Gold-Catalyzed Ammonium Acetate Assisted Cascade Cyclization of 2-Alkynylarylketones

Article abstract of DOI:10.1021/acs.joc.5b01939

An ammonium acetate assisted gold-catalyzed cascade cyclization reaction of 2-alkynylarylketones is described. Under the reported conditions, a gold-catalyzed intramolecular cyclization of 2-alkynylarylketones takes place through two competing reaction mechanisms?-?a 5-exo-dig or a 6-endo-dig cyclization-leading to two regioisomeric intermediates: isobenzofuranium or isobenzopyrylium. In the presence of ammonium acetate, the two intermediate compounds undergo further rearrangement to 2,3-disubstituted indenones and 1,3-disubstituted isoquinolines, respectively. While both reaction pathways proceed via a cyclization-rearrangement cascade, the gold-mediated 5-exo-dig process is especially notable, as it provides a novel cyclization protocol of 2-alkynylarylketones.

Full text of DOI:10.1021/acs.joc.5b01939

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Article
Gold-Catalyzed Ammonium Acetate-Assisted
Cascade Cyclization of 2-Alkynylarylketones
Maciej E. Domaradzki, Yuhua Long, Zhigang She, Xiaochen Liu, Gan Zhang, and Yu Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01939 • Publication Date (Web): 23 Oct 2015
Downloaded from http://pubs.acs.org on October 25, 2015
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The Journal of Organic Chemistry
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Gold-Catalyzed Ammonium Acetate-Assisted Cascade
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Cyclization of 2-Alkynylarylketones
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Maciej E. Domaradzki,a Yuhua Long,a Zhigang She, Xiaochen Liu, Gan Zhang, and Yu Chen*
Department of Chemistry and Biochemistry, Queens College and the Graduate Center of the City
University of New York, 65-30 Kissena Blvd., Flushing, New York 11367
yu.chen1@qc.cuny.edu
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ABSTRACT
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An ammonium acetate-assisted gold-catalyzed cascade cyclization reaction of 2-alkynylarylketones is
described. Under the reported conditions, a gold-catalyzed intramolecular cyclization of
2-alkynylarylketones takes place through two competing reaction mechanisms–a 5-exo-dig or a
6-endo-dig cyclization–leading to two regioisomeric intermediates: isobenzofuranium or
isobenzopyrylium. In the presence of ammonium acetate, the two intermediate compounds undergo
further rearrangement to 2,3-disubstituted indenones and 1,3-disubstituted isoquinolines, respectively.
While
both reaction pathways proceed via
a
cyclization-rearrangement
cascade,
a These authors have contributed equally to all the work described herein.
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the gold-mediated 5-exo-dig process is especially notable as it provides a novel cyclization protocol of
2-alkynylarylketones.
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INTRODUCTION
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The Lewis acid induced intramolecular electrophilic cyclization of o-alkynylarylcarbonyl
compounds has proven to be a versatile synthetic approach to a variety of biologically interesting
heterocycles and carbocycles.1,2 Among the o-alkynylarylcarbonyl compounds, o-alkynylarylaldehydes
have shown great versatility, displaying high reactivity as substrates for cyclization reactions.3 In
comparison to the many electrophilic cyclization reactions explored for o-alkynylarylaldehydes,
examples of cyclization reactions involving o-alkynylarylketones are relatively rare,4 possibly due to
their lower chemical reactivity than the aldehydes. The cyclizations of o-alkynylarylketones are usually
explored as an extension of the reaction scope of analogous o-alkynylarylaldehydes. In general, the
known cyclization processes of o-alkynylarylaldehydes and -ketones share the same isobenzopyrylium
intermediate, which reacts with either a nucleophile to furnish isochromene derivatives3a-c,5 (Scheme 1,
path a) or undergoes a cycloaddition with an alkene/alkyne moiety to generate polycyclic compounds
(Scheme 1, path b).6 Besides the two major reaction pathways, a few examples have demonstrated that
in the presence of a nitrogen nucleophile, such as ammonia,7 ammonium acetate,8 or primary amines,9
intramolecular cyclizations of o-alkynylarylaldehydes and -ketones lead to the formation of isoquinoline
derivatives (Scheme 1, path c). Although the two o-alkynylarylcarbonyl substrates often show similar
chemical reactivity, and lead to the same derivatives, it is known that o-alkynylarylaldehydes
preferentially undergo 6-endo-dig cyclizations to form isobenzopyrylium intermediates, whereas o-
alkynylarylketones often undergo 5-exo-dig cyclizations to form isobenzofuraniums, under similar
reaction conditions. While the reactivity of isobenzopyrylium intermediates generated from the
cyclization of o-alkynylarylcarbonyl compounds has been explored in numerous processes, such as
nucleophilic additions5 and cycloadditions,6 the reactivity of isobenzofuranium intermediates generated
in these electrophilic cyclization reactions have not yet been widely elucidated.10 Most of the known
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reactions of isobenzofuranium intermediates are limited to simple nucleophilic additions, which
exclusively lead to isobenzofuran derivatives (Scheme 1, path d).3h,11
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We previously developed a one-pot synthesis of isoquinolines by a palladium-catalyzed sequential
coupling–imination−annulation reaction,8a involving a key mechanistic step—the electrophilic
cyclization of o-alkynylarylaldehydes in the presence of in situ generated ammonia. When we attempted
to expand the substrate scope of this synthetic protocol to o-alkynylarylketones, we encountered limited
success, and the desired isoquinolines were only obtained in low yields (< 20%). The low chemical
reactivity observed for o-alkynylarylketones in our previous work prompted us to further explore their
reactivity in the electrophilic cyclization reactions. We hereby report our recent progress on this topic:
an ammonium acetate-assisted gold-catalyzed electrophilic cyclization of o-alkynylarylketones, through
a cascade cyclization-rearrangement process, leading to the formation of indenones and isoquinolines
(Scheme 1, path e).
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Scheme 1. Intramolecular Cyclization Reactions of o-Alkynylarylaldehydes and –ketones.
RESULTS AND DISCUSSION
Our initial study focused on the cyclization reaction of the model substrate 1-(2-
(phenylethynyl)phenyl)ethan-1-one (1a). In the presence of 6 mol% of both NaAuCl4·2H2O and
AgSbF6, reaction of 1a led to partial decomposition and no useful product was obtained (Table 1, entry
1). During the course of studying this reaction, we found significant additive effects in this cyclization.
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In the presence of 1 equiv of ammonium acetate (NH4OAc), indenone 2a was obtained in 48% yield
together with 10% of isoquinoline 3a after 4 hours in a 70% conversion (Table 1, entry 2). Longer
reaction time did not improve the chemical yields but caused partial decomposition of the products.
Further investigation showed that in the presence of 2 equiv of pyridine N-oxide the reaction was
completed in 2 hours and the chemical yields of indenone 2a and isoquinoline 3a were enhanced to 53%
and 15%, respectively (Table 1, entry 3). Other ammonium salts such as ammonium carbonate
((NH4)2CO3) and ammonium formate (HCO2NH4) were also tested (Table 1, entries 4 and 5); however,
both producing slightly inferior results to NH4OAc. When L-proline was employed in this reaction to
replace NH4OAc, indenone 2a was isolated as the sole product, although only in moderate yield (51%;
Table 1, entry 6). Further investigation of additives, including several pyridine N-oxide derivatives and
diphenyl sulfoxide (Table 1, entries 7-11), showed that the highest yields of the cyclization products
were produced in the presence of 4-methoxypyridine N-oxide (Table 1, entry 7). No enhancement of
chemical yields were observed, when the loading of NH4OAc was increased to 1.5 equiv (Table 1, entry
12). When the loading of 4-methoxypyridine N-oxide was reduced to 1.2 equiv, the chemical yields of
2a and 3a were further raised to 69% and 19% (Table 1, entry 13). When NaAuCl4·2H2O was used as
the sole catalyst, the yield of 2a decreased to 46% while 3a was obtained in the same yield (Table 1,
entry 14). On the other hand, 3a was obtained as the only product in 74% yield when AgSbF6 was used
as the sole catalyst (Table 1, entry 15). Considering the formation of 2a involving an unprecedented
cyclization-rearrangement cascade reaction of o-alkynylarylketones, the conditions listed in entry 13 in
Table 1 were chosen to be tested with other substrates.
