Synthesis of heteroarylated ketones via bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic enones and dienones

Article abstract of DOI:10.1016/j.tet.2018.04.002

The development and optimization of bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to cyclic, β,β-disubstituted enones and dienones is described. Additions of a range of heteroarenes, including furan, th

Full text of DOI:10.1016/j.tet.2018.04.002

Accepted Manuscript
Synthesis of heteroarylated ketones via bismuth(III) triflate-promoted regioselective
1,4- and 1,6-additions of electron-rich heteroarenes to cyclic enones and dienones
Tanner L. Metz, Mingwan Leng, Joshua Evans, Levi M. Stanley
PII:
S0040-4020(18)30370-3
10.1016/j.tet.2018.04.002
TET 29417
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 January 2018
Revised Date: 2 April 2018
Accepted Date: 3 April 2018
Please cite this article as: Metz TL, Leng M, Evans J, Stanley LM, Synthesis of heteroarylated ketones
via bismuth(III) triflate-promoted regioselective 1,4- and 1,6-additions of electron-rich heteroarenes to
cyclic enones and dienones, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.002.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered .
Synthesis of heteroarylated ketones via
bismuth(III) triflate-promoted regioselective
1,4- and 1,6-additions of electron-rich
heteroarenes to cyclic enones and dienones
Leave this area blank for abstract info.
Tanner L. Metz, Mingwan Leng, Joshua Evans, and Levi M. Stanley
Department of Chemistry, Iowa State University and College of Chemistry, Beijing Normal University

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of heteroarylated ketones via bismuth(III) triflate-promoted regioselective
1,4- and 1,6-additions of electron-rich heteroarenes to cyclic enones and dienones
Tanner L. Metza, Mingwan Lenga,b, Joshua Evansa, and Levi M. Stanleya
aDepartment of Chemistry, Iowa State University, Ames, Iowa 50011, United States
bCollege of Chemistry, Beijing Normal University, Beijing 100875, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The development and optimization of bismuth(III) triflate-promoted regioselective 1,4- and 1,6-
additions of electron-rich heteroarenes to cyclic, β,β-disubstituted enones and dienones is
described. Additions of a range of heteroarenes, including furan, thiophene, pyrrole, and indole
nucleophiles, to cyclic, β,β-disubstituted enones occur to form all-carbon quaternary centers in
up to 88% yield. In addition, regioselective 1,6-additions of electron-rich heteroarenes to 3-
vinyl-2-cyclohexenone occur to produce a variety of δ-heteroarylated, β,β-disubstituted enones
in up to 93% yield. The high 1,6-selectivity for these reactions is attributed to the increased
steric bulk at the β-position relative to the δ-position, and no competing 1,4-conjugate addition
is observed.
Available online
Keywords:
Bismuth(III) triflate
Conjugate addition
1,6-Addition
Enone
2009 Elsevier Ltd. All rights reserved
.
Heteroarene
———
Corresponding author. Tel.: +1-515-294-3609; e-mail: lstanley@iastate.edu

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Bismuth(III) triflate has drawn the interest of synthetic
organic chemist as an inexpensive and environmentally friendly
Lewis acid catalyst and easily handled source of triflic acid.1
These attractive properties have led to the emergence of
bismuth(III) triflate as a privileged catalyst that has been utilized
in a wide range of organic transformations over the past decades.2
Among such transformations, 1,4-additions of electron-rich
heteroarenes to α,β-unsaturated ketones in the presence of
bismuth(III) triflate are a valuable set of reactions to generate β-
heteroarylated ketones. Until recently, these studies were limited
to 1,4-additions of indole nucleophiles to unsubstituted and β-
substituted, α,β-unsaturated carbonyl compounds and related
Michael acceptors.3
Our group has actively pursued a program aimed at
developing catalytic additions of aryl and heteroaryl nucleophiles
to construct quaternary carbon centers and sterocenters. Early
efforts from our laboratory focused on developing palladium-
catalyzed 1,4-additions of arylboron nucleophiles to β,β-
disubstituted enones.4 However, these processes do not
encompass additions of heteroarylboron nucleophiles due to the
relative instability of these reagents.5 To address this issue, we
recently reported direct additions of electron-rich heteroarenes to
β,β-disubstituted enones that are catalyzed by triflic acid
generated in situ from bismuth (III) triflate (Fig 1A).6 These
reactions encompass additions of furan, thiophene, pyrrole, and
indole nucleophiles to a variety of β,β-disubstituted enones to
construct heteroarylated all-carbon quaternary centers. During the
course of these studies, we observed that the addition reactions
are sensitive to the identity of β-substitutents present in the β,β-
disubstituted enone. For example, additions of 2,3-dimethylfuran
to cyclic enones containing relatively small alkyl substituents at
the β-position occur to form the β-heteroarylated ketone products
in good yields. However, additions to cyclic enones with
sterically demanding substituents at the β-position either do not
occur to form the β-heteroarylated ketone products or lead to 1,2-
addition and elimination sequences that generate heterarylated
dienes (Fig 1B).7 Based on these results, we hypothesized that we
could leverage the differences in reactivity and selectivity to
develop regioselective 1,6-additions of electron-rich heteroarenes
to β-vinylenones in the presence of bismuth(III) triflate to form
δ-heteroarylated enones.
During preliminary studies to develop regioselective 1,6-
additions of electron-rich heteroarenes, we noted that examples
of 1,6-additions of heteroarenes to para-quinone methides for the
synthesis of triarylmethanes are established (Fig 1C).8 However,
regioselective 1,6-additions of heteroarenes to dienones to
synthesize δ-heteroarylated, β,β-disubstituted enones are limited
to one report on additions of furans to steroidal dienones.9 The
development of 1,6-addition reactions that encompass additional
heteroarenes and dienone electrophiles would provide rapid
access to additional classes of δ-heteroarylated, β,β-disubstituted
enones with a synthetic handle for further functionalization (Fig
1D).
Fig 1. Regioselective 1,4-addition (A), 1,2-addition (B), and 1,6-additions (C-
E) of electron-rich heteroarenes enones and dienones.
In this article, we provide a full account of our studies to
develop 1,4-additions of heteroarenes to cyclic β,β-disubstituted
enones to generate quaternary carbon centers and related
regioselective 1,6-additions of heteroarenes to 3-vinyl-2-
cyclhexenone to generate δ-heteroarylated enones in the presence
of catalytic bismuth(III) triflate.
2. Development of 1,4-additions of electron-rich heteroarenes
to β,β-disubstituted enones to form quaternary carbon
centers
2.1. Identification of reaction conditions
Our studies to identify practical catalysts of 1,4-additions of
electron-rich heteroarenes to cyclic β,β-disubstituted enones
began by evaluating the reaction of 2,3-dimethylfuran (2a) with
3-methyl-2-cyclohexenone (1a) in the presence of a selection of
Lewis acid catalysts. These results are summarized in Table 1.

