Iodine-mediated aryl transfer reaction from arylhydrazine hydrochlorides to nitriles

Article abstract of DOI:10.1016/j.tet.2019.05.034

An iodine-promoted, metal-, base-, and solvent-free cross-coupling reaction was developed for the synthesis of various useful secondary amides via an aryl N-addition reaction of aryl groups to cyano groups. This aryl transfer reaction proceeds with arylhydrazine hydrochlorides serving as the aryl donors. A labelling experiment shows that the N atom in the product comes from the cyano group of the nitriles, which are low in cost. A plausible radical-driven mechanism is also proposed.

Full text of DOI:10.1016/j.tet.2019.05.034

Accepted Manuscript
Iodine-mediated aryl transfer reaction from arylhydrazine hydrochlorides to nitriles
Zhiguo Zhang, Xiang Li, Yinghua Li, Yan Guo, Xunan Zhao, Yan Yan, Kai Sun,
Guisheng Zhang
PII:
S0040-4020(19)30574-5
https://doi.org/10.1016/j.tet.2019.05.034
TET 30355
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 February 2019
Revised Date: 13 May 2019
Accepted Date: 15 May 2019
Please cite this article as: Zhang Z, Li X, Li Y, Guo Y, Zhao X, Yan Y, Sun K, Zhang G, Iodine-mediated
aryl transfer reaction from arylhydrazine hydrochlorides to nitriles, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.05.034.
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ACCEPTED MANUSCRIPT
Iodine-Mediated Aryl Transfer Reaction from Arylhydrazine Hydrochlorides to
Nitriles
Zhiguo Zhang,a* Xiang Li,a Yinghua Li,a Yan Guo,a Xunan Zhao,a Yan Yan,a Kai Sun,b Guisheng
Zhanga*
a
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals, Henan Key laboratory of Organic Functional Molecule
and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan
453007, China. E-mail: zhangzg@htu.edu.cn and zgs6668@yahoo.com, Fax: (+86)-373-332-5250.
b College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, China
Abstract. An iodine-promoted, metal-, base-, and solvent-free cross-coupling reaction was
developed for the synthesis of various useful secondary amides via an aryl N-addition reaction of
aryl groups to cyano groups. This aryl transfer reaction proceeds with arylhydrazine hydrochlorides
serving as the aryl donors. A labelling experiment shows that the N atom in the product comes from
the cyano group of the nitriles, which are low in cost. A plausible radical-driven mechanism is also
proposed.
Keywords: Arylhydrazine hydrochlorides; Nitrile N-addition; Aryl transfer reaction; Cross-coupling;
Iodine; Secondary amides
1. Introduction
C-N triple bonds1 are versatile functional groups in organic synthesis.2 The cyano group of nitriles
can undergo C-addition and N-addition reactions leading to C-C bond and C-N bond formation
(Scheme 1). C-addition to the cyano group of nitriles has been widely observed in reactions with
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various aryl donors, such as arylsulfinic acids,3 arylboronic acids,4 aryl iodides,5 benzoic acids,6
arenes,7 and hydrazines,8 frequently in the presence of Ni, Pd, Rh, or Cu transition-metal catalysts
(Scheme 1a). However, the N-addition reaction has rarely been achieved by cross-coupling of the
aryl and nitrile portion to produce amides or their analogs via C-N bond formation (Scheme 1b). To
the best of our knowledge, only two examples of this type of reaction have been described, both
involving Cu catalysts. In 2013, Chen and co-workers9 described, in two separate publications, the
concise construction of polycyclic quinolines via intramolecular [2+2+2] annulation of
diaryliodoniums, nitriles, and alkynes. The key intermediate N-phenyl nitrilium salt, which was
produced by tethering the aryl and nitrile portion via a N-addition reaction, was involved in these
regioselective processes. Furthermore, very recently, we developed a useful intermolecular phenyl
transfer reaction for the synthesis of N-phenyl amides, which, for the first time, were synthesized
starting from hydrazides and nitriles. The protocol proceeded via an oxidative cleavage reaction of
sp2 C-N bonds of phenylhydrazides to form a phenyl radical and the subsequent N-addition to the
cyano group (Scheme 1b).10 This metal-free N-phenylated reaction proceeded in the presence of
[bis-(trifluoroacetoxy)iodo]benzene (PIFA) under mild and solvent-free conditions. Despite the
considerable accomplishments achieved so far, the further development of practical, diverse, and
flexible N-addition reactions of cyano groups, hence leading to more functional molecules, is highly
desirable.
Scheme 1. The addition reactions of aryl donors to cyano groups.
Phenylhydrazine and its derivatives are an important moiety of various natural compounds with a
rich diversity of structures and bioactivities.11 In synthetic organic chemistry, these derivatives, such
as nitrilimines, are useful in addition reactions to generate nitrogen-containing heterocycles because
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of their high reactivity, low cost, and easy availability.12 Additionally, they often serve as
PhNH-group donors to access small organic molecules with desired functionality,13 such as in the
Fischer indole synthesis.14 Furthermore, many studies have reported that phenylhydrazines can be
decomposed into a phenyl group by expulsion of N2 under mild conditions, thence participating in
various coupling reactions to afford biaryls.15 However, to date, the phenyl donor chemistry of
phenylhydrazines toward the triple bonds of unsaturated compounds8-10,16 has been far less explored
than that toward other bond types.17 A noteworthy example with arylhydrazines serving as the aryl
donor was reported by Jiang’s group in 2017.8 They established a simple approach for the synthesis
of aryl ketones in the presence of a palladium catalyst, 2,2’-bipyridine, trifluoroacetic acid, and using
molecular oxygen as the sole oxidant starting from nitriles and arylhydrazines via a C-addition
reaction to the cyano group (Eq 1). Here, we describe our successful cross-coupling of arylhydrazine
hydrochlorides with nitriles in the presence of iodine and tert-butyl nitrite (t-BuONO) to produce
secondary amides under metal-, base-, and solvent-free conditions with a broad substrate scope (Eq
2). Obviously, the advantage of the direct N-addition to the cyano group is to allow the introduction
of an aryl directly to the nitrogen atom and facilitate various useful amides18 without the need for
pre-prepared carbonyl-containing starting materials and metal catalysts.
2. Results and discussion
We began our study with the selection of phenylhydrazine hydrochloride (1a) and benzonitrile
(2a) as model substrates to optimize the reaction conditions (Table 1). Initially, we treated 1a and 2a
(10 equiv) with 2 equiv of iodine and 2 equiv of t-BuONO at 25 °C (Table 1, entry 1). To our delight,
N-phenylated product 3a was isolated in 62% yield as a white solid, along with a trace amount of
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by-product 4a after 5 h. Further investigation indicated that the amount of iodine had little effect on
the yield of product 3a (Table 1, entries 2–5). It should be emphasized that the reaction showed a
very low efficiency in the absence of iodine or t-BuONO (Table 1, entries 6 and 7). These
observations show that both of those reagents are indispensable to this aryl transfer reaction.
Experimentally, the reaction was found to be improved when we increased the amount of t-BuONO,
and the reaction performance was optimized when 1.5 equiv of t-BuONO was employed (Table 1,
entries 8–12). The amount of starting material 2a, serving as both aryl acceptor and solvent, was also
screened. It was found that using more than 5 equiv of compound 2a allowed the reaction mixture to
form a homogeneous solution and gave a higher yield of 3a than when using a lower loading of 2a
(Table 1, entries 13 and 14). However, increasing the reaction temperature was unable to improve the
yield of 3a (Table 1, entries 15 and 16). Other commercially available nitrites, such as isopropyl
nitrite (i-PrONO), isobutyl nitrite (i-BuONO), isopentyl nitrite (i-PenONO), n-butyl nitrite
(n-BuONO), and n-hexyl nitrite (n-HexONO), were also tested in the reaction. All of them showed a
lower efficiency than that of t-BuONO (Table 1, entries 17–21). Next, other phenylhydrazines were
also investigated systematically. Under the optimized conditions, various phenylhydrazide
derivatives phenylhydrazine (1b), N’-phenylacetohydrazide (1c), N’-phenylbenzenesulfonohydrazide
(1d), and 4-methyl-N’-phenylbenzenesulfonohydrazide (1e) gave the amide 3a in 39–48% yield, as
well as 9–27% yield of by-product 4a (Table 1, entries 22–25).
Table 1
Survey of the reaction conditions.a
Entry
1
I2/equiv
2
RONO/equiv
t/h 3a/% 4a/%
62 Trace
1
t-BuONO/2
5
1a
4