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Table 1. Optimization of Reaction Conditions for the Cyclization of o-Alkynylarylketones.a
entry
catalyst (mol %)
additive (equiv)
yield (%)b
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2a, 3a
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1c
2d
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NaAuCl4·2H2O /AgSbF6 (6/6)
-
-, -
NaAuCl4·2H2O /AgSbF6 (6/6)
NaAuCl4·2H2O /AgSbF6 (6/6)
NH4OAc (1 equiv)
48, 10
53, 15
NH4OAc (1 equiv),
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Pyridine N-Oxide (2 equiv)
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NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
(NH4)2CO3 (1 equiv),
50, 14
43, 13
51, -
Pyridine N-Oxide (2 equiv)
HCO2NH4 (1 equiv),
Pyridine N-Oxide (2 equiv)
L-Proline (1 equiv),
Pyridine N-Oxide (2 equiv)
NH4OAc (1 equiv), 4-
Methoxypyridine N-Oxide
(2 equiv)
59, 18
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NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NH4OAc (1 equiv), 4-
Nitropyridine N-Oxide (2
equiv)
41, 12
37, 12
56, 15
47, 20
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NH4OAc (1 equiv), 2,6-
Dichloropyridine N-Oxide
(2 equiv)
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NH4OAc (1 equiv),
Quinoline N-Oxide (2
equiv)
NH4OAc (1 equiv),
Diphenylsulfoxide
(2
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equiv)
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NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O/AgSbF6 (6/6)
NaAuCl4·2H2O (12)
NH4OAc (1.5 equiv), 4-
55, 20
69, 19
46, 19
-, 74
Methoxypyridine N-Oxide
(2 equiv)
NH4OAc (1 equiv), 4-
Methoxypyridine N-Oxide
(1.2 equiv)
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NH4OAc (1 equiv), 4-
Methoxypyridine N-Oxide
(1.2 equiv)
AgSbF6 (12)
NH4OAc (1 equiv), 4-
Methoxypyridine N-Oxide
(1.2 equiv)
a General procedure: The catalyst, additives, substrate 1a (110.2 mg, 0.5 mmol), and CH3CN (4 mL)
were added to a 4-dram vial. The reaction mixture was purged with argon, sealed, and stirred at 85 °C
for 2 h. b Isolated yields after column chromatography. c Reaction was stopped after 8 h. d Reaction was
stopped after 4 h and 30% of 1a was recovered.
A variety of 2-alkynylarylketones, including those with aryl, alkenyl, and alkyl groups at the distal
position of the alkyne triple bond, were then subjected to the optimized reaction conditions (Table 2,
entries 1-10). Based on these results, electron-donating and electron-withdrawing groups are found to be
compatible on both the distal and proximal phenyl rings, relative to the alkyne triple bond (Table 2,
entries 2 to 6), although lower yields for indenones are obtained when an electron-withdrawing
substituent such as an ester group is present at the para-position of the distal phenyl ring (Table 2, entry
4) or when an electron-donating substituent such as a methoxy group is present at the para-position of
the proximal phenyl ring (Table 2, entry 5). Additionally, the introduction of a sterically hindered
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α-naphthyl group at the distal position of the triple bond leads to a lower chemical yield for indenone
(35%) but an increased yield of isoquinoline (42%; Table 2, entry 7). Alkenyl and alkyl moieties at the
distal position of the triple bond are also compatible, but likewise lower the yield of the indenone
products (Table 2, entries 8-10). When a sterically hindered tert-butyl group is present, a low conversion
of the starting material (40%) is observed during the cyclization, even after an elongated reaction time
(Table 2, entry 10).
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Aside from acetophenone substrates, several other species were also investigated to further elucidate
the regioselectivity of the cyclization process. As with acetophenone, benzophenone moieties lead to
both the indenone and isoquinoline products (Table 2, entries 11 and 12). However, the cyclization of
the benzaldehyde substrate occurs only via a 6-endo-dig route, leading regiospecifically to isoquinoline
(Table 2, entry 13). Likewise, the cyclization of 1-(3-(arylethynyl)thiophen-2-yl)ethan-1-ones, which
has the ketone and alkynyl moieties at the ortho-positions of the 5-membered heterocyclic ring-system,
proceeds exclusively via a 6-endo-dig cyclization, affording only thieno[2,3-c]pyridines (Table 2,
entries 14 and 15).
Table 2. Gold-Catalyzed Cyclization of o-Alkynylarylketones and -aldehydes.a
entry
1
substrate 1
product 2 & 3 / yieldb
2c
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Me
MeO
O
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OMe
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a
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See the Experimental Section for the general procedure.
Isolated yields after column
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chromatography. c When L-proline was employed to replace NH4OAc, indenone 2b was isolated as the
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d
sole product in 29% yield. When L-proline was employed to replace NH4OAc, indenone 2i was
isolated as the sole product in 30% yield. e Reaction was stopped after 8 h, and 60% of starting material
1j was recovered.
The reaction presumably begins with a gold-catalyzed intramolecular electrophilic cyclization,
proceeding via one of two possible reaction pathways—a 6-endo-dig or 5-exo-dig cyclization (Scheme
2). When a 6-endo-dig cyclization takes place, the isobenzopyrylium intermediate 4 forms. The
nucleophilic addition of ammonia to 4 leads to the isochromene intermediate 5. After protonation of the
oxygen atom of isochromene 5, the carbon-oxygen bond dissociates to form enol 6, which subsequently
tautomerizes to ketone 7. An intramolecular nucleophilic addition of the imino group to the ketone
carbonyl group forms cyclized intermediate 8. Following dehydration, the final isoquinoline product is
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produced, together with the regenerated catalyst. Alternatively, when a 5-exo-dig cyclization takes
place, the isobenzofuranium intermediate 9 forms. The nucleophilic addition of ammonia to 9 leads to
the isobenzofuran intermediate 10. After protonation of the oxygen atom of isobenzofuran 10, the
carbon-oxygen bond is cleaved to form enol 11, which subsequently cyclizes via an intramolecular
nucleophilic addition to the imino group to form indanone intermediate 12. After elimination of
ammonia, the indenone is produced together with the regenerated catalyst. In both cases the role of
ammonium acetate is to trap the oxonium intermediates (4 and 9) and drive the reaction in the forward
direction. Our results showed that both NaAuCl4 and AgSbF6 were effective catalysts for the cyclization
of 2-alkynylarylketones though they displayed different regioselectivity. AgSbF6 induces a regiospecific
6-endo-dig cyclization (Table 1, entry 15), while NaAuCl4 leads to the formation of a mixture of 6-
endo-dig and 5-exo-dig cyclization products (Table 1, entry 14). In the current reaction protocol,
AgSbF6 presumably activates the gold catalyst by abstracting the chloride ions,12 and the combination of
NaAuCl4 and AgSbF6 provides superior result to the sole NaAuCl4 catalyst (Table 1, entries 13 and 14).
