Copper promoted aerobic oxidative c(sp3)-c(sp3) bond cleavage of n-(2-(pyridin-2-yl)-ethyl)anilines

Article abstract of DOI:10.1021/acs.joc.9b02919

A strategy of aerobic oxidative C(sp³)-C(sp³) bond cleavage of N-ethylaniline derivatives bearing azaarenes for the synthesis of N-aryl formamides has been developed. This approach was carried out smoothly with the CuI/TEMPO/air system to give N-aryl formamides in yields of 50-90%. With this methodology, a mutagenically active compound was constructed in 90% yield. Moreover, the reaction also provided a one-pot synthetic tool for accessing a promoter of hematopoietic stem cells by difunctionalization in 61% yield.

Full text of DOI:10.1021/acs.joc.9b02919

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Note
Copper Promoted Aerobic Oxidative C(sp3)-C(sp3)
Bond Cleavage of N-(2-(Pyridin-2-yl)-ethyl)anilines
Yang Yu, Yong Zhang, Chengyu Sun, Lei Shi, Wei Wang, and Hao Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02919 • Publication Date (Web): 15 Jan 2020
Downloaded from pubs.acs.org on January 15, 2020
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Copper Promoted Aerobic Oxidative C(sp3)-C(sp3) Bond
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Cleavage of N-(2-(Pyridin-2-yl)-ethyl)anilines
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Yang Yu,† Yong Zhang,† Chengyu Sun,† Lei Shi,§ Wei Wang†,‡,* and Hao Li†,*
†State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy,
East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
‡Department of Pharmacology and Toxicology, and BIO5 Institute, University of Arizona, 1703 E. Mabel St., P. O. Box
210207, Tucson, AZ 85721-0207, USA
§Corporate R&D Division, Firmenich Aromatics (China) Co., Ltd., Shanghai, 201108, China
Supporting Information Placeholder
0.8 equiv CuI
2.0 equiv DBU
2.0 equiv TEMPO
65 oC, toluene
GWE
H
N
N
O
Ar
Ar
Ar
N
N
or
N
H
H
H
NO2
EWG = NO2 or CN
air
23 examples
up to 90% yield
aromatic secondary
amines
ABSTRACT: A strategy of aerobic oxidative C(sp3)-C(sp3) bond cleavage of N-ethylaniline derivatives bearing azaarenes for the
synthesis of N-aryl formamides has been developed. This approach was carried out smoothly with the CuI/TEMPO/air system to
give N-aryl formamides in yields of 50 to 90%. With this methodology, a mutagenically active compound was constructed in 90%
yield. Moreover, the reaction also provided a “one-pot” synthetic tool for accessing a promoter of hematopoietic stem cells by
difunctionalization in 61% yield.
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C(sp3)-C(sp3) bond activation is gaining increasing attention in organic synthesis. Although many
examples of strained C(sp3)-C(sp3) bond activation have been reported,1 the activation of unstrained
C(sp3)-C(sp3) bond is still a challenging subject due to the high bond-dissociation energy and lack of
selectivity.2 Recently, several strategies to cleave inert C(sp3)-C(sp3) bonds have been developed:
-elimination,3 oxidative cleavage,4 reductive scission,5 cross alkane metathesis6 and nucleophilic
substitution.7 Among them, the oxidative cleavage of C(sp3)-C(sp3) bonds adjacent to tertiary
aliphatic amines is of particular interest as the generated electrophilic iminium ions may serve as a
reactive intermediate to install a broad range of complex structures. For example, Wang reported
that Bu4NI and TBHP promoted oxidative functionalization of tertiary amines to synthesize
methylene-bridged bis-1,3-dicarbonyl compounds.8 In addition, Opatz demonstrated the -bond
fragmentation of 1-benzyl-1,2,3,4-tetrahydroisoquinolines.9 Wang and co-workers realized the
C(sp3)-C(sp3) bond cleavage of 1,2-diamines by a photocatalytic system to obtain iminium ions and
C-radicals (Scheme 1, eq 1),10 and Sarpong developed a new approach for the cleavage of inert
C(sp3)-C(sp3) bond via silver-mediated ring-opening fluorination from N-acyl (Bz) unstrained cyclic
amines in 2018 (Scheme 1, eq 2).11 Very recently, a copper-catalyzed selective cleavage of
C(sp3)-C(sp3) single bonds within amines using high pressure air has been developed by Beller’s
group.12 However, in contrast to tertiary aliphatic amines and N-Bz aliphatic secondary amines,
unprotected secondary aromatic amines are able to form stable N,N,-diphenylhydrazines by a
dehydrogenative homocoupling reaction under oxidative conditions13 (we also found this
phenomenon in our study). Additionally, they can easily bind the transition metal catalysts and
inhibit catalytic cycles.14 The scission of unstrained C(sp3)-C(sp3) bonds in the presence of adjacent
secondary aromatic amines is unprecedented.
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Scheme 1. The C(sp3)-C(sp3) bond cleavage strategies of amines.
5
6
1) Wang's work
5 mol % Ru(bpy)3Cl2
silica gel
5.0 equiv H2O
O
7
8
9
N
N
N
1.0 equiv Cs2CO3
MeCN, rt, 60 h,1 atm O2
visible light
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symmetric aliphatic
diamines
2) Sarpong's work
4.0 equiv Selectfluor
4.0 equiv AgBF4
N
Bz
N
O
Bz
acetone: H2O (1:9)
40 oC, 1 h
F
N-Pg aliphatic amines
3) This work
H
0.8 equiv CuI
2.0 equiv DBU
2.0 equiv TEMPO
H
N
N
O
N
65 oC, toluene
NO2
air
aromatic secondary
amines
Although the C(sp3)-C(sp) and C(sp3)-C(sp2) bond cleavage of unprotected secondary aromatic
amine derivatives have been developed by Li and Wang respectively, 15-16 the C(sp3)-C(sp3) bond
cleavage of secondary aromatic amines has not been realized. Very recently, we introduced a
copper-promoted intramolecular C-H oxidative amination reaction for the synthesis of aziridine
derivatives.17 In this C-N bond formation reaction, a radical was proposed to form at the benzylic
position of azaarenes followed by the annulation with secondary amines. In the continuation of our
research concerning potential divergent synthetic methodologies and C-C bond functionalization,18
we questioned whether the substrates could be oxidized to enamine intermediates and then react with
molecular oxygen to form 1,2-dioxetanes. Afterwards, C(sp3)-C(sp3) bond and O-O bond cleavage
lead to N-aryl formamides, which have been widely employed in the preparation of bioactive
compounds and fine chemical intermediates (Scheme 1, eq 3).19 Herein, we reported the cleavage of
unstrained C(sp3)-C(sp3) bond adjacent to aromatic secondary amines to synthesize N-aryl
formamides with air as the terminal oxidant under mild condition.
