Rate dependence on inductive and resonance effects for the organocatalyzed enantioselective conjugate addition of alkenyl and alkynyl boronic acids to β-indolyl enones and β-pyrrolyl enones

Article abstract of DOI:10.3390/molecules26061615

Two key factors bear on reaction rates for the conjugate addition of alkenyl boronic acids to heteroaryl-appended enones: the proximity of inductively electron-withdrawing heteroatoms to the site of bond formation and the resonance contribution of available heteroatom lone pairs to stabilize the developing positive charge at the enone β-position. For the former, the closer the heteroatom is to the enone β-carbon, the faster the reaction. For the latter, greater resonance stabilization of the benzylic cationic charge accelerates the reaction. Thus, reaction rates are increased by the closer proximity of inductive electron-withdrawing elements, but if resonance effects are involved, then increased rates are observed with electron-donating ability. Evidence for these trends in isomeric substrates is presented, and the application of these insights has allowed for reaction conditions that provide improved reactivity with previously problematic substrates.

Full text of DOI:10.3390/molecules26061615

molecules
Article
Rate Dependence on Inductive and Resonance Effects for the
Organocatalyzed Enantioselective Conjugate Addition of
Alkenyl and Alkynyl Boronic Acids to β-Indolyl Enones and
β-Pyrrolyl Enones
Amy Boylan 1 , Thien S. Nguyen 1,2, Brian J. Lundy 1,3, Jian-Yuan Li 1,4, Ravikrishna Vallakati 1,5
,
Sasha Sundstrom 1,6 and Jeremy A. May 1,
*
1
Department of Chemistry, University of Houston, 3585 Cullen Blvd., Fleming Building 112,
Houston, TX 77204-5003, USA; amy.boylan1@gmail.com (A.B.); thiensnguyen@gmail.com (T.S.N.);
brianjlundy@yahoo.com (B.J.L.); Jian-Yuan.Li@bcm.edu (J.-Y.L.); vallark@gmail.com (R.V.);
sasha.oley@gmail.com (S.S.)
Graduate School of Energy, Environment, Water and Sustainability (EEWS), Korea Advanced Institute of
Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea
Baker Hughes, 17021 Aldine Westfield Rd, Houston, TX 77073, USA
Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Vallark Pharma Pvt. Ltd., Genome Valley, Turkapally, Hyderabad 500078, India
Department of Chemistry and Biochemistry, Baylor Sciences Bldg. D.208, One Bear Place #97348,
Waco, TX 76798, USA
2
3
4
5
6
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Boylan, A.; Nguyen, T.S.;
Lundy, B.J.; Li, J.-Y.; Vallakati, R.;
Sundstrom, S.; May, J.A. Rate
Dependence on Inductive and
Resonance Effects for the
*
Correspondence: jmay@uh.edu; Tel.: +1-832-842-8808
Abstract: Two key factors bear on reaction rates for the conjugate addition of alkenyl boronic acids to
heteroaryl-appended enones: the proximity of inductively electron-withdrawing heteroatoms to the
site of bond formation and the resonance contribution of available heteroatom lone pairs to stabilize
the developing positive charge at the enone
is to the enone -carbon, the faster the reaction. For the latter, greater resonance stabilization
of the benzylic cationic charge accelerates the reaction. Thus, reaction rates are increased by the
closer proximity of inductive electron-withdrawing elements, but if resonance effects are involved,
then increased rates are observed with electron-donating ability. Evidence for these trends in isomeric
substrates is presented, and the application of these insights has allowed for reaction conditions that
provide improved reactivity with previously problematic substrates.
Organocatalyzed Enantioselective
Conjugate Addition of Alkenyl and
Alkynyl Boronic Acids to β-Indolyl
Enones and β-Pyrrolyl Enones.
Molecules 2021, 26, 1615.
β-position. For the former, the closer the heteroatom
β
https://doi.org/10.3390/
molecules26061615
Academic Editor: Marcelo
Daniel Preite
Keywords: enantioselective conjugate addition; heterocycles; pyrrole; indole
Received: 28 January 2021
Accepted: 8 March 2021
Published: 14 March 2021
1. Introduction
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Heteroaromatics routinely appear as key pharmacophores in small molecule drugs [1–5]
as common motifs in natural products [ ], and as important functional groups in ma-
terials [ ]. The ability to synthesize heteroaromatic systems attached to stereocenters is
,
6–8
9
becoming increasingly important, especially as greater three-dimensionality in compounds
is increasingly desired (Figure 1) [10–16].
Concordantly, many recent reports have described efforts to develop new strategies
and catalysts to synthesize heteroaryl-bearing stereocenters with absolute stereocontrol.
Copyright:
© 2021 by the authors.
To cite limited examples, transition metal-mediated couplings [17
tions [27 29], C—H functionalizations [30 35], Friedel–Crafts reactions [36
jugate additions have provided significant advances [87 107]. We have contributed to
this area by demonstrating that
-chiral heterocycles can be synthesized through 3,30-
(bisperfluoroaryl)-BINOL ( )-catalyzed conjugate addition of aryl, alkenyl, and alkynyl
boronic acids and trifluoroborate salts to -heteroaryl-appended enones and enals [87 90].
When heteroaryl trifluoroborate salts are used as nucleophiles, bis-heteroaryl stereocenters
–
26], Petasis-like reac-
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This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
–
–
–86], and con-
–
α
6
β
–
Molecules 2021, 26, 1615. https://doi.org/10.3390/molecules26061615
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1615
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are formed [90]. We have consistently encountered two problematic but synthetically
important substrates, however:
This was especially vexing as the
enantioselective synthesis of flinderole C (
β
-(2-indolyl)-enones and
-chiral indole was a proposed intermediate for an
). This report describes why these substrates
β-(pyrrolyl)-enones (Figure 2).
α
8
1
are problematic, how resonance effects impact the reaction rate and success, and how to
increase these substrates’ reactivity.
Figure 1. Examples of chiral heteroaromatic compounds.
Figure 2. Problematic substrates for organocatalyzed conjugate addition.
The use of boronate esters and boronic acids as nucleophiles in catalyzed conjugate
additions to enones dates to Suzuki [99
metal-catalyzed and organocatalyzed enantioselective versions of this reaction. For the lat-
ter cases, examples exist of BINOL-based ligands pioneered by Chong [113
116], h-hydroxy
acids reported by Sugiura [117 120], and thiourea catalysts from Takemoto [121]. Those re-
,108–112]. More recent efforts have led to transition
–
–
ports, however, primarily dealt with aryl-substituted stereocenter formation, and so they
offered little information on how to address heterocycle incorporation and the problematic
2-indole and 2-pyrrole substrates.
2. Results
In looking at data collected from the many heteroaromatic substrates that we had
examined, patterns emerged for how the point of enone attachment on furan, pyridine,
and imidazole rings affected the reaction rate (Figure 3). In the furanyl enone 11, where the
enone is attached at the 2-position, the conjugate addition reaction occurs in only 8 h,
while its counterpart, 12, which is attached at the 3-position, is not complete until 24 h.
Pellegrinet and Goodman established that the initial step in the organocatalyzed conjugate
addition mechanism is the formation of a discreet Lewis acid/base adduct between the
enone and the catalyst ligated boronate ester [118
resonance structures that stabilize the putative Lewis acid/base interaction for the 2- and
3-furan isomers (19 and 21, Figure 4) [122 123]. Since the difference in reaction rate was not
,122]. One may draw equally viable
,

Molecules 2021, 26, 1615
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readily correlated to resonance stabilization, we considered the possibility that proximity
to the furan oxygen played a role. Similarly, in β-pyridyl-enones, the reactivity does not
correlate to any typical resonance effects in that the 2-pyridine and 4-pyridine substrates do
not exhibit similar rates. Rather, the trend still appears correlated with the proximity of the
heteroatom to the reacting site, with 2-pyridyl 13 being formed within 3 h and 4-pyridyl
15 taking 21 h for complete reaction, which again implicates inductive electronic effects.
Recruitment of the Lewis acidic nucleophile by the pyridyl nitrogen in a similar manner to
Takemoto’s work [121] cannot be fully ruled out, either. For the imidazole substrates 16
and 17, similar resonance structures may be drawn for either isomer as seen for the furans,
so resonance effects did not explain the reactivity difference. Again, having more nitrogens
closer to the site of reactivity as seen in the 2-imidizole isomer gave a faster reaction than
for the 4-imidazole isomer. Taken together, these substrates suggest that proximity to the
inductively electron-withdrawing heteroatom in a heteroaromatic substituent accelerates
this conjugate addition. They also exhibited high levels of enantioselectivity.
Figure 3. Reaction times for series of heteroaromatic substrates.
Figure 4. Resonance stabilization of Lewis acid/base interactions.
However, the trend described in the previous paragraph is opposite to that for the
indole-substituted enones, where the high-performing 3-indole substrates bear the nitrogen
further from the enone
Moreover, inconsistent and unpredictable yields of
thought for the discrepancy was that the enone
3-positions, which would increase steric repulsion at the reactive site. However, con-
trol experiments with 22 25 in Figure 6 dispelled that notion, as the inferior reactivity was
β
-carbon than the poor-performing 2-indolo-enones (Figure 5).
were routinely obtained. An early
has substitution at both the 2- and
8
7
–

