Copper-Catalyzed N-Formylation of Amines through Tandem Amination/Hydrolysis/Decarboxylation Reaction of Ethyl Bromodifluoroacetate

Article abstract of DOI:10.1021/acs.joc.8b01555

Ethyl bromodifluoroacetate (BrCF₂COOEt) was first used as the N-formylating reagent in the copper-catalyzed N-formylation of amines. A range of primary, secondary, cyclic arylamines, and aliphatic amines underwent the N-formylation smoothly to furnish the N-formamides in moderate-to-excellent yields.

Full text of DOI:10.1021/acs.joc.8b01555

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Note
Copper-Catalyzed N-Formylation of Amines through Tandem Amination/
Hydrolysis/Decarboxylation Reaction of Ethyl Bromodifluoroacetate
Xiao-Fang Li, Xing-Guo Zhang, Fan Chen, and Xiao-Hong Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01555 • Publication Date (Web): 19 Sep 2018
Downloaded from http://pubs.acs.org on September 19, 2018
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Copper-Catalyzed N-Formylation of Amines
through Tandem
Amination/Hydrolysis/Decarboxylation
Reaction of Ethyl Bromodifluoroacetate
XiaoꢀFang Li, XingꢀGuo Zhang*, Fan Chen, XiaoꢀHong Zhang*
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College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou
325035, China. EꢀMail: zxg@wzu.edu.cn; kamenzxh@wzu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is
accepted if required according to the journal that you are submitting your paper
to)
Abstract
2
Ethyl bromodifluoroacetate (BrCF COOEt) was firstly used as the Nꢀformylating
reagent in the copperꢀcatalyzed Nꢀformylation of amines. A range of primary,
secondary, cyclic arylamines and aliphatic amines underwent the Nꢀformylation
smoothly to furnish the Nꢀformamides in moderate to excellent yields.
NꢀFormylation of amines is an important and useful reaction in synthetic
chemistry because this transformation provides direct access for the synthesis of
structurally diverse formamides, which are widely featured in natural products or
1
2
3
4
pharmaceuticals. For example, leucovorin, formoterol and orlistat contain the
formamide moiety. In addition, Nꢀformyl derivatives are very useful reagents in
5
Vilsmeier formylation reactions and often used as the precursor to provide isocyanide,
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formamidines, aryl amides, isocyanates, and nitriles. Generally, Nꢀformylation
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reaction of amines were commonly realized using formylating reagents such as formic
11
12
13
acid or formate, N, Nꢀdimethylformamide, acetic formic anhydride, ammonium
14
15ꢀ18
formate, and some special reagents.
In addition, in the presence of metal catalyst,
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paraformaldehyde and methanol
can also serve as the formylating reagents to
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provide Nꢀformamides. However, many Nꢀformylation reactions suffered from long
reaction time, high temperature and poor functional group tolerance. Therefore, the
development of new Nꢀformylating reagent for the formylation is still desirable.
As a cheap, stable and readily available chemical, ethyl bromodifluoroacetate
(BrCF
radical process, metalꢀcatalyzed coupling reactions or Reformatsky reactions.
Recently, Song’s group developed a radicalꢀinvolved method for the synthesis of
2
COOEt) was often used to construct various difluoroacetylated molecules via
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3,3ꢀdifluoroꢀ2ꢀoxindole derivatives using copperꢀcatalyzed difluoroacetylation of
24
2
aniline with BrCF COOEt via C–H activation followed by intramolecular amidation.
However, we accidentally found that ethyl bromodifluoroacetate could act as
Nꢀformylating reagent during our preparation of fluorinated compound. Herein, we
wished to report a copperꢀcatalyzed Nꢀformylation of arylamines using ethyl
bromodifluoroacetate as formyl source.
The reaction of Nꢀmethylaniline 1a with 2.0 equiv of ethyl bromodifluoroacetate
was chosen as the model reaction to optimize the reaction conditions (Table 1). Initially,
2 2
the reaction was conducted in the presence of 10 mol % Cu O, H O (6.0 eq.) and 1.0
o
equiv of K
2
CO
3
in dry MeCN at 110 C for 12h, product 2a was isolated in 32% yield
(
entry 1). Encouraged by these results, different solvents (entries 2ꢀ4), copper (I)
catalysts (entries 5ꢀ8), base (entries 9ꢀ11), some ligands (entries 12ꢀ15) were
investigated, respectively. The results showed that CuOAc, Cs CO and Xꢀphos were
the most suitable reagents for the NꢀFormylation, giving the target product 2a in 82%
entry 15). When the loading of BrCF COOEt was decreased to 1.5 equiv, the yield of
2
3
(
2
the formylating product 2a was reduced seriously (entry 16). It is well known that the
solvent N, Nꢀdimethylformamide (DMF) can also serve as a precursor to generate
12
formamides.
Therefore, the reaction of 1a was conducted in the absence of
BrCF
2
COOEt, but the reaction was totally kept intact, which suggested BrCF
2
COOEt
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really acted as the Nꢀformylating reagent (entry 17).
a
Table 1. Screening Conditions
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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Entry
Catalyst
Ligand
Base
Solvent
MeCN
DMF
1,4ꢀdioxane
DCE
Yield (%)
32
38
25
ND
35
29
20
53
32
1
2
3
4
5
6
7
8
9
Cu
Cu
Cu
Cu O
CuCl
2
2
2
O
O
O
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
K
K
K
2
2
2
CO
CO
CO
3
3
3
K CO3
2
2
2
K CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CuI
K
2
K
2
K
2
CO
CO
CO
3
3
3
CuOTf
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
Na
K
Cs
Cs
Cs
Cs CO3
Cs CO3
Cs
Cs
2
CO
PO
3
1
1
0
1
ꢀ
ꢀ
3
4
48
61
65
44
2
2
2
CO
CO
CO
3
3
3
12
13
14
15
16
17
Bpy
1,10ꢀphen
PPh3
Xꢀphos
Xꢀphos
Xꢀphos
72
2
82
2
b
2
CO
CO
3
51
c
2
3
DMF
ND
a
Reaction conditions: 1a (0.2 mmol), BrCF
2
COOEt (0.4 mmol), catalyst (0.02
O (1.2 mmol), dry solvent (2
mmol), ligand (0.04 mmol), base (0.2 mmol), H
mL), 110 °C, 12 h. isolated yield;
BrCF COOEt.
