Gold(I)-catalyzed regioselective inter-/intramolecular addition cascade of di- and triynes for direct construction of substituted naphthalenes

Article abstract of DOI:10.1021/jo300771f

The gold-catalyzed cascade intermolecular addition-intramolecular carbocyclization reaction of dialkynylbenzenes was developed. In this reaction, regioselective addition of an external nucleophile toward the terminal alkyne and subsequent 6-endo-dig cyclization proceeded to give the 1,3-disubstituted naphthalenes in good yields. The direct synthesis of disubstituted chrysenes via a gold-catalyzed addition and double cyclization cascade using a triyne-type substrate was also achieved.

Full text of DOI:10.1021/jo300771f

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pubs.acs.org/joc
Gold(I)-Catalyzed Regioselective Inter-/Intramolecular Addition
Cascade of Di- and Triynes for Direct Construction of
Substituted Naphthalenes
Saori Naoe, Yamato Suzuki, Kimio Hirano, Yusuke Inaba, Shinya Oishi, Nobutaka Fujii,*
and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: The gold-catalyzed cascade intermolecular
addition−intramolecular carbocyclization reaction of dialky-
nylbenzenes was developed. In this reaction, regioselective
addition of an external nucleophile toward the terminal alkyne
and subsequent 6-endo-dig cyclization proceeded to give the
1,3-disubstituted naphthalenes in good yields. The direct
synthesis of disubstituted chrysenes via a gold-catalyzed addition and double cyclization cascade using a triyne-type substrate was
also achieved.
derivatives.8 The nucleophilic addition of external nucleophiles
to diynes 3 bearing internal and terminal alkyne moieties regio-
selectively proceeds at the internal alkyne to produce 4 (eq 2).
INTRODUCTION
■
In recent years, atom-economical efficient transformations have
attracted attention in view of environmentally benign syntheses.1
Cascade reactions involving such transformations are especially
useful for step-economical direct syntheses of complex molecules
reducing formation of waste products.2 Intra- or intermolecular
addition reactions to alkynes, which are being explored due to
recent significant advances in the development of alkynophilic
π-acidic catalysts such as gold complexes,3,4 are important
primary reactions for such strategies.5
During our studies on intramolecular reaction cascades
As part of our program toward direct syntheses of useful
using carbamate 6 for investigation of double hydroarylation,
heterocyclic compounds, we have been engaged in the develop-
we observed unexpected formation of naphthalene derivatives 7
ment of gold-catalyzed intramolecular hydroamination/
(43%) and 8a (41%) both bearing an ethoxy group (Scheme 1).
hydroarylation cascade of dienyne-type anilines for synthesis of
Formation of 7 can be explained by gold-catalyzed inter-
aryl-annulated carbazoles.6 We successfully applied this reaction
molecular addition of ethanol toward the propargylamine
to polyenyne-type anilines to produce highly fused carbazoles
moiety of 6 followed by 6-endo-dig cyclization. The naphthalene
by consecutive hydroarylation.7 In these intramolecular reaction
8a lacking the aminomethyl group would be formed by a gold-
cascades, the alkyne that participates in the first nucleophilic
catalyzed retro-Mannich reaction to furnish gold acetylide A
addition (hydroamination) among the several alkynes can be
followed by the same reaction sequence (ethanol addition and
predicted from the substrate structures. By contrast, when
6-endo-dig cyclization).9 Addition of ethanol proceeded
applying this method to intermolecular reactions using external
exclusively at the terminal alkyne moiety of the intermediate B.
nucleophiles, the regioselectivity issue arises, i.e. which of the two
Hence, we expected that diynes bearing terminal and internal
regioisomeric products 1 and 2 predominates (eq 1). Recently,
alkynes would be promising substrates for a regioselective gold-
catalyzed inter/intramolecular addition cascade of dialkynyl-
benzenes with external nucleophiles (eq 2).8 In this paper, the
cascade cyclization of di- and triyne derivatives, which provides
convenient access to 1,3-disubstituted naphthalene derivatives,10
benzofuran, benzothiophene, and chrysenes, is described.11
Mechanistic consideration on the naphthalene formation is also
presented.
Liu and co-workers reported ruthenium-catalyzed naphthalene
formation via nucleophilic addition/insertion cascade of
dialkynylbenzenes to afford 1,2-disubstituted naphthalene
Received: April 15, 2012
Published: May 8, 2012
© 2012 American Chemical Society
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catalyst (2 mol %, entry 11). When using N-methylaniline
(PhNHMe) as the external nucleophile, the desired product 8b
formed by nucleophilic carbon−nitrogen bond formation was
obtained in an excellent yield (93%, entry 12). Use of IPrAuCl
or AgOTf alone proved unsuccessful (entries 13 and 14). The
reaction with AuCl bearing no ligand gave 8b in only 5% yield
(entry 15).
Scheme 1. Unexpected Regioselective Formation of
1-Ethoxy-3-phenylnaphthalenes
Using the optimized conditions described in entries 11 and
12 [2 mol % IPrAuCl/AgOTf and 1.1 equiv of NuH in 1,2-
dichloroethane (DCE), Table 1], the reaction scope with
various substrates and nucleophiles was investigated (Table 2).
The use of aliphatic alcohols resulted in desired products 8c
and 8d in moderate yields (65% and 64%, respectively). As
the nitrogen nucleophiles, the electron density of the aniline
benzene had a small influence on reactivity (8b, 8e and 8f;
92%−quant). Similarly, the reaction with N-benzylaniline and
the protected hydrazine derivative gave the desired products 8g
and 8h in good yields (78% and 77%, respectively). Use of
heteroaromatic rings such as indole and pyrrole as carbon
nucleophiles afforded the desired biaryl products formed via
nucleophilic C−C bond formation in moderate to good yields
(8i−k).14 For diynes, the internal alkyne bearing an alkyl group
(R2 = propyl) resulted in the desired product 8l in 68% yield.
Moreover, a range of substituents (R1 and R2) were tolerated,
including benzene rings bearing an electron-withdrawing
or -donating group (8m and 8n; 86% and 90%, respectively).
Mechanistic Consideration. A plausible catalytic cycle
of the gold-catalyzed naphthalene formation is shown in
Scheme 2. As described previously, this reaction would proceed
through a stepwise pathway including (1) intermolecular nucleo-
philic addition to 9a onto terminal alkyne or gold acetylide as
depicted in A, (2) protodeauration of B, (3) intramolecular
nucleophilic addition of the resulting enol ether/enamine-type inter-
mediate C, and (4) aromatization of D involving protodeauration
(1,3-proton shift and/or intermolecular protonation) leading
to the naphthalenes 8. To support this catalytic cycle including
RESULTS AND DISCUSSION
■
Naphthalene Synthesis. Initially, we investigated the reac-
tion of 9a under the conditions shown in Scheme 1. When
dialkynylbenzene 9a was treated with 5 mol % of Ph3PAuCl/
AgOTf in EtOH (10a) at 80 °C for 1.5 h, naphthalene
derivative 8a was obtained in 36% yield (Table 1, entry 1). As
expected, addition of EtOH regioselectively proceeded at the
terminal alkyne of 9a.12 The reaction at lower temperature (rt)
or use of AgNTf2 instead of AgOTf was less effective (entries 2
and 3). Use of a bulky and electron-donating phosphine ligand
(XPhos or JohnPhos) considerably decreased the yields (entries
4 and 5). Use of an N-heterocyclic carbene (NHC) ligand
IPr [IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene] in
place of PPh3 exhibited more efficient conversion to 8a (44%,
entry 6). Decreasing the loading of EtOH improved the yields
slightly (48−50%, entries 9 and 10), probably by suppressing
side reactions with excess EtOH.13 Interestingly, the most
efficient conversion was observed by decreasing the loading of
a
Table 1. Optimization of Reaction Conditions
c
b
entry
catalyst (mol %)
NuH (10)
(EtOH)
solvent
EtOH
T (°C)
time (h)
yield (%)
1
2
Ph3PAuCl/AgOTf (5)
Ph3PAuCl/AgOTf (5)
Ph3PAuCl/AgNTf2 (5)
XPhosAuCl/AgNTf2 (5)
JohnPhosAuCl/AgNTf2 (5)
IPrAuCl/AgOTf (5)
IPrAuCl/AgNTf2 (5)
IPrAuCl/AgNTf2 (5)
IPrAuCl/AgOTf (5)
IPrAuCl/AgOTf (5)
IPrAuCl/AgOTf (2)
IPrAuCl/AgOTf (2)
IPrAuCl (2)
80
rt
1.5
26
0.5
0.5
24
1
36
11
30
15
<6
44
36
31
48
50
61
93
nr
(EtOH)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
AcOH/EtOH
DCE
3
(EtOH)
80
rt
4
(EtOH)
5
(EtOH)
rt
6
(EtOH)
80
80
rt
7
(EtOH)
0.25
2
8
(EtOH)
9
(EtOH)
80
50
50
50
50
50
50
1
10
EtOH (10a)
EtOH (10a)
PhNHMe (10b)
PhNHMe (10b)
PhNHMe (10b)
PhNHMe (10b)
4
d
11
DCE
2
d
12
DCE
7
d
13
d
DCE
24
24
22
14
AgOTf (2)
DCE
nr
d
15
AuCl (2)
DCE
5
a
b
c
d
Reactions were carried out using 9a (0.1 mmol) and 10 (1.1 equiv). DCE = 1,2-dichloroethane. PhNHMe = N-methylaniline. 0.17 mmol of 9a
was used.
