Gold-Catalyzed Hydroarylation of N-Aryl Alkynamides for the Synthesis of 2-Quinolinones

Article abstract of DOI:10.1021/acs.joc.6b02984

A mild method for the synthesis of 2-quinolinones via hydroarylation of N-aryl alkynamides is reported. While traditional methods have relied on the use of strong Br?nsted or Lewis acids, this report describes the development of mild reaction conditions that yield 2-quinolinones in good to excellent yield using a commercially available gold catalyst. Substrates bearing a variety of functional groups are presented, with N-substitution proving to be key to the reactivity of several substrates.

Full text of DOI:10.1021/acs.joc.6b02984

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Article
Gold-Catalyzed Hydroarylation of N-Aryl
Alkynamides for the Synthesis of 2-Quinolinones
Taylor Vacala, Lauren P. Bejcek, Chloe G. Williams, Alexandra C. Williamson, and Paul A. Vadola
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02984 • Publication Date (Web): 07 Feb 2017
Downloaded from http://pubs.acs.org on February 8, 2017
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The Journal of Organic Chemistry
Gold-Catalyzed Hydroarylation of N-Aryl Alkynamides for the Synthesis of 2-Quinolinones
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Taylor Vacala, Lauren P. Bejcek, Chloé G. Williams, Alexandra C. Williamson, and Paul A. Vadola*
Department of Chemistry, DePaul University, 1110 West Belden Avenue, Chicago, Illinois, 60614
Corresponding Author
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* pvadola@depaul.edu
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R'
R'
• 2-Quinolinone → Bioactive Motif
• Diverse substitution patterns
[Au] 5 mol %
• Simple substrate preparation
• Commercially available catalyst:
Au(XPhos)(SbF6)•MeCN
DCE, 50 ºC
25 examples
N
O
N
O
R
R
Me
Me
MeO
Br
MeO
Me
Br
N
O
MeO
N
O
N
H
99%
O
MeO
N
H
O
HN
Bn
75%
70%
98%
Abstract: A mild method for the synthesis of 2ꢀquinolinones via hydroarylation of Nꢀaryl alkynamides
is reported. While traditional methods have relied on the use of strong Brønsted or Lewis acids, this reꢀ
port describes the development of mild reaction conditions that yield 2ꢀquinolinones in good to excelꢀ
lent yield using a commercially available gold catalyst. Substrates bearing a variety of functional groups
are presented, with Nꢀsubstitution proving to be key to the reactivity of several substrates.
Introduction:
The intramolecular coupling of arenes with C–C πꢀbonds is a versatile approach to the synthesis of a wide arꢀ
ray of heterocyclic compounds. Depending on the nature of the cyclization substrate, various mechanisms can
be engaged leading to significant structural variation from comparatively similar compounds. For example, orꢀ
thoꢀhalogenated arenes (1, Figure 1) have been reported to yield 5ꢀexoꢀcyclization products (2) under palladium
catalysis via carbopalladation of the alkyne πꢀbond followed by reaction with a coupling partner.1,2 Several reꢀ
ports have also been published that describe palladiumꢀcatalyzed 5ꢀexoꢀcyclization processes where the ortho
position is a hydrogen.3 Alternatively, under Lewis acidic conditions, the nonꢀhalogenated compounds favor 6ꢀ
endoꢀcyclization, particularly when electronically biased alkyne coupling partners are employed (i.e., α,βꢀ
unsaturated carbonyl compounds) (1 → 3).4
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Figure 1. Divergent cyclizations of Nꢀaryl alkynamides
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Aryl alkynoate esters have been widely studied in the latter context and have been shown to afford coumarins
under a number of Lewis acidic reaction conditions.5 Surprisingly, far fewer investigations of Nꢀaryl alkynaꢀ
mide hydroarylation (1 → 3) have been reported, despite the value of the resulting 2ꢀquinolinone products in
medicinal chemistry (Figure 2).6,7 The majority of methods disclosed rely on stoichiometric or superꢀ
stoichiometric amounts of highly Brønsted or Lewis acidic promoters.4
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In regards to the use of mild Lewis acids for the hydroarylation Nꢀaryl alkynamides, Tanaka and coworkers
have published two catalytic systems employing palladium7a and gold7b preꢀcatalysts in conjunction with chiral
ligands. However, these report focused solely on the enantioselective synthesis of axially chiral 4ꢀnaphthylꢀ2ꢀ
quinolinones products. Here we report the development of a general and catalytic method for the hydroarylation
of Nꢀaryl alkynamides, with good functional group tolerance. This approach grants access to an array of 2ꢀ
quinolinones under mild reactions conditions, with substitution on the amide nitrogen playing a key role in
modulating substrate reactivity.
Figure 2. Representative bioactive 2ꢀquinolinones
Results and Discussion:
We began our investigation into potential catalysts by screening an array of gold complexes along with silver
salt activators that have been demonstrated to catalyze the activation of alkynes towards nucleophiles.8 The use
of 5 mol % of Au(PPh3)Cl as a preꢀcatalyst in 1,2ꢀdichloroethane (DCE, 0.1 M) at 50 °C activated by 5 mol %
AgOTf led to a modest 59% yield of the 2ꢀquinoline product 8a (entry 1, Table 1). Evaluation of alternative silꢀ
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ver salt activators revealed a significant counterꢀion effect, with AgN(Tf)2 delivering an 80% yield of 8a (entry
4). We next examined alternative gold(I) complexes with AgN(Tf)2 as the optimized activator (entries 5ꢀ9) and
found Au(XPhos)Cl to be a far superior preꢀcatalyst providing a 96% yield of the 8a after 1 hour at 50 °C.
Moreover, the commercially available preꢀactivated airꢀstable complex Au(XPhos)(SbF6)•MeCN was even
more effective, affording 8a in a quantitative yield in 4 hours at room temperature with catalyst loadings as low
as 2.5 mol % (entries 10ꢀ12).
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Table 1. Optimization of N-Aryl Alkynamides Hydroarylation Conditions
a. All reactions were stirred at 50 °C and analyzed after 20 hours unless otherwise noted; b. Isolated yields; c.
monitored by TLC to determine actual reaction endpoint.
Our initial probe of substrate scope began by subjecting Nꢀaryl alkynamide 9a to our optimized reaction conꢀ
ditions: 2.5 mol % of Au(XPhos)(SbF6)•MeCN in DCE (0.1 M) at room temperature. While we suspected the
absence of a second activating group on the arene might decrease the reactivity of this substrate in comparison
to 8a we were surprised by the magnitude of the decrease with the regioisomeric products 10a and 11a being
formed in a combined 13% yield and 73% of the starting amide being recovered (Table 2, entry 1). Increases in
reaction temperature to 50 °C and 80 °C, along with increased catalyst loadings of 5% and 10% failed to deliver
the products in greater than 47% combined yield (entry 8; 10 mol % at 80 °C).
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The poor mass recovery of many of these reactions, particularly entries 3ꢀ8, prompted a closer examination of
the crude reaction mixtures by GCꢀMS and 1H NMR, which revealed significant amide hydrolysis, especially in
the reactions conducted above room temperature. In order to combat hydrolysis, several reactions were conꢀ
ducted employing 10 mol % catalyst at 80 °C in the presence of drying agents: 4 Å molecular sieves, MgSO4,
and Na2SO4 (Table 2, entries 9ꢀ11). While all of these reactions led to higher yields of the product mixture, the
use of 4 Å molecular sieves was most promising, affording not only the highest yield (64%) for the reaction of
9a, but also excellent mass recovery of 97%. Thus, it would appear that for substrates with minimally activated
arenes the rate of cyclization decreases allowing the rate of hydrolysis to become competitive, which leads to
significant cleavage of the amide bond of the substrate.
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Table 2. Effect of N-Substitution on Reactivity
a. All reactions were run with Au(XPhos)SbF6•MeCN and analyzed after 20 hours; b. 1H NMR yields deterꢀ
mined using dibenzyl ether as an external standard; c. reaction run for 40 hours.
With the issue of substrate decomposition in mind, we sought to slow the rate of hydrolysis by adding a seꢀ
cond substituent to the amide nitrogen. We expected that conversion to the tertiary amide would both increase
the steric environment around the amide carbonyl, thereby impeding nucleophilic addition to the carbonyl,
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while also decreasing the electrophilicity of the carbonyl carbon due to the increased electron donating ability of
the disubstituted nitrogen.
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The Nꢀbenzyl derivative 9b was prepared and subjected to 5 mol % of catalyst at 80 °C. The impact of Nꢀ
substitution was dramatic. The Nꢀsubstituted 2ꢀquinolinone products 10b and 11b were isolated in a combined
92% yield (Table 2, entry 12). Further analysis of the reaction parameters revealed a return to the original optiꢀ
mized conditions of 5 mol % Au(XPhos)(SbF6)•MeCN in DCE at room temperature, which afforded 10b and
11b in 87% (entry 14). In an attempt to improve the regioselectivity of the transformation we ran the reaction of
9b at ꢀ12 °C. After 36 hours the progress of the reaction stalled at 48% conversion, with only a minor improveꢀ
ment in selectivity from 1.7:1.0 (10b:11b) at room temperature to 1.9:1.0 at ꢀ12 °C (entry 15). From these colꢀ
lective investigations of reaction conditions we concluded that secondary amide substrates require a highly acꢀ
tivated arene for the rate of hydroarylation to exceed that of hydrolysis, while tertiary amides provide a higher
barrier to hydrolysis thus favoring the desired cyclization pathway.
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In addition to the impact on substrate reactivity, substitution on the amide nitrogen provides an additional
point of functionalization allowing for greater variation in the target 2ꢀquinolinone products. To further investiꢀ
gate the tolerance for Nꢀsubstitution, we prepared a series of substrates represented by the general structure 9
(Figure 3) bearing a selection of Nꢀsubstituents. The reaction of the Nꢀcinnamyl substrate 9d was particularly
interesting given the absolute selectivity exhibited for alkyne activation over the alkene. Moreover, the allyl
group present in products 10d and 11d provides a handle from which an array of potential derivatives could be
prepared.
