Synthesis of imides by palladium-catalyzed C-H functionalization of aldehydes with secondary amides

Article abstract of DOI:10.1002/chem.201202601

An efficient palladium-catalyzed C-H functionalization of aldehydes with various N-substituted N-heteroarene-2-carboxamides has been developed for the synthesis of secondary imides. The reaction tolerates various functionalities, such as methoxy, fluoro, chloro, and bromo groups. A tentative radical mechanism for a PdII/PdIV catalytic cycle is proposed. Copyright

Full text of DOI:10.1002/chem.201202601

FULL PAPER
DOI: 10.1002/chem.201202601
À
Synthesis of Imides by Palladium-Catalyzed C H Functionalization of
Aldehydes with Secondary Amides
Yong-Jun Bian,[a] Chao-Yue Chen,[a] and Zhi-Zhen Huang *[a, b, c]
À
Abstract: An efficient palladium-catalyzed C H functionalization of aldehydes
À
with various N-substituted N-heteroarene-2-carboxamides has been developed for
the synthesis of secondary imides. The reaction tolerates various functionalities,
such as methoxy, fluoro, chloro, and bromo groups. A tentative radical mechanism
for a PdII/PdIV catalytic cycle is proposed.
Keywords: aldehydes · C H activa-
tion · imides · palladium · picolina-
mides
Introduction
N-methyl amide as an intramolecular acylation) under
copper catalysis mediated by N-bromo- or N-chlorosuccini-
mide (NBS or NCS, respectively).[8] However, to the best of
Imide moieties are present in a wide variety of natural prod-
ucts.[1] There are several strategies for the synthesis of imide
derivatives, for example, acylation of amides with carboxylic
acid derivatives,[2] direct oxidation of amides,[3] and the
Mumm rearrangement of isoimides.[4] Among them, acyla-
tion of amides with anhydrides or acyl chlorides is a typical
strategy.[2a–d,h] For example, under sulfuric acid catalysis, pri-
mary amides could be acylated with anhydrides at 1008C to
give primary imides in 44–64% yield.[2b] Secondary imides,
in which each nitrogen atom bears a substituent, are a main
class of imides. Although many secondary imide derivatives
possess important biological activities,[5] there are only a few
reports on their synthesis.[6] In 2002, Yamada et al. found
that some cyclic secondary amides reacted with anhydrides
to furnish cyclic secondary imides in the presence of
MgBr2·OEt2.[6a] Recently much attention was attracted to ac-
À
our knowledge, no successful reports of intermolecular C H
functionalization of aldehydes with secondary acyclic amides
has been disclosed. Considering that the pyridin-2-yl group
in a secondary picolinamide can promote activation of the
À
nearby N H moiety by palladium to form a five-membered
palladacycle intermediate,[9] which may increase the reactivi-
ty of the nitrogen atom, we embarked on an investigation
into the acylation of various N-heteroarene-2-carboxamides
with aldehydes. Herein, we present our recent results on the
À
palladium-catalyzed acyl C H functionalization of alde-
hydes with various N-substituted N-heteroarene-2-carboxa-
mides for the synthesis of secondary imides.
