Mn(II)-Catalyzed N -Acylation of Amines

Article abstract of DOI:10.1055/s-0037-1610267

A practical protocol has been developed here for the Mn(II)-catalyzed N -acylation of amines with high yields using N, N -dimethylformamide and other amides as the carbonyl source. The protocol is simple, does not require any acid, base, ligand, or other additives, and encompasses a broad substrate scope for primary, secondary, and heterocyclic amines.

Full text of DOI:10.1055/s-0037-1610267

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
J. Ma et al.
Paper
Synthesis
Mn(II)-Catalyzed N-Acylation of Amines
R3
Juan Ma
O
R1
O
R
R3
R4
R1
Scalable;
No additive;
Mn-catalyzed reaction;
Broad substrate scope;
[Mn]
Jingyu Zhang
Hang Gong*
N
R4
N
R2
H N
+
+
H
N
R2
R
R1, R2, R3, R4 = H or alkyl; R = H, alkyl or aryl
Up to 99% yield
DMF and other amides as carbonyl source
The Key Laboratory for Green Organic Synthesis and Application
of Hunan Province; The Key Laboratory of Environmentally
Friendly Chemistry and Application of the Ministry of Education
College of Chemistry, Xiangtan University, Xiangtan 411105,
P. R of China
hgong@xtu.edu.cn
R1
Received: 28.02.2018
Accepted after revision: 11.08.2018
Published online: 04.09.2018
R1
H
X
R2
(A)
R2
DOI: 10.1055/s-0037-1610267; Art ID: ss-2018-f0450-op
C-H activation
(X = C or functional group)
R1
R2
R1
R2
O
O
R1
OH
S
R2
Abstract A practical protocol has been developed here for the Mn(II)-
catalyzed N-acylation of amines with high yields using N,N-dimethylfor-
mamide and other amides as the carbonyl source. The protocol is sim-
ple, does not require any acid, base, ligand, or other additives, and en-
R
OH
H
R1
R2 R1
OR2
OH
Mn
(B) Oxidation
(C) Reduction
R1
R2
R1
OH
R1
O
R
O
S O
compasses
a broad substrate scope for primary, secondary, and
R1
R2
R1
R2
R2
heterocyclic amines.
(D)
Polymerization
R1
+
polyolefin
R2
Key words synthetic methodology, N-acylation, manganese, amide,
catalytic reaction
R1
O
R1
Mn
O
(E)
R3
?
N
R2
H
N
R2
+
R
N
R4
N-acylation
R
Metal-catalyzed reactions have recently been well de-
veloped, with reliance on the noble metals for major ad-
vances.1 There is great interest in using earth-abundant, in-
expensive, and non-toxic metals to replace the noble metals
in catalytic reactions due to their sustainable development
and economic considerations. However, it is a considerable
challenge to use non-toxic metals because of their relatively
lower catalytic activity. In this respect, manganese, which is
known as the twelfth most abundant element in the Earth’s
crust and the third most abundant transition metal, has ex-
hibited low toxicity2 and low cost,3 and is strongly competi-
tive with traditional noble metal catalysts.4
Recently, many Mn-catalyzed organic reactions have
been developed, resulting in an upsurge in Mn-catalyzed
chemistry. Among them, the Mn-catalyzed C–H activation
reactions are some of the most widely investigated (Scheme
1, A).4a,5 Other Mn-catalyzed reactions, such as oxidation
(Scheme 1, B),6 reduction (Scheme 1, C),7 polymerization
(Scheme 1, D),8 and other types of reactions9 have also been
reported. Despite the considerable development of Mn-cat-
alyzed chemistry, the N-acylation of amines has not yet
been reported (Scheme 1, E).
Scheme 1 Mn-catalyzed reactions
N-Acylation of amines is a very important organic reac-
tion.10 Moreover, the amide building block is widely present
in pharmaceuticals, such as formoterol,11a lacosamide,11b
tetrahydrolipstatin,11c leucovorin,11d natural products,11e
and functional materials11f (Figure 1). Several carbonyl
sources, such as N,N-dimethylformamide (DMF)/N,N-di-
methylacetamide (DMA),12 formic acid/formate,13 metha-
nol,14 esters,15 and others16 have been applied to the N-acy-
lation of amines. DMF is widely used as an inexpensive and
readily available solvent in the organic synthesis industry
and laboratory research. As a compound that contains an al-
dehyde and an amino group, DMF has been widely applied
as a versatile precursor in forms such as -NMe2, -CHO, -CO,
-CONMe2, and -Me.17 N-Acylation of amines has been re-
ported using DMF as a carbonyl source in the presence of
various catalysts, such as Pd,18 Ni,12a Ce,12b Fe,12c,d Cu,12e L-
proline,12f boronic acid12g and its derivatives,12h,i imidaz-
ole12j and its derivatives,12k and hydroxylamine hydrochlo-
ride.12l However, these reactions frequently suffer from
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
J. Ma et al.
Paper
Synthesis
drawbacks: the use of complex and costly catalysts or stoi-
chiometric catalysts, requirement of additives, limited sub-
strate scope, difficulty in isolation and purification, or
lengthy preparation. Thus, a more optimal reaction consists
of using the earth-abundant metal manganese to catalyze
the N-acylation of amines.
Cl2·2H2O, FeCl3, PdCl2, and NiCl2·6H2O were also investigated
as catalysts, and only moderate yields were achieved (en-
tries 7–11). Decreasing the reaction temperature (entry 12)
or reducing the reaction time (entry 13) proved to be unfa-
vorable to this transformation. Additionally, the presence of
air is harmful to this reaction (entry 14).
OMe
Table 1 Selected Optimization Resultsa
CHO
H
O
OMe
NH2
OH
N
H
[Mn] (x mol%)
O
H
H
N
HN
N
DMF (1.0 mL), T °C, t h, Ar
N
H
O
HO
Entry
[Mn] (mol%)
Temp (°C)
Time (h) Yield (%)
Formoterol
Lacosamide
bronchodilator
anticonvulsant
1
2
–
150
150
150
150
150
150
150
150
150
150
150
130
150
150
10
10
10
10
10
10
10
10
10
10
10
10
6
23
66
73
91
73
76
41
48
55
43
57
58
60
62
nHexyl
O
MnCl2·4H2O (5)
MnCl2·4H2O (10)
MnCl2·4H2O (15)
Mn(OAc)3·2H2O (15)
Mn(OAc)2·4H2O (15)
CoCl2 (15)
O
3
H
O
NH
O
O
O
4
N
N
H
N
CO2H
5
HN
H
nDec
H2N
N
N
HO2C
O
H
H
6
Tetrahydrolipstatin
antiobesity agent
Leucovorin
adjuvant for tumor treatment
7
8
CuCl2·2H2O (15)
FeCl3 (15)
9
R'
R
N
H
N
10
11
12
13
14b
PdCl2 (15)
H
O
S
NiCl2·6H2O (15)
MnCl2·4H2O (15)
MnCl2·4H2O (15)
MnCl2·4H2O (15)
O
O
N
O
CO2H
N
R
n
R'
10
Penicillin G
antibiotic (nature product)
Polyamides (imides)
high-performance polymers
a Reaction conditions: benzylamine (0.2 mmol), catalyst (x mol%), DMF (1.0
mL), under argon unless otherwise indicated. Yields were determined by 1H
NMR spectroscopy using nitroethane as an internal standard.
b Under an atmosphere of air.
Figure 1 Amide-containing biologically active molecules and polymers
Herein, a highly efficient MnCl2·4H2O-catalyzed strategy
for the N-acylation of amines using DMF and other amides
as a carbonyl sources is reported (Scheme 1, E). This strate-
gy is simple and cost-effective because the reagents and
catalyst are inexpensive and do not require any acid, base,
ligand, or other additives. A broad substrate scope is given,
and primary, secondary, and heterocyclic amines with vari-
ous functional groups can be converted into the desired N-
acylation product with moderate to excellent yields. Fur-
thermore, other amides such as formamide, N-methylfor-
mamide, N-ethylformamide, and acetamide can also serve
as carbonyl sources to achieve the N-amidation reaction
with excellent yields.