The rate enhancement and increase in yield observed for the reaction of benzylated substrate 9b proved to be
a general pattern for all Nꢀsubstituted amides. While the regioselectivities for these substrates were minimal, in
all cases the regioisomers were easily separable by column chromatography.
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Figure 3. Investigation of Nꢀsubstituted substrates
We next investigated the effect of substitution at the alkynyl position of the amide substrates (Figure 4). Given
the preparation of our substrates from alkynoic acids, alternate substituents can be introduced at the 4ꢀposition
of the product simply by varying the alkynoic acid coupling partner or by functionalization of the terminal alꢀ
kynyl amide substrate 7b (R = H). For example 7c (R = Ph) was prepared by acylation with phenylpropiolic acꢀ
id, while selective βꢀbromination of 7b with NBS and AgNO3 afforded 7d (R = Br). All of the substrates in the
series performed well, giving modest yields of the 2ꢀquinolinones. The cyclization of the βꢀphenyl substrate 7c
is particularly interesting given the significant steric crowding between the phenyl ring and 5ꢀmethoxy group in
the product 8c.
Figure 4. Investigation of alkynyl substitution
Our final investigation of substrate scope explored variations around the aromatic ring of the substrate, with
probes into the steric and electronic allowances of the transformation (Table 3). The orthoꢀmethylated substrates
12aꢀc furnished the corresponding 2ꢀquinolinones in good yields, with significant variability depending on the
nature of the Nꢀsubstituent. The presence of the orthoꢀmethyl group was not entirely benign as substrate 12c (R
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= Bn) furnished a 75% yield of the product, while the nonꢀorthoꢀmethylated analog 9a gave an 87% yield under
identical reaction conditions.
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Table 3. Substitution on the Aromatic Ring
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a. All reactions conducted at 50 °C in DCE (0.1 M) with 5 mol % Au(XPhos)SbF6•MeCN unless otherwise
noted. b. Reaction conducted at 80 °C with 4 Å molecular sieves.
Substrates 14a, 14b, and 16 probed the electronics of the substrates by introducing deactivating groups, broꢀ
mine and methyl ester, para to the amide nitrogen. The reactions of substrates 14a and 14b were particularly
interesting in that the effect of Nꢀsubstitution on the product yields was highly significant. After 24 hours at 80
°C the nonꢀsubstituted substrate 14a failed to go to completion, delivering the product 15a in 19% yield, with
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significant hydrolysis of the starting amide also being observed. The Nꢀbenzyl analog 14b, however, afforded
15b in 75% yield after only 8 hours at 50 °C.
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Substrate 18 replaced the strong donating methoxy groups for significantly weaker methyl groups, while 20
removed all substituents. To our surprise both substrates afforded the target products. While the yield of 21 was
low, 38%, the fact that the substrate reacted to such a significant degree is a reflection of the high reactivity of
the catalyst. The electronꢀrich substrates 22 and 24 both proved highly regioselective, with 22 curiously affordꢀ
ing only a single regioisomer. It should also be noted that the successful cyclization of 24 was not obvious from
the outset as the primary amino group could serve as a competing ligand for the gold center, which could in turn
deactivate the catalyst.
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The cyclization of a selection of nonꢀaniline derived substrates provided an expansion of the utility of the
transformation (Table 4). Many of these compounds exhibited greater fluorescence than the products discussed
in Table 3. In fact, the nonꢀNꢀbenzyl analogs of compounds 30 and 32 have been previously studied for their
photophysical properties,9 along with the 7ꢀaminoꢀ2ꢀquinolinone 25, which is marketed as the fluorescent laser
dye carbostyril 124.
Table 4. Non-aniline Derived Substrates
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a. All reactions conducted in DCE (0.1 M) with 5 mol % Au(XPhos)SbF6•MeCN.
While the introduction of the benzyl group onto the nitrogen of the substrates had a significant effect on both
the yield and rate of several reactions above, the requirement for such a group limited the pool of accessible 2ꢀ
quinilinones. To resolve this issue we sought to develop conditions to debenzylate the amide nitrogen and reveal
the secondary amide products. Under 1 atm of hydrogen gas in neat acetic acid we found we could debenzylated
2ꢀquinolinone 19 with Pd/C after 5 hours at 70 °C (Scheme 1). Following filtration through Celite and neutraliꢀ
zation of the solution pure product 39 was isolated in 96% yield.
Scheme 1. Debenzylation of N-Benzyl-2-Quinolinones
Conclusion:
In summary, we have identified the commercially available complex Au(XPhos)SbF6•MeCN as a highly effiꢀ
cient catalyst for the hydroarylation of Nꢀaryl alkynamides to yield 2ꢀquinolinones. Employing catalyst loadings
as low as 2.5 mol % at 50 °C, or room temperature in some cases, an array of substrates were cyclized exhibitꢀ
ing both electronꢀdonating and electronꢀwithdrawing groups, as well as orthoꢀsubstituents. For secondary amide
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substrates, with an arene of low to moderate nucleophilicity, hydrolysis of the amide bond provided to be a
competing process. Tertiary amides, however, exhibited excellent reactivity and provided significantly higher
yields of the tertiary amide analogs. Moreover, the nature of the additional Nꢀsubstituent appeared to have little
impact on the success of the reaction, with a range of groups being tolerated.
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Experimental Section:
General Comments
All manipulations of air and/or water sensitive compounds were performed using standard Schlenk techniques.
Nitrogen was purified by passage through Drierite. Nuclear Magnetic Resonance spectra were recorded at 300
1
K on a 300 MHz Fourier transform spectrometer. H NMR spectra recorded in CDCl3 were referenced to TMS
(0.00 ppm). Spectra in DMSOꢀd6 were referenced to the solvent residual peak (2.50 ppm). 13C NMR recorded in
CDCl3 or DMSOꢀd6 were referenced to the residual solvent peak (77.16 ppm and 39.52 ppm respectively).
Manual flash column chromatography was conducted on SILICYCLE silica gel (230ꢀ400 mesh). Automated
flash column chromatography was conducted using RediSep Rf normalꢀphase silica flash columns. Mass specꢀ
tra were recorded on a QꢀTOF ESI spectrometer. Reactions were monitored by TLC analysis using
EtOAc/hexanes and/or Et2O/hexanes mixtures as the eluent and visualized using UV light followed by potassiꢀ
um permanganate stain and/or ceric ammonium molybdate stain.
Part 1. General Procedures for N-Aryl Alkynamide Substrate Synthesis:
General Procedures for the Reductive Amination of Aniline Derivatives.
Following a literature procedure,10 to a solution of amine (1 equiv) in DCM (0.5 M) was added AcOH (1.1
equiv), followed by benzaldehyde (1.1 equiv). The mixture was cooled to 0 ºC and NaBH(OAc)3 (1.5 equiv)
was added portionwise. The resulting solution was stirred at room temperature and monitored by TLC. Upon
complete consumption of the aniline the mixture was diluted with one volume of DCM and washed with NaOH
aq. (1 M). The organic layer was dried over MgSO4 and concentrated to afford the benzyl amine derivative.
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Yields were typically near quantitative and the product thus isolated was pure enough for use in the subsequent
acylation reaction without further purification.
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General Procedures for the Acylation of Aniline Derivatives with Alkynoic Acids.
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Acylation Method A: To a solution of alkynoic acid (1.5 equiv) in THF (0.2 M) was added SOCl2 (1.5 equiv)
in one portion, followed by five drops of DMF. The resulting solution was stirred at room temperature for 40
minutes. The mixture was then cooled to 0 ºC in an iceꢀwater bath and N,Nꢀdiisopropylethylamine (3 equiv)
was added, followed by the requisite aniline derivative (1 equiv). The reaction mixture was allowed to slowly
warm to room temperature. Upon consumption of the starting material as determined by TLC the reaction mixꢀ
ture was poured into a separatory funnel and diluted with 4 volumes of water. The solution was extracted three
times with EtOAc. The combined extracts were then washed with 10% HCl (aq.), saturated NaHCO3 (aq.), and
brine. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated by rotary
evaporation to yield the amide. In several instances 1H NMR revealed the product to be pure. Otherwise the imꢀ
pure amide was purified via column chromatography on silica gel eluting with ethyl acetate and hexanes.
Acylation Method B: To a solution of alkynoic acid (1.5 equiv) in ethyl acetate (0.8 M) was added Nꢀmethyl
morpholine (1.5 equiv), followed by slow addition of isopropyl chloroformate (1.0 M solution in toluene, 1.5
equiv). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then filtered to
remove the precipitated ammonium salt and the filtrate was concentrated to yield the mixed carbonic acid anhyꢀ
dride as a golden oil. The oil was dissolved in DMF (2.0 M) and added slowly to a solution of the appropriate
amine (1.0 equiv) in DMF (0.5 M) at room temperature. The reaction is monitored by GCꢀMS. After complete
consumption of the aniline was observed the mixture was poured into 5 volumes of water and extracted three
times with ethyl acetate. The combined organic layers were then washed with 10% HCl (aq), followed by satuꢀ
rated NaHCO3 (aq), and lastly dried over MgSO4. The mixture was filtered and the filtrate was concentrated to
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yield the crude amide. In many instances 1H NMR revealed the product to be pure. Otherwise the impure amide
was purified via column chromatography on silica gel eluting with ethyl acetate and hexanes.
