Visible-Light-Mediated Synthesis of Amides from Aldehydes and Amines via in Situ Acid Chloride Formation

Article abstract of DOI:10.1021/acs.joc.5b02726

An efficient visible-light photocatalysis-based one-pot amide synthesis method was developed; visible-light irradiation of a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-chlorosuccinimide using a Ru(bpy)₃Cl₂ photocatalyst afforded an acid chloride, which subsequently reacted with amine to yield the corresponding amide. The reaction was used to synthesize moclobemide and a D3 receptor intermediate.

Full text of DOI:10.1021/acs.joc.5b02726

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Article
Visible-light-mediated synthesis of amides from
aldehydes and amines via in-situ acid chloride formation
Naeem Iqbal, and Eun Jin Cho
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02726 • Publication Date (Web): 02 Feb 2016
Downloaded from http://pubs.acs.org on February 5, 2016
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Visible-light-mediated synthesis of amides from aldehydes and
amines via in-situ acid chloride formation
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a
Naeem Iqbal and Eun Jin Cho*
,b
a
Department of Chemistry and Applied Chemistry, Hanyang University, Ansan 426-791, Republic of Korea
b
Department of Chemistry, Chung-Ang University, Seoul 156-756, Republic of Korea
[
Phone: (82)-2-820-5946, E-mail: ejcho@cau.ac.kr]
ABSTRACT
An efficient visible-light photocatalysis-based one-pot amide synthesis method was developed;
visible-light irradiation of a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-
chlorosuccinimide using Ru(bpy) Cl2 photocatalyst afforded an acid chloride, which
3
subsequently reacted with amine to yield the corresponding amide. The reaction was used to
synthesize moclobemide and a D3 receptor intermediate.
Introduction
The amide bond is one of the most important bonds in biological macromolecules, and almost
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5% of the drug molecules contain an amide bond. Because of the high stability, polarity, and
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conformational diversity of amide bonds, they have been used in synthetic intermediates to
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g
functional materials. Owing to the importance of amide bonds, intensive efforts have been
made to develop methods for the construction of the amide bonds. Conventionally, amide bonds
are constructed by coupling of carboxylic acid derivatives with amines using certain activating
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groups [Figure 1. (1)]. Recently, a plethora of methods have been developed for the construction
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of amide bonds, including the transition-metal-catalyzed and N-heterocyclic carbene (NHC)-
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5–7
catalyzed oxidative amidation of aldehydes with amines. However, these direct oxidative
amidation of aldehydes has some limitations, mainly the limited substrate scope of amines, and
thus the acylation of amines by activated acid derivatives is still the major method for the
synthesis of amides. Therefore, alternative efforts have been made for the conversion of
aldehydes to activated intermediates that can be utilized in situ for the synthesis of amides.
Recently, Yamamoto, Barbas, and Luca independently reported the synthesis of amides from
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,9,10
aldehydes through the formation of activated intermediates via acyl radicals [Figure 1. (2)].
The facile synthesis of active intermediates from aldehydes prompted us to develop a visible-
light-induced one-pot method for the synthesis of amides. In the process, an acyl radical
generated from an aldehyde by visible-light photocatalysis using tert-butyl hydrogen peroxide
(
TBHP) as the oxidant was converted to the corresponding acid chloride intermediate by
11,12
abstracting a Cl radical from N-chlorosuccinimide (NCS).
Then, the addition of an amine to
the acid chloride intermediate afforded the corresponding amide [Figure 1. (3)].
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Figure 1. Amide bond formation via active intermediates.
Results and Discussion
First, benzaldehyde (1a) was converted into benzoyl chloride using TBHP and NCS as the
source of Cl in CH CN, and only 30% of benzoyl chloride (2a) was obtained (Table 1, entry 1).
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We envisioned that the combined use of visible-light photocatalytic conditions would accelerate
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3,14
the reaction since TBHP can produce radicals under visible-light conditions.
To our delight,
the use of Ru(bpy) Cl under visible-light irradiation increased the yield of 2a to 78% (Table 1,
3
2
entry 2). A control experiment showed that the reaction requires visible-light irradiation for a
satisfactory conversion of benzaldehyde to benzoyl chloride (Table 1, entry 3). A decrease in the
amount of NCS decreased the yield of the reaction, and a further increase in the amount of NCS
did not increase the yield (Table 1, entries 4–6). On the other hand, the yield of the reaction
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increased with a less amount of TBHP, even a catalytic amount of TBHP was effective contrary
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reaction or acts as an initiator (Table 1, entries 7–11).