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a,b
Table 2. Substrate Scope
Scheme 3. Reaction of the Silyl Enol Ether 11
derivatives 8o and 8p as the silyl ether and alcohol forms,
respectively, was observed.
To obtain further mechanistic insights especially on the gold
acetylide formation, we next conducted deuterium-labeling
experiments (Scheme 4). The reaction of the labeled substrate
Scheme 4. Isotopic Labeling Experiments
9a-d (93%-d) with EtOH (10 equiv) under the standard
conditions gave the corresponding naphthalene derivative 8a
with a loss of deuterium labeling (≤10%-d, Scheme 4, eq 3).
This suggests that gold acetylide is efficiently generated in
the reaction. Isolation of the unlabeled substrate 9a with a
decreased deuterium content (<20%-d) from the reaction
mixture before completion indicates that the D−H exchange by
protonation of the gold acetylide is also promoted, presumably
a
Unless otherwise stated, the reaction was carried out using 9 (0.17
b
c
mmol) and 10 (1.1 equiv). DCE = 1,2-dichloroethane. 5.0 equiv of
10c (BuOH) or 10d (i-BuOH) was used.
Scheme 2. A Plausible Catalytic Cycle
+
with cogenerated EtODH+ or EtOH2 . Similarly, when the
reaction of the unlabeled substrate 9a was carried out in excess
EtOD (Scheme 4, eq 4), a high deuterium incorporation
(88−97%) was observed at the 2- and 4-positions of 8a.
Interestingly, the reaction with a decreased amount of EtOH
(10 equiv, Scheme 4, eq 5), we observed a significant decrease
of the deuterium incorporation at the 4-position (64%-d).
When the reaction was conducted using 1.1 equiv of EtOD
(Scheme 4, eq 6), deuterium contents at the 4- and 2-position
dropped to 18% and 61%, respectively.
The deuterium experiments using unlabeled 9a using EtOD
(Scheme 4, eqs 4−6) provide important information on the
reaction mechanism (Scheme 5). Thus, the reaction of the
π-complex A-h with EtOD before H−D exchange would produce
8a-dh bearing a hydrogen atom at the 4-position through
preferential 1,3-proton shift from D-dh (Scheme 5, eq 7).15
intermediacy of C, we prepared a related silyl enol ether 11 and
subjected to the cyclization conditions (Scheme 3). As we
expected, clean conversion to the corresponding naphthol
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On the other hand, decomposition of D-dh by EtOD/EtOD2+
(instead of 1,3-proton shift) will afford 8a-dd (Scheme 5, eq 7).
Scheme 6. Conversion of Gold Acetylide Complex 9a-Au
Scheme 5. Proposed Mechanism by the Experimental
Results
Application to Construction of Other Fused Rings.
Next, the reaction of heteroaromatic ring derivatives 12a and
12b was investigated (Scheme 7). When thiophene 12a was
a
Scheme 7. Reaction of Heteroaromatic Compounds
a
Reaction conditions: 12 (0.16 mmol), 10b (1.1 equiv), IPrAuCl/
AgOTf (5 mol % for 13a; 10 mol % for 13b), DCE, 80 °C.
treated with 5 mol % of IPrAuCl/AgOTf and 1.1 equiv of
N-methylaniline (10b) in DCE at 80 °C for 4 h, the
benzothiophene derivative 13a was obtained in 75% yield. A
limitation of the reaction can be seen in synthesis of amino-
benzofuran derivative 13b in low yield (35%) by using an
increased amount (10 mol %) of IPrAuCl/AgOTf.
Finally, biscyclization of triyne-type substrate 14 through
intermolecular nucleophilic addition and intramolecular double
carbocyclization cascade was investigated (Scheme 8). When
The reaction after gold acetylide formation (Scheme 5, eq 8) or
deuterium incorporation (Scheme 5, eq 9) furnishes 8a-dd
bearing two deuteriums at the 2- and 4-positions via deauration.
Considering the lower deuterium incorporation at the 4-position
when using a decreased amount of EtOD (18−64%-d, eqs 5
and 6 in Scheme 4) compared with the case using excess EtOD
(88%-d, Scheme 4, eq 4), it is reasonable that both of the path-
ways (Scheme 5, eq 7) and (eq 8)/(eq 9) would be involved: an
increased amount of EtOD accelerates the intermolecular reaction
of D-dh (eq 7) with EtOD/EtOD2+ over 1,3-shift, as well as the
H−D exchange from A-h to A-d. Relatively lower deuterium
content (61%-d) at the 2-position in the case using 1.1 equiv of
EtOD (Scheme 4, eq 6) can be rationalized by two possibilites:
relatively unfavorable 1,3-deuterium shift over 1,3-proton shift
from D-dh (Scheme 5, eq 7) in the more dominated pathway and
nucleophilic addition of cogenerated EtOH which should not
be negligible here. Overall, interconversion between the terminal
alkynes and gold acetylides would be one of the important factors
for the regioselective intermolecular nucleophilic addition to the
terminal alkyne moiety in addition to the steric reason.
a
Scheme 8. Application to Consecutive Cyclization
a
Reaction conditions: (for 15a) 14 (0.09 mmol), IPrAuCl/AgNTf2
The remaining unsolved problem was the possibility of the
intermolecular nucleophilic addition onto the gold acetylide
A-Au (Scheme 5, eq 8). Thus, we prepared gold acetylide
complex 9a-Au according to the reported procedure16 and
examined its reactivity. When 9a-Au was treated under the
standard cyclization conditions using 10b (1.1 equiv) without
the gold catalyst, only gradual decomposition of 9a-Au was
observed without producing the naphthalene 8b (Scheme 6).
Similarly, addition of the AgOTf (2 mol %) did not promote the
reaction. In sharp contrast, addition of the gold catalyst IPrAuCl/
AgOTf (2 mol %) to 9a-Au in DCE sufficiently promoted the
naphthalene formation to afford 8b quantatively. Thus, the gold
acetylide complex 9a-Au has proven to have sufficient reactivity
toward the intermolecular nucleophilic addition. This is good
accordance with the well-documented dual activation mechanism
in gold-catalyzed cycloisomerization of 1,5-enynes and 1,5-
allenynes, supported by calculations and tracking experiments.17
(5 mol %), EtOH (solvent), 80 °C; (for 15b) 14 (0.11 mmol), 10b
(1.1 equiv), IPrAuCl/AgNTf2 (10 mol %), DCE, 80 °C.
the triyne 14 was treated with 5 mol % of IPrAuCl/AgNTf2
in EtOH at 80 °C for 1 h, the chrysene derivative 15a was
obtained in 74% yield.18 An improved result was obtained using
N-methylaniline as the external nucleophile (92%). From these
observations, the inter-/intramolecular nucleophilic addition
cascade is also useful for atom-economical syntheses of not only
the 1,3-disubstituted naphthalenes but also the corresponding
fused naphthalenes.