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Part 2. Synthesis and Characterization of N-Aryl Alkynamide Substrates:
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N-(3,5-dimethoxyphenyl)but-2-ynamide (7a). Acylation method A was followed using 2ꢀbutynoic acid and
3,5ꢀdimethoxyaniline (5 mmol). Extractive workꢀup afforded pure amide 7a (832 mg, 76%) as an amorphous
beige solid. 1H NMR (CDCl3, 300 MHz) δ 7.33 (bs, 1H), 6.73 (d, J = 2.1 Hz, 2H), 6.25 (t, J = 2.1 Hz, 1H), 3.78
(s, 6H), 2.00 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 161.1, 151.2, 139.3, 98.3, 97.2, 84.6, 75.5, 55.5, 3.9; FTꢀIR
(cmꢀ1) 3285, 3163, 3146, 3003, 2962, 2918, 2847, 2233, 1651, 1614, 1553, 1456, 1421, 1283, 1265, 1205, 1153,
1065, 843; HRMS (ES+) m/z calcd. for C12H14NO3 [M+H]+ 220.0974, found 220.0978.
N-(3,5-dimethoxyphenyl)prop-2-ynamide (7b). A previously reported procedure was followed.11 To a soluꢀ
tion of propiolic acid (1.2 equiv) in dichloromethane (DCM, 0.25 M) cooled to 0 ºC in an iceꢀwater bath was
added diisopropylcarbodiimide (1.5 equiv). The solution was stirred for 5 minutes at 0 ºC, after which 3,5ꢀ
dimethoxyaniline (6 mmol, 1 equiv) was added, followed by a solution of 4ꢀ(dimethylamino)pyridine in DCM
(10 mol %, 0.5 M). The reaction mixture was allowed to warm slowly to room temperature. Upon consumption
of the starting material as determined by TLC, the reaction mixture was passed through a pad of Celite, which
was washed with a minimal amount of EtOAc. The filtrate was concentrated by rotary evaporation and the reꢀ
sulting residue was purified by flash column chromatography on silica gel eluting with a gradient of EtOAc/Hex
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0ꢀ40% to afford amide 7b (324 mg, 26%) as an amorphous pale yellow solid. H NMR (CDCl3, 300 MHz) δ
7.53 (bs, 1H), 6.74 (d, J = 2.4 Hz, 2H), 6.27 (t, J = 2.1 Hz, 1H), 3.78 (s, 6H), 2.92 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 161.3, 138.8, 98.5, 97.7, 77.8, 74.2, 55.6; FTꢀIR (cmꢀ1) 3298, 3277, 3246, 2993, 2912, 2849, 2363,
2112, 1655, 1601, 1549, 1460, 1420, 1263, 1238, 1209, 1198, 1165, 1149, 1072, 1063, 968; HRMS (ES+) m/z
calcd. for C11H12NO3 [M+H]+ 206.0817, found 206.0822.
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N-(3,5-dimethoxyphenyl)-3-phenyl-prop-2-ynamide (7c). Acylation method A was followed using pheꢀ
nylpropiolic acid and 3,5ꢀdimethoxyaniline (5 mmol). Extractive workꢀup afforded pure amide 7c (1.22 g, 87%)
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as an amorphous beige solid. H NMR (CDCl3, 300 MHz) δ 7.58 (d, J = 6.9 Hz, 2H), 7.50ꢀ7.39 (m, 4H), 6.80
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(d, J = 2.1 Hz, 2H), 6.28 (s, 1H), 3.80 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 161.2, 151.2, 139.2, 132.8, 130.5,
128.7, 120.0, 98.4, 97.4, 85.9, 83.6, 55.6; FTꢀIR (cmꢀ1) 3276, 3148, 3062, 3002, 2959, 2938, 2840, 2210, 1832,
1774, 1609, 1555, 1482, 1455, 1424, 1343, 1300, 1208, 1158, 1069, 1027, 961, 923, 838, 757, 730, 688; HRMS
(ES+) m/z calcd. for C17H16NO3 [M+H]+ 282.1130, found 282.1133.
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3-bromo-N-(3,5-dimethoxyphenyl)propiolamide (7d). Following a literature procedure for terminal alkyne
bromination,12 amide 7b (103 mg, 0.5 mmol, 1 equiv) was weighed into a 20 mL vial and dissolved in acetone
(12.5 mL). AgNO3 (43 mg, 0.25 mmol, 0.5 equiv) was added and the mixture stirred for 5 minutes at room temꢀ
perature. The vial was then cooled to 0 ºC and NBS (94 mg, 0.525 mmol, 1.05 equiv) was added. The vial was
wrapped in foil and stirred in the dark for 2 hours at 0 ºC. The resulting heterogeneous mixture was filtered
through Celite and the filtrate was concentrated onto Celite and purified via automated flash column chromatogꢀ
raphy eluting with a gradient of EtOAc/Hex 0ꢀ30%. The product 7d (69 mg, 49%) was isolated as an amorꢀ
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phous white solid. H NMR (CDCl3, 300 MHz) δ 7.65 (bs, 1H), 6.74 (s, 2H), 6.26 (s, 1H), 3.77 (s, 6H); C
NMR (CDCl3, 75 MHz) δ 161.2, 149.5, 138.8, 98.5, 97.6, 75.7, 55.6, 52.0; FTꢀIR (cmꢀ1) 3295, 2975, 2917,
2852, 1665, 1624, 1596, 1536, 1466, 1440, 1403, 1391, 1366, 1277, 1230, 1212, 1169, 1144, 976, 848, 818,
766; HRMS (ES+) m/z calcd. for C11H11BrNO3 [M+H]+ 283.9922, found 283.9927.
N-(3,5-dimethoxyphenyl)pent-2-ynamide (7e). Acylation method A was followed using 2ꢀpentynoic acid and
3,5ꢀdimethoxyaniline (3 mmol). Extractive workꢀup afforded pure amide 7e (552 mg, 79%) as a viscous syrup
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that solidified after 12 hours at ꢀ10 ºC. H NMR (CDCl3, 300 MHz) δ 7.40 (bs, 1H), 6.74 (d, J = 2.1 Hz, 2H),
6.25 (t, J = 2.1 Hz, 1H), 3.78 (s, 6H), 2.35 (quart, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 161.2, 151.2, 139.3, 98.3, 97.2, 89.8, 75.6, 55.6, 12.9, 12.6; FTꢀIR (cmꢀ1) 3271, 3097, 3065, 2978,
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2939, 2839, 2230, 1640, 1611, 1550, 1453, 1418, 1273, 1202, 1153, 1070; HRMS (ES+) m/z calcd. for
C13H16NO3 [M+H]+ 233.1052, found 233.1054.
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3-Cyclopropyl-N-(3,5-dimethoxyphenyl)propiolamide (7f). Acylation method A was followed using 3ꢀ
cyclopropylpropiolic acid and 3,5ꢀdimethoxyaniline (3 mmol). Extractive workꢀup, followed by automated colꢀ
umn chromatography on silica gel eluting with a gradient of EtOAc/Hex 0ꢀ40% afforded pure amide 7f (618
mg, 84%) as an amorphous white solid. 1H NMR (CDCl3, 300 MHz) δ 7.90 (bs, 1H), 6.77 (s, 2H), 6.23 (s, 1H),
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3.75 (s, 6H), 1.33 (broad multiplet, 1H), 0.90ꢀ0.87 (broad multiplet, 4H); C NMR (CDCl3, 75 MHz) δ 161.0,
151.4, 139.4, 98.3, 97.0, 92.3, 71.3, 55.5, 9.1, ꢀ0.6; FTꢀIR (cmꢀ1) 3278, 3094, 3004, 2958, 2938, 2839, 2224,
1614, 1550, 1456, 1421, 1279, 1195, 1153, 1066; HRMS (ES+) m/z calcd. for C14H16NO3 [M+H]+ 245.1052,
found 245.1052.
N-(3-methoxyphenyl)but-2-ynamide (9a). Acylation method A was followed using 2ꢀbutynoic acid and mꢀ
anisidine (5 mmol). Extractive workꢀup afforded pure amide 9a (841 mg, 89%) as an amorphous white solid. 1H
NMR (CDCl3, 300 MHz) δ 7.35 (bs, 1H), 7.26ꢀ7.19 (m, 2H, partly obscured by residual solvent peak), 6.97 (d,
J = 8.1 Hz, 1H), 6.68 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 3.80 (s, 3H), 2.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
160.2, 151.2, 138.7, 129.8, 112.1, 110.6, 105.8, 84.6, 75.5, 55.4, 3.8; FTꢀIR (cmꢀ1) 3275, 3138, 3088, 2953,
2916, 2843, 2235, 1643, 1609, 1543, 1458, 1427, 1267, 1159, 1047; HRMS (ES+) m/z calcd. for C11H12NO2
[M+H]+ 190.0868, found 190.0872.
N-(3-methoxyphenyl)-N-methylbut-2-ynamide (9c). Acylation method A was followed using 2ꢀbutynoic acꢀ
id and Nꢀmethylꢀ3ꢀmethoxyaniline (3 mmol). The mixture was stirred overnight. Extractive workꢀup, followed
by automated column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0ꢀ40% afforded amꢀ
ide 9c (296 mg, 49%) as an orange oil. The NMR spectra revealed a mixture of atropisomers. The following 1H
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NMR chemical shifts correspond to the major atropisomer. H NMR (CDCl3, 300 MHz) δ 7.31 (multiplicity
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obscured by residual solvent peak, 1H), 6.89ꢀ6.82 (m, 3H), 3.83 (s, 3H), 3.30 (s, 3H), 2.07 (s, 3H); C NMR
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(CDCl3, 75 MHz) δ 160.0, 154.2, 144.2, 129.7, 119.3, 113.2, 112.9, 89.8, 74.0, 55.4, 36.3, 3.9; FTꢀIR (cmꢀ1)
2935, 2918, 2837, 2235, 1637, 1597, 1489, 1366, 1319, 1232; HRMS (ES+) m/z calcd. for C12H14NO2 [M+H]+
204.1025, found 204.1029.