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Table 1: Optimization of Reaction Conditions of C(sp3)-C(sp3) bond cleavage.a
5
6
7
8
H
H
0.8 equiv copper
2.0 equiv TEMPO
N
N
O
N
2.0 equiv base
solvent, 65 oC, air
NO2
1a
2a
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entry
1
copper
CuI
base
solvent
dioxane
DMSO
DMF
yield (%)b
36
DBU
DBU
DBU
DBU
TBD
2
CuI
N.R.
8
3
CuI
4
CuI
toluene
toluene
78
5
CuI
N.R.
N.R.
N.R.
21
6
CuI
DMAP
DABCO
DBU
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7
CuI
8
Cu(OAc)2
CuBr
CuI
9
DBU
72
10c
11d
12e
13f
DBU
51
CuI
DBU
62
CuI
DBU
65
CuI
DBU
23
a
A solution of 1a (0.2 mmol), copper salt (0.16 mmol) and TEMPO (0.4 mmol) with base (0.4 mmol) in the
solvent stated (1.5 mL) was stirred for 2 h at 65 oC. b Isolated yield. c 0.1 mmol CuI was used. d 0.1 mmol TEMPO
was used e Under O2 atmosphere. f The reaction was carried out at rt.
In an initial attempt on the formation of N-aryl formamides, a solution of aniline 1a (1.0 equiv) in
the presence of CuI (0.8 equiv), DBU (2.0 equiv) and TEMPO (2.0 equiv) in dioxane was stirred for
2 h at 65 °C. The desired formamide product 2a was obtained in 36% yield (Table 1, entry 1). Next,
the reaction conditions were optimized to improve the reaction yield. The solvent screening revealed
that polar aprotic solvent such as DMSO and DMF afforded the products in very poor yields (entries
2-3). In comparison, the nonpolar solvent toluene afforded a much higher yield (78%, entry 4). In
addition to DBU, other organic bases such as 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine
(TBD), 1,4-diazabicyclo[2.2.2]octane (DABCO), and N,N,-dimethylpyridin-4-amine (DMAP), were
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also examined in toluene but only gave trace amount of products (entries 5-7). When screening
different copper salts, Cu(OAc)2 was found much less effective (21%, entry 8) and CuBr gave
slightly lower yield than CuI (72%, entry 9). Lowering the loading of the copper salt or TEMPO also
decreased the reaction yields (entries 10-11). Additionally, when the reaction was carried out under
O2 atmosphere, the desired product was obtained in 65% yield (entry 12). Notably, the yield was
significantly lower at room temperature (23%, entry 13).
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Scheme 2. Scope of CuI-promoted synthesis of N-aryl formamides via C(sp3)-C(sp3) cleavage.a
0.8 equiv CuI
2.0 equiv DBU
2.0 equiv TEMPO
H
N
N
H
O
N
R
R
toluene, 65 o
air
C
EWG
O
EWG = NO2 or CN
2
1
H
H
H
N
H
N
O
N
O
N
O
F3C
F
Cl
2a
EWG = NO2, , 78%
2b
EWG = NO2, , 75%
2d
EWG = NO2, , 50 %
2c
EWG = NO2, , 80 %
H
O
H
N
N
H
H
O
O
N
O
N
F3CO
O
2h
EWG = NO2, ,71%
2e
EWG = NO2, , 80%
2f
EWG = NO2, , 51%
2g
EWG = NO2, , 79%
H
N
H
O
H
H
O
N
O
N
O
N
O
S
F
2i
EWG = NO2, , 83%
2k
2l
EWG = NO2, , 84%
EWG = NO2, , 68%
2j
EWG = NO2, , 61%
H
H
H
O
N
H
O
O
N
N
O
N
CF3
EWG = NO2, , 48%
Cl
2p
EWG = NO2, , 55%
2n
2o
EWG = NO2, , 71%
2m
, 65%
EWG = NO2,
H
O
N
H
H
O
N
O
N
H
N
O
N
2t
EWG = NO2, , 73%
2s
EWG = NO2, , 65%
2q
EWG = NO2, , 50 %
2r
EWG = NO2, , 77%
H
H
NO2 standard
condition
O
N
O
N
H
N
Ph
N
2a b
2a
, 56%
EWG = CN,
,
70%
N
1v
H
N
H
N
N
N
unsuccessful Ph
Ph
Ph
Ph
examples:
CO2Me
O
NO2
1y,
1x
, N.R.
N.R.
1w,
N.R.
a Reaction conditions: a solution of 1 (0.2 mmol), CuI (0.16 mmol), DBU (0.4 mmol) and TEMPO (0.4 mmol) in
toluene (1.5 mL) was stirred for 2 h at 65 oC. Isolated yield. b 6-(2-(Phenylamino)ethyl)nicotinonitrile 1u was used
as substrate.
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With the optimal reaction conditions established, we then examined the substrate scope of
CuI-promoted C(sp3)-C(sp3) activation process for the formation of N-aromatic formamides 2. As
shown in Scheme 2, almost all of the tested combinations produced the desired N-aromatic
formamides 2 with moderate to good isolated yields. The reaction has a high tolerance to
substituents on the para position of the phenyl ring: para-F, para-Cl, and para-Me only had a slight
impact on the yield (2b-2c, 2e). Even aniline 1d bearing a para-CF3 group reacted smoothly to
afford N-aromatic formamide 2d in 50% yield. Other anilines bearing various electron-donating
para-substituents on the phenyl ring were also suitable substrates for this protocol (2f-2k). Similarly,
we noted that the meta-substituted amines could also smoothly engage in this process to afford the
corresponding N-aromatic formamides 2l-2o in moderate to good yields. A steric effect was seen in
substrates bearing ortho-substituents: ortho-Me and ortho-Ph afforded the corresponding products in
moderate yields (2p-2q). Furthermore, the aniline with two substituents of the phenyl ring gave
N-formylation product 2r and 2s in 77% and 65% yields respectively. The reaction was also very
effective for the construction of N-heterocyclic formamide 2t in 73% yield. To further expand the
scope of the reaction, N-ethylaniline derivatives bearing functionalities different from para-nitro
azaarenes were investigated. By replacing NO2 in 1a with the slightly weaker electron-withdrawing
group CN (1u), the same product 2a was obtained in 70% yield. When switching from 1a to
N-(2-(3-nitropyridin-4-yl)ethyl)aniline (1v), the reaction still afforded the corresponding product 2a
in acceptable yield (56%). However, when methyl 6-(2-(phenylamino)ethyl)nicotinate 1w or
1-phenyl-3-(phenylamino)propan-1-one 1x were used as the starting substrates, no bond cleavage
was observed. When N-methyl-N-(2-(5-nitropyridin-2-yl)ethyl)aniline 1y was used as the starting
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substrate under the standard reaction condition, no N-methyl-N-phenylformamide was detected at all.