3
We initially evaluated RuCl3·xH2O based on the high activity of
hexafluoro-2-propanol and phenol, afforded ketone 3a in
significantly lower yields (entries 8-9).
ACCEPTED MANUSCRIPT
this catalyst for the conjugate addition of indole to progesterone;
however, the ketone product 3a was generated in modest yield
(60%, entry 1).10 We were pleased to find that running the model
reaction in the presence of scandium(III) and bismuth(III) triflate
salts led to the formation of ketone product 3a in increased
yields. (74-76%, entries 2-3). Previous studies have established
that triflic acid can be derived from the hydrolysis of bismuth(III)
triflate, and the observed catalytic activities may be attributed to
either Brønsted and/or Lewis acid activation.11 We next carried
out the model reaction in the presence of triflic acid to determine
whether triflic acid derived from hydrolysis of bismuth(III)
triflate is an active catalyst (entry 4). When the model conjugate
addition reaction is run the presence of 10 mol % triflic acid, the
ketone product 3a is formed in 67% yield (entry 4). This result
suggests that bismuth(III) triflate is being hydrolyzed to triflic
acid, and that the model reaction proceeds by Brønsted acid
catalysis. To verify this mode of activation, we conducted our
model reaction in the presence of catalytic amounts of
bismuth(III) triflate and 2,6-di-tert-butylpyridine. Under these
reaction conditions ketone 3a was not generated, suggesting that
triflic acid is serving as the active catalyst (entry 7). We chose to
proceed with further studies using bismuth(III) triflate as a
convenient source of triflic acid.
Table 2
Evaluation of reaction solventsa
entry
solvent
protic co-solvent
methanol
methanol
methanol
methanol
-
yield b 3a (%)
1
2
3
4
5
6
7
8
9
acetonitrile
1,4-dioxane
dichloroethane
toluene
76
55
48
44
22
62
64
21
34
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
ethanol
2-propanol
phenol
HFIP
a Conditions: Reactions were performed with 3-methyl-2-
cyclohexenone 1a (0.25 mmol), 2,3-dimethylfuran 2a (0.50 mmol),
Bi(OTf)3 (0.013 mmol), solvent/cosolvent (10:1, 0.5 mL), 60 °C for
1h.
Table 1
Catalyst identificationa
b
Determined by 1H NMR spectroscopy using dibromomethane as an
internal standard
Table 3
Optimization of substrate concentrationsa
entry
Lewis acid catalyst
RuCl3·xH2O
Sc(OTf)3
additive (mol %)
yield b 3a (%)
1
-
60
74
76
67
0
2
-
3
4c
Bi(OTf)3
-
TfOH
-
5
Bi(OTf)3
2,6-di-tert-
entry
ratio 1a:2a
1:2
Bi(OTf)3 (x mol %) yield b 3a (%)
butylpyridine (15)
1
2c
3
4
5
6
7
5
76
76
62
89
98
98
82
98
a Conditions: Reactions were performed with 3-methyl-2-
cyclohexenone 1a (0.25 mmol), 2,3-dimethylfuran 2a (0.50 mmol),
catalyst (0.013 mmol), acetonitrile/methanol (10:1, 0.5 mL), 60 °C
for 1h.
1:2
5
1:1
5
2:1
5
Determined by 1H NMR spectroscopy using dibromomethane as an
b
3:1
5
internal standard.
c 10 mol % TfOH.
3:1
2.5
1
3:1
8c
3:1
1
a
Identification of triflic acid derived from bismuth(III) triflate
as a promising catalyst prompted us to investigate the effects of
solvent on the yield of the model reaction. These results are
summarized in Table 2. Unfortunately, variation of the identity of
the aprotic and protic components of our binary solvent system
did not lead to improved yields of ketone 3a. Conducting the
model reaction in the presence less polar solvents afforded the
corresponding ketone product 3a in reduced yields (entries 2-4).
Running the model reaction in the absence of a protic co-solvent
had a deleterious impact on the reaction and led to the formation
of 3a in only 22% yield. (entry 5). We also evaluated the effect of
different protic co-solvents. Running the model reaction in the
presence of ethanol or 2-propanol resulted in a slight decrease in
yield of the corresponding ketone product 3a (entries 6-7).
However, the use of more acidic protic co-solvents, such as
Conditions: Reactions were performed with 3-methyl-2-
cyclohexenone 1a (0.25-0.75 mmol), 2,3-dimethylfuran 2a (0.50-
0.25 mmol), Bi(OTf)3 (0.0025-0.013 mmol) MeCN/MeOH (10:1,
0.5 mL), 60 °C for 1h.
b
Determined by 1H NMR spectroscopy using
dibromomethane as an internal standard.
c Reaction ran for 2 hours.
To improve the yield of our model reaction, we investigate the
impact of reaction time and substrate concentration. Running the
model reaction for longer periods of time failed to deliver the
corresponding ketone product 3a in increased yield (compare
Table 3, entries 1 and 2). This observation led us to hypothesize
that inhibition of the catalyst by ketone 3a may be significant as
the reaction progresses. With this hypothesis in mind, we
examined the impact of increasing the concentration of 3-methyl-

4
Tetrahedron
2-cyclohexenone 1a relative to 2,3-dimethyl furan 2a. We
observed for enones 1f, 1g, and 1h is attributed to the increased
ACCEPTED MANUSCRIPT
found that running the reaction in the presence of excess enone
enabled the construction of the desired ketone product 3a in
good-to-excellent yields (89-98%, entries 3-5). In the presence of
excess enone, the loading of bismuth(III) triflate can be lowered
to 2.5 mol % without impacting the yield of 3a (entry 6). Upon
lowering the catalyst loading to 1 mol %, the model reaction
generated 3a in 82% yield; however, if the reaction time is
increased, product 3a is generated in 98% yield (entries 7 and 8).
steric bulk at the β-position.
Table 5
Scope of enone substratesa
2.2. Determination of substrate scope
To establish the scope of heteroarene nucleophiles, additions
of a variety of electron-rich heteroarenes to 3-methyl-2-
cyclohexenone 1a were conducted under the reaction conditions
identified in entry 6 of Table 3. These results are summarized in
Table 4. As noted above, the addition of 2,3-dimethyl furan 2a to
1a occurs in high yield and 3a is isolated in 88% yield. The
conjugate addition reactions are not limited to furan nucleophiles.
The addition of 2-methoxythiophene 2b, 2-methylpyrrole 2c, and
indole 2d to 3-methyl-2-cyclohexenone 1a occur to form ketone
products 3b and 3c in 70% yield and 3d in 63% yield. The
reduced yield observed for the addition of indole 2d to 1a
prompted us to reinvestigate reaction parameters to improve the
yield of this reaction. We found that the yield of 3d can be
improved to 84% by running the reaction with 5 equiv of enone
1a for 3 h.
Table 4
Scope of heteroarene nucleophilesa
a Conditions: Reactions were performed with 1 (0.75 mmol), 2,3-
dimethylfuran 2a (0.25 mmol), Bi(OTf)3 (0.0063 mmol),
MeCN/MeOH (10:1, 0.5 mL), 60 °C for 1h.
3. Development of regioselective 1,6-additions of electron-rich
heteroarenes to 3-vinyl-2-cyclohexenone
3.1. Identification of reaction conditions
The impact that identity of the β-substituent has on 1,4-
additions of heteroarenes to cyclic β,β-disubstituted enones led us
to hypothesize that regioselective 1,6-additions of electron-rich
heteroarenes to 3-vinyl-2-cyclohexenone could occur to generate
δ-heteroarylated, β,β-disubstituted enones. To test this
hypothesis, we examined the model 1,6-addition of indole 2d to
3-vinyl-2-cyclohexenone 4.12 These results are summarized in
Table 6.
a Conditions: Reactions were performed with 3-methyl-2-
cyclohexenone 1a (0.75 mmol), heteroarene 2 (0.25 mmol), Bi(OTf)3
(0.0063 mmol), MeCN/MeOH (10:1, 0.5 mL), 60 °C for 1h.
Replicating the reaction conditions described for the 1,4-
addition of indole 2d to 3-methyl-2-cyclohexenone 1a in Table 4,
the addition of 2d to 4 occurred with complete regioselectivity to
generate 3-(2-(1H-indol-3-yl)ethyl)cyclohex-2-en-1-one 5a in
99% yield (entry 1). As shown previously, the 1,4-addition of
indole 2d required high concentrations of the enone substrate 1a
to obtain the corresponding ketone product 3d in high yields. In
contrast, the ratio of dienone to indole in the model 1,6-addition
reaction can be lowered to 2:1 without significant impact to the
yield of δ-heteroarylated, β,β-disubstituted enone 5a (entries 2
and 3). The yield of 5a does decrease significantly when the
model 1,6-addition reaction is conducted with a 1:1 ratio of
dienone 4:indole 2d (entry 4), and extended reaction time did not
lead to higher yield of 5a (entry 5).
b Reaction was performed with 3-methyl-2-cyclohexenone 1a (1.25
mmol) for 3h.
Next, we tested a variety of cyclic, β,β-disubstituted enones
to establish the scope of the enone electrophiles. These reactions
are summarized in Table 5. Additions of 2,3-dimethyl furan to
the cyclic five- and seven-membered β,β-disubstituted enones 1b
and 1c generated ketone products 3e and 3f in high yields.
Additions to 3-ethyl-2-cyclohexenone 1d and 3-benzyl-2-
cyclohexenones 1e occurred to form the corresponding ketone
products 3g and 3h in 65% and 53% yield. However, the
conjugate additions of 2,3-dimethylfuran 2a to cyclic enones
containing bulkier β-substituents, such as 3-isopropyl-2-
cyclohexenone 1f, 3-cyclohexyl-2-cyclohexenone 1g, and 3-
phenyl-2-cyclohexenone 1h, did not occur. The lack of reactivity
We also conducted control experiments to gain insight into the
identity of the active catalyst (Table 6, entries 6 and 7). Running
the model 1,6-addition reaction in the presence of 10 mol %

