Synthesis of 2-phenylnaphthalenes through gold-catalyzed dimerization via a highly selective carbon nucleophile pathway

Article abstract of DOI:10.1021/jo200352j

A protocol for the facile synthesis of 2-phenylnaphthalene has been developed. The benzyl carbon acts as a nucleophilic center in the presence of the amide nitrogen and acetate oxygen, affording the selective formation of a naphthalene scaffold through th

Full text of DOI:10.1021/jo200352j

ARTICLE
pubs.acs.org/joc
Synthesis of 2-Phenylnaphthalenes through Gold-Catalyzed
Dimerization via a Highly Selective Carbon Nucleophile Pathway
Sinan Wang, Lei Zhang, Xiao Ding, Yu Zhou, Jinfang Wang, Hualiang Jiang, and Hong Liu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, People’s Republic of China
S Supporting Information
b
ABSTRACT: A protocol for the facile synthesis of 2-phenyl-
naphthalene has been developed. The benzyl carbon acts as a
nucleophilic center in the presence of the amide nitrogen and
acetate oxygen, affording the selective formation of a naphtha-
lene scaffold through the dimerization of the reactants.
’ INTRODUCTION
model substrate. The results are shown in Table 1, from which it
can be seen that no reaction occurred when the gold salt alone was
used asthe catalyst (entries 1 and 2, Table 1). A trace amount of 2a
was observed when the reaction was carried out in the presence of
AuCl3/AgSbF6 as the catalyst (entry 3, Table 1).The reaction
proceeded to completion when using AgOTf/Au(PPh3)Cl or
AgSbF6/Au(PPh3)Cl as the catalyst, affording 2a in 61% or 63%
yield, respectively (entries 4 and 5, Table 1). Subsequently, it was
found that the optimum temperature for this reaction was 70 °C
with argon protection (entries 6ꢀ8, Table 1). Different solvents
were screened, and polar solvents such as DMSO, DMSO/H2O,
and THF were shown to be ineffective. Nonpolar solvents such as
dichloromethane performed better, and anhydrous toluene was
found to be the most effective (entries 9ꢀ12, Table 1).
In recent years, there has been tremendous growth in the
number of gold-catalyzed reactions reported.1 In particular, gold
salts have been proven to be soft, carbophilic Lewis acids for the
electrophilic activation of alkynes. Thus, gold complexes are
efficient in promoting a number of nucleophilic addition reac-
tions to form various carbonꢀheteroatom bonds.2,3 However,
nucleophilic addition reactions using carbon nucleophiles such as
electron-rich arenes and 1,3-dicarbonyl compounds are still
reported occasionally.4 In such reactions, the nucleophilicity of
the oxygen or nitrogen is usually superior to that of the carbon
nucleophiles, and the reactions usually proceed through a CꢀO
or CꢀN bond formation pathway. Therefore, the highly selective
gold-catalyzed addition of carbon nucleophiles to alkynes re-
mains a challenge in modern organometallic catalysis.5
It has been our long-term goal to develop a novel and
convenient method for the synthesis of potentially useful hetero-
cycles using transition-metal catalysts.6 We have previously
reported a regiocontrolled intramolecular addition, in which
the carbonyl oxygen acts as the nucleophile.7 In another case,
in a regioselective intramolecular hydroamidation process fol-
lowing the 7-endo-dig pathway, the amide NH acts as the
nucleophile.8 Hashmi et al. described a gold-catalyzed dimeriza-
tion of o-alkynylbenzyl alcohols and a gold-catalyzed desymme-
trisation of symmetrical substrates.9 In this paper, we report an
unexpected gold-catalyzed dimerization in which the benzyl
carbon of the R-aryl acetamide or R-aryl acetate compounds
acts as the nucleophile. Products formed via the benzyl carbon
nucleophilic pathway were obtained with high selectivity in the
presence of carbonyl oxygen and amide nitrogen atoms.
The structure of 2a was confirmed by 1H NMR and 13C NMR
spectroscopy, mass spectrometry, and X-ray crystallography.10
As shown in Scheme 1, there are three possible nucleophilic
centers in the substrate: the amide nitrogen, carbonyl oxygen, and
benzyl carbon. Therefore, the reaction could occur through
different routes. Intramolecular nucleophilic attack of the amide
nitrogen would give product A1 or A2 (path A), whereas
intramolecular addition of the carbonyl group would give product
B1or B2 (path B). C1or C2 could be obtained ifthereaction were
to proceed through the intramolecular addition of the benzyl
carbon. In fact, we observed an unexpected dimerization of the
reactant, giving rise to product D (path D). There are two possible
reasons for this surprising result: (1) dual activation of the
carbonyl and benzyl groups in the substrate enhances the nucleo-
philicity of the benzyl carbon, and (2) the conjugated π system of
the dimerized product is thermodynamically favorable.11 Both
these factors would result in the benzyl carbon being more
nucleophilic than the amide nitrogen and the carbonyl oxygen.
Using the optimized reaction conditions, we went on to
examine the scope of the substrate for this reaction. This chemistry
’ RESULTS AND DISCUSSION
The reaction conditions for the formation of dimerized
2-phenylnaphthalene were optimized using different catalysts,
various reaction temperatures, solvents, and reaction times.
N-Butyl-2-(2-ethynylphenyl)acetamide (1a) was chosen as the
Received: February 17, 2011
Published: April 24, 2011
r
2011 American Chemical Society
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was first probed by varying the R1 group: the reaction proceeded
satisfactorily whether R1 was a nonsubstituted amide (entry 2,
Table 2), a monosubstituted alkyl amide (entries 1 and 3,
Table 2), or a disubstituted alkyl amide (entry 4, Table 2). When
the R1 group was an aryl amide, it was found that the dimerization
yield depended on the substituents. When R1 was an electron-
donating aryl amide, the reaction proceeded well and the
corresponding product 2f was obtained in 83% yield (entry 6,
Table 2). However, for an electron-withdrawing aryl amide, only a
moderate yield was obtained (entry 7, Table 2). No product was
obtained when R1 was a heteroaryl amide (entry 8, Table 2).