CONCLUSION
■
We developed a novel gold-catalyzed cascade reaction for direct
construction of naphthalenes. The reaction of di- and
trialkynylbenzene derivatives produced the 1,3-disubstituted
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naphthalenes and disubstituted chrysenes, respectively, through
regioselective intermolecular addition of an external nucleo-
phile such as alcohols, amines, and heteroarenes followed by
(consecutive) 6-endo-dig carbocyclization(s).
Scheme 9. Preparation of 9c
EXPERIMENTAL SECTION
■
General Methods. All reactions under argon atmosphere were
performed using syringe−septum cap techniques and all glassware was
dried in an oven at 80 °C for 2 h prior to use. For flash chromato-
graphy, silica gel or NH2 silica gel was employed. Thin-layer
chromatography was performed on TLC silica gel 60 F254 (layer
thickness 0.25 mm), which was developed using standard visualizing
agents: UV fluorescence (254 nm) and anisaldehyde with heating.
Melting points were measured by a hot-stage melting point apparatus
1
(uncorrected). In H NMR spectra, chemical shifts are reported in δ
(ppm) relative to TMS as internal standard. In 13C NMR spectra,
1
1
chemical shifts are referenced to the residual solvent signal. H NMR
(OCH3); H NMR (500 MHz, CDCl3) δ 3.29 (s, 1H), 3.84 (s, 3H),
3.93 (s, 3H), 6.87 (dd, J = 8.5, 2.6 Hz, 1H), 7.06 (d, J = 2.6 Hz, 1H),
7.46 (d, J = 8.5 Hz, 1H), 7.61−7.63 (m, 2H), 8.02−8.03 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 52.3, 55.5, 79.9, 82.0, 90.7, 92.4, 115.5,
116.4, 117.3, 127.7, 127.0, 129.5 (2C), 129.8, 131.7 (2C), 134.0, 159.5,
166.5. Anal. Calcd for C19H14O3: C, 78.61; H, 4.86. Found: C, 78.42;
H, 4.66.
Methyl 3-Bromo-4-[(trimethylsilyl)ethynyl]benzoate (20).
Compound 19 was prepared through diazotization and iodination
of the corresponding amine according to the reported method.24 To
a stirred suspension of 1925 (1.02 g, 3.00 mmol), PdCl2(PPh3)2
(52.6 mg, 0.08 mmol) and CuI (14.3 mg, 0.08 mmol) in THF
(10 mL) under argon were added Et3N (2.1 mL, 15.0 mmol) and
trimethylsilylacetylene (0.5 mL, 3.60 mmol). After stirring at rt for
12 h, the reaction mixture was diluted with EtOAc and filtered through
a short pad of silica gel. The filtrate was concentrated in vacuo and
the residue was chromatographed on silica gel (hexane) to afford 20
(939 mg, quant) as a yellow oil. All spectral data were in good
agreement with those reported.26
Methyl 3-[(4-Methoxyphenyl)ethynyl]-4-[(trimethylsilyl)-
ethynyl]benzoate (21). The coupling of 20 and 1-ethynyl-4-
methoxybenzene was carried out according to the method reported
as follows:23 to a stirred suspension of 20 (636 mg, 2.00 mmol),
PdCl2(PhCN)2 (23.0 mg, 0.06 mmol) and CuI (7.6 mg, 0.04 mmol)
in 1,4-dioxane (2 mL) were added diisopropylamine (0.8 mL,
6.00 mmol), 1-ethynyl-4-methoxybenzene (0.3 mL, 2.20 mmol) and
tri-tert-butylphosphine (30 μL, 0.12 mmol). After stirring at rt
overnight, the reaction mixture was diluted with EtOAc and filtered
through a short pad of silica gel. The filtrate was concentrated in vacuo
and the residue was chromatographed on silica gel (hexane) to afford
21 (750.7 mg, quant) as a yellow oil: IR (neat) 2252 (CC), 2209
(CC), 1723 (CO), 1320 (SiCH3), 1289, 1247 (OCH3); 1H
NMR (500 MHz, CDCl3) δ 0.28 (s, 9H), 3.84 (s, 3H), 3.92 (s, 3H),
6.88−6.90 (m, 2H), 7.49−7.51 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.88
(dd, J = 8.0, 1.7 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 0.0 (3C), 52.4, 55.4, 86.3, 94.5, 101.9, 103.0, 114.1
(2C), 115.2, 126.8, 128.3, 129.5, 129.7, 132.4, 132.7, 133.4 (2C),
160.1, 166.1; HRMS (FAB) calcd for C22H22O3Si (M+) 362.1338,
found 362.1337.
spectra are tabulated as follows: chemical shift, multiplicity (b = broad,
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), number
of protons, and coupling constant(s). Magnetic sector-based mass
spectrometer was used for exact mass (HRMS) measurement.
Preparation of Starting Materials. 1-Ethynyl-2-(phenylethynyl)-
benzene (9a),6a 1-ethynyl-2-(pent-1-ynyl)benzene (9b),19 methyl
4-(methylamino)benzoate (10e),20 and N-benzylaniline (10g)21 were
prepared according to the literature.
Methyl 4-[(2-Bromo-5-methoxyphenyl)ethynyl]benzoate
(17). To a stirred suspension of 1622 (775 mg, 2.48 mmol), methyl
4-ethynylbenzoate (476 mg, 2.97 mmol), PdCl2(PPh3)2 (43.5 mg,
0.06 mmol), and CuI (11.8 mg, 0.06 mmol) in THF (8 mL) under
argon was added Et3N (1.7 mL, 12.4 mmol). After being stirred at rt
for 4 h, the reaction mixture was diluted with EtOAc and filtered
through a short pad of silica gel. The filtrate was concentrated in vacuo
and the residue was chromatographed on silica gel (hexane/EtOAc =
50/1) to afford 17 (841 mg, 98%) as colorless crystals: mp 105−106 °C;
IR (neat) 2360 (CC), 1709 (CO), 1274 (OCH3); 1H NMR (500
MHz, CDCl3) δ 3.81 (s, 3H), 3.93 (s, 3H), 6.79 (dd, J = 9.2, 2.9 Hz,
1H), 7.09 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.63−7.65 (m,
2H), 8.03−8.04 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 52.3, 55.6,
90.9, 92.7, 116.5, 117.0, 117.9, 125.4, 127.5, 129.6 (2C), 129.9, 131.6
(2C), 133.2, 158.5, 166.5. Anal. Calcd for C17H13BrO3: C, 59.16; H,
3.68. Found: C, 59.16; H, 3.80.
Methyl 4-[[5-Methoxy-2-[(trimethylsilyl)ethynyl]phenyl]-
ethynyl]benzoate (18). The coupling of 17 and trimethylsilylace-
tylene was carried out according to the method reported as follows:23
to a stirred suspension of 17 (690 mg, 2.00 mmol), PdCl2(PhCN)2
(23.0 mg, 0.06 mmol), and CuI (7.6 mg, 0.04 mmol) in 1,4-dioxane (2
mL) under argon were added diisopropylamine (0.8 mL, 6.00 mmol),
trimethylsilylacetylene (0.3 mL, 2.20 mmol), and tri-tert-butylphos-
phine (30 μL, 0.12 mmol). After being stirred at rt for 3 h, the reaction
mixture was diluted with EtOAc and filtered through a short pad of
silica gel. The filtrate was concentrated in vacuo and the residue was
chromatographed on silica gel (hexane/EtOAc = 50/1) to afford 18
(776.7 mg, quant) as colorless crystals: mp 73 °C; IR (neat) 2362,
2148 (CC), 1718 (CO), 1308 (SiCH3), 1268, 1231 (OCH3); 1H
NMR (500 MHz, CDCl3) δ 0.25 (s, 9H), 3.83 (s, 3H), 3.93 (s, 3H),
6.85 (dd, J = 8.6, 2.9 Hz, 1H), 7.03 (d, J = 2.9 Hz, 1H), 7.43 (d, J = 8.6
Hz, 1H), 7.61−7.62 (m, 2H), 8.02−8.04 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 0.0 (3C), 52.1, 55.4, 91.0, 92.3, 97.0, 103.2, 115.3,
116.2, 118.3, 126.7, 127.8, 129.4 (2C), 129.6, 131.5 (2C), 133.6, 159.2,
166.5; HRMS (FAB) calcd for C22H22O3Si (M+) 362.1338, found
362.1335.