While the specific role of 4-methoxypyridine N-oxide is unclear, it is hypothesized to function as an
accelerant that stabilizes the gold(III) catalyst, thus increasing the turnover number of both cyclization
processes.13 We also cannot rule out the possibility that 4-methoxypyridine N-oxide plays the role as a
buffer to maintain an optimal pKa value of the reaction medium for the cascade cyclization.14
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Scheme 2. Proposed Mechanism for Gold-Catalyzed Cyclization of o-Alkynylarylketones.
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CONCLUSION
An ammonium acetate-assisted gold-catalyzed cascade cyclization of 2-alkynylarylketones is
described. The cyclization process is initiated by one of two competing reactions—a 5-exo-dig or a 6-
endo-dig cyclization—of the carbonyl group with the alkyne triple bond, leading to isobenzofuranium or
isobenzopyrylium intermediates, respectively. The two intermediates tandemly undergo an ammonium
acetate-assisted rearrangement and a subsequent cyclization to generate two different species: indenone
and isoquinoline. The methodology reported herein is notable as it describes the first documented
example of an isobenzofuranium intermediate undergoing a novel cascade reaction. Further exploration
into the processes controlling the regioselectivity of this cascade and into the chemical reactivity of the
isobenzofuranium intermediates are currently underway in our laboratory and will be reported in due
course.
EXPERIMENTAL SECTION
General information. All reactions were carried out in sealed 4-/6-dram vials, unless otherwise
indicated. All commercially available chemicals were used as received without further purification,
unless otherwise noted. All 1H and 13C NMR spectra were recorded at 500 or 400 MHz and 125 or 100
MHz, respectively, using CDCl3 as the solvent. The chemical shifts of all 1H and 13C NMR spectra are
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referenced to the residual signal of CDCl3 (δ 7.26 ppm for the 1H NMR spectra and δ 77.23 ppm for the
13C NMR spectra). High resolution mass analysis was carried out on a high resolution mass
spectrometer using electrospray ionization (ESI) mode with a time-of-flight (TOF) mass analyzer.
Samples were dissolved in methylene chloride and methanol and analyzed via flow injection into the
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mass
spectrometer
at
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flow
rate
of
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200 µL/min. The mobile phase was 90:10 methanol: water, with 0.1% formic acid. The mass
spectrometer was operated in positive ion mode and the melting points are uncorrected.
The 2-alkynylarylketone/2-alkynylarylaldehyde materials (1) were prepared by Sonogashira
coupling15 of 2-bromoarylketone/2-bromoarylaldehyde with terminal alkynes, except compounds 1c,
1d,
1g
and
1q.
1-(2-Ethynylphenyl)ethanone
(1q)
was
prepared
from
1-(2-
((trimethylsilyl)ethynyl)phenyl)ethan-1-one (1p) via a cesium fluoride mediated desilylation reaction.
Compounds 1c, 1d and 1g were prepared by Sonogashira coupling of 1q with aryl iodides.
General procedure for the preparation of 2-alkynylarylketones and aldehydes (1).
A 6-dram vial was charged with 2-bromoarylketone (2.0 mmol), a terminal alkyne (2.2 mmol),
Pd(PPh3)2Cl2 (28.1 mg, 0.04 mmol), CuI (7.6 mg, 0.04 mmol), and Et3N (14 mL). The vial was then
purged with argon and sealed. The reaction mixture was stirred at 80 °C for 18 h, until the
disappearance of starting material was observed, as monitored by thin layer chromatography. The
reaction mixture was diluted with diethyl ether (40 mL) and washed with brine (40 mL), and the
aqueous phase was then extracted with diethyl ether (2 × 20 mL). The combined organic layers were
dried over anhydrous MgSO4 and concentrated using a rotary evaporator under reduced pressure (20
mmHg); the resulting residue was purified by flash column chromatography on silica gel (eluent:
hexane/ethyl acetate).
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1-(2-(Phenylethynyl)phenyl)ethanone (1a)
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This product was obtained as a light brown oil (286.4 mg, 65% yield); H NMR (500 MHz, CDCl3) δ
7.76 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.54–7.57 (m, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.36–7.41
(m, 4H), 2.80 (s, 3H). The 1H NMR spectral data are in good agreement with the literature data.16
1-(2-((4-Methoxyphenyl)ethynyl)phenyl)ethanone (1b)
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This product was obtained as a light brown oil (160.2 mg, 32% yield); H NMR (500 MHz, CDCl3) δ
7.75 (dd, J = 7.8, 1.0 Hz, 1H), 7.61 (dd, J = 7.7, 0.6 Hz, 1H), 7.45–7.51 (m, 3H), 7.38 (dt, J = 7.7, 1.0
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Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 2.80 (s, 3H). The H NMR spectral data are in good
agreement with the literature data.17
1-(5-Methoxy-2-((4-methoxyphenyl)ethynyl)phenyl)ethanone (1e)
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This product was obtained as a light brown oil (229.9 mg, 41% yield); H NMR (500 MHz, CDCl3) δ
7.52 (d, J = 8.6 Hz, 1H), 7.44–7.47 (m, 2H), 7.26 (d, J = 2.8 Hz, 1H), 7.01 (dd, J = 8.6, 2.7 Hz, 1H),
6.87–6.90 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 200.8, 160.0,
159.4, 142.1, 135.3, 133.0, 118.3, 115.4, 114.6, 114.3, 113.1, 94.1, 87.4, 55.7, 55.5, 30.5; IR (neat, cm-
1)  2922, 1715, 1697, 1595, 1509, 1490, 1455, 1379, 1208, 1083, 1025, 853, 829, 755, 712, 696;
HRMS (ESI) calcd for C18H17O3 (M + H)+ 281.1172, Found: 281.1175.
1-(4-Fluoro-2-(phenylethynyl)phenyl)ethanone (1f)
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This product was obtained as a light yellow oil (333.6 mg, 70% yield); H NMR (500 MHz, CDCl3) δ
7.82 (dd, J = 8.8, 5.9 Hz, 1H), 7.53–7.57 (m, 2H), 7.37–7.39 (m, 3H), 7.31 (dd, J = 9.1, 2.4 Hz, 1H),
7.07–7.11 (m, 1H), 2.78 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 198.7, 164.1 (d, JC-F = 250.9 Hz), 136.9
(d, JC-F = 3.0 Hz), 131.83, 131.75, 129.3, 128.7, 124.6 (d, JC-F = 10.4 Hz), 122.5, 120.6 (d, JC-F = 23.2
Hz), 115.9 (d, JC-F = 21.5 Hz), 96.4, 87.7 (d, JC-F = 2.6 Hz), 30.1; IR (neat, cm-1)  2970, 1735, 1683,
1595, 1558, 1490, 1447, 1418, 1364, 1266, 1228, 1216, 1098, 1066, 1024, 925, 877, 826, 756, 688;
HRMS (ESI) calcd for C16H12FO (M + H)+ 239.0867. Found: 239.0868.
1-(2-(Cyclohex-1-en-1-ylethynyl)phenyl)ethanone (1h)
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This product was obtained as a light brown oil (152.5 mg, 34% yield); H NMR (500 MHz, CDCl3) δ
7.70 (dd, J = 7.9, 1.1 Hz, 1H), 7.50 (d, J = 7.9, 1.2 Hz, 1H), 7.41 (dt, J = 7.3, 1.2 Hz, 1H), 7.33 (dt, J =
7.7, 1.3 Hz, 1H), 6.24–6.26 (m, 1H), 2.74 (s, 3H), 2.22–2.25 (m, 2H), 2.14–2.18 (m, 2H), 1.66–1.71 (m,
2H), 1.60–1.65 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 201.0, 140.8, 136.4, 133.9, 131.4, 128.8, 127.9,
122.5, 120.8, 97.4, 86.2, 30.3, 29.0, 26.0, 22.4, 21.6; IR (neat, cm-1)  2925, 1696, 1587, 1464, 1426,
1355, 1281, 1239, 1091, 1025, 958, 756; HRMS (ESI) calcd for C16H17O (M + H)+ 225.1274, Found:
225.1275.
