. However, other photocatalysts, such as Ir(ppy)2(bpy)PF6, Ru(ppy)3Cl2 and Eosin
Y do not work. Next, our attentions were paid on screening the additives to improve the efficiency of the
reaction.14 When Li2CO3, Na2CO3 or NaHCO3 was added, the reaction gave much higher yields (Table 1,
entries 2-4), however, the byproducts (see supporting information) were also obtained. So we turned to use a
weaker base like KH2PO4, a lower yield was observed without any byproducts (Table 1, entry 5). On the other
hand, water was introduced as an additive because it could serve as a hydrogen donor in the reaction.15 To our
delight, the yield could be increased to 85% when 5 equivalents of water was used as the additive (Table 1,
entry 6). By increasing the amount of water to 20 equivalents, a significantly increase of yield was observed
and an 88% isolated yield was obtained (Table 1, entry 7). There is no influence on the yield when the amount
of water was further increased (Table 1, entry 8). We then screened the solvents in the presence of water as
the additive. Among solvents tested, DMF was proved to be the best choice for this reaction (Table 1, entries
9-12). The control experiments showed that both photocatalyst and visible light were essential for this reaction.
When the reactions were conducted without catalyst or visible light, no product was formed (Table 1, entries
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13 and 14).
Table 1: Optimization of reaction conditionsa
Entry
Cat. (2% mol)
Add. (eq)
Solvent
Conv.(%)
Yieldb(%)
1
2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
-----
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
CH3CN
DCM
MeOH
DMF
36
88
26
50
Li2CO3(1)
Na2CO3(1)
NaHCO3(1)
KH2PO4(1)
H2O(5)
3
100
88
63
4
40
5
53
43
6
100
100
100
85
85
7
H2O(20)
H2O(50)
H2O(20)
H2O(20)
H2O(20)
H2O(20)
H2O(20)
93(88) c
93
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9
72
10
11
12
13d
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52
50
43
<5
0
trace
0
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-----
H2O(20)
DMF
0
0
a Reaction conditions: 1a (0.25 mmol), catalyst (2% mol), addition, solvent (2.5
mL), rt, 12 h, under N2 atmosphere. b Determined by 1H NMR analysis with 4,4'-
Ditert-butyl-1,1'-biphenyl as an internal standard. c The value in parentheses was
isolated yield. d In the dark.
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With the optimized reaction conditions in hand, we studied the substrate scope of this reaction. As shown in
Table 2, a variety of substituted substrates, including methyl and halogen groups on the para-position of the
N-phenyl (SO2) ring, were compatible under the optimized reaction conditions, providing the desired products
in good yields (Table 2, 2a-d); Substrates with strong electron-withdrawing group (trifluoromethyl) on the N-
phenyl (SO2) ring at the para-position gave the desired products 2e in 29% yield and a byproduct (2-bromo-
2-methyl-N-phenylpropanamide) was obtained with 30% yield; When the phenyl ring was functionalized with
strong electron-donating groups, such as a methoxy group, a lower yield of the desired product 2f was obtained
and some of the starting material remained unchanged. It is worth noting that a minor steric hindrance did not
impose any negative effect on yield; on the contrary, a better migration ability led to a better yield. As a result,
when 2-bromo-2-methyl-N-phenyl-N-(o-toluenesulfonyl)propanamide (1g) was introduced, a quantitative
yield of product 2g could be afforded, in contrast to the substrate 2-bromo-2-methyl-N-phenyl-N-(m-
toluenesulfonyl)propanamide(1h), which gave the desired product 2h in 76% yield. The substrate with methyl
group on the N-phenyl (SO2) ring at the meta-position gave the desired products 2h in 76%. In addition, when
the standard reaction condition was applied to substrates with only one α-methyl substituent or no substituent
on the carbonyl, no products (2i, 2j) were observed, this might be ascribed to the instability of the formed
radical intermediate. As shown in Table 1, the conversion could be increased with the added base. Using 1
equivalent of Li2CO3 instead of water, the desired product 2i was obtained in 34% yield. However, under the
same reaction conditions for 1i, no product was obtained for substrate 1j. When 2,2-difluoro-N,2-
diphenylacetamide was introduced in this reaction, the desired product 2k could be obtained with 26% yield.
Finally, the product 2m could be obtained in 58% yield when the heterocyclic substrate 1m was introduced.
However, the reaction did not work when the arenesulfonyl was replaced by an alkyl sulfonyl group (2l) in the
presence of either water or lithium carbonate. This might be ascribed to the lower migration nature of methyl
than phenyl.
Table 2: Substrate scope of substituted sulfonyl groups and α-bromoacetamide a
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Subsequently, different substituent groups on the aryl ring of amides were also examined as shown in Table
3. Amides with electron-donating groups on the phenyl ring, such as methyl, methoxy group, gave the desired
products in high yields (Table 3, 2n, 2o). When the phenyl ring was functionalized with electron-withdrawing
groups, such as Cl, Br or CF3, high yields of the desired products were also obtained (Table 3, 2p-2r). Besides,
as shown in Table 3, the steric hindrance of the substituents has little effect on the reaction. Thus, the product
2s could be obtained from its corresponding starting material with good yields, and the position of substituents
on the aryl ring of amides has little effect on the reaction (Table 3, 2o, 2s-2u). None of desired product 2v or
2w was obtained when the N-phenyl group was replaced by an N-alkyl group.