Molecules 2021, 26, 1615
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clearly due to the indole position of substitution and therefore more likely to be due to
the system’s electronics. We reasoned that for these substrates, resonance effects might
have played a larger role than the inductive effects seen in Figure 3. A relationship study
for resonance effects and reaction rates using a Hammett plot analysis of aryl-substituted
enones shed some mechanistic insight on what may have been occurring for the indole
substrates [124]. In that study, a clear Hammett parameter correlation was seen for electron-
donating substituents on the β-aromatic ring accelerating the reaction, which suggested
that the stabilization of the benzylic cationic charge in 27b increased the reaction rate,
likely because the formation of zwitterionic intermediate 27a is necessary for the reaction
(Figure 6). While the resonance structures for charge stabilization for the 2/3-furan and
2/4-imidazole substrates were similar, those for the indoles 28 and 30 are quite different
in relative energy because of the additional fused aromatic ring. The 3-indoloenone can
stabilize the charge with the resonance structure 29b, which maintains the aromaticity in
the fused benzene ring, but similar resonance stabilization in the 2-indoloenone 31b would
require the loss of aromaticity. This phenomenon is the reason behind the well-established
Friedel–Crafts reactivity patterns seen for indoles, where electrophilic substitution pref-
erentially occurs at the 3-position, and would also make the enone 28 more Lewis basic
than 30. To compensate for this energy difference, we proposed that we needed to make
the 2-indoles more electron-rich for the key Lewis acid/base interaction illustrated in 31a
.
Figure 5. Indole control experiments.
We also looked more closely at the problems with pyrrole substrates. Control exper-
iments showed that the issues stemmed both from high reactivity found in the starting
materials and even greater instability of the products. As evidence of the latter, when pure
ketone
9 was reintroduced to the reaction conditions, it readily decomposed. When the
starting material alone was stirred with the base and no other reactants, it also formed a
new unstable product which could not be isolated or fully characterized. After the conju-
gate addition, the pyrrole in 32 is electron-rich and nucleophilic, has no protecting group,
and bears no steric blocking groups (Figure 7). Various side reactions were consequently
seen, such as a pyrrole nitrogen attack on the ketone carbonyl, forming a cyclized product
that could be observed in the NMR of the crude reaction mixture but was not stable enough
to isolate [19,20]. The Lewis acidic catalyst complex was thought to be promoting the side
reactions, and so a less electron-deficient BINOL catalyst was sought as well as milder
reaction conditions.
Initially, we thought that a base additive could deprotonate the hydrogen of the pyrrole
or indole substituent, at least partially, which would result in a greater electron density
in the ring [124,125]. That electron density would then in turn be donated to activate the
enone as in Figure 8. As a result, we evaluated a variety of bases to test this theory (Table 1).
Note that in the original conditions reported for boronic acid nucleophiles (see Figure 2),

Molecules 2021, 26, 1615
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Mg(Ot-Bu)2 is used only in sufficient quantities to deprotonate the catalyst. Moreover,
t-BuOH replicated its effects, suggesting that their function was most likely to serve as
a proton transfer agent. The Mg salt was usually slightly better, so metal coordination
or pH adjustment may play a role in those conditions. Regardless, Mg(Ot-Bu)2 did not
provide useful reactivity for 2-indole substrates (22 and 23, Figure 5). The carbonate bases
generally outperformed the other bases in 24 h of reaction (entries 2–6). More soluble bases,
such as Cs2CO3 and Na2CO3, produced less of the conjugate addition product compared
to a less soluble base, such as (NH4)2CO3 (entries
(NH4)2CO3 to dissolve in the solution. Bases that were stronger also resulted in a significant
decrease in yield (entry , and 17). Overall, the use of a full equivalent of (NH4)2CO3 and
3–6). It usually took several hours for the
8, 9
3,3’-diiodo-BINOL (34, Table 1) as a catalyst significantly addressed the deficient reactivity
of the indole substrates and the hyper-reactivity of the pyrrole compounds.
Figure 6. Stabilization of the zwitterionic intermediate.
Figure 7. Pyrrole problems.
Figure 8. Pyrrole substrates (NMR spectra and HPLC data in Supplementary Materials).

Molecules 2021, 26, 1615
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Table 1. Optimizations of additives with 2-pyrrolyl enone. 0.20 mmol 27 with 0.02 mmol catalyst
(20 mol %), 0.4 mmol of boronic acid, 0.4 mmol additive, 100 mg 4 Å MS, and 4 mL PhMe, stirred at
reflux for 24 h.
Entry
Additive
Yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Mg(Ot-Bu)2
(NH4)2CO3
K2CO3
Cs2CO3
Li2CO3
Na2CO3
K3PO4
NaHMDS
LiHMDS
KOH
10%
64%
53%
35%
29%
4%
34%
13%
6%
5%
4%
4%
3%
NaOH
KOt-Bu
NaOt-Bu
LiOt-Bu
NH4Cl
NH4HSO4
DBU
0%
2%
0%
3%
Since (NH4)2CO3 showed much better outcomes for the pyrrole substrate, we tested
those conditions on a variety of indoles and pyrroles, which provided a variety of interest-
ing results (Figure 8). We found that when we protected the unsubstituted 2-pyrrolyl-enone
34, we obtained nearly identical results to the unprotected version (33). This outcome in-
validated our initial hypothesis for the role of a base in deprotonating an indole or pyrrole
nitrogen. We also found that as more substituents were incorporated onto the pyrrole,
the desired reactivity faltered (35–37). In a control experiment, when the purified products
were reintroduced into the reaction conditions, they decomposed. Another indication of
how reactive these substituted pyrrole substrates are is that they decompose in ambient
lighting more quickly than the unsubstituted starting material 9. Due to this high reac-
tivity, the most substituted products are not stable enough to be isolated in useful yield.
Another possibility for decreased conjugate addition yields could be a result of sterics.
As more substituents are added to the ring, especially at the 3-position of the pyrrole,
the sterics of these substituents could be causing allylic strain, inhibiting the conjugate
addition reaction, and allowing more time for side reactions and decomposition to occur.
A similar trend with pyrroles has been observed by the Qiu group [124].
A control experiment of stirring the pyrrolyl-enone with just (NH4)2CO3 in toluene
without light at 90 ◦C without a catalyst or organoboron nucleophile resulted in an un-
wanted reaction that produced a side product too unstable to isolate. This indicated to us
that the base has both an advantageous effect on the conjugate addition and an adverse ef-
fect on the starting material stability, creating a conflicted system. Typically, trifluoroborate
salts work better in conjugate addition reactions because of their prolonged stability over
their boronic acid counterparts [124]. Interestingly, though, in all of the pyrrole substrates
(Figure 10) and some of the indole substrates (Figure 9), the boronic acids resulted in higher
yields than their trifluoroborate counterparts. These findings led us to believe the base,
(NH4)2CO3, could also be helping to promote boroxine formation from the boronic acid
or maintain a favorable pKa for the conjugate addition reaction to occur. For the indole
substrates in Figure 9, (NH4)2CO3 also improved the yield for the conjugate addition

