Palladium-catalyzed C8 alkylation of 1-naphthylamides with alkyl halides via bidentate-chelation assistance

Article abstract of DOI:10.1021/jo500932x

A Pd-catalyzed regioselective alkylation of C8-H bonds in 1-naphthylamides containing a quinolinamide or picolinamide moiety as a bidentate directing group with alkyl halides is reported. The amide directing group can be easily hydrolyzed under basic conditions. Various alkyl halides including alkyl iodides and benzyl bromide or chloride can be employed as coupling partners, exclusively providing 8-alkyl-1-naphthylamide derivatives.

Full text of DOI:10.1021/jo500932x

Note
pubs.acs.org/joc
Palladium-Catalyzed C8 Alkylation of 1‑Naphthylamides with Alkyl
Halides via Bidentate-Chelation Assistance
Lehao Huang,*,‡ Xudong Sun,† Qian Li,† and Chenze Qi*,†
†Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Institute of Applied Chemistry, Shaoxing
University, Shaoxing, Zhejiang 312000, People’s Republic of China
‡Wenzhou Medical University Renji College, Wenzhou, Zhejiang 325035, People’s Republic of China
S
* Supporting Information
ABSTRACT: A Pd-catalyzed regioselective alkylation of C8−
H bonds in 1-naphthylamides containing a quinolinamide or
picolinamide moiety as a bidentate directing group with alkyl
halides is reported. The amide directing group can be easily
hydrolyzed under basic conditions. Various alkyl halides
including alkyl iodides and benzyl bromide or chloride can
be employed as coupling partners, exclusively providing 8-
alkyl-1-naphthylamide derivatives.
irect and selective functionalization of C−H bonds has
yl)picolinamide was alkylated using n-octyl iodide in 49% yield
Demerged as one of the most promising and powerful at 140 °C.
synthetic tools for the creation of C−C bonds.1 The usual
approach is to use monodentate directing groups to achieve o-
C−H functionalization.2 Despite the broad utility of this
approach, the exploration of novel types of directing groups is
still very important to meet a synthetic task. Bidentate directing
groups have recently attracted considerable attention of
researchers because of their unique potential for the activation
of inert C−H bonds. Considerable progress has been
accomplished by various research groups, who have mainly
focused on the use of 8-aminoquinoline or picolinamide
analogues as the auxiliary groups.3 Among these impressive
efforts, direct alkylations of β-C−H bonds in carboxylic acids4
and γ-C−H bonds in amines5 with alkyl halides have been
accomplished. As an example of the alkylation of β-C−H bonds
in carboxylic acids, in 2010 the Daugulis group reported the
palladium-catalyzed alkylation of β-C−H bonds in propionic or
benzoic acid derivatives with primary alkyl iodides or benzyl
bromides by employing an 8-aminoquinoline auxiliary.4a This
methodology has been used by Shi et al. in β-C−H alkylation of
α-amino acid derivatives.4b Also, the groups of Chatani,
Ackermann, and Ge have recently described the nickel-
catalyzed direct alkylation of β-C−H bonds in aromatic and
aliphatic carboxylic acids with alkyl iodides or bromides by
employing 8-aminoquinoline as a bidentate directing group.4c−e
As an example of the alkylation of γ-C−H bonds in amines, in
2011 Chen and co-workers reported the palladium-catalyzed
ortho alkylation of picolinamide-protected benzylamine sub-
strates with alkyl halides.5a Subsequently, they extended the
method to the alkylation of γ-C−H bonds in aliphatic amine
substrates with primary alkyl iodides.5b In these trans-
formations, the direct alkylation of C−H bonds in aromatic
amines with alkyl halides is limited to an example reported very
recently by the Daugulis group5c in which N-(naphthalen-1-
Our group has a strong interest in the functionalization of 1-
naphthylamine scaffolds, which widely exist in dyes6 and
electroluminescent materials7 as an important structural unit. In
2013, we reported the quinolinamide-directed regioselective C8
arylation of 1-naphthylamides with aryl iodides under the
catalysis of Pd(OAc)2 (Scheme 1, eq 1).8 Compared with the
realized C−H bond arylation, C−H bond alkylation is more
challenging because the oxidative addition of alkyl halides is
unfavorable and the resulting alkylmetal intermediates tend to
undergo β-hydride elimination reactions. Encouraged by these
results on C8 arylation of 1-naphthylamides, we proceeded to
investigate whether the bidentate directing group could also
facilitate the C8 alkylation of 1-naphthylamides with alkyl
halides (Scheme 1, eq 2).