5
triflic acid led to the formation of 5a in only 50% yield (entry 6).
However, the addition of indole 2d to 4 in the presence of triflic
acid is not regioselective. The 1,4- and 1,6-addition products are
formed in a nearly 1:1 ratio. We also ran the model reaction in
the presence of 2.5 mol % bismuth(III) triflate and 7.5 mol %
ketones. Additions of indoles containing electron-withdrawing
ACCEPTED MANUSCRIPT
substituents at the 5- and 7-positions with 4 occurred to form
enone products 5h-5k in moderate yields (40-57%). The addition
of 5-methoxyindole 2o and 7-methoxyindole 2p to 3-vinyl-2-
cyclohexenone 4 occurred to form the corresponding enones 5l
and 5m in 61% and 64% yield. These 1,6-addition reactions were
not limited to the addition of indole nucleophiles, and the
additions of 2-methylpyrrole 2c, 2-methoxythiophene 2b, and
2,3-dimethylfuran 2a to 4 occurred to generate the corresponding
δ-heteroarylated, β,β-disubstituted enones 5n-5p in 48-67%
yield.
2,6-di-tert-butylpyridine (entry 7).
Under these reaction
conditions, δ-heteroarylated, β,β-disubstituted enone 5a is formed
in a modest 70% yield, but the addition occurs with complete
regioselectivity for the 1,6-addition product 5a. Taken together
these results suggest that both triflic acid and a Lewis acidic
bismuth species are active catalysts of 1,6-addition. However,
the complete regioselectivity observed for entry 7 suggests that
the 1,6-addition reaction proceeds through a bismuth-catalyzed
pathway. Notably, the identification of a bismuth-catalyzed 1,6-
addition pathway contrasts the related 1,4-additions of
heteroarenes that have been determined to proceed via Brønsted
acid catalysis.
Table 7
Scope of heteroarene nucleophilesa
Table 6
Impact of 3-vinyl-2-cyclohexenone concentrationa
entry
ratio 4:2d
time (h)
yield b 5a (%)
1
5:1
3:1
2:1
1:1
1:1
2:1
2:1
3
99
99
97
75
71
50
70
2
3
3
3
4
3
5
24
3
6 c
7 d
3
a Conditions: Reactions were performed with 3-methyl-2-
cyclohexenone 1a (0.25-1.25mmol), indole 2d (0.25 mmol),
Bi(OTf)3 (0.0063 mmol) MeCN/MeOH (10:1, 0.5 mL), 60 °C for 3
h.
b
Determined by 1H NMR spectroscopy using dibromomethane as an
internal standard.
c 10 mol % TfOH.
d Reaction was run in the presence of 7.5 mol % 2,6-di-tert-
butylpyridine.
3.2. Scope of heteroarene nucleophiles
After identifying practical reaction conditions for the
regioselective 1,6-addition of indole 2d to 3-vinyl-2-
cyclohexenone 4 (Table 6, entry 3), we proceeded to evaluate
1,6-additions of
a
variety of electron-rich heteroarene
nucleophiles. These results are summarized in Table 7. As shown
above, the addition of indole 2d to 4 occurs in in high yield and
product 5a is isolated in 86% yield. Additions of methylated
indoles occur to form the corresponding enone products 5b-5g.
Additions of N-methyl-, 2-methyl-, 4-methyl-, 5-methyl-, 6-
methyl-, and 7-methylindole to 4 generated enones 5b-5g in 42-
93% yield. The reactivity of 2-methylindole 2f and 4-
methylindole 2g in 1,6-addition reactions contrasts their
reactivity in 1,4-additions to 3-methyl-2-cyclohexenone 1a,
which did not occur to form the corresponding β-heteroarylated
a Conditions: Reactions were performed with 4 (0.80 mmol),
heteroarene
2
(0.40 mmol), Bi(OTf)3 (0.010 mmol),
MeCN/MeOH (10:1, 0.8 mL), 60 °C for 3 h.
Despite the many electron-rich heteroarenes that undergo 1,6-
additions to construct heteroarylated δ-heteroarylated β,β-
disbustituted enones, there a number of substrates that did not
undergo the desired 1,6-addition reaction under our reaction

6
Tetrahedron
conditions. Additions of less nucleophilic heteroarenes,
ACCEPTED MANUSCRIPT
including
2-bromofuran,
and
2-methylthiophene,
benzothiophene, and benzofuran, to 3-vinyl-2-cyclohexenone 4
did not occur.
3.3. Competition experiments
To gain insight into the relative rates of 1,4-addition and 1,6-
addition reactions in our studies, we carried out a competition
experiment between 3-methyl-2-cyclohexenone 1a and 3-vinyl-2-
cyclohexenone 4 (eq 1). The addition of indole to an equimolar
mixture of 1a and 4 in the presence of 2.5 mol % bismuth(III)
triflate occurs to form an 8.4:1 ratio of 1,6-addition:1:4-addition
products (5a:3d). This result clearly indicates that the rate of 1,6-
addition to 3-vinyl-2-cyclohexenone 4 is significantly higher than
the rate of 1,4-addition to 3-methyl-2-cyclohexenone 1a in
reactions promoted by bismuth(III) triflate and provides further
insight into the high preference for 1,6- versus 1,4-selectivity in
additions of heteroarenes to 3-vinyl-2-cyclohexenone 4.
We also performed competition experiments between a
selection of electronically distinct indole nucleophiles to gain
additional insight into the reactivity of these heteroarenes in 1,6-
addition reactions. We conducted a series of competition
experiments between indole 2d, 5-bromoindole 2m, and 5-
methoxyindole 2o with 3-vinyl-2-cyclohexenone 4 (eq 2-4). The
competition experiment between indole 2d and 5-methoxyindole
2o formed enones 5l and 5a in a 1.9:1 ratio favoring the addition
of 5-methoxyindole (eq 2). The observed relative rates of
addition of 5-methoxyindole and indole are consistent with
nucleophilicity parameters determined for these heterocycles.13
Similar trends are observed for the competition experiment
between indole 2a and 5-bromoindole 2m (eq 3) and the
competition experiment between 5-bromoindole 2m and 5-
methoxyindole 2o (eq 4). In each of these experiments the
observed relative rates are consistent with the nucleophilicity
parameters for these heterocycles and favor addition of the more
electron-rich heteroarene.
3.4. Synthetic transformation of enone 5a
Prior to the current study, 1,6-additions of electron-rich
heteroarenes to dienones have been limited to a select few
examples. The most common approach involves heteroarene
addition to para-quinone methides that do not generate products
that retain the electrophilic enone functionality, but instead
isomerize to generate triarylmethanes.8 The bismuth-catalyzed
1,6-addition reactions reported in our study lead to δ-
heteroarylated, β,β-disubstituted enones that still possess a key
enone functional group handle for further functionization. To
demonstrate the synthetic utility of the δ-heteroarylated, β,β-
disubstituted enone products, we sought to develop a palladium-
catalyzed 1,4-addition of an arylboron nucleophile to enable
rapid synthesis of β-arylated, δ-heteroarylated ketones that
contain a quaternary carbon center at the β-position.14 We
investigated the reaction of 3-(2-(1H-indol-3-yl)ethyl)cyclohex-
2-en-1-one 5a with 4-biphenylboronic acid to show proof-of-
concept. The addition of 4-biphenylboronic acid to 5a forms the
corresponding β-arylated, δ-heteroarylated ketone product 6 in
51% yield when the reaction is run in the presence of a catalyst
prepared in situ from palladium trifluoroacetate and 2,2′-
bipyridine (eq 5). Although we have not investigated the scope of
additional nucleophiles that could participate in 1,4-additions to
our δ-heteroarylated, β,β-disubstituted enone products, this result
clearly demonstrates the potential synthetic utility of these
compounds.