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Table 1. Oxidation of aldehyde to acid halide
O
O
1 mol% Ru(bpy) Cl2
3
NCS, oxidant
H
Cl
solvent (0.2 M), rt
Blue LEDs (7 W), 24 h
1
a
2a
yield (%)b
entry
Oxidant
equiv)
equiv of
solvent
variations
(
NCS
2a
tBuOOH (4.0)
tBuOOH (4.0)
tBuOOH (4.0)
1
2
3
3.0
3.0
3.0
CH3CN
no Ru(bpy) Cl2
30
78
32
3
CH CN
3
CH CN
no light
3
tBuOOH (4.0)
tBuOOH (4.0)
tBuOOH (4.0)
tBuOOH (2.5)
tBuOOH (1.3)
tBuOOH (1.0)
tBuOOH (0.6)
4
5
6
7
8
9
1.5
2.0
3.5
3.0
3.0
3.0
3.0
CH CN
17
56
70
82
84c
80
75
3
CH CN
3
CH CN
3
CH3CN
CH3CN
CH3CN
CH3CN
10
11 tBuOOH (0.25)
3.0
-
CH3CN
68
46d
84
0
tBuOOH (1.3)
12
CH3CN NBS (3.0 equiv)
tBuOOH (1.3)
13
3.0
3.0
CH Cl2
2
14 tBuOOH (1.3)
DMF
tBuOOH (1.3)
tBuOOH (1.3)
1
1
1
1
1
2
2
5
6
7
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9
0
1
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
CH OH
38
85
3
CH CN
0.25 M
3
t
BuOOH (1.3)
CH CN
3
0.1 M
64
t
BuOOH (1.3)
CH CN
3
2.0 mol% cat.
0.5 mol% cat.
0.1 mol% cat.
84
tBuOOH (1.3)
tBuOOH (1.3)
CH CN
80
3
CH CN
77
3
O2
CH CN
3
trace
0
22
-
CH CN Degassed CH CN
3
3
a
b
reaction scale: 1a (0.1 mmol), yields based on GCMS using dodecane as the internal standard, addition of benzyl
c
d
amine afforded the corresponding amide in 78% yield, yield of benzoyl bromide, which was formed along with
benzoic acid and tert-butyl ester.
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The use of N-bromosuccinimide (NBS) instead of NCS afforded a mixture of undesired
products because of the higher reactivity of benzoyl bromide compared to benzoyl chloride
(
Table 1, entry 12). Different photocatalysts including Ru(phen) Cl , fac-Ir(ppy) , fac-Ir(dFppy) ,
3 2 3 3
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and Ir(dtbbpy)(ppy) PF were investigated; they showed a similar reactivity. Among the catalysts,
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Ru(bpy) Cl was selected because of its low cost and easy availability. CH CN was the best
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2
3
solvent (Table 1, entries 13–15). The concentration studies showed that the use of 0.25 M
concentration provided the best results (Table 1, entries 8, 16, and 17). Although a satisfactory
conversion was achieved even by using 0.1 mol% of the photocatalyst, 1 mol% of the
photocatalyst was selected for further studies for the reproducible results (Table 1, entries 8 and
18–20). When O was used as the oxidant, the yield decreased significantly (Table 1, entries 21
2
and 22).
With the optimized conditions for the conversion of aldehydes to acid chlorides, a one-pot
method was developed for the synthesis of amides. The addition of benzyl amine to a reaction
mixture of benzoyl chloride (2a) afforded N-benzylbenzamide (3a) in 78% yield. This one-pot
method was applied for the synthesis of amides from diverse benzaldehyde derivatives 1 (Table
2). The reactions of aldehydes bearing both electron-rich and deficient aryl substituents
proceeded smoothly, affording the corresponding amides 3 in good yields. The substituents at the
ortho position of the aryl ring did not affect the reactivity (3b and 3i). The reaction tolerated the
presence of a nitrile group (3k) and halides including fluoro (3g), chloro (3h), 3i), and bromo
(3j). However, some side reactions were also observed. In the reactions of 1b, 1c, and 1d, the
benzylic chlorination afforded 5–10% of chlorinated products along with the desired amides 3b,
3c, and 3d, respectively. In the reaction of 1f, aryl chlorinated products were also detected.
Aliphatic aldehydes were not suitable substrates because the decarbonylative products were
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obtained. This is probably because of the lower stability of aliphatic acyl radicals compared to
the benzoyl radical, causing the degradation of radicals before the abstraction of a chlorine
radical from NCS.
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Table 2. Amide Synthesis from aldehydes via acid chlorides: substrate scope with respect to
a,b
benzaldehydes
1
mol% Ru(bpy) Cl
3 2
O
O
O
tBuOOH (1.3 equiv)
Bn
Bn
Bn
H
Cl H2N
N
NCS (3 equiv)
R
R
R
H
CH CN (0.25 M), rt
Blue LEDs (7 W), 24 h
3 h
3
1
2
3
O
O
O
O
Bn
Bn
Bn
N
N
N
N
H
H
H
H
Me
3b, 65%
Me
3a, 78%
3c, 70%
3d, 72%
O
O
O
O
Bn
Bn
Bn
Bn
Bn
Bn
N
H
N
H
N
N
H
H
Ph
Br
F
Cl
3
e, 85%
3f, 83%
3g, 84%
3h, 83%
Cl
O
O
O
O
Bn
Bn F3C
N
N
H
N
N
H
H
H
Cl
NC
3
i, 77%
3j, 87%
3k, 79%
3l, 76%
a
b
reaction scale: 1 (1.0 mmol), benzyl amine (1.5 mmol). Isolated yields based on the average of two runs.