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6-(2-Acetylphenyl)hex-5-ynenitrile (1i)
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This product was obtained as a yellow oil (169.0 mg, 40% yield); H NMR: (400 MHz, CDCl3) δ 7.66
(dd, J = 7.7, 1.0 Hz, 1H), 7.48 (dd, J = 7.6, 1.0 Hz, 1H), 7.40 (td, J = 7.6, 1.5 Hz, 1H), 7.34 (td, J = 7.6,
1.4 Hz, 1H), 2.60–2.65 (m, 5H), 2.41–2.50 (m, 2H), 1.93–1.99 (m, 2H). The 1H NMR spectral data are
in good agreement with the literature data.18
1-(2-(3,3-Dimethylbut-1-yn-1-yl)phenyl)ethan-1-one (1j)
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This product was obtained as yellow oil (280.4 mg, 70% yield); H NMR: (400 MHz, CDCl3) δ 7.64
(dd, J = 7.8, 1.0 Hz, 1H), 7.44 (dd, J = 7.7, 0.9 Hz, 1H), 7.35 (td, J = 7.6, 1.5 Hz, 1H), 7.28 (td, J = 7.6,
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1.4 Hz, 1H), 2.71 (s, 3H), 1.32 (s, 9H). The H NMR spectral data are in good agreement with the
literature data.19
Phenyl(2-(phenylethynyl)phenyl)methanone (1k)
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This product was obtained as a light yellow oil (254.1 mg, 45% yield); H NMR (500 MHz, CDCl3) δ
7.88–7.90 (m, 2H), 7.62 (dd, J = 7.3, 1.1 Hz, 1H), 7.57–7.60 (m, 1H), 7.51–7.55 (m, 2H), 7.44–7.50 (m,
3H), 7.18–7.25 (m, 3H), 7.03–7.05 (m, 2H). The 1H NMR spectral data are in good agreement with the
literature data.20
(2-((4-Methoxyphenyl)ethynyl)phenyl)(phenyl)methanone (1l)
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This product was obtained as a light brown oil (324.9 mg, 52% yield); H NMR (500 MHz, CDCl3) δ
7.89 (d, J = 7.3 Hz, 2H), 7.57–7.60 (m, 2H), 7.41–7.53 (m, 5H), 6.97 (d, J = 8.8 Hz, 2H), 6.73 (d, J =
13
8.7 Hz, 2H), 3.76 (s, 3H); C NMR (125 MHz, CDCl3) δ 197.4, 159.9, 141.4, 137.5, 133.3, 133.1,
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132.5, 130.5, 130.4, 128.9, 128.5, 128.0, 122.4, 114.8, 113.9, 95.5, 86.5, 55.4; IR (neat, cm-1)  2932,
2834, 2216, 1735, 1665, 1605, 1594, 1510, 1465, 1449, 1436, 1365, 1316, 1289, 1250, 1178, 1149,
1091, 1026, 960, 936, 880, 830, 805, 788, 770; HRMS (ESI) calcd for C22H17O2 (M + H)+ 313.1223,
Found: 313.1226.
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2-(Phenylethynyl)benzaldehyde (1m)
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This product was obtained as a light brown oil (325.9 mg, 79% yield); H NMR (500 MHz, CDCl3) δ
10.66 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.57–7.59 (m,
2H), 7.47 (t, J = 7.5 Hz, 1H), 7.39–7.41 (m, 3H). The 1H NMR spectral data are in good agreement with
the literature data.21
1-(3-(Phenylethynyl)thiophen-2-yl)ethanone (1n)
This product was obtained as a yellow solid (353.0 mg, 78% yield): mp = 45.5–46.8 °C; 1H NMR (500
MHz, CDCl3) δ 7.53–7.75 (m, 3H), 7.38–7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.83 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 191.3, 145.8, 133.0, 132.1, 131.6, 129.3, 128.8, 125.6, 122.5, 96.9, 84.8, 29.2; IR
(neat, cm-1)  3079, 2205, 1738, 1648, 1595, 1517, 1485, 1442, 1405, 1379, 1293, 1243, 1216, 1098,
1070, 1043, 1018, 992, 920, 846, 755; HRMS (ESI) calcd for C14H11OS (M + H)+ 227.0525, Found:
227.0529.
1-(3-((4-Methoxyphenyl)ethynyl)thiophen-2-yl)ethanone (1o)
This product was obtained as a light yellow solid (256.3 mg, 50% yield): mp = 97.2–98.8 °C; 1H NMR
(500 MHz, CDCl3) δ 7.54 (d, J = 4.9 Hz, 1H), 7.47–7.49 (m, 2H), 7.21 (d, J = 5.1 Hz, 1H), 6.90–6.92
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(m, 2H), 3.85 (s, 3H), 2.83 (s, 3H); C NMR (125 MHz, CDCl3) δ 191.4, 160.5, 145.2, 133.2, 132.9,
132.1, 126.1, 114.6, 114.4, 97.2, 83.8, 55.6, 29.2; IR (neat, cm-1)  2915, 2839, 2200, 1638, 1601, 1519,
1497, 1405, 1384, 1291, 1242, 1176, 1161, 1111, 1027, 991, 921, 850, 835, 811, 747; HRMS (ESI)
calcd for C15H13O2S (M + H)+ 257.0631, Found: 257.0633.
1-(2-((Trimethylsilyl)ethynyl)phenyl)ethan-1-one (1p)
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This product was obtained as a light yellow oil (341.8 mg, 79% yield); H NMR (500 MHz, CDCl3) δ
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7.6, 1.4 Hz, 1H), 2.74 (s, 3H), 0.26 (s, 9H). The H NMR spectral data are in good agreement with the
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literature data.22
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Procedure for the preparation of 1-(2-ethynylphenyl)ethanone (1q).
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A 6-dram vial was charged with 1-(2-((trimethylsilyl)ethynyl)phenyl)ethanone (1p, 432.8 mg, 2.0
mmol), CsF (455.7 mg, 3.0 mmol) and methanol (12 mL). The reaction mixture was stirred at 35 °C for
18 h, until the disappearance of the starting material as monitored by thin layer chromatography.
Methanol was removed using a rotary evaporator, under reduced pressure (20 mmHg). The residue was
dissolved in diethyl ether (30 mL) and washed with brine (30 mL). The aqueous phase was extracted
with diethyl ether (20 mL). The combined organic layers were dried over anhydrous MgSO4, and
concentrated using a rotary evaporator, under reduced pressure (20 mmHg). The residue was purified by
flash column chromatography on silica gel (eluent: hexanes/ethyl acetate), to afford a light yellow oil
(181.7 mg, 63% yield); 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H),
7.41–7.47 (m, 2H), 3.39 (s, 1H), 2.72 (s, 3H). The 1H NMR spectral data are in good agreement with the
literature data.22
General procedure for the preparation of 2-alkynylarylketones (1c, 1d, 1g).
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A 6-dram vial was charged with 1-(2-ethynylphenyl)ethanone (1q, 144.2 mg, 1.0 mmol), an aryl iodide
(1.1 mmol), Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol), CuI (3.8 mg, 0.02 mmol), and Et3N (7 mL). The vial
was then purged with argon and sealed. The reaction mixture was stirred at room temperature for 18 h,
until the disappearance of starting material was observed, as monitored by thin layer chromatography.
The reaction mixture was diluted with diethyl ether (40 mL) and washed with brine (40 mL), and the
aqueous phase was then extracted with diethyl ether (2 × 20 mL). The combined organic layers were
dried over anhydrous MgSO4, concentrated using a rotary evaporator, under reduced pressure (20
mmHg). The resulting residue was purified by flash column chromatography on silica gel (eluent:
hexanes/ethyl acetate).