Methyl 4-[(2-Ethynyl-5-methoxyphenyl)ethynyl]benzoate
(9c) (Scheme 9). To the solution of 18 (294.9 mg, 0.80 mmol) in
MeOH (8 mL) was added K2CO3 (331.7 mg, 2.40 mmol). After being
stirred at rt for 4.5 h, the mixture was diluted with Et2O and filtered
through a short pad of silica gel. The filtrate was concentrated in
vacuo, and the residue was chromatographed on silica gel (hexane)
to afford 9c (154.9 mg, 67%) as orange crystals: mp 113−115 °C; IR
(neat) 3267 (CCH), 2208 (CC), 1720 (CO), 1275, 1232
Methyl 4-Ethynyl-3-[(4-methoxyphenyl)ethynyl]benzoate
(9d) (Scheme 10). To a stirred solution of 21 (262 mg, 0.70
mmol) in MeOH (7 mL) was added K2CO3 (300 mg, 2.20 mmol).
After being stirred at rt for 2 h, the mixture was neutralized with satu-
rated aqueous citric acid and diluted with EtOAc. The organic layer
was separated, washed with water and brine, and dried over MgSO4.
The solvent was removed in vacuo and the residue was chromato-
graphed on silica gel (hexane) to afford the title compound 9d (114.8
mg, 55%) as colorless crystals: mp 133−134 °C; IR (neat) 3252 (C
1
CH), 2209 (CC), 1729 (CO), 1286, 1247 (OCH3); H NMR
(500 MHz, CDCl3) δ 3.50 (s, 1H), 3.83 (s, 3H), 3.93 (s, 3H), 6.88−
6.90 (m, 2H), 7.50−7.52 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.90 (dd,
J = 8.0, 1.7 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 52.4, 55.3, 81.7, 83.7, 85.9, 94.6, 114.1 (2C), 114.9, 127.0,
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7.28 (d, J = 1.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 0.0 (3C),
92.2, 104.5, 106.6, 114.8, 136.8, 143.9; HRMS (FAB) calcd for
C9H12BrOSi (MH+) 242.9835, found 242.9826.
Scheme 10. Preparation of 9d
Trimethyl[[3-(phenylethynyl)furan-2-yl]ethynyl]silane (26).
The coupling of 25 and ethynylbenzene was carried out according
to the method reported as follows:23 to a stirred suspension of 25
(355 mg, 1.46 mmol), PdCl2(PhCN)2 (33.6 mg, 0.09 mmol) and CuI
(16.7 mg, 0.09 mmol) in 1,4-dioxane (3 mL) under argon were added
diisopropylamine (1.0 mL, 7.30 mmol), ethynylbenzene (0.17 mL,
1.60 mmol), and tri-tert-butylphosphine (40 μL, 0.18 mmol). After
being stirred at rt for 6 h, the reaction mixture was diluted with EtOAc
and filtered through a short pad of silica gel. The filtrate was con-
centrated in vacuo, and the residue was chromatographed on silica gel
(hexane) to afford 26 (313 mg, 81%) as a dark amber oil: IR (neat)
2252 (CC), 2157 (CC); 1H NMR (500 MHz, CDCl3) δ 0.29 (s,
9H), 6.48 (d, J = 1.7 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.33−7.35 (m,
3H), 7.50−7.51 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 0.0 (3C),
80.8, 93.4, 95.1, 104.6, 113.47, 113.51, 113.7, 123.6, 128.6 (2C), 131.9
(2C), 143.26, 143.29; HRMS (FAB) calcd for C17H17OSi (MH+)
265.1043, found 265.1039.
128.2, 128.4, 130.1, 132.58, 132.64, 133.4 (2C), 160.1, 165.9; HRMS
(FAB) calcd for C19H14O3 (M+) 290.0943, found 290.0942.
Trimethyl[[3-(phenylethynyl)thiophen-2-yl]ethynyl]silane
(23). The coupling of 227 and ethynylbenzene was carried out
according to the method reported as follows:23 to a stirred suspension
of 22 (714 mg, 2.75 mmol), PdCl2(PhCN)2 (63.4 mg, 0.17 mmol),
and CuI (31.5 mg, 0.17 mmol) in 1,4-dioxane (5.5 mL) were added
diisopropylamine (1.9 mL, 13.7 mmol), ethynylbenzene (0.4 mL,
3.3 mmol), and tri-tert-butylphosphine (80 μL, 0.33 mmol). After
being stirred at rt for 6 h, the reaction mixture was diluted with EtOAc
and filtered through a short pad of silica gel. The filtrate was concentrated
in vacuo, and the residue was chromatographed on silica gel (hexane) to
afford 23 (705 mg, 91%) as a pale yellow oil; IR (neat) 2144 (CC); 1H
NMR (400 MHz, CDCl3) δ 0.28 (s, 9H), 7.05 (d, J = 5.4 Hz, 1H), 7.16
(d, J = 5.4 Hz, 1H), 7.33−7.36 (m, 3H), 7.52−7.54 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 0.0 (3C), 83.9, 93.7, 96.6, 103.7, 123.3, 126.1,
126.2, 127.7, 128.4, 128.5 (2C), 129.3, 131.7 (2C); HRMS (FAB) calcd
for C17H17SSi (MH+) 281.0815, found 281.0804.
2-Ethynyl-3-(phenylethynyl)furan (12b) (Scheme 12). To the
solution of 26 (268 mg, 1.00 mmol) in MeOH (10 mL) was added
Scheme 12. Preparation of 12b
2-Ethynyl-3-(phenylethynyl)thiophene (12a) (Scheme 11).
To a stirred solution of 23 (671.9 mg, 2.40 mmol) in MeOH (24 mL)
Scheme 11. Preparation of 12a
K2CO3 (451 mg, 3.0 mmol). After being stirred at rt for 1.5 h, the
mixture was diluted with Et2O and filtered through a short pad of silica
gel. The filtrate was concentrated in vacuo, and the residue was
chromatographed on silica gel (hexane) to afford 12b (159 mg, 81%)
1
as a dark amber oil: IR (neat) 3302 (CCH), 2253 (CC); H
NMR (500 MHz, CDCl3) δ 3.66 (s, 1H), 6.51 (d, J = 1.7 Hz, 1H),
7.34−7.35 (m, 4H), 7.52−7.53 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 72.8, 79.8, 85.7, 94.7, 113.3, 113.7, 122.9, 128.3 (2C), 128.6,
131.6 (2C), 139.0, 143.4; HRMS (FAB) calcd for C14H9O (MH+)
193.0648, found 193.0646.
was added K2CO3 (993 mg, 7.20 mmol). After being stirred at rt for
5 h, the mixture was diluted with Et2O and filtered through a short pad
of silica gel. The filtrate was concentrated in vacuo and the residue was
chromatographed on silica gel (hexane) to afford 12a (457 mg, 92%)
as an amber oil: IR (neat) 3299 (CCH), 2248 (CC), 2102 (CC);
1H NMR (500 MHz, CDCl3) δ 3.62 (s, 1H), 7.07 (d, J = 5.2 Hz, 1H),
7.20 (d, J = 5.2 Hz, 1H), 7.33−7.36 (m, 3H), 7.54−7.55 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 76.0, 83.3, 85.3, 93.5, 122.9, 124.7, 126.4,
127.9, 128.3 (2C), 128.5, 129.5, 131.7 (2C); HRMS (FAB) calcd for
C14H9S (MH+) 209.0419, found 209.0416.