Further, we studied the substrate scope with respect to different amines for the synthesis of
amides (Table 3). Both aromatic and aliphatic amines participated well in the reaction. In general,
benzyl amines (4e and 4f) showed better reactivity. The successful amide formation with an
aminopyridine (4d) indicates that the reaction can be applied to the synthesis of amide bonds
containing heterocycles, important structural motifs in many applications including
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pharmaceuticals.
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Table 3. Amide Synthesis from aldehydes via acid chlorides: Substrate scope with respect to
a,b
amines
1
mol% Ru(bpy) Cl2
O
3
O
O
R2 R1
tBuOOH (1.3 equiv)
R2
N
H
Cl
H
N
NCS (3 equiv)
R1
CH CN (0.25 M), rt
Blue LEDs (7 W), 24 h
3 h
3
1a
2a
4
F
O
O
O
O
N
Ph
N
H
Ph
N
Ph
N
H
Ph
N
H
Br
O
H
Br
4
a, 68%
4b, 64%
4c, 66%
4d, 58%
O
O
Ph
N
Ph
N
H
H
Ph
N
H
4
OMe
F
4e, 82%
4f, 79%
4g, 73%
O
O
O
N
Ph
N
Ph
N
Ph
N
H
4h, 61%
4i, 63%
4j, 62%
a
b
reaction scale: 1 (1.0 mmol), amine (1.5 mmol). Isolated yields based on the average of two runs.
The facile reaction developed in this study prompted us to synthesize some drug molecules
1
6
using the reaction conditions. An antidepressant moclobemide (6) was synthesized from 4-
chlorobenzaldehyde (1h) and 2-morpholinoethan-1-amine (5) in 77% yield [Scheme 1. (1)]. A
D3 receptor intermediate 11 was also synthesized from 4-bromobenzaldehyde (1i) and an amine
intermediate 10 in 65% yield; compound 11 was converted to D3 receptor GR103691 following
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a known procedure [Scheme 1. (2)]. These results indicate that the developed method for the
synthesis of amides is applicable to the synthesis of natural products and pharmaceutically and
industrially relevant compounds.
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Scheme 1. Synthesis of antidepressant Moclobemide 6 and D3 receptor GR103691.
1
mol% Ru(bpy) Cl
O
O
3
2
O
tBuOOH (1.3 equiv)
N
Cl
H N
(1)
H
2
NCS (3 equiv)
5
CH CN (0.25 M), rt
Blue LEDs (7 W), 24 h
Cl
Cl
3
2h
1h
O
O
Moclobemide
(antidepressant)
N
N
H
Cl
6
, 77%
O
Br
N
N
K CO (2 equiv)
O
2
3
+
N
OMe
N
N
O
O
OMe CH CN, 50 oC
HN
3
9
7
90%
8
N H (4 equiv)
2 4
MeOH, 64 oC, 86%
O
1 mol% Ru(bpy) Cl
tBuOOH (1.3 equiv)
O
N
3
2
N
OMe
H
Cl
H N
2
NCS (3 equiv)
10
(2)
Br
Br
CH CN (0.25 M), rt
Blue LEDs (7 W), 24 h
3
1i
2i
O
N
O
N
N
OMe
N
N
OMe
H
N
ref. 16a
H
D3 receptor
GR103691
Br
11, 65%
D3 receptor intermediate
O
Next, a one-pot method was investigated for the synthesis of esters from aldehydes and alcohols
instead of amines. Although various alcohols, such as methanol, ethanol, isopropanol, hexanol,
benzyl alcohol, and phenol were tried, only reaction with methanol afforded the corresponding
methyl benzoate 12 in a reasonable yield (Scheme 2).
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Scheme 2. Visible-light-mediated ester synthesis from benzaldehyde and methanol.
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Figure 2. Proposed mechanism
Based on the results of the above mentioned studies, a plausible mechanism is proposed for the
18
synthesis of amides using benzaldehyde 1a and benzyl amine outlined in Figure 2. The
II 2+
photoexcitation of [Ru (bpy) ] produces the metal-to-ligand charge-transfer excited state
3
III
-
2+
t
[
Ru bpy• (bpy) ] , which is oxidatively quenched by a single-electron transfer to BuOOH,
2
t
generating the key intermediates BuO• and OH, along with [Ru (bpy) ] . Hydrogen
-
III
3+
3
t
t
11
abstraction by BuO• from benzaldehyde (1a) affords acyl radical 2a′ and BuOH. This acyl
radical further abstracts a Cl radical from NCS, generating succinimide radical intermediate A
and benzoyl chloride (2a). Then, the addition of benzyl amine to the reaction mixture affords N-
benzylbenzamide (3a) by a substitution reaction. On the other hand, a single-electron transfer
t
from BuOO , which is generated by the deprotonation of BuOOH with OH, to [Ru (bpy) ]
-
t
-
III
3+
3
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II 2+ 11
regenerates the photocatalyst, [Ru (bpy) ] . The conversion of aldehydes to acid chlorides
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works even with a sub-stoichiometric amount of TBHP (Table 1, entries 9 and 10); this is
t
supported by the following pathways: (a) BuOO• abstracts a H• from aldehyde 1a, affording 2a′
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intermediate and regenerating TBHP, (b) the H• abstraction by succinimide radical A from
aldehyde C–H also generates 2a′ with succinimide B.