Results and Discussion
À
tivation of the acyl C H bond in aldehydes as an elegant
acylation strategy.[7,8] However, only Zhao et al. reported
The reaction of N-benzylpicolinamide (1a) with 4-chloro-
benzaldehyde (2a) was chosen as a model reaction to ex-
plore and optimize the C H bond functionalization reac-
À
the synthesis of imides by C H functionalization of alde-
À
hydes with a range of amides (various primary amides, one
example of a secondary cyclic amide, and one example of an
tion. Gratifyingly, the desired imide 3aa was obtained in
26% yield when palladium(II) acetate ([PdACTHNURGTNEUNG(OAc)2]) and
tert-butyl hydroperoxide (TBHP) were used as catalyst and
oxidant, respectively, in toluene (Table 1, entry 1). Subse-
quently, various palladium and other transition-metal cata-
lysts were examined in the reaction (see Table 1, entries 2–8
and the Supporting Information, respectively). Among
[a] Y.-J. Bian, C.-Y. Chen, Prof. Z.-Z. Huang
Key Laboratory of Mesoscopic Chemistry
of the Ministry of Education
School of Chemistry and Chemical Engineering
Nanjing University
Nanjing 210093 (P. R. China)
them, [PdACHTUNGTRNENUG(PPh3)2ACHTUGNTREN(NUGN OAc)2] proved to be best catalyst and
Fax : (+86)025-83686231
gave 3aa in 55% yield (Table 1, entry 8). The effect of the
oxidant on the reaction was also examined. It was found
that only a trace amount of 3aa was obtained when either
tert-butyl peroxide (TBP) or K2S2O8 were used as the oxi-
dant instead of TBHP (Table 1, entries 10 and 11). Our ex-
periments also showed that use of oxygen as an oxidant was
ineffective for the reaction (Table 1, entry 9). The solvent
choice was also crucial for this reaction. Solvation in
CH3CN resulted in a 68% yield of 3aa (Table 1, entry 14),
whereas the use of THF, 1,2-dichloroethane (DCE), DMF,
E-mail: huangzz@nju.edu.cn
[b] Prof. Z.-Z. Huang
Department of Chemistry
Zhejiang University
Hangzhou 310028 (P. R. China)
[c] Prof. Z.-Z. Huang
State Key Laboratory of Elemento-organic Chemistry
Nankai University
Tianjin 300071 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202601.
Chem. Eur. J. 2013, 19, 1129 – 1133
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1129

À
Table 1. Optimization of the C H functionalization of aldehyde 2a with
picolinamide 1a to give secondary imide 3aa.[a]
Entry
[M]
[Pd(OAc)2]
[PdCl2]
[Pd(PPh3)2Cl2]
[PdCl2A
(dppf)][c]
(dba)2][d]
(PPh3)4]
(tfa)2][e]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
(PPh3)2A(OAc)2]
Oxidant
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
G
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
O2 (1 atm)
TBP
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
2
28
50
<5
0
53
28
55
0
10
<5
46
23
68
51
52[f]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
ACHTUNGTRENNUNG
R
ACHTUNGTRENNUNG
N
CHTUNGTRENNUNG
9
R
CHTUNGTRENNUNG
10
11
12
13
14
15
16
R
G
N
C
N
CHTUNGTRENNUNG
R
E
DCE
N
E
CH3CN
benzene
CH3CN
T
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[a] A mixture of 1a (0.25 mmol), 2a (0.5 mmol), catalyst (0.025 mmol,
10 mol%), and oxidant (2.0 equiv) in solvent (1 mL) was stirred at 1208C
for 24 h. [b] Yield of isolated products. [c] dppf=1,1’-bis(diphenylphos-
phino)ferrocene. [d] dba=dibenzylideneacetone. [e] tfa=trifluoroacetate.
[f] Reaction temperature was 1008C.
or benzene led to lower yields (see Table 1, entries 12, 13,
and 15 and the Supporting Information). The yield de-
creased when the reaction temperature was below 1208C
(Table 1, entry 16). Notably, in the absence of a palladium
catalyst, 3aa was not obtained. When the pyridin-2-yl group
À
Scheme 1. Palladium-catalyzed C H functionalization of aldehydes for
the synthesis of secondary imides 3. A mixture of 1 (0.25 mmol), alde-
hyde
2 (0.5 mmol), [PdACHTUNGTREG(NNUN PPh3)2ACTHUNGRTENN(UGN OAc)2] (0.025 mmol, 10 mol%), and
TBHP (2.0 equiv) in CH3CN (1 mL) was stirred at 1208C for 24 h; yields
of isolated products are given.
À
of 1a was replaced by a phenyl group, the desired C H
functionalization reaction of 2a did not occur.