Table 3: Substrate scope of substituted amidesa
On the basis of above results, a plausible mechanism was proposed to account for this visible light-induced
aryl migration reaction (Scheme 2). Firstly, the iridium catalyst was excited to *fac-[Ir(ppy)3] species under
visible light irradiation，then it underwent a single electron transfer process with 1 to afford an α-alkyl radical
intermediate I and IrIV metal complex (which may be reduced by the solvent).11a,16 A 5-ipso cyclization then
took place on the sulfonyl aromatic ring, generating aryl radical II, which would undergo rapid desulfonylation
to form the key amidyl radical III. The amidyl radical III could undergo hydrogen abstraction (HA) from the
solvent or water to give amides 2 as the target product.
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Scheme 2. Proposed mechanism of aryl migrations reaction
CONCLUSION
In summary, an efficient visible light-induced aryl migration/desulfonylation reaction has been developed to
form multi-substituted N,2-diarylacetamides. This photocatalytic approach provided a novel access to
reconstruct complex compounds characterized by its operational simplicity and high yields under mild
conditions. The application of visible light-induced method and the concept of aryl migration to construct
useful molecules is ongoing in our lab.
EXPERIMENTAL SECTION
General Procedures. Unless otherwise noted, all reactions were carried out under an atmosphere of nitrogen
using standard Schlenk techniques. Commercially available reagents were used without further purification.
Anhydrous DMF, DMA, CH3CN, DCM were freshly distilled from calcium hydride. Anhydrous MeOH was
1
distilled over magnesium under nitrogen. HNMR spectra were recorded at 400 MHz with TMS as internal
standard. 13C NMR spectra were recorded at 100 MHz and referenced to the central peak of 77.00 ppm for
CDCl3. Coupling constants (J) are reported in Hz and refer to apparent peak multiplications. 19F NMR was
recorded at 376 MHz using CF3COOH as an external standard. Mass spectroscopy data were collected on an
HRMS-ESI of Q-TOF Mass Spectrometer. Irradiation of photochemical reactions was carried out using a 23W
household compact fluorescent lamp purchased from Philips. Flash column chromatography was performed on
o
silica gel (300-400 mesh) with petroleum (bp. 60-90 C) and the indicated solvent, which are listed below as
volume/volume ratios.
Typical Procedure for the Preparation of 1a-1u, 1w17
A mixture of aniline (10.0 mmol) and triethylamine (10.0 mmol) in DCM (20.0 mL), sulfonyl chlorides (10.0
mmol) in DCM (10.0 mL) was added dropwise over a period of 1 h and stirred at room temperature for 6-10
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h. After completion, the reaction was quenched with a 5% sodium carbonate solution (20.0 mL). Then the
solution was transferred into the separating funnel, the organic phase was washed twice with water (20 mL),
dried over Na2SO4 and concentrated under reduced pressure to afford the corresponding secondary
sulfonamide, which was used to the next reaction without further purification.
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i
To a solution of the crude sulfonamide in DCM (20.0 mL) and Pr2NEt (12.0 mmol), The 2-bromo-2-
methylpropionyl bromide (12.0 mmol) was added dropwise slowly at room temperature in 3 h，and stirred at
room temperature for 6-10 h. After completion, the reaction was quenched with H2O (20.0 mL) and extracted
with DCM (3×25.0 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed
under reduced pressure. The crude product was purified by recrystallization to give 2-bromo-N-aryl-N-
(arenesulfonyl)amide.
2-Bromo-2-methyl-N-phenyl-N-(phenylsulfonyl)propanamide (1a): White solid, 3.1 g, 81% yield, mp:
1
153.3-155.6 ºC. H NMR (400 MHz, CDCl3): δ 7.94–7.96 (m, 2H), 7.68–7.62 (m, 2H), 7.56–7.40 (m, 7H),
1.63 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.4, 138.1, 135.3, 133.8, 131.7, 130.4, 129.4, 128.9,
128.6, 58.3, 32.3. HRMS-ESI (m/z): Calculated for C16H1679BrNNaO3S (M+Na)+: 403.9932, Found: 403.9931.
2-Bromo-N-(4-chlorophenyl)sulfonyl)-2-methyl-N-phenylpropanamide (1b)： White solid, 3.4 g, 56%
yield. mp: 127.2-128.5 ºC. 1H NMR (400 MHz, CDCl3): δ 7.93–7.85 (m, 2H), 7.56–7.37 (m, 7H), 1.63 (s, 6H).
13C {1H} NMR (100 MHz, CDCl3): δ 171.7, 140.5, 136.4, 135.2, 131.6, 130.9, 130.5, 129.1, 128.9, 58.2, 32.3
HRMS-ESI (m/z): Calculated for C16H1679BrClNO3S (M+H)+: 415.9723, Found: 415.9705.