In conclusion, we developed an efficient one-pot method for the synthesis of amides from
aldehydes and amines. The amide bonds were constructed from aldehydes via the in-situ
formation of acid chlorides using Ru(bpy) Cl as the photocatalyst and TBHP as the oxidant
3
2
under visible-light irradiation. The new method is a practical and efficient for the synthesis of
amides from different benzaldehyde derivatives and diverse aliphatic and aromatic amines. The
process was successfully applied to the synthesis of drug molecules, an antidepressant
moclobemide and a D3 receptor intermediate.
EXPERIMENTAL SECTION
General experimental procedure for amide synthesis
An oven-dried resealable tube, equipped with a magnetic stir bar, was charged with an aldehyde
(1.0 mmol), Ru(bpy) Cl (1 mol%), TBHP (1.3 equiv), NCS (3.0 equiv), and CH CN (0.25 M).
3 2 3
The tube was stoppered with a silicone septa screw-cap and placed under blue LEDs at room
temperature. After 24 h irradiation, amine (1.5 equiv) was added, and the reaction was stirred for
3 h. The progress of the reaction was monitored by TLC and GC. After the completion of the
reaction, the reaction mixture was diluted with ethyl acetate. After the aqueous work-up, the
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organic layers were combined, dried over MgSO , and concentrated in vacuo. The residue was
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purified by flash column chromatography, affording the desired amide product.
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In the reactions for 4h, 6, and 11, before the addition of amines, the reaction mixture was
concentrated in vacuo, dissolved in a 1% TEA/hexane solution and filtered.
Analytic Data for amides
5
e
1
N-benzylbenzamide (3a): white solid (165 mg, 78%); H NMR (600 MHz, CDCl ) δ 7.77
3
(d, J = 7.8 Hz, 2H), 7.48–7.42 (m, 1H), 7.40–7.34 (m, 2H), 7.34–7.28 (m, 4H), 7.28–7.24 (m,
1
3
1
1
6
H), 6.84 (bs, 1H), 4.57 (d, J = 6.0 Hz, 2H). C NMR (151 MHz, CDCl ) δ 167.6, 138.5, 134.5,
3
31.6, 128.8, 128.7, 127.9, 127.6, 127.2, 44.2. IR (neat): νmax = 3318, 3058, 1639, 1538, 1310,
-1
91 cm ; R 0.45 (hexane/ethyl acetate 2:1).
f
1
9b
1
white solid (146 mg, 65%); H NMR (600 MHz,
N-benzyl-2-methylbenzamide (3b):
CDCl ) δ 7.39 − 7.27 (m, 7H), 7.24 − 7.15 (m, 2H), 6.20 (bs, 1H), 4.60 (d, J = 6.0 Hz, 2H),
3
1
3
2
.44 (s, 3H). C NMR (151 MHz, CDCl ) δ 170.0, 138.1, 136.5, 136.1, 131.1, 130.0, 128.8,
3
127.8, 127.2, 126.7, 125.7, 43.9, 19.8. IR (neat): νmax = 3308, 1647, 1541, 1200, 1000, 735, 698
-1
cm ; R 0.36 (hexane/ethyl acetate 3:1).
f
5
e
1
N-benzyl-4-methylbenzamide (3c): white solid (158 mg, 70%); H NMR (600 MHz,
CDCl ) δ 7.69 (d, J = 8.4 Hz, 2H), 7.38–7.32 (m, 4H), 7.31–7.27 (m, 1H), 7.22 (d, J = 8.4 Hz,
3
13
2
1
1
H), 6.47 (bs, 1H), 4.63 (d, J = 6.0 Hz, 2H), 2.39 (s, 3H). C NMR (151 MHz, CDCl ) δ 167.5,
3
42.2, 138.5, 131.7, 129.4, 129.0, 128.1, 127.8, 127.2, 44.3, 21.6. IR (neat): νmax = 3309, 1637,
-1
544, 1506, 907, 841, 721 cm ; R 0.36 (hexane/ethyl acetate 3:1).
f
1
N-benzyl-4-isopropylbenzamide (3d): white solid (182 mg, 72%); H NMR (600 MHz,
CDCl ) δ 7.73 (d, J = 8.4 Hz, 2H), 7.38–7.33 (m, 4H), 7.32–7.26 (m, 1H), 7.28 (d, J = 8.4 Hz,
3
2H), 6.39 (bs, 1H), 4.65 (d, J = 6.0 Hz, 2H), 2.95 (hept, J = 7.2 Hz, 1H), 1.26 (d, J = 6.6 Hz, 6H).
1
3
C NMR (151 MHz, CDCl ) δ 167.5, 153.0, 138.5, 132.1, 129.0, 128.1, 127.8, 127.3, 126.9,
3
-1
44.3, 34.3, 24.0. IR (neat): νmax = 3319, 1636, 1541, 1506, 1311, 852, 697 cm ; R 0.45
f
(hexane/ethyl acetate 3:1).