We initiated our studies by exploring reaction conditions for
the envisioned direct C8 alkylation of N-(naphthalen-1-
yl)picolinamide (1a) with 1-iodobutane (2c) (Table 1). To
our delight, the desired alkylated product 3c was generated in
67% yield under the original C8 arylation conditions8 (entry 1).
Screening of solvents indicated that 1,4-dioxane gave a higher
yield (entries 2−6). A control experiment without the use of an
additive resulted in a drastically decreased yield (entry 7),
which showed that an inorganic base additive is necessary for
the transformation. Variation of the type of additive was also
investigated (entries 8−15). The use of AgOAc as a halide
scavenger was inefficient (entry 8). The examined inorganic
base and organic acid additives displayed lower efficiencies
(entries 9−15); even K2CO3 and Cs2CO3 completely sup-
pressed the formation of product 3c (entries 10 and 12). It was
mentioned that the C2-alkylated product was not detected in
Received: April 28, 2014
© XXXX American Chemical Society
A
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Note
Scheme 1. Pd(II)-Catalyzed Regioselective C8 Functionalization of 1-Naphthylamides
a
monoalkylation product 3e with a trace amount of dialkylation
(entry 5); the reserved iodo functional group added flexibility
to further elaborate the alkylated product. The dialkylation
product 3ea was obtained in 29% yield when 3e was used as the
alkylation reagent in place of 2e under the standard conditions
(entry 6), indicating that the picolinamide moiety in 3e
probably retarded the reaction. Unexpectedly, secondary alkyl
iodides 2f−h were found to be reactive, albeit in lower yields,
showing that steric hindrance clearly reduced the reactivity
(entries 7−9). In addition, benzyl bromide (2i) and benzyl
chloride (2j) could also be employed effectively in the reaction
to give the desired products (entries 10 and 11). However,
when butyl iodide was replaced with butyl bromide, no product
was obtained.
Table 1. Optimization of the Reaction Conditions
b
entry catalyst (mol %)
additive
KOAc
solvent
xylene
yield (%)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
67
20
26
8
KOAc
toluene
3
KOAc
DMSO
4
KOAc
ClCH2CH2Cl
t-BuOH
5
KOAc
5
6
KOAc
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
72
5
7
−
We next examined the effect of the directing group (Scheme
2). When the analogue naphthylquinoline-2-carboxamide 1b
was used in place of 1a as the substrate, the 1-naphthylamide
1b could be alkylated by straight-chain primary alkyl iodides
such as methyl iodide 2a, n-propyl iodide 2b, n-butyl iodide 2c,
and 10-iododecyl iodide 2e in moderate to good yields under
the standard reaction conditions (Scheme 2, 3j−m). No
coupling, including C2 alkylation reactions, occurred when the
corresponding amide N-(naphthalen-1-yl)benzamide (1c) or
tert-butyl N-naphthalen-1-ylcarbamate (1d) was used as the
8
AgOAc
NaOAc
K2CO3
Na2CO3
Cs2CO3
HOAc
32
25
9
c
c
10
11
12
13
14
15
16
17
18
N.D. (80)
42
N.D. (21)
20
CF3COOH
(BnO)2PO2H
KOAc
8
10
52
c
c
Pd(PPh3)2Cl2
Pd2(dba)3
KOAc
trace (92)
N.D. (94)
1
substrate in place of 1a (see the H NMR spectra of the crude
KOAc
products 1c and 1d in the Supporting Information), indicating
that the coordination in a bidentate N,N fashion is a vital step
for the reaction to proceed.
a
Reaction conditions: 1a (0.25 mmol), Pd catalyst (0.0375 mmol), 2c
(1.0 mmol), additive (0.5 mmol), solvent (5 mL), 130 °C, 24 h.