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2
3
1.5
1
t-BuONO/2
t-BuONO/2
t-BuONO/2
t-BuONO/2
t-BuONO/1.5
----
5
8
5
5
5
6
6
6
6
6
6
5
5
5
5
5
5
5
5
5
6
5
8
8
63 Trace
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
65
64
57
7
6
4
4
0.5
0.2
--
5
10
0
6
7
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
5
0
8
t-BuONO/0.2
t-BuONO/0.5
t-BuONO/1
t-BuONO/1.5
t-BuONO/3
t-BuONO/1.5
t-BuONO/1.5
t-BuONO/1.5
t-BuONO/1.5
i-PrONO/1.5
i-BuONO/1.5
i-PenONO/1.5
n-BuONO/1.5
n-HexONO/1.5
t-BuONO/1.5
t-BuONO/1.5
t-BuONO/1.5
t-BuONO/1.5
19 Trace
58 Trace
61 Trace
64 Trace
9
10
11
12
13b
14c
15d
16e
17
18
19
20
21
22
23
24
25
59
7
40 Trace
56 Trace
43
46
48
59
59
51
63
41
39
43
48
0
0
0
0
0
0
0
20
27
9
13
5

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a
Unless otherwise indicated, all reactions were carried out with 1a (0.3 mmol), 2a, I2, and nitrites
under solvent-free and open-air conditions.
b 3.0 equiv of 2a was used.
c 5.0 equiv of 2a was used.
d 50 oC was used.
e 75 oC was used.
The optimized conditions were identified as 1 equiv of 1 and 10 equiv of 2 in the presence of 0.5
equiv of iodine and 1.5 equiv of t-BuONO under solvent-free conditions at 25 °C (Table 1, entry 11).
The scope of this intermolecular cross-coupling reaction using various starting materials 2 was then
investigated (Table 2). The phenyl group (2a) and a variety of substituted phenyls with an
electron-donating group (EDG) (e.g., –OMe) (2b–d) or an electron-withdrawing group (EWG) (e.g.,
–CO2Et) (2e–f) at the ortho-, meta-, or para-position could be well tolerated for the reaction, and
gave the amide products 3a–f in the yields of 34–73%. Except for the desired product 3f, 15% of
N-(2-nitrophenyl)-3-(methoxycarbonyl)benzamide (4f) was isolated simultaneously in the reaction
between 1a and 2f. However, we found that the nitrification product 4f could be suppressed
completely if the reaction was carried out under N2 atmosphere. It was deduced that the NO radicals
derived from the t-BuONO were oxidized to nitro radicals (·NO) by air,19 which served as the nitro
group donor of the nitrification.20 The reaction proceeded well for the starting materials 2-furonitrile
(2g) and 2-thiophenecarbonitrile (2h) and afforded two commercialized products, 3g and 3h, in 47%
and 57% yields, respectively. Interestingly, six other functionalized nitrile substrates 2i–n smoothly
afforded useful 3i–n as the sole products in 45–66% yields, under the optimal conditions, without
affecting the active cyclopropyl moiety, active methylene moiety, and C=C double bond functional
groups of these substrates. These observations indicated the flexibility and controllability of this
iodine-mediated aryl transfer reaction. To verify the convenience and flexibility of this approach and
obtain structurally diverse amides, several random commercially available hydrazines (or their
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hydrochloride) 1, including tert-butylhydrazine hydrochloride (1f), 4-hydrazinylpyridine
hydrochloride
(1g),
2-chloro-3-hydrazinylpyrazine
hydrochloride
(1h),
and
3-chloro-6-hydrazinylpyridazine hydrochloride (1i), were employed in the reaction. All of them
could react with 2a and gave the corresponding amides 3o–r in 46–68% yields. Despite the relatively
low yields, this is a new and alternative approach to access these types of amides. In addition, other
aryl donors including sodium benzenesulfinate, benzoic acid, phenylboronic acid, and iodobenzene
were also employed to the reaction, but the reaction did not occur, and starting materials were
recovered.
Table 2
Extension of the reaction scope.a
Entry
1
t/h
6
1
2
3
3a: 64%
1a
(2a)
2
3
5
6
3b: 73%
3c: 58%b
1a
1a
(2b)
(2c)
4
5
6
7
5
6
6
6
3d: 45%
3e: 35%
3f: 34%c
3g: 47%d
1a
1a
1a
1a
(2d)
(2e)
(2f)
(2g)
8
9
6
6
3h: 57%
3i: 65%
1a
1a
(2h)
(2i)
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10
11
12
5
5
5
3j: 66%
3k: 65%
3l: 64%
1a
1a
1a
(2j)
(2k)
(2l)
13
14
5
9
3m: 50%
3n: 45%
1a
1a
(2m)
(2n)
15
16
17
18
5.5 3o: 68%
1f 2a
1g 2a
1h 2a
1i 2a
6
6
6
3p: 46%
3q: 53%
3r: 51%
a Unless otherwise indicated, all reactions were carried out with 1 (0.3 mmol), 2 (3 mmol), t-BuONO
(53 ꢀL, 0.45 mmol), I2 (38 mg, 0.15 mmol) under solvent-free conditions and air atmosphere at
25 °C.
b Along with 10% of N-(4-iodophenyl)-3-methoxybenzamide (5c).
c Along with 15% of N-(2-nitrophenyl)-3-(methoxycarbonyl)benzamide (4f).
d Along with 18% of N-(4-iodophenyl)furan-2-carboxamide (5g).
It was found that a mixture of N-phenylamides (3s–u) and para-iodine-substituted amides (5s–u)
was generated when starting materials acetonitrile (2s), pentanenitrile (2t), and pivalonitrile (2u)
reacted with 1a, respectively,21 and the products 3s–u could be completely converted to the
N-(4-iodophenyl)amides 5s–u when the reaction time was prolonged to 12 h (Table 3).
Advantageously, the strategy of prolonging the reaction time to obtain a single product avoided the
need for isolation of the mixture of compounds 3s–u and 5s–u, which proved to have the same
polarity in TLC. Furthermore, we found that the iodination reaction – unlike the nitrification reaction
– could not be inhibited under N2 atmosphere. Interestingly, a particular nitrile 2v reacted with 1a
and smoothly afforded the useful 4v as the sole product with the yield of 48% in 6 h. This
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observation also discloses that the iodination occurs after the aryl transfer reaction. Moreover, the
obtained iodine-substituted amides are suitable for further functionalization, such as by the Heck
reaction, and the Suzuki and Stille cross-coupling reactions.
Table 3
Extension of the reaction scope.a
Entry Substrate 2 t/h
Product 5
1
2
3
4
MeCN (2s) 12
nBuCN (2t) 12
tBuCN (2u) 12
PhOCN (2v) 6
5s: 65%
5t: 57%
5u: 60%
5v: 48%
a
Unless otherwise indicated, all reactions were carried out with 1a (0.3 mmol), 2 (3 mmol),
t-BuONO (53 ꢀL, 0.45 mmol), I2 (38 mg, 0.15 mmol) under solvent-free conditions and air
atmosphere at 25 °C.
The synthesis of chiral amides via the aryl transfer reaction was also investigated (Eq 1). It was
found that the desired chiral amides (R)-2-oxo-1-phenyl-2-(phenylamino)ethyl acetate (3w) and
(R)-2-((4-iodophenyl)amino)-2-oxo-1-phenylethyl acetate (5w) could be isolated in 38% and 11%
yield, respectively, when 1a and optically pure substrate (R)-cyano(phenyl)methyl acetate (2w) were
employed in the reaction.22 The α value of (S)-3w in the literature is [α]20 = +74.9° (c = 3.65, CHCl3),
while in our experiment, the [α]D25.5 value of 3w was observed as -64.5° (c = 0.2, CH2Cl2), revealing
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that the (R)-configuration was mainly formed (Eq 3).23 These observations also disclosed that the
absolute configuration in the transformation remained essentially unchanged.
Finally, to demonstrate the synthetic potential of this reaction, an intramolecular generation of
phenanthridin-6(5H)-one
(3x)
was
conducted.
Starting
material
2’-hydrazinyl-[1,1’-biphenyl]-2-carbonitrile (6) was readily converted to phenanthridin-6(5H)-one
(3x) in 47%
yield under the optimal
conditions, along with by-product
2’-iodo-[1,1’-biphenyl]-2-carbonitrile (3x’) (Eq 4).24
Radical trapping experiments were conducted to clarify whether a radical process was involved in
the transformation. It was found that compound 3a was not formed when 1 equiv of radical
scavengers, including 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), N-tert-butyl-α-phenylnitrone
(PBN), and galvinoxyl were added in the reaction mixture, in separate experiments, under the
standard conditions. Under these conditions, the conversion was completely inhibited and none of
the desired product 3 was formed. These results implied that radicals were involved in the
transformation (Table 4). In addition, a separate reaction from N-phenylacetamide to 5s was also
inhibited by adding 1 equiv of TEMPO, which suggested a radical pathway maybe involved from
N-phenylacetamide to 5s. Moreover, in our recent work, we have demonstrated by a labelling
experiment that the nitrogen source of the products 3 comes from the nitriles 2, rather than the
hydrazines.10 In the present work, the labelling experiment showed that the N atom in the final
products likewise came from the cyano group of the nitriles (2) (Eq 5). In addition, no target product
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3a was generated in reactions performed in the absence of either I2 or t-BuONO (Table 1, entries 6