[(3-Bromofuran-2-yl)ethynyl]trimethylsilane (25). The cou-
pling 24 and trimethylsilylacetylene was carried out according to the
reported method as follows:7 to a stirred suspension of 24 (1.00 g,
4.40 mmol), PdCl2(PPh3)2 (101 mg, 0.14 mmol) and CuI (52.7 mg,
0.28 mmol) in Et3N (5.9 mL) under argon was added tri-
methylsilylacetylene (0.73 mL, 5.30 mmol). After being stirred at
80 °C overnight, the reaction mixture was diluted with EtOAc and
filtered through a short pad of silica gel. The filtrate was concentrated
in vacuo and the residue was chromatographed on silica gel (hexane)
to afford 25 (627 mg, 58%) as an amber oil: IR (neat) 2158 (CC);
1H NMR (500 MHz, CDCl3) δ 0.27 (s, 9H), 6.45 (d, J = 1.8 Hz, 1H),
1-(Deuterioethynyl)-2-(phenylethynyl)benzene (9a-d). 1-
Ethynyl-2-(phenylethynyl)benzene (9a-d) was prepared according
to the reported method as follows:16 n-butyllithium (1.5 M in hexane,
260 μL, 0.39 mmol) was added to a mixture of 1-ethynyl-2-
(phenylethynyl)benzene (9a) (66.1 mg, 0.33 mmol) in anhydrous
diethyl ether (16 mL) under argon atmosphere at −78 °C. After being
stirred for 30 min, the reaction mixture was quenched with D2O. The
aqueous layer was extracted three times with dichloromethane. The
organic layer was dried over MgSO4 and filtrated. Evaporation of
the solvent gave 9a-d (73.0 mg, quant) as a colorless oil: IR (neat)
2585 (CCD), 2249 (CC), 2218 (CC); 1H NMR (500 MHz,
CDCl3) δ 3.36 (s, 0.07H), 7.27−7.38 (m, 5H), 7.54−7.57 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 81.1, 87.8, 92.1, 93.5, 123.2, 124.6,
126.3, 127.9, 128.3 (2C), 128.45, 128.48, 128.5, 131.8 (2C), 132.6;
HRMS (FAB) calcd for C16H10D (MH+) 204.0918, found
204.0917.
Gold(I)-Catalyzed Naphthalene Formation by Intermolecu-
lar/Intramolecular Addition Cascade. General Procedure: Syn-
thesis of 1-Ethoxy-3-phenylnaphthalene (8a) (Table 1, Entry 11).
To a stirred suspension of 1-ethynyl-2-(phenylethynyl)benzene (9a)
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(33.8 mg, 0.17 mmol), IPrAuCl (2.1 mg, 3.4 μmol), and AgOTf
(0.9 mg, 3.4 μmol) in 1,2-dichloroethane (DCE) (0.9 mL) under
argon was added ethanol (10a) (0.01 mL, 0.19 mmol), and the
resulting mixture was stirred at 50 °C for 2 h. The reaction mixture
was concentrated in vacuo. The residue was chromatographed on silica
gel (hexane) to afford 8a (25.5 mg, 61%) as pale yellow crystals:
mp 78−81 °C; IR (neat) 1233 (OCH2); 1H NMR (500 MHz, CDCl3)
δ 1.58 (t, J = 6.9 Hz, 3H), 4.29 (q, J = 6.9 Hz, 2H), 7.05 (s, 1H),
7.37 (t, J = 7.4 Hz, 1H), 7.46−7.49 (m, 4H), 7.61 (s, 1H), 7.70 (d, J =
7.4 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 14.9, 63.8, 104.6, 118.2, 122.0, 124.9,
125.1, 126.8, 127.3, 127.4 (2C), 127.7, 128.8 (2C), 134.6, 138.9, 141.7,
155.1; HRMS (FAB) calcd for C18H17O (MH+) 249.1274, found
249.1278.
N-Methyl-N,3-diphenylnaphthalen-1-amine (8b) (Table 1, Entry
12). The diyne 9a (22.6 mg, 0.11 mmol) was converted to 8b
(31.6 mg, 93%) by reaction with N-methylaniline (10b) (0.01 mL,
0.12 mmol) in the presence of IPrAuCl (1.4 mg, 2.2 μmol) and AgOTf
(0.6 mg, 2.2 μmol) in DCE (0.6 mL) at 50 °C for 7 h: yellow oil; IR
(neat) 1397 (NAr); 1H NMR (500 MHz, CDCl3) δ 3.43 (s, 3H), 6.67
(d, J = 8.0 Hz, 2H), 6.74 (t, J = 7.2 Hz, 1H), 7.14−7.18 (m, 2H), 7.35
(t, J = 7.2 Hz, 1H), 7.39−7.51 (m, 4H), 7.67−7.69 (m, 3H), 7.87 (d,
J = 8.6 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 40.3, 113.6 (2C), 117.3, 123.8, 124.3, 124.9, 126.4,
126.7, 127.3 (2C), 127.5, 128.8, 128.9 (2C), 129.0 (2C), 130.4, 135.4,
139.3, 140.5, 145.9, 150.1; HRMS (FAB) calcd for C23H20N (MH+)
310.1590, found 310.1583.
1-Butoxy-3-phenylnaphthalene (8c) (Table 2). The diyne 9a (34.7
mg, 0.17 mmol) was converted to 8c (30.8 mg, 65%) by reaction with
1-butanol (10c) (0.08 mL, 0.85 mmol) in the presence of IPrAuCl
(2.1 mg, 3.4 μmol) and AgOTf (0.9 mg, 3.4 μmol) in DCE (0.9 mL)
at 50 °C for 6 h: pale yellow needles; mp 49 °C; IR (neat) 1234
(OCH2); 1H NMR (500 MHz, CDCl3) δ 1.04 (t, J = 7.4 Hz, 3H), 1.62
(qt, J = 7.4, 7.4 Hz, 2H), 1.91−1.97 (m, 2H), 4.22 (t, J = 6.3 Hz, 2H),
7.05 (d, J = 1.1 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.44−7.51 (m, 4H),
7.60 (s, 1H), 7.69−7.71 (m, 2H), 7.83 (d, J = 7.4 Hz, 1H), 8.28 (d, J =
8.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 19.5, 31.4, 67.9,
104.6, 118.1, 122.0, 125.0, 125.1, 126.8, 127.3, 127.4 (2C), 127.7,
128.8 (2C), 134.6, 139.0, 141.7, 155.3; HRMS (FAB) calcd for
C20H20O (M+) 276.1514, found 276.1514.
(25.7 mg, 0.19 mmol) in the presence of IPrAuCl (2.1 mg, 3.4 μmol)
and AgOTf (0.9 mg, 3.4 μmol) in DCE (0.9 mL) at 50 °C for 24 h:
yellow oil; IR (neat) 1285 (NAr), 1242 (OCH3); 1H NMR (400 MHz,
CDCl3) δ 3.40 (s, 3H), 3.74 (s, 3H), 6.67−6.70 (m, 2H), 6.75−6.78
(m, 2H), 7.33−7.51 (m, 5H), 7.60 (d, J = 1.7 Hz, 1H), 7.67−7.69 (m,
2H), 7.92−7.93 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 41.1, 55.7,
114.5 (2C), 116.1 (2C), 123.5, 123.6, 124.0, 126.1, 126.5, 127.3 (2C),
127.5, 128.7, 128.8 (2C), 130.1, 135.3, 139.2, 140.7, 144.9, 146.9,
152.4; HRMS (FAB) calcd for C24H21NO (M+) 339.1623, found
339.1622.