2
b.
c
2
BrCF COOEt (0.3 mmol); Without
2
With the optimal reaction conditions in hand, the substrate scope of a variety of
aromatic amines was next investigated (Table 2). Nꢀmethylanilines with both
electronꢀdonating and electronꢀwithdrawing groups underwent the Nꢀformylation
smoothly, affording the products 2b - 2m in moderate to good yields.
Nꢀ(4ꢀiodophenyl)ꢀNꢀmethylformamide 2g was also obtained in a moderate yield (52%),
which could provide potential handles for further modification. For metaꢀsubstituted
Nꢀmethylanilines, such as 3ꢀmethyl, 3ꢀmethoxy, 3ꢀchloro and 3ꢀbromo amine, the
Nꢀformylation occurred smoothly, giving the corresponding formamides 2j - 2m in
good yields. Unfortunately, the Nꢀformylation of Nꢀmethylanilines bearing orthoꢀ
group did not work owing to the steric hindrance.
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Subsequently, various Nꢀsubstituted anilines were evaluated and the results
demonstrated that steric effects had obvious influence on the formylating reaction
yields. For example, formamides 2n ꢀ 2s were isolated in lower yields (32ꢀ55%).
Nevertheless, ligand Bpy was more suitable for the formylation of
Nꢀ(3ꢀ(pꢀtolyl)propꢀ2ꢀynꢀ1ꢀyl)aniline 1t. Notably, cyclic arylamines 1u ꢀ 1y also
participated in the reaction well to give the desired formamides 2u ꢀ 2y in 61ꢀ80%
yields.
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a
Table 2. Scope with respect to the amine
a
Reaction conditions: 1 (0.2 mmol), BrCF
CO (1.0 eq.), H
2h; isolated yield; Bpy instead of Xꢀphos.
2
COOEt (0.4 mmol, 2.0 eq.), CuOAc (10
mol %), Xꢀphos (20 mol%), Cs
1
2
3
2
O (6.0 eq.), dry DMF (2 mL), 110 °C,
b
As for aromatic primary amines, methyl, methoxyl, tertꢀbutyl, fluoride, chloride,
bromide and trifluoromethyl substituted anilines 3a ꢀ 3h underwent the Nꢀformylation
successfully to furnish Nꢀphenylformamides 4a ꢀ 4h in 40ꢀ84% yields (Table 3).
Significantly, when the Nꢀformylation of aliphatic amine such as
Nꢀmethylꢀ2ꢀphenylethanamine 3i was carried out under the optimal conditions, the
formamide 4i was also obtained in 35% yield.
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a
Table 3. Scope with respect to the aromatic primary and aliphatic amines
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
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0
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2
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H
N
H
H
N
O
N
O
O
H C
3
H CO
3
4a, 55%
4b, 61%
4c, 75%
H
H
H
N
O
N
O
N
O
t-Bu
F
Cl
4
d, 84%
4e, 53%
4h, 40%
4f, 65%
H
H
N
CH3
N
O
N
O
O
Br
F3C
4g, 65%
4i, 35%
a
Reaction conditions: 3 (0.2 mmol), BrCF
2
COOEt (0.4 mmol, 2.0 eq.), CuOAc (10
O (6.0 eq.), dry DMF (2 mL), 110 °C,
mol %), Xꢀphos (20 mol%), Cs CO (1.0 eq.), H
2
3
2
12h; isolated yield.
To prove the reaction mechanism, some control experiments were conducted as
2
5
2
shown in Scheme 1. Another reagent, sodium bromodifluoroacetate (BrCF COONa)
was used as formyl source in the reaction with Nꢀmethyl aniline, the formamide 2a was
isolated in 65% yield (eq. 1, Scheme 1). In addition, amine 1u was conducted with
2
BrCF COOEt for 30 min, an aminated product 5 was obtained and identified (eq. 2).
The formylated product 2u could be obtained when the isolated compound 5 was
conducted under the standard reaction conditions (eq. 3). These results suggested that
the
amination/hydrolysis/decarboxylation process. Furthermore, 0.1 mL H
into the reaction using the anhydrous DMF as solvent, the product 2a was isolated in
Nꢀformylation
reaction
might
proceed
via
a
tandem
18
2
O was added
1
8
16
7
2 % yield with the ratio of O ꢀ2a: O ꢀ2a in 4:1 according to the GC results and
HRMS (eq. 4). These results suggested that the oxygen atom of Nꢀformylating group
might derive from the water.
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Scheme 1 Control experiments
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On the basis of the obtained experimental results, a plausible mechanism is
proposed for this Nꢀformylation (Scheme 2). Initially, BrCF COOEt undergoes the
amination reaction with Nꢀmethylaniline to furnish intermediate A in the presence
2
2
6
of CuOAc, Cs
2
CO
3
and Xꢀphos.
Subsequently, the defluorinative hydrolysis of
intermediate A affords intermediate oxoacetate B, which was proved in the control
experiment (eq. 2, Scheme 1). Oxoacetate B is further hydrolyzed to give the
oxoacetic acid C. Finally, the decarboxylation of intermediate C occurs to produce
2
7
the Nꢀformylated product 2a.