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19f
N-benzyl-4-(tert-butyl)benzamide (3e): white solid (227 mg, 85%); H NMR (600 MHz,
1
CDCl ) δ 7.77 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.37–7.32 (m, 4H), 7.31–7.28 (m,
3
1
3
1
H), 6.48 (bs, 1H), 4.64 (d, J = 6.0 Hz, 2H), 1.44 (s, 9H). C NMR (151 MHz, CDCl ) δ 167.4,
3
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
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2
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4
5
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7
8
9
0
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2
3
4
5
6
7
8
9
0
150.1, 138.3, 132.6, 129.0, 128.1, 127.8, 127.2, 126.5, 44.3, 40.3, 26.7. IR (neat): νmax = 3318,
-1
1
732, 1708, 1540, 1152, 698, 645 cm ; R 0.52 (hexane/ethyl acetate 2:1).
f
19c 1
N-benzyl-[1,1'-biphenyl]-4-carboxamide (3f): white solid (239 mg, 83%); H NMR (600
MHz, CDCl ) δ 7.87 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.61–7.57 (m, 2H), 7.47–7.43
3
(m, 2H), 7.40–7.37 (m, 1H), 7.37–7.33 (m, 4H), 7.32–7.28 (m, 1H), 6.66 (bs, 1H), 4.66 (d, J =
1
3
6
1
6
.0 Hz, 2H). C NMR (151 MHz, CDCl ) δ 167.3, 144.5, 140.1, 138.4, 133.1, 129.1, 129.0,
3
28.2, 128.1, 127.8, 127.7, 127.4, 127.4, 44.3. IR (neat): νmax = 3326, 1701, 1636, 1541, 745,
-1
92 cm ; R 0.52 (hexane/ethyl acetate 2:1).
f
7
N-benzyl-4-fluorobenzamide (3g): white solid (193 mg, 84%); H NMR (600 MHz,
e
1
CDCl ) δ 7.79 (dd, J = 9.0 Hz, JH-H = 5.4 Hz, 2H), 7.36–7.31 (m, 4H), 7.31–7.27 (m, 1H),
3
H-F
1
.07 (dd, JH-F = 9.0 Hz, JH-H = 8.4 Hz, 2H), 6.62 (bs, 1H), 4.60 (d, J = 6.0 Hz, 2H). C NMR
3
7
(
151 MHz, CDCl ) δ 166.6, 164.9 (d, J = 252.17 Hz), 138.3, 130.7 (d, J = 3.02 Hz), 129.5 (d, J =
3
9
.06 Hz), 129.0, 128.1, 127.8, 115.8, 115.7, 44.4. IR (neat): νmax = 1654, 1497, 1264, 906, 726
-1
cm ; R 0.39 (hexane/ethyl acetate 3:1).
f
5
N-benzyl-4-chlorobenzamide (3h): white solid (204 mg, 83%); H NMR (600 MHz,
e
1
CDCl ) δ 7.72 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.37–7.31 (m, 4H), 7.31–7.27 (m,
3
1
3
1
H), 6.54 (bs, 1H), 4.61 (d, J = 5.4 Hz, 2H). C NMR (151 MHz, CDCl ) δ 166.5, 138.2, 138.0,
3
132.9, 129.0, 128.6, 128.1, 127.9, 44.4. IR (neat): νmax = 3309, 1637, 1552, 1487, 1320, 1013,
-1
8
49, 711, 669 cm ; R 0.58 (hexane/ethyl acetate 2:1).
f
1
N-benzyl-2,4-dichlorobenzamide (3i): white solid (216 mg, 77%); H NMR (600 MHz,
CDCl ) δ 7.58 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.38–7.32 (m, 4H), 7.32–7.26 (m,
3
1
3
2
H), 6.65 (bs, 1H), 4.61 (d, J = 6.0 Hz, 2H). C NMR (151 MHz, CDCl ) δ 165.6, 137.7, 137.0,
3
133.5, 131.7, 131.4, 130.2, 129.0, 128.0, 127.9, 127.7, 44.5. IR (neat): νmax = 3263, 1644, 1587,
-1
1
540, 830, 743, 693 cm ; R 0.58 (hexane/ethyl acetate 2:1).
f
7e
N-benzyl-4-bromobenzamide (3j): white solid (252 mg, 87%); H NMR (600 MHz,
1
CDCl ) δ 7.65 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.38–7.31 (m, 4H), 7.31–7.28 (m,
3
1
3
1H), 6.42 (bs, 1H), 4.62 (d, J = 5.4 Hz, 2H). C NMR (151 MHz, CDCl ) δ 166.6, 138.1, 133.4,
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32.0, 129.1, 128.8, 128.2, 128.0, 126.5, 44.5. IR (neat): νmax = 3311, 1638, 1549, 1322, 1011,
-1
47, 669 cm ; R 0.58 (hexane/ethyl acetate 2:1).