Initially, the reaction of benzylamine with DMF in the
presence of MnCl2·4H2O was selected as the model reaction
(Table 1). Various reaction conditions were confirmed, in-
cluding the type and the amount of Mn catalyst, reaction
temperature, reaction time, and the reaction atmosphere.
The results indicated that the conversion rate is very poor
in the absence of Mn catalyst (entry 1). An excellent yield of
91% was achieved when using MnCl2·4H2O (15 mol%) as the
catalyst (entry 4). Other metal salts, such as CoCl2, Cu-
After optimization, N-formylation of various amines,
such as primary, secondary, and heterocyclic amines, using
DMF as the reagent was conducted (Scheme 2). The reac-
tion proceeded well when using tetrahydroisoquinoline or
its analogues as secondary amine substrates giving 2a–g in
good to excellent yields. Different functional groups on the
benzene ring such as methoxy, bromide, and nitro were
compatible with this reaction. However, the nitro group,
which is known as an electron-withdrawing group, has a
negative influence on this transformation, i.e. the reaction
of 7-nitro-1,2,3,4-tetrahydroisoquinoline with DMF gave
2d in only 68% yield. When using heterocyclic amines as
substrates, excellent yields were also achieved, i.e. the for-
mation of 2f,g. Other secondary amines, including circular
and linear amines, smoothly underwent the transformation
to give products 2h–p in moderate to excellent yields in
most cases. In particular, N-formylfluoxetine (2o), which
has been applied as a marker for fluoxetine,19 was obtained
in a good 68% yield. However, the alkyl substitution on ni-
trogen resulted in obvious steric hindrance and subsequent
lower 45–74% yields in the formation of 2j–o.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
J. Ma et al.
Paper
Synthesis
R1
R1
MnCl2 · 4H2O (15 mol%)
N
CHO
N
R2
CHO
CHO
H
N
+
N
H
+
150 °C, 10 h, Ar
R2
0.2 mmol
1 mL
MeO
N
N
N
N
Br
O2N
CHO
CHO
2a 80% (89%)
CHO
2b 81%
2c 89%
2d 68%
N
N
CHO
N
N
CHO
N
CHO
N
CHO
S
2e 81%
2i 99%
2f 93%
2g 96%
2h 81%
N
N
CHO
N
N
CHO
CHO
CHO
CHO
MeO
MeO
2j 45%
2k 43%
2l 54%
CHO
N
N
Ph
MeO
MeO
N
CHO
N
CHO
O
4-F3CC6H4
N-formylfluoxetine
2o 68%
MeO
2m 74%
2n 55%
2p 99%a
NH
NH
NH
HN
CHO
CHO
OHC
CHO
2q 91%
2r 81%
2s 91%
2t 61%
CHO
OH
N
H
N
CHO
NH
H
nC12H25
CHO
CHO
N
H
MeO2C
2u 73%
2v 82%
2w 93%
2x 88%
MeO
ref. 20
ref. 20
ilicifoline B
natural product
pseudopalmatine
natural product
NH
2y
MeO
OHC
N-formylhomoveratrylamine
2y 91%
Scheme 2 Substrate scope of amines. Reagents and conditions: amine (0.2 mmol), MnCl2·4H2O (15 mol%), DMF (1.0 mL), sealed tube, argon atmo-
sphere, 150 °C, 10 h. Isolated yields are given (NMR yield is given in brackets, nitroethane as internal standard). a H2NCHO as carbonyl source.
This successful protocol for the N-formylation of sec-
ondary amines was expanded to primary amines, and an ef-
ficiency greater than that for secondary amines was ob-
tained i.e. for 2q–y. This efficiency was likely the result of
the less alkyl substituent on nitrogen, and subsequently, a
smaller steric hindrance, which resulted in an increased
yield. However, the methyl substituent at the α-position of
nitrogen also results in obvious steric hindrance, e.g. in the
formation of 2t. Remarkably, a substrate with an acid/base
sensitive ester group also proceeded well to give 2u.
Additionally, a hydroxy group in the substrate had no
adverse effect on this reaction, e.g. the formation of 2w. The
N-formylation of primary amines is a valuable organic reac-
tion. For instance, the natural molecule homoveratrylamine
(3,4-dimethoxyphenethylamine) was converted to N-
formylation product 2y, which can then be applied as a pre-
cursor for preparing the natural products pseudopalmatine,
8-oxopseudopalmatine, and ilicifoline B.20 Phenylglycine
methyl ester also was examined as substrate, however, only
decarboxylation product 2q was isolated in 59% yield.
To validate the practicability of the strategy, further ex-
trapolation for the N-acylation of tetrahydroisoquinoline
using various carbonyl sources was conducted (Table 2).
The results indicated that formamide, N-methylformamide,
and N-ethylformamide can also serve as carbonyl sources to
achieve the N-acylation reaction in excellent yields (entries
1–3). Moreover, when acetamide and propanamide were
used, the N-acetylation and N-propanoylation products
were obtained in excellent 86% and 87% yields, respectively
(entries 4 and 5). Benzamide was also tested as the carbonyl
source, but the product 2zb was obtained in only 25% yield,
which may be due to the steric hindrance of the carbonyl
source.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
J. Ma et al.
Paper
Synthesis
Table 2 Substrate Scope of Amidesa
R1
O
R1
O
MnCl2 · 4H2O (15 mol%)
N
R2
N
R2
H
NH3
+
+
R3
NH2
150 °C, 10 h, Ar
R3
R1
R3
N
R1
MnCl2 · 4H2O (15 mol%)
+
H
N H
+
N
R3
N
O
150 °C, 10 h, Ar
R2
R2
O
N
N
N
O
N
CH3
O
0.2 mmol
1 mL or 1 gram
CH3
O
CH3
2z 86%
2zc 94%
2zd 96%
Entry Amide
Product
Yield (%)
91
O
O
CH3
NH
O
N
CH3
N
1
2a
N
N
N
N
O
CH3
H
NH2
CHO
CHO
CHO
S
2ze 83%
2za 87%
2zf 85%
2zg 86%
O
2
2a
2a
93 (98)b
89 (93)b
O
H
N
H
N
N
N
O
N
C2H5
C2H5
O
O
C2H5
3
2zh 92%
2zi 95%
H
N
H
O
O
C2H5
NH
N
C2H5
N
O
O
C2H5
4
2z
86
87
25
S
NH2
O
O
2zj 82%
2zk 60%
2zl 65%
Scheme 3 Substrate scope of acetylation and propanoylation of
N
5
6
2za
2zb
amine. Reagents and conditions: amine (0.2 mmol), MnCl2·4H2O (15
mol%), amide (1 g), sealed tube, argon atmosphere, 150 °C, 10 h. Isolat-
ed yields are given.
NH2
O
O
O
N
NH2
hedral intermediate I. Afterward, with a proton transfer, the
sterically congested intermediate I eliminates dimethyl-
amine to give intermediate II. Finally, the target molecule
T.M. in intermediate II is replaced by DMF to finish the cata-
lytic cycle.
a Reaction conditions: amine (0.2 mmol), MnCl2·4H2O (15 mol%), amide
(1.0 mL; entries 4–6, 1 g), sealed tube, argon atmosphere, 150 °C, 10 h.
Isolated yields are given.
b NMR yield with nitroethane as an internal standard.
(A) Gram-scale reaction:
Based on the good results of N-acetylation and N-propa-
noylation of 1a, the N-acylation and N-propanoylation were
extrapolated to several amines (Scheme 3). As expected,
both the primary and secondary amine are converted into
the desired products 2z,za,zc–zl in good to excellent yields.