Scheme 2 Possible Mechanism
In conclusion, we have developed an efficient protocol of copperꢀcatalyzed
Nꢀformylation of amines using ethyl bromodifluoroacetate as the Nꢀformylating
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reagent. A variety of amines including primary, secondary and cyclic amines, can
participate in the Nꢀformylation smoothly under ambient conditions, giving a series
of Nꢀformamides in moderate to excellent yields. Control experiments suggest that
the
Nꢀformylation
might
proceed
via
the
tandem
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
5
5
5
5
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0
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amination/hydrolysis/decarboxylation process. The reaction represents the first
utilization of ethyl bromodifluoroacetate as the Nꢀformylating reagent.
Experimental Section
General Information:
1
Chemicals were either purchased or purified by standard techniques. H NMR
1
3
1
and C NMR spectra were measured on a 500 MHz spectrometer (500 MHz for H
13
1
and 125 MHz for C) or a 400 MHz spectrometer (400 MHz for H), using CDCl
3
as the solvent with tetramethylsilane (TMS) as an internal standard at room
temperature. Chemical shifts are given in δ relative to TMS, the coupling constants
J are given in Hz. High resolution mass spectra were recorded on an ESIꢀQꢀTOF
mass spectrometry. All reactions under air atmosphere were conducted using
standard Schlenk techniques. Melting points were measured on X4 melting point
apparatus and uncorrected after recrystallization from ethyl acetate. Column
chromatography was performed using EM Silica gel 60 (300ꢀ400 mesh).
General Procedure for the Synthesis of formamides derivatives 2a-2y, 4a-4i.
1
a-1y, 3a-3i (0.2 mmol), BrCF
2
COOEt (0.4 mmol), CuOAc (10 mol %),
(1.0 eq.) and H O (6.0 eq.) were added to a
Xꢀphos (20 mol%) (Bpy for 1t), Cs CO
2
3
2
Schlenk tube, and then solvent of dry DMF (2.0 mL) was added. The mixture was then
stirred at 110 °C for 12 h under air atmosphere. After the reaction was complete, the
mixture was poured into ethyl acetate and evaporated under vacuum. The resulting
crude product was purified by flash column chromatography on silica gel using
petroleum ether/ethyl acetate (10:1 to 5:1) as the eluent to give the pure products 2a-2y,
4a-4i.
Procedure for the Conversion of 5 to 2u.
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2
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2
2
2
2
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5
5
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5
6
5
2 3 2
(0.2 mmol), CuOAc (10 mol %), Xꢀphos (20 mol%), Cs CO (1.0 eq.), H O (6.0
eq.) and dry DMF (2.0 mL) were added to a Schlenk tube. The mixture was stirred at
110 °C for 2 h under air atmosphere, then 2 M HCl (1 mL) was added and heated for
another 12 h. After the reaction was finished, the mixture was poured into ethyl acetate
and evaporated under vacuum. The residue was purified by flash column
chromatography using petroleum ether/ethyl acetate (5:1) to afford the desired product
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2
u.
18f
NꢀmethylꢀNꢀphenylformamide (2a) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (22.2 mg, 82% yield). H NMR (400 MHz, CDCl
3
) δ 8.52 (s, 1H), 7.46 (t,
1
3
J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.2 Hz, 2H), 3.36 (s, 3H). C
NMR (125 MHz, CDCl ) δ 162.4, 142.4, 129.7, 126.5, 122.5, 32.2. GCꢀMS (EI, 70
3
eV) m/z (%) 134.75 (60.08), 105.85 (100.00), 93.85 (28.25), 78.90 (17.38), 77.90
(
9.21), 50.90 (14.94).
1
8f
NꢀmethylꢀNꢀ(pꢀtolyl)formamide (2b) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (25.3 mg, 85% yield). H NMR (500 MHz, CDCl
3
) δ 8.34 (s, 1H), 7.13 (d,
13
J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 3.21 (s, 3H), 2.28 (s, 3H). C NMR (125
3
MHz, CDCl ) δ 162.4, 139.8, 136.4, 130.2, 122.7, 32.3, 20.9. GCꢀMS (EI, 70 eV)
m/z (%) 148.75 (50.05), 119.90 (100.00), 107.85 (41.74), 79.90 (14.94), 64.90
(13.0).
1
8f
Nꢀ(4ꢀmethoxyphenyl)ꢀNꢀmethylformamide (2c)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
1
title compound as a Yellow oil (26.4 mg, 80% yield). H NMR (500 MHz, CDCl
3
) δ
8
3
.33 (s, 1H), 7.08 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H), 3.25 (s,
1
3
3
H). C NMR (125 MHz, CDCl ) δ 162.5, 158.4, 135.4, 124.8, 114.9, 55.7, 32.8.
GCꢀMS (EI, 70 eV) m/z (%) 164.75 (67.51), 121.90 (100.00), 107.90 (14.62), 93.90
25.27), 64.90 (13.88), 51.90 (6.12).
Nꢀ(4ꢀfluorophenyl)ꢀNꢀmethylformamide (2d)
(
1
8f
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
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title compound as a Yellow oil (24.2 mg, 79% yield). H NMR (500 MHz, CDCl
3
) δ
1
3
8
.38 (s, 1H), 7.15 ꢀ 7.13 (m, 2H), 7.11 ꢀ 7.08 (m, 2H), 3.28 (s, 3H). C NMR (125
MHz, CDCl ) δ 162.4, 161.6 (d, J = 245.0 Hz), 138.6, 124.9, 116.7 (d, J = 22.5 Hz),
2.7. GCꢀMS (EI, 70 eV) m/z (%) 152.75 (39.89), 123.85 (100.00), 111.85 (34.00),
4.80 (18.98), 74.90 (13.55), 50.90 (2.93).