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1-(2-(p-Tolylethynyl)phenyl)ethanone (1c)
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This product was obtained as a light brown oil (142.9 mg, 61% yield); H NMR (500 MHz, CDCl3) δ
7.75 (dd, J = 7.8, 1.3 Hz, 1H), 7.62 (dd, J = 7.7, 1.1 Hz, 1H), 7.44–7.49 (m, 3H), 7.39 (dt, J = 7.5, 1.2
1
Hz, 1H), 7.18 (d, J = 7.9 Hz, 2H), 2.80 (s, 3H), 2.38 (s, 3H). The H NMR spectral data are in good
agreement with the literature data.17
Methyl 4-((2-acetylphenyl)ethynyl)benzoate (1d)
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This product was obtained as a yellow solid (200.4 mg, 72% yield): mp = 118.3–119.1 °C; H NMR
(500 MHz, CDCl3) δ 8.03–8.05 (m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.62 (d, J =
8.0 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 3.94 (s, 3H), 2.78 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 200.2, 166.7, 140.9, 134.3, 131.69, 131.67, 130.1, 129.8, 129.1, 129.0, 127.8, 121.3,
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94.0, 91.5, 52.5, 30.0; IR (neat, cm-1)  2924, 1719, 1684, 1431, 1407, 1365, 1275, 1217, 1104, 1017,
931, 876, 823, 796, 762, 729, 697; HRMS (ESI) calcd for C18H15O3 (M + H)+ 279.1016, Found:
279.1019.
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1-(2-(Naphthalen-1-ylethynyl)phenyl)ethanone (1g)
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This product was obtained as a yellow solid (183.8 mg, 68% yield): mp = 92.1–93.2 °C; 1H NMR (500
MHz, CDCl3) δ 8.52 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.77–7.82 (m, 3H), 7.64 (dt, J = 8.2,
1.2 Hz, 1H), 7.52–7.57 (m, 2H), 7.43–7.50 (m, 2H), 2.83 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 200.4,
140.7, 134.4, 133.5, 133.4, 131.6, 130.9, 129.5, 129.1, 128.5, 127.3, 126.8, 126.4, 125.5, 122.1, 120.8,
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93.4, 30.1 (fewer C signals were observed due to signal overlapping); IR (neat, cm-1)  3056, 2201,
1734, 1682, 1589, 1540, 1506, 1478, 1436, 1354, 1290, 1268, 1243, 1162, 1014, 956, 879, 802, 768;
HRMS (ESI) calcd for C20H15O; (M + H)+ 271.1117, Found: 271.1120.
General procedure for the gold-catalyzed intramolecular cyclization of 2-alkynylarylketones and -
aldehydes.
A 4-dram vial was charged with NaAuCl4·2H2O (11.9 mg, 0.03 mmol), AgSbF6 (10.3 mg, 0.03 mmol),
NH4OAc (38.5 mg, 0.5 mmol), 4-methoxypyridine N-oxide (75.1 mg, 0.6 mmol), 2-alkynylarylketone
(1, 0.5 mmol) and acetonitrile (4 mL). The vial was purged with argon and sealed. The reaction mixture
was stirred at 85 °C for 2 h. After cooling to room temperature, the resulting mixture was diluted with
diethyl ether (15 mL) and washed with brine (15 mL). The aqueous phase was extracted with diethyl
ether (2 × 10 mL). The combined organic layers were dried over anhydrous MgSO4, and concentrated
using a rotary evaporator, under reduced pressure (20 mmHg). The residue was purified by flash column
chromatography on silica gel (eluent: hexanes/ethyl acetate).
3-Methyl-2-phenyl-1H-inden-1-one (2a)
This compound was obtained as a light brown oil (76.0 mg, 69% yield): 1H NMR (500 MHz, CDCl3) δ
7.49 (d, J = 6.9 Hz, 1H), 7.41–7.46 (m, 5H), 7.34–7.36 (m, 1H), 7.25–7.28 (m, 1H), 7.17 (d, J = 7.2 Hz,
1H), 2.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.7, 154.9, 146.1, 133.8, 133.6, 131.3, 130.6, 129.7,
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129.1, 128.5, 127.9, 122.3, 119.6, 12.8; HRMS (ESI) calcd for C16H13O (M + H)+ 221.0961, Found:
221.0961. The 1H and 13C NMR spectral data are in good agreement with the literature data.23
1-Methyl-3-phenylisoquinoline (3a)
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This compound was obtained as a light yellow oil (20.8 mg, 19% yield): 1H NMR (500 MHz, CDCl3) δ
8.14 (dd, J = 8.2, 1.3 Hz, 3H), 7.93 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.68 (dt, J = 6.8, 1.1 Hz, 1H),
7.56–7.59 (m, 1H), 7.49–7.52 (m, 2H), 7.40 (tt, J = 7.4, 1.8 Hz, 1H), 3.05 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 158.8, 150.2, 140.0, 136.9, 130.3, 128.9, 128.5, 127.8, 127.2, 127.0, 126.8, 125.9, 115.5, 22.9;
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HRMS (ESI) calcd for C16H14N (M + H)+ 220.1121, Found: 220.1119. The H and C NMR spectral
data are in good agreement with the literature data.24
2-(4-Methoxyphenyl)-3-methyl-1H-inden-1-one (2b)
This compound was obtained as an orange solid (87.6 mg, 70% yield): mp = 106.6–107.4 °C; 1H NMR
(500 MHz, CDCl3) δ 7.47 (d, J = 7.0 Hz, 1H), 7.41 (td, J = 7.7, 1.0 Hz, 1H), 7.37–7.39 (m, 2H), 7.25 (t,
J = 7.3 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.98 (dd, J = 6.9, 1.9 Hz, 2H), 3.85 (s, 3H), 2.31 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 197.1, 159.3, 153.6, 146.3, 133.8, 133.1, 131.0, 130.6, 128.8, 123.7, 122.2,
119.4, 114.0, 55.5, 12.8; IR (neat, cm-1)  2919, 2849, 1707, 1611, 1591, 1508, 1547, 1378, 1247, 1176,
1113, 1080, 1024, 1004, 861, 822, 795, 758; HRMS (ESI) calcd for C17H15O2 (M + H)+ 251.1067,
Found: 251.1068.
3-(4-Methoxyphenyl)-1-methylisoquinoline (3b)
This compound was obtained as a beige solid (17.5 mg, 14% yield): mp = 56.1–57.3 °C; 1H NMR (500
MHz, CDCl3) δ 8.08–8.11 (m, 3H), 7.84 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.63–7.66 (m, 1H), 7.52–7.55
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(m, 1H), 7.02–7.05 (m, 2H), 3.88 (s, 3H), 3.03 (s, 3H); C NMR (125 MHz, CDCl3) δ 160.1, 158.6,
149.9, 137.0, 132.7, 130.1, 128.4, 127.6, 126.6, 126.4, 125.8, 114.30, 114.28, 55.6, 22.9; HRMS (ESI)
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calcd for C17H16NO (M + H)+ 250.1226, Found: 250.1227. The H and C NMR spectral data are in
good agreement with the literature data.25
3-Methyl-2-(p-tolyl)-1H-inden-1-one (2c)
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The product was obtained as a beige solid (59.8 mg, 51% yield): mp = 80.3–82.3 °C; H NMR (500
MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz, 1H), 7.40 (dt, J = 7.6, 1.0 Hz, 1H), 7.31–7.33 (m, 2H), 7.23–7.26
(m, 3H), 7.14 (d, J = 7.2 Hz, 1H), 2.39 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.9,
154.3, 146.2, 137.8, 133.8, 133.6, 130.6, 129.6, 129.2, 129.0, 128.4, 122.3, 119.5, 21.6, 12.8; IR (neat,
cm-1)  2922, 2852, 1716, 1635, 1540, 1418, 1375, 1324, 1265, 1216, 1204, 1165, 1114, 1066, 1015,
926, 861, 806, 760; HRMS (ESI) calcd for C17H15O (M + H)+ 235.1117, Found: 235.1118.