The dimerization also proceeded successfully when the sub-
strate contained an ester group, giving 2i in 72% yield (entry 9,
Table 2).
Next, we studied the reaction scope by varying the substitu-
ents on the benzene ring of the reactant. As shown in Table 3, we
obtained the desired products in high yields when the aromatic
ring was substituted with electron-donating groups such as MeO
(entries 1ꢀ3, Table 3) and Me (entry 4, Table 3) as well as
weakly electron-withdrawing groups such as halide atoms (entry
6, Table 3). In comparison, only a trace amount of product was
obtained when R2 was a strongly electron-withdrawing substi-
tuent such as ꢀCF3 (entry 5, Table 3).
Table 1. Optimization of the Reaction Conditionsa
To gain insight into the mechanism of the reaction, we carried
out labeling studies using deuterated starting materials or sol-
vents, and the results are shown in Scheme 2. The reaction of
[D3]-1a in deuterated benzene under the optimized conditions
afforded [D6]-2a (eq 1). The hydrogen atoms in the newly
formed benzene and in the methyl group were deuterated. This
indicates that one molecule of 1a offers its benzyl carbon, two
phenyl carbons, and one acetylenyl carbon, while another
molecule of 1a provides its two acetylenyl carbons to form the
new benzene. [D3]-1a in benzene gave the same result, and 1a in
deuterated benzene gave the nondeuterated product showing
that the solvent did not participate in the reaction (eqs 2 and 3).
We then conducted the reaction of 1a with an excess of a terminal
alkyne, and fortunately, product N-butyl-4-methyl-2-phenyl-
1-naphthamide was obtained in 66% yield (eq 4). A crossover
experiment of deuterated and undeuterated substrates was also
performed (eqs 5 and 6). The hydrogen atoms in the newly
formed methyl group were deuterated when deuterated 1a was
used. In contrast, the hydrogen atom in the newly formed
benzene was deuterated when deuterated phenylacetylene was
used. We speculate that in the dimerization reaction, one of the
deuterated methyl hydrogen atoms originated from the terminal
alkynyl hydrogen and the other two came from the benzyl
hydrogen atoms. The deuterated hydrogen in the newly formed
benzene came from the terminal hydrogen in the alkyne of the
other molecule of 1a.
entry
catalyst
Au(PPh3)Cl
condition
yieldb (%)
1
2
100 °C, PhMe, 5 h
100 °C, PhMe, 5 h
70 °C, PhMe, 8 h
100 °C, PhMe, 5 h
100 °C, PhMe, 5 h
80 °C, PhMe, 5 h
70 °C, PhMe, 8 h
25 °C, PhMe, 24 h
80 °C, DMSO, 24 h
80 °C, DMSO/H2O, 24 h
80 °C, THF, 16 h
80 °C, CH2Cl2, 16 h
tracec
0d
NaAuCl4
e
3
AgSbF6/AuCl3
trace
61
4
AgOTf/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
AgSbF6/Au(PPh3)Cl
5
63
6
73
7
81/70f
trace
0c
0c
tracec
8
9
10
11
12
65
a Reactions were performed under Ar with 10 mol % of the catalyst.
b Yields of isolated products. c 1a was recovered. d Complicated reaction
mixture but no 2a. e 15 mol % of AgSbF6 and 5 mol % of AuCl3.
f Reaction performed without argon protection.
In accordance with our labeling studies, we propose a mechan-
ism accounting for the formation of product 2, as depicted in
Scheme 1. Possible Reaction Pathways of N-Butyl-2-(2-ethynylphenyl)acetamide
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Table 2. Reaction Scope of the Dimerization to Synthesize
Substituted 2-Phenylnaphthalenea
and the catalyst is regenerated. This proposed mechanism is
consistent with the results of our labeling studies.
’ CONCLUSION
In conclusion, we have demonstrated a simple gold-catalyzed
protocol for the synthesis of substituted 2-phenylnaphthalene
derivatives, which are the scaffold of a marketed acne treatment
medicine adapalene (differin), and can be frequently found in
pharmaceuticals, natural products, and agrochemicals.15 The
unexpected dimerization gave high yields when the R1 group
was an alkyl amide, an electron-donating aryl amide, or an ester.
The reaction was also tolerant to an aromatic ring with electron-
donating substituents. In this reaction, the benzyl carbon in the
substrates of R-arylacetamides or R-arylacetates acted as a
nucleophilic center, which has not been reported previously.
The nucleophilic carbon selectively afforded a naphthalene
scaffold in the presence of amide nitrogen and acetate oxygen
atoms through the dimerization of the reactants. This means that
the gold catalyst could be used with a wider range of reactants to
form novel carbonꢀcarbon bonds. Further studies of this reac-
tion and the application of this methodology are underway.
’ EXPERIMENTAL SECTION
Typical Procedures for the Synthesis of N-Butyl-2-(2-ethy-
nylphenyl)acetamide (1a). SOCl2 (10 mL) was added to 2-iodo-
phenylacetic acid (262 mg, 1.0 mmol), and the solution was refluxed for
2 h. Excess SOCl2 was removed under vacuum. The residue was dissolved
in CH2Cl2 (5.0 mL), and 1-butylamine (73 mg, 1.0 mmol) was added.