Isolated yields. The isolated yield of recycled substrate 1a is shown
b
c
On the basis of previous studies,4a,d,8,10 the C−H alkylation
reaction likely proceeds through a sequential C−H activation
(palladation)/oxidative addition pathway, and a Pd(II)/(IV)
manifold might be operative. Although previous theoretical
calculations on the analogous C−H arylation reaction8 proved
that a sequential oxidative addition/C−H activation pathway
was unfavorable, the pathway could not be excluded.11
Futhermore, the amide directing group could be simply
hydrolyzed (Scheme 3). The alkylated substrate 3c was heated
with NaOH in ethanol at 130 °C to afford 8-butylnaphthalen-1-
amine (3q) in 65% yield.
in parentheses.
these reactions. Other palladium catalysts such as PdCl2,
Pd(PPh3)2Cl2, and Pd2(dba)3 were investigated. Product 3c
was obtained in 52% yield when PdCl2 was used as the catalyst
(entry 16). However, Pd(PPh3)2Cl2 and Pd2(dba)3 were almost
inactive, presumably because the ligands hindered the
coordination of catalyst with the substrate (entries 17 and
18). Therefore, the optimal reaction was achieved with 2 equiv
of KOAc as the additive in 1,4-dioxane at 130 °C for 24 h
(Table 1, entry 6).
In conclusion, we have developed a methodology for the Pd-
catalyzed, bidentate-auxiliary-directed regioselective alkylation
of 1-naphthylamides with alkyl halides. A broad range of
primary alkyl iodides as well as benzyl bromide and chloride are
competent reagents in this transformation. In particular, the use
of MeI provides an efficient and straightforward method for
preparing high-value methylation products from readily
available precursors. The picolinamide directing group is simply
With the optimized reaction conditions in hand, we explored
the substrate scope of the alkyl halides. As shown in Table 2,
various straight-chain primary alkyl iodides presented great
compatibility with the reaction conditions (entries 1−5). It is
worth mentioning that MeI (2a) was identified as the superior
methylation reagent to afford the corresponding product in
high yield (entry 1).9 Moreover, alkyl diiodide 2e also
participated well in the reaction to afford predominantly the
B
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Note
a
Table 2. Scope of Alkyl Iodides
a
Reaction conditions: 1a (0.25 mmol, 62 mg), Pd(OAc)2 (0.0375 mmol, 9 mg), RI (1.0 mmol), KOAc (0.5 mmol, 49 mg), 1,4-dioxane (5 mL), 130
b
c
d
e
°C, 24 h. Isolated yields. Isolated yield on a 4.04 mmol scale for 24 h. Substrate 1a on a 0.18 mmol scale. Reaction in xylene (5 mL) for 4 h.
f
Reaction in xylene (5 mL) for 48 h.
N-naphthalen-1-ylcarbamate (1d)14 were prepared by known
methods. Other materials were purchased from common commercial
sources and used without additional purification.
detached under basic conditions, providing a synthetic method
for 8-alkyl-1-naphthylamines.
Preparation of Amide Compounds 1a and 1b.8,12 Picolinic
acid or quinoline-2-carboxylic acid (20 mmol), naphthalen-1-amine
(20 mmol, 2.86 g), and Et3N (40 mmol, 5.6 mL) were dissolved in
CH2Cl2 (40 mL), and POCl3 (3.76 mL) was added dropwise at 0 °C.
The reaction mixture was stirred at 0 °C for 0.5 h. Subsequently, the
reaction was performed at room temperature for about 2 h until
naphthalen-1-amine was consumed completely. At the conclusion of
the reaction, the reaction mixture was allowed to cool to 0 °C, and
ice−water was added slowly to quench the reaction. The organic layer
was collected, and the aqueous phase was extracted with CH2Cl2 (3 ×
20 mL). The combined organic phases were washed with saturated
NaHCO3 (2 × 40 mL) and dried over MgSO4. The solvent was
evaporated under reduced pressure, and the residue was crystallized
from CH2Cl2/petroleum ether to give the desired product.
EXPERIMENTAL SECTION
■
General Methods. The reactions were carried out in oven-dried
flasks under air, unless otherwise stated. 1H NMR spectra were
recorded using a 400 MHz spectrometer, and the chemical shifts are
reported in δ units, parts per million relative to the internal standard
TMS (0 ppm) for CDCl3 (7.26 ppm). The peak patterns are indicated
as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q,
quartet; m, multiplet. Coupling constants (J) are reported in hertz. 13C
NMR spectra were measured using a 100 MHz spectrometer relative
to the internal solvent signal (center peak is 77.00 ppm in CDCl3).
Electrospray ionization (ESI) high-resolution mass spectrometry
(HRMS) was performed on an FT-ICR spectrometer. Amide
derivatives 1a and 1b were synthesized according to the literature
procedures.8,12 N-(Naphthalen-1-yl)benzamide (1c)13 and tert-butyl
C
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Note
Scheme 2. Screening of 1-Naphthylamide Auxiliaries
127.4, 126.4, 125.5, 125.3, 123.5, 122.7, 25.1; HRMS (ESI) calcd for
C17H14N2O [M + H]+ 263.1179, found 263.1175.