This revealed that the proton of N-H is also essential in this reaction.
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Scheme 3. The application of C(sp3)-C(sp3) bond cleavage process.
0.8 equiv CuI
2.0 equiv DBU
2.0 equiv TEMPO
O
O
NO2
O
toluene, 65 oC, air
90%
N
H
N
N
N
H
H
2z
1z
mutagenically active
O
0.8 equiv CuI
2.0 equiv DBU
2.0 equiv TMEPO
H
N
H
N
H
toluene, 65 oC, air
61%
O
NO2
1aa
2aa
promoter of HSC
Formamide substructures are frequently encountered in many bioactive compounds. To test the
applicability of our methodology, the mutagenically active molecule 2z was synthesized by this
C(sp3)-C(sp3) activation strategy.19b The process proceeded readily with higher yield than any other
reported method (90%). Furthermore, by unifying oxidative benzylic C-H cabonylation and
C(sp3)-C(sp3) activation in one-pot, we successfully realized the difunctionalization of 1aa to obtain
fluorenone formamide 2aa which has been used in maintaining and expanding of hematopoietic
stem cells (HSC) in 61% yield (Scheme 3).19f To test the practicality of this methodology, a
gram-scale reaction using substrate 1a was carried out to give product 2a in 70% yield.
Scheme 4. Control experiments.
0.8 equiv CuI
H
2.0 equiv DBU
2.0 equiv TEMPO
N
O
N
N
Ph
H
5.0 equiv H2O
toluene, 65 oC, air
N
N
Ph
NO2
1a
57%
NO2
CN
3a
Ph
0.8 equiv CuI
2.0 equiv DBU
H
N
N
N
N
N
N
Ph
Ph
toluene, 65 o
air
C
CN
1u
CN
4u
15%
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In order to understand the reaction mechanism, two control experiments were performed (Scheme
4). When 5.0 equiv of H2O was added into the reaction system under air atmosphere, the reaction
gave TEMPO addition product 3a in 57% yield, and no desired N-phenylformamide 2a was obtained.
The addition of H2O was thought to inhibit the formation of iminium intermediate. Additionally,
without the addition of TEMPO, N,N,-diphenylhydrazine 4u was formed by using 1u as the substrate
in 15% yield, indicating a vital role of TEMPO as an additive in the transformation.
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Scheme 5. The proposed mechanism for C(sp3)-C(sp3) bond cleavage.
TEMPO or O2
Cu(II) Cu(I)
H2O
O2N
O2N
Ph
Ph
N
N
N
N
H
I
1a
DBU
- H
O2N
O2N
+ H
Ph
Ph
N
N
N
N
H
II
III
O2
O2N
Ph
O
O2N
NH
Ph
+
N
H
N
H
N
CHO
O
O
5a
IV
2a
0.8 equiv CuI
2.0 equiv. DBU
2.0 equiv TEMPO
O2N
or
O2N
complex
mixture
N
6a
COOH
65 oC, toluene
air
N
5a
CHO
Although the details of this C(sp3)-C(sp3) bond cleavage remains uncertain, a plausible mechanism
is illustrated in Scheme 5. The iminium intermediate I is generated in the existence of copper salt
and oxidant (TEMPO or O2).16 With the strong electron withdrawing group NO2, intermediate I is
easily deprotonated to intermediate II by DBU. Enamine intermediate III is formed and reacts with
oxygen to form 1,2-dioxetane intermediate IV. Finally, the fragmentation of IV sequentially
underwent the C-C bond and O-O bond cleavage to furnish the desired product 2a.20 In addition, we
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tried to identify the pyridine component by using commercially available 5-nitropicolinaldehyde (5a)
and 5-nitropicolinic acid (6a) as reference standards. Unfortunately, neither 5a nor 6a was stable
under the standard conditions. However, a mass peak corresponding to 5a was detected in the study
of the reaction mixture (Supporting Information).
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In summary, we have developed an efficient copper-promoted oxidative cleavage of C(sp3)-C(sp3)
bond adjacent to secondary aromatic amines providing N-aromatic formamides. A wide scope of
substituents on the aniline portion was tolerated to give the products in moderate to good yields.
Both TEMPO and oxygen played very important roles in this reaction. The methodology has been
successfully applied for the synthesis of a mutagenically active molecule in 90% yield and a HSC
active molecule in 61% yield, respectively. Further exploration of this organic transformation and
the application of this methodology in the synthesis of more biologically relevant molecules are
underway in our laboratories.
EXPERIMENT SECTION
General Information
Unless otherwise noted, all reagents were obtained commercially and used without further
purification. Unless otherwise specified, all other reagents were purchased from Acros, Aldrich,
1
Fisher, Adamas-beta Co. Ltd. or TCI and used without further purification. H NMR spectra was
1
recorded at 400 MHz, 13C NMR spectra was recorded at 100 MHz. H NMR spectra was recorded
with tetramethylsilane (δ = 0.00 ppm) as internal reference; 13C NMR spectra was recorded with
CDCl3 (δ = 77.00 ppm) as internal reference. Chemical shifts were reported in parts per million
(ppm, δ) downfield from tetramethylsilane. Proton coupling patterns are described as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Chromatography was carried out
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with silica gel (200-300 mesh) using mixtures of petroleum ether (Bp 60-80 ºC) and ethyl acetate as
eluents. Mass Spectra were obtained from the mass spectrometry facility of East China University of
Science and Technology.
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General procedure for the preparation of substrates: To a solution of 5-nitro-2-vinylpyridine
(0.4 mmol, 120 mg) and aromatic amines 7 (0.8 mmol, 2 equiv) in toluene (2 mL) was added
Yb(OTf)3 (0.02 mmol, 12.4 mg). The resulting solution was stirred for 2 h at 65 oC by oil bath. After
the reaction was completed, the reaction mixture was directly purified by column chromatography
(petroleum ether: ethyl acetate = 20:1~4:1) to give the corresponding product. Other Michael
addition product was prepared according to the literature.17
4-(tert-Butyl)-N-(2-(5-nitropyridin-2-yl)ethyl)aniline(1f), yellowish solid, 87 mg (81%). Mp
84-86 °C. 1H NMR (400 MHz, CDCl3): δ 9.31 (d, J = 2.4 Hz, 1H), 8.31 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H), 7.29 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 3.53 (t, J = 6.0 Hz,
13
2H), 3.15 (t, J = 6.0 Hz, 2H), 1.20 (s, 9H) ppm. C{1H} NMR (100 MHz, CDCl3): δ 165.8, 144.2,
143.8, 141.8, 139.6, 130.3, 125.1, 122.5, 111.7, 42.2, 36.8, 32.8, 30.5 ppm. HRMS (EI-TOF) m/z
calcd for C17H21N3O2: 299.1634, found 299.1630.