and 7). These facts indicated that both I2 and t-BuONO are indispensable to the transformation.
Table 4
Radical trapping experiments.a
Radical scavenger (1 equiv) Yield of 3a/%
No Scavenger
TEMPO
64
0
PBN
0
Galvinoxyl
0
a
Unless otherwise indicated, all reactions were carried out with 1a (0.3 mmol), 2a (3 mmol),
t-BuONO (53 ꢀL, 0.45 mmol), I2 (38 mg, 0.15 mmol), and radical scavenger (0.3 mmol) under
solvent-free conditions and air atmosphere at 25 °C.
Based on the results of these control experiments and information from previous works, a
plausible mechanism is proposed in Scheme 2. It was envisioned that the homolysis of t-BuONO
under the reaction conditions gave tert-butoxyl radicals and NO radicals.19 Then, the tert-butoxyl
radicals reacted with the initiator iodine to afford tert-butyl hypoiodite25 and iodine radicals.26 Next,
the in situ-generated iodine radicals reacted with the phenylhydrazine hydrochlorides (1) to form the
aryl radicals A with the release of N2 and HI.15b,27 Subsequently, the addition of the aryl radicals to 2
produced intermediate B.28 We speculate that the steric hindrance of the N position is less than the C
position in the nitrile group, which resulted in the N-addition of the transformation. Finally, this
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intermediate was trapped by the tert-butoxyl radicals to generate the intermediate C, ultimately
leading to the amide 3 in the presence of a proton.9a,10 After this desired reaction, an iodination29 or a
nitrification20 were possible, resulting in the production of para-iodinated product 5 or
ortho-nitrogenated product 4 via a radical process.
Scheme 2. Proposed mechanism.
3. Conclusion
In summary, an iodine-promoted and t-BuONO-assisted intermolecular cross-coupling reaction
was developed via relatively a rare N-addition reaction to the cyano group of nitriles. The protocol
allows the introduction of an aryl, derived from arylhydrazine hydrochlorides, directly to the
nitrogen atom of the nitriles, avoiding the pre-preparation of carbonyl-containing starting materials.
In addition, this reaction proceeded under metal-, base-, and solvent-free conditions and produced
structurally diverse N-aryl amides with a broad substrate scope.
4. Experimental section
4.1. General methods
All reactions were carried out under air atmosphere, unless otherwise indicated. Other all reagents
were purchased from commercial sources and used without further treatment, unless otherwise
indicated. The petroleum ether (PE) used refers to the fraction of petroleum with a boiling point of
1
13
60–90 °C. Ethyl acetate is abbreviated as EA. H and C NMR spectra were recorded on a Bruker
Avance/600 (1H: 600 MHz, 13C: 150 MHz at 25 °C) or Bruker Avance/400 (1H: 400 MHz, 13C: 100
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MHz at 25 °C) spectrometer using TMS as an internal standard. Data are represented as follows:
chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, dd = double doublet, t =
triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz). All high-resolution mass spectra
(HRMS) were measured on a mass spectrometer using electrospray ionization (ESI-oa-TOF), and the
1
purity of all samples used for HRMS (>95%) were confirmed by H and 13C NMR spectroscopic
analysis. Melting points were measured on a melting point apparatus equipped with a thermometer
and were uncorrected. All reactions were monitored by thin layer chromatography with GF254 silica
gel coated plates. Flash chromatography was carried out on silica gel (200–300 mesh).
4.2. Typical Experimental Procedure
4.2.1. For 3 (3a as an example)
To a round-bottom flask (25 mL) was added phenylhydrazine hydrochloride 1a (43 mg, 0.3 mmol),
benzonitrile 2a (0.3 mL, 3 mmol), t-BuONO (53 ꢀL, 0.45 mmol), I2 (38 mg, 0.15 mmol), the mixture
o
was well stirred for 6 h at 25 C (the whole process was closely monitored by TLC). Then the
reaction mixture was purified by a flash silica gel column chromatography (eluent: Petroleum ether
(PE)/Ethyl acetate (EA) = 10:1) to give N-phenylbenzamide 3a as a white solid (38 mg, 64%).
4.2.2. For 2r30
To a round-bottom flask (50 mL) was added acetic anhydride (188 ꢀL, 2 mmol), DMAP (67 ꢀL,
0.5 mmol), (R)-2-hydroxy-2-phenylacetonitrile (119 ꢀL, 1 mmol) in tetrahydrofuran (5 mL), the
mixture was stirred for 10 h at room temperature. (the whole process was closely monitored by TLC).
The reaction was poured into water (5 mL), and the mixture was stirred vigorously for 30 min. The
aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phases were washed
with 1 M aq HCl (15 mL), saturated aq NaHCO3 (15 mL), water (15 mL) and brine (15 mL), and
dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the
(R)-cyano(phenyl)methyl acetate 2r as a colorless oil (149 mg, 85%).
4.2.3. For 531
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To a round-bottom flask (50 mL) was added 1-iodo-2-nitrobenzene (249 mg, 1 mmol),
(2-cyanophenyl)boronic acid (220 mg, 1.5 mmol), Pd(OAc)2 (1 mg, 0.5% mmol), K3PO4 (425 mg, 2
o
mmol) in ethylene glycol, the mixture was well stirred for 5 h at 80 C (the whole process was
closely monitored by TLC). After cooling, the mixture was added to brine. The mixture was
extracted with diethyl ether. The organic phase was evaporated under reduced pressure, the reaction
mixture was purified by
a
flash silica gel column chromatography to give
2’-nitro-(1,1’-biphenyl)-2-carbonitrile 7 as a gray solid (101 mg, 45%).
To a round-bottom flask (50 mL) was added 2’-nitro-(1,1’-biphenyl)-2-carbonitrile (224 mg, 1
mmol), Fe (336 mg, 6 mmol) in acetic acid, the mixture was well stirred for 13 h at 40 oC (the whole
process was closely monitored by TLC). After cooling, the mixture was added to brine. The
production of slag was filtered off and washed with CH2Cl2 and Et2O. The organic phase was
evaporated under reduced pressure to give 2’-amino-[1,1’-biphenyl]-2-carbonitrile 8 as a gray solid
(126 mg, 85%).
To a round-bottom flask (50 mL) was added NaNO2 (83 mg, 1.2 mmol) in water (0.5 mL),
2’-amino-[1,1’-biphenyl]-2-carbonitrile (118 mg, 1 mmol) in concentrated HCl (2 mL), the mixture
was well stirred for 1 h at 0 oC. Then, solution of SnCl2 (450 mg, 2 mmol) inconcentrated HCl (1.5
mL) was added at 0 °C and the resulting mixture was stirred for 2 h at room temperature. The formed
precipitation was filtered off and washed with EtOH and Et2O. The finalcompound was dried under
the vacuum to give 2’-hydrazinyl-[1,1’-biphenyl]-2-carbonitrile 6 as a white solid (84mg, 45%).
4.3. Analytical Data
4.3.1. (R)-cyano(phenyl)methyl acetate (2w)
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a white solid (148
mg, 85%); 1H NMR (400 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.40-7.32 (m, 3H), 6.32 (s, 1H), 2.07 (s,
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3H). 13C NMR (150 MHz, CDCl3) δ 168.9, 131.8, 130.4, 129.3, 127.9, 116.1, 62.9, 20.5. HRMS
(ESI), m/z calcd. for C10H9NNaO2 ([M+Na]+) 198.0525, found: 198.0529.
4.3.2. N-phenylbenzamide (3a)10
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (38 mg,
64%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 2H), 7.80 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H),
7.56 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.16 (t, J = 7.4 Hz, 1H).
4.3.3. 4-methoxy-N-phenylbenzamide (3b)10
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (50 mg,
73%); 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.63 (d, J = 7.8 Hz, 2H),
7.37 (t, J = 7.8 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H).
4.3.4. 3-methoxy-N-phenylbenzamide (3c)10
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (39 mg,
58%); 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 1.5 Hz, 1H),
7.40 - 7.36 (m, 7.2 Hz, 4H), 7.16 (t, J = 7.4 Hz, 1H), 7.12-7.07 (m, 1H), 3.88 (s, 3H).
4.3.5. 2-methoxy-N-phenylbenzamide (3d)10
The product was isolated by flash chromatography (eluent: PE/EA = 50/1) as a white solid (31 mg,
1
45%); H NMR (400 MHz, CDCl3)
δ 9.80 (s, 1H), 8.30 (d, J = 8.0, 1H), 7.68 (d, J = 7.6 Hz, 2H),
7.54-7.46 (m, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.15-7.12 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 4.07 (s, 3H).
4.3.6. methyl 4-(phenylcarbamoyl)benzoate (3e)10
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (27 mg,
35%); 1H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 2H), 7.94 (d, J = 7.8 Hz, 2H), 7.82 (s, 1H),
7.65 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 3.96 (s, 3H).
15