Scheme 3. Hydrolysis of Amide 3c
N-(8-Propylnaphthalen-1-yl)picolinamide (3b). 55 mg, 76% yield;
light-yellow solid after purification by column chromatography (eluent,
ethyl acetate/petroleum ether = 1/10 v/v); mp 115−116 °C; 1H
NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H),
8.35 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.88 (t, J = 8.0 Hz,
1H), 7.73 (t, J = 8.6 Hz, 2H), 7.46 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H),
7.29 (d, J = 6.8 Hz, 1H), 3.25 (t, J = 8.0 Hz, 2H), 1.67 (m, 2H), 0.80
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 150.1,
148.1, 137.7, 137.6, 136.2, 132.6, 129.8, 128.0, 127.9, 127.4, 126.5,
125.4, 125.1, 124.5, 122.7, 39.5, 25.8, 14.0; HRMS (ESI) calcd for
C19H18N2O [M + H]+ 291.1492, found 291.1489.
N-(Naphthalen-1-yl)picolinamide (1a, CAS no. 75358-95-1).10
2.98 g, 60% yield; pink solid; mp 128−129 °C; H NMR (400 MHz,
CDCl3) δ 10.75 (s, 1H), 8.70 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 7.2 Hz,
1H), 8.36 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.91 (m, 2H),
7.70 (d, J = 8.4 Hz, 1H), 7.55 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 162.3, 150.1, 148.2, 137.8, 134.1, 132.4, 128.8, 126.5, 126.4, 126.3,
126.0, 125.9, 125.0,122.5, 120.5, 118.6; HRMS (ESI) calcd for
C16H12N2O [M + H]+ 249.1022, found 249.1020.
1
N-(8-Butylnaphthalen-1-yl)picolinamide (3c). 55 mg, 72% yield;
light-yellow solid after purification by column chromatography (eluent,
ethyl acetate/petroleum ether = 1/10 v/v); mp 115−116 °C; 1H
NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H),
8.35 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.88 (t, J = 7.8 Hz,
1H), 7.73 (t, J = 9.6 Hz, 2H), 7.47 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H),
7.29 (d, J = 7.2 Hz, 1H), 3.27 (t, J = 8.0 Hz, 2H), 1.63 (m, 2H), 1.22
(m, 2H), 0.78 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
162.5, 150.2, 148.1, 137.8, 137.7, 136.2, 132.6, 129.5, 127.9, 127.8,
127.4, 126.5, 125.5, 125.1, 124.5, 122.7, 37.3, 34.8, 22.7, 14.0; HRMS
(ESI) calcd for C20H20N2O [M + H]+ 305.1648, found 305.1643.
N-(8-Decylnaphthalen-1-yl)picolinamide (3d). 78 mg, 80% yield;
light-yellow viscous liquid after purification by column chromatog-
N-(Naphthalen-1-yl)quinoline-2-carboxamide (1b, CAS no.
1
298193-67-6). 4.29 g, 72% yield; pink solid; mp 146−147 °C; H
NMR (400 MHz, CDCl3) δ 10.95 (s, 1H), 8.43 (d, J = 8.4 Hz, 2H),
8.36 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz,
1H), 7.91 (d, J = 8.0 Hz, 2H), 7.81 (t, J = 7.2 Hz, 1H), 7.71 (d, J = 8.4
Hz, 1H), 7.59 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 162.4, 149.9,
146.3, 138.0, 134.2, 132.5, 130.4, 129.9, 129.5, 128.9, 128.2, 127.9,
126.5, 126.3, 126.1, 126.0, 125.1, 120.5, 118.8, 118.7; HRMS (ESI)
calcd for C20H14N2O [M + H]+ 299.1179, found 299.1182.
1
raphy (eluent, ethyl acetate/petroleum ether = 1/10 v/v); H NMR
(400 MHz, CDCl3) δ 10.49 (s, 1H), 8.62 (d, J = 4.0 Hz, 1H), 8.36 (d,
J = 8.0 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.74
(d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.47 (m, 2H), 7.35 (t, J =
7.6 Hz, 1H), 7.29 (d, J = 6.0 Hz, 1H), 3.26 (t, J = 8.0 Hz, 2H), 1.63
(m, 2H), 1.19 (m, 14H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 162.5, 150.2, 148.1, 137.9, 137.7, 136.2, 132.5, 129.5,
127.9, 127.4, 126.5, 125.5, 125.1, 124.6, 122.7, 37.7, 32.9, 31.9, 29.8,
29.7, 29.6, 29.5, 29.4, 22.8, 14.2; HRMS (ESI) calcd for C26H32N2O
[M + H]+ 389.2587, found 389.2583.