Molecules 2021, 26, 1615
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product. The unsubstituted indoles 28 and 39 resulted in moderate yields with both the
boronic acid and trifluoroborate salt. The mono-substituted indoles 40 and 41 resulted in
better yields when the trifluoroborate salt nucleophile was used compared to when the
boronic acid was used. Both the pyrrole and indole products were formed with excellent
enantioselectivity (Figures 8 and 9).
Figure 9. Indole substrates (NMR spectra and HPLC data in Supplementary Materials).
A variety of alkenyl boronic acids also show compatibility with these reaction condi-
tions with the problematic 2-pyrroyl-enone (Figure 10). In most cases, the products that
were formed in fair to good yields show excellent enantioselectivity (44–48).
Figure 10. 2-pyrrolyl-enone with boronic acids (NMR spectra and HPLC data in Supplementary Materials).
3. Conclusions
Two problematic series of substrates, β-(2-indole)-enones and β-(2-pyrrole)-enones,
were thoroughly examined in the enantioselective organocatalyzed conjugate addition of
alkenyl boronic acids or trifluoroborates. Analysis of isomer-related reaction rate trends
showed that (1) the proximity of a heteroatom to the enone β-carbon was favorable to the
reaction rate and (2) increased resonance electron donation also increased the reaction rate.
The use of (NH4)2CO3 promoted the conjugate addition reaction better than Mg(Ot-Bu)2
or other additives. The use of a less electron-deficient catalyst in conjunction with the new

Molecules 2021, 26, 1615
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base minimized side product formation and provided the most advantageous environment
for the conjugate addition to sensitive substrates to date.
4. Materials and Methods
4.1. Materials
Commercially available compounds were purchased from Aldrich (Burlington, MA,
USA), Acros (Geel, Belgium), Alfa Aesar (Ward Hill, MA, USA), Ark Pharm (Chicago, IL,
USA), and Combi-block (San Diego, CA, USA) and were used without further purification.
4.2. General Considerations
All reactions were carried out in flame- or oven-dried glassware. THF, toluene, and
CH2Cl2 were purged with argon and dried over activated alumina columns. Flash chro-
matography was performed on 60 Å silica gel (EMD Chemicals Inc (St. Louis, MO, USA)).
Preparative plate chromatography was performed on EMD silica gel plates, 60 Å, with
UV-254 indicator. Chemical names were generated using Cambridge Soft ChemBioDraw
Ultra 12.0. Analysis by HPLC was performed on a Shimadzu Prominence LC (LC-20AB)
equipped with an SPD-20A UV-Vis detector and a Chiralpak or Chiralcel (250
column (see below for column details). Analytical thin layer chromatography was per-
×
4.6 mm)
1
formed on EMD silica gel/TLC plates with a fluorescent detector at 254 nm. The H
and 13C-NMR spectra were recorded on a JEOL ECA-600, JEOL ECA-500, or ECX-400P
spectrometer using residual solvent peak as an internal standard (CDCl3: 7.26 ppm for
1H-NMR and 77.0 ppm for 13C-NMR; C6D6: 7.15 ppm for 1H-NMR and 128.6 ppm for
13C-NMR).
HPLC Columns for Separation of Enantiomers:
Chiralpak AY-3: Amylose tris-(5-chloro-2-methylphenylcarbamate) coated on 3
silica gel; Chiralpak AD-H: Amylose tris-(3,5-dimethylphenylcarbamate) coated on 5
silica gel; Chiralpak ID: Amylose tris-(3-chlorophenylcarbamate) immobilized on 5
µm
µm
µm
silica gel; Chiralcel OJ-H: Cellulose tris-(4-methylbenzoate) coated on 5
µm silica gel;
Chiralcel OD-H: Cellulose tris-(3,5-dimethylphenylcarbamate) coated on 5
µm silica gel;
Chiralpak AS-H: Amylose tris-[(S)-α-methylbenzylcarbamate) coated on 5 µm silica gel.
(E)-4-(furan-2-yl)but-3-en-2-one(11) [48], (E)-4-(furan-3-yl)but-3-en-2-one(12) [48], (E)-4-
(pyridin-2-yl)but-3-en-2-one (13) [48], (S)-6-methyl-4-(pyridin-3-yl)hept-5-en-2-one(14) [48],
(S)-6-methyl-4-(pyridin-4-yl)hept-5-en-2-one (15) [48], (S)-4-(1H-imidazol-2-yl)-6-methylhept-
5-en-2-one (16) [48], (S)-4-(1H-imidazol-5-yl)-6-methylhept-5-en-2-one (17) [48],(E)-4-(1H-pyrrol-
2- yl)but-3-en-2-one [48],(E)-4-(1-benzyl-1H-pyrrol-2-yl)but-3-en-2-one [89],(E)-4-(1H-indol-3-
yl)but-3-en-2-one and Benzyl (E)-(2-(2-(3-oxobut-1-en-1-yl)-1H-indol-3-yl)ethyl)carbamate [87],
benzyl (S,E)-(2-(2-(5-oxo-1-phenylhex-1-en-3-yl)-1H-indol-3-yl)ethyl)carbamate [87], tert-
butyl (S,E)-3-(2-(((benzyloxy)carbonyl)amino)ethyl)-2-(5-oxo-1-phenylhex-1-en-3-yl)-1H-
indole-1- carboxylate [87], 1,2 (E)-4-(1H-indol-2-yl)but-3-en-2-one (30) [87], (E)-4-(1H-
pyrrol-3-yl)but-3-en-2-one [87], (S)-4-(1H-indol-2-yl)-6-methylhept-5-en-2-one (22) [87], (S)-
6-methyl-4-(1H-pyrrol-2-yl)hept-5-en-2-one (10) [87], (S)-4-(1H-indol-2-yl)-6-methylhept-
5-en-2-one, (S,E)-4-(1H-indol-3-yl)-6-phenylhex-5-en-2-one(67) [87], benzyl (S,E)-(2-(2-(5-
oxo-1-phenylhex-1-en-3-yl)-1H-indol-3-yl)ethyl)carbamate (42) [48], tert-butyl (S,E)-3-(2-
(((benzyloxy)carbonyl)amino)ethyl)-2-(5-oxo-1-phenylhex-1-en-3-yl)-1H-indole-1- carboxy-
late(43) [87], (S,E)-6-phenyl-4-(1H-pyrrol-2-yl)hex-5-en-2-one (33) [89], (S,E)-4-(1H-indol-2-
yl)-6-phenylhex-5-en-2-one (39) [48], and (E)-4-(1-benzyl-1H-pyrrol-2-yl)but-3-en-2-one [48
]
were synthesized following literature procedures.
4.3. General Procedure for the Synthesis of Starting Materials (Enone)
Carboxaldehyde (2 mmol), 1-(triphenylphosphoranylidene)-2-propanone (1.2 equiv,
764 mg), and toluene (4 mL) were added to a flask equipped with a stir bar and a condenser.
The reaction mixture was refluxed for 10 h. After completion, the reaction mixture was
concentrated via rotary evaporation. The crude mixture was purified via flash column
chromatography with an appropriate eluent on silica gel.