The reaction mixture was stirred for 2 h. The solvent was removed under
reduced pressure. The crude product was dissolved in Et3N (5.0 mL), and
then (trimethylsilyl) acetylene (117.6 mg, 1.2 mmol), Pd(PPh3)2Cl2
(70.2 mg, 0.1 mmol), and CuI (1.9 mg, 0.01 mmol) were added. The
resulting mixture was heated under Ar protection at 70 °C. The reaction
was monitored by TLC. After the starting materials were completely
consumed, the solvent was removed under reduced pressure, and the
residue was purified bya flash column chromatography (petroleum ether/
ethyl acetate = 4/1, v/v, as an eluent) to yield N-butyl-2-(2-((tri-
methylsilyl)ethynyl)phenyl)acetamide in90% yield. Thenitwas dissolved
in 1:1 MeOH/CH2Cl2 (8 mL), and K2CO3 was added (552 mg, 4.0 mmol).
After being stirred at room temperature for 2 h, the reaction mixture was
quenched with water (10 mL) and then extracted with ethyl acetate
(30mL). The organic layerwasisolated, washedwith brine, and dried over
MgSO4. Filtration to remove MgSO4 followed by concentration under
vacuum afforded 1a as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.54
(d, J = 7.2 Hz, 1H), 7.36ꢀ7.29 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 5.52
(br s, 1H), 3.76 (s, 2H), 3.33 (s, 1H), 3.19 (q, J = 6.6 Hz, 2H), 1.46ꢀ1.36
(m, 2H), 1.32ꢀ1.20 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 170.0, 137.7, 133.0, 129.9, 129.4, 127.2, 121.9, 81.8, 81.8,
42.4, 39.3, 31.4, 19.9, 13.6; ESI-MS m/z [M þ H]þ 216.1; HRMS (ESI)
calcd for C14H17NONa [M þ Na] þ 238.1208, found 238.1217.
a The reaction was performed with AgSbF6 (10 mol %) and Au(PPh3)Cl
(10 mol %) in anhydrous toluene under Ar protection at 70 °C unless
otherwise noted. b Yields of isolated products. c The reaction was carried
out for 1 h at 60 °C. d 1h was recovered.
1
2-(2-Ethynylphenyl)acetamide (1b): H NMR (CDCl3, 300
MHz) δ 7.60 (d, J = 8.1 Hz, 1H), 7.37ꢀ7.29 (m, 2H), 7.20ꢀ7.15 (m,
1H), 5.54 (br s, 2H), 3.74 (s, 2H), 3.22 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 177.5, 135.8, 132.8, 129.9, 129.0, 127.4, 122.5, 81.9, 81.4, 39.4;
ESI-MS m/z [M þ H]þ 160.1; HRMS (ESI) calcd for C10H9NONa
[M þ Na]þ 182.0582, found 182.0578.
Scheme 3. The dimerization is initiated through activation of the
terminal alkyne moiety of 1 by the AgSbF6/Au(PPh3)Cl catalyst
system12 to form the Auꢀalkyne π-complex A. A subsequent
attack by the benzyl carbon atom on the activated terminal alkyne
of another molecule of 1 leads to the intermediate C;13 this is
followed by intramolecular cyclization to give intermediate D.14
Then, with double-bond transfer, the final product 2 is produced
2-(2-Ethynylphenyl)-N-methylacetamide (1c): 1H NMR
(CDCl3, 300 MHz) δ 7.53 (d, J = 7.2 Hz, 1H), 7.36ꢀ7.33 (m, 2H),
7.29ꢀ7.25 (m, 1H), 5.50 (br s, 1H), 3.76 (s, 2H), 3.33 (s, 1H), 2.76
(d, J = 4.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.9, 137.5, 133.1,
130.1, 129.5, 127.4, 122.1, 82.0, 81.7, 42.3, 26.5; ESI-MS m/z [M þ H]þ
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Table 3. Reaction Scope of the Dimerization to Synthesize Substituted 2-Phenylnaphthalenea
a The reaction was performed with AgSbF6 (10 mol %) and Au(PPh3)Cl (10 mol %) in anhydrous toluene under Ar protection at 70 °C unless
otherwise noted. b Yields of isolated products. c Complicated reaction mixture.
174.1; HRMS (ESI) calcd for C11H11NONa [M þ Na]þ 196.0738,
found 196.0728.
NMR (CDCl3, 100 MHz) δ 168.4, 137.8, 137.2, 133.2, 130.0, 129.7,
128.9, 127.6, 124.3, 121.8, 119.8, 82.2, 82.1, 43.5; ESI-MS m/z
[M þ H]þ 236.1; HRMS (ESI) calcd for C16H13NONa [M þ Na]þ
258.0895, found 258.0874.
2-(2-Ethynylphenyl)-N-(4-methoxyphenyl)acetamide (1f):
1H NMR (CDCl3, 300 MHz) δ 7.58 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 7.5
Hz, 1H), 7.38ꢀ7.29 (m, 4H), 6.82 (d, J = 7.8 Hz, 2H), 5.30 (br s, 1H),
3.91 (s, 2H), 3.77 (s, 3H), 3.41 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
168.3, 156.4, 137.3, 133.2, 130.8, 130.0, 129.6, 127.5, 121.9, 121.8, 114.0,
82.2, 82.0, 55.4, 43.2; ESI-MS m/z [M þ H]þ 266.1; HRMS (ESI) calcd
for C17H15NO2Na [M þ Na]þ 288.1000, found 288.1008.
2-(2-Ethynylphenyl)-N,N-dimethylacetamide (1d): 1H NMR
(CDCl3, 300 MHz): δ 7.50 (d, J = 5.7 Hz, 1H), 7.33ꢀ7.31 (m, 2H),
7.23ꢀ7.21 (m, 1H), 3.91 (s, 2H), 3.29 (s, 1H), 3.01 (s, 3H), 2.98 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 170.6, 137.7, 132.7, 129.1, 128.8, 126.6,
121.7, 81.9, 81.4, 38.8, 37.5, 35.5; ESI-MS m/z [M þ H]þ 188.1; HRMS
(ESI) calcd for C12H13NONa [M þ Na]þ 210.0895, found 210.0878.