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N-Benzyl-N-(3-methoxyphenyl)but-2-ynamide (9b). The general procedure for reductive amination was folꢀ
lowed using mꢀanisidine (7.5 mmol) to afford Nꢀbenzylꢀ3ꢀmethoxyaniline (1.51 g, 94%). The crude amine (4
mmol) was then acylated with 2ꢀbutynoic acid following method A. Extractive workꢀup, followed by chromaꢀ
tography on silica gel eluting with EtOAc/Hex 30% afforded amide 9b (785 mg, 70%) as a viscous pale golden
oil. The NMR spectra revealed a mixture of atropisomers. The following 1H NMR chemical shifts correspond to
the major atropisomer. 1H NMR (CDCl3, 300 MHz) δ 7.92ꢀ7.18 (m, 6H), 6.83 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H),
6.76 (d, J = 8.7 Hz, 1H), 4.92 (s, 2H), 3.72 (s, 3H), 1.74 (s, 3H); Due to the complexity of the spectrum of the
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atropisomeric mixture the following 13C NMR data includes all recorded chemical shifts. C NMR (CDCl3, 75
MHz) δ 160.0, 154.4, 142.9, 137.0, 129.9, 129.7, 128.8, 128.6, 127.9, 127.6, 120.8, 114.1, 113.8, 90.6, 74.2,
55.5, 52.4, 4.1; FTꢀIR (cmꢀ1) 3066, 3032, 3008, 2928, 2840, 2254, 2229, 1634, 1605, 1492, 1450, 1437, 1391,
1370, 1287, 1203, 1170, 1081, 1031, 960, 734, 700; HRMS (ES+) m/z calcd. for C18H18NO2 [M+H]+ 280.1338,
found 280.1335.
N-cinnamyl-N-(3-methoxyphenyl)but-2-ynamide (9d). To a solution of mꢀanisidine (4.45 mL, 1.1 equiv) in
benzene [1.5 M] was added MgSO4 (4.33g, 1 equiv), followed by cinnamaldehyde (4.5 mL, 1 equiv). The soluꢀ
tion was stirred at room temperature for 2 hours after which it was filtered through Celite and concentrated. The
crude imine was then dissolved in methanol [0.3 M] and cooled to 0 ºC. To the resulting solution was added
NaBH4 (1.68 g, 1.25 equiv) portionwise. The mixture was then warmed to room temperature and stirred for 2
hours after which the reaction was quenched with aqueous NaOH [1 M]. The mixture was then diluted with waꢀ
ter and extracted with EtOAc. The combined extracts were dried over MgSO4 and concentrated by rotary evapꢀ
oration to yield Nꢀcinnamylꢀ3ꢀmethoxyaniline (>99%) as a red oil. The crude Nꢀcinnamylꢀ3ꢀmethoxyaniline
(439 mg, 1.84 mmol) was then acylated with 2ꢀbutynoic acid according to method B. Extractive workꢀup, folꢀ
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lowed by automated column chromatography eluting with a gradient of EtOAc/Hex 0ꢀ50% to afforded amide
9d (271 mg, 48%) as a viscous golden oil. The NMR spectra revealed a mixture of atropisomers. The following
1H NMR chemical shifts correspond to the major atropisomer. 1H NMR (CDCl3, 300 MHz) δ 7.32ꢀ7.20 (apparꢀ
ent m, 6H), 6.87ꢀ6.81 (apparent m, 3H), 6.43 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 15.9 Hz, J = 6.6 Hz, 1H), 4.47
(d. J = 6.0 Hz, 2H), 3.76 (s, 3H), 1.73 (s, 3H); The following 13C NMR chemical shifts correspond to the major
atropisomer. 13C NMR (CDCl3, 75 MHz) δ 159.9, 153.9, 142.9, 136.5, 133.4, 129.7, 128.5, 127.7, 126.4, 123.7,
120.5, 113.9, 113.5, 90.1, 74.1, 55.4, 51.0, 3.9; FTꢀIR (cmꢀ1) 3057, 3027, 3007, 2957, 2940, 2917, 2833, 2255,
2229, 1635, 1600, 1490, 1450, 1432, 1389, 1315, 1282, 1239, 1199, 1175, 1045, 967, 785, 749, 733, 695;
HRMS (ES+) m/z calcd. for C20H20NO2 [M+H]+ 306.1494, found 306.1494.
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N-(3-methoxyphenyl)-N-phenylbut-2-ynamide (9e). Following a modified literature procedure13 amide 9a
(189 mg, 1.0 mmol, 1 equiv) was weighed into a flame dried round bottom flask and dissolved in anhydrous
toluene (20 mL) under nitrogen. Ph2IOTf (645 mg, 1.5 mmol, 1.5 equiv) was added and the reaction stirred at
room temperature for 30 minutes. NaH 60% in mineral oil (60 mg, 1.5 mmol, 1.5 equiv) was then added and the
mixture stirred at room temperature overnight. The mixture was then treated with MeOH (5 mL) and concenꢀ
trated by rotary evaporation. The resulting residue was concentrated onto Celite and purified via automated
flash column chromatography eluting with a gradient of EtOAc/Hex 0ꢀ40% to afford the product 9f (120 mg,
45%) as a brown oil that solidified upon standing under vacuum. The NMR spectra revealed an unresolved mixꢀ
ture of atropisomers. 1H NMR (DMSOꢀd6, 300 MHz) δ 7.41ꢀ7.28 (m, 6H), 6.96ꢀ6.89 (m, 3H), 3.75 (s, 3H), 1.79
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(s, 3H); C NMR (CDCl3, 75 MHz) δ 160.0, 153.7, 143.4, 142.5, 141.3, 129.7, 129.1, 128.7, 127.9, 126.5,
126.1, 121.2, 118.5, 114.6, 113.5, 112.2, 91.5, 74.8, 55.4, 4.03; HRMS (ES+) m/z calcd. for C17H16NO2 [M+H]+
266.1181, found 266.1182.
N-(3-methoxy-2-methylphenyl)but-2-ynamide (12a). Acylation method B was followed using 2ꢀbutynoic acꢀ
id and 2ꢀmethylꢀ3ꢀmethoxyaniline (15 mmol). Extractive workꢀup, followed by automated column chromatogꢀ
raphy on silica gel eluting with a gradient of EtOAc/Hex 0ꢀ40% afforded product 12a (2.80 g, 92%) as an
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amorphous white solid. H NMR (CDCl3, 300 MHz) δ 7.40 (d, J = 8.1 Hz, 1H), 7.30 (bs, 1H), 7.15 (d, J = 8.1
Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 2.00 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 157.9,
151.5, 135.8, 126.7, 118.3, 116.1, 107.8, 84.4, 75.5, 55.8, 10.0, 3.9; FTꢀIR (cmꢀ1) 3481, 3062, 3029, 2999, 2923,
2836, 2250, 2220, 1634, 1584, 1471, 1437, 1400, 1312, 1261, 1178, 1136, 1077, 1027, 956, 788, 729, 717, 700;
HRMS (ES+) m/z calcd. for C12H14NO2 [M+H]+ 204.1025, found 204.1030.
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N-(3-methoxy-2-methylphenyl)-N-methylbut-2-ynamide (12b). To a flameꢀdried flask was added amide 12a
(406 mg, 2.0 mmol), followed by THF (10 mL). The mixture was cooled to 0 ºC and NaH 60% in mineral oil
(120 mg, 3 mmol) was added. The mixture was stirred at 0 ºC for 30 minutes, after which methyl iodide (187
mg, 3 mmol) was added. The mixture was allowed to slowly warm to room temperature and stirred overnight,
after which the mixture was concentrated onto Celite and purified by automated column chromatography on
silica gel eluting with a gradient of EtOAc/Hex 0ꢀ50% to afford 12b (312 mg, 72%) as a colorless oil. The
NMR spectra revealed a mixture of atropisomers. The following 1H NMR chemical shifts correspond to the maꢀ
jor atropisomer. 1H NMR (CDCl3, 300 MHz) δ 7.19 (t, J = 7.8 Hz, 1H), 6.87ꢀ6.73 (m, 2H), 3.87 (s, 3H), 3.20 (s,
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3H), 2.11 (s 3H), 1.70 (s, 3H); C NMR (CDCl3, 75 MHz) δ 158.6, 154.9, 143.0, 126.8, 125.3, 120.5, 118.9,
110.1, 89.1, 74.1, 56.0, 35.9, 10.8, 4.1; FTꢀIR (cmꢀ1) 3003, 2920, 2840, 2237, 1638, 1592, 1479, 1437, 1375,
1320, 1257, 1194, 1178, 1144, 1073, 880, 821, 788, 738, 717; HRMS (ES+) m/z calcd. for C13H16NO2 [M+H]+
218.1181, found 218.1181.
N-Benzyl-N-(3-methoxy-2-methylphenyl)but-2-ynamide (12c). To a flameꢀdried flask was added amide 12a
(406 mg, 2.0 mmol), followed by THF (10 mL). The mixture was cooled to 0 ºC and NaH 60% in mineral oil
(120 mg, 3 mmol) was added. The mixture was stirred at 0 ºC for 30 minutes, after which benzyl bromide (0.36
mL, 3 mmol) was added. The mixture was allowed to slowly warm to room temperature and stirred overnight,
after which the mixture was concentrated onto Celite and purified by automated column chromatography on
silica gel eluting with a gradient of EtOAc/Hex 0ꢀ40% to afford 12c (381 mg, 65%) as a viscous colorless oil.