The optimal reaction conditions were [PdACTHUNGTRENNG(U PPh3)2ACHTUNTGERN(NUGN OAc)2]
(10 mol%) as the catalyst, TBHP as an oxidant, CH3CN as
the solvent, and a reaction temperature of 1208C. Under
these conditions it was found that secondary picolinamides
1a–i and various aryl aldehydes 2a–f were able to smoothly
undergo the coupling reaction to give the desired imides
3aa–gf in satisfactory yields (Scheme 1). N-Aryl-substituted
picolinamides could not perform the coupling reaction with
aldehydes, probably due to steric hindrance and electronic
effects. Our experiments demonstrated that the reaction tol-
erates various functionalities, such as methoxy, fluoro,
chloro, and bromo groups. Electron-withdrawing or elec-
tron-donating substituents on the benzene rings of the aro-
matic aldehydes led to similar yields of 3 (Scheme 1; 3aa
and 3ab versus 3ac–ae). When an aliphatic aldehyde was
employed in the reaction none of the desired imide was ob-
tained under the optimal conditions. Similarly to N-benzyl
picolinamides 1a–d, N-alkyl picolinamides 1 f–g resulted in
N-alkyl imides 3 fa and 3ga in good yields. When pyrazine-
2-carboxamides 1h and 1i were employed, the desired
imides 3ha and 3ia were obtained in satisfactory yields. This
suggests that the pyrazin-2-yl group can play an analogous
role to the pyridin-2-yl group. Moreover, our experiments
indicated that 2-naphthaldehyde (2 f) was a suitable partner
for the coupling reaction and gave the desired products 3 ff
and 3gf in moderate yields.
Next, we carried out an experiment to remove one of the
acyl groups of imide 3aa. After treatment of imide 3aa with
NaOMe in a mixture of MeOH and THF at room tempera-
ture, the picolinoyl group was selectively cleaved from 3aa
to produce N-benzyl-4-chlorobenzamide (4a) in good yield
(Scheme 2).[10]
In addition, we performed the coupling reaction of quino-
line-2-carboxamide (1j) with 2a under the optimized condi-
tions. Although the desired imide 3ja was obtained, the
Scheme 2. Cleavage of the picolinoyl group from imide 3aa.
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À
C H Functionalization of Aldehydes with Secondary Amides
FULL PAPER
yield was quite low. Five-membered N-heteroarene carboxa-
mides, isoxazole-3-carboxamides 1k and 1l and thiazole-2-
À
carboxamide 1m, were also examined in the C H function-
alization of 2a. It was found that 1k and 1l resulted in satis-
factory yields of imides 3ka and 3la, respectively. Thiazole-
2-carboxamide 1m led to the desired imide 3ma in a rela-
tively lower yield (45%; Scheme 3).
À
Scheme 4. A tentative mechanism for the palladium-catalyzed C H func-
tionalization of aldehyde 2 with picolinamide 1.
under mild conditions, to give the corresponding secondary
imides in satisfactory yields. The reaction tolerates various
functionalities, such as methoxy, fluoro, chloro, and bromo
groups. A tentative radical mechanism for a PdII/PdIV cata-
lytic cycle was proposed. The reactions of N-heteroarene-2-
carboxamides with substrates other than aldehydes to form
À
Scheme 3. C H functionalization of aldehyde 2a with quinoline-2-car-
boxamide (1j) and five-membered N-heteroarene carboxamides 1k–m.
À
various C N bonds are currently underway.