Molecules 2021, 26, 1615
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4.3.1. (E)-4-(5-methyl-1H-pyrrol-2-yl)but-3-en-2-one
See the general procedure for enone formation above; in addition, the reaction was
shielded from light by covering the reaction and product with aluminum foil. The product
will decompose in prolonged exposure to light. An amount of 1 g of 5-methyl-1H-pyrrole-
2-carbaldehyde was used. The crude reaction mixture was purified via flash column
chromatography with a 10–20% gradient of ethyl acetate in hexanes as eluent on silica gel.
Yield: 56%
1H-NMR (500 MHz, chloroform-D)
δ 8.45 (s, 1H), 7.51 (d, J = 16.0 Hz, 1H), 7.08 (s, 1H),
6.82 (s, 1H), 6.48−6.43 (m, 2H), 2.32 (s, 3H)
1H-NMR (600 MHz, Benzene-D6)
1.96 (s, 3H), 1.33(s, 3H).
δ
7.18 (s, 2H), 6.39 (s, 1H), 6.34 (s, 1H), 5.93 (s, 1H),
δ 198.6, 133.6, 121.4, 119.1, 117.6 113.3, 110.8, 110.0,
13C-NMR (126 MHz, chloroform-D)
31.3, 13.9
IR(neat): 3283, 1613, 1560, 1477, 1423, 1358, 1263, 959, 764, 700, 489 cm−1
HRMS-ESI m/z Calculated for C9H11NO [M + H]+ 150.0913, found 150.0916.
4.3.2. (E)-4-(3,5-dimethyl-1H-pyrrol-2-yl)but-3-en-2-one
See the general procedure for enone formation above; in addition, the reaction was
shielded from light by covering the reaction and product with aluminum foil. The product
will decompose in prolonged exposure to light. An amount of 1 g of 3,5-dimethyl-1H-
pyrrole-2-carbaldehyde was used. The crude reaction mixture was purified via flash
column chromatography with a 10–20% gradient of ethyl acetate in hexanes as eluent on
silica gel. Yield: 70%
1H-NMR (400 MHz, chloroform-D)
δ 8.53 (s, 1H), 7.41 (d, J = 15.6 Hz, 1H), 6.16 (d,
J = 16.0 Hz, 1H), 5.89 (d, J = 17.8 Hz, 1H), 2.29 (d, J = 11.2 Hz, 6H), 2.18 (s, 3H), 1.80 (s, 2H)
13C-NMR (101 MHz, chloroform-D)
13.5, 11.5
δ 198.4, 131.1, 130.6, 127.2, 112.3, 111.2, 31.1, 13.8,
IR (neat): 3292, 3246, 1600, 1559, 1433, 1358, 1258, 953, 839, 785, 711, 668 cm−1
HRMS-ESI m/z Calculated for C10H13NO [M + Na]+ 290.1515, found 290.1525.
4.3.3. (E)-4-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)but-3-en-2-one
See the general procedure for enone formation above; in addition, the reaction was
shielded from light by covering the reaction and product with aluminum foil. The product
will decompose in prolonged exposure to light. An amount of 1 g of 4-ethyl-3,5-dimethyl-
1H-pyrrole-2-carbaldehyde was used. The crude reaction mixture was purified via flash
column chromatography with a 10–20% gradient of ethyl acetate in hexanes as eluent on
silica gel. Yield: 55%
IR(neat): 3254, 2961, 2912, 2855, 1612, 1570, 1444, 1253, 950 cm−1
.
HRMS-ESI m/z Calculated for C12H17NO [M + H]+ 192.1383, found 192.1386.
4.3.4. (E)-4-(3-methyl-1H-indol-2-yl)but-3-en-2-one
A mixture of 3-methyl-1H-indole-2-carbaldehyde (0.1 mmol), but-3-yn-2-one (0.15 mmol),
and Sc(OTf)3 (10 mol%) in MeCN (0.5 mL) was stirred at 21 ◦C for the appropriate time.
After complete conversion, as indicated by TLC, the reaction mixture was diluted with
H2O and extracted with EtOAc. The combined organic layers were dried over MgSO4,
concentrated in vacuo, and purified by column chromatography with a 5–30% gradient of
ethyl acetate in hexanes as eluent on silica gel.
1H-NMR (500 MHz, chloroform-D):
δ 8.60 (brs, NH), 7.66 (d, J = 16.5 Hz, 1H), 7.58 (d,
J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H) 7.29–7.25 (m, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.50 (d,
J = 16.5 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H).
13C-NMR (125 MHz, chloroform-D):
119.9, 119.9, 111.1, 27.4, 9.0.
δ 198.1, 137.7, 131.1, 129.9, 129.0, 125.4, 122.8, 119.9,
IR(neat): 3299, 1634, 1598, 1257, 1235, 953, 747, 622, 459 cm−1
.
HRMS-ESI m/z Calculated for C13H13NO [M + H]+ 200.1070, found 200.1072.

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4.4. Procedure for Boronic Acid Synthesis: 2-Methylprop-1-Enylboronic Acid
LiCl (1.008 g, 24 mmol, 1.2 equiv) was added to a 250 mL flask and the flask was
flame dried under high vacuum. The flask was then back filled with argon. Then, 0.5 M
2-Methyl-1-propenyl magnesium bromide in THF (◦40 mL, 20 mmol, 1.0 equiv) and Et2O
78 C. Trimethyl borate (2.5 mL, 22 mmol,
(50 mL) were added. The solution was cooled to
−
1.1 equiv) was added dropwise and the reaction was allowed to slowly warm to room
temperature and stir overnight. The next day, it was quenched with 1 M HCl (30 mL) until
the reaction mixture became clear and then stirred for 1 h. It was then extracted with Et2O
(3 times) and washed with sat. aqueous NaHCO3 and brine solution. The organic layer
was dried with Na2SO4 and then concentrated via rotary evaporation. The crude solid was
purified via column chromatography with a 20–30% gradient of ethyl acetate in hexanes as
eluent on silica gel to afford a white solid (1.105 g, 11.06 mmol, 55% yield). All spectral
properties were identical to those reported in the literature.
4.5. General Procedure for 1,4-Conjugate Addition (Mg(t-BuO)2 as Additive)
Here, 4 Å powdered molecular sieves (100 mg) were added to a flask equipped with
a stir bar and a condenser and the flask was flame dried under high vacuum. The flask
was then back filled with argon. The heterocycle-appended enone (0.2 mmol, 1.0 equiv),
Mg(t-BuO)2 (3.4 mg, 0.02 mmol, 0.1 equiv), boronic acid (3 equiv), and BINOL catalyst
(0.04 mmol, 0.2 equiv) were then added. Freshly dried toluene (4 mL) was added and the
reaction was heated to reflux in a 70–78 ◦C oil bath and allowed to stir at this temperature
(see each product for specific reaction times). After completion, methanol was added and
the reaction mixture was concentrated via rotary evaporation. The crude reaction mixture
was then dry loaded onto silica gel and purified via flash column chromatography on silica
gel with appropriate eluents. All spectral properties.
(S)-6-methyl-4-(1H-pyrrol-2-yl)hept-5-en-2-one (10)
1H-NMR (400 MHz, chloroform-D):
δ 8.41 (brs, NH), 6.66 (dd, J = 4.0, 2.4 Hz, 1H), 6.11 (dd,
J = 5.6, 2.8 Hz, 1H), 5.89–5.88 (m, 1H), 5.27–5.24 (m, 1H), 4.11 (ddd, J = 9.5, 6.8, 6.8 Hz, 1H),
2.89 (dd, J = 17.2, 7.6 Hz, 1H), 2.73 (dd, J = 17.2, 6.0 Hz, 1H), 2.14 (s, 3H), 1.75 (d, J = 1.6 Hz,
3H), 1.70 (d, J = 1.6 Hz, 3H).
13C-NMR (125 MHz, chloroform-D):
32.4, 30.6, 25.8,18.0.
δ 208.8, 134.5, 133.4, 125.0, 116.5, 108.0, 103.8, 50.0,
4.6. General Procedure for 1,4-Conjugate Addition ((NH4)2CO3 as an Additive)
Here, 4 Å powdered molecular sieves (100 mg) were added to a flask equipped with
a stir bar and a condenser and the flask was flame dried under high vacuum. The flask
was then back filled with argon. The heterocycle-appended enone (0.2 mmol, 1.0 equiv),
(NH4)2CO3 (38 mg, 0.4 mmol, 2.0 equiv), boronic acid (2 equiv), and BINOL catalyst
(0.04 mmol, 0.2 equiv) were then added. Freshly dried toluene (4 mL) was added and
◦
the reaction was heated to 90 C in an oil bath and allowed to stir at this temperature
for 24 h. After completion, the reaction mixture was concentrated via rotary evaporation.
The crude reaction mixture was then dry loaded onto silica gel and purified via flash
column chromatography on silica gel with eluents of 10–30% ethyl acetate in hexanes.
(S,E)-4-(3-methyl-1H-indol-2-yl)-6-phenylhex-5-en-2-one(40)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–30% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (500 MHz, chloroform-D)
δ 8.31 (s, 1H), 7.67 (d, J = 16.0 Hz, 1H), 7.59 (d, J = 8.0 Hz,
1H), 7.35–7.27 (m, 2H), 7.12 (t, J = 7.4 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 3.50 (s, 1H), 2.45 (s,
3H), 2.41 (s, 3H), 1.36–1.25 (m, 1H)
13C-NMR (101 MHz, chloroform-D)
δ
184.5, 138.9, 128.6, 128.4, 127.6, 126.5, 125.8, 124.9,
124.3, 122.9, 121.2, 110.6, 108.7, 74.5, 35.5, 19.0, 13.3
IR(neat): 3090, 3070, 3035, 1477, 1034, 669 cm−1
.