2-(2-Ethynylphenyl)-N-phenylacetamide (1e): 1H NMR
(CDCl3, 300 MHz) δ 7.59 (d, J = 7.2 Hz, 1H), 7.45ꢀ7.37 (m, 5H),
7.34ꢀ7.28 (m, 2H), 7.11ꢀ7.06 (m, 1H), 3.93 (s, 2H), 3.44 (s, 1H); 13C
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Scheme 2. Labeling Studies
Scheme 3. Proposed Mechanism for the Dimerization of 1 to 2
2-(2-Ethynylphenyl)-N-(4-(trifluoromethyl)phenyl)aceta-
150.1, 145.5, 136.5, 133.1, 129.9, 129.5, 127.5, 121.9, 113.7, 82.2, 81.9, 43.0;
ESI-MS m/z [M þ H]þ 237.0; HRMS (ESI) calcd for C15H13N2O [M þ
H]þ 237.1028, found 237.1044.
1
mide (1g): H NMR (CDCl3, 300 MHz) δ 7.61ꢀ7.52 (m, 5H),
7.43ꢀ7.34 (m, 2H), 7.31 (dd, J = 7.2 Hz, 1.8 Hz, 1H), 5.31 (s, 1H), 3.95
(s, 2H), 3.45 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 168.6, 140.8,
136.7, 133.4, 130.1, 129.9, 128.5, 127.8, 126.2, 126.2, 121.8, 119.3, 82.4,
82.1, 43.6; ESI-MS m/z [M þ H]þ 303.9; HRMS (ESI) calcd for
C17H12NOF3Na [M þ Na]þ 326.0769, found 326.0778.
1
Methyl 2-(2-ethynylphenyl)acetate (1i): H NMR (CDCl3,
300 MHz) δ 7.52 (d, J = 7.5 Hz, 1H), 7.35ꢀ7.30 (m, 2H), 7.27 (d, J = 7.8
Hz, 1H), 3.89 (s, 2H), 3.71 (s, 3H), 3.28 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 171.4, 136.5, 132.7, 129.7, 128.9, 127.1, 122.3, 81.5, 81.5, 52.0,
39.5; LRMS (EI) m/z 174 (Mþ); HRMS (EI) m/z calcd for C11H10O2
(Mþ) 174.0681, found 174.0681.
2-(2-Ethynylphenyl)-N-(pyridin-4-yl)acetamide (1h): 1H NMR
(CDCl3, 300 MHz) δ 8.63 (br s, 1H), 8.42 (d, J = 6.3 Hz, 2H), 7.54 (d, J =
7.5 Hz, 1H), 7.45 (d, J = 6.3 Hz, 2H), 7.35 (m, 2H), 7.27 (dd, J = 7.5 Hz, 2.1
Hz, 1H), 3.92 (s, 2H), 3.38 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 169.6,
N-Butyl-2-(2-ethynyl-5-methoxyphenyl)acetamide (1j):
1H NMR (CDCl3, 300 MHz) δ 7.44 (d, J = 8.4 Hz, 1H), 6.87 (d,
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J = 2.7 Hz, 1H), 6.78 (dd, J = 8.4 Hz, 2.7 Hz, 1H), 5.62 (br s, 1H), 3.81 (s,
3H), 3.70 (s, 2H), 3.24 (s, 1H), 3.22ꢀ3.16 (m, 2H), 1.43ꢀ1.38 (m, 2H),
1.28ꢀ1.25 (m, 2H), 0.90ꢀ0.84 (m, 3H); 13C NMR (CDCl3, 100 MHz)
δ 170.0, 160.2, 139.5, 134.4, 115.1, 113.9, 113.4, 82.0, 80.4, 55.4, 42.8,
39.4, 31.5, 19.9, 13.7; ESI-MS m/z [M þ H]þ 246.1; HRMS (ESI) calcd
for C15H19NO2Na [M þ Na]þ 268.1313, found 268.1309.
2-(2-(2-Amino-2-oxoethyl)phenyl)-4-methyl-1-naphtha-
mide (2b). Compound 2b was obtained as a white solid after purifi-
cation by flash chromatography (PE/EA = 1:1) in 78% yield: 1H NMR
(CDCl3, 300 MHz) δ 8.09ꢀ7.96 (m, 2H), 7.61ꢀ7.58 (m, 2H),
7.39ꢀ7.28 (m, 4H), 7.22 (s, 1H), 4.96 (br s, 2H), 3.81 (d, J = 15.6 Hz,
1H), 3.47 (d, J = 15.0 Hz, 1H), 2.72 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 172.2, 169.3, 140.7, 136.8, 136.3, 132.3, 131.6, 130.8, 130.0, 129.9,
129.5, 128.2, 128.1, 127.1, 126.7, 126.3, 125.8, 124.3, 39.7, 19.6; ESI-MS
m/z [M þ H]þ 319.1; HRMS (ESI) calcd for C20H18N2O2Na
[M þ Na]þ 341.1266, found 341.1265.
N-Butyl-2-(2-ethynyl-4-methoxyphenyl)acetamide (1k):
1H NMR (CDCl3, 300 MHz): δ 7.21 (d, J = 8.4 Hz, 1H), 7.02 (d, J =
2.1 Hz, 1H), 6.88 (dd, J = 8.7 Hz, 2.7 Hz, 1H), 5.52 (br s, 1H), 3.78 (s,
3H), 3.66 (s, 2H), 3.29 (s, 1H), 3.21ꢀ3.15 (m, 2H), 1.41ꢀ1.34 (m, 2H),
1.28ꢀ1.21 (m, 2H), 0.88ꢀ0.82 (m, 3H); 13C NMR (CDCl3, 100 MHz)
δ 170.6, 158.4, 131.1, 129.8, 122.9, 117.6, 116.0, 81.7, 81.6, 55.3, 41.5,
39.3, 31.4, 19.9, 13.6; ESI-MS m/z [M þ H]þ 246.1; HRMS (ESI) calcd
for C15H19NO2Na [M þ Na]þ 268.1313, found 268.1323.