When 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO), a
radical scavenger, was added to the reaction of 1a with 2a
the formation of imide 3aa was completely suppressed. We
captured most of the 4-chlorobenzoyl radical in its ester
form with TEMPO (see the Supporting Information).[11]
This result suggests that aldehyde participates in the cou-
pling reaction as an acyl radical species. Thus, a tentative
mechanism for this reaction is proposed (Scheme 4). Initial-
Experimental Section
À
General procedure for the C H functionalization of aldehydes with N-
heteroarene-2-carboxamides: A solution of 1 (0.25 mmol), aromatic alde-
hyde
2 (0.50 mmol), and [PdACHTUNERTGGUNN(N PPh3)2ACHTNUGRTEN(UNNG OAc)2] (19 mg, 0.025 mmol,
10 mol%) in CH3CN (1.0 mL) was stirred at RT for 2 min in a reaction
tube. TBHP (0.50 mmol, 5.5m in decane) was added dropwise at RT. The
reaction mixture was stirred at 1208C for 24 h. After the reaction, the
mixture was concentrated in vacuo. The residue was purified by column
chromatography (silica gel, petroleum ether/EtOAc) to afford the desired
imide 3.
Compound 3aa: White solid; m.p. 119–1208C; 1H NMR (300 MHz,
CDCl3): d=8.33 (dq, J=5.0, 0.9 Hz, 1H), 7.74 (dt, J=7.8, 0.9 Hz, 1H),
7.61 (td, J=7.8, 1.8 Hz, 1H), 7.54–7.51 (m, 2H), 7.42–7.37 (m, 2H), 7.36–
7.29 (m, 2H), 7.28–7.22 (m, 1H), 7.18–7.14 (m, 1H), 7.11–7.07 (m, 2H),
5.25 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=173.0, 171.5, 152.0,
148.1, 137.8, 137.2, 136.9, 136.0, 129.9, 128.6, 128.5, 128.4, 127.6, 126.1,
125.0, 50.4 ppm; MS (ESI): m/z: 351.00 [M+H]+; HRMS (ESI): m/z
calcd for C20H15ClN2NaO2: 373.0720 [M+Na]+; found: 373.0717.
Compound 3ab: White solid; m.p. 120–1218C; 1H NMR (300 MHz,
CDCl3): d=8.33 (dq, J=5.0, 0.9 Hz, 1H), 7.74 (dt, J=8.1, 0.9 Hz, 1H),
7.62 (td, J=7.8, 1.8 Hz, 1H), 7.53–7.51 (m, 2H), 7.35–7.29 (m, 4H), 7.27–
7.22 (m, 3H), 7.19–7.14 (m, 1H), 5.24 ppm (s, 2H); 13C NMR (75 MHz,
CDCl3): d=173.1, 171.4, 152.0, 148.1, 137.2, 137.0, 136.5, 131.4, 130.0,
128.6, 128.5, 127.6, 126.4, 126.1, 125.0, 50.4 ppm; MS (ESI): m/z: 394.95
[M+H]+; HRMS (ESI): m/z calcd for C20H16BrN2O2: 395.0395 [M+H]+;
found: 395.0408.
ly, the picolinamide 1 chelates with [PdACHTUNTGRNEUNG(OAc)2L2] to gener-
ate a dimeric palladacycle complex (5).[9] At the same time,
TBHP dissociates into a tert-butoxy and a hydroxy radi-
cal.[12] Aldehyde 2 is deprived of its hydrogen atom by the
tert-butoxy radical to form an acyl radical. The acyl radical
and the hydroxy radical attach to palladacycle complex 5 to
generate PdIV-complex 6 in the presence of a ligand. Reduc-
tive elimination of 6 results in the desired imide 3 and PdII-
complex 7. Ligand exchange in complex 7 with HOAc re-
generates [Pd
cycle.
N
Conclusion
À
We have developed an efficient palladium-catalyzed C H
functionalization of aldehydes with various N-substituted N-
heteroarene-2-carboxamides for the synthesis of secondary
imides. A range of secondary picolinamides and various aryl
aldehydes could undergo the coupling reaction smoothly,
1
Compound 3ac: White solid; m.p. 83–848C; H NMR (300 MHz, CDCl3):
d=8.32 (d, J=5.1 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.58–7.52 (m, 3H),
7.47–7.43 (m, 2H), 7.35–7.30 (m, 2H), 7.27–7.17 (m, 2H), 7.13–7.08 (m,
3H), 5.27 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=174.1, 171.8,
152.5, 148.1, 137.5, 137.4, 136.7, 131.6, 128.7, 128.6, 128.5, 128.1, 127.5,
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Z.-Z. Huang et al.