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HRMS-ESI m/z Calculated for C21H21NO [M + Na]+ 326.1515, found 326.1518.
(S,E)-4-(2-methyl-1H-indol-3-yl)-6-phenylhex-5-en-2-one(41)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–30% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (600 MHz, Benzene-D)
δ 7.60 (d, J = 7.6 Hz, 1H), 7.17–7.11 (m, 5H), 7.01 (t,
J = 7.2 Hz, 3H), 6.94 (t, J = 7.2 Hz, 1H), 6.50 (dd, J = 15.8, 5.5 Hz, 1H), 6.40 (d, J = 15.8 Hz,
1H), 6.36 (s, 1H), 4.40 (q, J = 6.4 Hz, 1H), 2.87 (q, J = 8.5 Hz, 1H), 2.57 (dd, J = 16.5, 5.5 Hz,
1H), 2.06 (s, 3H), 1.44 (s, 3H)
13C-NMR (101 MHz, chloroform-D)
δ 208.0, 135.5, 132.2, 129.3, 128.5, 128.4, 127.1, 126.3,
121.0, 119.3, 119.2, 110.6, 48.2, 35.1, 30.9, 12.2.
IR(neat): 3091, 3071, 3035, 1477, 1035, 668 cm−1
.
HRMS-ESI m/z Calculated for C21H21NO [M + H]+ 326.1515, found 326.1520.
(S,E)-4-(5-methyl-1H-pyrrol-2-yl)-6-phenylhex-5-en-2-one (35)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–30% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (400 MHz, chloroform-D)
δ 8.04 (s, 1H), 7.36–7.28 (m, 4H), 7.23 (d, J = 6.6 Hz, 1H),
6.48 (d, J = 16.2 Hz, 1H), 6.30 (q, J = 7.9 Hz, 1H), 5.78 (d, J = 11.4 Hz, 2H), 4.05–4.01 (m, 1H),
3.03–2.89 (m, 2H), 2.22 (s, 3H), 2.17 (s, 3H)
13C-NMR (101 MHz, chloroform-D)
δ 208.2, 131.8, 130.8, 130.5, 128.7, 128.4, 127.6, 127.3,
126.4, 105.7, 104.7, 48.9, 37.0, 30.8, 13.1.
IR(neat): 3090, 3070, 3035, 1959, 1814, 1477, 1034, 668 cm−1
.
HRMS-ESI m/z Calculated for C17H19NO [M + Na]+ 276.1359, found 276.1358.
(S,E)-4-(3,5-dimethyl-1H-pyrrol-2-yl)-6-phenylhex-5-en-2-one (36)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–30% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (400 MHz, chloroform-D)
δ 7.86 (s, 1H), 7.36–7.28 (m, 5H), 7.22–7.18 (m, 1H),
6.36 (d, J = 2.3 Hz, 1H), 5.65 (s, 1H), 4.07 (dd, J = 11.5, 6.3 Hz, 1H), 2.94 (d, J = 6.4 Hz, 2H),
2.19 (s, 3H), 2.13 (s, 3H), 2.02 (s, 3H).
13C-NMR (101 MHz, chloroform-D)
δ 208.2, 137.1, 130.8, 129.7, 128.6, 127.4, 126.3, 126.0,
114.6, 108.2, 48.5, 35.5, 30.7, 29.8, 13.1, 11.2
IR(neat): 3090, 3070, 3035, 1959, 1814, 1477, 1034, 668 cm−1
.
HRMS-ESI m/z Calculated for C18H21NO [M + Na]+ 290.1515, found 290.1525.
(S,E)-4-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-6-phenylhex-5-en-2-one(37)
See the general procedure for enone formation above. The crude reaction mixture
could not be purified, so an NMR standard, 4-methylnitrobenzoate, was used to obtain
the yield. All reactants were added to the reaction mixture along with 0.1 mmol of 4-
methylnitrobenzoate. The aryl peaks for the 4-methylnitrobenzoate were compared with
the typical quartet around 4.0–4.4 ppm, indicating that the beta-bond formed during the
conjugate addition reaction.
(S,E)-6-phenyl-4-(1H-pyrrol-3-yl)hex-5-en-2-one (38)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–30% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (500 MHz, chloroform-D)
δ 8.08 (s, 1H), 7.34 (d, J = 7.4 Hz, 2H), 7.28 (d, J = 7.4 Hz,
2H), 7.18 (t, J = 7.2 Hz, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 6.42 (d, J = 15.5 Hz, 1H), 6.30 (q,
J = 7.8 Hz, 1H), 6.13 (s, 1H), 4.03 (q, J = 7.3 Hz, 1H), 2.86 (qd, J = 15.8, 7.2 Hz, 2H), 2.12 (s, 3H).
13C-NMR (151 MHz, Benzene-D)
δ
204.4, 138.7, 137.3, 133.6, 132.1, 129.9, 128.5, 128.4, 128.3,
128.0, 127.9, 127.8, 127.6, 127.3, 127.2, 126.6, 126.3, 121.7, 107.6, 106.1, 50.1, 48.3, 35.3, 29.7

Molecules 2021, 26, 1615
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IR(neat): 3090, 3080, 3035, 1959, 1814, 1477, 1034, 668 cm−1
.
HRMS-ESI m/z Calculated for C16H17NO [M + Na]+ 262.1202, found 262.1208.
(S,E)-4-(1H-pyrrol-2-yl)-6-(p-tolyl)hex-5-en-2-one (44)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–20% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (600 MHz, Benzene-D)
δ 7.52 (s, 1H), 7.29–7.22 (m, 2H), 7.12 (t, J = 7.6 Hz, 2H),
7.06–7.03 (m, 1H), 6.38–6.23 (m, 2H), 5.98 (d, J = 2.7 Hz, 2H), 3.95 (q, J = 6.9 Hz, 1H),
2.53–2.34 (m, 2H), 1.93 (t, J = 15.5 Hz, 3H), 1.58 (s, 3H)
13C-NMR (151 MHz, Benzene-D)
δ 206.0, 134.7, 132.9, 130.2, 129.3, 128.3, 127.9, 127.8, 127.6,
126.4, 116.9, 108.2, 104.9, 48.6, 36.8
IR(neat): 3380, 3022, 2920, 1706, 1512, 1358, 967, 794, 720 cm−1
.
HRMS-ESI m/z Calculated for C17H19NO [M + Na]+ 276.1359, found 276.1361.
(S,E)-6-([1,10-biphenyl]-4-yl)-4-(1H-pyrrol-2-yl)hex-5-en-2-one (45)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–20% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (600 MHz, Benzene-D)
δ 7.72 (s, 1H), 7.47 (dd, J = 23.7, 7.9 Hz, 4H), 7.27 (d,
J = 8.2 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 6.9 Hz, 1H), 6.41–6.24 (m, 4H), 6.09 (s, 1H)
3.97 (q, J = 6.9 Hz, 1H), 2.48 (q, J = 8.2 Hz, 1H), 2.35 (dd, J = 17.2, 6.2 Hz, 1H), 1.56 (s, 3H)
,
13C-NMR (151 MHz, chloroform-D) 208.2, 130.7, 128.9, 127.4, 127.0, 126.8, 117.3, 108.2, 104.7,
100.0, 77.3, 77.1, 76.9, 74.8, 49.0, 36.9, 11.3
IR(neat): 3334, 3027, 2925, 1697, 964, 720, 691 cm−1
.
HRMS-ESI m/z Calculated for C22H21NO [M + Na]+ 338.1515, found 338.1520.
(S,E)-4-(1H-pyrrol-2-yl)-6-(4-(trifluoromethyl)phenyl)hex-5-en-2-one (46)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–20% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (600 MHz, Benzene-D)
δ 7.72 (s, 1H), 7.47 (dd, J = 23.7, 7.9 Hz, 4H), 7.27 (d,
J = 8.2 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 6.9 Hz, 1H), 6.41–6.24 (m, 4H), 6.09 (s, 1H)
3.97 (q, J = 6.9 Hz, 1H), 2.48 (q, J = 8.2 Hz, 1H), 2.35 (dd, J = 17.2, 6.2 Hz, 1H), 1.56 (s, 3H)
,
13C-NMR (151 MHz, chloroform-D)
δ 208.0, 133.4, 132.7, 129.4, 126.5, 125.6, 117.4, 108.2,
104.9, 77.3, 77.1, 76.9, 76.8, 48.9, 36.8, 30.7
IR(neat): 3407, 2924, 1704, 1363, 1325, 1222, 529 cm−1
HRMS-ESI m/z Calculated for C17H16F3NO [M + H]+ 308.1257, found 308.1254.
(S,E)-4-(1H-pyrrol-2-yl)non-5-en-2-one (47)
See the general procedure for enone formation above. The crude reaction mixture
was purified via flash column chromatography with a 10–20% gradient of ethyl acetate in
hexanes as eluent on silica gel.
1H-NMR (600 MHz, chloroform-D)
δ 8.38 (s, 1H), 6.68 (q, J = 2.3 Hz, 1H), 6.11 (q, J = 3.0 Hz,
1H), 5.88 (s, 1H), 5.55–5.54 (m, 2H), 3.87 (q, J = 6.6 Hz, 1H), 2.90–2.72 (m, 2H), 2.16 (d,
J = 20.6 Hz, 3H), 2.02–1.99 (m, 2H), 1.42–1.36 (m, 2H), 0.90–0.87 (m, 3H)
13C-NMR (151 MHz, chloroform-D)
76.9, 49.4, 36.7, 34.6, 30.7, 22.6, 13.8
δ 208.7, 134.1, 131.8, 130.6, 116.9, 108.0, 104.3, 77.3, 77.1,
IR(neat): 3378, 2957, 2927, 1704, 1357, 966, 712 cm−1
.
HRMS-ESI m/z Calculated for C13H19NO [M + Na]+ 228.1359, found 228.1359.
Supplementary Materials: The following are available online.
Author Contributions: A.B. and J.A.M. wrote the paper. J.A.M. generated core hypotheses, super-
vised the project, and trained personnel. A.B. performed the experiments and analyzed the data in
Figures 9 and 10 and Table 1. T.S.N. performed initial explorations of pyrrole substrates with early