N-Benzyl-N,3-diphenylnaphthalen-1-amine (8g). The diyne 9a
(33.6 mg, 0.17 mmol) was converted to 8g (50.1 mg, 78%) by reaction
with N-benzylaniline (10g)21 (0.03 mL, 0.18 mmol) in the presence of
IPrAuCl (2.0 mg, 3.3 μmol) and AgOTf (0.9 mg, 3.3 μmol) in DCE
(0.9 mL) at 50 °C for 4 h: yellow crystals; mp 128−131 °C; IR (neat)
1
1336 (NAr); H NMR (500 MHz, CDCl3) δ 5.07 (s, 2H), 6.64−6.66
(m, 2H), 6.70−6.74 (m, 1H), 7.08−7.13 (m, 2H), 7.22−7.24 (m, 1H),
7.30−7.53 (m, 9H), 7.62−7.64 (m, 2H), 7.73 (d, J = 2.0 Hz, 1H), 7.88
(d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ 57.1, 114.1 (2C), 117.6, 123.9, 124.7, 126.2,
126.4, 126.6, 126.9, 127.0 (2C), 127.3 (2C), 127.5, 128.6 (2C), 128.87
(2C), 128.94, 128.95 (2C), 130.2, 135.6, 139.15, 139.16, 140.5, 144.5,
149.5. Anal. Calcd for C29H23N: C, 90.35; H, 6.01; N, 3.63. Found: C,
90.56; H, 6.06; N, 3.61.
Methyl 2-Benzyl-2-(3-phenylnaphthalen-1-yl)hydrazinecarboxylate
(8h). The diyne 9a (33.4 mg, 0.17 mmol) was converted to 8h
(48.8 mg, 77%) by reaction with methyl 2-benzylhydrazinecarbox-
ylate (10h) (32.7 mg, 0.18 mmol) in the presence of IPrAuCl (2.0
mg, 3.3 μmol) and AgOTf (0.9 mg, 3.3 μmol) in DCE (0.8 mL) at
50 °C for 2 h: pale yellow crystals; mp 137 °C; IR (neat) 1712
1
(CO), 1246 (OCH3); H NMR (500 MHz, CDCl3) δ 3.62 (s,
3H), 4.71 (br s, 2H), 6.49 (br s, 1H), 7.31 (dd, J = 6.7, 1.7 Hz, 1H),
7.34−7.39 (m, 5H), 7.47 (dd, J = 7.7, 7.7 Hz, 2H), 7.52−7.54
(m, 3H), 7.65 (d, J = 7.4 Hz, 2H), 7.83 (s, 1H), 7.89−7.90 (m, 1H),
8.41−8.43 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 52.3 (br),
60.0 (br), 117.1 (br), 123.2, 123.5, 126.0, 126.5, 127.36 (2C),
127.38, 127.7, 127.8 (2C), 128.46 (2C), 128.53, 128.8 (2C), 129.1
(2C), 134.9, 136.2 (br), 138.1, 141.0, 146.3 (br), 155.8 (br);
HRMS (FAB) calcd for C25H23N2O2 (MH+) 383.1754, found
383.1760.
3-(3-Phenylnaphthalen-1-yl)-1H-indole (8i). The diyne 9a (32.8
mg, 0.16 mmol) was converted to 8i (52.9 mg, quant) by reaction
with indole (10i) (20.6 mg, 0.18 mmol) in the presence of IPrAuCl
(2.0 mg, 3.2 μmol) and AgOTf (0.8 mg, 3.2 μmol) in DCE
(0.8 mL) at 50 °C for 2 h. For column chromatography, NH2
silica gel (hexane/EtOAc = 50/1) was employed: dark yellow oil; IR
1-Isobutoxy-3-phenylnaphthalene (8d). The diyne 9a (33.7 mg,
0.17 mmol) was converted to 8d (29.3 mg, 64%) by reaction with
isobutanol (10d) (0.08 mL, 0.83 mmol) in the presence of IPrAuCl
(2.1 mg, 3.3 μmol) and AgOTf (0.9 mg, 3.3 μmol) in DCE (0.9 mL)
1
at 50 °C for 24.5 h: yellow oil; IR (neat) 1230 (OCH); H NMR
(500 MHz, CDCl3) δ 1.07 (t, J = 7.4 Hz, 3H), 1.44 (d, J = 6.3 Hz,
3H), 1.75−1.83 (m, 1H), 1.90−1.94 (m, 1H), 4.61−4.64 (m, 1H),
7.07 (d, J = 1.1 Hz, 1H), 7.35−7.39 (m, 1H), 7.44−7.49 (m, 4H), 7.59
(s, 1H), 7.68−7.70 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 9.9, 19.3, 29.4, 75.3, 106.1,
118.0, 122.3, 125.0, 125.8, 126.7, 127.3, 127.5 (2C), 127.8, 128.8 (2C),
134.9, 139.0, 141.8, 154.3; HRMS (FAB) calcd for C20H21O (MH+)
277.1587, found 277.1577.
1
(neat) 3468 (NH); H NMR (500 MHz, CDCl3) δ 7.13−7.15 (m,
1H), 7.26−7.30 (m, 1H), 7.37−7.40 (m, 3H), 7.49−7.53 (m, 5H), 7.76−
7.78 (m, 2H), 7.89 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 8.07−
8.08 (m, 2H), 8.33 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 111.3,
116.6, 120.1, 120.3, 122.5, 123.6, 125.0, 125.8, 126.2, 126.4, 127.32, 127.35,
127.5 (2C), 127.7, 128.6, 128.8 (2C), 131.8, 133.5, 134.3, 136.1, 138.2,
141.1; HRMS (FAB) calcd for C24H18N (MH+) 320.1434, found
320.1431.
Methyl 4-[Methyl(3-phenylnaphthalen-1-yl)amino]benzoate
(8e). The diyne 9a (35.2 mg, 0.17 mmol) was converted to 8e
(71.1 mg, quant) by reaction with methyl 4-(methylamino)benzoate
(10e)20 (30.9 mg, 0.19 mmol) in the presence of IPrAuCl (2.2 mg,
3.5 μmol) and AgOTf (0.9 mg, 3.5 μmol) in DCE (0.9 mL) at
50 °C for 6 h: yellow oil; IR (neat) 1702 (CO), 1397 (NAr),
2-(3-Phenylnaphthalen-1-yl)-1H-pyrrole (8j). The diyne 9a (33.1
mg, 0.16 mmol) was converted to 8j (21.4 mg, 50%) by reaction
with pyrrole (10j) (0.01 mL, 0.18 mmol) in the presence of IPrAuCl
(2.1 mg, 3.3 μmol) and AgOTf (0.9 mg, 3.3 μmol) in DCE (0.8 mL)
at 50 °C for 26 h. For column chromatography, NH2 silica gel
1
1
(hexane) was employed: dark brown oil; IR (neat) 3349 (NH); H
1278 (OCH3); H NMR (500 MHz, CDCl3) δ 3.49 (s, 3H), 3.83
NMR (400 MHz, CDCl3) δ 6.44 (dd, J = 5.7, 2.8 Hz, 1H), 6.56−6.57
(m, 1H), 6.99−7.00 (m, 1H), 7.38−7.40 (m, 1H), 7.47−7.54 (m, 4H),
7.73−7.74 (m, 2H), 7.78 (d, J = 1.7 Hz, 1H), 7.93−7.94 (m, 1H), 8.00
(s, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.46 (br s, 1H); 13C NMR (125
MHz, CDCl3) δ 109.55, 109.64, 118.5, 125.3, 125.6, 125.8, 126.38,
126.38, 127.4 (2C), 127.5, 128.7, 128.9 (2C), 130.5, 130.6, 132.1,
134.4, 138.2, 140.8; HRMS (FAB) calcd for C20H16N (MH+)
270.1277, found 270.1276.
(s, 3H), 6.60 (d, J = 8.6 Hz, 2H), 7.41−7.51 (m, 5H), 7.70−7.72
(m, 4H), 7.84 (d, J = 9.2 Hz, 2H), 7.98 (d, J = 8.0 Hz, 1H), 8.06
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 40.2, 51.5, 112.0 (2C),
118.3, 123.2, 125.2, 125.4, 126.8, 126.9, 127.2 (2C), 127.7, 128.93,
128.94 (2C), 129.8, 131.2 (2C), 135.4, 139.3, 140.1, 144.2, 153.2,
167.3; HRMS (FAB) calcd for C25H22NO2 (MH+) 368.1645, found
368.1644.