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4.3.7. methyl 3-(phenylcarbamoyl)benzoate (3f)10
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (26 mg,
34%); 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 7.2 Hz, 1H),
7.90 (s, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.18 (t, J =
7.2 Hz, 1H), 3.97 (s, 3H).
4.3.8. N-phenylfuran-2-carboxamide (3g)10
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (26 mg,
47%); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 0.8 Hz, 1H),
7.37 (t, J = 7.8 Hz, 2H), 7.25 (d, J = 3.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.57 (dd, J = 3.4, 1.8 Hz,
1H).
4.3.9. N-phenylthiophene-2-carboxamide (3h)10
The product was isolated by flash chromatography (eluent: PE/EA = 30/1) as a white solid (34 mg,
57%); 1H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 7.8 Hz, 2H), 7.62 (s, 2H), 7.56 (s, 1H), 7.41 (d, J =
7.8 Hz, 2H), 7.14 (s, 1H).
4.3.10. N,2-diphenylacetamide (3i)10
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (41 mg,
65%); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 4H), 7.34 (d, J = 7.6 Hz, 3H), 7.29 (d, J =
7.6 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.00 (s 1H), 3.75 (s, 2H).
4.3.11. N,1-diphenylcyclopropane-1-carboxamide (3j)32
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a white solid (47 mg,
o
66%); mp: 122-125 C; 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.8 Hz, 2H), 7.44 (t, J = 7.8 Hz,
2H), 7.38 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 7.04 (t, J = 7.2 Hz,
16