2-Bromo-N-((4-bromophenyl)sulfonyl)-2-methyl-N-phenylpropanamide (1c): White solid, 1.7 g, 37%
yield. mp: 126.6-128.9 ºC. 1H NMR (400 MHz, CDCl3): δ 7.83–7.77 (m, 2H), 7.72–7.63 (m, 2H), 7.54–7.36
(m, 5H), 1.64 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.7, 137.0, 135.1, 131.9, 131.6, 131.0, 130.5,
129.2, 129.1, 58.2, 32.3. HRMS-ESI (m/z): Calculated for C16H1679Br81BrNO3S (M+H)+: 461.9197, Found:
461.9188.
2-Bromo-2-methyl-N-phenyl-N-tosylpropanamide (1d): White solid, 3.4 g, 85% yield. mp: 131.3-133.2 ºC.
1H NMR (400 MHz, CDCl3): δ 7.86–7.80 (m, 2H), 7.53–7.38 (m, 5H), 7.33–7.31 (m, 2H), 2.45 (s, 3H), 1.63
(s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.4, 144.9, 135.4, 135.1, 131.8, 130.3, 129.5, 129.2, 128.9,
58.4, 32.4, 21.7. HRMS-ESI (m/z): Calculated for C17H1979BrNO3S (M+H)+: 396.0269, Found: 396.0258.
2-Bromo-2-methyl-N-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)propanamide (1e): White solid, 1.4
1
g, 31% yield. mp: 136.2-139.7 ºC. H NMR (400 MHz, CDCl3): δ 8.08–8.06 (m, 2H), 7.81–7.79 (m, 2H),
7.54–7.40 (m, 5H), 1.64 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.9, 141.7, 135.1, 131.6, 130.7, 130.4
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(q, J = 41.8 Hz), 130.0, 129.2, 125.8 (q, J = 3.6 Hz), 123.1 (q, J = 271.4 Hz), 58.1, 32.3. HRMS-ESI (m/z):
Calculated for C17H1579BrF3NO3S (M+H)+: 449.9986, Found: 449.9988.
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2-Bromo-N-((4-methoxyphenyl)sulfonyl)-2-methyl-N-phenylpropanamide (1f): White solid, 3.3 g, 80%
yield，mp: 154.8–156.5 ºC. 1H NMR (400 MHz, CDCl3): δ 7.95–7.84 (m, 2H), 7.58–7.37 (m, 5H), 7.03–6.93
(m, 2H), 3.89 (s, 3H), 1.63 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.4, 163.8, 135.5, 131.8, 131.7,
130.2, 128.8, 113.7, 58.4, 55.6, 32.4. HRMS-ESI (m/z): Calculated for C17H1979BrNO4S (M+H)+: 412.0218,
Found: 412.0208.
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2-Bromo-2-methyl-N-phenyl-N-(o-tolylsulfonyl)propanamide (1g): White solid, 3.0 g, 75% yield. mp:
1
112.2-114.7 ºC. H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.0 Hz, 1H), 7.62–7.56 (m, 2H), 7.55–7.45 (m,
4H), 7.38 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 2.67 (s, 3H), 1.59 (s, 6H). 13C {1H} NMR (100 MHz,
CDCl3): δ 171.2, 138.8, 137.0, 134.5, 133.6, 132.4, 132.0, 131.7, 130.5, 129.0, 126.1, 58.4, 32.3, 20.8. HRMS-
ESI (m/z): Calculated for C17H1979BrNO3S (M+H)+: 396.0269, Found: 396.0263.
2-Bromo-2-methyl-N-phenyl-N-(m-tolylsulfonyl)propanamide (1h) White solid, 1.8 g, 75% yield. mp:
99.3-100.3 ºC. 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.56–7.36 (m, 7H), 2.44
(s, 3H), 1.63 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.3, 138.7, 137.9, 135.3, 134.5, 131.7, 130.3,
129.6, 128.8, 128.4, 126.4, 58.4, 32.3, 21.3. HRMS-ESI (m/z): Calculated for C17H1979BrNO3S (M+H)+:
396.0269, Found: 396.0278.
2-Bromo-N-phenyl-N-(phenylsulfonyl)propanamide (1i): White solid, 3.1 g, 83% yield. mp: 128.6-131.3
ºC. 1H NMR (400 MHz, CDCl3): δ 8.10–8.03 (m, 2H), 7.69 (m, 1H), 7.62–7.48 (m, 5H), 7.39 (m, 2H), 4.01
(q, J = 6.8 Hz, 1H), 1.66 (d, J = 6.8 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 168.9, 138.1, 134.8, 134.1,
130.5, 130.2, 129.8, 129.1, 128.8, 39.4, 20.8. HRMS-ESI (m/z): Calculated for C15H1579BrNO3S (M+H)+:
367.9956, Found: 367.9958.
2-Bromo-N-phenyl-N-(phenylsulfonyl)acetamide (1j): Brown solid, 3.1 g, 87% yield. mp: 122.8-124.2 ºC.