N-(4-Methoxyphenyl)-N-methyl-3-phenylnaphthalen-1-amine
(8f). The diyne 9a (34.5 mg, 0.17 mmol) was converted to 8f
(53.0 mg, 92%) by reaction with 4-methoxy-N-methylaniline (10f)
3-(3-Phenylnaphthalen-1-yl)-1-(triisopropylsilyl)-1H-pyrrole (8k).
The diyne 9a (30.4 mg, 0.15 mmol) was converted to 8k (24.4 mg,
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38%) by reaction with 1-(triisopropylsilyl)-1H-pyrrole (10k) (0.04
mL, 0.16 mmol) in the presence of IPrAuCl (1.9 mg, 3.0 μmol) and
AgOTf (0.8 mg, 3.0 μmol) in DCE (0.8 mL) at 50 °C for 6 h:
amber oil; IR (neat) 2867, 2946 (CH); 1H NMR (500 MHz,
CDCl3) δ 1.17 (d, J = 7.4 Hz, 18H), 1.51−1.53 (m, 3H), 6.64 (dd,
J = 2.9, 1.4 Hz, 1H), 6.91−6.93 (m, 1H), 7.02−7.03 (m, 1H), 7.37
(t, J = 7.4 Hz, 1H), 7.45−7.48 (m, 4H), 7.76−7.77 (m, 3H), 7.91−
7.94 (m, 2H), 8.34 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 11.8 (3C), 17.9 (6C), 112.5, 123.5, 124.2, 124.3, 125.2,
125.6, 125.9, 126.1, 126.3, 127.2, 127.5 (2C), 128.5, 128.8 (2C),
131.3, 134.3, 135.6, 138.2, 141.4; HRMS (FAB) calcd for
C29H36NSi (MH+) 426.2612, found 426.2603.
(125 MHz, CDCl3) δ −4.14, 18.5, 25.9, 112.4, 119.0, 122.5, 125.2,
126.6, 127.1, 127.3 (3C), 128.0, 128.8 (2C), 135.1, 138.9, 141.3,
152.1; HRMS (FAB) calcd for C22H26OSi (M) 334.1753, found
334.1753.
N-Methyl-N,5-diphenylbenzo[b]thiophen-7-amine (13a)
(Scheme 7). 2-Ethynyl-3-(phenylethynyl)thiophene (12a) (34.1 mg,
0.16 mmol) was converted to 13a (38.7 mg, 75%) by reaction with
N-methylaniline (10b) (0.02 mL, 0.18 mmol) in the presence of
IPrAuCl (5.1 mg, 8.2 μmol) and AgOTf (2.1 mg, 8.2 μmol) in DCE
1
(0.8 mL) at 80 °C for 4 h: amber oil; IR (neat) 1366 (NAr); H
NMR (500 MHz, CDCl3) δ 3.44 (s, 3H), 6.84−6.86 (m, 3H),
7.20−7.23 (m, 3H), 7.34 (t, J = 6.8 Hz, 1H), 7.39−7.40 (m, 2H),
7.43−7.45 (m, 3H), 7.63−7.64 (m, 2H), 7.88 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ 39.7, 116.4 (2C), 118.9, 119.2, 120.6, 124.5,
124.9, 127.2, 127.4 (2C), 128.8 (2C), 129.0 (2C), 135.9, 139.4,
141.1, 142.0, 143.7, 148.4; HRMS (FAB) calcd for C21H18NS
(MH+) 316.1154, found 316.1152.
N-Methyl-N-phenyl-3-propylnaphthalen-1-amine (8l). 1-Ethynyl-
2-(pent-1-ynyl)benzene (9b) (26.0 mg, 0.15 mmol) was converted to
8l (29.1 mg, 68%) by reaction with N-methylaniline (10b) (0.02 mL,
0.17 mmol) in the presence of IPrAuCl (1.9 mg, 3.1 μmol) and AgOTf
(0.8 mg, 3.1 μmol) in DCE (0.8 mL) at 50 °C for 10 h: yellow oil; IR
1
(neat) 1396 (NAr); H NMR (500 MHz, CDCl3) δ 0.97 (t, J = 7.2
N-Methyl-N,5-diphenylbenzofuran-7-amine (13b) (Scheme 7). 2-
Ethynyl-3-(phenylethynyl)furan (9c) (31.6 mg, 0.16 mmol) was
converted to 13b (17.2 mg, 35%) by reaction with N-methylaniline
(10b) (0.02 mL, 0.18 mmol) in the presence of IPrAuCl (10.2 mg,
20 μmol) and AgOTf (4.2 mg, 20 μmol) in DCE (0.8 mL) at 80 °C
Hz, 3H), 1.70−1.73 (m, 2H), 2.72 (t, J = 7.4 Hz, 2H), 3.38 (s, 3H),
6.61 (d, J = 8.6 Hz, 2H), 6.71 (dd, J = 7.2, 7.2 Hz, 1H), 7.13−7.17 (m,
2H), 7.23−7.24 (m, 1H), 7.33−7.38 (m, 1H), 7.45 (dd, J = 7.2, 7.2
Hz, 1H), 7.56 (s, 1H), 7.82 (dd, J = 9.5, 8.6 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 13.8, 24.4, 38.0, 40.2, 113.4, 117.0, 123.6, 125.2,
125.4, 126.2, 126.8, 127.1, 127.9, 128.9, 129.6, 131.8, 135.2, 141.1,
145.1, 150.1; HRMS (FAB) calcd for C20H22N (MH+) 276.1747,
found 276.1745.
1
for 27 h: amber oil; IR (neat) 1369 (NAr); H NMR (500 MHz,
CDCl3) δ 3.49 (s, 3H), 6.81 (d, J = 1.7 Hz, 1H), 6.85 (t, J = 7.4 Hz,
1H), 6.90 (d, J = 8.0 Hz, 2H), 7.22−7.24 (m, 3H), 7.32 (t, J = 7.4 Hz,
1H), 7.37 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 7.4, 7.4 Hz, 2H), 7.57−
7.58 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 39.7, 107.1, 115.7,
116.0 (2C), 119.2, 120.2, 127.0, 127.4 (2C), 128.7 (2C), 128.9 (2C),
129.8, 133.3, 137.5, 141.4, 145.4, 148.6, 148.9; HRMS (FAB) calcd for
C21H18NO (MH+) 300.1383, found 300.1384.
12-Ethoxy-5-phenylchrysene (15a) (Scheme 8). 1-Ethynyl-2-[[2-
(phenylethynyl)phenyl]ethynyl]benzene (14) (27.1 mg, 0.09 mmol)
was converted to 15a (23.2 mg, 74%) by reaction with ethanol
(10a) in the presence of IPrAuCl (2.8 mg, 4.5 μmol) and AgNTf2
(1.8 mg, 4.5 μmol) in ethanol (0.9 mL) under reflux for 1 h: pale
yellow crystals: mp 147−148 °C; IR (neat) 1230 (OCH2); 1H
NMR (500 MHz, CDCl3) δ 1.68 (t, J = 6.9 Hz, 3H), 4.49 (q, J = 6.9
Hz, 2H), 7.11−7.14 (m, 1H), 7.40−7.47 (m, 6H), 7.65−7.67 (m,
2H), 7.59−7.62 (m, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 6.3
Hz, 1H), 8.00 (s, 1H), 8.44 (dd, J = 8.0, 1.1 Hz, 1H), 8.66 (d, J =
8.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.9, 63.8, 98.6,
121.9, 122.5, 123.0, 125.0, 125.4, 126.1, 126.6, 126.8, 127.0, 128.42,
128.44, 128.7, 128.8 (2C), 129.0 (2C), 129.5, 130.9, 131.6, 131.7,
138.3, 145.7, 153.8; HRMS (FAB) calcd for C26H21O (MH+)
349.1587, found 349.1583.