7
4. Conclusion
(10:1) solution (0.5 mL). The vial was sealed with a
ACCEPTED MANUSCRIPT
PFTE/silicone-lined septum cap. The reaction was heated to 60
°C and allowed to stir at this temperature for 1 h. The mixture
was cooled and concentrated under reduced pressure. The crude
reaction mixture was purified by flash column chromatography
on silica gel (5:1 hexane/ether) to yield a clear colorless oil (46.2
mg, 0.220 mmol, 88%).
In summary, we have developed a series of 1,4- and 1,6-
additions of electron-rich heteroarenes that occur in the presence
of
bismuth(III) triflate. The 1,4-additions of heteroarenes
encompass reactions of indole, pyrrole, thiophene, and furan
nucleophiles with a selection of cyclic β,β-disubstituted enones.
These 1,4-addition processes enable rapid synthesis of a range of
β-heteroarylated cyclic ketones containing a quaternary carbon
center in up to 88% yield. Control experiments point to triflic
acid derived from bismuth triflate as the active catalyst required
for these 1,4-additions of heteroarenes. The sensitivity of these
acid-catalyzed 1,4-additions to the identity of the substiuent at
the β-position of the enone substrate has also led to the
development of bismuth-catalyzed 1,6-additions of heteroarenes
to a cyclic β-vinylenone. The 1,6-additions of heteroarenes to 3-
vinyl-2-cyclohexenone also encompass indole, pyrrole,
thiophene, and furan nucleophiles and lead to the formation of a
variety of δ-heteroarylated, β,β-disubstituted enones in up to 93%
5.3. Spectroscopic data for β-heteroarylated ketones
5.3.1. 3-(4,5-dimethylfuran-2-yl)-3-methylcyclhexan-1-one (3a).
Synthesized according to the general procedure and purified by
flash column chromatography (5:1 hexane/ether) to afford a
colorless oil (46.2 mg, 0.220 mmol, 88%). 1H NMR (600 MHz,
CDCl3): δ 5.80 (s, 1H), 2.74 (d, J = 14.4 Hz, 1H), 2.36-2.26 (m,
3H), 2.24-2.20 (m, 1H), 2.18 (s, 3H), 1.90-1.86 (m, 4H), 1.76-
1.62 (m, 2H), 1.32 (s, 3H). 13C NMR (150 MHz, CDCl3): δ
210.9, 156.5, 145.9, 114.0, 108.3, 51.9, 40.7, 40.3, 35.9, 27.3,
22.1, 11.2, 9.8. HRMS (ESI) calcd. for C13H19O2+ [M+H]+
207.1380, found 207.1381.
yield.
In contrast to the 1,4-addition processes, control
5.3.2. 3-(5-methoxythiophen-2-yl)-3-methylcyclhexan-1-one (3b).
Synthesized according to the general procedure and purified by
flash column chromatography (5:1 hexane/ether) to yield an
experiments clearly show that the 1,6-addition reactions are
bismuth-catalyzed process and that the bismuth catalyst plays a
key role in the nearly complete selectivity for 1,6-addition. The
δ-heteroarylated, β,β-disubstituted enones generated from our
1,6-addition reactions have significant potential to serve as
valuable synthetic building blocks. We have demonstrated one
such application through the palladium-catalyzed conjugate
addition of an arylboronic acid to form a β-arylated, δ-
heteroarylated ketone containing a quaternary carbon center at
the β-position.
1
orange oil (39.3 mg, 0.175 mmol, 70%). H NMR (600 MHz,
CDCl3): δ 6.38 (d, J = 3.6 Hz, 1H), 5.93 (d, J = 3.6 Hz, 1H), 3.83
(s, 3H), 2.77 (d, J = 14.4 Hz, 1H), 2.39 (d, J = 14.4 Hz, 1H),
2.35-2.23 (m, 2H), 2.07-1.99 (m, 1H), 1.92-1.84 (m, 2H), 1.81-
1.73 (m, 1H), 1.35 (s, 3H). 13C NMR (150 MHz, CDCl3): δ
210.6, 164.7, 139.0, 120.6, 102.6, 60.2, 53.6, 42.2, 40.7, 39.5,
31.2, 22.1. HRMS (ESI) calcd. for C12H17O2S+ [M+H]+ 225.0955,
found 225.0952.
5. Experimental
5.3.3. 3-(5-methyl-1H-pyrrol-2-yl)-3-methylcyclhexan-1-one (3c).
Synthesized according to the general procedure and purified by
flash column chromatography (5:1 hexanes/ether) to yield a
5.1 Materials and methods
Indole, 7-methoxyindole, 7-bromoindole, 7-cyanoindole, N-
methylindole, 2-methylpyrrole were purchased from AK
Scientific and used without further purification. 7-Methylindole,
2-methylindole, and bismuth(III) triflate were purchased from
Sigma-Aldrich and used without further purification. 6-
Methylindole, 5-methylindole, and 4-methylindole were
purchased from Combi-Blocks and used without further
purification. 2-Phenylindole, 2-methoxythiophene, 3-methyl-2-
cyclohexenone were purchased from TCI America and used
without further purification. Anhydrous acetonitrile and methanol
were purchased from Sigma-Aldrich and used as received. Enone
substrates were either purchased from TCI America (3-methyl-2-
cyclohexenone) or were prepared according to literature
procedure.15 Flash column chromatography was performed on
SiliFlash® P60 silica gel (40-63ꢀm, 60Å) or using a Teledyne
Isco Combiflash® Rf system with RediSep GoldTM columns
using hexanes/ethyl acetate or hexanes/ether. Reaction products
were visualized on TLC under UV light or by staining with
KMnO4. HRMS (ESI) analysis was performed at the Iowa State
University Chemical Instrumentation Facility on an Agilent 6540
QTOF spectrometer. 1H and 13C NMR spectra were acquired on
Varian MR-400 MHz and Bruker Avance III 600 MHz
spectrometers at the Iowa State University Chemical
Instrumentation Facility. Chemical shifts are reported in ppm
relative to a residual solvent peak (CDCl3 = 7.26 ppm for 1H and
77.16 ppm for 13C). Coupling constants are reported in hertz.
1
white solid (33.6 mg, 0.174 mmol, 70%). H NMR (600 MHz,
CDCl3): δ 7.64 (br, s, 1H), 5.79 (m, 1H), 5.75 (m, 1H), 2.74 (ddd,
J = 14.4, 1.6, 1.6 Hz, 1H), 2.36 (d, J = 14.4 Hz, 1H), 2.33-2.26
(m, 2H), 2.23 (s, 3H), 2.08-1.98 (m, 1H), 1.92-1.80 (m, 2H),
1.75-1.63 (m, 1H), 1.32 (s, 3H). 13C NMR (150 MHz, CDCl3): δ
211.4, 136.4, 126.9, 105.8, 105.0, 53.1, 40.9, 39.7, 38.0, 29.5,
22.4, 13.2. HRMS (ESI) calcd. for C12H18NO+ [M+H]+ 192.1394,
found 192.1390.
5.3.4.
3-(1H-indol-3-yl)-3-methylcyclohexan-1-one
(3d).
Synthesized according to the general procedure using (5.00 equiv
of 3-methyl-2-cyclohexenone and purified by flash column
chromatography (hexanes/ethyl acetate = 95:5 to 85:15) to yield
a white solid (48.1 mg, 0.210 mmol, 84%).1H NMR (600 MHz,
CDCl3): δ 8.03 (br, s, 1H), 7.76 (d J = 7.8 Hz, 1H), 7.37 (d J =
7.8 Hz, 1H), 7.19 (dd, J = 8.4, 7.8 Hz, 1H), 7.10 (dd, J = 8.4, 7.8
Hz, 1H) , 6.96 (d, J = 2.4 Hz, 1H), 2.91 (d, J = 14.4 Hz, 1H),
2.62-2.55 (m, 2H), 2.48 (d, J = 14.4 Hz, 1H), 2.36-2.24 (m, 2H),
1.96-1.79 (m, 3H), 1.53 (s, 3H). 13C NMR (150 MHz, CDCl3): δ
212.8, 137.4, 125.1, 122.2, 122.0, 121.9, 120.9, 119.1, 111.7,
54.4, 41.1, 40.2, 36.7, 29.4, 22.5. HRMS (ESI) calcd. for
C15H18NO+ [M+H]+ 228.1394, found 228.1390.
5.3.5.
3-(4,5-dimethylfuran-2-yl)-3-methylcyclopentan-1-one
(3e). Synthesized according to the general procedure and purified
by flash column chromatography (5:1 hexanes/ethyl acetate) to
1
yield a yellow oil (36.2 mg, 0.188 mmol, 75%). H NMR (600
MHz, CDCl3): δ 5.80 (s, 1H), 2.65 (d, J = 18.0 Hz, 1H), 2.39-
2.28 (m, 3H), 2.20 (d, J = 18.0 Hz, 1H), 2.15 (s, 3H), 1.97-1.90
(m, 1H), 1.88 (s, 3H), 1.41 (s, 3H). 13C NMR (150 MHz, CDCl3):
δ 218.7, 157.0, 146.3, 114.2, 107.3, 51.4, 40.7, 37.1, 35.3, 25.9,
5.2. Representative procedure for the 1,4-addition of
electron-rich heteroarenes to β,β-disubstituted enones
To a 1 dram vial was added Bi(OTf)3 (4.2 mg, 0.0063 mmol,
0.025 equiv), 2,3-dimethylfuran (26 ꢀL, 0.25 mmol), 3-methyl-2-
cyclohexenone (82.6 mg, 0.75 mmol), and acetonitrile/methanol
+
11.4, 10.0. HRMS (ESI) calcd. for C12H17O2 [M+H]+ 193.1223,
found 193.1227.