N-(8-(10-Iododecyl)naphthalen-1-yl)picolinamide (3e). 94 mg,
73% yield; light-yellow solid after purification by column chromatog-
raphy (eluent, ethyl acetate/petroleum ether = 1/10 v/v); mp 162−
163 °C; 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.63 (d, J = 4.8
Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.92 (t, J =
8.0 Hz, 1H), 7.74 (t, J = 9.4 Hz, 2H), 7.48 (m, 2H), 7.35 (t, J = 7.2 Hz,
1H), 7.29 (d, J = 6.8 Hz, 1H), 3.26 (t, J = 8.0 Hz, 2H), 3.15 (t, J = 6.8
Hz, 2H), 1.77 (m, 2H), 1.62 (m, 2H), 1.22 (t, J = 7.2 Hz, 12H); 13C
NMR (100 MHz, CDCl3) δ 162.4, 150.2, 148.0, 137.8, 137.7, 136.2,
Typical Procedure for Alkylation Products 3a−o and 3ea. A
mixture of naphthylamide (0.25 mmol, 1.0 equiv), Pd(OAc)2 (0.0375
mmol, 15 mol %), alkyl iodide (1.0 mmol, 4.0 equiv), anhydrous
KOAc (0.5 mmol, 2.0 equiv), and 1,4-dioxane (5 mL) was placed in a
35 mL Schlenk tube with a rubber plug under air. The tube was heated
at 130 °C for 24 h. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate (5 mL), filtered through Celite,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography with ethyl acetate/petroleum ether to afford
the desired product.
N-(8-Methylnaphthalen-1-yl)picolinamide (3a). 54 mg, 82% yield;
light-yellow solid after purification by column chromatography (eluent,
ethyl acetate/petroleum ether = 1/10 v/v); mp 184−185 °C; 1H
NMR (400 MHz, CDCl3) δ 10.59 (s, 1H), 8.63 (d, J = 4.4 Hz, 1H),
8.34 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.89 (t, J = 7.6 Hz,
1H), 7.71 (t, J = 7.2 Hz, 2H), 7.47 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H),
7.25 (d, J = 7.2 Hz, 1H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
162.4, 150.1, 148.2, 137.7, 135.8, 133.2, 132.6, 130.1, 128.1, 127.7,
D
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Note
132.5, 129.5, 127.9, 127.4, 126.5, 125.5, 125.1, 124.6, 122.7, 37.6, 33.5,
32.7, 30.5, 29.6, 29.5, 29.4, 29.3, 28.5, 7.5; HRMS (ESI) calcd for
C26H31IN2O [M + H]+ 515.1554, found 515.1547.
N-(8-Propylnaphthalen-1-yl)quinoline-2-carboxamide (3k). 65
mg, 76% yield; light-yellow solid after purification by column
chromatography (eluent, ethyl acetate/petroleum ether = 1/10 v/v);
mp 100−101 °C; 1H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 8.47
(d, J = 8.4, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H),
8.06 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.78 (m, 3H), 7.65
(t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.36 (m, 2H), 3.36 (t, J =
8.0 Hz, 2H), 1.76 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 162.6, 150.0, 146.4, 137.9, 137.5, 136.2, 132.6, 130.4,
129.8, 129.7, 129.5, 128.2, 128.0, 127.9, 127.4, 125.4, 125.2, 124.5,
119.1, 39.5, 25.6, 14.0; HRMS (ESI) calcd for C23H20N2O [M + H]+
341.1648, found 341.1645.
N-(8-Butylnaphthalen-1-yl)quinoline-2-carboxamide (3l). 68 mg,
77% yield; light-yellow solid after purification by column chromatog-
raphy (eluent, ethyl acetate/petroleum ether = 1/10 v/v); mp 101−
102 °C; 1H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.46 (d, J = 8.8
Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.04 (d, J
= 7.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.82−7.73 (m, 3H), 7.64 (t, J
= 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.39−7.31 (m, 2H), 3.38 (t, J
= 7.6 Hz, 2H), 1.72−1.65 (m, 2H), 1.18−1.08 (m, 2H), 0.71 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 150.0, 146.4, 137.9,
137.7, 136.2, 132.6, 130.4, 129.6, 129.5, 128.2, 128.0, 127.9, 127.8,
127.6, 125.5, 125.2, 124.7, 119.1, 37.3, 34.6, 22.5, 14.0; HRMS (ESI)
calcd for C24H22N2O [M + H]+ 355.1805, found 355.1800.