1H NMR (400 MHz, CDCl3): δ 8.7–8.05 (m, 2H), 7.73–7.66 (m, 1H), 7.61–7.49 (m, 6H), 7.38–7.31 (m, 2H),
3.62 (s, 2H).13C{1H} NMR (100 MHz, CDCl3): δ 165.3, 138.0, 135.1, 134.2, 130.6, 130.0, 129.9, 129.1, 128.8,
28.9. HRMS-ESI (m/z): Calculated for C14H1379BrNO3S (M+H)+: 353.9800, Found: 353.9803.
2-Bromo-2,2-difluoro-N-phenyl-N-(phenylsulfonyl)acetamide (1k): White solid, 2.5 g, 65% yield. mp:
165.8-167.2 ºC. 1H NMR (400 MHz, CDCl3): δ 8.11–8.02 (m, 2H), 7.74 (m, 1H), 7.64–7.45 (m, 5H), 7.35 (m,
2H). 19F NMR (376 MHz, CDCl3): δ 23.62. 13C {1H} NMR (100 MHz, CDCl3): δ 157.7 (t, J = 28.3 Hz), 137.1,
134.8, 133.1, 130.92, 130.89, 129.7, 129.2, 129.1, 110.4 (t, J = 317.0 Hz). HRMS-ESI (m/z): Calculated for
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C14H1179BrF2NO3S (M+H)+: 389.9611, Found: 389.9594.
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2-Bromo-2-methyl-N-(methylsulfonyl)-N-phenylpropanamide (1l): White solid, 2.5 g, 79% yield. mp:
110.7-111.8 ºC. 1H NMR (400 MHz, CDCl3): δ 7.52–7.45 (m, 5H), 3.41 (s, 3H), 1.71 (s, 6H). 13C {1H} NMR
(100 MHz, CDCl3): δ 172.7, 134.9, 131.2, 130.4, 129.6, 129.1, 42.6, 40.7, 32.3. HRMS-ESI (m/z): Calculated
for C11H1479BrNO3S (M+H)+: 319.9956, Found: 319.9926.
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2-Bromo-2-methyl-N-phenyl-N-(thiophen-2-ylsulfonyl)propanamide (1m): White solid, 2.5 g, 41% yield.
mp: 130.5-132.3 ºC. 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 3.6, 1.2 Hz, 1H), 7.72 (dd, J = 4.8, 1.2 Hz,
1H), 7.53-7.36 (m, 5H) 7.13 (dd, J = 4.8, 3.6 Hz, 1H), 1.68 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.0,
137.4, 136.2, 135.2, 134.5, 131.5, 130.5, 129.0, 127.0, 58.3, 32.4. HRMS-ESI (m/z): Calculated for
C14H1579BrNO3S2 (M+H)+: 387.9677, Found: 387.9674.
2-Bromo-N-(4-methoxyphenyl)-2-methyl-N-(phenylsulfonyl)propanamide (1n): White solid, 3.6 g, 88%
yield. mp: 168.7-170.5 ºC. 1H NMR (400 MHz, CDCl3): δ 7.97–7.95 (m, 2H), 7.71–7.61 (m, 1H), 7.55–7.51
(m, 2H), 7.38–7.28 (m, 2H), 7.04–6.89 (m, 2H), 3.87 (s, 3H), 1.65 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3):
δ 171.5, 160.9, 138.1, 133.7, 133.0, 129.4, 128.6, 127.5, 114.0, 58.3, 55.5, 32.4.. HRMS-ESI (m/z): Calculated
for C17H1979BrNO4S (M+H)+: 412.0218, Found: 412.0218.
2-Bromo-2-methyl-N-(phenylsulfonyl)-N-(p-tolyl)propanamide (1o): White solid, 3.7 g, 94% yield. mp:
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87.0-88.5 ºC. H NMR (400 MHz, CDCl3): δ 8.00-7.92 (m, 2H), 7.65 (m, 1H), 7.53 (m, 2H), 7.29 (m, 4H),
2.43 (s, 3H), 1.63 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.4, 140.8, 138.2, 133.7, 132.6, 131.5, 129.6,
129.4, 128.6, 58.3, 32.4, 21.4.HRMS-ESI (m/z): Calculated for C17H1979BrNO3S (M+H)+: 396.0269, Found:
396.0263.
2-Bromo-N-(4-bromophenyl)-2-methyl-N-(phenylsulfonyl)propanamide (1p): White solid, 2.4 g, 53%
yield. mp: 174.2-177.9 ºC. 1H NMR (400 MHz, CDCl3): δ 7.95–7.93 (m, 2H), 7.67 m, 1H), 7.62–7.51 (m, 4H),
7.33–7.28 (m, 2H), 1.67 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.1, 137.8, 134.4, 134.0, 133.3, 132.2,
129.4, 128.7, 124.8, 57.9, 32.3 HRMS-ESI (m/z): Calculated for C16H1679Br81BrNO3S (M+H)+: 461.9197,
Found: 461.9202.
2-Bromo-N-(4-chlorophenyl)-2-methyl-N-(phenylsulfonyl)propanamide (1q): White solid, 2.3 g, 56%
yield. mp: 156.2-160.5 ºC.1H NMR (400 MHz, CDCl3): δ 7.94 (m, 2H), 7.70–7.63 (m, 1H), 7.55 (m, 2H),
7.46–7.41 (m, 2H), 7.39–7.33 (m, 2H), 1.67 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.1, 137.8, 136.6,
134.0, 133.8, 133.0, 129.4, 129.2, 128.7, 57.9, 32.3. HRMS-ESI (m/z): Calculated for C16H1679BrClNO3S
(M+H)+: 415.9723, Found: 415.9706.