8
f
1
9c
1
white solid (187 mg, 79%); H NMR (600 MHz,
N-benzyl-4-cyanobenzamide (3k):
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16
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18
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CDCl ) δ 7.87 (d, J = 8.4, 2H), 7.64 (d, J = 8.4, 2H), 7.36–7.24 (m, 5H),7.23 (bs, 1H) 4.58 (d, J
3
1
3
=
5.6, Hz, 2H). C NMR (151 MHz, CDCl ) δ 165.9, 138.2, 137.8, 132.4, 128.8, 127.9, 127.8,
3
-1
1
18.1, 114.9, 44.2. IR (neat): νmax = 3309, 1708, 1540, 1158, 906, 722 cm ; R 0.41
f
(
hexane/ethyl acetate 3:1).
N-benzyl-3-(trifluoromethyl)benzamide (3l): white solid (212 mg, 76%); H NMR (600
MHz, CDCl ) δ 8.05 (t, J = 1.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.53
1
9d
1
3
(
dd, J = 7.8 Hz, 1H), 7.37–7.32 (m, 4H), 7.32–7.27 (m, 1H), 6.77 (bs, 1H), 4.62 (d, J = 5.4 Hz,
1
3
2
H). C NMR (151 MHz, CDCl ) δ 166.2, 138.0, 135.4, 131.3 (q, J = 32.78 Hz), 130.5, 129.4,
3
129.0, 128.3 (q, J = 3.6 Hz), 128.1, 128.0, 124.3 (q, J = 3.6 Hz), 123.9 (q, J = 272.71 Hz), 44.5.
-1
IR (neat): νmax = 3295, 1641, 1541, 1333, 1278, 1168, 1125, 696 cm ; R 0.41 (hexane/ethyl
f
acetate 3:1).
5b
1
N-phenylbenzamide (4a): white solid (134 mg, 68%); H NMR (600 MHz, DMSO-d ) δ
6
1
0.03 (bs, 1H), 7.93 (dd, J = 8.4, 1.2 Hz, 2H), 7.75 (dd, J = 8.4, 1.2 Hz, 2H), 7.49 (tt, J = 7.2, 1.2
Hz, 1H), 7.44 (dd, J = 8.4, 1.2 Hz, 2H), 7.27 (dd, J = 8.4, 7.2 Hz, 2H), 7.04 (tt, J = 7.2, 1.2 Hz,
1
3
1
H). C NMR (151 MHz, DMSO-d ) δ 164.7, 137.9, 134.0, 130.0, 127.2, 126.9, 126.4, 122.4,
6
-1
1
19.3. IR (neat): νmax = 3347, 1652, 1525, 1407, 1216, 827, 716, 644 cm ; R 0.41
f
(
hexane/ethyl acetate 3:1).
N-(2-bromophenyl)benzamide (4b): white solid (177 mg, 64%); H NMR (600 MHz,
CDCl ) δ 8.56 (dd, J = 8.4, 1.2 Hz, 1H), 8.47 (bs, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.63–7.55 (m,
1
9g
1
3
2
H), 7.55–7.49 (m, 2H), 7.38 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.02 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H).
13
C NMR (151 MHz, CDCl ) δ 165.5, 136.0, 134.8, 132.5, 132.4, 129.2, 128.8, 127.3, 125.5,
3
-1
1
22.0, 113.9. IR (neat): νmax = 3280, 1653, 1529, 1435, 1308, 750, 706 cm ; R 0.51
f
(hexane/ethyl acetate 5:1).
5
N-(4-fluorophenyl)benzamide (4c): white solid (142 mg, 66%); H NMR (600 MHz,
b
1
DMSO-d ) δ 10.22 (bs, 1H), 7.97–7.90 (m, 2H), 7.79 (dd, JH-F = 9 Hz, JH-H = 5.4 Hz, 2H), 7.53
6
1
3
(
tt, J = 7.2, 1.6 Hz, 1H), 7.48 (m, 2H), 7.11–7.05 (m, 2H). C NMR (151 MHz, DMSO-d ) δ
6
163.9, 156.8 (d, J = 241.6), 133.9, 133.3, 129.8, 126.6, 126.0, 120.6, 113.3 (d, J = 22.65). IR
-1
(
neat): νmax = 3343, 1654, 1537, 1438, 750, 690 cm ; R 0.45(hexane/ethyl acetate 3:1).
f
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N-(2-bromopyridin-3-yl)benzamide (4d): white solid (161 mg, 58%); H NMR (600 MHz,
1
CDCl ) δ 8.86 (dd, J = 8.4, 1.8 Hz, 1H), 8.49 (bs, 1H), 8.13 (dd, J = 4.8, 1.8 Hz, 1H), 7.93 (dd, J
3
=
8.4, 1.2 Hz, 2H), 7.60 (tt, J = 7.5, 1.6 Hz, 1H), 7.53 (dd, J = 7.8, 7.7 Hz, 2H), 7.32 (dd, J = 7.8,
1
3
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
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4.8 Hz, 1H). C NMR (151 MHz, CDCl ) δ 165.7, 144.8, 134.0, 133.9, 133.6, 132.8, 130.3,
3
-
1
29.3, 128.9, 127.3, 123.9. IR (neat): νmax = 3403, 1684, 1508, 1488, 1381, 1297, 1048, 706 cm
1
;
Rf 0.34 (hexane/ethyl acetate 3:1).