Importantly, the gram-scale reaction of natural com-
pound 1y using only 5 mol% MnCl2·4H2O as catalyst was
conducted (Scheme 4), and an excellent yield of 84% was
achieved with a slightly extended reaction time (20 h). The
gram-scale N-acetylation reaction of benzylamine (1q) also
achieved with an excellent yield of 85%. To examine the re-
action mechanism, radical inhibition experiments were
conducted using benzylamine/DMF/MnCl2·4H2O together
with 1 equiv butylated hydroxytoluene (BHT) or 2,2,6,6-te-
tramethylpiperidine-1-oxyl (TEMPO) as blocker, resulting
in the desired product 2q in 42% and 56% yield (NMR yield),
respectively. In our opinion, this reaction is not a radical
process, but instead, is a nucleophilic process.
MeO
MeO
MeO
MnCl2 · 4H2O (5 mol%)
N
CHO
+
NH
NH2
150 °C, 20 h, Ar
MeO
OHC
homoveratrylamine (1y) 15 mL
N-formylhomoveratrylamine (2y)
Isolate yield: 972 mg (84%)
1 g (5.52 mmol, 0.931 mL)
O
O
NH2
MnCl2 · 4H2O (5 mol%)
N
H
H2N
+
150 °C, 48 h, Ar
Condition 1 and 2
N-benzylformamide (2q)
Isolate yield: 1.18 g (85%)
benzylamine (1q) 5 g
1 g (9.33 mmol, 1.02 mL)
(B) Radical inhibition experiments:
O
CHO
NH2
N
H
N
C
+
H
Condition 1: Standard reaction conditions, BHT 1 equiv, NMR yield 42%;
Condition 2: Standard reaction conditions, TEMPO 1 equiv, NMR yield 56%.
Scheme 4 Gram-scale reactions and radical inhibition experiments
Based on the radical inhibition experiments and the re-
ported metal-catalyzed N-formylation reactions,12a a rea-
sonable mechanism is proposed (Scheme 5). First, the car-
bonyl group of DMF is activated by MnCl2 via coordination.
Subsequently, the activated DMF undergoes nucleophilic at-
tack by the amine, which results in the formation of a tetra-
In summary, an efficient manganese-catalyzed N-acyla-
tion of amines using DMF and other amides as carbonyl
sources was developed. The advantages of this strategy are
the use of a metal as the catalyst that is richly abundant and
inexpensive, the unencumbered availability of various in-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

E
J. Ma et al.
Paper
Synthesis
N-Benzylformamide (2q); Gram-Scale Synthesis
O
O
N
H
A solution of benzylamine (1q; 1 g, 9.33 mmol), MnCl2·4H2O (92.4 mg,
5 mol%) in acetamide (5 g) was stirred in a sealed microwave reaction
tube (120 mL) under an atmosphere of argon at 150 °C for 48 h. The
mixture was cooled to r.t., and water (30 mL) was added; the mixture
was extracted with CH2Cl2 (4 × 20 mL). The combined organic layers
were dried (anhyd Na2SO4), the solution was evaporated under vacu-
um, and the residue was purified by column chromatography (silica
gel, petroleum ether/EtOAc 3:1 with 1% Me3N) to obtain the pure
product; yield: 1180 mg (85%).
(T.M.)
R1
H
N
R2
MnCl2
O
N
H
O
H
MnCl2
O
MnCl2
R1
N
(II)
R1
H
HN
R2
N
R2
H
N
O
1,2,3,4-Tetrahydroisoquinoline-2-carbaldehyde (2a)21
MnCl2
N
H
Purified by TLC; yellow oil; isolated yield: 25.8 mg (80%); 1H NMR
yield: 89%.
N
R1
R2
(I)
IR (neat): 3151, 1672, 1584, 1498, 1282, 1164, 1049, 930, 882, 751
Scheme 5 Proposed mechanism for N-formylation using MnCl2·4H2O
as catalyst
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 0.38 H)*, 8.19 (s, 0.62 H)**,
7.22–7.08 (m, 4 H), 4.68 (1.24 H)**, 4.54 (0.75 H)*, 3.78 (t, J = 6.2 Hz,
0.74 H)*, 3.64 (t, J = 5.8 Hz, 1.27 H)**, 2.92–2.85 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 161.6**, 161.1*, 134.3*, 133.4**,
132.1*, 131.6**, 129.1*, 128.8**, 127.0, 126.6–126.4 (m), 125.8, 47.2*,
43.1**, 42.2**, 37.9*, 29.6**, 27.8*.
expensive amides as the carbonyl source, the lack of re-
quirement for any acid, base, ligand, or other additives,
broad substrate scopes, and high yields.
HRMS (ESI): m/z [M + Na]+ calcd for C10H11NNaO: 184.0733; found:
184.0733.
Preparative TLC was performed for product purification using Sorbent
Silica Gel 60 F254 TLC plates and visualized with UV light. IR spectra
were recorded on a new FT infrared spectrometer. 1H, 13C, and 19F
NMR spectra were recorded on 400, 100, and 377 MHz NMR spec-
trometers using CDCl3 as solvent unless otherwise stated. HRMS were
made by means of ESI. Melting points were measured on micromelt-
ing point apparatus and uncorrected. Unless otherwise noted, all re-
agents were weighed and handled in air, and all reactions were car-
ried out in a sealed tube under an atmosphere of argon. Unless other-
wise noted, all reagents were purchased from reagent company, and
used without further purifications.
6-Methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbaldehyde (2b)22
Purified by TLC; yellow solid; yield: 30.9 mg (81%); mp 63–64 °C.
IR (neat): 3140, 1672, 1612, 1508, 1402, 1312, 1277, 1241, 1119 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 0.40 H)*, 8.17 (s, 0.60 H)**,
7.04–6.99 (m, 1 H), 6.78–6.74 (m, 1 H), 6.65 (d, J = 10.0 Hz, 1 H), 4.60
(s, 1.24 H)**, 4.47 (s, 0.77 H)*, 3.77–3.73 (m, 3.76 H), 3.61 (t, J = 5.8 Hz,
1.24 H)**, 2.87–2.81 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 161.5**, 161.1*, 158.4*, 158.1**,
135.6*, 134.7**, 127.5**, 126.8*, 124.3*, 123.7**, 113.6*, 113.4**,
112.9**, 112.7*, 55.2 (s), 46.7*, 43.1**, 41.7**, 37.8*, 29.9**, 28.1*.
In NMR spectra ** indicates the major rotamer and * indicates the mi-
nor rotamer.
HRMS (ESI): m/z [M + HCO2H – H]– calcd for C12H14NO4: 236.0917;
found: 236.0921.
N-Substituted Formamides 2; General Procedure
A solution of amine (0.2 mmol) and MnCl2·4H2O (5.9 mg, 15 mol%) in
DMF (1.0 mL) was stirred in a sealed microwave reaction tube under
an atmosphere of argon at 150 °C for 10 h. The mixture was cooled to
r.t., and water (10 mL) was added; the mixture was extracted with
EtOAc (3 × 15 mL). The combined organic layers were dried (anhyd
Na2SO4), the solvent was evaporated under vacuum, and the crude
product was purified by preparative TLC (silica gel, petroleum
ether/EtOAc) to obtain the pure product.
7-Bromo-1,2,3,4-tetrahydroisoquinoline-2-carbaldehyde (2c)
Purified by TLC; yellow solid; yield: 42.5 mg (89%); mp 58–60 °C.
IR (neat): 3140, 1672, 1402, 1191, 1157, 1116, 1075, 932, 829 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.24 (s, 0.37 H)*, 8.19 (s, 0.63 H)**,
7.34–7.26 (m, 2 H), 7.02 (t, J = 8.8 Hz, 1 H), 4.66 (s, 1.31 H)**, 4.52 (s,
0.72 H)*, 3.78 (t, J = 6.2 Hz, 0.72 H)*, 3.65 (t, J = 5.8 Hz, 1.32 H)**, 2.86
(t, J = 5.8 Hz, 1.28 H)**, 2.82 (t, J = 6.0 Hz, 0.80 H)*.