N,4-Dimethyl-2-(2-(2-(methylamino)-2-oxoethyl)phenyl)-
1-naphthamide (2c). Compound 2c was obtained as a white solid
after purification by flash chromatography (PE/EA = 2:1) in 80% yield:
1H NMR (CDCl3, 300 MHz) δ 8.12ꢀ8.00 (m, 2H), 7.58ꢀ7.53
(m, 2H), 7.32ꢀ7.32 (m, 4H), 7.13 (s, 1H), 6.10 (br s, 1H), 3.70
(d, J = 14.7 Hz, 1H), 3.37 (d, J = 15.6 Hz, 1H), 2.70 (s, 3H), 2.69 (d, J =
4.8 Hz, 3H), 2.51 (d, J = 5.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 172.1, 169.9, 140.7, 135.3, 135.0, 133.6, 132.9, 131.8, 130.7, 130.1,
129.6, 128.1, 127.7, 127.1, 126.9, 126.6, 126.3, 124.0, 40.8, 26.4, 26.3,
19.6; ESI-MS m/z [M þ H]þ 347.1; HRMS (ESI) calcd for C22H22-
N2O2Na [M þ Na]þ 369.1579, found 369.1591.
N-Butyl-2-(2-ethynyl-4,5-dimethoxyphenyl)acetamide (1l):
1H NMR (CDCl3, 300 MHz): δ 6.99 (s, 1H), 6.83 (s, 1H), 5.62 (br s,
1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.69 (s, 2H), 3.26 (s, 1H), 3.20 (q, J =
6.6 Hz, 2H), 1.49ꢀ1.37 (m, 2H), 1.36ꢀ1.21 (m, 2H), 0.88 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 170.4, 150.1, 147.9, 131.4, 115.0,
113.6, 112.5, 82.2, 80.3, 56.0, 42.2, 39.4, 31.5, 20.0, 13.7; ESI-MS m/z
[M þ H]þ 276.1; HRMS (ESI) calcd for C16H21NO3Na [M þ Na]þ
298.1419, found 298.1409.
2-(2-(2-(Dimethylamino)-2-oxoethyl)phenyl)-N,N,4-tri-
methyl-1-naphthamide (2d). Compound 2d was obtained as a
white solid after purification by flash chromatography (PE/EA = 2:1) in
84% yield: 1H NMR (CDCl3, 300 MHz) δ 8.08ꢀ8.04 (m, 1H),
7.73ꢀ7.70 (m, 1H), 7.59ꢀ7.55 (m, 2H), 7.36ꢀ7.29 (m, 4H), 7.18
(s, 1H), 3.79 (d, J = 16.2 Hz, 1H), 3.54 (d, J = 15.9 Hz, 1H), 2.93 (s, 3H),
2.82 (s, 3H), 2.74 (s, 3H), 2.70 (s, 3H), 2.64 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 171.7, 169.9, 139.9, 136.0, 135.1, 134.8, 131.7, 129.9, 129.5,
129.3, 128.7, 128.1, 128.0, 127.0, 126.2, 125.9, 125.5, 124.4, 40.9, 38.3,
37.5, 35.3, 34.2, 19.3; ESI-MS m/z [M þ H]þ 375.1; HRMS (ESI) calcd
for C24H26N2O2Na [M þ Na]þ 397.1892, found 397.1905.
N-Butyl-2-(2-ethynyl-5-methylphenyl)acetamide (1m): 1H
NMR (CDCl3, 300 MHz): δ 7.43 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.08
(d, J = 7.8 Hz, 1H), 5.64 (br s, 1H), 3.71 (s, 2H), 3.30 (s, 1H), 3.24ꢀ3.18
(m, 2H), 2.36 (s, 3H), 1.45ꢀ1.40 (m, 2H), 1.32ꢀ1.27 (m, 2H),
0.91ꢀ0.86 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.2, 139.8,
137.6, 132.9, 130.7, 128.1, 118.8, 81.8, 81.1, 42.3, 39.4, 31.4, 21.4, 19.9,
13.6; ESI-MS m/z [M þ H]þ 230.1; HRMS (ESI) calcd for C15H19NO-
Na [M þ Na]þ 252.1364, found 252.1370.
N-Butyl-2-(2-ethynyl-4-(trifluoromethyl)phenyl)acetamide
(1n): 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 1H), 7.59 (d, J = 7.8 Hz,
1H), 7.51 (d, J = 7.8 Hz, 1H), 5.57 (br s, 1H), 3.78 (s, 2H), 3.41 (s, 1H),
3.23 (q, J = 6.6 Hz, 2H), 1.47ꢀ1.36 (m, 2H), 1,35ꢀ1.25 (m, 2H), 0.89
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.1, 141.5, 130.5,
129.8, 129.6, 125.9, 124.8, 122.7, 83.2, 80.6, 42.2, 39.5, 31.5, 19.9, 13.6;
ESI-MS m/z [M þ H]þ 284.1; HRMS (ESI) calcd for C15H16NOF3Na
[M þ Na]þ 306.1082, found 306.1079.