Molecules 2021, 26, 1615
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method optimization. B.J.L. discovered the issue at hand and performed the experiments in Figure 7
and other early trials. J.-Y.L. conducted initial trials and optimizations with pyrrole substrates to
establish feasibility, writing. R.V., idea for deprotonation of nitrogen, early trials, and writing of
the manuscript. S.S. idea for (NH4)2CO3 as an additive. All authors have read and agreed to the
published version of the manuscript.
Funding: We wish to thank the Welch foundation (grant E-1744) and the National Science Foundation
(grant CHE-1352439) for funding the support for this research. Li is grateful to Joan and Herman Suit
for financial support through the Eby Nell McElrath Fellowship.
Data Availability Statement: The data presented in this study are available in this article and in the
Supplementary Information file.
Acknowledgments: High-resolution mass spectrometry data were obtained as fee-for-hire by the
Mass Spectrometry facility at UT Austin.
Conflicts of Interest: The authors declare no conflict of interest.
References and Note
1.
Riviere, J.E.; Brooks, J.D.; Collard, W.T.; Deng, J.; de Rose, G.; Mahabir, S.P.; Merritt, D.A.; Marchiondo, A.A. Prediction of
Formulation Effects on Dermal Absorption of Topically Applied Ectoparasiticides Dosed in Vitro on Canine and Porcine Skin
Using a Mixture-Adjusted Quantitative Structure Permeability Relationship. J. Vet. Pharmacol. Ther. 2014, 37, 435–444. [CrossRef]
Wong, D.T.; Bymaster, F.P. Dual serotonin and noradrenaline uptake inhibitor class of antidepressants—Potential for greater
efficacy or just hype? In Progress in Drug Research; Glasel, J.A., Kolb, V.M., Skatrud, P.L., Ford, J.W., Stevens, E.B., Treherne, J.M.,
Packer, J., Bushfield, M., Wong, D.T., Bymaster, F.P., et al., Eds.; Progress in Drug Research; Birkhäuser: Basel, Switzerland, 2002;
pp. 169–222, ISBN 978-3-0348-8183-8.
2.
3.
4.
5.
Bertolini, S.; Bon, G.B.; Campbell, L.M.; Farnier, M.; Langan, J.; Mahla, G.; Pauciullo, P.; Sirtori, C.; Egros, F.; Fayyad, R.; et al.
Efficacy and Safety of Atorvastatin Compared to Pravastatin in Patients with Hypercholesterolemia. Atherosclerosis 1997
130, 191–197. [CrossRef]
,
Lind, T.; Rydberg, L.; Kylebäck, A.; Jonsson, A.; Andersson, T.; Hasselgren, G.; Holmberg, J.; Röhss, K. Esomeprazole Provides Im-
proved Acid Control vs. Omeprazole In Patients with Symptoms of Gastro-Oesophageal Reflux Disease. Aliment. Pharmacol. Ther.
2000, 14, 861–867. [CrossRef] [PubMed]
Moussa, I.; Oetgen, M.; Roubin, G.; Colombo, A.; Wang, X.; Iyer, S.; Maida, R.; Collins, M.; Kreps, E.; Moses, J.W. Effectiveness of
Clopidogrel and Aspirin versus Ticlopidine and Aspirin in Preventing Stent Thrombosis after Coronary Stent Implantation.
Circulation 1999, 99, 2364–2366. [CrossRef]
6.
7.
Fernandez, L.S.; Buchanan, M.S.; Carroll, A.R.; Feng, Y.J.; Quinn, R.J.; Avery, V.M. Flinderoles A–C: Antimalarial Bis-Indole
Alkaloids from Flindersia Species. Org. Lett. 2009, 11, 329–332. [CrossRef] [PubMed]
Hu, Y.; Potts, M.B.; Colosimo, D.; Herrera-Herrera, M.L.; Legako, A.G.; Yousufuddin, M.; White, M.A.; MacMillan, J.B. Dis-
coipyrroles A–D: Isolation, Structure Determination, and Synthesis of Potent Migration Inhibitors from Bacillus hunanensis. J. Am.
Chem. Soc. 2013, 135, 13387–13392. [CrossRef] [PubMed]
8.
9.
Vallakati, R.; May, J.A. Biomimetic Synthesis of the Antimalarial Flindersial Alkaloids. J. Am. Chem. Soc. 2012, 4. [CrossRef]
Kotkar, D.; Joshi, V.; Ghosh, P.K. Towards Chiral Metals. Synthesis of Chiral Conducting Polymers from Optically Active
Thiophene and Pyrrole Derivatives. J. Chem. Soc. Chem. Commun. 1988, 917–918. [CrossRef]
10. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success.
J. Med. Chem. 2009, 52, 6752–6756. [CrossRef]
11. Hung, A.W.; Ramek, A.; Wang, Y.; Kaya, T.; Wilson, J.A.; Clemons, P.A.; Young, D.W. Route to Three-Dimensional Fragments
Using Diversity-Oriented Synthesis. Proc. Natl. Acad. Sci. USA 2011, 108, 6799–6804. [CrossRef]
12. Hajduk, P.J.; Galloway, W.R.J.D.; Spring, D.R. A Question of Library Design. Nature 2011, 470, 42–43. [CrossRef]
13. Twigg, D.G.; Kondo, N.; Mitchell, S.L.; Galloway, W.R.J.D.; Sore, H.F.; Madin, A.; Spring, D.R. Partially Saturated Bicyclic
Heteroaromatics as an Sp3-Enriched Fragment Collection. Angew. Chem. Int. Ed. 2016, 55, 12479–12483. [CrossRef] [PubMed]
14. Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. MedChemComm 2013, 4, 515–519. [CrossRef]
15. Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B.M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key
Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740–751. [CrossRef]
16. Prosser, K.E.; Stokes, R.W.; Cohen, S.M. Evaluation of 3-Dimensionality in Approved and Experimental Drug Space. ACS Med.
Chem. Lett. 2020, 11, 1292–1298. [CrossRef] [PubMed]
17. Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z. Enantioselective Oxidative Cross-Coupling Reaction of 3-Indolylmethyl C–H Bonds
with 1,3-Dicarbonyls Using a Chiral Lewis Acid-Bonded Nucleophile to Control Stereochemistry. Angew. Chem. Int. Ed. 2010
49, 5558–5562. [CrossRef]
,
18. Ohmura, T.; Awano, T.; Suginome, M. Stereospecific Suzuki-Miyaura Coupling of Chiral
α-(Acylamino)Benzylboronic Esters
with Inversion of Configuration. J. Am. Chem. Soc. 2010, 132, 13191–13193. [CrossRef] [PubMed]