N,N′-(8,8′-(Decane-1,10-diyl)bis(naphthalene-8,1-diyl))-
dipicolinamide (3ea). 33 mg, 29% yield; light-yellow solid after
purification by column chromatography (eluent, ethyl acetate/
1
petroleum ether = 1/3 v/v); mp 103−104 °C; H NMR (400 MHz,
CDCl3) δ 10.49 (s, 2H), 8.61 (d, J = 4.8 Hz, 2H), 8.36 (d, J = 7.6 Hz,
2H), 8.00 (d, J = 7.2 Hz, 2H), 7.89 (t, J = 8.0 Hz, 2H), 7.76 (m, 4H),
7.51 (t, J = 8.0 Hz, 2H), 7.45 (dd, J = 4.8, 7.6 Hz, 2H), 7.38 (t, J = 7.2
Hz, 2H), 7.31 (d, J = 7.2 Hz, 2H), 3.28 (t, J = 8.0 Hz, 4H), 1.62 (m,
4H), 1.10 (m, 8H), 0.98 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
162.5, 150.2, 148.0, 137.8, 137.7, 136.2, 132.5, 129.5, 127.9, 127.4,
126.5, 125.5, 125.1, 124.6, 122.7, 37.6, 32.7, 29.6, 29.5, 29.4; HRMS
(ESI) calcd for C42H42N4O2 [M + H]+ 635.3381, found 635.3375.
N-(8-Isopropylnaphthalen-1-yl)picolinamide (3f). 26 mg, 36%
yield; light-yellow viscous liquid after purification by column
chromatography (eluent, ethyl acetate/petroleum ether = 1/10 v/v);
1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.66 (d, J = 4.4 Hz,
1H), 8.39 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.95 (t, J = 7.6
Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.49 (m,
4H), 4.24 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 162.3, 150.2, 148.1, 144.4, 137.7, 136.1, 132.2, 128.1, 127.6,
127.1, 126.5, 125.5, 125.1, 125.0, 124.4, 122.7, 30.1, 25.3; HRMS
(ESI) calcd for C19H18N2O [M + H]+ 291.1492, found 291.1487.
N-(8-Cyclopentylnaphthalen-1-yl)picolinamide (3g). 30 mg, 38%
yield; light-yellow viscous liquid after purification by column
chromatography (eluent, ethyl acetate/petroleum ether = 1/10 v/v);
1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 8.65 (d, J = 4.8 Hz,
1H), 8.39 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.94 (t, J = 7.6
Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.52 (m,
3H), 7.42 (t, J = 8.0 Hz, 1H), 4.21 (m, 1H), 2.23 (m, 2H), 1.76 (m,
4H), 1.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.1, 150.2,
148.0, 141.4, 137.7, 136.0, 132.4, 127.8, 127.6, 127.5, 126.5, 125.4,
125.1, 125.0, 124.4, 122.8, 43.2, 35.8, 25.0; HRMS (ESI) calcd for
C21H20N2O [M + H]+ 317.1648, found 317.1652.
N-(8-(10-Iododecyl)naphthalen-1-yl)quinoline-2-carboxamide
(3m). 102 mg, 72% yield; light-yellow solid after purification by
column chromatography (eluent, ethyl acetate/petroleum ether = 1/
1
10 v/v); mp 159−160 °C; H NMR (400 MHz, CDCl3) δ 10.70 (s,
1H), 8.47 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.8
Hz, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.77 (m,
3H), 7.66 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6
Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 3.36 (t, J = 8.0 Hz, 2H), 3.13 (t, J =
7.2 Hz, 2H), 1.68 (m, 4H), 1.22 (m, 2H), 1.04 (m, 6H), 0.90 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 162.6, 150.1, 146.4, 137.9, 137.8,
136.2, 132.6, 130.3, 129.7, 129.6, 129.5, 128.2, 128.0, 127.9, 127.6,
125.5, 125.2, 124.7, 119.1, 37.7, 33.5, 32.5, 30.4, 29.6, 29.4, 29.3, 29.1,
28.4, 7.5; HRMS (ESI) calcd for C30H33IN2O [M + H]+ 565.1710,
found 565.1701.