4-Methyl-2-(2-(2-oxo-2-(phenylamino)ethyl)phenyl)-N-
phenyl-1-naphthamide (2e). Compound 2e was obtained as a
white solid after purification by flash chromatography (PE/EA = 4:1) in
77% yield: 1H NMR (CDCl3, 300 MHz) δ 8.91 (br s, 1H), 8.22 (d, J =
6.3 Hz, 1H), 8.04 (d, J = 6.3 Hz, 1H), 7.94 (br s, 1H), 7.60ꢀ7.57 (m,
2H), 7.41ꢀ7.27 (m, 8H), 7.26ꢀ7.14 (m, 5H), 7.09ꢀ6.98 (m, 2H), 3.96
(d, J = 15.3 Hz, 1H), 3.57 (d, J = 15.3 Hz, 1H), 2.74 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 169.9, 167.7, 140.3, 137.9, 137.7, 136.0, 135.1,
132.6, 131.9, 130.6, 130.1, 129.8, 128.7, 128.4, 127.6, 127.5, 127.2, 126.5,
126.3, 124.4, 124.2, 120.6, 119.8, 42.0, 19.7; ESI-MS m/z [M þ H]þ
470.9; HRMS (ESI) calcd for C32H26N2O2Na [M þ Na]þ 493.1892,
found 493.1888.
N-(4-Methoxyphenyl)-2-(2-(2-(4-methoxyphenylamino)-
2-oxoethyl)phenyl)-4-methyl-1-naphthamide (2f). Compound
2f was obtained as a white solid after purification by flash chromatography
(PE/EA=4:1) in83%yield:1HNMR(CDCl3, 300 MHz) δ8.85 (br s, 1H),
8.21 (m, 1H), 8.04 (m, 1H), 7.81 (br s, 1H), 7.72 (m, 1H), 7.71ꢀ7.42
(m, 4H), 7.27ꢀ7.11 (m, 6H), 6.77ꢀ6.73 (m, 2H), 6.69ꢀ6.60 (m, 2H), 3.94
(d,J= 15.0 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.55 (d, J= 15.0 Hz, 1H), 2.74
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.7, 167.5, 156.5, 156.2, 140.4,
135.9, 135.1, 134.1, 133.3, 132.8, 132.0, 131.0, 130.9, 130.7, 130.2, 129.9,
129.0, 128.8, 128.2, 127.6, 127.1, 126.5, 125.3, 124.2, 122.5, 121.7, 55.4, 41.8,
19.7; ESI-MS m/z[Mþ H]þ 531.0; HRMS (ESI) calcd for C34H30N2O4Na
[M þ Na]þ 553.2103, found 553.2105.
N-Butyl-2-(4-chloro-2-ethynylphenyl)acetamide (1o): 1H
NMR (CDCl3, 300 MHz) δ 7.43 (d, J = 1.8 Hz, 1H), 7.39 (d, J =
8.1 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 5.36 (br s, 1H), 3.51
(s, 2H), 3.39 (s, 1H), 3.26ꢀ3.20 (m, 2H), 1.45ꢀ1.39 (m, 2H),
1.32ꢀ1.25 (m, 2H), 0.92ꢀ0.87 (m, 3H); 13C NMR (CDCl3, 100 MHz)
δ 170.3, 134.6, 133.4, 133.2, 130.8, 129.7, 121.8, 82.8, 43.0, 39.5, 31.5,
20.0, 13.7; ESI-MS m/z [M þ H]þ 250.1; HRMS (ESI) calcd for
C14H16NOClNa [M þ Na]þ 272.0818, found 272.0823.
General Procedure for the Synthesis of N-Butyl-2-(2-
(2-(butylamino)-2-oxoethyl)phenyl)-4-methyl-1-naphtha-
mide (2a). To a solution of 1a (0.2 mmol) in 2 mL of anhydrous
toluene was added AgSbF6 (10 mol %)/Au(PPh3)Cl (10 mol %). The
reaction mixture was heated at 70 °C in a sealed tube under argon
protection for 8 h. After the reaction was cooled to ambient temperature,
the solvent was evaporated under reduced pressure, and the residue was
purified by a flash column chromatography to give 2a as a white solid
(PE/EA = 4:1) in 81% yield: 1H NMR (CDCl3, 300 MHz) δ 8.11ꢀ8.09
(m, 1H), 8.01ꢀ7.99 (m, 1H), 7.55ꢀ7.53 (m, 2H), 7.34ꢀ7.27 (m, 4H),
7.13 (s, 1H), 6.04 (br s, 1H), 3.69 (d, J = 11.1 Hz, 1H), 3.34 (d, J =
11.1 Hz, 1H), 3.23ꢀ3.11 (m, 2H), 2.88ꢀ2.87 (m, 2H), 2.69 (s, 3H),
1.72 (br s, 1H), 1.11ꢀ1.00 (m, 8H), 0.78ꢀ0.70 (m, 6H); 13C NMR
(CDCl3, 100 MHz) δ 171.2, 169.0, 140.6, 135.0, 134.7, 133.8, 133.2,
131.8, 130.8, 130.1, 129.9, 128.0, 127.6, 127.1, 126.8, 126.7, 126.2, 123.9,
41.2, 39.4, 39.3, 31.1, 30.9, 19.9, 19.8, 19.6, 13.8, 13.6; ESI-MS m/z
[M þ H]þ 431.3; HRMS (ESI) calcd for C28H34N2O2Na [M þ Na]þ
453.2518, found 453.2505.