4-Methoxy-N-(2-(5-nitropyridin-2-yl)ethyl)aniline(1g), yellowish solid, 94 mg (86%). Mp
69-71 °C. 1H NMR (400 MHz, CDCl3): δ 9.39 (d, J = 2.4 Hz, 1H), 8.38 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H), 7.36 (d, J = 8.4 Hz, 1H), 6.79 (m, 2H), 6.61 (m, 2H), 3.75 (s, 3H), 3.57 (t, J = 6.0 Hz, 2H), 3.21
(t, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 166.8, 152.4, 144.9, 142.8, 141.7,
131.4, 123.6, 115.0, 114.5, 55.8, 44.0, 37.7 ppm. HRMS (EI-TOF) m/z calcd for C14H15N3O3:
273.1113, found 273.1111.
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N-(2-(5-Nitropyridin-2-yl)ethyl)-4-(trifluoromethoxy)aniline(1h), orange solid, 99 mg (76%).
Mp 101-103 °C. 1H NMR (400 MHz, CDCl3): δ 9.39 (d, J = 2.8 Hz, 1H), 8.40 (dd, J1 = 8.4 Hz, J2 =
2.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.59 (m, 2H), 4.19 (brs, 1 H), 3.60 (t,
J = 6.0 Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 166.4, 146.5,
144.9, 142.9, 140.6, 131.5, 123.6, 122.5, 118.2 (JC-F = 253.7 Hz), 113.2, 43.0, 37.4 ppm. HRMS
(EI-TOF) m/z calcd for C14H12N3O3 F3: 327.0831, found 327.0832.
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N-(2-(5-Nitropyridin-2-yl)ethyl)-[1,1'-biphenyl]-4-amine(1i), yellow solid, 73 mg (57%). Mp
119-121 °C. 1H NMR (400 MHz, CDCl3): δ 9.41 (d, J = 2.8 Hz, 1H), 8.40 (dd, J1 = 8.4 Hz, J2 = 2.4
Hz, 1H), 7.53 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 2H), 7.44 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 2H), 7.41-7.36
(m, 3H), 7.27 (m, 1H), 6.70 (m, 2H), 4.15 (brs, 1H), 3.67 (t, J = 7.2 Hz, 2H), 3.15 (t, J = 6.4 Hz, 2H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 166.6, 147.0, 145.0, 142.9, 141.1, 131.5, 130.8, 128.7,
128.1, 126.3, 126.2, 123.6, 113.2, 42.6, 37.6 ppm. HRMS (EI-TOF) m/z calcd for C19H17N3O2:
319.1321, found 319.1322.
4-(Benzyloxy)-N-(2-(5-nitropyridin-2-yl)ethyl)aniline(1j), yellowish solid, 126 mg (80%). Mp
80-82 °C. 1H NMR (400 MHz, CDCl3): δ 9.39 (d, J = 2.4 Hz, 1H), 8.30 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H), 7.42- 7.31 (m, 6H), 6.85 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 4.99 (s, 2H), 3.57 (t, J =
6.0 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 166.8, 151.6, 144.9,
142.8, 142.0, 137.5, 131.4, 128.5, 127.8, 127.5, 123.6, 116.2, 114.3, 70.8, 43.9, 37.7 ppm. HRMS
(EI-TOF) m/z calcd for C20H19N3O3: 349.1426, found 349.1424.
4-(Methylthio)-N-(2-(5-nitropyridin-2-yl)ethyl)aniline(1k), yellowish solid, 61 mg (53%). Mp
76-78 °C. 1H NMR (400 MHz, CDCl3): δ 9.30 (d, J = 2.4 Hz, 1H), 8.29 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H), 7.26 (d, J = 8.4 Hz, 1H), 7.13 (m, 2H), 6.48 (m, 2H), 4.07 (brs, 1H), 3.50 (t, J = 6.0 Hz, 2H),
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3.13 (t, J = 6.0 Hz, 2H), 2.32 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 145.4, 143.8,
141.8, 130.4, 130.3, 123.7, 122.6, 112.5, 41.8, 36.4, 18.0 ppm. HRMS (EI-TOF) m/z calcd for
C14H15N3O2S: 289.0885, found 289.0883.
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2-Methyl-N-(2-(5-nitropyridin-2-yl)ethyl)aniline(1p), yellowish solid, 67 mg (65%). Mp 60-62
°C. 1H NMR (400 MHz, CDCl3): δ 9.30 (d, J = 2.4 Hz, 1H), 8.29 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H),
7.26 (d, J = 8.4 Hz, 1H), 7.05 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.59 (m, 2H), 4.00 (brs, 1H), 3.55 (t,
J = 6.4 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H), 2.00 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
165.8, 144.6, 143.7, 141.8, 130.4, 129.2, 126.1, 122.6, 122.5, 121.2, 116.2, 108.6, 41.8, 36.4, 16.4
ppm. HRMS (EI-TOF) m/z calcd for C14H15N3O2: 257.1164, found 257.1165.
N-(2-(5-Nitropyridin-2-yl)ethyl)-[1,1'-biphenyl]-2-amine(1q), yellowish solid, 73 mg (57%).
Mp 126-128 °C. 1H NMR (400 MHz, CDCl3): δ 9.20 (d, J = 2.8 Hz, 1H), 8.32 (dd, J1 = 8.4 Hz, J2 =
2.8 Hz, 1H), 7.42-7.34 (m, 3H), 7.28-7.23 (m, 4H), 7.07 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 6.80-6.76
(m, 2H), 3.61 (t, J = 6.4 Hz, 2H), 3.18 (t, J = 6.4 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
166.5, 144.7, 144.5, 142.7, 139.2, 131.3, 130.3, 129.4, 128.8, 128.7, 127.3, 123.5, 117.4, 110.6,
43.0, 37.3 ppm. HRMS (EI-TOF) m/z calcd for C19H17N3O2: 319.1321, found 319.1320.