3
3
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18f
Nꢀ(4ꢀchlorophenyl)ꢀNꢀmethylformamide (2e)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a Yellow solid (21.0 mg, 62% yield), m.p. 50 ꢀ 52 C
1
(uncorrected). H NMR (500 MHz, CDCl
3
) δ 8.40 (s, 1H), 7.31 (d, J = 8.5 Hz, 2H),
1
3
7
1
.04 (d, J = 8.5 Hz, 2H), 3.22 (s, 3H). C NMR (125 MHz, CDCl
3
) δ 162.0, 140.9,
32.2, 129.9, 123.7, 32.2. GCꢀMS (EI, 70 eV) m/z (%) 168.70 (56.11), 141.75
(
31.62), 139.80 (100.00), 127.80 (59.54), 74.90 (27.56), 50.95 (10.08).
18e
Nꢀ(4ꢀbromophenyl)ꢀNꢀmethylformamide (2f)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a White solid (26.0mg, 61% yield), m.p. 69 ꢀ 71 C (uncorrected).
1
3
H NMR (400 MHz, CDCl ) δ 8.45 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.05 (d, J =
1
3
8
3
.8 Hz, 2H), 3.29 (s, 3H). C NMR (125 MHz, CDCl ) δ 162.0, 141.4, 132.9,
1
23.9, 119.9, 32.1. GCꢀMS (EI, 70 eV) m/z (%) 214.60 (100.00), 212.60 (98.28),
85.65 (73.23), 183.65 (74.99), 104.90 (85.48), 76.90 (45.87).
1
2
8
Nꢀ(4ꢀiodophenyl)ꢀNꢀmethylformamide
(2g)
:
Purification
by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a White solid (27.1 mg, 52 % yield), m.p. 87 ꢀ 89 C
1
(
uncorrected). H NMR (400 MHz, CDCl
3
) δ 8.46 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H),
) δ 162.0, 142.1,
13
6
1
.93 (d, J = 8.8 Hz, 2H), 3.29 (s, 3H). C NMR (125 MHz, CDCl
3
38.9, 124.1, 90.6, 32.0. GCꢀMS (EI, 70 eV) m/z (%) 260.55 (100.00), 231.60
(
29.26), 219.55 (37.03), 130.85 (15.46), 105.90 (14.35), 76.95 (24.33), 50.95
(7.18).
1
8g
NꢀmethylꢀNꢀ(4ꢀ(trifluoromethyl)phenyl)formamide (2h) : Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a White solid (32.1 mg, 79% yield), m.p. 265 ꢀ 267 C
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
(
3
uncorrected). H NMR (400 MHz, CDCl ) δ 8.59 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H),
1
3
7
.29 (d, J = 8.4 Hz, 2H), 3.35 (s, 3H). C NMR (125 MHz, CDCl ) δ 162.0, 145.3,
3
128.4 (q, J = 32.5 Hz), 127.05, 124.0 (q, J = 268.8 Hz), 121.6, 31.8. GCꢀMS (EI, 70
eV) m/z (%) 202.65 (82.13), 173.70 (100.00), 144.70 (24.65), 133.80 (10.47), 94.85
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
14.66), 74.90 (11.38).
29
Nꢀ(4ꢀcyanophenyl)ꢀNꢀmethylformamide (2i)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a White solid (11.2 mg, 35% yield), m.p. 96 ꢀ 98 C (uncorrected).
1
H NMR (500 MHz, CDCl
3
) δ 8.66 (s, 1H), 7.73 ꢀ 7.69 (m, 2H), 7.30 ꢀ 7.28 (m,
H), 3.36 (s, 3H). C NMR (125 MHz, CDCl ) δ 161.5, 145.9, 133.7, 121.1, 118.1,
09.4, 31.3. GCꢀMS (EI, 70 eV) m/z (%) 159.80 (36.90), 130.85 (100.00), 103.90
1
3
2
1
3
(
19.83), 76.95 (13.68), 50.95 (7.64).
29
NꢀmethylꢀNꢀ(mꢀtolyl)formamide (2j) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (23.6 mg, 79% yield). H NMR (500 MHz, CDCl ) δ 8.47 (s, 1H), 7.32 ꢀ
3
7
.29 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 3.32 (s, 3H), 2.40
1
3
(
s, 3H). C NMR (125 MHz, CDCl
3
) δ 162.3, 142.2, 139.7, 129.4, 127.2, 123.1,
19.5, 32.0, 21.4. GCꢀMS (EI, 70 eV) m/z (%) 148.80 (62.26), 119.90 (100.00),
0.85 (33.40), 76.90 (18.33), 50.95 (7.19).
1
9
3
0
Nꢀ(3ꢀmethoxyphenyl)ꢀNꢀmethylformamide (2k)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a White solid (24.8 mg, 75% yield)，m.p. 305 ꢀ 307 C
1
(
uncorrected). H NMR (400 MHz, CDCl
3
) δ 8.50 (s, 1H), 7.33 ꢀ 7.29 (m, 1H), 6.82
ꢀ
6.80 (m, 1H), 6.77 ꢀ 6.75 (m, 1H), 6.70 ꢀ 6.69 (m, 1H), 3.82 (s, 3H), 3.30 (s, 3H).
1
3
C NMR (125 MHz, CDCl ) δ 162.4, 160.7, 143.6, 130.5, 114.7, 111.6, 108.8,
3
5
5.6, 32.2. GCꢀMS (EI, 70 eV) m/z (%) 164.75 (71.64), 136.85 (55.72), 95.90
(100.00), 76.95 (23.38).