The NMR spectra revealed a mixture of atropisomers. The following 1H NMR chemical shifts correspond to the
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major atropisomer. H NMR (CDCl3, 300 MHz) δ 7.28ꢀ7.19 (m, 5H), 7.05 (t, J = 8.1 Hz, 1H), 6.80 (d, J = 8.1
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3H), 1.68 (s, 3H); Due to the complexity of the spectrum of the atropisomeric mixture the following C NMR
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data includes all recorded chemical shifts. C NMR (CDCl3, 75 MHz) δ 158.4, 154.9, 141.2, 136.7, 129.5,
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128.8, 128.6, 128.5, 128.3, 128.1, 127.7, 126.7, 126.3, 125.9, 121.8, 120.1, 110.0, 109.9, 89.3, 74.1, 55.8, 51.9,
10.8, 4.4, 4.0; FTꢀIR (cmꢀ1) 3029, 2999, 2916, 2853, 2252, 2218, 1634, 1584, 1472, 1434, 1396, 1308, 1258,
1174, 1130, 1077, 1031, 955, 787, 733, 719, 702; HRMS (ES+) m/z calcd. for C19H20NO2 [M+H]+ 294.1494,
found 294.1497.
N-(4-Bromo-3-methoxyphenyl)but-2-ynamide (14a). Acylation method A was followed using 2ꢀbutynoic acꢀ
id and 4ꢀbromoꢀ3ꢀmethoxyaniline (2.5 mmol). Extractive workꢀup afforded pure amide 14a (612 mg, 92%) as
an amorphous beige solid. 1H NMR (CDCl3, 300 MHz) δ 7.57 (bs, 1H), 7.45ꢀ7.42 (m, 2H), 6.80 (d, J = 8.7 Hz,
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1H), 3.89 (s, 3H), 1.99 (s, 3H); C NMR (CDCl3, 75 MHz) δ 156.3, 151.1, 138.1, 133.2, 112.6, 106.7, 104.4,
85.2, 75.4, 56.4, 3.9; FTꢀIR (cmꢀ1) 3275, 3117, 3052, 3009, 2966, 2940, 2919, 2830, 2232, 1654, 1597, 1532,
1490, 1463, 1403, 1317, 1261, 1205, 1179, 1136, 1023, 846, 808, 739, 622; HRMS (ES+) m/z calcd. for
C11H11BrNO2 [M+H]+ 267.9973, found 267.9974.
N-Benzyl-N-(4-bromo-3-methoxyphenyl)but-2-ynamide (14b). The general procedure for reductive aminaꢀ
tion was followed using 4ꢀbromoꢀ3ꢀmethoxyaniline (1.52 g, 7.5 mmol) to afford Nꢀbenzylꢀ4ꢀbromoꢀ3ꢀ
methoxyaniline (1.6 g, 73%). The crude amine (1.47 g, 5 mmol) was then acylated with 2ꢀbutynoic acid followꢀ
ing method A. Extractive workꢀup, followed by flash column chromatography on silica gel eluting with
EtOAc/Hex 20% afforded 14b (1.3 g, 73%) as a golden oil. The NMR spectra revealed a mixture of atropisoꢀ
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mers. The following H NMR chemical shifts correspond to the major atropisomer. H NMR (CDCl3, 300
MHz) δ 7.47 (d, J = 8.4 Hz, 1H), 7.26ꢀ7.19 (m, 6H), 6.62ꢀ6.50 (m, 2H), 4.91 (s, 2H), 3.72 (s, 3H), 1.76 (s, 3H);
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recorded chemical shifts. C NMR (CDCl3, 75 MHz) δ 156.1, 154.1, 142.0, 136.8, 133.4, 129.0, 128.9, 128.7,
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128.0, 127.9, 121.8, 120.0, 112.6, 111.3, 91.0, 74.1, 56.4, 56.3, 52.3, 4.1; FTꢀIR (cmꢀ1) 3066, 3028, 2919, 2849,
2254, 1637, 1582, 1487, 1449, 1384, 1318, 1299, 1250, 1207, 1057, 1025, 961, 853, 809, 732, 700, 713, 666;
HRMS (ES+) m/z calcd. for C18H17BrNO2 [M+H]+ 358.0443, found 358.0438.
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Methyl 4-(N-benzylbut-2-ynamido)-2-methoxybenzoate (16). The general procedure for reductive amination
was followed using methyl 4ꢀaminoꢀ2ꢀmethoxybenzoate (906 mg, 5 mmol) to afford methyl 4ꢀ(benzylamino)ꢀ2ꢀ
methoxybenzoate (1.12 g, 83%). The crude amine (814 mg, 3 mmol) was then acylated with 2ꢀbutynoic acid
following method B. Extractive workꢀup, followed by automated column chromatography on silica gel eluting
with a gradient of EtOAc/Hex 0ꢀ40% afforded 16 (607 mg, 60%) as a golden oil. The NMR spectra revealed a
mixture of atropisomers. The following 1H NMR chemical shifts correspond to the major atropisomer. 1H NMR
(CDCl3, 300 MHz) δ 7.76 (d, J = 8.1 Hz, 1H), 7.29 (peak obscured by residual solvent peak, 4H), 7.22 (peak
partly obscured by residual solvent peak, 1H), 6.77 (dd, J = 8.1 Hz, J = 1.8 Hz, 1H), 6.61 (s, 1H), 4.94 (s, 2H),
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3.88 (s, 3H), 3.73 (s, 3H), 1.83 (s, 3H); C NMR (CDCl3, 75 MHz) δ 165.7, 159.2, 153.5, 146.0, 136.4, 132.0,
128.4, 127.5, 119.6, 119.1, 112.2, 90.8, 73.8, 55.9, 51.9, 51.7, 3.7; FTꢀIR (cmꢀ1) 3027, 3002, 2946, 2916, 2843,
2252, 2227, 1729, 1635, 1601, 1576, 1496, 1433, 1385, 1293, 1242, 1138, 1091, 1024, 960, 773, 699; HRMS
(ES+) m/z calcd. for C20H20NO4 [M+H]+ 338.1392, found 338.1393.
N-benzyl-N-(3,5-dimethylphenyl)but-2-ynamide (18). The general procedure for reductive amination was
followed using 3,5ꢀdimethylaniline (242 mg, 2 mmol) to afford Nꢀbenzylꢀ3,5ꢀdemethylaniline (414 mg, 98%).
The crude amine (359 mg, 1.7 mmol) was then acylated with 2ꢀbutynoic acid following method A. Extractive
workꢀup, followed by automated column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0ꢀ
25% afforded 18 (283 mg, 60%) as a colorless oil. The NMR spectra revealed a mixture of atropisomers. The
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following H NMR chemical shifts correspond to the major atropisomer. H NMR (CDCl3, 300 MHz) δ 7.29ꢀ
7.19 (apparent m, 5H), 6.90 (s, 1H), 6.70 (s, 2H), 4.90 (s, 2H), 2.25 (s, 6H), 1.73 (s, 3H); Due to the complexity
of the spectrum of the atropisomeric mixture the following 13C NMR data includes all recorded chemical shifts.
13C NMR (CDCl3, 75 MHz) δ 154.5, 141.7, 138.6, 137.1, 129.6, 128.6, 128.4, 127.8, 127.5, 125.9, 124.7, 90.3,
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74.3, 52.4, 21.2, 4.1; FTꢀIR (cmꢀ1) 3036, 2917, 2852, 2252, 1634, 1595, 1472, 1454, 1433, 1389, 1323, 1244,
1078, 1030, 964, 855, 732, 706; HRMS (ES+) m/z calcd. for C19H20NO [M+H]+ 278.1545, found 278.1549.
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N-benzyl-N-phenylbut-2-ynamide (20). Acylation method B was followed using 2ꢀbutynoic acid and Nꢀ
benzylaniline (733 mg, 4 mmol). Extractive workꢀup, followed by automated column chromatography on silica
gel eluting with a gradient of EtOAc/Hex 0ꢀ20% afforded 20 (87%, 866 mg) as a colorless oil. The NMR specꢀ
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tra revealed a mixture of atropisomers. The following H NMR chemical shifts correspond to the major atroꢀ
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pisomer. H NMR (CDCl3, 300 MHz) δ 7.31ꢀ7.20 (apparent m, 8H), 7.09ꢀ7.07 (apparent m, 2H), 4.93 (s, 2H),
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1.70 (s, 3H); Due to the complexity of the spectrum of the atropisomeric mixture the following C NMR data
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includes all recorded chemical shifts. C NMR (CDCl3, 75 MHz) δ 154.4, 141.7, 136.9, 136.8, 129.1, 128.9,
128.6, 128.5, 128.4, 127.9, 127.7, 127.5, 126.8, 90.5, 74.1, 52.2, 4.2, 3.9; FTꢀIR (cmꢀ1) 3260, 3062, 3037, 2921,
2848, 2253, 2231, 1953, 1885, 1810, 1745, 1639, 1594, 1495, 1455, 1437, 1392, 1318, 1295, 1280, 1222, 1156,
1028, 962, 771, 728, 698, 638; HRMS (ES+) m/z calcd. for C17H16NO [M+H]+ 250.1232, found 250.1237.