125.7, 124.9, 50.3 ppm; MS (ESI): m/z: 317.05 [M+H]+; HRMS (ESI): m/
z calcd for C20H17N2O2: 317.1290 [M+H]+; found: 317.1300.
Compound 3ha: White solid; m.p. 139–1408C; 1H NMR (300 MHz,
CDCl3): d=8.87 (d, J=1.2 Hz, 1H), 8.15 (d, J=0.9 Hz, 1H), 7.49–7.42
(m, 4H), 7.36–7.26 (m, 3H), 7.18–7.15 (m, 2H), 5.22 (s, 2H), 2.51 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=172.7, 170.0, 156.6, 145.3, 144.4,
142.2, 138.5, 136.8, 135.2, 130.1, 128.74, 128.67, 128.4, 127.8, 50.4,
21.8 ppm; MS (ESI): m/z: 366.00 [M+H]+; HRMS (ESI): m/z calcd for
C20H16ClN3NaO2: 388.0829 [M+Na]+; found: 388.0812.
Compound 3ia: Colorless oil; 1H NMR (300 MHz, CDCl3): d=8.85 (s,
1H), 8.11 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 4.00
(t, J=7.2 Hz, 2H), 2.48 (s, 3H), 1.74 (quintet, J=7.8 Hz, 2H), 1.39
(sextet, J=7.5 Hz, 2H), 0.93 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=173.0, 170.2, 156.4, 145.2, 144.6, 142.1, 138.5, 135.2, 130.1,
128.8, 47.3, 31.0, 21.8, 20.2, 13.8 ppm; MS (ESI): m/z: 332.10 [M+H]+;
HRMS (ESI): m/z calcd for C17H19ClN3O2: 332.1166 [M+H]+; found:
332.1181.
Compound 3ad: White solid; m.p. 108–1098C; 1H NMR (300 MHz,
CDCl3): d=8.32 (d, J=4.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59–7.52
(m, 3H), 7.37–7.21 (m, 5H), 7.11 (dd, J=6.9, 5.1 Hz, 1H), 6.91 (d, J=
8.1 Hz, 2H), 5.25 (s, 2H), 2.20 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=174.1, 171.8, 152.6, 148.1, 142.3, 137.5, 136.6, 134.7, 128.9, 128.8,
128.51, 128.49, 127.5, 125.6, 124.8, 50.3, 21.4 ppm; MS (ESI): m/z: 331.00
[M+H]+; HRMS (ESI): m/z calcd for C21H18N2NaO2: 353.1266 [M+Na]+
; found: 353.1274.
1
Compound 3ae: White solid; m.p. 81–828C; H NMR (300 MHz, CDCl3):
d=8.31 (d, J=4.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.58–7.51 (m, 3H),
7.46–7.41 (m, 2H), 7.36–7.20 (m, 3H), 7.09 (dd, J=7.5, 5.1 Hz 1H), 6.62–
6.57 (m, 2H), 5.24 (s, 2H), 3.68 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=173.5, 171.6, 162.3, 152.6, 148.1, 137.5, 136.7, 131.0, 129.8, 128.52,
128.49, 127.5, 125.6, 124.7, 113.4, 55.3, 50.3 ppm; MS (ESI): m/z: 347.05
[M+H]+; HRMS (ESI): m/z calcd for C21H18N2NaO3: 369.1215 [M+Na]+
; found: 369.1210.