1
8e
Nꢀ(3ꢀchlorophenyl)ꢀNꢀmethylformamide (2l)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
1
title compound as a Yellow oil (23.0 mg, 68% yield). H NMR (500 MHz, CDCl
3
) δ
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.50 (s, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.08 (d,
1
3
J = 8.0 Hz, 1H), 3.31 (s, 3H). C NMR (125 MHz, CDCl ) δ 161.9, 143.5, 135.4,
3
130.7, 126.4, 122.3, 120.2, 31.9. GCꢀMS (EI, 70 eV) m/z (%) 168.70 (59.94),
1
41.75 (33.17), 139.80 (100.00), 127.80 (27.52), 99.85 (25.16), 76.95 (39.62).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
9
Nꢀ(3ꢀbromophenyl)ꢀNꢀmethylformamide (2m)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
1
title compound as a Yellow oil (29.4 mg, 69% yield). H NMR (500 MHz, CDCl
3
) δ
8
.49 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.12 (d,
1
3
J = 8.0 Hz, 1H), 3.30 (s, 3H). C NMR (125 MHz, CDCl
3
) δ 161.9, 143.6, 130.9,
1
2
29.3, 125.2, 123.2, 120.6, 31.9. GCꢀMS (EI, 70 eV) m/z (%) 214.60 (98.79),
12.60 (100.00), 185.65 (69.10), 183.65 (67.90), 105.90 (89.62), 76.95 (76.82).
18e
NꢀethylꢀNꢀphenylformamide (2n)
: Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (13.7 mg, 46% yield). H NMR (500 MHz, CDCl
3
) δ 8.35 (s, 1H), 7.40
(t, J = 8.0 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H), 3.85 (q, J =
1
3
7
1
.0 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H). C NMR (125 MHz, CDCl
3
) δ 162.0, 140.9,
29.6, 126.8, 124.3, 40.1, 13.0. GCꢀMS (EI, 70 eV) m/z (%) 148.80 (37.09), 120.85
(
40.59), 105.90 (100.00), 76.90 (40.21), 50.90 (14.75).
18e
NꢀallylꢀNꢀphenylformamide (2o)
: Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (16.4 mg, 51% yield). H NMR (500 MHz, CDCl
3
) δ 8.39 (s, 1H), 7.30
(
t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 5.80 ꢀ 5.72 (m,
1
3
1
3
H), 5.12 ꢀ 5.07 (m, 2H), 4.33 (d, J = 5.5 Hz, 2H). C NMR (125 MHz, CDCl ) δ
1
61.9, 141.2, 132.5, 129.6, 126.7, 123.6, 117.6, 47.9. GCꢀMS (EI, 70 eV) m/z (%)
60.75 (22.83), 132.75 (14.12), 131.85 (100.00), 105.90 (34.84), 103.90 (35.59),
6.90 (46.59), 50.90 (15.77).
1
7
3
1
NꢀphenylꢀNꢀ(propꢀ2ꢀynꢀ1ꢀyl)formamide (2p)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
1
title compound as a Yellow oil (16.9 mg, 53% yield). H NMR (500 MHz, CDCl
3
) δ
8
.34 (s, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 8.0 Hz,
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
2
1
H), 4.47 (d, J = 2.0 Hz, 2H), 2.15 (s, 1H). C NMR (125 MHz, CDCl
3
) δ 161.6,
40.3, 129.6, 127.2, 123.8, 78.3, 72.2, 34.4. GCꢀMS (EI, 70 eV) m/z (%) 158.75
(17.00), 157.80 (15.52), 131.85 (45.72), 129.85 (100.00), 105.90 (17.11), 103.90
29.78), 76.90 (61.63), 50.90 (23.12).
Nꢀ(cyanomethyl)ꢀNꢀphenylformamide Purification by column
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8e
(2q)
:
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
1
title compound as a Yellow oil (15.4 mg, 48% yield). H NMR (400 MHz, CDCl
3
) δ
8
.43 (s, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz,
1
3
2H), 4.68 (s, 2H). C NMR (125 MHz, CDCl
3
) δ 161.7, 139.0, 130.3, 128.4, 124.2,
1
14.9, 33.2. GCꢀMS (EI, 70 eV) m/z (%) 159.55 (36.06), 130.75 (44.99), 104.80
(
100.00), 103.85 (50.83), 91.80 (49.58), 76.90 (48.45), 50.90 (23.63).
32
N,Nꢀdiphenylformamide (2r) : Purification by column chromatography on silica
gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (12.6 mg, 32% yield). H NMR (500 MHz, CDCl
3
) δ 8.60 (s, 1H), 7.35 ꢀ
1
3
7.31 (m, 4H), 7.25 ꢀ 7.19 (m, 4H), 7.10 (d, J = 7.5 Hz, 2H). C NMR (125 MHz,
CDCl ) δ 160.9, 141.0, 138.9, 128.9, 128.3, 126.2, 126.0, 125.3, 124.3. GCꢀMS (EI,
0 eV) m/z (%) 196.75 (100.00), 167.80 (62.40), 166.85 (34.56), 103.90 (30.73),
6.95 (45.96), 50.95 (30.25).
3
7
6
19
NꢀbenzylꢀNꢀphenylformamide (2s) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (23.2 mg, 55% yield). H NMR (500 MHz, CDCl
3
) δ 8.46 (s, 1H), 7.25 ꢀ
1
3
7
.22 (m, 2H), 7.18 ꢀ 7.13 (m, 6H), 7.00 (d, J = 7.3 Hz, 2H), 4.90 (s, 2H). C NMR
(
125 MHz, CDCl ) δ 162.4, 141.1, 136.8, 129.6, 128.7, 128.0, 127.5, 126.9, 124.2,
3
4
6
8.9. GCꢀMS (EI, 70 eV) m/z (%) 210.75 (36.35), 90.90 (100.00), 76.95 (13.46),
4.95 (14.48), 50.95 (5.20).
NꢀphenylꢀNꢀ(3ꢀ(pꢀtolyl)propꢀ2ꢀynꢀ1ꢀyl)formamide (2t): Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a White solid (37.9 mg, 76% yield) ， m.p. 48 ꢀ 50 C
1
(
ꢀ
uncorrected). H NMR (400 MHz, CDCl
3
) δ 8.41 (s, 1H), 7.41 ꢀ 7.37 (m, 2H), 7.30
7.28 (m, 3H), 7.30 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H), 4.71 (s, 2H), 2.27
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(
s, 3H). C NMR (125 MHz, CDCl
3
) δ 161.8, 140.5, 138.6, 131.7, 129.7, 129.1,
+
1
27.2, 124.0, 119.4, 84.1, 83.1, 35.4, 21.5. HRMS (ESI) Calcd for C H NNaO
17 15
+
([M + Na] ) 272.1046, Found: 272.1038.