Molecules 2021, 26, 1615
14 of 17
19. Taylor, B.L.H.; Swift, E.C.; Waetzig, J.D.; Jarvo, E.R. Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Alkyl Ethers:
Enantioselective Synthesis of Diarylethanes. J. Am. Chem. Soc. 2011, 133, 389–391. [CrossRef]
20. Zhou, Q.; Srinivas, H.D.; Dasgupta, S.; Watson, M.P. Nickel-Catalyzed Cross-Couplings of Benzylic Pivalates with Arylboroxines:
Stereospecific Formation of Diarylalkanes and Triarylmethanes. J. Am. Chem. Soc. 2013, 135, 3307–3310. [CrossRef] [PubMed]
21. Do, H.-Q.; Chandrashekar, E.R.R.; Fu, G.C. Nickel/Bis(Oxazoline)-Catalyzed Asymmetric Negishi Arylations of Racemic
Secondary Benzylic Electrophiles to Generate Enantioenriched 1,1-Diarylalkanes. J. Am. Chem. Soc. 2013, 135, 16288–16291.
[CrossRef] [PubMed]
22. Sun, C.; Potter, B.; Morken, J.P. A Catalytic Enantiotopic-Group-Selective Suzuki Reaction for the Construction of Chiral
Organoboronates. J. Am. Chem. Soc. 2014, 136, 6534–6537. [CrossRef] [PubMed]
23. Wang, G.; Xin, X.; Wang, Z.; Lu, G.; Ma, Y.; Liu, L. Catalytic Enantioselective Oxidative Coupling of Saturated Ethers with
Carboxylic Acid Derivatives. Nat. Commun. 2019, 10, 559. [CrossRef]
24. Yu, J.; Ying, P.; Wang, H.; Xiang, K.; Su, W. Mechanochemical Asymmetric Cross-Dehydrogenative Coupling Reaction: Liquid-
Assisted Grinding Enables Reaction Acceleration and Enantioselectivity Control. Adv. Synth. Catal. 2020, 362, 893–902. [CrossRef]
25. Schäfer, P.; Palacin, T.; Sidera, M.; Fletcher, S.P. Asymmetric Suzuki-Miyaura Coupling of Heterocycles via Rhodium-Catalysed
Allylic Arylation of Racemates. Nat. Commun. 2017, 8, 15762. [CrossRef] [PubMed]
26. Brambilla, M.; Tredwell, M. Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Secondary α-(Trifluoromethyl)Benzyl
Tosylates. Angew. Chem. Int. Ed. 2017, 56, 11981–11985. [CrossRef] [PubMed]
27. Shintani, R.; Narui, R.; Tsutsumi, Y.; Hayashi, S.; Hayashi, T. Design and Synthesis of New Chiral Phosphorus–Olefin Bidentate
Ligands and Their Use in the Rhodium-Catalyzed Asymmetric Addition of Organoboroxines to N-Sulfonyl Imines. Chem. Commun.
2011, 47, 6123–6125. [CrossRef] [PubMed]
28. Shintani, R.; Takeda, M.; Soh, Y.-T.; Ito, T.; Hayashi, T. Rhodium-Catalyzed Asymmetric Addition of Potassium Organotrifluorob-
orates to N -Sulfonyl Ketimines. Org. Lett. 2011, 13, 2977–2979. [CrossRef] [PubMed]
29. DeAngelis, A.; Shurtle, V.W. Rhodium(II)-Catalyzed Enantioselective C-H Functionalization of Indoles. J. Am. Chem. Soc. 2011, 4.
[CrossRef] [PubMed]
30. Unaleroglu, C.; Aytac, S.; Temelli, B. Copper Triflate Catalyzed Regioselective Alkylation of Pyrrole: Conversion of 2-Alkylated
Pyrroles to Novel Pyrrolizine Derivatives by Self-Cyclization. Heterocycles 2007, 71, 2427. [CrossRef]
31. Jensen, K.B.; Thorhauge, J.; Hazell, R.G.; Jørgensen, K.A. Catalytic Asymmetric Friedel–Crafts Alkylation of
β,γ-Unsaturated
α
-Ketoesters: Enantioselective Addition of Aromatic C H Bonds to Alkenes. Angew. Chem. Int. Ed. 2001, 40, 160–163. [CrossRef]
−
32. Friis, S.D.; Pirnot, M.T.; Buchwald, S.L. Asymmetric Hydroarylation of Vinylarenes Using a Synergistic Combination of CuH and
Pd Catalysis. J. Am. Chem. Soc. 2016, 138, 8372–8375. [CrossRef] [PubMed]
33. Odachowski, M.; Bonet, A.; Essafi, S.; Conti-Ramsden, P.; Harvey, J.N.; Leonori, D.; Aggarwal, V.K. Development of Enantiospecific
Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds. J. Am. Chem. Soc. 2016, 138, 9521–9532. [CrossRef]
34. Zhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z.L.; Sigman, M.S.; Biscoe, M.R. Enantiodivergent Pd-Catalyzed C–C Bond Formation
Enabled through Ligand Parameterization. Science 2018, 362, 670–674. [CrossRef] [PubMed]
35. Myhill, J.A.; Wilhelmsen, C.A.; Zhang, L.; Morken, J.P. Diastereoselective and Enantioselective Conjunctive Cross-Coupling
Enabled by Boron Ligand Design. J. Am. Chem. Soc. 2018, 140, 15181–15185. [CrossRef] [PubMed]
36. Bandini, M.; Melloni, A.; Umani-Ronchi, A. New Catalytic Approaches in the Stereoselective Friedel-Crafts Alkylation Reaction.
Angew. Chem. Int. Ed. 2004, 43, 550–556. [CrossRef]
37. Rowland, G.B.; Rowland, E.B.; Liang, Y.; Perman, J.A.; Antilla, J.C. The Highly Enantioselective Addition of Indoles to N-Acyl
Imines with Use of a Chiral Phosphoric Acid Catalyst. Org. Lett. 2007, 9, 2609–2611. [CrossRef]
38. Li, G.; Rowland, G.B.; Rowland, E.B.; Antilla, J.C. Organocatalytic Enantioselective Friedel-Crafts Reaction of Pyrrole Derivatives
with Imines. Org. Lett. 2007, 9, 4065–4068. [CrossRef]
39. Matsuzawa, H.; Kanao, K.; Miyake, Y.; Nishibayashi, Y. Remarkable Effect of N -Substituent on Enantioselective Ruthenium-
Catalyzed Propargylation of Indoles with Propargylic Alcohols. Org. Lett. 2007, 9, 5561–5564. [CrossRef]
40. Kanao, K.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Ruthenium-Catalyzed Enantioselective Propargylation of Indoles with
Propargylic Alcohols. Synthesis 2008, 2008, 3869–3873. [CrossRef]
41. You, S.-L.; Cai, Q.; Zeng, M. Chiral Brønsted Acid Catalyzed Friedel–Crafts Alkylation Reactions. Chem. Soc. Rev. 2009
38, 2190–2201. [CrossRef]
,
42. Pathak, T.P.; Gligorich, K.M.; Welm, B.E.; Sigman, M.S. Synthesis and Preliminary Biological Studies of 3-Substituted Indoles
Accessed by a Palladium-Catalyzed Enantioselective Alkene Difunctionalization Reaction. J. Am. Chem. Soc. 2010, 132, 7870–7871.
[CrossRef] [PubMed]
43. Cera, G.; Crispino, P.; Monari, M.; Bandini, M. Stereoselective Synthesis of Tetracyclic Indolines Viagold-Catalyzed Cascade
Cyclization Reactions. Chem. Commun. 2011, 47, 7803–7805. [CrossRef] [PubMed]
44. Rauniyar, V.; Wang, Z.J.; Burks, H.E.; Toste, F.D. Enantioselective Synthesis of Highly Substituted Furans by a Copper(II)-Catalyzed
Cycloisomerization-Indole Addition Reaction. J. Am. Chem. Soc. 2011, 133, 8486–8489. [CrossRef] [PubMed]
45. He, Y.; Lin, M.; Li, Z.; Liang, X.; Li, G.; Antilla, J.C. Direct Synthesis of Chiral 1,2,3,4-Tetrahydropyrrolo[1,2-a]Pyrazines via a
Catalytic Asymmetric Intramolecular Aza-Friedel-Crafts Reaction. Org. Lett. 2011, 13, 4490–4493. [CrossRef]
46. Cera, G.; Chiarucci, M.; Mazzanti, A.; Mancinelli, M.; Bandini, M. Enantioselective Gold-Catalyzed Synthesis of Polycyclic
Indolines. Org. Lett. 2012, 14, 1350–1353. [CrossRef]