3,4-Dimethyl-N-(2-(5-nitropyridin-2-yl)ethyl)aniline(1r), orange solid, 77 mg (71%). Mp 61-63
°C. 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.30 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.28 (d, J =
8.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.38 (m, 1H), 6.33 (dd, J1 = 8.0 Hz, J2 = 2.8 Hz, 1H), 3.52 (t, J
= 6.0 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H), 2.12 (s, 3H), 2.08 (s, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ 166.9, 145.7, 144.8, 137.5, 131.4, 130.3, 125.9, 123.6, 115.0, 110.5, 42.3, 37.8, 20.1, 18.7
ppm. HRMS (EI-TOF) m/z calcd for C15H17N3O2: 271.1321, found 271.1317.
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N-(2-(5-Nitropyridin-2-yl)ethyl)-5,6,7,8-tetrahydronaphthalen-1-amine(1s), yellow solid, 86
mg (72%). Mp 64-66 °C. 1H NMR (400 MHz, CDCl3): δ 9.38 (d, J = 2.8 Hz, 1H), 8.38 (dd, J1 = 8.4
Hz, J2 = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.51 (m, 2H), 4.04 (brs, 1H),
3.61 (t, J = 6.4 Hz, 2H), 3.25 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.32 (t, J = 6.4 Hz, 2H),
1.84 (m, 2H), 1.72 (m, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 166.9, 145.3, 144.8, 142.9,
137.9, 131.5, 126.1, 123.6, 121.4, 118.6, 106.8, 42.9, 37.5, 30.1, 23.8, 23.1, 22.7 ppm. HRMS
(EI-TOF) m/z calcd for C17H19N3O2: 297.1477, found 297.1476.
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N-(2-(5-Nitropyridin-2-yl)ethyl)quinolin-6-amine(1t), yellow solid, 66 mg (56%). Mp 129-131
°C. 1H NMR (400 MHz, CDCl3): δ 9.41 (d, J = 2.4 Hz, 1H), 8.62 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H),
8.39 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.38 (d, J
= 8.4 Hz, 1H), 7.29 (m, 1H), 7.08 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 3.73
(t, J = 6.4 Hz, 2H), 3.30 (t, J = 6.4 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 174.3, 166.4,
146.1, 145.6, 144.9, 143.0, 142.9, 134.0, 131.6, 130.1, 123.7, 121.5, 103.2, 103.1, 42.7, 37.1 ppm.
HRMS (EI-TOF) m/z calcd for C16H14N4O2: 294.1117, found 294.1118.
6-(2-(Phenylamino)ethyl)nicotinonitrile(1u), orange solid, 63 mg (70%). Mp 72-74 °C. 1H NMR
(400 MHz, CDCl3): δ 8.83 (d, J = 1.6 Hz, 1H), 7.85 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.17 (m, 1H),
6.71 (t, J = 1.6 Hz, 2H), 6.63 (m, 1H), 6.60 (m, 2H), 4.05 (br, 1H), 3.58 (t, J = 6.8 Hz, 2H), 3.16 (t, J
= 6.8 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 164.5, 152.2, 147.7, 139.5, 129.4, 123.5,
117.7, 116.8, 113.0, 107.7, 42.8, 37.8 ppm. HRMS (ESI-TOF) calcd for [M+H]+ C14H14N3 :
224.1188, found 224.1189.
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N-(2-(5-Nitropyridin-2-yl)ethyl)-4-phenoxyaniline(1z), orange solid, 84 mg (63%). Mp 111-113
°C. 1H NMR (400 MHz, CDCl3): δ 9.40 (d, J = 2.4 Hz, 1H), 8.40 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H),
7.38 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 7.29 (m, 2H), 7.00 (t, J = 8.8 Hz, 1H), 6.91 (m, 4H), 6.63 (m,
2H), 4.00 (brs, 1H), 3.60 (t, J = 6.0 Hz, 2H), 3.24 (t, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ 166.6, 159.0, 148.0, 144.9, 144.2, 142.9, 131.5, 129.5, 123.6, 122.0, 121.3, 117.1, 114.0,
43.5, 37.6 ppm. HRMS (EI-TOF) m/z calcd for C19H17N3O3: 335.1270, found 335.1269.
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N-(2-(5-Nitropyridin-2-yl)ethyl)-9H-fluoren-2-amine(1aa), orange solid, 27 mg (20%). Mp
154-156 °C. 1H NMR (400 MHz, CDCl3): δ 9.34 (d, J = 2.8 Hz, 1H), 8.31 (dd, J1 = 8.4 Hz, J2 = 2.8
Hz, 1H), 7.53 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H),
7.10 (m, 1H), 6.76 (m, 1H), 6.57 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 3.74 (s, 2H), 3.61 (t, J = 6.4 Hz,
2H), 3.18 (t, J = 6.4 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 165.6, 146.1, 144.2, 143.9,
141.2, 141.1, 131.3, 130.4, 125.6, 123.9, 123.7, 122.6, 119.7, 117.5, 111.1, 110.1, 108.4, 42.2, 36.6,
35.9 ppm. HRMS (EI-TOF) m/z calcd for C20H17N3O2: 331.1321, found 331.1317.
Typical procedure for synthesis of C(sp3)-C(sp3) bond cleavage product (2a as an example):
A 10 mL round bottom flask was equipped with magnetic stir bar and cooling coil was charged with
N-(2-(5-nitropyridin-2-yl)ethyl)aniline (1a, 0.2 mmol, 49 mg), toluene (1.5 mL). Then, DBU (0.4
mmol, 60 μL), TEMPO (0.4 mmol, 62 mg) and CuI (0.16 mmol, 38 mg) were added to the solution.
The reaction mixture was exposed to the open air and was stirred for 2 h at 65 oC by oil bath. After
the reaction was completed, the reaction mixture was directly purified by column chromatography
[100 g silica gel was treated with 2 mL aqua ammonia (25% m/m)] with petroleum ether/CH2Cl2 =
1:1 to give C(sp3)-C(sp3) bond cleavage product 2a in 78% yield.
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N-Phenylformamide(2a), yellow oil, 19 mg (78%). 1H NMR (400 MHz, DMSO-d6): δ 10.2 (brs,
0.78H), 8.78 (d, J = 11.2 Hz, 0.22H), 8.27 (d, J = 2.0 Hz, 0.60H), 7.59 (d, J = 7.6 Hz, 1.22H), 7.32
(t, J = 7.6 Hz, 1.66H), 7.19 (d, J = 7.6 Hz, 0.44H), 7.07 (q, J = 5.6 Hz, 0.84H) ppm. 13C{1H} NMR
(100 MHz, DMSO-d6): δ 163.0, 160.1, 138.7, 138.6, 129.8, 129.3, 124.1, 124.0, 119.6, 118.0 ppm.
The spectroscopic data matched that previously reported20b.