4-Methyl-2-(2-(2-oxo-2-(4-(trifluoromethyl)phenylami-
no)ethyl)phenyl)-N-(4-(trifluoromethyl)phenyl)-1-naphtha-
mide (2g). Compound 2g was obtained as a yellow solid after purifi-
cation by flash chromatography (PE/EA = 4:1) in 42% yield: 1H NMR
(CDCl3, 300 MHz) δ 9.13 (br s, 1H), 8.17 (br s, 1H), 8.03ꢀ8.02
(m, 2H), 7.74ꢀ7.71 (m, 3H), 7.60ꢀ7.26 (m, 12H), 4.03 (d, J = 16.2 Hz,
1H), 3.66 (d, J = 16.2 Hz, 1H), 2.75 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 170.4, 167.9, 141.1, 140.2, 136.4, 134.2, 134.0, 132.8, 132.3, 132.0,
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ARTICLE
130.9, 129.8, 129.3, 129.2, 128.8, 128.6, 128.5, 128.1, 127.8, 127.5, 126.7,
125.9, 124.2, 120.0, 119.6, 119.3, 42.0, 19.7; ESI-MS m/z [M þ H]þ
607.0; HRMS (ESI) calcd for C34H24F6N2O2Na [M þ Na]þ 629.1640,
found 629.1642.
169.3, 137.7, 137.6, 136.6, 134.8, 133.1, 133.1, 130.9, 130.7, 130.0, 129.8,
128.4, 127.8, 127.0, 125.4, 123.8, 41.2, 39.4, 39.3, 31.1, 31.0, 21.8, 21.1,
19.9, 19.8, 19.6, 13.8, 13.6; ESI-MS m/z [M þ H]þ 459.2; HRMS (ESI)
calcd for C30H38N2O2Na [M þ Na]þ 481.2831, found 481.2816.
N-Butyl-2-(2-(2-(butylamino)-2-oxoethyl)-5-chlorophen-
yl)-6-chloro-4-methyl-1-naphthamide (2o). Compound 2o was
obtained as a white solid after purification by flash chromatography (PE/
Methyl 2-(2-(2-Methoxy-2-oxoethyl)phenyl)-4-methyl-
1-naphthoate (2i). Compound 2i was obtained as oil after purifica-
1
tion by flash chromatography (PE/EA = 8:1) in 72% yield: H NMR
1
EA = 1:1) in 70% yield: H NMR (CDCl3, 300 MHz) δ 7.89 (d, J =
(CDCl3, 300 MHz) δ 8.09ꢀ8.05 (m, 1H), 7.99ꢀ7.96 (m, 1H),
7.61ꢀ7.58 (m, 2H), 7.39ꢀ7.29 (m, 3H), 7.26ꢀ7.21 (m, 2H), 3.69
(s, 1H), 3.60 (s, 3H), 3.54 (s, 3H), 3.52 (s, 1H), 2.73 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 172.2, 169.3, 140.6, 136.9, 136.3, 132.3, 131.6,
130.9, 130.0, 129.9, 129.5, 128.2, 128.0, 127.1, 126.7, 126.3, 125.8, 124.3,
51.8, 51.8, 38.6, 19.6; ESI-MS m/z [M þ H]þ 348.8; HRMS (ESI) calcd
for C22H20O4Na [M þ Na]þ 371.1259, found 371.1273.
8.4 Hz, 1H), 7.40ꢀ7.28 (m, 3H), 7.25ꢀ7.19 (m, 2H), 7.05 (s, 1H), 5.97
(br s, 1H), 3.65 (d, J = 14.7 Hz, 1H), 3.27 (d, J = 14.7 Hz, 1H),
3.18ꢀ3.10 (m, 2H), 2.93ꢀ2.86 (m, 2H), 2.67 (s, 3H), 1.11ꢀ1.01
(m, 8H), 0.79ꢀ0.70 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 171.3,
169.3, 140.9, 137.8, 137.6, 136.7, 134.7, 133.2, 133.2, 131.0, 130.7, 130.2,
129.8, 128.3, 128.0, 127.0, 125.6, 123.8, 41.4, 39.5, 39.2, 31.2, 31.0, 20.0,
19.9, 19.7, 13.9, 13.6; ESI-MS m/z [M þ H]þ 499.2; HRMS (ESI) calcd
for C28H32N2O2Cl2Na [M þ Na]þ 521.1739, found 521.1754.
Procedure for the Synthesis of Deuterated N-Butyl-2-
(2-ethynylphenyl)acetamide. To a solution of 10 mol % of 1,5,
7-triazabicyclo[4.4.0]dec-5-ene (5.5 mg, 0.04 mmol) in 3 mL of CDCl3
was added 1a (86 mg, 0.4 mmol). The reaction mixture was stirred
at room temperature for 12 h and quenched with 1 N HCl (1 mL). The
organic layer was washed with water and brine, dried over anhydrous
Na2SO4, and filtered. Filtrate was concentrated to afford deuterated 1a.
Procedure for the Synthesis of N-Butyl-4-methyl-2-phen-
yl-1-naphthamide. To a solution of 1a (0.2 mmol, 1 equiv) in 1 mL
of anhydrous toluene and phenylacetylene (4.0 mmol, 20 equiv) was
added AgSbF6 (10 mol %)/Au(PPh3)Cl (10 mol %). The reaction
mixture was heated at 70 °C in a sealed tube under argon protection for
8 h. After the reaction was cooled to ambient temperature, the solvent was
evaporated under reduced pressure, and the residue was purified by flash
column chromatography to give 4 as a white solid (PE/EA = 4:1) in 66%
yield: 1H NMR (CDCl3, 300 MHz) δ 8.13ꢀ8.10 (m, 1H), 8.05ꢀ8.01
(m, 1H), 7.58ꢀ7.55 (m, 3H), 7.43ꢀ7.36 (m, 4H), 7.14 (s, 1H), 5.39
(br s, 1H), 3.27ꢀ3.20 (m, 2H), 2.74 (s, 3H), 1.20ꢀ1.13 (m, 2H),
1.03ꢀ0.96 (m, 2H), 0.76 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ169.5, 140.6, 136.0, 135.9, 132.2, 131.6, 130.4, 128.8, 128.4,
128.1, 127.7, 127.5, 126.9, 126.2, 124.1, 39.5, 31.0, 19.7, 19.6, 13.7; ESI-
MS m/z [M þ H]þ 318.1; HRMS (ESI) calcd for C22H23NONa
[M þ Na]þ 340.1677, found 340.1696.