ACCEPTED MANUSCRIPT
2H), 1.72-1.71 (m, 2H), 1.17-1.16 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 172.2, 139.5, 138.0,
131.3, 129.5, 129.0, 128.5, 124.3, 119.7, 31.4, 16.3. HRMS (ESI), m/z calcd. for C16H15NONa
([M+Na]+) 260.1046, found: 260.1047.
4.3.12.
methyl 3-oxo-3-(phenylamino)propanoate (3k)10
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a white solid (38 mg,
65%); 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H),
7.13 (t, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.49 (s, 2H).
4.3.13. 2-oxo-N,2-diphenylacetamide (3l)10
The product was isolated by flash chromatography (eluent: PE/EA = 40/1) as a white solid (43 mg,
64%); 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.46-8.40 (m, 2H), 7.70 (t, J = 6.2 Hz, 2H), 7.66
(d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H).
4.3.1
4. N-phenylcinnamamide (3m)10
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a white solid (34 mg,
50%); 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 15.6 Hz, 1H), 7.63 (s, 2H), 7.54 (s, 2H), 7.43-7.33
(m, 6H), 7.14 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H).
4.3.15. ethyl (Z)-3-phenyl-2-(phenylcarbamoyl)acrylate (3n)33
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (40 mg,
45%); mp: 150-158 oC; 1H NMR (600 MHz, CDCl3) δ 7.81 (s, 1H), 7.59 (d, J = 6.6 Hz, 2H), 7.57 (s,
1H), 7.52 (d, J = 7.8 Hz, 2H), 7.35 (m, 5H), 7.16 (t, J = 7.5 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.35 (t,
J = 7.2 Hz, 3H). HRMS (ESI), m/z calcd. for C18H17NO3Na ([M+Na]+) 318.1101, found: 318.1103.
4.3.16.
N-(tert-butyl)-4-methoxybenzamide (3o)34
The product was isolated by flash chromatography (eluent: PE/EA = 40/1) as a white solid (36 mg,
17

ACCEPTED MANUSCRIPT
68%); mp: 112-113 oC; 1H NMR (600 MHz, CDCl3) δ 77.71 (d, J = 7.8 Hz, 2H), 7.46 (t, J = 7.8 Hz,
1H), 7.40 (t, J = 7.2 Hz, 2H), 5.95 (s, 1H), 1.47 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 167.0, 136.1,
131.2, 128.6, 126.8, 51.7, 29.0. HRMS (ESI), m/z calcd. for C11H15NONa ([M+Na]+) 200.1042,
found: 200.1046.
4.3.17. N-(pyridin-4-yl)benzamide (3p)35
The product was isolated by flash chromatography (eluent: PE/EA = 1/2) as a white solid (27 mg,
46%); mp: 208-210 oC; 1H NMR (600 MHz, CDCl3) δ 8.56 (s, 2H), 8.03 (s, 1H), 7.88 (d, J = 7.2 Hz,
2H), 7.63 (d, J = 4.2 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H). 13C NMR (150 MHz,
CDCl3) δ 166.3, 150.8, 145.3, 134.2, 132.7, 129.1, 127.3, 114,0. HRMS (ESI), m/z calcd. for
C12H11N2O ([M+H]+) 199.0866, found: 199.0868.
4.3.18. N-(3-chloropyrazin-2-yl)benzamide (3q)
The product was isolated by flash chromatography (eluent: PE/EA = 5/1) as a white solid (37 mg,
o
1
53%); mp: 195-197 C; H NMR (600 MHz, CDCl3) δ 8.59 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.95
(d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H). 13C NMR (150 MHz, CDCl3) δ
164.8, 145.5, 141.5, 139.5, 139.3, 133.7, 133.1, 129.2, 127.7. HRMS (ESI), m/z calcd. for
C11H8ClN3ONa ([M+Na]+) 256.0244, found: 256.0248.
4.3.19. N-(6-chloropyridazin-3-yl)benzamide (3r)35
The product was isolated by flash chromatography (eluent: PE/EA = 3/1) as a white solid (36 mg,
o
51%); mp: 193-196 C; 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.67 (d, J = 9.6 Hz, 1H),
7.98-7.93 (m, 2H), 7.67-7.60 (m, 1H), 7.53-7.58 (m, 3H).13C NMR (150 MHz, CDCl3) δ 166.5,
159.5, 154.7, 152.6, 133.2, 130.1, 129.2, 127.5, 121.3. HRMS (ESI), m/z calcd. for C11H8ClN3ONa
([M+Na]+) 256.0249, found: 256.0248.
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ACCEPTED MANUSCRIPT
4.3.20.
(R)-2-oxo-1-phenyl-2-(phenylamino)ethyl
acetate
(3w)
and
(R)-2-((4-iodophenyl)amino)-2-oxo-1-phenylethyl acetate (5w)
The product was isolated by flash chromatography (eluent: PE/EA = 7/1) as a white solid (31 mg,
49%) with a 3 : 1 of 3w : 5w; 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.64-7.60 (m, 1H),
7.55-7.46 (m, 5H), 7.43-7.35 (m, 5H), 7.35-7.29 (m, 3H), 7.13 (t, J = 7.4 Hz, 1H), 6.20 (s, 1H), 2.25
(s, 3H). 13C NMR (151 MHz, CDCl3) δ 169.1, 166.3, 138.0, 136.9, 135.2, 129.3, 129.1, 128.9, 127.5,
125.0, 121.8, 120.1, 75.7, 21.1. HRMS (ESI), m/z calcd. for C16H15NO3Na ([M+Na]+) 292.0944,
found: 292.0949.
4.3.21. phenanthridin-6(5H)-one (3x)36
The product was isolated by flash chromatography (eluent: PE/EA = 15/1) as a white solid (27 mg,
47%); mp: >300 oC; 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.4 Hz, 1H), 8.58-8.54 (m, 1H), 8.50
(d, J = 8.4 Hz, 1H), 8.13-8.09 (m, 1H), 7.96-7.90 (m, 1H), 7.81-7.67 (m, 3H). HRMS (ESI), m/z
calcd. for C13H9NONa ([M+Na]+) 218.0576, found: 218.0576.
4.3.22. 2’-iodo-[1,1’-biphenyl]-2-carbonitrile (3x’)37
The product was isolated by flash chromatography (eluent: PE/EA = 25/1) as a white solid (22 mg,
24%); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.54 (dd, J = 8.0, 1.6 Hz, 1H), 8.49
(dd, J = 8.4, 0.8 Hz, 1H), 8.10 (dd, J = 8.2, 1.0 Hz, 1H), 7.92 (m, 1H), 7.74 (m 3H). HRMS (ESI),
m/z calcd. for C13H9IN ([M+H]+) 305.9774, found: 305.9781.
4.3.23. N-(2-nitrophenyl)benzamide (4a)38
1
The product was isolated by flash chromatography (eluent: PE/EA = 25/1) as a yellow solid; H
NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 9.02 (d, J = 8.4, 1H), 8.29 (d, J = 8.4, 1H), 8.01 (d, J = 7.2
Hz, 2H), 7.76-7.69 (m, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.25-7.19 (m, 1H).
19