8
Tetrahedron
ACCEPTED MANUSCRIPT
5.3.6.
3-(4,5-dimethylfuran-2-yl)-3-methylcycloheptan-1-one
NMR (600 MHz, CDCl3): δ 7.58 (d, J = 7.8 Hz, 1H), 7.31 (d, J =
(3f). Synthesized according to the general procedure and purified
by flash column chromatography (5:1 hexanes/ether) to yield a
colorless oil (43.7 mg, 0.198 mmol, 79%). H NMR (600 MHz,
CDCl3): δ 5.75 (s, 1H), 2.98 (d, J = 13.8 Hz, 1H), 2.62 (d, J =
13.8 Hz, 1H), 2.42 (dd, J = 6.0, 6.0 Hz, 2H), 2.22-2.17 (m, 1H),
2.14 (s, 3H), 1.87 (s, 3H), 1.79-1.67 (m, 5H), 1.22 (s, 3H). 13C
NMR (150 MHz, CDCl3): δ 213.4, 158.2, 145.7, 114.1, 107.0,
54.1, 44.3, 42.2, 37.6, 28.0, 25.6, 24.1, 11.4, 10.0. HRMS (ESI)
calcd. for C14H21O2+ [M+H]+ 221.1536, found 221.1539.
7.8 Hz, 1H), 7.24 (dd, J = 7.8, 7.2 Hz, 1H), 7.12 (dd, J = 7.8, 7.2
Hz, 1H), 6.84 (s, 1H), 5.98 (s, 1H), 3.75 (s, 3H), 2.98 (t, J =7.8
Hz, 2H), 2.63 (t, J = 7.8 Hz, 2H), 2.38 (dd, J = 6.6, 6.6 Hz, 2H),
2.34 (dd, J = 6.0, 6.0 Hz, 2H), 2.00 (ddd, J = 13.2, 6.6, 6.0 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 200.0, 166.2, 137.1, 127.7,
126.2, 126.0, 121.8, 118.9, 118.8, 113.7, 109.4, 38.8, 37.5, 32.7,
30.0, 23.0, 22.8. HRMS (ESI) calcd. for C17H20NO+ [M+H]+
254.1539, found 254.1560.
1
5.5.3.
3-(2-(2-methyl-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
5.3.7. 3-(4,5-dimethylfuran-2-yl)-3-ethylcyclhexan-1-one (3g).
Synthesized according to the general procedure and purified by
flash column chromatography (hexanes/ethyl acetate = 100:0 to
(5c). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
1
to 70:30) to yield a white solid (60.0 mg, 0.237 mmol, 60%). H
1
90:10) to yield a colorless oil (35.2 mg, 0.163 mmol, 65%). H
NMR (600 MHz, CDCl3): δ 7.91 (br, s, 1H), 7.47 (d, J = 7.2 Hz,
1H), 7.27 (d, J = 7.2 Hz, 1H), 7.13 (dd, J = 7.8, 7.2 Hz, 1H), 7.10
(dd, J = 7.8, 7.2 Hz, 1H), 5.95 (s, 1H), 2.91 (t, J = 7.8 Hz, 2H),
2.52 (t, J = 7.8 Hz, 2H), 3.37 (dd, J = 6.6, 6.6 Hz, 2H), 2.53 (s,
3H), 2.31 (dd, J = 6.0, 6.0 Hz, 2H), 1.98 (ddd, J = 13.2, 6.6, 6.0
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 200.1, 166.6, 135.4,
131.0, 128.4, 126.0, 121.2, 119.4, 117.8, 110.6, 110.5, 39.0, 37.5,
30.2, 22.9, 22.5, 11.8. HRMS (ESI) calcd. for C17H20NO+
[M+H]+ 254.1539, found 254.1561.
NMR (400 MHz, CDCl3): δ 5.76 (s, 1H), 2.67 (dd, J = 14.4 Hz,
1H), 2.32-2.21 (m, 3H), 2.17-2.12 (m, 4H), 1.85-1.78 (m, 4H),
1.77-1.68 (m, 2H), 1.58-1.50 (m, 2H), 0.70 (dt, J = 7.8, 2.8 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 211.2, 154.3, 146.1, 114.0,
110.8, 49.4, 44.3, 41.1, 34.4, 33.7, 22.00, 11.4, 10.0, 8.4. HRMS
(ESI) calcd. for C14H21O2+ [M+H]+ 221.1539, found 221.1537.
5.3.8. 3-benzyl-3-(4,5-dimethylfuran-2-yl)cyclhexan-1-one (3h).
Synthesized according to the general procedure and purified by
flash column chromatography (5:1 hexanes/ethyl acetate) to yield
a colorless oil (37.4 mg, 0.134 mmol, 53%). 1H NMR (600 MHz,
CDCl3): δ 7.23-7.15 (m, 3H), 6.81 (d, J = 6.5 Hz, 2H), 5.62 (s,
1H), 3.02 (d, J = 13.2 Hz, 1H), 2.85 (d, J = 13.2 Hz, 1H), 2.45 (d,
J = 14.2 Hz, 1H), 2.33-2.23 (m, 3H), 2.20 (s, 3H), 2.22 (m, 1H),
1.89-1.81 (m, 4H), 1.75 (m, 1H), 1.55-1.43 (m, 1H). 13C NMR
(150 MHz, CDCl3): δ 211.0, 153.4, 146.1, 137.0, 130.4, 127.9,
126.5, 114.3, 111.9, 49.0, 47.8, 45.0, 40.9, 34.3, 21.9, ll.4, 10.0.
5.5.4. 3-(2-(4-methyl-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5d). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
1
to 70:30) to yield a white solid (62.0 mg, 0.245 mmol, 61%). H
NMR (600 MHz, CDCl3): δ 8.12 (br, s, 1H), 7.19 (d, J = 7.8 Hz,
1H), 7.07 (dd, J = 7.8, 7.2 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.86
(d, J = 7.2 Hz, 1H), 6.01 (s, 1H), 3.15 (t, J = 7.8 Hz, 2H), 2.72 (s,
3H), 2.62 (t, J = 7.8 Hz, 2H), 2.40 (dd, J = 6.6, 6.6 Hz, 2H), 2.36
(dd, J = 6.0, 6.0 Hz, 2H), 2.02 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ 200.1, 166.1, 136.9, 130.8,
126.0, 125.8, 122.4, 121.5, 121.3, 116.3, 109.3, 40.0, 37.5, 30.1,
25.1, 22.9, 20.5. HRMS (ESI) calcd. for C17H20NO+ [M+H]+
254.1539, found 254.1558.
+
HRMS (ESI) calcd. for C19H23O2 [M+H]+ 283.1693, found
283.1697.
5.4. Representative procedure for the 1,6-addition of
electron-rich heteroarenes to 3-vinyl-2-cyclohexenone
To a 1 dram vial was added Bi(OTf)3 (6.7 mg, 0.010 mmol,
0.025 equiv), indole (47 mg, 0.40 mmol), 3-vinyl-2-
cyclohexenone (97.7 mg, 0.80 mmol), and acetonitrile/methanol
5.5.5.
3-(2-(5-methyl-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5e). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
to 70:30) to yield a white solid (68.9 mg, 0.272 mmol, 68%). H
(10:1) solution (0.8 mL). The vial was sealed with
a
1
PFTE/silicone-lined septum cap. The reaction was heated to 60
°C and allowed to stir at this temperature for 3 h. The mixture
was cooled and concentrated under reduced pressure. The crude
reaction mixture was purified by flash column chromatography
on silica gel (hexanes/ethyl acetate = 80:20 to 70:30) to yield a
white solid (82.1 mg, 0.343 mmol, 86%).
NMR (600 MHz, CDCl3): δ 8.07 (br, s, 1H), 7.37 (s, 1H), 7.25
(d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 5.99
(s, 1H), 2.96 (t, J = 7.8 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H), 2.48 (s,
3H), 2.38 (dd, J = 6.6, 6.6 Hz, 2H), 2.34 (dd, J = 6.0, 6.0 Hz,
2H), 2.00 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 200.1, 166.4, 134.8, 128.7, 127.5, 126.0, 123.9, 121.5,
118.4, 114.8, 111.0, 38.6, 37.5, 30.0, 23.1, 22.9, 21.7. HRMS
(ESI) calcd. for C17H20NO+ [M+H]+ 254.1539, found 254.1554.
5.5. Spectroscopic data for δ-heteroarylated enones
5.5.1.
3-(2-(1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5a).
5.5.6.
3-(2-(6-methyl-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
Synthesized according to the general procedure and purified by
flash column chromatography (hexanes/ethyl acetate = 80:20 to
(5f). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
to 70:30) to yield a white solid (94.3 mg, 0.372 mmol, 93%). H
1
70:30) to yield a white solid (82.1 mg, 0.343 mmol, 86%). H
1
NMR (600 MHz, CDCl3): δ 7.98 (br, s, 1H), 7.59 (d, J = 7.8 Hz,
1H), 7.37 (d, J = 7.8 Hz, 1H), 7.21 (dd, J = 7.8, 7.2 Hz, 1H), 7.13
(dd, J = 7.8, 7.2 Hz, 1H), 6.99 (d, J = 1.2 Hz, 1H), 5.97 (s, 1H),
2.99 (t, J = 7.8 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H), 2.37 (dd, J =
6.6, 6.6 Hz, 2H), 2.33 (dd, J = 6.0, 6.0 Hz, 2H), 1.99 (ddd, J =
13.2, 6.6, 6.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 200.1,
166.3, 136.4, 127.3, 126.1, 122.3, 121.4, 119.5, 118.7, 115.3,
111.4, 38.6, 37.5, 30.0, 23.1, 22.9. HRMS (ESI) calcd. for
C16H18NO+ [M+H]+ 240.1383, found 240.1395.
NMR (600 MHz, CDCl3): δ 8.05 (br, s, 1H), 7.47 (d, J = 7.8 Hz,
1H), 7.15 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.89 (s, 1H), 5.99 (s,
1H), 2.97 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.8 Hz, 2H), 2.48 (s,
3H), 2.38 (dd, J = 6.6, 6.6 Hz, 2H), 2.33 (dd, J = 6.0, 6.0 Hz,
2H), 1.99 (ddd, J = 12.6, 6.6, 6.0 Hz, 2H). 13C NMR (150 MHz,
CDCl3): δ 200.2, 166.6, 136.9, 131.9, 125.9, 125.1, 121.1, 120.8,
118.3, 114.9, 111.3, 38.6, 37.4, 29.9, 23.1, 22.8, 21.8. HRMS
(ESI) calcd. for C17H20NO+ [M+H]+ 254.1539, found 254.1559.
5.5.7.
3-(2-(7-methyl-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
5.5.2.
3-(2-(1-methyl-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5g). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
to 70:30) to yield a white solid (72.3 mg, 0.285 mmol, 71%). H
(5b). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
to 70:30) to yield a colorless oil (43.0 mg, 0.170 mmol, 42%). 1H
1