N-(4-methoxybenzyl)benzamide (4e): white solid (198 mg, 82%); H NMR (600 MHz,
CDCl ) δ 7.78 (d, J = 8.4 Hz, 2H), 7.48 (tt, J = 7.5, 1.4 Hz, 1H), 7.41 (dd, J = 7.8, 7.7 Hz, 2H),
4
f
1
3
7
3
1
.28 (dd, J = 8.4, 6.6 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.40 (s, 1H), 4.57 (d, J = 6.0 Hz, 2H),
13
.80 (s, 3H). C NMR (151 MHz, CDCl ) δ 167.5, 159.3, 134.7, 131.7, 130.5, 129.5, 128.8,
3
27.1, 114.4, 55.5, 43.9. IR (neat): νmax = 3308, 3062, 1636, 1534, 1511, 1301, 1246, 1033, 695
-1
cm ; R 0.36 (hexane/ethyl acetate 2:1).
f
1
9c
1
white solid (181 mg, 79%); H NMR (600 MHz,
N-(4-fluorobenzyl)benzamide (4f):
CDCl ) δ 7.81 – 7.77 (m, 2H), 7.51 (tt, J = 7.5, 1.4 Hz, 1H), 7.44 (dd, J = 7.8, 7.7 Hz, 2H), 7.33
3
13
dd, J = 8.4, 5.4 Hz, 2H), 7.04 (dd, J = 8.7, 2H), 6.41 (bs, 1H), 4.62 (d, J = 5.4 Hz, 2H). C
(
NMR (151 MHz, CDCl ) δ 167.5, 163.5 (d, J = 326 Hz), 134.4 (d, J = 48 Hz), 131.9, 129.8 (d, J
3
= 10 Hz), 128.9, 127.1, 115.9, 115.8, 43.6. IR (neat): νmax = 3310, 1637, 1541, 1510, 1222, 692
-1
cm ; R 0.43 (hexane/ethyl acetate 2:1).
f
7d
1
N-hexylbenzamide (4g): colorless liquid (150 mg, 73%); H NMR (600 MHz, CDCl ) δ
3
7
.76 (dd, J = 8.4, 7.2 Hz, 2H), 7.44 (tt, J = 7.2, 1.7 Hz, 1H), 7.36 (dd, J = 7.8 Hz, 2H), 6.60 (bs,
1H), 3.40 (td, J = 7.2, 6.0 Hz, 2H), 1.57 (tt, J = 7.2 Hz, 2H), 1.40–1.30 (m, 2H), 1.30–1.23 (m,
1
3
4
4
0
H), 0.86 (t, J = 7.2 Hz, 3H). C NMR (151 MHz, CDCl ) δ 167.8, 135.0, 131.3, 128.6, 127.0,
3
-1
0.3, 31.6, 29.7, 26.8, 22.7, 14.1. IR (neat): νmax = 3310, 1635, 1540, 1490, 1309, 693 cm ; R
f
.40 (hexane/ethyl acetate 3:1).
1
9c
1
N-(2-(diethylamino)ethyl)benzamide (4h): colorless liquid (134 mg, 61%); H NMR (600
MHz, CDCl ) δ 8.77 (bs, 1H), 8.01 (dd, J = 8.4, 1.2 Hz, 2H), 7.44 (tt, J = 7.5, 1.6 Hz, 1H), 7.39
3
(
dd, J = 7.2, 6.0 Hz, 2H), 3.84 (dd, J = 10.8, 6.0 Hz, 2H), 3.22 (t, J = 5.4 Hz, 2H), 3.11 (q, J =
13
7
.2 Hz, 4H), 1.34 (t, J = 7.2 Hz, 6H). C NMR (151 MHz, CDCl ) δ 167.9, 133.3, 132.0, 128.7,
3
-1
1
27.7, 53.0, 48.5, 36.0, 9.1. IR (neat): νmax = 3363, 1637, 1539, 1488, 1308, 694 cm ; R 0.42
f
(ethyl acetate/methanol 2:1).
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5e
phenyl(piperidin-1-yl)methanone (4i): colorless liquid (119 mg, 63%); H NMR (600 MHz,
1
CDCl ) δ 7.43–7.35 (m, 5H), 3.77–3.65 (m, 2H), 3.40–3.28 (m, 2H), 1.76–1.60 (m, 4H), 1.59 –
3
1
3
1
.41 (m, 2H). C NMR (151 MHz, CDCl ) δ 170.6, 136.5, 129.5, 128.5, 127.0, 49.0, 43.4, 26.7,
3
-1
10
11
12
13
14
15
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17
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19
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33
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35
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37
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39
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25.8, 24.7. IR (neat): νmax = 1713, 1625, 1444, 1274, 1003, 707 cm ; R 0.37 (hexane/ethyl
f
acetate 2:1).