1
8e
Indolineꢀ1ꢀcarbaldehyde (2u) : Purification by column chromatography on silica
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
o
1
White solid (19.1 mg, 65% yield), m.p. 57 ꢀ 59 C (uncorrected). H NMR (400
MHz, CDCl ) δ 9.00 (major rotamer, s, 1H), 7.31 ꢀ 7.28 (m, 1H), 7.25 ꢀ 7.20 (m,
H), 7.11 ꢀ 7.07 (m, 1H), 4.11 (t, J = 8.5 Hz, 2H), 3.20 (t, J = 8.5 Hz, 2H). C NMR
(125 MHz, CDCl ) δ 159.4, 157.7, 141.4, 141.3, 132.1, 127.78, 127.75, 126.2,
25.0, 124.7, 124.4, 116.9, 109.6, 47.1, 44.8, 27.9, 27.4. GCꢀMS (EI, 70 eV) m/z
3
1
3
2
3
1
(
%) 146.80 (42.48), 117.90 (100.00), 90.90 (27.34), 64.90 (9.74), 50.90 (3.62).
33
2
ꢀmethylindolineꢀ1ꢀcarbaldehyde (2v) : Purification by column chromatography
on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound
1
as a Yellow oil (19.7 mg, 61% yield). H NMR (400 MHz, CDCl
3
) δ 8.89 (s, 1H),
7.23 ꢀ 7.12 (m, 3H), 7.06 ꢀ 7.02 (m, 1H), 4.77 ꢀ 4.42 (m, 1H), 3.35 ꢀ 3.33 (m, 1H),
1
3
2
1
5
1
3
3
.76 ꢀ 2.63 (m, 1H), 1.42 ꢀ 1.34 (m, 3H). C NMR (125 MHz, CDCl ) δ 159.5,
57.6, 140.6, 140.5, 130.8, 130.4, 127.7, 126.4, 125.1, 124.6, 124.4, 116.9, 109.7,
4.8, 53.3, 36.4, 36.0, 23.4, 20.5. GCꢀMS (EI, 70 eV) m/z (%) 160.80 (37.66),
17.90 (100.00), 90.90 (28.43), 64.90 (12.55), 50.90 (5.54).
3
2
,4ꢀdihydroquinolineꢀ1(2H)ꢀcarbaldehyde (2w)
:
Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
1
title compound as a Yellow oil (23.8 mg , 74% yield). H NMR (500 MHz, CDCl )
3
δ 8.69 (d, J = 8.5 Hz, 1H), 7.11 ꢀ 7.00 (m, 4H), 3.73 ꢀ 3.71 (m, 2H), 2.74 ꢀ 2.71 (m,
13
2
1
1
H), 1.88 ꢀ 1.86 (m, 2H). C NMR (125 MHz, CDCl
3
) δ 161.1, 137.4, 129.7, 129.0,
27.2, 124.6, 117.1, 40.4, 27.2, 22.4. GCꢀMS (EI, 70 eV) m/z (%) 160.80 (53.02),
31.85 (100.00), 117.90 (37.13), 76.95 (25.83), 50.90 (12.10).
3
4
2Hꢀbenzo[b][1,4]thiazineꢀ4(3H)ꢀcarbaldehyde (2x) : Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
o
title compound as a White solid (25.8 mg, 72% yield), m.p. 65 ꢀ 67 C (uncorrected).
1
3
H NMR (500 MHz, CDCl ) δ 8.60 (s, 1H), 7.22 ꢀ 7.20 (m, 1H), 7.12 ꢀ 7.10 (m,
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5
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13
2
H), 7.06 ꢀ 7.04 (m, 1H), 4.06 ꢀ 4.04 (m, 2H), 3.13 ꢀ 3.11 (m, 2H). C NMR (125
MHz, CDCl ) δ 161.2, 135.2, 127.6, 126.6, 125.9, 125.4, 120.7, 38.6, 27.4. GCꢀMS
3
(EI, 70 eV) m/z (%) 178.70 (67.41), 135.80 (100.00), 163.70 (29.87), 108.85
(
38.80), 76.95 (21.97), 50.95 (12.61).
Hꢀbenzo[b][1,4]oxazineꢀ4(3H)ꢀcarbaldehyde (2y) : Purification by column
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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4
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7
8
9
0
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2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4
2
chromatography on silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the
1
title compound as a Yellow oil (26.1 mg, 80% yield). H NMR (400 MHz, CDCl
3
) δ
8
.84 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H), 6.96 ꢀ 6.91 (m, 2H),
1
3
4.24 (t, J = 4.8 Hz, 2H), 3.93 (t, J = 4.8 Hz, 2H). C NMR (125 MHz, CDCl
3
) δ
61.0, 159.2, 145.7, 145.5, 125.8, 125.7, 125.1, 122.1, 121.5, 121.1, 118.2, 117.2,
16.5, 65.4, 65.1, 44.0, 37.7. GCꢀMS (EI, 70 eV) m/z (%) 162.75 (96.79), 117.90
1
1
(
64.25), 119.90 (100.00), 105.90 (36.20), 76.95 (33.02), 50.90 (25.82).
18e
Nꢀphenylformamide (4a) : Purification by column chromatography on silica gel
(
petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a Yellow
1
oil (13.3 mg, 55% yield). H NMR (500 MHz, CDCl ) δ 8.71 (s, 1H), 8.36 (s, 1H),
3
1
3
7
.80 (br, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.37 ꢀ 7.30 (m, 2H), 7.20 ꢀ 7.09 (m, 2H). C
NMR (125 MHz, CDCl ) δ 162.9, 159.3, 137.1, 136.9, 129.9, 129.2, 125.4, 124.9,
20.2, 119.0. GCꢀMS (EI, 70 eV) m/z (%) 120.85 (100.00), 92.85 (71.91), 65.90
53.31), 64.90 (23.80), 50.90 (7.46).