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2-Bromo-2-methyl-N-(phenylsulfonyl)-N-(4-(trifluoromethyl)phenyl)propanamide (1r): White solid, 2.0
g, 45% yield. mp: 159.4-161.2 ºC. 1H NMR (400 MHz, CDCl3): δ 7.95–7.92 (m, 2H), 7.76–7.65 (m, 3H), 7.56
(m, 4H), 1.67 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.3, 138.8, 137.8, 134.1, 132.2, 129.5, 128.9 (q,
J = 63.9 Hz), 128.8, 126.1 (q, J = 3.6 Hz), 126.0, 123.4 (q, J = 270.9 Hz), 57.9, 32.3. HRMS-ESI (m/z):
Calculated for C17H1679BrF3NO3S (M+H)+: 449.9986, Found: 449.9983.
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2-Bromo-2-methyl-N-(phenylsulfonyl)-N-(o-tolyl)propanamide (1s): White solid, 2.2 g, 55% yield. mp:
100.0-101.2ºC. 1H NMR (400 MHz, CDCl3): δ 8.06–8.03 (m, 2H), 7.70–7.63 (m, 1H), 7.56 (m, 2H), 7.41 (m,
2H), 7.36–7.26 (m, 2H), 2.43 (s, 3H), 1.74 (s, 3H), 1.45 (s, 3H).13C {1H} NMR (100 MHz, CDCl3): δ 170.8,
140.6, 138.6, 134.9, 134.0, 131.8, 131.6, 130.8, 129.8, 128.7, 126.5, 58.2, 33.3, 30.5, 19.4. HRMS-ESI (m/z):
Calculated for C17H1979BrNO3S (M+H)+: 396.0269, Found: 396.0252
2-Bromo-2-methyl-N-(phenylsulfonyl)-N-(m-tolyl)propanamide (1t): White solid, 3.5 g, 89% yield. mp:
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108.8-110.0 ºC. H NMR (400 MHz, CDCl3): δ 7.99–7.93 (m, 2H), 7.69–7.62 (m, 1H), 7.58–7.50 (m, 2H),
7.33 (m, 2H), 7.29–7.26 (m, 1H), 7.24–7.18 (m, 1H), 2.40 (s, 3H), 1.62 (s, 6H). 13C {1H} NMR (100 MHz,
CDCl3): δ 171.3, 139.0, 138.1, 135.0, 133.7, 132.3, 131.1, 129.3, 128.6, 128.5, 58.4, 32.3, 21.2. HRMS-ESI
(m/z): Calculated for C17H1979BrNO3S (M+H)+: 396.0269, Found: 396.0284.
2-Bromo-N-(3,5-dimethylphenyl)-2-methyl-N-(phenylsulfonyl)propanamide (1u): White solid, 3.7 g, 90%
yield. mp: 119.6-120.6 ºC. 1H NMR (400 MHz, CDCl3): δ 8.00–7.93 (m, 2H), 7.69–7.61 (m, 1H), 7.58–7.47
(m, 2H), 7.13 (s, 1H), 7.04 (s, 2H), 2.35 (s, 3H), 1.61 (s, 3H).13C NMR (100 MHz, CDCl3): δ 171.4, 138.7,
138.2, 134.8, 133.7, 132.0, 129.4, 129.2, 128.5, 58.5, 32.4. HRMS-ESI (m/z): Calculated for C18H2079BrNO3S
(M+H)+: 410.0426, Found: 410.0414.
N-Benzyl-2-bromo-2-methyl-N-(phenylsulfonyl)propanamide (1w): White solid, 3.4 g, 85% yield. mp:
120.6-122.6 ºC. 1H NMR (400 MHz, CDCl3): δ 7.76–7.74 (m, 2H), 7.56 (m, 1H), 7.42 (m, 2H), 7.36–7.27 (m,
5H), 5.56 (s, 2H), 1.88 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.1, 138.7, 136.3, 133.5, 128.9, 128.6,
128.3, 127.6, 126.7, 57.0, 52.1, 32.0. HRMS-ESI (m/z): Calculated for C17H1979BrNO3S (M+H)+: 396.0269,
Found: 396.0273.
Procedure for the Preparation of 1v18
A mixture of KOH (20.0 mmol) and MeNH2 • HCl (10.0 mmol) in H2O (10 mL) was stirred at room
temperature. DCM (10 mL) and arenesulfonylchlorides (10.0 mmol) were added. After stirring for 1 h (the
reaction was monitored by TLC), the reaction mixture was extracted with DCM, and dried over anhydrous
Na2SO4. The solvent was evaporated to afford the product, which was used in the next step without purification.
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To a solution of the crude sulfonamide in DCM (20 mL) and Pr2NEt (12 mmol), The 2-bromo-2-
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methylpropionyl bromide (12 mmol) was added dropwise slowly at room temperature in 3 h，and stirred at
room temperature for 6-10 h. After completion, the reaction was quenched with H2O (20 mL) and extracted
with DCM (3×25 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed
under reduced pressure. The crude product was purified by recrystallization to give 2-bromo-2-methyl-N-
phenyl-N-(phenylsulfonyl)propanamide (1v) as a white solid.