7a
1
N,N-dibutylbenzamide (4j): colorless liquid (145 mg, 62%); H NMR (600 MHz, CDCl ) δ
3
7.38 – 7.30 (m, 5H), 3.48 (t, J = 7.8 Hz, 2H), 3.18 (t, J = 7.8 Hz, 2H), 1.65 (tt, J = 7.8 Hz, 2H),
1.46 (tt, J = 7.8 Hz, 2H), 1.43–1.32 (m, 2H), 1.21-1.05 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 0.76 (t,
1
3
J = 7.2 Hz, 3H). C NMR (151 MHz, CDCl ) δ 171.4, 137.2, 128.8, 128.1, 126.2, 48.6, 44.3,
3
-1
30.6, 29.5, 20.1, 19.5, 13.7, 13.4. IR (neat): νmax = 2956, 1627, 1421, 1296, 1100, 698 cm ; R
f
0.49 (hexane/ethyl acetate 5:1).
1
4-chloro-N-(2-morpholinoethyl)benzamide (6): white solid (207 mg, 77%); H NMR (600
6
1
MHz, CDCl ) δ 7.71 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.79 (bs, 1H), 3.75–3.65 (m,
3
1
3
4
1
1
H), 3.58–3.50 (m, 2H), 2.63–2.56 (m, 2H), 2.57–2.43 (m, 4H). C NMR (151 MHz, CDCl ) δ
3
66.5, 137.8, 133.2, 129.0, 128.6, 67.1, 57.0, 53.5, 36.3. IR (neat): νmax = 3309, 1646, 1541,
-1
487, 1312, 1116, 1093, 860 cm ; R 0.50 (ethyl acetate/methanol 4:1).
f
1
7b
2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)isoindoline-1,3-dione (9):
Yellowish
1
solid; H NMR (600 MHz, CDCl ) δ 7.82 (dd, J = 5.4, 3.0 Hz, 2H), 7.69 (dd, J = 5.4, 3.0 Hz,
3
2H), 6.97 (ddd, J = 7.8, 7.2, 2.4 Hz, 1H), 6.92 (dd, J = 7.8, 2.4 Hz, 1H), 6.89 (ddd, J = 7.5, 1.4
Hz, 1H)6.83 (dd, J = 7.8, 1.2 Hz, 1H), 3.84 (s, 3H), 3.71 (t, J = 7.8 Hz, 2H), 3.21–2.95 (m, 4H),
2.73–2.55 (m, 4H), 2.44 (t, J = 7.8 Hz, 2H), 1.72 (tt, J = 7.8 Hz, 2H), 1.57 (tt, J = 7.8 Hz, 2H).
1
3
C NMR (151 MHz, CDCl ) δ 168.6, 152.4, 141.5, 134.0, 132.3, 123.3, 123.0, 121.1, 118.3,
3
111.3, 58.2, 55.4, 53.5, 50.7, 38.0, 26.7, 24.3. IR (neat): νmax = 3280, 1653, 1529, 1435, 1308,
-1
50, 706 cm ; R 0.68 (ethyl acetate/methanol 10:1).
7
f
1
7b
4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-1-amine (10):
greenish yellow viscous
1
liquid; H NMR (600 MHz, CDCl ) δ 6.98 (dd, J = 7.8, 7.2 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H),
3
6.91 (dd, J = 7.8, 7.2 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 3.85 (s, 3H), 3.25–3.0 (m, 4H), 2.73 (t, J
=
7.2 Hz, 2H), 2.70–2.58 (m, 4H), 2.42 (t, J = 7.2 Hz, 2H), 2.33 (bs, 2H), 1.58 (tt, J = 7.2 Hz,
1
3
2H), 1.51 (tt, J = 7.2 Hz, 2H). C NMR (151 MHz, CDCl ) δ 152.5, 141.5, 123.1, 121.2, 118.4,
3
111.4, 58.7, 55.6, 53.6, 50.8, 42.0, 31.6, 24.6. IR (neat): νmax = 1499, 1450, 1238, 1118, 1025,
-
1
7
46 cm ; R 0.52 (chloroform/methanol/ammonia solution 85:13:2).
f
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17b
4
-bromo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide (11):
light green
1
solid (290 mg, 65%); H NMR (600 MHz, CDCl ) δ 7.63 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz,
3
2
H), 7.0 (dd, J = 7.6 Hz, 1H), 6.92 (dd, J = 7.6 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.85(d, J = 7.8
0
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Hz, 1H), 3.85 (s, 3H), 3.46 (td, J = 6.0 Hz, 2H), 3.15–2.95 (m, 4H), 2.70–2.55 (m, 4H), 2.46 (t, J
1
3
=
7.2 Hz, 2H), 1.72 – 1.58 (m, 4H), C NMR (151 MHz, CDCl ) δ 167.0, 152.4, 141.3, 134.1,
3
1
31.9, 128.8, 126.0, 123.2, 121.2, 118.36, 111.38, 58.2, 55.6, 53.61, 50.63, 40.3, 27.6, 24.6. IR
-1
(
neat): νmax = 3289, 1634, 1541, 1499, 1239, 1010, 729 cm ; R 0.45 (ethyl acetate/methanol 4:1).
f
ACKNOWLEDGEMENTS
This work was supported by the National Research Foundation of Korea [NRF-
2
014R1A1A1A05003274, NRF-2014-011165, and NRF-2012M3A7B4049657].
SUPPORTING INFORMATION
Characterization and spectral data of compounds are available free of charge via the Internet at
http://pubs.acs.org.
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