9
NMR (600 MHz, CDCl3): δ 8.07 (br, s, 1H), 7.45 (d, J = 7.8 Hz,
1H), 7.07 (dd, J = 7.8, 7.2 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.98
(s, 1H), 5.98 (s, 1H), 2.99 (t, J = 7.8 Hz, 2H), 2.65 (t, J = 7.8 Hz,
2H), 2.49 (s, 3H), 2.38 (dd, J = 6.6, 6.6 Hz, 2H), 2.34 (dd, J =
6.0, 6.0 Hz, 2H), 2.00 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H). 13C NMR
(150 MHz, CDCl3): δ 200.2, 166.5, 136.0, 126.8, 126.0, 122.7,
121.1, 120.6, 119.6, 116.4, 115.6, 38.6, 37.5, 30.0, 23.2, 22.8,
16.7. HRMS (ESI) calcd. for C17H20NO+ [M+H]+ 254.1539,
found 254.1560.
1H), 7.01 (d, J = 1.8 Hz, 1H), 6.95 (s, 1H), 6.87 (dd, J = 8.4,
ACCEPTED MANUSCRIPT
1.8 Hz, 1H), 5.98 (s, 1H), 3.87 (s, 3H), 2.94 (t, J = 7.8 Hz, 2H),
2.63 (t, J = 7.8 Hz, 2H), 2.37 (dd, J = 6.6, 6.6 Hz, 2H), 2.33 (dd,
J = 6.0, 6.0 Hz, 2H), 1.99 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H). 13
C
NMR (150 MHz, CDCl3): δ 200.2, 166.5, 154.0, 131.6, 127.6,
126.0, 122.2, 114.7, 122.2, 112.1, 100.7, 56.1, 38.3, 37.4, 30.0,
23.0, 22.8. HRMS (ESI) calcd. for C17H20NO2 [M+H]+
+
270.1589, found 270.1490.
5.5.13. 3-(2-(7-methoxy-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5m). Synthesized according to the general procedure and
purified by flash column chromatography (hexanes/ethyl acetate
= 80:20 to 70:30) to yield a white solid (65.4 mg, 0.243 mmol,
5.5.8.
3-(2-(5-cyano-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5h). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 60:40
1
1
to 50:50) to yield a white solid (42.0 mg, 0.159 mmol, 40%). H
61%). H NMR (600 MHz, CDCl3): δ 8.30 (br, s, 1H), 7.19 (d, J
NMR (600 MHz, CDCl3): δ 8.41 (br, s, 1H), 7.93 (s, 1H), 7.44-
7.41 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 5.91 (s, 1H), 2.98 (t, J =
7.8 Hz, 2H), 2.63 (t, J = 7.8 Hz, 2H), 2.37 (dd, J = 6.6, 6.6 Hz,
2H), 2.34 (dd, J = 6.0, 6.0 Hz, 2H), 2.00 (ddd, J = 13.2, 6.6, 6.0
Hz, 2H). 13C NMR (150 MHz, CDCl3): δ 200.0, 165.3, 138.1,
127.2, 126.3, 125.3, 124.5, 123.6, 120.8, 116.2, 112.3, 102.7,
38.3, 37.5, 29.9, 22.8, 22.6. HRMS (ESI) calcd. for C17H17N2O+
[M+H]+ 265.1335, found 265.1343.
= 7.8 Hz, 1H), 7.05 (dd, J = 7.8, 7.8 Hz, 1H), 6.95 (s, 1H), 6.66
(d, J = 7.8 Hz, 1H), 5.98 (s, 1H), 3.96 (s, 3H), 2.97 (t, J = 7.8 Hz,
2H), 2.63 (t, J = 7.8 Hz, 2H), 2.37 (dd, J = 6.6, 6.6 Hz, 2H), 2.32
(dd, J = 6.0, 6.0 Hz, 2H), 1.98 (ddd, J = 12.6, 6.6, 6.0 Hz, 2H).
13C NMR (150 MHz, CDCl3): δ 200.1, 166.4, 146.3, 128.6,
126.9, 126.0, 121.0, 119.8, 115.5, 111.4, 102.0, 55.4, 38.6, 37.4,
+
29.9, 23.2, 22.8. HRMS (ESI) calcd. for C17H20NO2 [M+H]+
270.1589, found 270.1507.
5.5.9.
3-(2-(7-cyano-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
5.5.14. 3-(2-(5-methyl-1H-pyrrol-2-yl)ethyl)cyclohex-2-en-1-one
(5n). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
to 70:30) to yield a yellow solid (54.2 mg, 0.266 mmol, 67%). 1H
NMR (600 MHz, CDCl3): δ 7.78 (br, s, 1H), 5.92 (s, 1H), 5.79-
5.78 (m, 1H), 5.76-5.75 (m, 1H), 2.77 (t, J = 7.8 Hz, 2H), 2.54 (t,
J = 7.8 Hz, 2H), 2.37 (dd, J = 6.6, 6.6 Hz, 2H), 2.30 (dd, J = 6.0,
6.0 Hz, 2H), 2.24 (s, 3H), 2.00 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H).
13C NMR (150 MHz, CDCl3): δ 200.0, 165.7, 129.4, 126.7,
125.9, 106.0, 105.5, 38.1, 37.5, 30.0, 25.5, 22.8, 13.1. HRMS
(5i). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 60:40
to 50:50) to yield a white solid (49.6 mg, 0.188 mmol, 47%). H
1
NMR (600 MHz, CDCl3): δ 8.27 (br, s, 1H), 7.51 (d, J = 7.8 Hz,
1H), 7.35 (d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 7.01 (dd, J = 7.8, 7.8
Hz, 1H), 5.96 (s, 1H), 2.96 (t, J = 7.8 Hz, 2H), 2.62 (t, J = 7.8
Hz, 2H), 2.37 (dd, J = 6.6, 6.6 Hz, 2H), 2.31 (dd, J = 6.0, 6.0 Hz,
2H), 1.98 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H). 13C NMR (150 MHz,
CDCl3): 200.0, 165.9, 141.2, 135.1, 128.5, 126.1, 124.6, 122.0,
120.6, 118.0, 116.5, 105.0, 38.4, 37.5, 30.0, 23.1, 22.8. HRMS
(ESI) calcd. for C17H17N2O+ [M+H]+ 265.1335, found 265.1355.
+
(ESI) calcd. for C14H21O2 [M+H]+ 221.1536, found 221.1539.
HRMS (ESI) calcd. for C13H18NO+ [M+H]+ 204.1383, found
204.1394
5.5.10.
3-(2-(5-bromo-1H-indol-3-yl)ethyl)cyclohex-2-en-1one
(5j). Synthesized according to the general procedure and purified
5.5.15. 3-(2-(5-methoxythiophen-2-yl)ethyl)cyclohex-2-en-1-one
(5o). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
by flash column chromatography (hexanes/ethyl acetate = 80:20
1
to 70:30) to yield a white solid (72.0 mg, 0.226 mmol, 57%). H
1
NMR (600 MHz, CDCl3): δ 8.24 (br, s, 1H), 7.69 (s, 1H), 7.26
(dd, J = 8.4, 1.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.97 (s, 1H),
5.93 (s, 1H), 2.92 (t, J = 7.8 Hz, 2H), 2.60 (t, J = 7.8 Hz, 2H),
2.37 (dd, J = 6.6, 6.6, Hz, 2H), 2.32 (dd, J = 6.0, 6.0 Hz, 2H),
1.99 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 200.1, 165.9, 135.0, 129.1, 126.2, 125.1, 122.7, 121.4,
114.9, 112.83, 112.78, 38.4, 37.5, 30.0, 22.84, 22.83. HRMS
(ESI) calcd. for C16H17BrNO+ [M+H]+ 318.0488, found
318.0506.
to 70:30) to yield a yellow oil (46.3 mg, 0.196 mmol, 49%). H
NMR (600 MHz, CDCl3): δ 6.37 (d, J = 3.6 Hz, 1H), 5.97 (d, J =
3.6 Hz, 1H), 5.89 (s, 1H), 3.84 (s, 3H), 2.88 (t, J = 7.8 Hz, 2H),
2.52 (t, J = 7.8 Hz, 2H), 2.35 (dd, J = 6.6, 6.6 Hz, 2H), 2.29 (dd,
J = 6.0, 6.0 Hz, 2H), 1.99 (ddd, J = 13.2, 6.6, 6.0 Hz, 2H). 13C
NMR (150 MHz, CDCl3): δ 199.8, 164.6, 164.5, 129.5, 126.4,
121.7, 103.1, 60.3, 39.8, 37.5, 29.9, 28.1, 22.8. HRMS (ESI)
calcd. for C13H17O2S+ [M+H]+ 237.0944, found 237.0957.
5.5.16. 3-(2-(4,5-dimethylfuran-2-yl)ethyl)cyclohex-2-en-1-one
(5p). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
to 70:30) to yield a colorless oil (41.9 mg, 0.192 mmol, 48%). 1H
NMR (600 MHz, CDCl3): δ 5.88 (s, 1H), 5.76 (s, 1H), 2.74 (t, J =
7.8 Hz, 2H), 2.51 (t, J = 7.8 Hz, 2H), 2.35 (dd, J = 6.6, 6.6 Hz,
2H), 2.28 (dd, J = 6.0, 6.0 Hz, 2H), 2.14 (s, 3H), 1.98 (ddd, J =
13.2, 6.6, 6.0 Hz, 2H), 1.87 (s, 3H). 13C NMR (150 MHz,
CDCl3): δ 199.9, 165.2, 151.2, 145.9, 126.1, 114.4, 108.8, 37.5,
36.6, 29.8, 25.7, 22.8, 11.4, 10.0. HRMS (ESI) calcd. for
C14H19O2+ [M+H]+ 219.1380, found 219.1388.
5.5.11. 3-(2-(7-bromo-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5k). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
1
to 70:30) to yield a white solid (61.8 mg, 0.194 mmol, 49%). H
NMR (600 MHz, CDCl3): δ 8.35 (br, s, 1H), 7.68 (s, 1H), 7.25
(d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 5.93
(s, 1H), 2.91 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 7.8 Hz, 2H), 2.37
(dd, J = 6.6, 6.6 Hz, 2H), 2.32 (6.0, 6.0 Hz, 2H), 1.98 (ddd, J =
12.6, 6.6, 6.0 Hz, 2H). 13C NMR (150 MHz, CDCl3): δ 200.2,
166.2, 135.0, 129.0, 126.1, 124.9, 122.8, 121.3, 114.7, 112.9,
112.6, 38.4, 37.4, 29.9, 22.8, 22.8. HRMS (ESI) calcd. for
C16H17BrNO+ [M+H]+ 318.0488, found 318.0505.
5.6. Experimental procedure for competition experiments
5.6.1. A competition experiment for generating heteroarylated
products 3d and 5a was carried out by the following procedure.
To a 1 dram vial was added Bi(OTf)3 (4.1 mg, 0.0063 mmol,
0.025 equiv) indole (29.3 mg, 0.25 mmol), 3-methyl-2-
cyclohexenone (55.1 mg, 0.500 mmol), 3-vinyl-2-cyclohexenone
(61.3 mg, 0.500 mmol), and acetonitrile/methanol (10:1) solution
5.5.12. 3-(2-(5-methoxy-1H-indol-3-yl)ethyl)cyclohex-2-en-1-one
(5l). Synthesized according to the general procedure and purified
by flash column chromatography (hexanes/ethyl acetate = 80:20
to 70:30) to yield a white solid (68.9 mg, 0.256 mmol, 64%). H
NMR (600 MHz, CDCl3): δ 8.13 (br, s, 1H), 7.24 (d, J = 8.4 Hz,
1