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N-(4-Fluorophenyl)formamide(2b), brown solid, 21 mg (75%). H NMR (400 MHz, CDCl3): δ
8.50 (d, J = 11.2 Hz, 0.40H), 8.29 (s, 0.58H), 7.74 (brs, 0.39H), 7.45 (m, 1.15H), 7.23 (m, 0.87H),
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7.01-6.93 (m, 2.57H) ppm. C{1H} NMR (100 MHz, CDCl3): δ 162.3, 159.4 (d, JC-F = 243.2 Hz),
158.7, 158.5 (d, JC-F = 242.7 Hz), 132.0, 131.8, 121.0, 120.0, 115.5 (d, JC-F = 22.8 Hz), 114.6 (d, JC-F
= 22.8 Hz) ppm. The spectroscopic data matched that previously reported21a.
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N-(4-Chlorophenyl)formamide(2c), yellow solid, 25 mg (80%). H NMR (400 MHz, CDCl3): δ
8.58 (d, J = 11.2 Hz, 0.41H), 8.30 (s, 0.60H), 8.12 (brs, 0.37H), 7.43 (m, 1.23H), 7.34-7.27 (m,
0.42H), 7.25-7.21 (m, 0.92H), 7.21-7.19 (m, 0.75H), 6.97 (m, 0.80H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δ 161.3, 157.9, 134.3, 134.2, 129.8, 129.7, 128.9, 128.1, 120.2, 119.1 ppm. The
spectroscopic data matched that previously reported21a.
N-(4-(Trifluoromethyl)phenyl)formamide(2d), brown solid, 19 mg (50%). 1H NMR (400 MHz,
CDCl3): δ 8.73 (m, 0.28H), 8.37 (brs, 0.61H), 7.62-7.51 (m, 2.59H), 7.19-7.12 (m, 0.55H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ 162.7, 159.7, 140.0, 139.9, 138.8, 126.3 (q, JC-F = 33.8 Hz),
126.4, 124.1 (q, JC-F = 270.0 Hz), 119.8, 117.9 ppm. The spectroscopic data matched that previously
reported21a.
N-p-Tolylformamide(2e), yellow solid, 22 mg (80%). 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J =
11.6 Hz, 0.49H), 8.38 (s, 0.92H), 7.42 (d, J = 8.0 Hz, 0.39H), 7.15 (t, J = 8.8 Hz, 0.98H), 7.11 (m,
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1.98H), 6.98 (d, J = 8.0 Hz, 1.09H), 2.33 (m, 3.00H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
163.0, 159.1, 135.1, 134.5, 134.3, 134.1, 130.2, 129.5, 120.1, 119.1, 20.9, 20.8 ppm. The
spectroscopic data matched that previously reported21a.
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N-(4-(tert-Butyl)phenyl)formamide(2f), yellow solid, 18 mg (51%). H NMR (400 MHz,
CDCl3): δ 8.58 (d, J = 11.2 Hz, 0.45H), 8.29 (s, 0.39H), 7.72 (br, 0.40H), 7.39 (d, J = 8.8 Hz,
0.82H), 7.29 (t, J = 8.8 Hz, 1.86H), 6.95 (d, J = 8.4 Hz, 0.94H), 1.24 (m, 9.00H) ppm.13C{1H} NMR
(100 MHz, CDCl3): δ 161.8, 158.0, 147.5, 146.8, 133.2, 133.0, 125.6, 124.9, 118.8, 117.8, 33.4,
33.3, 30.3, 28.7 ppm. The spectroscopic data matched that previously reported21a.
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N-(4-Methoxyphenyl)formamide(2g), yellow solid, 24 mg (79%). H NMR (400 MHz, CDCl3):
δ 8.43 (m, 0.46H), 8.26 (d, J = 1.6 Hz, 0.52H), 7.39 (brs, 0.47H), 7.38 (dd, J1 = 10.8 Hz, J2 = 2.4 Hz,
1.08H), 6.96 (dd, J1 = 6.4 Hz, J2 = 2.4 Hz, 1.01H), 8.84 (brs, 0.47H), 6.81-6.79 (m, 2.02H), 3.73 (m,
3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 161.8, 157.7, 156.7, 155.7, 128.8, 128.4, 120.8,
120.7, 113.9, 113.3, 54.6, 54.4 ppm. The spectroscopic data matched that previously reported21a.
N-(4-(Trifluoromethoxy)phenyl)formamide(2h), yellow oil, 29 mg (71%). 1H NMR (400 MHz,
CDCl3): δ 8.61 (d, J = 6.0 Hz, 0.37H), 8.33 (s, 0.62H), 8.03 (brs, 0.32H), 7.52 (d, J = 8.0 Hz, 1.28H),
7.31 (s, 0.64H), 7.15 (m, 2.00H), 7.05 (m, 0.75H) ppm.13C{1H} NMR (100 MHz, CDCl3): δ 162.2,
158.9, 154.5, 152.9, 147.0 (q, JC-F = 113.1 Hz), 145.7, 135.4, 135.3, 122.7, 121.9, 121.1, 119.1 (q,
JC-F = 253.3 Hz) ppm. The spectroscopic data matched that previously reported21b.
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N-([1,1'-Biphenyl]-4-yl)formamide (2i), yellow solid, 33 mg (83%). H NMR (400 MHz,
CDCl3): δ 8.65 (d, J = 11.6 Hz, 0.47H), 8.35 (d, J = 2.0 Hz, 0.53H), 7.56-7.49 (m, 5.50H), 7.39-7.35
(m, 2.06H), 7.30-7.26 (m, 1.11H), 7.08 (m, 1.45H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 161.2,
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157.8, 139.3, 139.0, 137.4, 136.8, 135.1, 134.8, 127.9, 127.7, 127.4, 126.7, 126.4, 126.2, 125.9,
125.8, 119.2, 118.1 ppm. The spectroscopic data matched that previously reported21b.
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N-(4-(Benzyloxy)phenyl)formamide(2j), yellow solid, 28 mg (61%). H NMR (400 MHz,
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CDCl3): δ 8.43 (d, J = 11.6 Hz, 0.44H), 8.21 (brs, 0.49H), 8.01 (d, J = 11.2 Hz, 0.40H), 7.37-7.24
(m, 6.74H), 6.95-6.83 (m, 3.01H), 4.96 (m, 2.00H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 162.2,
158.9, 145.7, 135.4, 135.3, 122.7, 121.9, 121.1, 119.1 (q, JC-F = 253.3 Hz) ppm. The spectroscopic
data matched that previously reported21c.