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2-Bromo-N,2-dimethyl-N-(phenylsulfonyl)propanamide (1v): White solid, 2.2 g, 70% yield, mp: 83.2-84.5
ºC. 1H NMR (400 MHz, CDCl3): δ 7.99 (m, 2H), 7.67–7.60 (m, 1H), 7.54 (m, 2H), 3.77 (s, 3H), 1.93 (s, 6H).
13C {1H} NMR (100 MHz, CDCl3): δ 170.4, 138.8, 133.8, 128.9, 128.4, 6.4, 36.2, 31.4. HRMS-ESI (m/z):
Calculated for C11H1579BrNO3S (M+H)+: 319.9956, Found: 319.9963.
A general procedure for fac-Ir(ppy)3-catalyzed intramolecular migration reaction.
A dried schlenk tube equipped with a stirrer bar which was evacuated and backfilled with nitrogen was added
substrate 1 (0.25 mmol), fac-Ir(ppy)3 (0.005 mmol) and H2O (5 mmol). Then 2.5 mL of DMF was added into
the reaction tube via a syringe. The reaction mixture was degassed by the freeze-pump-thaw method and then
irradiated with a 23W CFL (compact fluorescent light) (distance app. 5 cm) for 12 h. After the completion of
the reaction, the solvent was evaporated under reduced pressure. Then, the pure product was obtained by flash
column chromatography (PE:DCM=5:1) on silica gel.
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2-Methyl-N,2-diphenylpropanamide (2a): White solid, 52.1 mg, 87% yield. mp: 96.2-98.0 ºC. H NMR
(400 MHz, CDCl3): δ 7.48–7.22 (m, 10H), 7.10–7.03 (s, 1H), 1.67 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3):
δ 175.5, 144.5, 137.9, 128.9, 128.8, 127.3, 126.4, 124.0, 119.6, 48.0, 27.0. HRMS-ESI (m/z): Calculated for
C16H18NO (M+H)+: 240.1388, Found: 240.1381.
2-(4-Chlorophenyl)-2-methyl-N-phenylpropanamide (2b): White solid, 56.8 mg, 85% yield. mp: 112.9-
115.1 ºC. 1H NMR (400 MHz, CDCl3): δ 7.41–7.34 (m, 5H), 7.31–7.23 (m, 3H), 7.08 (m, 1H), 6.75 (s, 1H),
1.65 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 174.8, 143.1, 137.7, 133.3, 129.1, 128.9, 127.9, 124.3,
123.9, 119.7, 47.7, 27.0. HRMS-ESI (m/z): Calculated for C16H17ClNO (M+H)+: 274.0999, Found: 274.0991.
2-Methyl-N-phenyl-2-(p-tolyl)propanamide (2c): White solid, 61.3 mg, 77% yield. mp: 108.8-112.2 ºC. 1H
NMR (400 MHz, CDCl3): δ 7.57–7.49 (m, 2H), 7.41–7.24 (m, 6H), 7.15–7.02 (m, 1H), 6.76 (s, 1H), 1.65 (s,
6H). 13C {1H} NMR (100 MHz, CDCl3): δ 174.7, 143.7, 137.7, 132.0, 128.9, 128.2, 124.3, 121.4, 119.7, 47.7,
26.9. HRMS-ESI (m/z): Calculated for C16H1779BrNO (M+H)+: 318.0494, Found: 318.0496.
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2-Methyl-N-phenyl-2-(p-tolyl)propanamide (2d): White solid, 35.5 mg, 56% yield. mp: 85.5-86.1 ºC. H
NMR (400 MHz, CDCl3): δ 7.36–7.32 (m, 4H), 7.27–7.17 (m, 4H), 7.04 (m, 1H), 6.84 (s, 1H), 2.36 (s,
3H),1.64 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 175.8, 141.4, 137.9, 137.0, 129.6, 128.8, 126.4, 124.0,
119.5, 47.6, 27.0, 21.0. HRMS-ESI (m/z): Calculated for C17H20NO (M+H)+: 254.1545, Found: 254.1525.
2-Methyl-N-phenyl-2-(4-(trifluoromethyl)phenyl)propanamide (2e): White solid, 22.3 mg, 29% yield. mp:
117.5-119.6 ºC. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.38 (d, J =
8.0 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 6.74 (s, 1H). 1.69 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): 174.4,
148.8, 137.6, 129.6 (q, J = 32.4 Hz), 126.8, 125.9 (q, J = 3.7 Hz), 124.4, 123.9 (t, J = 136.1 Hz), 119.8, 48.1,
27.0. HRMS-ESI (m/z): Calculated for C17H17F3NO (M+H)+: 308.1262, Found: 308.1252.
2-(4-Methoxyphenyl)-2-methyl-N-phenylpropanamide (2f): Pale-yellow solid, 22.2 mg, 33% yield. mp:
83.2-84.5 ºC. 1H NMR (400 MHz, CDCl3): δ 7.39–7.33 (m, 4H), 7.29–7.22 (m, 2H), 7.07–7.03 (m, 1H), 6.98–
6.90 (m, 2H), 6.85 (s, 1H), 3.83 (s, 3H), 1.64 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 175.9, 158.7, 137.9,
136.4, 128.8, 127.6, 124.0, 119.5, 114.2, 55.3, 47.3, 27.1. HRMS-ESI (m/z): Calculated for C17H20NO2 (M+H)+:
270.1494, Found: 270.1471.