13C NMR (100 MHz, CDCl3): δ = 161.6**, 161.0*, 134.2*, 133.8**,
133.3*, 132.4**, 130.8*, 130.5**, 130.1*, 129.7**, 129.3**, 128.7*,
120.2**, 119.9*, 46.8*, 42.9**, 41.7**, 37.6*, 29.2**, 27.4*.
N-(3,4-Dimethoxyphenethyl)formamide (2y); Gram-Scale Synthe-
sis
A solution of homoveratrylamine (1y; 1 g, 5.52 mmol) and MnCl2·4H2O
(54.3 mg, 5 mol%) in DMF (15 mL) was stirred in a sealed microwave
reaction tube (120 mL) under an atmosphere of argon at 150 °C for 20
h. The mixture was cooled to r.t., and water (50 mL) was added; the
mixture was extracted with EtOAc (3 × 20 mL). The combined organic
layers were dried (anhyd Na2SO4), the solvent was evaporated under
vacuum, and the crude product was purified column chromatography
(silica gel, petroleum ether/EtOAc 2:1 with 1% Me3N) to obtain the
pure product; yield: 972 mg (84%).
HRMS (ESI): m/z [M + NH4]+ calcd for C10H14BrN2O: 257.0284; found:
257.0275.
7-Nitro-1,2,3,4-tetrahydroisoquinoline-2-carbaldehyde (2d)
Purified by TLC; brown oil; yield: 28.0 mg (68%).
IR (neat): 3129, 1672, 1525, 1402, 1347, 1088, 855, 744, 531 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
J. Ma et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.29 (s, 0.37 H)* 8.24 (s, 0.63 H)**,
8.08–8.04 (m, 2 H), 7.33 (t, J = 9.0 Hz, 1 H), 4.79 (s, 1.25 H)**, 4.66 (s,
0.74 H)*, 3.85 (t, J = 6.0 Hz, 0.72 H)*, 3.72 (t, J = 6.0 Hz, 1.27 H)**, 3.03
(t, J = 6.0 Hz, 1.23 H)**, 2.99 (t, J = 6.0 Hz, 0.76 H)*.
13C NMR (100 MHz, CDCl3): δ = 161.5**, 161.0*, 146.7**, 146.5*,
142.1*, 141.1**, 133.7*, 133.4**, 130.3*, 130.0**, 122.1*, 121.9**,
121.6**, 121.2*, 47.0*, 42.4**, 42.0**, 37.2*, 29.9**, 28.1*.
4-Phenylpiperidine-1-carbaldehyde (2i)25
Purified by TLC; yellow solid; yield: 37.4 mg (99%); mp 98–99 °C.
IR (neat): 3140, 1675, 1653, 1402, 1170, 1064, 759, 699, 529 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.31 (t, J = 7.4 Hz, 2 H),
7.24–7.18 (m, 3 H), 4.56 (d, J = 13.6 Hz, 1 H), 3.73 (d, J = 13.2 Hz, 1 H),
3.19 (td, J = 12.9, 2.6 Hz, 1 H), 2.81–2.67 (m, 2 H), 1.92 (t, J = 15.8 Hz, 2
H), 1.67–1.54 (m, 2 H).
.
HRMS (ESI): m/z [M + CH3CO2H – H]– calcd for C12H13N2O5: 265.0819;
found: 265.0824.
13C NMR (100 MHz, CDCl3): δ = 160.8, 144.8, 128.5, 126.6, 126.5, 46.4,
42.8, 40.1, 33.8, 32.3.
HRMS (ESI): m/z [M + Na]+ calcd for C12H15NNaO: 212.1046; found:
212.1048.
1,3-Dihydro-2H-isoindole-2-carbaldehyde (2e)23
Purified by TLC; black oil; yield: 23.8 mg (81%).
IR (neat): 3140, 1668, 1465, 1402, 1159, 1092, 747 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.42 (s, 1 H), 7.31–7.27 (m, 4 H), 4.89
(s, 2 H), 4.76 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 161.5, 135.9, 135.2, 128.0, 127.6,
123.2, 122.8, 51.4, 49.8.
HRMS (ESI): m/z [M + Cl]– calcd for C9H9ClNO: 182.0367; found:
182.0368.
.
N-Benzyl-N-methylformamide (2j)26
Purified by TLC; yellow oil; yield: 13.4 mg (45%).
IR (neat): 3122, 1664, 1402, 1379, 1140, 1066, 1081, 705, 529 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.29 (s, 0.57 H)**, 8.17 (s, 0.43 H)*,
7.40–7.20 (m, 5 H), 4.53 (s, 0.84 H)*, 4.40 (s, 1.16 H)**, 2.85 (s, 1.30
H)*, 2.79 (s, 1.75 H)**.
13C NMR (100 MHz, CDCl3): δ = 162.8**, 162.6*, 135.9*, 135.6**,
128.9**, 128.7*, 128.2**, 128.1*, 127.6*, 127.4**, 53.5**, 47.7*, 34.0*,
29.4**.
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine-5-carbaldehyde (2f)12a
Purified by TLC; yellow oil; yield: 31.1 mg (93%).
IR (neat): 3129, 1705, 1670, 1433, 1402, 1314, 1176, 1043, 1018 cm–1
HRMS (ESI): m/z [M + CH3CO2H – H]– calcd for C11H14NO3: 208.0968;
found: 208.0971.
.
1H NMR (400 MHz, CDCl3): δ = 8.24 (s, 0.38 H)*, 8.20 (s, 0.62 H)**,
7.17–7.15 (m, 1 H), 6.80 (t, J = 4.4 Hz, 1 H), 4.60 (s, 1.28 H)**, 4.47 (s,
0.74 H)*, 3.86 (t, J = 5.8 Hz, 0.74 H)*, 3.69 (t, J = 5.8 Hz, 1.28 H)**, 2.93
(t, J = 5.8 Hz, 1.26 H)**, 2.88 (t, J = 5.8 Hz, 0.75 H)*.
13C NMR (100 MHz, CDCl3): δ = 161.7**, 161.4*, 133.8*, 132.1**,
130.8**, 130.7*, 125.0**, 124.3*, 123.8 (s), 45.7*, 43.7**, 40.6**, 37.9*,
25.8**, 24.4*.
N-Benzyl-N-ethylformamide (2k)27
Purified by TLC; yellow oil; yield: 14.0 mg (43%).
IR (neat): 3140, 1672, 1497, 1402, 1109, 1079, 740, 703, 528 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.26 (s, 0.50 H)*, 8.23 (s, 0.50 H)**,
7.39–7.21 (m, 5 H), 4.56 (s, 1.05 H)**, 4.40 (s, 1.00 H)*, 3.29 (q, J = 7.2
Hz, 0.99 H)*, 3.21 (q, J = 7.2 Hz, 1.08 H)**, 1.15 (t, J = 7.2 Hz, 1.54 H)**,
1.07 (t, J = 7.2 Hz, 1.49 H)*.
13C NMR (100 MHz, CDCl3): δ = 162.6, 136.4**, 136.1*, 128.8*, 128.6**,
128.1**, 128.00*, 127.5*, 127.4**, 50.8*, 44.7**, 41.4**, 36.7*, 14.3**,
12.1*.
HRMS (ESI): m/z [M + NH4]+ calcd for C8H13N2SO: 185.0743; found:
185.0735.
5,7-Dihydro-6H-pyrrolo[3,4-b]pyridine-6-carbaldehyde (2g)
Purified by TLC; black oil; yield: 28.4 mg (96%).
IR (neat): 3140, 1668, 1584, 1469, 1387, 1262, 1159, 1110 cm–1
HRMS (ESI): m/z [M + CH3CO2H – H]– calcd for C12H16NO3: 222.1125;
found: 222.1119.
.