10
Tetrahedron
ACCEPTED MANUSCRIPT
(0.5 mL). The vial was sealed with a PFTE/silicone-lined
PFTE/silicone-lined septum cap. The reaction was heated to 60
septum cap. The reaction was heated to 60 °C and allowed to stir
at this temperature for 3 h. The mixture was cooled and
concentrated under reduced pressure. The crude reaction mixture
was concentrated under reduced pressure. The crude mixture was
dissolved in CDCl3 with CH2Br2 as the internal standard. The
°C and allowed to stir at this temperature for 10 h. The mixture
was cooled to room temperature, and passed through a short plug
of silica gel (eluting with 20 mL of ethyl acetate). The crude
reaction mixture was purified by flash column chromatography
on silica gel (hexanes/ethyl acetate = 80:20 to 70:30) to yield a
1
1
ratio of products 5a:3d was determined to be 8.4:1 by H NMR
white solid (19.8 mg, 0.0507 mmol, 51%). H NMR (600 MHz,
spectroscopy. The 1H NMR yields of 5a and 3d were determined
CDCl3): δ 7.88 (br, s, 1H), 7.63-7.61 (m, 4H), 7.47-7.44 (m, 4H),
7.38 (d, J = 7.8 Hz, 1H), 7.35 (m, 1H), 7.32 ( d, J = 7.8 Hz, 1H),
7.16 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H), 7.07 (ddd, J = 7.8, 7.2, 1.2
Hz, 1H), 6.88 (s, 1H), 3.12 (d, J = 14.4 Hz, 1H), 2.62 (d, J = 14.4
Hz, 1H), 2.57 (ddd, J = 13.2, 13.2, 4.8 Hz, 1H), 2.40-2.35 (m,
3H), 2.31-2.28 (m, 1H), 2.18 (ddd, J = 13.2, 13.2, 4.4 Hz, 1H),
2.13-2.04 (m, 2H), 1.93-1.88 (m, 1H), 1.73-1.66 (m, 1H). 13C
NMR (150 MHz, CDCl3): δ 211.5, 144.1, 140.8, 139.2, 136.4,
128.9, 127.4, 127.3, 127.13, 127.11, 127.10, 122.1, 121.0, 120.9,
118.8, 116.5, 111.2, 51.1, 46.3, 44.0, 41.2, 36.9, 21.7, 19.5.
HRMS (ESI) calcd. for C28H28NO+ [M+H]+ 394.2165, found
394.2169.
to be 67% and 8%, respectively.
5.6.2. A competition experiment for generating δ-heteroarylated
enones 5a and 5l was carried out by the following procedure. To
a 1 dram vial was added Bi(OTf)3 (16.4 mg, 0.0250 mmol, 0.10
equiv), indole (58.6 mg, 0.50 mmol), 5-methoxyindole (73.6 mg,
0.50 mmol), 3-vinyl-2-cyclohexenone (30.5 mg, 0.25 mmol), and
acetonitrile/methanol (10:1) solution (0.5 mL). The vial was
sealed with a PFTE/silicone-lined septum cap. The reaction was
heated to 60 °C and allowed to stir at this temperature for 3 h.
The mixture was cooled and concentrated under reduced
pressure. The crude reaction mixture was concentrated under
reduced pressure. The crude mixture was dissolved in CDCl3
with CH2Br2 as the internal standard. The ratio of products 5l:5a
Acknowledgments
1
1
was determined to be 1.9:1 by H NMR spectroscopy. The H
NMR yields of 5l and 5a were determined to be 21% and 11%,
respectively.
We thank the Research Corporation for Science
Advancement, Iowa State University, and the Iowa State
University Center for Catalysis for supporting this work.
5.6.3. A competition experiment for generating δ-heteroarylated
enones 5a and 5j was carried out by the following procedure. To
a 1 dram vial was added Bi(OTf)3 (16.4 mg, 0.0250 mmol, 0.10
equiv), indole (58.6 mg, 0.50 mmol), 5-bromoindole (98.0 mg,
0.50 mmol), 3-vinyl-2-cyclohexenone (30.5 mg, 0.25 mmol), and
acetonitrile/methanol (10:1) solution (0.5 mL). The vial was
sealed with a PFTE/silicone-lined septum cap. The reaction was
heated to 60 °C and allowed to stir at this temperature for 3 h.
The mixture was cooled and concentrated under reduced
pressure. The crude reaction mixture was concentrated under
reduced pressure. The crude mixture was dissolved in CDCl3
with CH2Br2 as the internal standard. The ratio of products 5a:5j
Supplementary data
Supplementary data associated with this article can be found
in the online version, at DOI:
References and notes
1. (a) Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron
2002, 58, 8373-8397. (b) Organobismuth Chemistry, Suzuki, H.,
Matano, Y. 2001, Eds.; Elsevier: Amsterdam.
2. For reviews on the use of bismuth(III) triflate in organic synthesis,
see: (a) Gaspard-Iloughmane, H.; Le Roux, C. Trends Org. Chem.
2006, 11, 65-80. (b) Salvador, J. A.; Silvestre, S. M.; Pinto, R. M.
Molecules 2011, 16 (4), 2884-913.
3. (a) Alam, M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett. 2003,
44 (27), 5115-5119. (b) Yadav, J. S.; Reddy, B. V. S.; Swamy, T.
Tetrahedron Lett. 2003, 44 (51), 9121-9124. (c) Wabnitz, T. C.;
Yu, J. Q.; Spencer, J. B., Chem. Eur. J. 2004, 10, 484-493.
4. (a) Van Zeeland, R.; Stanley, L. M. ACS Catal. 2015, 5, 5203-
5206. (b) Gerten, A. L.; Stanley, L. M. Tetrahedron Lett. 2016,
57, 5460-5463. (c) Kadam, A. A.; Ellern, A.; Stanley, L. M. Org.
Lett. 2017, 19, 4062-4065.
5. (a) Thakur, A.; Zhang, K.; Louie, J. Chem. Commun. 2012, 48,
203-205. (b) Fleckenstein, C. A.; Plenio, H. J. Org. Chem. 2008,
73, 3236-3244. (c) Cox, P. A.; Leach, A. G.; Campbell, A. D.;
Lloyd-Jones, G. C. J. Am. Chem. Soc. 2016, 138, 9145-9157.
6. Metz, T. L.; Evans, J.; Stanley, L. M. Org. Lett. 2017, 19, 3442-
3445.
1
1
was determined to be 3.7:1 by H NMR spectroscopy. The H
NMR yields of 5a and 5j were determined to be 11% and 3%,
respectively.
5.6.4. A competition experiment for generating δ-heteroarylated
enones 5j and 5l was carried out by the following procedure. To a
1 dram vial was added Bi(OTf)3 (16.4 mg, 0.0250 mmol, 0.10
equiv), 5-bromoindole (98.0 mg, 0.50 mmol), 5-methoxyindole
(73.6 mg, 0.50 mmol), 3-vinyl-2-cyclohexenone (30.5 mg, 0.25
mmol), and acetonitrile/methanol (10:1) solution (0.5 mL). The
vial was sealed with a PFTE/silicone-lined septum cap. The
reaction was heated to 60 °C and allowed to stir at this
temperature for 3 h. The mixture was cooled and concentrated
under reduced pressure. The crude reaction mixture was
concentrated under reduced pressure. The crude mixture was
dissolved in CDCl3 with CH2Br2 as the internal standard. The
7. Metz, T. L.; Lutovsky, G. A.; Stanley, L. M. J. Org. Chem. Just
Accepted Manuscript, DOI: 10.1021/acs.joc.7b03045
1
8.
(a) Reddy, V.; Anand, R. V. Org. Lett. 2015, 17, 3390-3393. (b)
Wang, Z.; Wong, Y. F.; Sun, J. Angew. Chem., Int. Ed. 2015, 54,
13711-13714. (c) Gao, S.; Xu, X.; Yuan, Z.; Zhou, H.; Yao, H.;
Lin, A. Eur. J. Org. Chem. 2016, 3006-3012. (d) Goswami, P.;
Anand, V. R. ChemistrySelect 2016, 1, 2556-2559. (e) Xie, K.-X.;
Zhang, Z.-P.; Li, X. Org. Lett. 2017, 19, 6708-6711.
ratio of products 5l:5j was determined to be 10.3:1 by H NMR
1
spectroscopy. The H NMR yields of 5l and 5j were determined
to be 41% and 4%, respectively.
5.7. Procedure for the palladium-catalyzed 1,4-addition of 4-
biphenylboronic acid to 3-(2-(1H-indol-3-yl)ethyl)cyclohex-2-
en-1-one 5a
9. Pearlman, B. A.; Padill, A. G.; Hach, J. T.; Havens, J. L.; Pillai,
M. D. Org. Lett. 2006, 8, 2111-2113.
10. Tabatabaeian, K.; Mamaghani, M.; Mahmoodi, N.; Khorshidi, A.
Synth. Commun. 2010, 40, 1677-1684.
5.7.1. 3-(2-(1H-indol-3-yl)ethyl)-3-phenylcyclohexan-1-one (6).
Prepared according to a modified literature procedure.10d To a 1
dram vial was added Pd(OCOCF3)2 (3.3 mg, 0.0100 mmol), 2,2′-
bipyridine (1.9 mg, 0.0120 mmol), 4-PhC6H4B(OH)2 (59.7 mg,
0.30 mmol), enone 5a (23.9 mg, 0.10 mmol, 1.0 equiv) and were
dissolved in dichloroethane (0.2 mL). The vial was sealed with a
11. (a) Dumeunier, D.; Markò, I. E. Tetrahedron Lett. 2004, 45, 825-
829. (b) Yamamoto, H.; Futatsugi, K., Angew. Chem., Int. Ed.
2005, 44, 7723-7725. (c) Ollevier, T.; Nadeau, E. Org. Biomol.
Chem. 2007, 5, 3126-3134. (d) Kwie, F. H. A. B.-D., C.; Blonski,
C.; Lherbet, C. Synth. Commun. 2010, 40, 1082-1087.