N-Butyl-2-(2-(2-(butylamino)-2-oxoethyl)-4-methoxyph-
enyl)-7-methoxy-4-methyl-1-naphthamide (2j). Compound
2j was obtained as a white solid after purification by flash chromatog-
raphy (PE/EA = 2:1) in 77% yield: 1H NMR (CDCl3, 300 MHz) δ 7.89
(d, J = 9 Hz, 1H), 7.38 (d, J = 3 Hz, 1H), 7.26ꢀ7.24 (m, 1H), 7.22ꢀ7.16
(m, 1H), 6.96 (s, 1H), 6.88 (d, J = 2.7 Hz, 1H), 6.83 (dd, J = 8.1 Hz,
2.7 Hz, 1H), 5.29 (br s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.69 (d, J = 14.7
Hz, 1H), 3.29 (d, J = 14.7 Hz, 1H), 3.20ꢀ3.09 (m, 2H), 2.93ꢀ2.87
(m, 2H), 2.64 (s, 3H), 1.10ꢀ1.05 (m, 8H), 0.80ꢀ0.71 (m, 6H); 13C
NMR (CDCl3, 100 MHz) δ 171.1, 169.4, 159.2, 158.2, 135.3, 134.9,
134.5, 133.2, 132.9, 132.2, 131.0, 127.2, 126.0, 125.6, 118.7, 115.5, 112.4,
104.7, 55.4, 55.3, 41.5, 39.4, 39.3, 31.2, 31.1, 20.0, 19.8, 19.6, 13.8, 13.6;
ESI-MS m/z [M þ H]þ 491.2; HRMS (ESI) calcd for C30H38N2O4Na
[M þ Na]þ 513.2729, found 513.2727.
N-Butyl-2-(2-(2-(butylamino)-2-oxoethyl)-5-methoxyph-
enyl)-6-methoxy-4-methyl-1-naphthamide (2k). Compound
2k was obtained as a white solid after purification by flash chromatog-
raphy (PE/EA = 2:1) in 82% yield: 1H NMR (CDCl3, 300 MHz): δ 8.04
(d, J = 9.6 Hz, 1H), 7.46ꢀ7.42 (m, 2H), 7.23ꢀ7.19 (m, 2H), 7.11
(s, 1H), 6.90ꢀ6.87 (m, 1H), 5.77 (br s, 1H), 3.95 (s, 3H), 3.77 (s, 3H),
3.64 (d, J = 14.7 Hz, 1H), 3.28 (d, J = 14.7 Hz, 1H), 3.12ꢀ3.06 (m, 2H),
2.92ꢀ2.86 (m, 2H), 2.64 (s, 3H), 1.12ꢀ1.02 (m, 8H), 0.80ꢀ0.73
(m, 6H); 13C NMR (CDCl3, 100 MHz) δ 171.6, 169.1, 158.4, 157.9,
141.8, 133.7, 133.3, 132.5, 131.2, 129.9, 128.4, 128.0, 126.1, 125.3, 118.7,
114.9, 114.2, 102.9, 55.4, 55.3, 40.5, 39.5, 39.3, 31.2, 31.0, 19.9, 19.8,
19.8, 13.8, 13.6; ESI-MS m/z [M þ H]þ 491.2; HRMS (ESI) calcd for
C30H38N2O4Na [M þ Na]þ 513.2729, found 513.2749.
’ ASSOCIATED CONTENT
N-Butyl-2-(2-(2-(butylamino)-2-oxoethyl)-4,5-dimethoxy-
phenyl)-6,7-dimethoxy-4-methyl-1-naphthamide (2l). Com-
pound 2l was obtained as a white solid after purification by flash
chromatography (PE/EA = 4:1) in 80% yield: 1H NMR (CDCl3, 300
MHz) δ 7.45 (s, 1H), 7.40 (s, 1H), 7.20(s, 1H), 7.02(s, 1H), 6.89
(s, 1H), 6.85 (s, 1H), 6.82 (s, 1H), 4.04 (s, 3H), 3.99 (s, 3H), 3.91
(s, 3H), 3.83 (s, 3H), 3.74 (d, J = 15.3 Hz, 1H), 3.56ꢀ3.55 (m, 2H), 3.28
(d, J = 15.3 Hz, 1H), 2.96ꢀ2.91 (m, 2H), 2.64 (s, 3H), 1.18ꢀ1.05
(m, 8H), 0.81ꢀ0.72 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 171.6,
169.7, 149.9, 149.4, 148.3, 147.7, 133.5, 133.4, 130.9, 128.4, 127.8, 126.7,
125.0, 120.9, 115.8, 113.2, 112.8, 112.1, 56.0, 55.9, 55.9, 55.8, 40.9, 39.6,
39.3, 31.3, 31.1, 20.0, 19.9, 19.8, 13.7, 13.6; ESI-MS m/z [M ꢀ H]ꢀ
549.1; HRMS (ESI) calcd for C32H42N2O6Na [M þ Na]þ 573.2941,
found 573.2939.
S
Supporting Information. Experimental procedures, X-ray
b
structure of 2a, NMR spectra, and characterization for all new
materials. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: hliu@mail.shcnc.ac.cn.
’ ACKNOWLEDGMENT
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grant Nos. 20872153,
21021063, and 81025017).
N-Butyl-2-(2-(2-(butylamino)-2-oxoethyl)-4-methylphen-
yl)-4,7-dimethyl-1-naphthamide (2m). Compound 2m was ob-
tained as a white solid after purification by flash chromatography (PE/
1
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