N-(8-Cyclohexylnaphthalen-1-yl)picolinamide (3h). 13 mg, 15%
yield; light-yellow viscous liquid after purification by column
chromatography (eluent, ethyl acetate/petroleum ether = 1/10 v/v);
1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.67 (d, J = 4.4 Hz,
1H), 8.40 (d, J = 7.6 Hz, 1H), 7.96 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H),
7.72 (d, J = 8.0 Hz, 1H), 7.48 (m, 4H), 3.81 (t, J = 11.6 Hz, 1H), 2.04
(d, J = 12.0 Hz, 2H), 1.71 (d, J = 12.8 Hz, 2H), 1.51 (m, 3H), 1.13 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 150.1, 148.1, 143.5,
137.7, 136.1, 132.3, 128.2, 127.4, 127.3, 126.6, 125.5, 125.3, 125.2,
124.9, 122.8, 40.8, 35.7, 26.9, 26.3; HRMS (ESI) calcd for C22H22N2O
[M + H]+ 331.1805, found 331.1801.
N-(8-Benzylnaphthalen-1-yl)picolinamide (3i). 46 mg, 54% yield;
light-yellow solid after purification by column chromatography (eluent,
ethyl acetate/petroleum ether = 1/10 v/v); mp 172−173 °C; 1H
NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H),
8.18 (d, J = 8.0 Hz, 1H), 7.79 (m, 4H), 7.49 (t, J = 7.6 Hz, 1H), 7.38
(m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.14 (m, 3H), 6.85 (m, 2H), 4.66
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.0, 149.9, 147.9, 141.1,
137.4, 136.2, 134.2, 132.5, 131.4, 128.9, 128.7, 128.4, 128.3, 128.3,
126.3, 126.1, 126.0, 125.7, 125.5, 122.6, 42.1; HRMS (ESI) calcd for
C23H18N2O [M + H]+ 339.1492, found 339.1486.
Procedure for Hydrolysis of Amide 3c. N-(8-Butylnaphthalen-
1-yl)picolinamide (3c) (0.2 mmol) and NaOH (256 mg, 6.4 mmol)
were heated in ethanol (3 mL) for 18 h at 130 °C. After completion of
the reaction, the mixture was diluted with ethyl acetate (3 mL), filtered
through Celite, and concentrated in vacuo. The residue was purified by
silica gel column chromatography with ethyl acetate/petroleum ether
to afford the desired product.
8-Butylnaphthalen-1-amine (3p). 26 mg, 65% yield; brown oil
after purification by column chromatography (eluent, ethyl acetate/
petroleum ether = 1/20 v/v); 1H NMR (400 MHz, CDCl3) δ 7.60 (d,
J = 8.0 Hz, 1H), 7.27 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 7.2
Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 4.22 (s, 2H), 3.22 (t, J = 8.0 Hz,
2H), 1.73 (m, 2H), 1.47 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 144.1, 138.6, 136.7, 127.8, 127.6, 125.7, 125.3,
123.7, 120.4, 112.6, 37.1, 35.3, 22.8, 14.1; HRMS (ESI) calcd for
C14H17N [M + H]+ 200.1434, found 200.1428.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
N-(8-Methylnaphthalen-1-yl)quinoline-2-carboxamide (3j). 65
mg, 83% yield; light-yellow solid after purification by column
chromatography (eluent, ethyl acetate/petroleum ether = 1/10 v/v);
1
mp 173−174 °C; H NMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 8.44
(d, J = 8.8 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H),
8.14 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 6.8 Hz,
1H), 7.72 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 8.0
Hz, 1H), 7.34 (t, J = 6.8 Hz, 1H), 7.28 (d, J = 6.8 Hz, 1H), 3.09 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 162.4, 149.9, 146.4, 137.9,
135.9, 133.4, 132.5, 130.4, 130.2, 129.7, 129.5, 128.2, 127.9, 127.8,
127.7, 127.2, 125.6, 125.4, 122.8, 119.0, 25.4; HRMS (ESI) calcd for
C21H16N2O [M + H]+ 313.1335, found 313.1330.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hlh1023@163.com.
*E-mail: qichenze@usx.edu.cn.
Notes
The authors declare no competing financial interest.
E
dx.doi.org/10.1021/jo500932x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant 21172149), the Zhejiang Provincial Natural
Science Foundation of China (Grant LQ13B020001), Key Sci-
Tech Innovation Team Project of Zhejiang Province (Grants
2012R10014-14 and 2010R50014-18), and the Foundation of
Science and Technology Bureau of Shaoxing (2013B70018) for
financial support.