1H NMR (400 MHz, CDCl3): δ = 8.55–8.52 (m, 1 H), 8.48 (s, 0.60 H)**,
8.44 (s, 0.40 H)*, 7.67–7.62 (m, 1 H), 7.29–7.23 (m, 1 H), 4.95 (s, 0.79
H)*, 4.93 (s, 1.22 H)**, 4.81 (s, 2 H).
N-(4-Methoxybenzyl)-N-methylformamide (2l)
Purified by TLC; yellow oil; yield: 19.3 mg (54%).
13C NMR (100 MHz, CDCl3): δ = 161.6, 157.1*, 156.5**, 149.7*, 149.4**,
131.4**, 130.9*, 129.7**, 129.0*, 122.8**, 122.4*, 51.8**, 50.4*, 49.9*,
48.5**.
HRMS (ESI): m/z [M + H]+ calcd for C8H9N2O: 149.0709; found:
149.0710.
IR (neat): 3140, 1671, 1612, 1515, 1402, 1303, 1176, 1079, 1032 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 0.58 H)**, 8.08 (s, 0.42 H)*, 7.14
(d, J = 8.4 Hz, 0.86 H)*, 7.08 (d, J = 8.4 Hz, 1.15 H)**, 6.86–6.81 (m, 2 H),
4.41 (s, 0.86 H)*, 4.28 (s, 1.20 H)**, 3.76 (s, 1.78 H)**, 3.75 (s, 1.23 H)*,
2.78 (s, 1.30 H)*, 2.71 (s, 1.75 H)**.
13C NMR (100 MHz, CDCl3): δ = 162.5**, 162.4*, 159.3**, 159.0*, 130.3,
129.5*, 128.7**, 128.0*, 127.5**, 114.1**, 113.9*, 113.5, 55.2 (d, J = 4.4
Hz)**, 52.8*, 47.0**, 44.7*, 33.8*, 29.1**.
4-Phenylpiperazine-1-carbaldehyde (2h)24
Purified by TLC; yellow solid; yield: 30.8 mg (81%); mp 86–87 °C.
IR (neat): 3131, 1664, 1402, 1152, 1115, 529 cm–1
.
HRMS (ESI): m/z [M + NH4]+ calcd for C10H17N2O2: 197.1285; found:
1H NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.30–7.27 (m, 2 H), 6.94–
6.90 (m, 3 H), 3.69 (t, J = 5.2 Hz, 2 H), 3.51 (t, J = 5.0 Hz, 2 H), 3.15 (dt,
J = 15.2, 5.2 Hz, 4 H).
197.1304.
N-Methyl-N-phenethylformamide (2m)28
13C NMR (100 MHz, CDCl3): δ = 160.6, 150.8, 129.1, 120.7, 116.9, 50.3,
Purified by TLC; yellow oil; yield: 24.1 mg (74%).
IR (neat): 3140, 1666, 1402, 1152, 529 cm–1
.
49.2, 45.4, 39.8.
HRMS (ESI): m/z [M + K]+ calcd for C11H14N2KO: 229.0738; found:
229.0742.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
J. Ma et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 0.37 H)*, 7.80 (s, 0.63 H)**,
7.33–7.22 (m, 4 H), 7.14 (d, J = 7.2 Hz, 1 H), 3.56 (t, J = 7.6 Hz, 0.79 H)*,
3.47 (t, J = 7.0 Hz, 1.25 H),** 2.90–2.82 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 162.6**, 162.4*, 138.5*, 137.6**,
128.7**, 128.7*, 128.6**, 128.5*, 126.7**, 126.4*, 51.2**, 45.9*, 35.0*,
34.7**, 33.1*, 29.7*.
N-Benzylformamide (2q)14c
Purified by TLC; yellow solid; yield: 24.6 mg (91%); mp 54–58 °C.
IR (neat): 3140, 1666, 1402, 699, 526 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 0.87 H)**, 8.16 (d, J = 12 Hz,
0.13 H)*, 7.35–7.27 (m, 5 H), 6.08 (br s, 1 H), 4.48 (d, J = 6.0 Hz, 1.73
H)**, 4.41 (d, J = 6.4 Hz, 0.34 H)*.
.
HRMS (ESI): m/z [M + H]+ calcd for C10H13NO: 164.1070; found:
164.1071.
13C NMR (100 MHz, CDCl3): δ = 164.7*, 161.0**, 137.5**, 137.4*,
128.9*, 128.7**, 127.9*, 127.7**, 127.6**, 126.9*, 45.6*, 42.1**.
HRMS (ESI): m/z [M + H]+ calcd for C8H10NO: 136.0757; found:
136.0747.
N-Methyl-N-(naphthalen-1-ylmethyl)formamide (2n)
Purified by TLC; yellow oil; yield: 21.9 mg (55%).
IR (neat): 3140, 1672, 1510, 1402, 1258, 1161, 1081, 803, 779, 529
N-Phenethylformamide (2r)21
cm–1
.
Purified by TLC; yellow oil; yield: 24.1 mg (81%).
IR (neat): 3140, 1670, 1402, 1154, 689, 527 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.10 (s, 0.84 H)**, 7.89 (d, J = 12 Hz,
0.16 H)*, 7.32–7.20 (m, 5 H), 5.83 (br s, 1 H), 3.59–3.46 (m, 2 H), 2.86–
2.82 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 164.5*, 161.2**, 138.4**, 137.5*,
128.8–128.6 (m), 126.8*, 126.6**, 43.1*, 39.1**, 37.6*, 35.4**.
HRMS (ESI): m/z [M + Na]+ calcd for C9H11NNaO: 172.0733; found:
172.0741.
1H NMR (400 MHz, CDCl3): δ = 8.39 (s, 0.40 H)*, 8.17 (s, 0.60 H)**, 8.11
(d, J = 8.0 Hz, 0.64 H), 7.91–7.82 (m, 2.46 H), 7.55–7.30 (m, 4 H), 4.98
(s, 1.22 H)**, 4.88 (s, 0.78 H)*, 2.86 (s, 1.23 H)*, 2.75 (s, 1.78 H)**.
13C NMR (100 MHz, CDCl3): δ = 163.2*, 162.2**, 133.7, 131.4, 131.2**,
131.1*, 131.0*, 130.9**, 129.0*, 128.8**, 128.7*, 128.6**, 127.6*,
126.6*, 126.0**, 125.4*, 125.3*, 125.0**, 123.7*, 122.20, 50.9*, 45.8**,
33.9**, 29.9*.
.
HRMS (ESI): m/z [M + H]+ calcd for C13H14NO: 200.1070; found:
200.1069.
N-(3-Phenylpropyl)formamide (2s)14b
N-Formylfluoxetine (2o)
Purified by TLC; yellow oil; yield: 29.7 mg (91%).
IR (neat): 3122, 1666, 1402, 1154, 1113, 749, 701, 529 cm–1
Purified by TLC; yellow oil; yield: 45.8 mg (68%).
IR (neat): 3140, 1675, 1616, 1519, 1329, 1251, 1161, 1113, 1068 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 0.82 H)**, 7.99 (d, J = 12 Hz,
0.18 H)*, 7.32–7.17 (m, 5 H), 6.04 (br s, 1 H), 3.31 (q, J = 6.8 Hz, 1.64
H)**, 3.20 (q, J = 6.8 Hz, 0.36 H)*, 2.68–2.64 (m, 2 H), 1.89–1.82 (m, 2
H).
13C NMR (100 MHz, CDCl3): δ = 164.8*, 161.3**, 141.1**, 140.5*,
128.5*, 128.4**, 128.3**, 126.2*, 126.0**, 41.0*, 37.7**, 33.0**, 32.4*,
32.4*, 31.0**.