N-(benzo[d][1,3]dioxol-5-yl)-N-benzylbut-2-ynamide (22). The general procedure for reductive amination
was followed using benzo[d][1,3]dioxolꢀ5ꢀamine (686 mg, 5 mmol) to afford Nꢀbenzylbenzo[d][1,3]dioxolꢀ5ꢀ
amine (1.03 g, 91%). The crude amine (682 mg, 3 mmol) was then acylated with 2ꢀbutynoic acid following
method A. Extractive workꢀup, followed by automated column chromatography on silica gel eluting with a graꢀ
dient of EtOAc/Hex 0ꢀ30% afforded 22 (664 mg, 75%) as a golden oil. The NMR spectra revealed a mixture of
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atropisomers. The following H NMR chemical shifts correspond to the major atropisomer. H NMR (CDCl3,
300 MHz) δ 7.28ꢀ7.21 (apparent m, 5H), 6.70 (d, J = 8.7 Hz, 1H), 6.53ꢀ6.44 (apparent m, 2H), 5.98 (s, 2H),
4.86 (s, 2H), 1.77 (s, 3H); Due to the complexity of the spectrum of the atropisomeric mixture the following 13C
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NMR data includes all recorded chemical shifts. C NMR (CDCl3, 75 MHz) δ 154.7, 147.8, 147.3, 136.8,
135.6, 128.9, 128.8(4), 128.7(5), 128.6, 128.5, 128.0, 127.7, 127.5, 122.4, 121.9, 120.5, 119.5, 109.4, 108.9,
108.6, 108.3, 108.1, 101.8, 101.8, 90.8, 75.2, 56.6, 52.8, 52.5, 27.5, 4.3, 4.1; FTꢀIR (cmꢀ1) 3063, 3029, 2916,
2782, 2239, 1653, 1483, 1446, 1389, 1339, 1245, 1198, 110, 1037, 934, 810, 729, 703, 660; HRMS (ES+) m/z
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calcd. for C18H16NO3 [M+H]+ 294.1130, found 294.1133.
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N-(3-aminophenyl)but-2-ynamide (24). A modification of acylation method B was used. To a solution of 2ꢀ
butynoic acid (252 mg, 3 mmol, 1 equiv) in ethyl acetate (3.8 mL) was added Nꢀmethyl morpholine (0.33 mL, 3
mmol, 1.5 equiv), followed by slow addition of isopropyl chloroformate (3 mL, 3 mmol, 1.0 M solution in toluꢀ
ene, 1.5 equiv). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then
filtered to remove the precipitated ammonium salt and the filtrate was concentrated to yield the mixed carbonic
acid anhydride as a golden oil. The oil was dissolved in DMF (2 mL) and added slowly to a solution of the mꢀ
phenylenediamine (324 mg, 3 mmol, 1.0 equiv) in DMF (6 mL) at room temperature. After stirring the mixture
overnight it was poured into 5 volumes of water and extracted three times with ethyl acetate. The combined orꢀ
ganic layers were then dried over MgSO4. The mixture was filtered and the filtrate was concentrated by rotary
evaporation. The resulting solid was recrystallized from EtOAc and hexanes to afford 24 (408 mg, 78%) as a
white solid. The NMR spectra revealed a mixture of atropisomers. The following 1H NMR chemical shifts corꢀ
respond to the major atropisomer. 1H NMR (CDCl3, 300 MHz) δ 7.28 (bs, 1H), 7.15 (t, J = 1.8 Hz, 1H), 7.07 (t,
J = 7.8 Hz, 1H), 6.63 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H), 6.44 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H), 3.72 (bs, 2H), 2.00
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(s, 3H); C NMR (CDCl3, 75 MHz) δ 151.1, 147.4, 138.5, 129.9, 111.6, 109.7, 106.7, 84.4, 75.6, 3.9; FTꢀIR
(cmꢀ1) 3371, 2907, 2850, 2292, 1659, 1588, 1536, 1446, 1252; HRMS (ES+) m/z calcd. for C10H11N2O [M+H]+
175.0871, found 175.0874.
1-(7-methoxy-3,4-dihydroquinolin-1(2H)-yl)but-2-yn-1-one (27). Acylation method B was followed using 2ꢀ
butynoic acid and 7ꢀmethoxyꢀtetrohydroquinoline (2.3 mmol), which was prepared by a known literature proceꢀ
dure.14 Extractive workꢀup, followed by automated column chromatography on silica gel eluting with a gradient
of EtOAc/Hex 0ꢀ30% afforded 27 (492 mg, 93%) as an amorphous pale yellow solid. The NMR spectra reꢀ
vealed a mixture of conformers, likely due to slow changes between the pseudoꢀchair conformations of the piꢀ
peridinyl ring. 1H NMR (CDCl3, 300 MHz) δ 7.66 + 7.23 (bs + bs, 1Hcombined integration), 7.02 (d, J = 8.1 Hz, 1H),
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6.69 (bs, 1H), 4.02 (bs, 2H), 3.78 (s, 3H), 2.75 (bs, 2H), 1.97 (bs, 5H); C NMR (CDCl3, 75 MHz) δ 156.9,
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152.4, 137.7, 129.4, 121.4, 110.9, 109.4, 91.1, 74.3, 55.2, 46.9, 25.6, 23.2, 3.5; FTꢀIR (cmꢀ1) 3007, 2943, 2841,
2224, 1637, 1615, 1581, 1505, 1445, 1390, 1347, 1305, 1283, 1262, 1249, 1224, 1207, 1168, 1130, 1117, 1041,
938, 866, 807, 730; HRMS (ES+) m/z calcd. for C14H16NO2 [M+H]+ 230.1181, found 230.1184.
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N-Benzyl-N-(naphthalen-2-yl)but-2-ynamide (29). Acylation method A was followed using 2ꢀbutynoic acid
and 2ꢀaminonaphthalene (4 mmol). Extractive workꢀup, afforded the crude amide, which was used directly in
the next reaction. The crude amide (314 mg, 1.5 mmol) was added to a flameꢀdried flask, followed by THF (12
mL). The mixture was cooled to 0 ºC and NaH 60% in mineral oil (90 mg, 1.5 mmol) was added. The mixture
was stirred at 0 ºC for 30 minutes, after which benzyl bromide (0.27 mL, 1.5 mmol) was added. The mixture
was allowed to slowly warm to room temperature and stirred overnight. The mixture was then concentrated by
rotary evaporation and the residue was purified via flash column chromatography on silica gel eluting with a
gradient of EtOAc/Hex 10ꢀ20% to afford 29 (44%, 195 mg) as a viscous brown oil. The NMR spectra revealed
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a mixture of atropisomers. The following H NMR chemical shifts correspond to the major atropisomer. H
NMR (CDCl3, 300 MHz) δ 7.85ꢀ7.75 (apparent m, 3H), 7.56 (d, J = 1.5 Hz, 1H), 7.51ꢀ7.48 (apparent m, 2H),
5.02 (s, 2H), 1.64 (s, 3H); Due to the complexity of the spectrum of the atropisomeric mixture the following 13C
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NMR data includes all recorded chemical shifts. C NMR (CDCl3, 75 MHz) δ 154.5, 139.1, 136.8, 133.3,
132.5, 128.9, 128.7, 128.5, 128.1, 127.7, 127.6, 127.0, 126.6(2), 126.5(5), 126.4, 90.8, 74.3, 52.5, 3.9; FTꢀIR
(cmꢀ1) 3061, 3031, 2912, 2848, 2252, 2225, 1637, 1624, 1596, 1504, 1395, 1316, 1290, 1240, 1214, 1075, 1028,
962, 860, 818, 749, 730, 701, 675; HRMS (ES+) m/z calcd. for C21H18NO [M+H]+ 300.1388, found 300.1394.
N-benzyl-N-(naphthalen-1-yl)but-2-ynamide (31). The general procedure for reductive amination was folꢀ
lowed using 1ꢀaminonaphthalene (859 mg, 6 mmol) to afford Nꢀbenzylꢀ1ꢀaminonaphthelanene (1.12 g, 80%).
The crude Nꢀbenzylꢀ1ꢀaminonaphthelanene (700 mg, 3 mmol) was then acylated with 2ꢀbutynoic acid following
method B. Extractive workꢀup, followed by automated column chromatography on silica gel eluting with a graꢀ
dient of EtOAc/Hex 0ꢀ35% afforded 31 (753 mg, 84%) as a golden oil. The NMR spectra revealed a mixture of
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atropisomers. The following H NMR chemical shifts correspond to the major atropisomer. H NMR (CDCl3,
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300 MHz) δ 7.91ꢀ7.70 (apparent m, 3H), 7.55ꢀ7.46 (apparent m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.30ꢀ7.19 (apparꢀ
ent m, 5H), 6.98 (dd, J = 7.2 Hz, J = 0.9 Hz, 1H), 4.66 (d, J = 15.3 Hz, 1H), 4.30 (d, J = 14.1 Hz, 1H), 1.47 (s,
3H); Due to the complexity of the spectrum of the atropisomeric mixture the following 13C NMR data includes
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all recorded chemical shifts. C NMR (CDCl3, 75 MHz) δ 155.4, 137.6, 137.0, 134.6, 130.7, 129.4, 129.0,
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128.7, 128.6, 128.5(3), 128.4(6), 127.8, 127.7, 127.2, 126.5, 125.3, 122.7, 90.1, 74.2, 56.4, 52.0, 3.8; FTꢀIR
(cmꢀ1) 3059, 3026, 2917, 2851, 2254, 2221, 1633, 1595, 1401, 1386, 1293, 1253, 1225, 1074, 953, 776, 732,
700; HRMS (ES+) m/z calcd. for C21H18NO [M+H]+ 300.1388, found 300.1395.
N-(1H-indol-4-yl)but-2-ynamide (33). Acylation method A was followed using 2ꢀbutynoic acid and 4ꢀ
aminoindole (529 mg, 4 mmol). Extractive workꢀup, followed by automated column chromatography on silica
gel eluting with a gradient of EtOAc/Hex 0ꢀ45% afforded product 33 (264 mg, 33%) as an amorphous pale yelꢀ
low solid. 1H NMR (CDCl3, 300 MHz) δ 11.14 (bs, 1H), 10.34 (bs, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H),
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7.20 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.73 (s, 1H), 2.07 (s, 3H); C NMR (CDCl3, 75 MHz) δ
150.8, 136.7, 129.7, 124.4, 120.9, 120.5, 108.3, 99.6, 84.1, 76.3, 3.4; FTꢀIR (cmꢀ1) 3047, 2922, 2847, 2291,
1623, 1581, 1529, 1429, 1415, 1357, 1299, 1263, 1207, 1094, 901, 750; HRMS (ES+) m/z calcd. for C12H11N2O
[M+H]+ 199.0871, found 199.0875.