ACCEPTED MANUSCRIPT
4.3.24. methyl 3-((2-nitrophenyl)carbamoyl)benzoate (4f)39
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (14 mg,
15%); 1H NMR (600 MHz, CDCl3) δ 11.41 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.67 (s, 1H), 8.32-8.27
(m, 2H), 8.18 (d, J = 7.2 Hz, 1H), 7.77-7.73 (m, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 3.99 (s,
3H). HRMS (ESI), m/z calcd. for C15H13N2O5 ([M+H]+) 301.0819, found: 301.0815.
4.3.25. N-(4-iodophenyl)-3-methoxybenzamide (5c)40
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a white solid (11 mg,
10%); mp 92-93 oC; 1H NMR (600 MHz, CDCl3) δ 7.79 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.43 (d, J =
9 Hz, 3H), 7.37 (dd, J = 9.7, 8.2 Hz, 2H), 7.09 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H). HRMS (ESI), m/z
calcd. for C14H12INO2Na ([M+Na]+) 375.9805, found: 375.9805.
4.3.26. N-(4-iodophenyl)furan-2-carboxamide (5g)41
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a white solid (17 mg,
18%); 1H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.45 (s, 1H), 7.37 (d, J =
7.8 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 6.50 (s, 1H)
4.3.27. N-(4-iodophenyl)acetamide (5s)42
The product was isolated by flash chromatography (eluent: PE/EA = 7/1) as a white solid (50 mg,
65%); mp: 184-186 oC; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz,
2H), 7.21 (s, 1H), 2.17 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.3 (s), 137.9 (s), 137.6 (s), 121.6
(s), 87.5 (s), 24.7 (s). HRMS (ESI), m/z calcd. for C8H9INO ([M+H]+) 261.9723, found: 261.9722.
4.3.28. N-(4-iodophenyl)pentanamide (5t)43
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ACCEPTED MANUSCRIPT
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a yellow solid (52
mg, 57%); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.06 (s,
1H), 2.37-2.32 (m, 2H), 1.74-1.66 (m, 2H), 1.40 (dd, J = 15.0, 7.4 Hz, 2H), 0.95 (t, J = 7.0 Hz, 3H).
HRMS (ESI), m/z calcd. for C11H14INONa ([M+Na]+) 326.0012, found: 326.0010.
4.3.29. N-(4-iodophenyl)pivalamide (5u)44
The product was isolated by flash chromatography (eluent: PE/EA = 20/1) as a yellow solid (55
mg, 60%); mp: 148-149 oC; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8
Hz, 2H), 7.28 (s, 1H), 1.31 (s, 9H). HRMS (ESI), m/z calcd. for C11H14INONa ([M+Na]+) 326.0012,
found: 326.0010.
4.3.30. phenyl (4-iodophenyl)carbamate (5v)45
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a white solid (49 mg,
48%); mp: 158-159 oC; 1H NMR (400 MHz, DMSO) δ 10.38 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.43
(t, J = 7.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 19.6, 7.6 Hz, 3H). HRMS (ESI), m/z calcd.
for C13H10INO2Na ([M+Na]+) 361.9648, found: 361.9649.
4.3.31. 2’-hydrazinyl-[1,1’-biphenyl]-2-carbonitrile (6)
The product was isolated by flash chromatography (eluent: PE/EA = 1/1) as a white solid (84 mg,
1
45%); H NMR (600 MHz, DMSO) δ 14.61 (s, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.80 (d, J = 8.4 Hz,
1H), 8.64 (d, J = 7.8 Hz, 1H), 8.09 (t, J = 7.5 Hz, 1H), 7.86 (t, J = 7.5 Hz, 1H), 7.71 (t, J = 6.9 Hz,
13
2H), 7.56-7.52 (m, 1H). C NMR (150 MHz, DMSO) δ 154.9, 135.5, 134.1, 131.2, 129.5, 127.2,
125.6, 124.1, 119.4, 118.4, 118.0. HRMS (ESI), m/z calcd. for C13H12N3 ([M+H]+) 210.1026, found:
210.1028.
4.3.32. 2’-nitro-(1,1’-biphenyl)-2-carbonitrile (7)
21