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2-Methyl-N-phenyl-2-(o-tolyl)propanamide (2g): White solid, 62.7 mg, 99% yield. mp: 95.6-98.8 ºC. 1H
NMR (400 MHz, CDCl3): δ 7.51–7.49 (m, 1H), 7.36–7.34 (m, 2H), 7.32–7.18 (m, 6H), 7.11–7.03 (m, 1H),
6.85 (s, 1H), 2.31 (s, 3H), 1.66 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 171.2, 138.8, 137.1, 134.6, 133.7,
132.4, 132.0, 131.7, 130.5, 129.1, 126.1, 58.4, 32.4, 20.8. HRMS-ESI (m/z): Calculated for C17H20NO (M+H)+:
254.1545, Found: 254.1543.
2-Methyl-N-phenyl-2-(m-tolyl)propanamide (2h): White solid, 45.2 mg, 76% yield. mp: 109.9-112.2 ºC 1H
NMR (400 MHz, CDCl3) δ 7.44–7.22 (m, 7H), 7.14 (d, J = 7.2 Hz, 1H), 7.06 (td, J = 7.2, 0.8 Hz, 1H), 6.83 (s,
1H), 2.39 (s, 3H), 1.66 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 175.7, 144.4, 138.6, 138.0, 128.8, 128.1,
127.2, 124.0, 123.4, 119.6, 47.9, 27.0, 21.6. HRMS-ESI (m/z): Calculated for C17H20NO (M+H)+: 254.1545,
Found: 254.1540.
N,2-Diphenylpropanamide (2i):19 White solid, 19.0 mg, 34% yield. mp: 114.9-116.3 ºC. 1H NMR (400 MHz,
CDCl3): δ 7.47–7.21 (m, 1H), 7.17 (s, 1H), 7.06 (t, J = 7.2 Hz, 1H), 3.72 (q, J = 6.8 Hz, 1H), 1.69 (d, J = 7.2
Hz, 1H). 13C {1H} NMR (100 MHz, CDCl3): δ 175.6, 144.2, 137.0, 131.8, 129.1, 127.5, 126.4, 121.2, 116.6,
48.1, 26.9.
2,2-Difluoro-N,2-diphenylacetamide (2k):20 White solid, 16.1 mg, 26% yield. mp: 86.6-89.7 ºC. H NMR
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(t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 2H). 19F NMR (376 MHz, CDCl3): δ -24.68. 13C {1H} NMR (100 MHz,
CDCl3): δ 161.8 (t, J = 31.0 Hz), 136.0, 132.6 (t, J = 25.4 Hz), 131.1, 129.2, 128.7, 125.61, 125.58 (t, J =
6.1Hz), 120.1, 114.8 (t, J = 254.1 Hz). HRMS-ESI (m/z): Calculated for C14H12F2NO (M+H)+: 248.0887,
Found: 248.0885.
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2-Methyl-N-phenyl-2-(thiophen-2-yl)propanamide (2m): White solid, 35.3 mg, 76% yield. mp: 78.1-80.0
ºC. 1H NMR (400 MHz, CDCl3) δ 7.42–7.23 (m, 5H), 7.19 (s, 1H), 7.09 (m, 3H), 1.75 (s, 6H). 13C {1H} NMR
(100 MHz, CDCl3) δ 174.3, 149.7, 138.0, 129.1, 127.6, 125.6, 125.2, 124.5, 119.9, 46.5, 28.4. HRMS-ESI
(m/z): Calculated for C14H16NOS (M+H)+: 246.0953, Found: 246.0953.
N-(4-Methoxyphenyl)-2-methyl-2-phenylpropanamide (2n): White solid, 54.5 mg, 81% yield. mp: 134.3-
136.3 ºC. 1H NMR (400 MHz, CDCl3): δ 7.47–7.38 (m, 4H), 7.35–7.22 (m, 3H), 6.85–6.77 (m, 2H), 6.69 (s,
1H), 3.76 (s, 3H), 1.66 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 175.4, 156.2, 144.7, 131.0, 128.8, 127.2,
126.4, 121.5, 113.9, 55.4, 47.7, 27.0. HRMS-ESI (m/z): Calculated for C17H20NO2 (M+H)+: 270.1494, Found:
270.1473.
2-Methyl-2-phenyl-N-(p-tolyl)propanamide (2o): White solid, 51.3 mg, 81% yield. mp: 103.8-105.2 ºC. 1H
NMR (400 MHz, CDCl3): δ 7.47–7.35 (m, 4H), 7.35–7.28 (m, 1H), 7.25–7.22 (m, 2H), 7.06 (d, J = 8.4 Hz,
2H), 6.74 (s, 1H), 2.27 (s, 3H), 1.66 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 175.4, 144.6, 135.4, 133.7,
129.3, 128.9, 127.3, 126.5, 119.6, 47.9, 27.0, 20.8. HRMS-ESI (m/z): Calculated for C17H20NO (M+H)+:
254.1545, Found: 254.1546.