1
Compound 3 ff: White solid; m.p. 88–898C; H NMR (300 MHz, CDCl3):
d=8.26 (d, J=4.5 Hz, 1H), 7.90 (s, 1H), 7.76–7.60 (m, 5H), 7.50–7.37
(m, 3H), 6.97–6.93 (m, 1H), 4.10 (t, J=7.5 Hz, 2H), 1.91 (sextet, J=
7.5 Hz, 2H), 1.04 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=174.4, 172.0, 152.6, 148.0, 136.7, 135.1, 134.4, 131.8, 129.0, 128.9, 128.3,
128.0, 127.6, 126.8, 125.5, 125.3, 124.5, 48.9, 22.3, 11.6 ppm; MS (ESI): m/
z: 319.05 [M+H]+; HRMS (ESI): m/z calcd for C20H18N2NaO2: 341.1266
[M+Na]+; found: 341.1234.
Compound 3ba: White solid; m.p. 113–1148C; 1H NMR (300 MHz,
CDCl3): d=8.31 (d, J=4.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.61 (td, J=
7.7, 0.9 Hz, 1H), 7.55–7.48 (m, 2H), 7.41–7.35 (m, 2H), 7.16 (dd, J=6.8,
4.8 Hz, 1H), 7.11–7.07 (m, 2H), 7.03–6.95 (m, 2H), 5.20 ppm (s, 2H);
13C NMR (75 MHz, CDCl3): d=172.9, 171.4, 162.3 (d, J
151.9, 148.1, 137.8, 137.0, 136.0, 133.1 (d, J(C,F)=3.9 Hz), 130.5, 130.4,
(C,F)=21.3 Hz),
ACHTUNGTREN(NGNU C,F)=244.1 Hz),
1
Compound 3gf: White solid; m.p. 92–938C; H NMR (300 MHz, CDCl3):
AHCTUNGTRENNUNG
d=8.26 (dq, J=4.8, 0.6 Hz, 1H), 7.92 (s, 1H), 7.76–7.60 (m, 5H), 7.51–
7.39 (m, 3H), 6.99–6.94 (m, 1H), 4.22 (t, J=7.2 Hz, 2H), 3.56 (t, J=
6.3 Hz, 2H), 3.30 (s, 3H), 2.16 ppm (quintet, J=6.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=174.3, 172.0, 152.5, 148.0, 136.7, 134.9, 134.4, 131.8,
129.2, 128.9, 128.3, 128.0, 127.6, 126.7, 125.5, 125.3, 124.5, 70.5, 58.5, 44.8,
29.1 ppm; MS (ESI): m/z: 349.05 [M+H]+; HRMS (ESI): m/z calcd for
C21H20N2NaO3: 371.1372 [M+Na]+; found: 371.1355.
Compound 3ja: White solid; m.p. 130–1318C; 1H NMR (300 MHz,
CDCl3): d=8.06 (d, J=8.7 Hz, 1H), 7.97 (d, J=9.0 Hz, 1H), 7.81 (d, J=
8.4 Hz, 1H), 7.74–7.68 (m, 2H), 7.60–7.54 (m, 3H), 7.38–7.31 (m, 4H),
7.29–7.23 (m, 1H), 6.95–6.90 (m, 2H), 5.33 ppm (s, 2H); 13C NMR
(75 MHz, CDCl3): d=173.1, 171.5, 151.5, 145.8, 137.5, 137.32, 137.28,
136.5, 130.4, 129.7, 129.2, 128.7, 128.62, 128.57, 128.4, 128.3, 127.7, 127.6,
120.7, 50.4 ppm; MS (ESI): m/z: 401.00 [M+H]+; HRMS (ESI): m/z
calcd for C24H17ClN2NaO2: 423.0876 [M+Na]+; found: 423.0887.