ACCEPTED MANUSCRIPT
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a gray solid (101 mg,
1
45%); H NMR (400 MHz, DMSO) δ 8.23 (dd, J = 8.2, 1.1 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H),
13
7.92-7.87(m, 1H), 7.83-7.77 (m, 2H), 7.67-7.59 (m, 2H), 7.55 (d, J = 7.6 Hz, 1H). C NMR (150
MHz, DMSO) δ 148.3, 141.9, 134.4, 133.9, 133.0, 132.9, 131.0, 129.9, 129.4, 125.3, 117.9, 111.5.
HRMS (ESI), m/z calcd. for C13H9N3O2 ([M+H]+) 225.0659, found: 225.0661.
4.3.33. 2’-amino-[1,1’-biphenyl]-2-carbonitrile (8)
The product was isolated by flash chromatography (eluent: PE/EA = 10/1) as a gray solid (126 mg,
85%); 1H NMR (600 MHz, DMSO) δ 9.24 (d, J = 6.0 Hz, 1H), 9.11-8.90 (m, 2H), 8.43 (s, 1H), 8.27
(s, 1H), 8.14 (dd, J = 20.3, 6.1 Hz, 2H), 7.88 (s, 1H), 7.78 (s, 2H). 13C NMR (150 MHz, DMSO) δ
172.6, 156.1, 145.4, 133.9, 131.0, 129.1, 127.5, 126.0, 125.0, 123.0, 122.8, 122.2, 120.7, 119.1.
HRMS (ESI), m/z calcd. for C13H11N2 ([M+H]+) 195.0917, found: 195.0917.
Acknowledgements
We thank the NSFC (U1604285, 21772032 and 21702051), PCSIRT (IRT1061), the 111 Project
(D17007), Henan Provincial Natural Science Foundation (162300410180), Program for Innovative
Research Team of Science and Technology in the University of Henan Province (18IRTSTHN004),
Science & Technology Innovation Talents in Universities of Henan Province (17HASTIT002), Key
Project of Henan Educational Committee (18A150009).
References
1. Wang, T.; Jiao, N. Accounts Chem Res. 2014; 47: 1137-1145
.
2. a. Wang, M.-X. Accounts Chem Res. 2015; 48: 602-611; b. Bokach, N. A. Russian Chem Rev.
2010; 79: 89-100; c. Fleming, F. F.; Wang, Q. Z. Chem Rev. 2003; 103: 2035-2077; d. Vicente, J.;
Abad, J. A.; Lopez-Saez, M.-J.; et al. Chem Eur J. 2010, 16, 661-676; e. Enders, D.; Shilvock, J. P.
Chem Eur J. 2010; 16: 661-676; f. Zilberman, E. N. Russian Chem Rev. 1962; 31: 615-633; g.
22

ACCEPTED MANUSCRIPT
Zilberman, E. N. Russian Chem Rev.1960; 29: 331-344.
3. a. Chen, J.; Li, J.; Su, W. Molecules. 2014; 19: 6439; b. Wang, X.; Liu, M.; Xu, L.; et al. J Org
Chem. 2013; 78: 5273-5281; c. Behrends, M.; Sävmarker, J.; Sjöberg, P. J. R.; et al. ACS Catal.
2011; 1: 1455-1459; d. Miao, T.; Wang, G. W. Chem Commun. 2011; 47: 9501-9503; e. Liu, J.;
Zhou, X.; Rao, H.; et al. Chem Eur J. 2011; 17: 7996-7999.
4. a. Tsui, G. C.; Glenadel, Q.; Lau, C.; et al. Org Lett. 2011; 13: 208-211; b. Wong, Y. C.;
Parthasarathy, K.; Cheng, C. H. Org Lett. 2010; 12: 1736-1739; c. Zhou, C.; Larock, R. C. J Org
Chem. 2006; 71: 3551-3558; d. Zhao, B.; Lu, X. Org Lett. 2006; 8: 5987-5990; e. Zhao, B.; Lu, X.
Tetrahedron Lett. 2006; 47: 6765-6768; f. Ueura, K.; Satoh, T.; Miura, M. Org Lett. 2005; 7:
2229-2231.
5. Hsieh, J. C.; Chen, Y.-C.; Cheng, A.-Y.; et al. Org Lett. 2012; 14: 1282-1285.
6. Lindh, J.; Sjöberg, P. J. R.; Larhed, M. Angew Chem Int Ed. 2010; 49: 7733-7737.
7. Zhou, C.; Larock, R. C. J Am Chem Soc. 2004; 126: 2302-2303.
8. Wang, X.; Huang, Y.; Xu, Y.; et al. J Org Chem. 2017; 82: 2211-2218.
9. a. Wang, Y.; Chen, C.; Peng, J.; et al. Angew Chem Int Ed. 2013; 52: 5323-5327; b. Wang, Y.;
Chen, C.; Zhang, S.; et al. Org Lett. 2013; 15: 4794-4797.
10. Yan, Y.; Zhang, Z.; Wan, Y.; et al. J Org Chem. 2017; 82: 7957-7963.
11. a. Ma, C.; Li, Y.; Niu, S.; et al. J Nat Prod. 2011; 74: 32-37; b. Roullier, C.; Chollet-Krugler, M.;
Weghe, P. v. d.; et al. Med Chem Lett. 2010; 20: 4582-4586; c. Frank, E.; Mucsi, Z.; Zupko, I.; et
al. J Am Chem Soc. 2009; 131: 3894-3904.
12. a. Hariprasad, K. S.; Prasad, K. V.; Raju, B. C. Rsc Adv. 2016; 6: 108654-108661; b. Ferwanah,
A.-R.; Awadallah, A. Molecules. 2005; 10: 492; c. Léavai, A. Chem. 2002; 39: 1-13.
23

ACCEPTED MANUSCRIPT
13. Ma, C.; Zhang, J.; Li, J.; et al. Chem Commun. 2015; 51: 5732-5734.
14. a. Park, J.; Kim, S. Y.; Kim, J. E.; et al. Org Lett. 2014; 16: 178-181; b. Zhan, F.; Liang, G. Ange
Che Int Ed. 2013; 52: 1266-1269; c. Park, I. K.; Suh, S. E.; Lim, B. Y.; et al. Org Lett. 2009; 11:
5454-5456.
15. a. Chauhan, P.; Ravi, M.; Singh, S.; et al. Rsc Adv. 2016; 6: 109-118; b. Patil, P.; Nimonkar, A.;
Akamanchi, K. G. J Org Chem. 2014; 79: 2331-2336; c. Chauhan, P.; Ravi, M.; Singh, S.; et al.
Rsc Adv. 2014; 4: 43336-43340; d. Yao, P. Organomet Chem. 2014; 28: 194-197.
16. Zhao, Y. W.; Song, Q. L. Chem Commun. 2015; 51: 13272-13274.
17. a. Liu, Z.; Ji, H.; Gao, W.; et al. Chem Commun. 2017; 53: 6259-6262; b. Liu, Y.; Zhang, G.;
Huang, H. Org Lett. 2017; 19: 6674-6677; c. Zhang, F.; Zheng, D.; Lai, L.; et al. Org Lett. 2018;
20: 1167-1170.
18. a. Rao, C. B.; Yuan, J.; Zhang, Q.; et al. J Org Chem. 2018; 83: 2904-2911; b. Hu, Z.; Dong, J.;
Men, Y.; et al. Chem Commun. 2017; 53: 1739-1742; c. Song, R. J.; Liu, Y.; Hu, R.-X.; et al. Adv
Synth Catal. 2011; 353: 1467-1473.
19. a. Wang, Q.; Zhang, X.; Fan, X. Org Biomol Chem. 2018; 16: 7737-7747; b. Wang, F.; Zhang, T.;
Tu, H. Y.; et al. J Org Chem. 2017; 82: 5475-5480.
20. a. Zhang, X.W.; Xiao, Z. F.; Zhuang, Y. J.; et al. Adv Synth Catal. 2016; 358: 1942-1945; b. Hao,
X H.; Gao, P.; Song, X. R.; et al. Chem Commun. 2015; 51: 6839-6842; c. Yang, X. H.; Ouyang, X.
H.; Wei, W. T.; et al. Adv Synth Catal. 2015; 357: 1161-1166; d. Liu, B.; Song, R. J.; Ouyang, X.
H.; et al. Chem Commun. 2015; 51: 12819-12822; e. Ji, Y. f.; Yan, H.; Jiang, Q.-b. Eur J Org
Chem. 2015; 2051-2060; f. Hu, M.; Liu, B.; Ouyang, X.H.; et al. Adv Synth Catal. 2015; 357:
3332-3340; g. Shen, T.; Yuan, Y.; Jiao, N. Chem Commun. 2014; 50: 554-556; h. Liu, Y.; Zhang, J.
24