1-Methyl-3-(p-tolyl)isoquinoline (3c)
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This compound was obtained as a yellow solid (36.2 mg, 31% yield): mp = 83.2–84.8 °C; 1H NMR (500
MHz, CDCl3) δ 8.12 (dd, J = 8.5, 0.8 Hz, 1H), 8.04 (dd, J = 6.5, 1.6 Hz, 2H), 7.89 (s, 1H), 7.84 (d, J =
8.2 Hz, 1H), 7.64–7.67 (m, 1H), 7.54–7.57 (m, 1H), 7.31 (d, J = 8.0 Hz, 2H), 3.04 (s, 3H), 2.42 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 158.7, 150.2, 138.4, 137.2, 137.0, 130.2, 129.7, 127.7, 127.0, 126.8,
126.6, 125.8, 114.9, 22.9, 21.5; HRMS (ESI) calcd for C17H16N (M + H)+ 234.1277, Found: 234.1276.
The 1H and 13C NMR spectral data are in good agreement with the literature data.26
Methyl 4-(3-methyl-1-oxo-1H-inden-2-yl)benzoate (2d)
1
This compound was obtained as a yellow solid (54.3 mg, 39% yield): mp = 158.9–159.5 °C; H NMR
(500 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H), 7.49–7.51 (m, 3H), 7.44 (dt, J = 7.6, 0.9 Hz, 1H), 7.29 (t,
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J = 7.4 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 3.93 (s, 3H), 2.35 (s, 3H); C NMR (125 MHz, CDCl3) δ
196.0, 167.1, 156.4, 145.7, 136.1, 134.0, 132.6, 130.5, 129.7, 129.5, 129.2, 122.5, 120.0, 52.4, 13.0
(fewer 13C signals were observed due to signal overlapping); IR (neat, cm-1)  2923, 2851, 1716, 1705,
1609, 1591, 1507, 1456, 1428, 1408, 1279, 1190, 1106, 1081, 1028, 1004, 969, 946, 884, 867, 847, 820,
761, 754; HRMS (ESI) calcd for C18H15O3 (M + H)+ 279.1016, Found: 279.1018.
Methyl 4-(1-methylisoquinolin-3-yl)benzoate (3d)
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This compound was obtained as a white solid (37.4 mg, 27% yield): mp = 125.1–126.9 °C; H NMR
(500 MHz, CDCl3) δ 8.23 (dt, J = 8.7, 1.9 Hz, 2H), 8.17 (t, J = 1.6 Hz, 1H), 8.14–8.16 (m, 2H), 8.01 (s,
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1H), 7.89 (d, J = 8.5 Hz, 1H), 7.69–7.72 (m, 1H), 7.60–7.63 (m, 1H), 3.96 (s, 3H), 3.05 (s, 3H); C
NMR (125 MHz, CDCl3) δ 167.3, 159.1, 148.8, 144.3, 136.7, 130.5, 130.3, 129.8, 128.0, 127.6, 127.1,
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127.0, 125.9, 116.4, 52.4, 22.9; IR (neat, cm-1)  2922, 2852, 1738, 1711, 1617, 1565, 1456, 1443,
1414, 1383, 1364, 1332, 1317, 1272, 1230, 1217, 1103, 1015, 960, 902, 889, 863, 852, 824, 785; HRMS
(ESI) calcd for C18H16NO2 (M + H)+ 278.1176, Found: 278.1178.
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5-Methoxy-2-(4-methoxyphenyl)-3-methyl-1H-inden-1-one (2e)
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This compound was obtained as a pink solid (25.2 mg, 18% yield): mp = 119.3–120.9 °C; H NMR
(500 MHz, CDCl3) δ 7.43 (d, J = 8.1 Hz, 1H), 7.37–7.39 (m, 2H), 6.97–6.98 (m, 2H), 6.70 (d, J = 2.2
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Hz, 1H), 6.62 (dd, J = 7.7, 2.2 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H); C NMR (125 MHz,
CDCl3) δ 195.9, 164.9, 159.3, 151.1, 149.1, 134.5, 131.0, 124.1, 123.9, 123.4, 114.0, 109.9, 108.6, 55.9,
55.5, 12.6; IR (neat, cm-1)  2915, 2848, 1700, 1662, 1653, 1594, 1576, 1507, 1473, 1457, 1437, 1306,
1289, 1251, 1180, 1115, 1070, 1023, 1001, 829, 799, 780; HRMS (ESI) calcd for C18H16NaO3 (M +
Na)+ 303.0992, Found: 303.0991.
7-Methoxy-3-(4-methoxyphenyl)-1-methylisoquinoline (3e)
This compound was obtained as an orange solid (41.9 mg, 30% yield): mp = 130.5–132.2 °C; 1H NMR
(500 MHz, CDCl3) δ 8.05–8.06 (m, 2H), 7.78 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.29–7.33 (m, 2H),
7.01–7.03 (m, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 2.98 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.9, 158.0,
156.9, 148.3, 132.9, 132.5, 129.2, 128.1, 127.3, 122.9, 114.3, 114.2, 103.7, 55.63, 55.55, 23.0; IR (neat,
cm-1)  2914, 2849, 1593, 1569, 1511, 1308, 1283, 1247, 1233, 1218, 1175, 1069, 1030, 876, 824, 817,
779, 752; HRMS (ESI) calcd for C18H18NO2 (M + H)+ 280.1332, Found: 280.1335.
6-Fluoro-3-methyl-2-phenyl-1H-inden-1-one (2f)
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This compound was obtained as a beige solid (47.7 mg, 40% yield): mp = 105.7–107.8 °C; H NMR
(500 MHz, CDCl3) δ 7.43–7.46 (m, 2H), 7.39–7.41 (m, 2H), 7.34–7.37 (m, 1H), 7.21 (dd, J = 7.1, 2.4
Hz, 1H), 7.10–7.13 (m, 1H), 7.07 (dt, J = 8.8, 2.4 Hz, 1H), 2.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
195.0, 163.9 (d, JC-F = 250.5 Hz), 155.1, 141.4 (d, JC-F = 3.6 Hz), 134.0 (d, JC-F = 4.6 Hz), 133.0 (d, JC-F
= 7.4 Hz), 131.1, 129.6, 128.6, 128.0, 120.7 (d, JC-F = 7.8 Hz), 119.0 (d, JC-F = 22.2 Hz), 111.1 (d, JC-F
=
24.7 Hz), 13.0; IR (neat, cm-1)  3061, 2927, 1703, 1618, 1604, 1473, 1428, 1373, 1355, 1330, 1309,
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1271, 1220, 1203, 1098, 1076, 1027, 1013, 887, 839, 813, 793, 769; HRMS (ESI) calcd for C16H12FO
(M + H)+ 239.0867, Found: 239.0871.