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N-(4-(Methylthio)phenyl)formamide(2k), yellow oil, 28 mg (84%). H NMR (400 MHz,
CDCl3): δ 8.58 (d, J = 8.0 Hz, 0.44H), 8.27 (s, 0.87H), 7.40 (d, J = 8.4 Hz, 1.25H), 7.19-7.15 (m,
2.22H), 6.96 (d, J = 8.4 Hz, 0.91H), 2.40 (m, 3.00H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
162.7, 159.4, 135.3, 134.5, 134.4, 134.2, 128.4, 127.9, 120.8, 119.7, 16.6, 16.5 ppm. The
spectroscopic data matched that previously reported21b.
N-(3-Fluorophenyl)formamide(2l), yellow oil, 19 mg(68%). 1H NMR (400 MHz, CDCl3): δ 8.63
(d, J = 11.2 Hz, 0.41H), 8.32 (brs, 0.58H), 7.58 (brs, 0.43H), 7.43 (m, 0.68H), 7.28-7.20 (m, 1.16H),
7.11 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 0.70H), 6.85-6.72 (m, 1.63H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ 163.3 (d, JC-F = 245.6 Hz), 162.9 (d, JC-F = 243.7 Hz), 162.8, 159.6, 138.5 (d, JC-F = 10.1
Hz), 138.4 (d, JC-F = 10.1 Hz), 131.2, 130.3, 115.3, 114.0, 112.1 (d, JC-F = 21.0 Hz), 111.6 (d, JC-F
=
21.0 Hz), 107.7 (d, JC-F = 26.1 Hz), 105.9 (d, JC-F = 26.1 Hz) ppm. The compound was reported
previously20b.
N-(3-Chlorophenyl)formamide(2m), yellow solid, 20 mg (65%). 1H NMR (400 MHz, CDCl3): δ
8.68 (m, 0.43H), 8.39 (brs, 0.59H), 7.80 (m, 0.40H), 7.67 (t, J = 2.0 Hz, 0.67H), 7.38 (d, J = 8.4 Hz,
0.76H), 7.31-7.28 (m, 0.37H), 7.25 (m, 0.49H), 7.18-7.12 (m, 1.04H), 6.97 (d, J = 8.4 Hz, 0.42H)
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ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 161.9, 158.8, 137.1, 137.0, 134.3, 133.5, 129.8, 129.1,
124.3, 123.8, 119.2, 117.7, 117.1, 115.6 ppm. The spectroscopic data matched that previously
reported21d.
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N-(3-(Trifluoromethyl)phenyl)formamide(2n), brown solid, 18 mg (48%). 1H NMR (400 MHz,
CDCl3): δ 8.68 (d, J = 11.2 Hz, 0.37H), 8.49 (brs, 0.34H), 8.35 (s, 0.62H), 7.77 (s, 0.63H), 7.68 (m,
1.16H), 7.45-7.21 (m, 2.71H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 162.3, 159.2, 137.4, 132.3
(q, JC-F = 32.7 Hz), 131.7, 131.3, 130.5, 129.7, 123.7 (q, JC-F = 270.8 Hz), 123.5 (q, JC-F = 270.7 Hz),
122.9, 121.9 (q, JC-F = 3.8 Hz), 121.7, 121.4 (q, JC-F = 3.8 Hz), 116.7 (q, JC-F = 3.8 Hz), 115.4 (q, JC-F
= 3.8 Hz) ppm. The spectroscopic data matched that previously reported21e.
N-m-Tolylformamide(2o), yellow oil, 19 mg (71%). 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J =
11.6 Hz, 0.54H), 8.78 (d, J = 1.2 Hz, 0.48H), 7.70 (brs, 0.49H), 7.41 (m, 0.50H), 7.30 (m, 0.50H),
7.23 (m, 0.93H), 7.01 (brs, 0.34H), 6.96 (d, J = 7.6 Hz, 1.04H), 6.88 (m, 1.08H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δ 162.4, 158.8, 139.9, 139.2, 136.7, 136.5, 129.6, 129.0, 126.1, 125.7, 120.6,
119.6, 117.0, 115.9, 21.5, 21.4 ppm. The spectroscopic data matched that previously reported21b.
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N-o-Tolylformamide(2p), brown solid, 15 mg (55%). H NMR (400 MHz, CDCl3): δ 8.48 (m,
0.62H), 8.37 (brs, 0.39H), 7.85 (d, J = 8.0 Hz, 0.39H), 7.16-7.01 (m, 3.80H), 2.23 (s, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ 163.9, 159.6, 135.2, 134.7, 131.3, 130.6, 130.1, 129.1, 127.1,
126.7, 126.1, 125.6, 123.3, 120.9, 17.7, 17.6 ppm. The spectroscopic data matched that previously
reported21b.
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N-([1,1'-Biphenyl]-2-yl)formamide(2q), yellow solid, 20 mg (50%). H NMR (400 MHz,
CDCl3): δ 8.62 (d, J = 11.2 Hz, 0.44H), 8.32 (d, J = 7.6 Hz, 0.52H), 8.23 (d, J = 2.0 Hz, 0.49H),
7.46-7.21 (m, 7.46H), 7.17-7.13 (m, 1.31H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 161.9, 158.9,
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137.8, 137.3, 133.8, 133.7, 132.9, 131.9, 131.2, 130.2, 129.3, 129.2, 129.1, 128.8, 128.7, 128.2,
128.1, 125.3, 124.6, 121.4, 121.3, 118.1 ppm. The spectroscopic data matched that previously
reported21f.
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N-(3,4-Dimethylphenyl)formamide(2r), yellow solid, 23 mg (77%). H NMR (400 MHz,
CDCl3): δ 8.62 (m, 0.49H), 8.33 (m, 0.45H), 8.23 (m, 0.45H), 7.43 (brs, 0.36H), 7.24 (m, 0.46H),
7.05 (m, 0.64H), 6.85 (m, 1.05H), 6.82 (t, J = 9.2 Hz, 1.14H), 2.23 (m, 6H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δ 162.9, 159.1, 138.2, 137.4, 134.6, 134.4, 133.8, 133.2, 130.7, 130.0, 121.4,
120.5, 117.5, 116.4, 19.9, 19.2, 19.1 ppm. The spectroscopic data matched that previously
reported21f.
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N-(5,6,7,8-Tetrahydronaphthalen-1-yl)formamide(2s), brown solid, 23 mg (65%). H NMR
(400 MHz, CDCl3): δ 8.52 (d, J = 11.2 Hz, 0.66H), 8.43 (s, 0.28H), 7.89 (m, 0.63H), 7.30 (d, J = 7.6
Hz, 0.29H), 7.12 (m, 1.25H), 6.96 (m, 1.62H), 2.79 (m, 2H), 2.61 (m, 2H), 1.85 (d, J = 5.6 Hz, 2H),
1.77 (d, J = 5.6 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 163.4, 159.1, 139.2, 138.3,
134.8, 134.3, 128.8, 127.7, 127.1, 126.6, 126.1, 125.9, 120.5, 117.9, 29.8, 29.7, 24.6, 24.5, 22.8,
22.7, 22.5, 22.4 ppm. HRMS (EI-TOF) m/z calcd for C11H13NO:175.0997, found 175.0999. The
compound was reported previously 21g
.