Methyl 4-[7-Methoxy-4-[methyl(phenyl)amino]naphthalen-2-yl]-
benzoate (8m). Methyl 4-[(2-ethynyl-5-methoxyphenyl)ethynyl]-
benzoate (9c) (49.4 mg, 0.17 mmol) was converted to 8m (57.8
mg, 86%) by reaction with N-methylaniline (10b) (0.02 mL, 0.19
mmol) in the presence of IPrAuCl (2.1 mg, 3.4 μmol) and AgOTf
(0.9 mg, 3.4 μmol) in DCE (0.9 mL) at 50 °C for 7 h: orange
crystals; mp 150−151 °C; IR (neat) 1713 (CO), 1391 (NAr),
1
1276, 1231 (OCH3); H NMR (500 MHz, CDCl3) δ 3.43 (s, 3H),
3.94 (s, 6H), 6.66 (d, J = 8.0 Hz, 2H), 6.74 (t, J = 7.4 Hz, 1H), 7.10
(dd, J = 9.2, 2.9 Hz, 1H), 7.15−7.19 (m, 2H), 7.26 (d, J = 2.9 Hz,
1H), 7.51 (d, J = 1.7 Hz, 1H), 7.75−7.78 (m, 3H), 7.93 (d, J = 1.1
Hz, 1H), 8.12 (dd, J = 6.8, 1.7 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 40.3, 52.1, 55.4, 106.8, 113.7 (2C), 117.4, 119.6, 122.1,
123.7, 125.5, 126.2, 127.1 (2C), 128.97 (2C), 129.04, 130.1 (2C),
136.6, 138.7, 145.1, 146.2, 149.9, 158.4, 166.9. Anal. Calcd for
C26H23NO3: C, 78.57; H, 5.83; N, 3.52. Found: C, 78.30; H, 5.85;
N, 3.42.
Methyl 7-(4-Methoxyphenyl)-5-[methyl(phenyl)amino]-2-naph-
thoate (8n). Methyl 4-ethynyl-3-[(4-methoxyphenyl)ethynyl]benzoate
(9d) (49.8 mg, 0.17 mmol) was converted to 8n (60.8 mg, 90%) by
reaction with N-methylaniline (10b) (0.02 mL, 0.19 mmol) in the
presence of IPrAuCl (2.1 mg, 3.4 μmol) and AgOTf (0.9 mg, 3.4
μmol) in DCE (0.9 mL) at 50 °C for 10 h: colorless crystals; mp 133 °C;
N-Methyl-N,11-diphenylchrysen-6-amine (15b) (Scheme 8). 1-
Ethynyl-2-[[2-(phenylethynyl)phenyl]ethynyl]benzene (14) (31.9 mg,
0.11 mmol) was converted to 15b (39.4 mg, 92%) by reaction with
N-methylaniline (10b) (0.01 mL, 0.12 mmol) in the presence of
IPrAuCl (6.5 mg, 12 μmol) and AgNTf2 (4.1 mg, 12 μmol) in DCE
(0.6 mL) under reflux for 24 h: pale yellow powder: mp 172−175 °C;
1
IR (neat) 1710 (CO), 1368 (NAr), 1259, 1240 (OCH3); H NMR
(500 MHz, CDCl3) δ 3.44 (s, 3H), 3.87 (s, 3H), 3.98 (s, 3H), 6.67
(d, J = 8.6 Hz, 2H), 6.76 (t, J = 7.4 Hz, 1H), 7.00−7.03 (m, 2H), 7.16−
7.19 (m, 2H), 7.62−7.63 (m, 2H), 7.73 (d, J = 1.7 Hz, 1H), 7.90 (d,
J = 9.2 Hz, 1H), 7.96 (dd, J = 8.6, 1.7 Hz, 1H), 8.03 (s, 1H), 8.69 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 40.3, 52.2, 55.4, 113.8 (2C), 114.4
1
IR (neat) 1346 (NAr); H NMR (500 MHz, CDCl3) δ 3.54 (s, 3H),
6.75−6.77 (m, 3H), 7.13 (t, J = 7.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 2H),
7.39 (t, J = 7.7 Hz, 1H), 7.43−7.52 (m, 5H), 7.61−7.66 (m, 2H), 7.84
(s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.98 (d, J =
8.6 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.69 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 40.3, 113.7 (2C), 117.4, 120.6, 123.1, 123.9, 124.9,
126.2, 126.5, 126.7, 126.9, 127.0, 128.4, 128.96 (2C), 129.01 (2C),
129.1 (2C), 129.4, 129.7, 130.5, 130.9, 131.2, 131.5, 132.3, 138.2,
144.6, 145.5, 150.0; HRMS (FAB) calcd for C31H24N (MH+)
410.1903, found 410.1901.
(2C), 117.7, 124.1, 124.6, 125.3, 126.9, 128.2, 128.3 (2C), 129.0
(2C), 131.7, 132.1, 132.4, 134.6, 139.8, 145.9, 149.8, 159.6, 167.1. Anal.
Calcd for C26H23NO3: C, 78.57; H, 5.83; N, 3.52. Found: C, 78.33; H,
5.74; N, 3.48.
tert-Butyldimethyl[(3-phenylnaphthalen-1-yl)oxy]silane (8o)
(Scheme 3). tert-Butyldimethyl[[1-(2-(phenylethynyl)phenyl)vinyl]oxy]-
silane (11)27 (51.2 mg, 0.15 mmol) was converted to 8o (27.8 mg, 54%)
and 8p containing some impurities (8.4 mg, ca. 25%) by reaction in
the presence of IPrAuCl (1.9 mg, 3.1 μmol) and AgOTf (0.8 mg,
3.1 μmol) in DCE (0.8 mL) at 50 °C for 24 h. The spectral data for
8p was matched those presented in the literature.28 Compound
ASSOCIATED CONTENT
■
S
* Supporting Information
1
8o: orange oil; IR (neat) 1296 (Si-CH3), 1100 (Si−O); H NMR
Experimental procedures and compound characterization data
including NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(400 MHz, CDCl3) δ 0.33 (s, 6H), 1.12 (s, 9H), 7.13 (d, J = 1.4 Hz,
1H), 7.37 (t, J = 7.4 Hz, 1H), 7.43−7.51 (m, 5H), 7.66−7.68 (m,
3H), 7.84 (t, J = 4.6 Hz, 1H), 8.18 (d, J = 4.6 Hz, 1H); 13C NMR
4914
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The Journal of Organic Chemistry
Featured Article
108, 2089−2117. (c) Medarde, M.; Morgan, B. J.; Linton, E. C. J.
Enzyme Inhib. Med. Chem. 2004, 19, 521−540. (d) Kozlowski, M. C.;
Morgan, B. J.; Linton, E. C. Chem. Soc. Rev. 2009, 38, 3193−3207.
(e) Rokade, Y. B.; Sayyed, R. Z. Rasayan J. Chem. 2009, 2, 972−980.
(f) Lin, C. Y.; Wheelock, Å. M.; Morin, D.; Baldwin, R. M.; Lee, M. G.;
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16−27.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hohno@pharm.kyoto-u.ac.jp, nfujii@pharm.kyoto-u.ac.jp.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Encouragement
of Young Scientists (A) (H.O.), Scientific Research on
Innovative Areas “Integrated Organic Synthesis” (H.O.), and
the Targeted Proteins Research Program from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
Y.S. is grateful for Research Fellowships from the JSPS for
Young Scientists.
(11) For gold-catalyzed reactions of the related 1,2-diethynylbenzenes to
form indene derivatives; see: (a) Ye, L.; Wang, Y.; Aue, D. H.; Zhang, L. J.
Am. Chem. Soc. 2012, 134, 31−34. (b) Hashmi, A. S. K.; Braun, I.; Nosel,
̈
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Int. Ed. 2012, 51, 4456−4460. See also, ref 16.
̈
(12) The reaction of diyne 27 without having a terminal alkyne
moiety under the optimized reaction conditions (Table 1, entry 11)
produced an inseparable mixture of several compounds, which
contains the products with the desired mass number.
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