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6-Fluoro-1-methyl-3-phenylisoquinoline (3f)
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The product was obtained as a brown oil (46.3 mg, 39% yield): 1H NMR (500 MHz, CDCl3) δ 8.11-8.14
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(m, 3H), 7.85 (s, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.40–7.45 (m, 2H), 7.31 (dt, J = 8.8, 2.5 Hz, 1H), 3.02 (s,
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3H); C NMR (125 MHz, CDCl3) δ 163.3 (d, JC-F = 251.9 Hz), 158.7, 151.2, 139.6, 138.6 (d, JC-F
10.4 Hz), 129.0, 128.9 (d, JC-F = 10.6 Hz), 128.8, 127.2, 124.0, 117.1 (d, JC-F = 25.0 Hz), 115.0 (d, JC-F
=
=
5.0 Hz), 110.9 (d, JC-F = 20.4 Hz), 23.0; IR (neat, cm-1)  3062, 1716, 1625, 1601, 1570, 1443, 1362,
1268, 1225, 1215, 1135, 1027, 964, 882, 815, 775, 758; HRMS (ESI) calcd for C16H13FN (M + H)+
238.1027, Found: 238.1031.
3-Methyl-2-(naphthalen-1-yl)-1H-inden-1-one (2g)
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This product was obtained as a red solid (47.3 mg, 35% yield): mp = 100.4–102.2 °C; H NMR (500
MHz, CDCl3) δ 7.89 (t, J = 6.9 Hz, 2H), 7.70 (d, J = 8.2 Hz, 1H), 7.53–7.56 (m, 2H), 7.43–7.51 (m,
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3H), 7.31–7.35 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 2.11 (s, 3H); C NMR (125 MHz, CDCl3) δ 196.7,
157.6, 145.9, 134.2, 133.9, 133.8, 132.3, 130.9, 129.3, 129.2, 128.8, 128.7, 128.3, 126.2, 126.1, 125.5,
122.5, 119.7, 13.2 (fewer 13C signals were observed due to signal overlapping); IR (neat, cm-1)  3055,
2922, 285, 1701, 1596, 1459, 1378, 1314, 1171, 1085, 1026, 879, 807, 798; HRMS (ESI) calcd for
C20H15O (M + H)+ 271.1117, Found: 271.1114.
1-Methyl-3-(naphthalen-1-yl)isoquinoline (3g)
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This product was obtained as a beige solid (56.6 mg, 42% yield): mp = 86.5–88.0 °C; H NMR (500
MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.88 (d, J =
8.1 Hz, 1H), 7.79 (s, 1H), 7.69–7.75 (m, 2H), 7.64–7.67 (m, 1H), 7.57–7.60 (m, 1H), 7.51 (dt, J = 6.8,
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1.0 Hz, 1H), 7.45–7.48 (m, 1H), 3.09 (s, 3H); C NMR (125 MHz, CDCl3) δ 158.6, 151.8, 139.1,
136.6, 134.2, 131.8, 130.4, 128.7, 128.5, 127.9, 127.7, 127.3, 126.5, 126.4, 126.2, 126.0, 125.9, 125.6,
120.2, 22.8; IR (neat, cm-1)  3056, 2221, 1763, 1696, 1618, 1564, 1390, 1358, 1325, 1260, 1213, 1160,
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1147, 1018, 964, 903, 890, 873, 855, 804, 776; HRMS (ESI) calcd for C20H16N (M + H)+ 270.1277,
Found: 270.1278.
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2-(Cyclohex-1-en-1-yl)-3-methyl-1H-inden-1-one (2h)
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This product was obtained as a light brown oil (20.2 mg, 18% yield): H NMR (500 MHz, CDCl3) δ
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7.33–7.38 (m, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 6.7 Hz, 1H), 5.74–5.76 (m, 1H), 2.25–2.26 (m,
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2H), 2.18–2.20 (m, 2H), 2.18 (s, 3H), 1.70–1.73 (m, 2H), 1.65–1.68 (m, 2H); C NMR (125 MHz,
CDCl3) δ 197.6, 153.2, 146.4, 136.7, 133.5, 130.8, 130.0, 129.8, 128.5, 121.9, 119.2, 28.3, 25.7, 22.9,
22.2, 12.7; IR (neat, cm-1)  2930, 2855, 2430, 2360, 2017, 1704, 1612, 1590, 1170, 759; HRMS (ESI)
calcd for C16H17O (M + H)+ 225.1274, Found: 225.1275.
3-(Cyclohex-1-en-1-yl)-1-methylisoquinoline (3h)
This product was obtained as a brown oil (43.6 mg, 39% yield): 1H NMR (500 MHz, CDCl3) δ 8.06 (dd,
J = 8.2, 0.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.60–7.63 (m, 1H), 7.48–7.52 (m, 1H), 7.44 (s, 1H),
7.06–7.07 (m, 1H), 2.96 (s, 3H), 2.55–2.58 (m, 2H), 2.31–2.34 (m, 2H), 1.83–1.87 (m, 2H), 1.69–1.74
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(m, 2H); C NMR (125 MHz, CDCl3) δ 157.8, 151.2, 136.9, 135.8, 130.0, 128.3, 127.7, 126.6, 126.3,
125.8, 113.1, 26.23, 26.19, 23.2, 22.9, 22.5; HRMS (ESI) calcd for C16H18N (M + H)+ 224.1434, Found:
224.1430. The 1H and 13C NMR spectral data are in good agreement with the literature data.27
4-(3-Methyl-1-oxo-1H-inden-2-yl)butanenitrile (2i)
This product was obtained as an orange oil (37.0 mg, 35% yield); 1H NMR (400 MHz, CDCl3) δ 7.32–
7.35 (m, 2H), 7.17 (td, J = 7.1, 0.7 Hz, 1H), 7.04 (dd, J = 6.9, 1.0 Hz, 1H), 2.42 (t, J = 7.4 Hz, 2H), 2.33
(t, J = 7.1 Hz, 2H), 2.15 (s, 3H), 1.85 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 197.8, 155.8,
145.8, 133.6, 132.3, 130.6, 128.7, 121.8, 119.6, 119.2, 24.6, 21.8, 16.8, 11.7; IR (neat, cm-1)  2937,
2245, 1701, 1701, 1628, 1608, 1593, 1455, 1427, 1384, 1148, 1084, 987, 918, 755; HRMS (ESI) calcd
for C14H14NO (M + H)+ 212.1070, Found: 212.1074.
4-(1-Methylisoquinolin-3-yl)butanenitrile (3i)
This product was obtained as a brown oil (16.8 mg, 16% yield); 1H NMR (400 MHz, CDCl3) δ 8.08 (d,
J = 8.5 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.36 (s, 1H),
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3.02 (t, J = 7.2 Hz, 2H), 2.93 (s, 3H), 2.39 (t, J = 7.0 Hz, 2H), 2.14–2.22 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 158.9, 151.5, 136.6, 130.4, 127.0, 126.8, 126.3, 125.8, 119.9, 117.7, 36.5, 25.5, 22.5, 16.7; IR
(neat, cm-1)  2939, 2245, 1717, 1617, 1592, 1568, 1496, 1432, 1390, 1365, 1331, 1216, 1023, 954, 899,
828, 785; HRMS (ESI) calcd for C14H15N2 (M + H)+ 211.1230, Found: 211.1240.
2-(tert-Butyl)-3-methyl-1H-inden-1-one (2j)
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This product was obtained as a yellow solid (12.0 mg, 12% yield): mp = 57.0–58.0 °C; H NMR (500
MHz; CDCl3) δ 7.32–7.35 (m, 2H), 7.16 (td, J = 7.4, 0.6 Hz, 1H), 7.04–7.06 (m, 1H), 2.29 (s, 3H), 1.36
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(s, 9H); C NMR (125 MHz; CDCl3) δ 198.8, 151.2, 147.1, 140.3, 133.4, 130.7, 128.3, 121.4, 118.6,
34.1, 30.7, 13.4; HRMS (ESI) calcd for C14H17O (M + H)+ 201.1274, Found: 201.1276. The 1H and 13C
NMR spectral data are in good agreement with the literature data.28
3-(tert-Butyl)-1-methylisoquinoline (3j)
This product was obtained as a yellow oil (20.0 mg, 20% yield); 1H NMR (400 MHz, CDCl3) δ 8.06 (d,
J = 8.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.60 (td, J = 7.6, 0.8 Hz, 1H), 7.50 (td, J = 7.6, 1.2 Hz, 1H),
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7.44 (s, 1H), 2.95 (s, 3H), 1.44 (s, 9H); C NMR (100 MHz, CDCl3) δ 162.0, 157.4, 136.7, 129.6,
127.4, 126.1, 125.8, 125.6, 112.8, 37.1, 30.4, 22.8; IR (neat, cm-1)  2953, 2863, 1738, 1624, 1571,
1480, 1442, 1388, 1355, 1329, 1216, 1203, 1155, 928, 877, 847, 785; HRMS (ESI) calcd for C14H18N
(M + H)+ 200.1434, Found: 200.1434.