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 0.41 H)*, 7.99 (s, 0.59 H)**, 7.43
(d, J = 8.8 Hz, 2 H), 7.37–7.27 (m, 5 H), 6.90–6.86 (m, 2 H), 5.20 (dd, J =
8.8, 4.4 Hz, 0.42 H)*, 5.14 (dd, J = 8.8, 4.0 Hz, 0.61 H)**, 3.59–3.52 (m,
1.42 H)**, 3.42–3.35 (m, 0.62 H)*, 2.94 (s, 1.21 H)*, 2.90 (s, 1.84 H)**,
2.27–2.17 (m, 1.06 H), 2.15–2.04 (m, 1.15 H).
13C NMR (100 MHz, CDCl3): δ = 162.7**, 162.6*, 160.1*, 159.8**,
140.3*, 139.8**, 129.0**, 128.8*, 128.2**, 128.0*, 126.9–126.7 (m),
125.6*, 125.5**, 123.3–122.7 (m), 115.7*, 115.6**, 78.1*, 76.8**, 45.9**,
41.5*, 36.9**, 35.8*, 34.8*, 29.5**.
HRMS (ESI): m/z [M + Na]+ calcd for C10H13NNaO: 186.0889; found:
186.0897.
19F NMR (377 MHz, CDCl3): δ = –61.52 (s)*, –61.59 (s)**.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18F3NNaO2: 360.1182; found:
N-(1-Phenylethyl)formamide (2t)30
Purified by TLC; yellow oil; yield: 18.2 mg (61%).
360.1178.
IR (neat): 3100, 1662, 1534, 1497, 1402, 1238, 1118 cm–1
.
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline-2-carbaldehyde (2p)29
1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.38–7.25 (m, 5 H), 6.33
(br s, 1 H), 5.22–5.15 (m, 0.82 H)**, 4.71–4.64 (m, 0.19 H)*, 1.55 (d, J =
6.8 Hz, 0.53 H)*, 1.50 (d, J = 6.8 Hz, 2.47 H)**.
Purified by TLC; white solid; yield: 73.5 mg (99%); mp 147–148 °C.
IR (neat): 3138, 1664, 1517, 1402, 1260, 1236, 1113, 1027 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 160.3, 142.5, 128.8*, 128.6**, 127.7*,
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 0.39 H)*, 7.69 (s, 0.61 H)**,
6.83–6.56 (m, 4.76 H), 6.33 (s, 0.37 H), 5.52 (t, J = 6.2 Hz, 0.39 H),
4.60–4.56 (m, 0.61 H), 4.49–4.45 (m, 0.62 H), 3.87–3.84 (m, 9.71 H),
3.76 (s, 1.23 H), 3.69 (s, 1.28 H), 3.58–3.54 (m, 0.41 H), 3.31–3.24 (m,
0.40 H), 3.17–2.77 (m, 3.76 H), 2.73–2.59 (m, 1 H).
127.4**, 126.0**, 125.7*, 51.6*, 47.5**, 23.5*, 21.7**.
HRMS (ESI): m/z [M + H]+ calcd for C9H12NO: 150.0913; found:
150.0912.
Methyl 4-(Formamidomethyl)benzoate (2u)
13C NMR (100 MHz, CDCl3): δ = 161.4**, 161.3*, 149.1**, 148.7*, 148.3,
148.1, 147.9, 147.8, 147.6**, 147.3*, 130.0*, 129.7**, 127.4**, 127.1*,
126.2**, 125.4*, 122.0*, 121.8**, 112.8, 112.5, 111.6, 111.4, 111.3,
110.9, 110.4, 109.9, 59.0, 56.1, 56.0, 55.9, 55.9, 55.8, 55.8, 52.1, 43.1,
41.5, 40.9, 34.2, 29.1, 27.7.
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO5: 372.1806; found:
372.1812.
Purified by TLC; white solid; yield: 28.2 mg (73%); mp 119–120 °C.
IR (neat): 3153, 1731, 1655, 1400, 1280, 1101, 1019, 766, 705 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.30 (s, 0.87 H)**, 8.19 (d, J = 12 Hz,
0.13 H)*, 8.04–7.98 (m, 2 H), 7.36–7.32 (m, 2 H), 6.21 (br s, 1 H), 4.53
(d, J = 6.0 Hz, 1.79 H)**, 4.48 (d, J = 6.4 Hz, 0.27 H)*, 3.92 (s, 0.40 H)*,
3.91 (s, 2.68 H)**.
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
J. Ma et al.
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 166.8**, 164.7*, 161.2, 142.8**, 142.6*,
130.2*, 130.0**, 129.9*, 129.5**, 127.5**, 126.8*, 52.2*, 52.2**, 45.3*,
41.8**.
HRMS (ESI): m/z [M + Li]+ calcd for C10H11NLiO3: 200.0894; found:
200.0892.
N-Acetyl-1,2,3,4-tetrahydroisoquinoline (2z)34
Purified by TLC; yellow oil; yield: 30.1 mg (86%).
IR (neat): 3159, 3029, 2933, 1661, 1634, 1456, 1403, 1299, 1034 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.21–7.09 (m, 4 H), 4.72 (s, 1.13 H)**,
4.61 (0.87 H)*, 3.81 (t, J = 5.8 Hz, 0.85 H)*, 3.67 (t, J = 5.8 Hz, 1.15 H)**,
2.90 (t, J = 5.8 Hz, 1.22 H)**, 2.84 (t, J = 5.8 Hz, 0.89 H)*, 2.18 (s, 1.26
H)*, 2.17 (s, 1.67 H)**.
.
N-Dodecylformamide (2v)26
Purified by TLC; gray solid; yield: 34.9 mg (82%); mp 33–34 °C.
13C NMR (100 MHz, CDCl3): δ = 169.5**, 169.5*, 135.0*, 133.9**,
133.4**, 132.4*, 128.9*, 128.2**, 126.9*, 126.6**, 126.5**, 126.5*,
126.3**, 126.0*, 48.0*, 44.0**, 43.9**, 39.4*, 29.4**, 28.434*, 21.9*,
21.6**.
HRMS (ESI): m/z [M + HCO2H – H]– calcd for C12H14NO: 220.0968;
found: 220.0981.
IR (neat): 3122, 1670, 1401, 1150, 1113, 529 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 0.82 H)**, 8.03 (d, J = 12 Hz,
0.18 H)*, 5.63 (br s, 1 H), 3.28 (q, J = 6.8 Hz, 1.66 H)**, 3.20 (q, J = 6.8
Hz, 0.44 H)*, 1.53–1.48 (m, 2 H), 1.29–1.24 (m, 18 H), 0.87 (t, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.7*, 161.0**, 41.8*, 38.2**, 31.9**,
31.2*, 29.6–29.1 (m), 26.8**, 26.3*, 22.6, 14.1.
N-Propanoyl-1,2,3,4-tetrahydroisoquinoline (2za)35
HRMS (ESI): m/z [M + K]+ calcd for C13H27NKO: 252.1724; found:
Purified by TLC; yellow oil; yield: 32.9 mg (87%).
IR (neat): 3120, 2983, 1694, 1646, 1454, 1401, 1310, 1053 cm–1
.
252.1724.
1H NMR (400 MHz, CDCl3): δ = 7.21–7.08 (m, 4 H), 4.73 (s, 1.16 H)**,
4.61 (s, 0.94 H)*, 3.83 (t, J = 6.0 Hz, 0.96 H)*, 3.67 (t, J = 5.8 Hz, 1.12
H)**, 2.89 (t, J = 6.0 Hz, 1.30 H)**, 2.84 (t, J = 5.8 Hz, 0.88 H)*, 2.47–
2.40 (m, 2 H), 1.21–1.16 (m, 3 H).
N-(2-Hydroxy-2-phenylethyl)formamide (2w)31
Purified by TLC; yellow oil; yield: 30.7 mg (93%).
IR (neat): 3140, 1670, 1523, 1495, 1402, 1239, 1198, 1096, 915 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 172.8**, 172.8*, 135.2*, 134.1**,
133.7**, 132.7*, 128.9*, 128.2**, 126.9, 126.7, 126.5, 126.5, 126.3,
126.0, 47.2*, 44.2**, 43.1**, 39.7*, 29.5**, 28.5*, 27.0*, 26.8**, 9.4**,
9.3*.