Compound 3ka: Colorless oil; 1H NMR (300 MHz, CDCl3): d=7.49 (d,
J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 6.09 (s, 1H), 3.96 (t, J=7.5 Hz,
2H), 2.31 (s, 3H), 1.78 (sextet, J=7.5 Hz, 2H), 0.98 ppm (t, J=7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=172.8, 171.1, 164.4, 159.9, 138.4,
134.9, 130.0, 128.9, 101.7, 48.6, 22.2, 12.1, 11.4 ppm; MS (ESI): m/z:
307.05 [M+H]+; HRMS (ESI): m/z calcd for C15H15ClN2NaO3: 329.0669
[M+Na]+; found: 329.0673.
Compound 3la: Colorless oil; 1H NMR (300 MHz, CDCl3): d=7.36 (d,
J=8.7 Hz, 2H), 7.31–7.19 (m, 7H), 6.06 (s, 1H), 4.25 (t, J=7.5 Hz, 2H),
3.11 (t, J=7.5 Hz, 2H), 2.32 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=172.6, 171.1, 164.3, 159.7, 138.4, 137.9, 134.5, 130.0, 129.2, 128.8, 128.6,
126.8, 101.8, 48.2, 35.0, 12.1 ppm; MS (ESI): m/z: 369.05 [M+H]+;
HRMS (ESI): m/z calcd for C20H17ClN2NaO3: 391.0825 [M+Na]+; found:
391.0858.
129.9, 128.4, 125.6 (d,
JACTHNGUTRENNU(G C,F)=82.1 Hz), 115.4 (d, JAHCTUNGTRENNUNG
49.6 ppm; MS (ESI): m/z: 369.05 [M+H]+; HRMS (ESI): m/z calcd for
C20H15ClFN2O2: 369.0806 [M+H]+; found: 369.0805.
1
Compound 3ca: White solid; m.p. 96–978C; H NMR (300 MHz, CDCl3):
d=8.30 (d, J=4.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.59 (td, J=7.5,
1.2 Hz, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.39–7.35 (m, 2H), 7.28–7.26 (m,
2H), 7.15–7.07 (m, 3H), 5.19 ppm (s, 2H); 13C NMR (75 MHz, CDCl3):
d=172.8, 171.4, 151.8, 148.1, 137.9, 137.0, 135.9, 135.7, 133.5, 130.0, 129.9,
128.7, 128.4, 126.2, 125.1, 49.6 ppm; MS (ESI): m/z: 385.00 [M+H]+;
HRMS (ESI): m/z calcd for C20H14Cl2N2NaO2: 407.0330 [M+Na]+;
found: 407.0360.
Compound 3da: White solid; m.p. 197–1988C; 1H NMR (300 MHz,
CDCl3): d=8.32 (d, J=3.9 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.61 (t, J=
7.8 Hz, 1H), 7.40 (t, J=6.9 Hz, 4H), 7.17–7.07 (m, 5H), 5.20 (s, 2H),
2.30 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=173.0, 171.4, 152.1,
148.1, 137.8, 137.3, 136.9, 136.1, 134.2, 129.9, 129.3, 128.5, 128.4, 126.0,
125.0, 50.2, 21.2 ppm; MS (ESI): m/z: 365.10 [M+H]+; HRMS (ESI): m/z
calcd for C21H17ClN2NaO2: 387.0876 [M+Na]+; found: 387.0852.
Compound 3ea: Colorless oil; 1H NMR (300 MHz, CDCl3): d=8.32 (dq,
J=4.8, 0.9 Hz, 1H), 7.71 (dt, J=7.8, 0.9 Hz, 1H), 7.62 (td, J=7.5, 1.8 Hz,
1H), 7.36 (dt, J=8.7, 2.1 Hz, 2H), 7.31–7.27 (m, 4H), 7.25–7.14 (m, 2H),
7.11 (dt, J=9.0, 2.1 Hz, 2H), 4.32–4.27 (m, 2H), 3.18–3.13 ppm (m, 2H);
13C NMR (75 MHz, CDCl3): d=171.6, 152.1, 148.0, 138.4, 137.8, 137.0,
135.7, 130.0, 129.2, 128.5, 128.3, 126.6, 126.0, 124.9, 48.5, 35.0 ppm; MS
(ESI): m/z: 365.00 [M+H]+; HRMS (ESI): m/z calcd for C21H18ClN2O2:
365.1057 [M+H]+; found: 365.1080.