11
12. For reviews on 1,6-additions, see: (a) Cśakÿ, A. C.; Herrán, G.;
ACCEPTED MANUSCRIPT
Murcia, M. C. Chem. Soc. Rev. 2010, 39, 4080-4102. (b) Silva, E.
M. P.; Silva, A. M. S. Synthesis 2012, 44, 3109-3128. For related
examples of regioselective 1,6-conjugate additions, see: (c)
Hayashi, T.; Yamamoto, S.; Tokunaga, N. Angew. Chem., Int. Ed.
2005, 44, 4224-4227. (d) Fillion, E.; Wilsily, A.; Liao, E-T.
Tetrahedron: Asymmetry 2006, 17, 2957-2959. (e) Henon, H.;
Mauduit, M.; Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 9122-
9124.
13. Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;
Boubaker, T.; Ofial, R. A.; Mayr, H., J. Org. Chem. 2006, 71,
9088-9095.
14. For a review on palladium-catalyzed conjugate additions of
arylboronic acids for the construction of quaternary centers, see:
(a) Liu, Y.; Han, S. J.; Liu, W. B.; Stoltz, B. M. Acc. Chem. Res.
2015, 48, 740-751. For related examples of palladium-catalyzed
conjugate additions of aryl boronic acids, see: (b) Kikushima, K.;
Holder, J. C.; Gatti, M.; Stoltz, B. M. J. Am. Chem. Soc. 2011,
133, 6902-6905. (c) Holder, J. C.; Goodman, E. D.; Kikushima,
K.; Gatti, M.; Marziale, A. N.; Stoltz, B. M. Tetrahedron 2015,
71, 5781-5792. (d) Shockley, S. E.; Holder, J. C.; Stoltz, B. M.
Org. Process Res. Dev. 2015, 19, 974-981.
15. (a) Martin, J. A. N.; List, B. J. Am. Chem. Soc. 2006, 128, 13368-
13369. (b) Lifchifts, O.; Mahlau, M.; Reisinger, C. M.; Lee, A.;
Fares, C.; Polyak, I.; Gopakumar, G.; Thiel, W.; List, B. J. Am.
Soc. 2013, 135, 6677-6693. (c) Vuagnoux-d’Augustin, M.;
Alexakis, A. Chem. Eur. J. 2007, 13, 9647-9662.