2,3-Diphenyl-1H-inden-1-one (2k)
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This product was obtained as a red solid (55.1 mg, 39% yield): mp = 150.0–152.0 °C; H NMR (500
MHz, CDCl3) δ 7.59 (d, J = 6.7 Hz, 1H), 7.36–7.42 (m, 6H), 7.25–7.30 (m, 6H), 7.15 (d, J = 7.4 Hz,
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1H); C NMR (125 MHz, CDCl3) δ 196.8, 155.5, 145.4, 133.7, 132.9, 132.6, 130.93, 130.91, 130.2,
129.5, 129.2, 129.0, 128.7, 128.3, 127.9, 123.2, 121.5; HRMS (ESI) calcd for C21H15O (M + H)+
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283.1117, Found: 283.1120. The H and 13C NMR spectral data are in good agreement with the
literature data.29
1,3-Diphenylisoquinoline (3k)
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This product was obtained as an orange solid (35.2 mg, 25% yield): mp = 76.0–77.0 °C; 1H NMR (400
MHz, CDCl3) δ 8.21–8.23 (m, 2H), 8.13 (dd, J = 8.5, 0.7 Hz, 1H), 8.08 (s, 1H), 7.941 (d, J = 8.2 Hz,
1H), 7.81–7.83 (m, 2H), 7.69 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.48–7.59 (m, 6H), 7.42 (dm, J = 7.3 Hz,
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1H); C NMR (100 MHz, CDCl3) δ 160.6, 150.4, 140.1, 139.8, 138.0, 130.4, 130.3, 128.9, 128.8,
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128.7, 128.5, 127.8, 127.7, 127.3, 127.1, 126.0, 115.9; HRMS (ESI) calcd for C21H16N (M + H)+
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282.1277, Found: 282.1274. The H and 13C NMR spectral data are in good agreement with the
literature data.30
2-(4-Methoxyphenyl)-3-phenyl-1H-inden-1-one (2l)
This compound was obtained as a red solid (56.2 mg, 36% yield): mp = 117.0–117.5 °C; 1H NMR (500
MHz, CDCl3) δ 7.55 (d, J = 7.0 Hz, 1H), 7.37–7.42 (m, 5H), 7.34 (dt, J = 7.4, 1.0 Hz, 1H), 7.21–7.24
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(m, 3H), 7.10 (d, J = 7.1 Hz, 1H), 6.78–6.80 (m, 2H), 3.77 (s, 3H); C NMR (125 MHz, CDCl3) δ
197.2, 159.4, 154.0, 145.7, 133.6, 133.2, 132.0, 131.5, 130.9, 129.3, 129.0, 128.9, 128.7, 123.2, 123.1,
121.2, 113.8, 55.4; HRMS (ESI) calcd for C22H17O2 (M + H)+ 313.1223, Found: 313.1228. The 1H and
13C NMR spectral data are in good agreement with the literature data.31
3-(4-Methoxyphenyl)-1-phenylisoquinoline (3l)
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This compound was obtained as a yellow solid (42.0 mg, 27% yield): mp = 113.0–115.0 °C; H NMR
(500 MHz, CDCl3) δ 8.17–8.19 (m, 2H), 8.11 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H),
7.81–7.83 (m, 2H), 7.65–7.68 (m, 1H), 7.55–7.58 (m, 2H), 7.46–7.53 (m, 2H), 7.02–7.04 (m, 2H), 3.88
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(s, 3H); C NMR (125 MHz, CDCl3) δ 160.4, 160.3, 150.1, 140.1, 138.1, 132.4, 130.4, 130.2, 128.7,
128.48, 128.46, 127.7, 127.5, 126.7, 125.6, 114.8, 114.3, 55.6; IR (neat, cm-1)  3057, 2921, 2221,
1763, 1712, 1604, 1561, 1512, 1437, 1387, 1336, 1285, 1247, 1170, 1159, 1142, 1023, 976, 828, 806,
769; HRMS (ESI) calcd for C22H18NO (M + H)+ 312.1383, Found: 312.1384.
3-Phenylisoquinoline (3m)
This product was obtained as a light red solid (100.6 mg, 98% yield): mp = 103.1–104.2 °C; 1H NMR
(500 MHz, CDCl3) δ 9.35 (s, 1H), 8.13–8.15 (m, 2H), 8.07 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.86 (d, J =
8.1 Hz, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.51–7.54 (m, 2H), 7.41–7.45 (m, 1H);
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13C NMR (125 MHz, CDCl3) δ 152.6, 151.4, 139.8, 136.8, 130.7, 129.0, 128.7, 127.9, 127.7, 127.23,
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127.17, 127.07, 116.7; HRMS (ESI) calcd for C15H12N (M + H)+ 206.0964, Found: 206.0964. The H
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and 13C NMR spectral data are in good agreement with the literature data.30
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7-Methyl-5-phenylthieno[2,3-c]pyridine (3n)
9
This product was obtained as a yellow oil (72.1 mg, 64% yield): 1H NMR (500 MHz, CDCl3) δ 8.06 (d,
J = 7.4 Hz, 2H), 7.95 (s, 1H), 7.65 (d, J = 5.4 Hz, 1H), 7.49 (t, J = 7.3 Hz, 2H), 7.39–7.42 (m, 2H), 2.89
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13
(s, 3H); C NMR (125 MHz, CDCl3) δ 152.7, 152.0, 146.1, 140.2, 134.4, 131.4, 128.9, 128.4, 127.3,
124.2, 112.7, 23.9; IR (neat, cm-1)  3058, 1575, 1545, 1480, 1439, 1392, 1377, 1348, 1117, 1086,
1065, 1032, 862, 820, 772; HRMS (ESI) calcd for C14H12NS (M + H)+ 226.0685, Found: 226.0687.
5-(4-Methoxyphenyl)-7-methylthieno[2,3-c]pyridine (3o)
1
This product was obtained as a yellow solid (108.5 mg, 85% yield): mp = 82.1–83.3 °C; H NMR (500
MHz, CDCl3) δ 8.00 (d, J = 9.0 Hz, 2H), 7.89 (s, 1H), 7.65 (d, J = 5.5 Hz, 1H), 7.39 (d, J = 5.1 Hz, 1H),
7.01 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 2.86 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.1, 152.6, 151.8,
146.2, 133.8, 132.9, 131.4, 128.5, 124.2, 114.3, 111.9, 55.6, 24.0; IR (neat, cm-1)  1650, 1605, 1575,
1545, 1515, 1387, 1300, 1280, 1250, 1180, 1035, 830; HRMS (ESI) calcd for C15H14NOS (M + H)+
256.0791, Found: 256.0795.
Acknowledgments This paper is dedicated to the memory of Dr. Cliff Soll at Hunter College. We
thank Queens College and the City University of New York for financial support. YL thanks South
China Normal University for partial financial support.
Supporting Information Available Copies of 1H and 13C NMR spectra for the new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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