3
1
(
1
8f
NꢀpꢀTolylformamide (4b) : Purification by column chromatography on silica gel
(petroleum ether/ ethyl acetate = 7:1, v/v) affords the title compound as a White
o
1
solid (16.5mg, 61% yield), m.p. 53 ꢀ 55 C (uncorrected). H NMR (400 MHz,
CDCl ) δ 8.82 (d, J = 9.6 Hz, 0.5H), 8.63 (d, J = 11.2 Hz, 0.5H), 8.31 (s, 0.5H),
.01 (s, 0.5H), 7.42 (d, J = 8.4 Hz, 1H), 7.15 ꢀ 7.10 (m, 2H), 6.99 (d, J = 8.4 Hz,
3
8
1
1
1
3
H), 2.32 and 2.30 (s and s, 3H). C NMR (125 MHz, CDCl ) δ 163.2, 159.4,
3
35.2, 134.54, 134.48, 134.3, 130.3, 129.6, 120.3, 119.2, 20.9, 20.8. GCꢀMS (EI, 70
eV) m/z (%) 135.10 (50.44), 111.10 (13.87), 106.10 (100.00), 79.10 (13.58), 51.05
6.28).
(
1
8e
Nꢀ(4ꢀmethoxyphenyl)formamide (4c) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 7:1, v/v) affords the title compound as a
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Yellow oil (22.7 mg, 75% yield). H NMR (400 MHz, CDCl
3
) δ 8.49 (br, 1H), 8.29
(
s, 0.5H), 7.76 (s, 0.5H), 7.44 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.89 ꢀ
1
3
6.83 (m, 2H), 3.79 and 3.77 (s and s, 3H). C NMR (125 MHz, CDCl
57.7, 156.8, 130.1, 129.7, 122.0, 121.7, 115.0, 114.3, 55.7, 55.6. GCꢀMS (EI, 70
eV) m/z (%) 151.14 (100.00), 122.15 (16.02), 108.19 (92.05), 80.12 (32.40), 53.15
11.16).
Nꢀ(4ꢀ(tertꢀbutyl)phenyl)formamide column
3
) δ 159.3,
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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6
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8
9
0
1
2
3
4
5
6
7
8
9
0
(
35
(4d)
： Purification
by
chromatography on silica gel (petroleum ether/ ethyl acetate = 7:1, v/v) affords the
1
title compound as a Yellow oil (29.7 mg, 84% yield). H NMR (400 MHz, CDCl
3
) δ
8
.66 (s, 1H), 8.34 (br, 0.5H), 7.83 (br, 0.5H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 ꢀ 7.33
1
3
(
m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 1.31 and 1.30 (s and s, 9H). C NMR (125 MHz,
CDCl ) δ 163.0, 159.3, 148.6, 147.9, 134.5, 134.3, 126.7, 126.0, 120.0, 119.0, 34.5,
3
3
9
1.4. GCꢀMS (EI, 70 eV) m/z (%) 177.10 (26.50), 162.10 (100.00), 135.10 (25.64),
4.10 (12.24), 65.10 (8.82).
3
6
Nꢀ(4ꢀfluorophenyl)formamide (4e) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 7:1, v/v) affords the title compound as a
o
1
White solid (14.7 mg, 53% yield)，m.p. 63 ꢀ 65 C (uncorrected). H NMR (400
MHz, CDCl ) δ 8.59 (br, 0.5H), 8.36 (s, 0.5H), 8.16 (br, 0.5H), 7.53 ꢀ 7.49 (m, 1H),
3
1
3
7
2
.38 (s, 0.5H), 7.08 ꢀ 7.01 (m, 3H). C NMR (125 MHz, CDCl
3
) δ 161.8 (d, J =
48.8 Hz), 161.6, 159.8 (d, J = 236.3 Hz), 159.0, 132.97, 132.95, 122.0, 121.5,
116.7 (d, J = 22.5 Hz), 116.0 (d, J = 22.5 Hz). GCꢀMS (EI, 70 eV) m/z (%) 139.00
100.00), 111.15 (90.35), 84.16 (59.33), 83.00 (43.19), 57.10 (19.05).
(
3
6
Nꢀ(4ꢀchlorophenyl)formamide (4f) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 7:1, v/v) affords the title compound as a
o
1
White solid (20.2 mg, 65% yield)，m.p. 100 ꢀ 102 C (uncorrected). H NMR (400
MHz, CDCl ) δ 8.99 (s, 0.5H), 8.70 (s, 0.5H), 8.37 (s, 0.5H), 8.15 (s, 0.5H), 7.52 (d,
J = 8.4 Hz, 1H), 7.35 ꢀ 7.28 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H). C NMR (125 MHz,
CDCl ) δ 162.9, 159.5, 135.6, 135.5, 130.9, 130.0, 129.9, 129.2, 121.5, 120.2.
GCꢀMS (EI, 70 eV) m/z (%) 155.01 (84.32), 129.26 (33.56), 127.00 (100.00), 99.00
19.05), 92.18 (28.36).
3
1
3
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Nꢀ(4ꢀbromophenyl)formamide (4g)
Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 7:1, v/v) affords the title compound as a
o
1
White solid (25.9 mg, 65% yield)，m.p. 114 ꢀ 116 C (uncorrected). H NMR (400
MHz, DMSO) δ 10.36 (br, 1H), 8.32 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.53 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
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7
8
9
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
8
.8 Hz, 2H). C NMR (125 MHz, CDCl ) δ 167.7, 165.0, 143.1, 142.8, 137.3,
3
1
36.9, 126.4, 124.6, 120.6, 120.4. GCꢀMS (EI, 70 eV) m/z (%) 198.9 (100.00),
73.31 (81.45), 171.49 (83.65), 92.16 (55.23), 65.16 (54.32).