N-(Quinolin-6-yl)formamide(2t), black solid, 25 mg (73%). 1H NMR (400 MHz, CDCl3): δ 9.48
(d, J = 11.2 Hz, 0.21H), 9.33 (s, 0.46H), 8.85-8.73 (m, 0.97H), 8.43 (s, 0.50H), 8.36 (d, J = 2.4 Hz,
0.51H), 8.00 (d, J = 8.4 Hz, 0.97H), 7.93 (d, J = 5.2 Hz, 0.52H), 7.56 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz,
0.51H), 7.44 (m, 0.48H), 7.34 (m, 0.24H), 7.29 (q, J = 4.4 Hz, 0.51H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δ 162.9, 159.8, 149.7, 149.4, 145.8, 145.4, 136.2, 135.6, 135.4, 135.3, 131.2, 129.9,
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128.9, 123.3, 122.3, 122.2, 121.8, 116.8, 114.4 ppm. The spectroscopic data matched that previously
reported21h.
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N-(4-Phenoxyphenyl)formamide(2z), yellow solid, 38 mg (90%). 1H NMR (400 MHz, CDCl3): δ
8.51 (d, J = 11.6 Hz, 0.44H), 8.29 (d, J = 1.6 Hz, 0.56H), 7.62 (brs, 0.41H), 7.43(m, 1.18H), 7.26
(m, 2.05H), 7.23 (brs, 0.51H), 7.07-6.91 (m, 5.96H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ
162.6, 158.8, 157.3, 157.1, 155.1, 154.0, 132.2, 131.8, 129.9, 129.8, 123.6, 123.3, 121.8, 121.3,
120.1, 119.6, 118.8, 118.6 ppm. The spectroscopic data matched that previously reported19b.
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N-(9-oxo-9H-Fluoren-2-yl)formamide (2aa), brown solid, 27 mg (61%). H NMR (400 MHz,
DMSO-d6): δ 10.42 (s, 0.79H), 10.28 (d, J = 11.6 Hz, 0.21H), 8.85 (d, J = 11.2 Hz, 0.22H), 8.26 (m,
0.85H), 7.91 (d, J = 8.8 Hz, 0.21H), 7.86 (d, J = 1.6 Hz, 0.84H), 7.68-7.63 (m, 3.00H), 7.54-7.50 (m,
2.33H), 7.38-7.32 (m, 0.54H), 7.28-7.24 (m, 1.10H), 7.00 (m, 0.18H), 6.48 (m, 0.23H) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6): δ 192.8, 192.7, 162.5, 160.0, 144.0, 139.7, 139.4, 139.3, 138.7, 138.6,
135.5, 135.4, 134.6, 134.0, 133.4, 133.2, 128.7, 128.6, 124.7, 124.0, 122.8, 122.2, 121.8, 120.7,
114.7, 112.8 ppm. HRMS (EI-TOF) m/z calcd for C14H9NO2: 223.0633, found 223.0636. The
compound was reported previously 19f
.
Gram-scale reaction for the synthesis of 2a: A 50 mL round bottom flask was equipped with
magnetic stir bar and cooling coil was charged with N-(2-(5-nitropyridin-2-yl)ethyl)aniline (1a, 3.5
mmol, 0.85 g), toluene (12 mL). Then, DBU (7 mmol, 1.05 mL), TEMPO (7 mmol, 1.05 g) and CuI
(2.8 mmol, 0.53 g) were added to the solution. The reaction mixture was exposed to the open air and
o
was stirred for 2 h at 65 C by oil bath. After the reaction was completed, the reaction mixture was
directly purified by column chromatography [100 g silica gel was treated with 2 mL aqua ammonia
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(25% m/m)] with petroleum ether/CH2Cl2 = 1:1 to give C(sp3)-C(sp3) bond cleavage product 2a in
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6-(2-(phenylamino)ethyl)nicotinonitrile (1u, 0.2 mmol, 44.6 mg) in toluene (1.5 mL) was added
DBU (0.4 mmol, 60 μL) and CuI (0.16 mmol, 38 mg). The resulting solution was stirred for 2 h at
o
65 C under air atmosphere by oil bath. After the reaction was completed, the reaction mixture was
directly purified by column chromatography with petroleum ether/CH2Cl2 = 2:1 to give 4u in 15%
yield (6.8 mg).
6,6'-((1,2-Diphenylhydrazine-1,2-diyl)bis(ethane-2,1-diyl))dinicotinonitrile (4u), orange solid,
Mp 167-169 °C. 1H NMR (400 MHz, CDCl3): δ 8.70 (d, J = 2.0 Hz, 1H), 7.73 (dd, J1 = 8.0 Hz, J2 =
2.4 Hz, 1H), 7.15-7.09 (m, 3H), 6.77-6.69 (m, 3H), 3.84 (m, 2H), 3.16 (t, J = 7.6 Hz, 2H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ 163.7, 152.2, 148.0, 139.6, 129.4, 123.6, 119.1, 116.8, 113.0,
107.7, 49.4, 36.7 ppm. HRMS (ESI-TOF) calcd for [M+Na]+ C28H24N6Na : 467.1960, found
467.1961.
1
5-Nitropicolinaldehyde (5a), H NMR (400 MHz, DMSO-d6): δ 10.09 (d, J = 0.8 Hz, 1H), 9.56
13
(s, 1H), 8.81 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H) ppm. C{1H} NMR (100
MHz, DMSO-d6): δ 192.4, 155.7, 146.5, 145.8, 133.8, 122.9 ppm. The spectroscopic data matched
that previously reported22.
1
5-Nitropicolinic acid (6a), H NMR (400 MHz, DMSO-d6): δ 9.47 (bs, 1H), 8.76 (bs, 1H), 8.29
(bs, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 165.23, 153.4, 146.1, 145.1, 133.5, 125.8
ppm. The spectroscopic data matched that previously reported23.
ASSOCIATED CONTENT
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Supporting Information
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Experiment details and spectroscopic data. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
wwang@pharmacy.arizona.edu; hli77@ecust.edu.cn
Author Contributions
All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (21572054, 21572055 and
21738002), the program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher
Learning, the Fundamental Research Funds for the Central Universities and the China 111 Project (Grant B07023).
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