N-(1H-indol-5-yl)but-2-ynamide (35). Acylation method B was followed using 2ꢀbutynoic acid and 5ꢀ
aminoindole (397 mg, 3 mmol). Following the method B extractive workꢀup the resulting residue was dissolved
in hot EtOAc. The slow addition of hexanes led to precipitation of the product 35 (444 mg, 75%) as an amorꢀ
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phous white solid, which was isolated following filtration through filter paper and drying under vacuum. H
NMR (DMSOꢀd6, 300 MHz) δ 11.02 (bs, 1H), 10.38 (s, 1H), 7.86 (d, J = 0.9 Hz, 1H), 7.32ꢀ7.29 (apparent m,
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2H), 7.22 (dd, J = 8.6 Hz, J = 1.8 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 2.03 (s, 3H); C NMR (DMSOꢀd6, 75
MHz) δ150.2, 132.9, 130.6, 127.4, 126.0, 114.8, 111.2, 111.1, 101.2, 83.1, 76.3, 3.2; FTꢀIR (cmꢀ1) 2919, 2849,
2231, 2208, 1647, 1581, 1537, 1471, 1419, 1335, 1265, 1243, 1221, 873, 803, 766, 733, 696; HRMS (ES+) m/z
calcd. for C12H11N2O [M+H]+ 199.0871, found 199.0876.
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N-(1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-8-yl)but-2-ynamide (37). Acylation method A was folꢀ
lowed using 2ꢀbutynoic acid and 7ꢀaminojulolidine (206 mg, 1.1 mmol), which was prepared according to a
published procedure.15 Extractive workꢀup, followed by flash column chromatography on silica gel eluting with
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EtOAc/Hex 30% afforded product 37 (128 mg, 46%) as an amorphous yellow solid. H NMR (CDCl3, 300
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MHz) δ 7.04 (bs, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 3.10 (bs, 4H), 2.72 (bs, 2H), 2.62 (bs,
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2H), 1.99 (bs, 7H); C NMR (CDCl3, 75 MHz) δ 151.5, 143.7, 132.5, 127.1, 120.1, 114.4, 112.2, 83.9, 75.6,
50.3, 49.4, 27.7, 23.1, 22.1, 21.7, 3.9; FTꢀIR (cmꢀ1) 3325, 2928, 2854, 2237, 1649, 1599, 1523, 1491, 1438,
1393, 1304, 1275, 1198, 1124, 791, 731; HRMS (ES+) m/z calcd. for C16H19N2O [M+H]+ 255.1497, found
255.1496.
Part 3. General Procedure for N-Aryl Alkynamide Hydroarylation:
To a 4 mL vial was added Au(XPhos)(SbF6)•MeCN (5 mol %) followed by a Teflon coated micro stir bar,
benchꢀtop DCE (0.1 M), and lastly the Nꢀaryl alkynamide substrate. The vial was then capped with a Teflon
lined screw cap and placed into an aluminum heating block preꢀheated to 50 ºC. Upon complete consumption of
the starting material as judged by TLC (developing with mixtures of EtOAc in hexanes or benzene) the reaction
mixture was cooled to room temperature. For products that precipitated from solution a volume of hexanes
equal to that of the DCE employed was added to the solution and the vial was cooled to ꢀ15 ºC in a freezer for
30 minutes. The mixture was then filtered and the solid was washed with hexanes. For products that did not
precipitate from solution the reaction was concentrated via rotary evaporation and chromatographed on silica
gel eluting with mixtures of EtOAc and hexanes.
Part 4. 2-Quinolinone Product Characterization Data:
5,7-dimethoxy-4-methylquinolin-2(1H)-one (8a). The general hydroarylation procedure was followed using
0.2 mmol of substrate 7a. Following complete consumption of the starting material, as observed by TLC, the
heterogeneous mixture was filtered through filter paper. The solid was dried under vacuum to yield 8a (44 mg,
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>99%) as an amorphous white solid. 1H NMR (DMSOꢀd6, 300 MHz) δ 11.37 (bs, 1H), 6.44 (d, J = 2.4 Hz, 1H),
6.29 (d, J = 2.4 Hz, 1H), 6.01 (d, J = 0.9 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.51 (s, 3H) peak partly obscured
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by residual DMSO peak; C NMR (DMSOꢀd6, 75 MHz) δ 161.5, 161.3, 159.1, 148.6, 142.2, 118.1, 104.7,
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1229, 1208, 1141, 966, 824, 817. 769; HRMS (ES+) m/z calcd. for C12H14NO3 [M+H]+ 220.0974, found
220.0978.
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5,7-Dimethoxyquinolin-2(1H)-one (8b). The general hydroarylation procedure was followed using 0.2 mmol
of substrate 7b. Following complete consumption of the starting material, as observed by TLC, the solution was
concentrated onto Celite and purified via automated column chromatography on silica gel eluting with a gradiꢀ
ent of EtOAc/Hex 0ꢀ30% afforded the product 8b (68%) as an amorphous white solid. Spectral data matched
those previously reported for compound 8b.16
5,7-Dimethoxy-4-phenylquinolin-2(1H)-one (8c). The general hydroarylation procedure was followed using
0.2 mmol of substrate 7c. Following complete consumption of the starting material, as observed by TLC, the
heterogeneous mixture was filtered through filter paper. The solid was dried under vacuum to yield 8c as an
amorphous white solid. 1H NMR (DMSOꢀd6, 300 MHz) δ 11.68 (bs, 1H), 7.35ꢀ7.33 (m, 3H), 7.24ꢀ7.20 (m, 2H),
6.54 (d, J = 2.1 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.92 (s, 1H), 3.80 (s, 3H), 3.34 (s, 3H) peak partly obscured
by water peak at 3.33; 13C NMR (DMSOꢀd6, 75 MHz) δ 161.9, 161.2, 158.0, 151.0, 142.3, 141.2, 127.2, 127.1,
126.9, 119.0, 103.3, 93.9, 91.3, 55.4, 55.3; FTꢀIR (cmꢀ1) 2959, 2923, 2849, 1660, 1629, 1599, 1540, 1512, 1449,
1437, 1409, 1388, 1277, 1228, 1208, 1140, 984, 818, 759, 695; HRMS (ES+) m/z calcd. for C17H16NO3 [M+H]+
282.1130, found 282.1132.
4-bromo-5,7-dimethoxyquinolin-2(1H)-one (8d). The general hydroarylation procedure was followed using
0.2 mmol of substrate 7d. Following complete consumption of the starting material, as observed by TLC, the
heterogeneous mixture was filtered through filter paper. The solid was dried under vacuum to yield 8d (40 mg,
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70%) as an amorphous white solid. 1H NMR (DMSOꢀd6, 300 MHz) δ 11.80 (bs, 1H), 6.62 (s, 1H), 6.48 (s, 1H),
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6.39 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H); C NMR (DMSOꢀd6, 75 MHz) δ 162.3, 160.1, 157.5, 142.0, 130.6,
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123.0, 102.8, 94.4, 91.3, 55.8, 55.5; FTꢀIR (cmꢀ1) 2922, 2851, 1667, 1623, 1598, 1552, 1442, 1407, 1384, 1360,
1326, 1277, 1230, 1209, 1167, 1144, 1063, 1035, 1009, 977, 849, 817, 764; HRMS (ES+) m/z calcd. for
C11H11BrNO3 [M+H]+ 283.9922, found 283.9928.
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4-Ethyl-5,7-dimethoxyquinolin-2(1H)-one (8e). The general hydroarylation procedure was followed using 0.2
mmol of substrate 7e. Following complete consumption of the starting material, as observed by TLC, the heterꢀ
ogeneous mixture was filtered through filter paper. The solid was dried under vacuum to yield 8e (39 mg, 83%)
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as an amorphous white solid. H NMR (CDCl3, 300 MHz) δ 12.45 (bs, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.33 (s,
1H), 6.24 (d, J = 2.4 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.04 (quart, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 164.8, 162.0, 159.2, 156.7, 142.5, 116.3, 105.9, 94.7, 91.6, 55.8, 55.6, 30.1, 14.8,
0.1; FTꢀIR (cmꢀ1) 2959, 2913, 1654, 1608, 1547, 1455, 1385, 1313, 1276, 1213, 1200, 1165, 1139, 1084;
HRMS (ES+) m/z calcd. for C13H16NO3 [M+H]+ 233.1052, found 233.1055.
4-Cyclopropyl-5,7-dimethoxyquinolin-2(1H)-one (8f). The general hydroarylation procedure was followed
using 0.2 mmol of substrate 7f. Following complete consumption of the starting material, as observed by TLC,
the heterogeneous mixture was filtered through filter paper. The solid was dried under vacuum to yield 8f (36
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mg, 73%) as an amorphous white solid. H NMR (DMSOꢀd6, 300 MHz) δ 11.36 (bs, 1H), 6.43 (d, J = 2.4 Hz,
1H), 6.32 (d, J = 2.4 Hz, 1H), 5.83 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 2.61ꢀ2.57 (multiplet, 1H), 0.90ꢀ0.86 (apꢀ
parent quartet, J = 3.9 Hz, 2H), 0.68ꢀ0.63 (apparent quartet, J = 4.5 Hz, 2H); 13C NMR (DMSOꢀd6, 75 MHz) δ
161.8, 161.2, 159.2, 153.5, 142.2, 113.2, 105.0, 93.7, 91.2, 55.9, 55.2, 16.3, 8.2; FTꢀIR (cmꢀ1) 2914, 1663, 1602,
1541, 1442, 1387, 1273, 1203, 1162, 1135, 1002; HRMS (ES+) m/z calcd. for C14H16NO3 [M+H]+ 245.1052,
found 245.1053.