N-(4-Bromophenyl)-2-methyl-2-phenylpropanamide (2p): White solid, 46.1 mg, 58% yield. mp: 136.2-
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139.0 ºC. H NMR (400 MHz, CDCl3): δ 7.46–7.30 (m, 7H), 7.29–7.22 (m, 2H), 6.79 (s, 1H), 1.66 (s, 6H).
13C {1H} NMR (100 MHz, CDCl3): δ 175.6, 144.2, 137.0, 131.8, 129.1, 127.5, 126.4, 121.2, 116.6, 48.1, 26.9.
HRMS-ESI (m/z): Calculated for C16H1779BrNO (M+H)+: 318.0494, Found: 318.0473.
N-(4-Chlorophenyl)-2-methyl-2-phenylpropanamide (2q): White solid, 46.5 mg, 68% yield. mp: 133.6-
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135.1 ºC. H NMR (400 MHz, CDCl3): δ 7.47–7.28 (m, 7H), 7.24–7.18 (m, 2H), 6.76 (s, 1H), 1.66 (s, 6H).
13C {1H} NMR (100 MHz, CDCl3): δ 175.6, 144.2, 136.5, 129.0, 128.8, 127.5, 126.4, 120.9, 48.0, 26.9.
HRMS-ESI (m/z): Calculated for C16H17ClNO (M+H)+: 274.0999, Found: 274.0991.
2-Methyl-2-phenyl-N-(4-(trifluoromethyl)phenyl)propanamide (2r): White solid, 54.5 mg , 71% yield. mp:
104.2-105.9 ºC. 1H NMR (400 MHz, CDCl3): δ 7.55–7.39 (m, 8H), 7.37–7.34 (m, 1H), 6.90 (s, 1H), 1.68 (s,
6H). 13C {1H} NMR (100 MHz, CDCl3): δ 175.9, 144.1, 141.0, 129.1, 127.6, 126.4, 126.1 (q, J = 3.7 Hz),
125.8 (q, J = 32.6 Hz), 124.0 (q, J = 269.8 Hz), 119.1, 48.2, 26.9. HRMS-ESI (m/z): Calculated for
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C17H17F3NO (M+H)+: 308.1262, Found: 308.1259.
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2-Methyl-2-phenyl-N-(o-tolyl)propanamide (2s): White solid, 50.0 mg, 79% yield. mp: 87.0-88.5 ºC. H
NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.0 Hz, 1H), 7.54–7.47 (m, 2H), 7.46–7.38 (m, 2H), 7.36–7.30 (m,
1H), 7.17 (t, J = 7.6 Hz, 1H), 7.01 (m, 2H), 6.70 (s, 1H), 1.78 (s, 3H), 1.70 (s, 6H).13C {1H} NMR (100 MHz,
CDCl3): δ 175.6, 144.6, 135.8, 130.2, 129.0, 127.4, 126.7, 126.6, 124.5, 121.7, 48.0, 26.8, 16.9. HRMS-ESI
(m/z): Calculated for C17H20NO (M+H)+: 254.1545, Found: 254.1542.
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2-Methyl-2-phenyl-N-(m-tolyl)propanamide (2t): White solid, 50.1 mg, 79% yield. mp: 86.6-89.7 ºC. H
NMR (400 MHz, CDCl3): δ 7.47–7.37 (m, 4H), 7.34–7.30 (m, 1H), 7.28–7.23 (m, 1H), 7.18–7.08 (m, 2H),
6.87 (m, 1H), 6.76 (s, 1H), 2.29 (s, 3H), 1.66 (s, 6H).13C {1H} NMR (100 MHz, CDCl3): δ 175.5, 144.5, 138.8,
137.8, 129.0, 128.6, 127.3, 126.4, 124.9, 120.2, 116.6, 48.0, 27.0, 21.4. HRMS-ESI (m/z): Calculated for
C17H20NO (M+H)+: 254.1545, Found: 254.1549.
N-(3,5-Dimethylphenyl)-2-methyl-2-phenylpropanamide (2u): White solid, 47.5 mg, 71% yield. mp:
132.0-133.8 ºC. 1H NMR (400 MHz, CDCl3): δ 7.46–7.37 (m, 4H), 7.32 (m, 1H), 7.00 (s, 2H), 6.70 (s, 2H),
2.24 (s, 6H), 1.65 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ 175.5, 144.5, 138.6, 137.7, 128.9, 127.3, 126.4,
125.8, 117.2, 49.2, 48.0, 44.7, 27.0, 21.3. HRMS-ESI (m/z): Calculated for C18H22NO (M+H)+: 268.1701,
Found: 268.1698.
ASSOCIATED CONTENT
SUPPORTING INFORMATION
The NMR spectra is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
The authors acknowledge the financial support provided by the National Natural Science Foundation of China
(No. 21232003). We thank the Instrumental Analysis Center of Shanghai Jiao Tong University for
microanalysis.
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