1
1
8e
Nꢀ(4ꢀ(trifluoromethyl)phenyl)formamide (4h)
: Purification by column
chromatography on silica gel (petroleum ether/ ethyl acetate = 7:1, v/v) affords the
o
title compound as a White solid (15.1 mg, 40% yield)，m.p. 191 ꢀ 193 C
1
(
uncorrected). H NMR (400 MHz, CDCl
3
) δ 8.83 (br, 1H), 8.60 and 8.44 (s and s,
13
1
H), 7.68 (d, J = 8.8 Hz, 1H), 7.64 ꢀ 7.58 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H). C
3
NMR (125 MHz, CDCl ) δ 162.1, 159.2, 140.0, 127.3, 126.9 (q, J = 33.8 Hz),
1
26.6, 124.1 (q, J = 270.0 Hz), 119.8, 118.1. GCꢀMS (EI, 70 eV) m/z (%) 189.00
(100.00), 161.00 (67.99), 111.05 (79.21), 66.05 (25.58), 63.00 (15.44).
3
7
NꢀmethylꢀNꢀphenethylformamide (4i) : Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 7:1, v/v) affords the title compound as a
1
Colourless oil (11.4 mg, 35% yield). H NMR (400 MHz, CDCl
3
) δ 8.05 (s, 0.5H),
7
3
.83 (s, 0.5H), 7.36 ꢀ 7.31 (m, 2H), 7.28 ꢀ 7.25 (m, 2H), 7.17 (d, J = 7.2 Hz, 1H),
1
3
.60 and 3.50 (t and t, J = 7.2 Hz, 2H), 2.93 ꢀ 2.85 (m, 5H). C NMR (125 MHz,
) δ 162.7, 162.6, 138.7, 137.9, 128.9, 128.83, 128.78, 128.6, 126.9, 126.6,
1.3, 46.1, 35.1, 35.0, 33.3, 29.9. GCꢀMS (EI, 70 eV) m/z (%) 163.10 (22.86),
04.10 (82.83), 91.05 (13.51), 72.10 (100.00), 51.05 (3.99).
CDCl
3
5
1
Ethyl 2ꢀ(indolinꢀ1ꢀyl)ꢀ2ꢀoxoacetate (5): Purification by column chromatography on
silica gel (petroleum ether/ ethyl acetate = 10:1, v/v) affords the title compound as a
1
Yellow oil (5.7 mg, 13% yield). H NMR (400 MHz, CDCl
3
) δ 8.25 (d, J = 8.0 Hz,
1H), 7.31 ꢀ 7.27 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 4.29 (t,
1
3
J = 8.4 Hz, 2H), 3.26 (t, J = 8.3 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H). C NMR (125
MHz, CDCl ) δ 161.8, 157.7, 141.7, 132.0, 127.7, 125.2, 124.7, 117.9, 62.3, 48.5,
8.3, 14.0. HRMS (ESI) Calcd for C12
3
+
+
2
3
H13NNaO ([M + Na] ) 242.0788, Found:
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42.0792.
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Supporting Information Available: Copies of H and C NMR spectra for
product 2aꢀ2y, 4a-4i, and 5. These materials are available free of charge via the
Internet at http://pubs.acs.org.
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Acknowledgment. We thank the National Natural Science Foundation of China (No.
21302144 and 21272177) and Natural Science Foundation of Zhejiang Province (No.
LR15B020002) for financial support.
References:
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(
of 1ꢀFormylꢀ1,2ꢀdihydroquinoline Derivatives by a Lewis AcidꢀCatalyzed Cyclization
of oꢀ(1ꢀHydroxyꢀ2ꢀalkenyl)phenyl Isocyanides. Chem. Lett. 1995, 24, 575ꢀ576. (b) Fu,
P. P.; Boyer, J. H. Dehydrogenation of Secondary Formamides. J. Chem. Soc. Perkin
Trans. 1 1974, 19, 2246ꢀ2250.
0
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9
0
(10) Arlt, D.; Klein, G. Preparation of Nitriles From Formamides. U. S Patent 4419297,
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Krishnaiah, M.; Balasubramanyam, P.; Veeranjaneyulu, B.; Kumar, D. N. A
Remarkably Simple NꢀFormylation of Anilines using Polyethylene Glycol.
Tetrahedron Lett. 2008, 49, 2225ꢀ2227. (d) Rahman, M.; Kundu, D.; Hajra, A.; Majee,
o
A. Formylation without Catalyst and Solvent at 80 C. Tetrahedron Lett. 2010, 51,
2
2
896ꢀ2899. (e) Hill, D. R.; Hsiao, C. N.; Kurukulasuriya, R.; Wittenberger, S. J.
,2,2ꢀTrifluoroethyl Formate: A Versatile and Selective Reagent for the Formylation of
Alcohols, Amines, and NꢀHydroxylamines. Org. Lett. 2002, 4, 111ꢀ113. (f) Mona, H. S.;
Hashem, S. ZnO as a New Catalyst for NꢀFormylation of Amines under SolventꢀFree
Conditions. J. Org. Chem. 2006, 71, 6652ꢀ6654. (g) Luca, L. D.; Giacomelli, G.;
Porcheddu, A.; Salaris, M. A New, Simple Procedure for the Synthesis of Formyl
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Thermal and Microwaveꢀassisted NꢀFormylation using SolidꢀSupported Reagents.
Tetrahedron Lett. 2005, 46, 955ꢀ957.
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NꢀFormylation and NꢀAcylation of Amines. Org. Lett. 2017, 19, 2078ꢀ2081. (b)
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Vishwakarma, R. A.; Sawant, S. D. A Metalꢀfree Approach for Transamidation of
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Amides with Amines in Aqueous Media. Tetrahedron Lett. 2015, 56, 4775ꢀ4779.
(
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