HRMS (ESI): m/z [M + HCO2H – H]– calcd for C13H16NO3: 234.1125;
found: 234.1125.
1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 0.83 H)**, 7.86 (d, J = 12 Hz,
0.17 H)*, 7.34–7.27 (m, 5 H), 6.35 (br s, 1 H), 4.80 (dd, J = 8.6, 3.4 Hz,
0.84 H)**, 4.70 (dd, J = 7.4, 3.8 Hz, 0.18 H)*, 3.73–3.67 (m, 1.80 H)**,
3.45–3.37 (m, 0.19 H)*, 3.33–3.27 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 165.4*, 162.2**, 141.4**, 140.8*,
128.7*, 128.5**, 128.2*, 128.0**, 125.8*, 125.8**, 73.3*, 72.9**, 49.2*,
45.7**.
N-Benzoyl-1,2,3,4-tetrahydroisoquinoline (2zb)36
HRMS (ESI): m/z [M + H]+ calcd for C9H12NO2: 166.0863; found:
Purified by TLC; yellow oil; yield: 11.9 mg (25%).
166.0860.
IR (neat): 3153, 2363, 2345, 1633, 1402, 1299, 1258, 1107, 934 cm–1
.
N-Indan-1-ylformamide (2x)32
1H NMR (400 MHz, CDCl3): δ = 7.44 (m, 5 H), 7.22–7.17 (m, 4 H), 4.90
(s, 1.13 H)**, 4.59 (s, 0.87 H)*, 4.00 (s, 0.83 H)*, 3.65 (s, 1.20 H)**,
2.98–2.88 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 136.1, 132.9, 129.8, 128.5,
127.1–126.6 (m), 49.8, 45.3, 44.9, 40.5, 29.6, 28.3.
Purified by TLC; yellow solid; yield: 28.3 mg (88%); mp 109–110 °C.
IR (neat): 3118, 1640, 1547, 1402, 1154, 1115, 751, 529 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.24 (s, 0.89 H)**, 8.21 (s, 0.11 H)*,
7.30–7.19 (m, 4 H), 6.00 (br s, 1 H), 5.55 (q, J = 8.0 Hz, 0.80 H)**, 4.99
(q, J = 8.0 Hz, 0.19 H)*, 3.03–2.96 (m, 1 H), 2.92–2.84 (m, 1 H), 2.64–
2.55 (m, 1 H), 1.92–1.79 (m, 1 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C16H16NO: 238.1226; found:
238.1222.
13C NMR (100 MHz, CDCl3): δ = 163.8*, 160.9**, 143.3**, 142.5*,
128.4*, 128.1**, 127.0*, 126.8**, 125.0*, 124.8**, 123.9**, 123.7*, 57.4*,
53.2**, 35.1*, 33.9**, 30.2**, 29.8*.
HRMS (ESI): m/z [M + CH3CO2H – H]– calcd for C12H14NO3: 220.0968;
found: 220.0971.
N-(4-Phenylpiperazin-1-yl)acetamide (2zc)37
Purified by TLC; white solid; yield: 38.4 mg (94%); mp 80–82 °C.
IR (neat): 3138, 2822, 1655, 1500, 1402, 1232, 1158, 999, 760, 695
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.27 (m, 2 H), 6.94–6.89 (m, 3 H),
3.77 (t, J = 5.2 Hz, 2 H), 3.62 (t, J = 5.2 Hz, 2 H), 3.19–3.13 (m, 4 H), 2.14
(s, 3 H).
N-(3,4-Dimethoxyphenethyl)formamide (2y)33
Purified by TLC; yellow oil; yield: 38.0 mg (91%).
IR (neat): 3140, 3006, 2941, 1668, 1593, 1467, 1400, 1265, 1029 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 169.1, 151.0, 129.3, 120.6, 116.7, 49.8,
1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 0.85 H)**, 7.87 (d, J = 12 Hz,
0.15 H)*, 6.79–6.65 (m, 3 H), 5.93 (br s, 1 H), 3.83 (s, 3.73 H)**, 3.82 (s,
2.25 H)*, 3.51 (q, J = 6.4 Hz, 1.64 H)**, 3.41 (q, J = 6.4 Hz, 0.36 H)*,
2.77–2.71 (m, 2 H).
49.4, 46.3, 41.4, 21.4.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16N2NaO: 227.1155; found:
227.1157.
13C NMR (100 MHz, CDCl3): δ = 164.5*, 161.2**, 148.9*, 148.8**,
147.7*, 147.5**, 130.8**, 128.0*, 120.8*, 120.5**, 111.8*, 111.6**,
111.3*, 111.1**, 55.8**, 55.7*, 43.2*, 39.2**, 37.2*, 34.9**.
N-Methyl-N-phenethylacetamide (2zd)
Purified by TLC; pale yellow oil; yield: 34.1 mg (96%).
IR (neat): 3029, 2935, 1651, 1402, 1202, 1129, 1079, 1033, 1005 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H16NO3: 210.1125; found:
210.1122.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
J. Ma et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.33–7.15 (m, 5 H), 3.58 (t, J = 7.6 Hz,
0.98 H), 3.51 (t, J = 7.2 Hz, 1.02 H), 2.95 (s, 1.50 H), 2.88 (s, 1.50 H),
2.84 (t, J = 7.4 Hz, 2 H), 2.07 (s, 1.45 H), 1.85 (s, 1.48 H).
13C NMR (100 MHz, CDCl3): δ = 170.5, 170.4, 139.1*, 138.1**, 128.7,
128.7, 128.6, 128.4, 126.7, 126.2, 52.5**, 49.6*, 36.8*, 34.6**, 33.6**,
33.3*, 21.8*, 20.8**.
N-Methyl-N-phenethylpropanamide (2zi)
Purified by TLC; yellow oil; yield: 36.3 mg (95%).
IR (neat): 3152, 1649, 1402, 1152, 531 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.31–7.15 (m, 5 H), 3.58 (t, J = 7.6 Hz,
1.08 H)**, 3.50 (t, J = 7.4 Hz, 0.92 H)*, 2.96 (s, 1.39 H)*, 2.87 (s, 1.58
H)**, 2.84 (t, J = 7.4 Hz, 2 H), 2.30 (q, J = 7.2 Hz, 1.06 H)**, 2.12 (q, J =
7.6 Hz, 0.91 H)*, 1.14 (t, J = 7.4 Hz, 1.61 H)**, 1.03 (t, J = 7.4 Hz, 1.38
H)*.
.
HRMS (ESI): m/z [M + Na]+ calcd for C11H15NNaO: 200.1046; found:
200.1039.
13C NMR (100 MHz, CDCl3): δ = 173.7*, 173.5**, 139.3**, 138.2*,
128.8*, 128.7**, 128.4, 126.7*, 126.2**, 51.5*, 50.0**, 35.9*, 34.9**,
33.8**, 33.5*, 26.8**, 25.9*, 9.5*, 9.2**.
N-Methyl-N-(naphthalen-1-ylmethyl)acetamide (2ze)38
Purified by TLC; yellow oil; yield: 35.4 mg (83%).
IR (neat): 3140, 1655, 1402, 1262, 1163, 792 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C12H18NO: 192.1383; found:
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 0.66 H), 7.86–7.79
(m, 2.39 H), 7.58–7.21 (m, 4.17 H), 5.06 (s, 1.28 H)**, 4.98 (s, 0.72 H)*,
3.05 (s, 1.12 H)*, 2.83 (s, 1.89 H)**, 2.17 (s, 1.99 H)**, 2.12 (s, 1.23 H)*.
192.1379.