Compound 3 fa: Colorless oil; 1H NMR (300 MHz, CDCl3): d=8.30 (d,
J=4.5 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.61 (td, J=7.5, 1.2 Hz, 1H),
7.45 (d, J=8.7 Hz, 2H), 7.16–7.10 (m, 3H), 4.00 (t, J=7.5 Hz, 2H), 1.81
(sextet, J=7.5 Hz, 2H), 0.99 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=173.0, 171.6, 152.2, 148.0, 137.8, 137.0, 136.0, 130.0, 128.4,
125.9, 124.9, 48.9, 22.2, 11.5 ppm; MS (ESI): m/z: 302.95 [M+H]+;
HRMS (ESI): m/z calcd for C16H16ClN2O2: 303.0900 [M+H]+; found:
303.0916.
Compound 3ma: Colorless oil; 1H NMR (300 MHz, CDCl3): d=7.64 (d,
J=3.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.43 (d, J=3.0 Hz, 1H), 7.21 (d,
J=8.4 Hz, 2H), 4.03 (t, J=7.5 Hz, 2H), 1.83 (sextet, J=7.5 Hz, 2H),
1.00 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=172.7,
164.8, 163.0, 143.6, 138.2, 135.6, 130.0, 128.7, 125.7, 49.3, 22.3, 11.5 ppm;
MS (ESI): m/z: 309.00 [M+H]+; HRMS (ESI): m/z calcd for
C14H14ClN2O2S: 309.0465 [M+H]+; found: 309.0459.
Compound 3ga: Colorless oil; 1H NMR (300 MHz, CDCl3): d=8.30 (d,
J=4.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.62 (td, J=7.8, 1.5 Hz, 1H),
7.47 (d, J=8.4 Hz, 2H), 7.18–7.12 (m, 3H), 4.13 (t, J=7.2 Hz, 2H), 3.51
(t, J=6.0 Hz, 2H), 3.26 (s, 3H), 2.08 ppm (quintet, J=6.6 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=173.1, 171.7, 152.2, 148.0, 137.8, 136.9,
135.8, 130.1, 128.4, 125.9, 124.9, 70.4, 58.5, 44.9, 29.0 ppm; MS (ESI): m/z:
333.05 [M+H]+; HRMS (ESI): m/z calcd for C17H17ClKN2O3: 371.0565
[M+K]+; found: 371.0568.
Cleavage of the picolinoyl group from imide 3aa to give N-benzyl-4-
chlorobenzamide (4a):[10] NaOMe (2.7 mg, 0.05 mmol) was added to a
solution of imide 3aa (17.5 mg, 0.05 mmol) in MeOH (0.5 mL) and THF
(0.2 mL). The reaction mixture was stirred at RT for 5 h. After addition
of water (5 mL), the mixture was extracted with ethyl acetate (3ꢁ
10 mL). The combined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by TLC (silica gel,
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Chem. Eur. J. 2013, 19, 1129 – 1133

À
C H Functionalization of Aldehydes with Secondary Amides
FULL PAPER
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7.28 (m, 7H), 6.42 (brs, 1H), 4.64 ppm (d, J=5.7 Hz, 2H); MS (EI): m/z
(%): 245.0 (36) [M]+, 139.0 (100), 111.0 (26), 75.0 (10).
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Acknowledgements
Financial support from MOST of China (973 program 2011CB808600)
and National Natural Science Foundation of China (No. 21072091) are
gratefully acknowledged.
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Received: July 23, 2012
Revised: September 28, 2012
Published online: November 13, 2012
Chem. Eur. J. 2013, 19, 1129 – 1133
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www.chemeurj.org
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