REFERENCES
■
(1) For representative reviews of C−H functionalization, see:
(a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174. (b) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem.
Soc. Rev. 2009, 38, 3242. (c) Boorman, T. C.; Larrosa, I. Chem. Soc.
Rev. 2011, 40, 1910. (d) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev.
2011, 40, 1976. (e) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem.,
Int. Ed. 2014, 53, 74.
(2) For representative reviews of monodentate-group-assisted o-C−
H functionalization, see (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (c) Ackermann, L. Chem. Rev. 2011,
111, 1315. (d) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A.
Acc. Chem. Res. 2012, 45, 814. (e) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
(3) For a representative review of bidentate-group-assisted C−H
functionalization, see: (a) Rouquet, G.; Chatani, N. Angew. Chem., Int.
Ed. 2013, 52, 11726 and references cited therein. For representative
examples of bidentate-group-assisted C−H functionalization, see:
(b) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 898.
(c) Zhang, L.-S.; Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan,
F.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2014, 53, 3899.
(4) For representative examples of bidentate-group-assisted alkyla-
tion of β-C−H bonds in carboxylic acids, see: (a) Shabashov, D.;
Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. (b) Chen, K.; Hu, F.;
Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 3906. (c) Aihara, Y.;
Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308. (d) Song, W.; Lackner,
S.; Ackermann, L. Angew. Chem., Int. Ed. 2014, 53, 2477. (e) Wu, X.;
Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, 1789. (f) Asako, S.; Ilies,
L.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 17755.
(5) For representative examples of bidentate-group-assisted alkyla-
tion of γ-C−H bonds in amines, see: (a) Zhao, Y.; Chen, G. Org. Lett.
2011, 13, 4850. (b) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.;
Chen, G. J. Am. Chem. Soc. 2013, 135, 2124. (c) Nadres, E. T.; Santos,
G. I. F.; Shabashov, D.; Daugulis, O. J. Org. Chem. 2013, 78, 9689.
(6) (a) Merrington, J.; James, M.; Bradley, M. Chem. Commun. 2002,
140. (b) Patel, D. R.; Patel, K. C. Dyes Pigm. 2011, 90, 1. (c) Satam, M.
A.; Raut, R. K.; Telore, R. D.; Sekar, N. Dyes Pigm. 2013, 97, 32.
(d) Pasha, K.; Taylor, J. A. Dyes Pigm. 2013, 96, 397.
(7) (a) Banerjee, J.; Haldar, M. K.; Manokaran, S.; Mallik, S.;
Srivastava, D. K. Chem. Commun. 2007, 2723. (b) Hatakeyama, T.;
Hashimoto, S.; Nakamura, M. WO2010104047A1, 2010. (c) Kim, B.
Y.; Ahn, J. B.; Lee, J. S.; Kang, J. S.; Ahn, D. H.; Park, N. G.; Han, G.
H.; Min, B. U. KR2012095765A, 2012.
(8) Huang, L.; Li, Q.; Wang, C.; Qi, C. J. Org. Chem. 2013, 78, 3030.
(9) Schonherr, H.; Cernak, T. Angew. Chem., Int. Ed. 2013, 52, 12256.
̈
(10) (a) Nag, S.; Butcher, R. J.; Bhattacharya, S. Eur. J. Org. Chem.
2007, 1251. (b) Dasgupta, M.; Tadesse, H.; Blake, A. J.; Bhattacharya,
S. J. Organomet. Chem. 2008, 693, 3281.
(11) For representative examples of a sequential oxidative addition/
C−H activation pathway, see: (a) Racowski, J. M.; Ball, N. D.; Sanford,
M. S. J. Am. Chem. Soc. 2011, 133, 18022. (b) Hickman, A. J.; Sanford,
M. S. ACS Catal. 2011, 1, 170. (c) Maleckis, A.; Kampf, J. W.; Sanford,
M. S. J. Am. Chem. Soc. 2013, 135, 6618.
(12) Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang, Y. Org. Lett.
2012, 14, 1238.
(13) DeRuiter, J.; Swearingen, B. E.; Wandrekar, V.; Mayfield, C. A. J.
Med. Chem. 1989, 32, 1033.
(14) Jia, X.; Huang, Q.; Li, J.; Li, S.; Yang, Q. Synlett 2007, 806.
F
dx.doi.org/10.1021/jo500932x | J. Org. Chem. XXXX, XXX, XXX−XXX