N-Methyl-N-(naphthalen-1-ylmethyl)propanamide (2zj)
13C NMR (100 MHz, CDCl3): δ = 171.6*, 170.4**, 133.8**, 133.7*, 132.6,
131.6, 131.3, 130.6, 129.0, 128.5, 128.4, 128.0, 126.9, 126.5, 126.4,
126.0, 125.9, 125.5, 125.1, 123.8, 122.3*, 121.9**, 52.0*, 48.3**, 34.8**,
34.3*, 22.0**, 21.2*.
HRMS (ESI): m/z [M + Na]+ calcd for C14H15NNaO: 236.1046; found:
236.1041.
Purified by TLC; yellow oil; yield: 37.3 mg (82%).
IR (neat): 3144, 1651, 1510, 1403, 1256, 1120, 1066, 794 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 0.64 H), 7.92–7.78
(m, 2.39 H), 7.58–7.50 (m, 3.11 H), 7.32 (d, J = 7.2 Hz, 0.64 H), 7.20 (d,
J = 7.2 Hz, 0.37 H), 5.07 (s, 1.27 H)**, 4.99 (s, 0.73 H)*, 3.07 (s, 1.06 H)*,
2.82 (s, 1.89 H)**, 2.44–2.32 (m, 2 H), 1.22 (t, J = 7.4 Hz, 1.90 H), 1.14
(t, J = 7.6 Hz, 1.19 H).
13C NMR (100 MHz, CDCl3): δ = 174.7*, 173.6**, 133.8**, 133.7*,
132.9**, 131.7**, 131.6*, 130.6*, 129.0*, 128.5**, 128.3**, 127.9*,
127.0*, 126.4**, 126.0*, 125.9**, 125.6*, 125.1**, 123.9, 122.3*,
121.9**, 51.0*, 48.5**, 34.5*, 34.0**, 26.9**, 26.1*, 9.5*, 9.4**.
5-Acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (2zf)39
Purified by TLC; pale yellow oil; yield: 30.8 mg (85%).
IR (neat): 3111, 3014, 2928, 2850, 1634, 1403, 1241, 1217, 1010 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.16–7.13 (m, 1 H), 6.81–6.78 (m, 1 H),
4.67 (s, 1.05 H)**, 4.55 (s, 0.95 H)*, 3.91 (t, J = 5.6 Hz, 0.95 H)*, 3.74 (t,
J = 5.6 Hz, 1.07 H)**, 2.92 (t, J = 5.6 Hz, 1.08 H)**, 2.86 (t, J = 5.6 Hz,
0.93 H)*, 2.19 (s, 1.59 H)**, 2.17 (s, 1.38 H)*.
HRMS (ESI): m/z [M + Na]+ calcd for C15H17NNaO: 250.1202; found:
250.1196.
1-(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-5-yl)propan-1-one
(2zk)
13C NMR (100 MHz, CDCl3): δ = 169.6*, 169.4**, 134.3*, 132.3**,
132.0*, 131.0**, 125.1**, 124.3*, 123.5*, 123.3**, 46.3*, 44.1**, 42.3**,
39.4*, 25.5**, 24.6*, 21.9*, 21.5**.
Purified by TLC; pale yellow oil; yield: 23.4 mg (60%).
IR (neat): 3122, 1648, 1429, 1402, 1264, 1224, 1046, 889, 706 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C9H11NSNaO: 204.0454; found:
1H NMR (400 MHz, CDCl3): δ = 7.16–7.13 (m, 1 H), 6.82–6.78 (m, 1 H),
4.68 (s, 1.06 H)**, 4.55 (s, 0.94 H)*, 3.93 (t, J = 5.6 Hz, 0.96 H)*, 3.75 (t,
J = 5.8 Hz, 1.05 H)**, 2.91 (t, J = 5.6 Hz, 1.11 H)**, 2.86 (t, J = 5.6 Hz,
0.95 H)*, 2.48–2.39 (m, 2 H), 1.22–1.16 (m, 3 H).
204.0452.
N-Benzylacetamide (2zg)40
Purified by TLC; colorless solid; yield: 25.6 mg (86%); mp 62–63 °C.
13C NMR (100 MHz, CDCl3): δ = 172.9, 172.7, 134.5, 132.6, 132.1,
131.2, 125.2, 124.4, 123.5, 123.3, 45.4*, 43.3**, 42.6**, 39.7*, 27.0*,
26.8**, 25.7**, 24.7*, 9.5**, 9.3*.
HRMS (ESI): m/z [M + Na]+ calcd for C10H13NSNaO: 218.0610; found:
218.0603.
IR (neat): 3282, 1651, 1556, 1402, 1290, 1079, 1031 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H), 6.13 (br s, 1 H),
4.39 (d, J = 6.0 Hz, 2 H), 1.99 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.0, 138.2, 128.6, 127.8, 127.4, 43.6,
23.2.
.
HRMS (ESI): m/z [M + Na]+ calcd for C9H11NNaO: 172.0733; found:
172.0728.
N-Benzylpropanamide (2zl)41
Purified by TLC; yellow oil; yield: 21.2 mg (65%).
IR (neat): 3289, 1651, 1554, 1402, 1236, 1105, 1031, 732, 699 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m, 5 H), 5.93 (br s, 1 H),
4.42 (d, J = 5.6 Hz, 2 H), 2.24 (q, J = 7.6 Hz, 2 H), 1.17 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.6, 138.3, 128.6, 127.7, 127.4, 43.5,
29.6, 9.8.
.
1-(4-Phenylpiperazin-1-yl)propan-1-one (2zh)
Purified by TLC; yellow oil; yield: 40.2 mg (92%).
IR (neat): 3137, 1653, 1601, 1498, 1402, 1230, 1157, 1029 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.31–7.27 (m, 2 H), 6.94–6.89 (m, 3 H),
3.78 (t, J = 4.8 Hz, 2 H), 3.62 (t, J = 4.6 Hz, 2 H), 3.18–3.14 (m, 4 H), 2.39
(q, J = 7.6 Hz, 2 H), 1.18 (t, J = 7.6 Hz, 3 H).
.
HRMS (ESI): m/z [M + Na]+ calcd for C10H13NNaO: 186.0889; found:
186.0890.
13C NMR (100 MHz, CDCl3): δ = 172.2, 150.9, 129.1, 120.4, 116.5, 49.6,
49.3, 45.2, 41.3, 26.4, 9.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H18N2NaO: 241.1311; found:
241.1305.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
J. Ma et al.
Paper
Synthesis
Funding Information
Vogt, M.; DeRose, V. J.; Burgess, K. J. Am. Chem. Soc. 2002, 124,
11946. (f) Wu, M.; Wang, B.; Wang, S.; Xia, C.; Sun, W. Org. Lett.
2009, 11, 3622. (g) Maayan, G.; Christou, G. Inorg. Chem. 2011,
50, 7015.
Financial support from the National Natural Science Foundation of
China (No. 21402168), Scientific Research Foundation of Hunan Pro-
vincial Education Department (No. 15B232) is gratefully acknowl-
(7) (a) Vasilenko, V.; Blasius, C. K.; Wadepohl, H.; Gade, L. H. Angew.
Chem. Int. Ed. 2017, 56, 8393. (b) Bauer, J. O.; Chakraborty, S.;
Milstein, D. ACS Catal. 2017, 7, 4462. (c) Bruneau-Voisine, A.;
Wang, D.; Dorcet, V.; Roisnel, T.; Darcel, C.; Sortais, J.-B. Org.
Lett. 2017, 19, 3656. (d) Ma, X.; Zuo, Z.; Liu, G.; Huang, Z. ACS
Omega 2017, 2, 4688. (e) Elangovan, S.; Garbe, M.; Jiao, H.;
Spannenberg, A.; Junge, K.; Beller, M. Angew. Chem. Int. Ed.
2016, 55, 15364.
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610267.
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Lankinen, M. P.; Kettunen, M.; Leskelä, M.; Repo, T. Organome-
tallics 2007, 26, 980. (b) Nabika, M.; Seki, Y.; Miyatake, T.;
Ishikawa, Y.; Okamoto, K.; Fujisawa, K. Organometallics 2004,
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