ACCEPTED MANUSCRIPT
L.; Song, R. J.; et al. Angew Chem Int Ed. 2014; 53: 9017-9020; i. Miao, C. X.; Yu, B.; He, L. N.
Green Chem. 2011; 13: 541-544; j. Taniguchi, T.; Yajima, A.; Ishibashi, H. Adv Synth Catal. 2011;
353: 2643-2647; k. Koley, D.; Colón, O. C.; Savinov, S. N. Org Lett. 2009; 11: 4172-4175.
21. The reaction of 2i and 1a as the example, under the optimal conditions after 4 h: The yield of 3i:
31%, yield of 4i: 48%.
22. Compounds 3w and 3w’ were isolated in the ratio of Ca. 3:1. And complex mixture was formed
if we prolonged the reaction times.
23. a. Jursic, B. S.; Goldberg, S. I. J Org Chem. 1992; 57: 7172-717; b. The α value was measured
with a mixture of 3w and 5w in the ratio of 3:1. They are difficult to be separated because they have
same polarity. Please see the SI for more information.
24. a. Feng, M.; Tang, B.; Wang, N.; et al. Angew Chem Int Ed. 2015; 54: 14960-14964; b. Vetica, F.;
Pelosi, A.; Gambacorta, A.; et al. Eur J Org Chem.2014; 2014: 1899-N190; c. Xie, L. Y.; Duan, Y.;
Lu, L. H.; et al. Acs Sustain Chem Eng. 2017; 5: 10407-10412.
25. Astakhova, V. V.; Moskalik, M. Y.; Ganin, A. S.; et al. ChemistrySelect. 2018; 3: 5960-5964.
26. Zheng, L.; Zhou, Z. Z.; He, Y. T.; et al. J Org Chem. 2016; 81: 66-76.
27. a. Hou, Y.; Zhu, L.; Hu, H.; et al. New J Chem. 2018; 42: 8752-8755; b. Bao, Y.; Yang, X.; Zhou,
Q.; Yang, F. Org Lett. 2018; 20: 1966-1969; c. Taniguchi, T.; Imoto, M.; Takeda, M.; et al.
Synthesis-Stuttgart. 2017; 49: 1623-1631; d. Senadi, G. C.; Guo, B.-C.; Hu, W.-P.; et al. Chem
Commun. 2016; 52: 11410-11413; e. Hofmann, J.; Jasch, H.; Heinrich, M. R. J Org Chem. 2014;
79: 2314-2320.
28. Lin, J.; Yuan, S.; Song, X.; et al. Chinese J Org Chem. 2016; 36: 1790-1796.
29. a. Sanabria, C. M.; do Casal, M. T.; de Souza, R. B. A.; et al. Synthesis-Stuttgart. 2017; 49:
25

ACCEPTED MANUSCRIPT
1648-1654; b. Aihara, Y.; Chatani, N. ACS Catal. 2016; 6: 4323-4329; c. Hodgson, H. H.;
Marsden, E. J Chem Soc (Resumed). 1937; 1365-1366.
30. Álvarez-Calero, J. M.; Jorge, Z. D.; Massanet, G. M. Org Lett. 2016; 18: 6344-6347.
31. a. Liu, C.; Han, N.; Song X. X.; et al. Eur J Org Chem. 2010; 29: 5548-5551; b. Sergei, O.;
Kristyna, B.; Igor, Popa.; et al. Org Lett. 2015; 17: 180-183.
32. Zhang, Z. G.; Zhang, Y. C.; Huang, G. Q.; et al. Org Chem Front. 2017; 4: 1372-1375.
33. Luo, L.; Tao, K.; Peng, X.; et al. RSC Adv. 2016; 6: 104463-104466.
34. Kotha, S. S.; Badigenchala, S.; Sekar, G. Adv Synth Catal. 2015; 357: 1437-1445.
35. Vrijdag, J. L.; Delgado, F.; Borggraeve, W. M. D. Chem Commun. 2014; 50: 15094-15097.
36. Cailly, T.; Fabis, F.; Rault, S. Tetrahedron, 2006; 62: 5862-5867.
37. Chen, W. L.; Chen, C. Y.; Chen, Y. F.; et al. C. Org Lett. 2015; 17: 1613-1616.
38 Shugrue, C. R.; DeFrancisco, J. R.; Metrano, A. J.; et al. Org Biomol chem. 2016; 14: 2223-2227.
39. Bridger, G.; Skerlj, R.; Kaller, A.; et al. WO 2002034745. 2002
40. Prasad, D. J.; Sekar, G. Org Biomol Chem. 2013; 11: 1659-1665.
41. Redon, S.; Kabri, Y.; Crozet, M D.; et al. Tetrahedron Lett. 2014; 55: 5052-5054.
42. Xu, S.; Chen, H. H.; Dai, J. J.; et al. Org Lett. 2014; 16: 2306-2309.
43. Mori, A.; Akahoshi, I.; Hashimoto, M.; et al. Liq Cryst. 2010; 37: 1361-1372.
44. Chen, J.; Xiong, X.; Chen, Z.; et al. Synlett. 2015; 26: 2831-2834.
45. Yokoyama, A.; Maruyama, T.; Tagami, K.; et al. Org Lett. 2008; 10: 3207-3210.
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