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7-Methoxy-4-methylquinolin-2(1H)-one (10a). Substrate 9a (0.2 mmol) was added to a 4 mL vial followed by
Au(XPhos)(SbF6)•MeCN (10 mol %), 4Å molecular sieves (200 wt. % with respect to the substrate mass), a
Teflon coated micro stir bar, and DCE (0.1 M). The vial was placed in a heating block preꢀheated to 80 ºC. Folꢀ
lowing complete consumption of the starting material, as observed by TLC, the solution was concentrated onto
Celite and purified via automated column chromatography on silica gel eluting with a gradient EtOAc/Hex 0ꢀ
60% to afford the product mixture 10a and 10b (64%; 42% yield of regioisomer 10a) as an amorphous white
solid. Compound 10a has been previously characterized and reported.17 Comparison of the spectral data for our
mixture of 10a and 10b to the reported data confirmed the identity of the major component of our mixture as
10a.
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5-Methoxy-4-methylquinolin-2(1H)-one (11a). The product was obtained as the minor component of a mixꢀ
ture with regioisomer 10a as described in detail above from substrate 9a. Spectral assignments of 11a were
made based on comparison of the obtained mixture of 10a and 11a to published spectra of pure 10a.17 1H NMR
(CDCl3:DMSOꢀd6, 300 MHz) δ 11.61 (bs, 1H), 7.34 (t, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H),
6.61 (d, J = 7.2 Hz, 1H), 6.33 (s, 1H), 3.88 (s, 3H), 2.65 (s, 3H); 13C NMR (CDCl3:DMSOꢀd6, 75 MHz) δ 162.6,
157.9, 149.7, 140.4, 130.2, 120.6, 114.1, 108.8, 103.2, 55.1, 24.6; FTꢀIR for the mixture of 10a and 10b (cmꢀ1)
2956, 2917, 2846, 1669, 1626, 1609, 1554, 1520, 1472, 1442, 1417, 1391, 1263, 1252, 1215, 1181, 1098, 1029,
855, 809, 729. HRMS for the mixture of 10a and 10b (ES+) m/z calcd. for C11H12NO2 [M+H]+ 190.0868,
found 190.0871.
N-Methyl-7-methoxy-4-methylquinolin-2(1H)-one (10c). The general hydroarylation procedure was followed
using 0.5 mmol of substrate 9c. Following complete consumption of the starting material, as observed by TLC,
the solution was concentrated onto Celite and purified via automated column chromatography on silica gel elutꢀ
ing with a gradient of EtOAc/Hex 0ꢀ60% to afford the product 10c (53%; total yield of regioisomers 10c and
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11c was 80%) as an amorphous pale yellow solid. H NMR (DMSOꢀd6, 300 MHz) δ 7.68 (d, J = 8.4 Hz, 1H),
6.91 (s, 1H), 6.91ꢀ6.87 (dd, 1H, partly obscured by singlet at 6.91), 6.34 (s, 1H), 3.89 (s, 3H), 3.56 (s, 3H), 2.38
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(s, 3H); C NMR (DMSOꢀd6, 75 MHz) δ 161.3, 161.2, 146.4, 141.2, 126.8, 117.3, 114.6, 109.4, 98.9, 55.5,
28.8, 18.4; FTꢀIR (cmꢀ1) 2946, 2843, 1653, 1623, 1597, 1559, 1456, 1387, 1370, 1327, 1302, 1237, 1177, 1066,
1036, 972, 861, 822; HRMS (ES+) m/z calcd. for C12H14NO2 [M+H]+ 204.1025, found 204.1028.
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N-Methyl-5-methoxy-4-methylquinolin-2(1H)-one (11c). The product (11c. 27%) was obtained as an amorꢀ
phous pale yellow solid as the minor component of a mixture with regioisomer 10c as described in detail above
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from substrate 9c. H NMR (d6ꢀDMSO, 300 MHz) δ 7.53 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.85 (d,
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J = 8.4 Hz, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.55 (s, 3H), 2.55 (s, 3H); C NMR (d6ꢀDMSO, 75 MHz) δ 160.4,
158.3, 146.9, 141.5, 131.2, 120.4, 110.9, 107.7, 104.6, 55.9, 29.5, 24.6; FTꢀIR (cmꢀ1) 2971, 2933, 2841, 1645,
1582, 1489, 1468, 1435, 1389, 1338, 1263, 1235, 1153, 1111. 1069, 1019, 860; HRMS (ES+) m/z calcd. for
C12H14NO2 [M+H]+ 204.1025, found 204.1028.
N-Benzyl-7-methoxy-4-methylquinolin-2(1H)-one (10b). The general hydroarylation procedure was followed
using 0.5 mmol of substrate 9c. Following complete consumption of the starting material, as observed by TLC,
the solution was concentrated onto Celite and purified via automated column chromatography on silica gel elutꢀ
ing with a gradient of EtOAc/Hex 0ꢀ40% to afford the product 10b (55%; total yield of regioisomers 10b and
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11b was 87%) as a golden oil. H NMR (CDCl3, 300 MHz) δ 7.59 (d, J = 8.7 Hz, 1H), 7.31ꢀ7.19 (apparent m,
6H), 6.77 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.54 (s, 1H), 5.52 (s, 2H), 3.72 (s, 3H), 2.45
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(s, 3H); C NMR (CDCl3, 75 MHz) δ 162.9, 161.5, 147.1, 140.9, 136.8, 128.9, 127.3, 126.8, 126.7, 118.2,
115.8, 109.6, 99.9, 55.4, 46.0, 19.2; FTꢀIR (cmꢀ1) 3092, 3062, 3033, 3010, 2975, 2937, 2893, 1651, 1621, 1591,
1560, 1497, 1458, 1440, 1394, 1378, 1322, 1286, 1237, 1224, 1192, 1179, 1112, 1100, 1080, 1036, 863, 858,
837, 728, 709; HRMS (ES+) m/z calcd. for C18H18NO2 [M+H]+ 280.1338, found 280.1334.
N-Benzyl-5-methoxy-4-methylquinolin-2(1H)-one (11b). The product (11b. 32%) was obtained as a golden
oil as the minor component of a mixture with regioisomer 10b as described in detail above from substrate 9b.
1H NMR (CDCl3, 300 MHz) δ 7.31ꢀ7.16 (apparent m, 6H), 6.85 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H),
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6.54 (s, 1H), 5.53 (s, 2H), 3.87 (s, 3H), 2.67 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 162.2, 159.0, 148.6, 141.4,
136.8, 130.8, 128.8, 127.2, 126.5, 121.2, 112.6, 108.6, 104.2, 55.7, 46.4, 25.4; FTꢀIR (cmꢀ1) 3061, 3034, 2973,
2937, 2842, 1650, 1590, 1564, 1498, 1469, 1456, 1440, 1386, 1365, 1330, 1307, 1267, 1222, 1151, 1115, 1070,
1030, 937, 908, 860, 789, 737, 717; HRMS (ES+) m/z calcd. for C18H18NO2 [M+H]+ 280.1338, found 280.1334.
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1-Cinnamyl-7-methoxy-4-methylquinolin-2(1H)-one (10d). The general hydroarylation procedure was folꢀ
lowed using 0.3 mmol of substrate 9d. Following complete consumption of the starting material, as observed by
TLC, the solution was concentrated onto Celite and purified via automated column chromatography on silica
gel eluting with a gradient of EtOAc/Hex 0ꢀ40% to afford the product 10d (46%; total yield of regioisomers
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10d and 11d was 72%) as an amorphous pale yellow solid. H NMR (CDCl3, 300 MHz) δ 7.62 (d, J = 8.7 Hz,
1H), 7.33ꢀ7.24 (apparent m, 5H), 6.88 (d, J = 2.1 Hz, 1H), 6.82 (dd, J = 9.0 Hz, J = 2.1 Hz, 1H), 6.57ꢀ6.49 (apꢀ
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parent m, 2H), 6.29 (dt, J = 15.9 Hz, J = 5.1 Hz, 1H), 5.09 (d, J = 4.2 Hz, 2H), 3.87 (s, 3H), 2.45 (s, 3H); C
NMR (CDCl3, 75 MHz) δ 161.6, 146.9, 141.0, 136.5, 132.5, 128.6, 127.8, 126.8, 126.5, 124.0, 118.4, 115.9,
109.3, 99.8, 55.6, 44.3, 19.2; FTꢀIR (cmꢀ1) 3052, 3026, 3000, 2926, 2843, 1647, 1621, 1590, 1555, 1442, 1394,
1315, 1237, 1175, 1079, 1031, 962; HRMS (ES+) m/z calcd. for C20H20NO2 [M+H]+ 306.1494, found 306.1495.
1-Cinnamyl-5-methoxy-4-methylquinolin-2(1H)-one (11d). The product (11d. 32%) was obtained as an
amorphous pale yellow solid as the minor component of a mixture with regioisomer 10d as described in detail
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above from substrate 9d. H NMR (CDCl3, 300 MHz) δ 7.41 (t, J = 8.4 Hz, 1H), 7.32ꢀ7.19 (apparent m, 5H),
7.02 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.51ꢀ6.46 (apparent m, 2H), 6.29 (d, J = 16.2 Hz, 1H), 5.11
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(s, 2H), 3.89 (s, 3H), 2.66 (s, 3H); C NMR (CDCl3, 75 MHz) δ 159.0, 148.4, 141.4, 136.6, 132.2, 130.8,
128.6, 127.7, 126.5, 124.0, 121.4, 112.6, 108.3, 104.1, 55.7, 44.7, 25.4; FTꢀIR (cmꢀ1) 3058, 3024, 2967, 2833m
2837, 1653, 1589, 1466, 1436, 1263, 1145, 1112, 1028, 964, 854, 791, 742; HRMS (ES+) m/z calcd. for
C20H20NO2 [M+H]+ 306.1494, found 306.1496.
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