Molecules 2021, 26, 1615
15 of 17
47. Zhuo, M.-H.; Jiang, Y.-J.; Fan, Y.-S.; Gao, Y.; Liu, S.; Zhang, S. Enantioselective Synthesis of Triarylmethanes by Chiral Imi-
dodiphosphoric Acids Catalyzed Friedel–Crafts Reactions. Org. Lett. 2014, 16, 1096–1099. [CrossRef]
48. Lundy, B.J.; Jansone-Popova, S.; May, J.A. Enantioselective Conjugate Addition of Alkenylboronic Acids to Indole-Appended
Enones. Org. Lett. 2011, 13, 4958–4961. [CrossRef]
49. Miyazaki, Y.; Zhou, B.; Tsuji, H.; Kawatsura, M. Nickel-Catalyzed Asymmetric Friedel-Crafts Propargylation of 3-Substituted
Indoles with Propargylic Carbonates Bearing an Internal Alkyne Group. Org. Lett. 2020, 22, 2049–2053. [CrossRef]
50. Uchikura, T.; Suzuki, R.; Suda, Y.; Akiyama, T. Enantioselective Synthesis of 2-Substituted Indoles Bearing Trifluoromethyl
Moiety by the Friedel-Crafts Alkylation Reaction of 4,7-Dihydroindole with N H Trifluoromethyl Ketimines. ChemCatChem
−
2020, 12, 4784–4787. [CrossRef]
51. Wang, C.-J.; Yang, Q.-Q.; Wang, M.-X.; Shang, Y.-H.; Tong, X.-Y.; Deng, Y.-H.; Shao, Z. Catalytic Asymmetric 1,4-Type
Friedel–Crafts (Hetero)Arylations of 1-Azadienes: The Highly Enantioselective Syntheses of Chiral Hetero-Triarylmethanes.
Org. Chem. Front. 2020, 7, 609–616. [CrossRef]
52. Gao, Y.; Wang, X.; Wei, Z.; Cao, J.; Liang, D.; Lin, Y.; Duan, H. Asymmetric Synthesis of Spirooxindole-Pyranoindole Products via
Friedel–Crafts Alkylation/Cyclization of the Indole Carbocyclic Ring. New J. Chem. 2020, 44, 9788–9792. [CrossRef]
53. Deng, X.; Wang, Y.; Zhang, S.; Li, L.; Li, G.; Zhao, G.; Tang, Z. An Organocatalytic Asymmetric Friedel–Crafts Reaction of
2-Substituted Indoles with Aldehydes: Enantioselective Synthesis of α-Hydroxyl Ketones by Low Loading of Chiral Phosphoric
Acid. Chem. Commun. 2020, 56, 2499–2502. [CrossRef]
54. Kim, Y.; Lee, J.; Jung, J.; Kim, S.-G. Chiral Brønsted Acid-Catalyzed Friedel–Crafts Reaction of 3-Indolylsulfamidates with Indoles:
Synthesis of Enantioenriched Bisindolylmethane Sulfamates. Tetrahedron Lett. 2019, 60, 1625–1630. [CrossRef]
55. Sato, R.; Tosaka, T.; Masu, H.; Arai, T. Catalytic Asymmetric Synthesis of Chiral Bis(Indolyl)Methanes Using a Ts-PyBidine–Nickel
Complex. J. Org. Chem. 2019, 84, 14248–14257. [CrossRef]
56. Huang, T.; Zhao, Y.; Meng, S.; Chan, A.S.C.; Zhao, J. C7-Functionalization of Indoles via Organocatalytic Enantioselective Friedel-
Crafts Alkylation of 4-Amino-Indoles with 2-Butene-1,4-Diones and 3-Aroylacrylates. Adv. Synth. Catal. 2019, 361, 3632–3638.
[CrossRef]
57. Zhu, W.-J.; Gong, J.-F.; Song, M.-P. Synthesis of Chiral Bis(3-Indolyl)Methanes Bearing a Trifluoromethylated All-Carbon
Quaternary Stereocenter via Nickel-Catalyzed Asymmetric Friedel–Crafts Alkylation Reaction. J. Org. Chem. 2020, 85, 9525–9537.
[CrossRef]
58. Zhao, Y.; Cai, L.; Huang, T.; Meng, S.; Chan, A.S.C.; Zhao, J. Solvent-Mediated C3/C7 Regioselective Switch in Chiral Phos-
phoric Acid-Catalyzed Enantioselective Friedel-Crafts Alkylation of Indoles with α-Ketiminoesters. Adv. Synth. Catal. 2020,
362, 1309–1316. [CrossRef]
59. Schlegel, M.; Coburger, P.; Schneider, C. A Novel Sc(OTf)3-Catalyzed (2 + 2 + 1)-Cycloannulation/Aza-Friedel-Crafts Alkylation
Sequence toward Multicyclic 2-Pyrrolines. Chem. Eur. J. 2018, 24, 14207–14212. [CrossRef]
60. Yonesaki, R.; Kondo, Y.; Akkad, W.; Sawa, M.; Morisaki, K.; Morimoto, H.; Ohshima, T. 3-Mono-Substituted BINOL Phosphoric
Acids as Effective Organocatalysts in Direct Enantioselective Friedel–Crafts-Type Alkylation of N-Unprotected α-Ketiminoester.
Chem. Eur. J. 2018, 24, 15211–15214. [CrossRef] [PubMed]
61. Staleva, P.; Hernández, J.G.; Bolm, C. Mechanochemical Copper-Catalyzed Asymmetric Michael-Type Friedel–Crafts Alkylation
of Indoles with Arylidene Malonates. Chem. Eur. J. 2019, 25, 9202–9205. [CrossRef] [PubMed]
62. Yarlagadda, S.; Sridhar, B.; Subba Reddy, B.V. Oxidative Asymmetric Aza-Friedel-Crafts Alkylation of Indoles with 3-Indolinone-
2-Carboxylates Catalyzed by a BINOL Phosphoric Acid and Promoted by DDQ. Chem. Asian J. 2018, 13, 1327–1334. [CrossRef]
63. Yang, Z.-T.; Yang, W.-L.; Chen, L.; Sun, H.; Deng, W.-P. Organocatalytic Enantioselective Aza-Friedel-Crafts Reactions of
Pyrazolinone Ketimines with Hydroxyindoles and Electron-Rich Phenols. Adv. Synth. Catal. 2018, 360, 2049–2054. [CrossRef]
64. Rahman, A.; Xie, E.; Lin, X. Organocatalytic Asymmetric Synthesis of Benzazepinoindole Derivatives with Trifluoromethylated
Quaternary Stereocenters by Chiral Phosphoric Acid Catalysts. Org. Biomol. Chem. 2018, 16, 1367–1374. [CrossRef]
65. Hatano, M.; Mochizuki, T.; Nishikawa, K.; Ishihara, K. Enantioselective Aza-Friedel-Crafts Reaction of Indoles with Ketimines
Catalyzed by Chiral Potassium Binaphthyldisulfonates. ACS Catal. 2018, 8, 349–353. [CrossRef]
66. Ma, J.; Kass, S.R. Asymmetric Arylation of 2,2,2-Trifluoroacetophenones Catalyzed by Chiral Electrostatically-Enhanced Phospho-
ric Acids. Org. Lett. 2018, 20, 2689–2692. [CrossRef]
67. Glavacˇ, D.; Zheng, C.; Dokli, I.; You, S.-L.; Gredicˇak, M. Chiral Brønsted Acid Catalyzed Enantioselective Aza-Friedel-Crafts
Reaction of Cyclic α-Diaryl N-Acyl Imines with Indoles. J. Org. Chem. 2017, 82, 8752–8760. [CrossRef] [PubMed]
68. Arai, T.; Tsuchida, A.; Miyazaki, T.; Awata, A. Catalytic Asymmetric Synthesis of Chiral 2-Vinylindole Scaffolds by Friedel–Crafts
Reaction. Org. Lett. 2017, 19, 758–761. [CrossRef] [PubMed]
69. Chen, H.-X.; Zhang, Y.; Zhang, Y.; He, X.; Zhang, Z.-W.; Liang, H.; He, W.; Jiang, X.; Chen, X.; Qiu, L. Synthesis of Six-Membered
Spirooxindoles via a Chiral Brønsted Acid-Catalyzed Asymmetric Intramolecular Friedel-Crafts Reaction. RSC Adv. 2018
8, 37035–37039. [CrossRef]
,
70. Xun, W.; Xu, B.; Chen, B.; Meng, S.; Chan, A.S.C.; Qiu, F.G.; Zhao, J. Regio and Enantioselective Organocatalytic Friedel-Crafts
Alkylation of 4-Aminoindoles at the C7-Position. Org. Lett. 2018, 20, 590–593. [CrossRef]
71. Zhao, Y.; Wang, L.; Zhao, J. Chiral Phosphoric Acid Catalyzed Aza-Friedel-Crafts Alkylation of Indoles with Cyclic Aryl
α-Ketimino Esters. Tetrahedron Lett. 2017, 58, 213–217. [CrossRef]

Molecules 2021, 26, 1615
16 of 17
72. Stemper, J.; Isaac, K.; Ghosh, N.; Lauwick, H.; Le Duc, G.; Retailleau, P.; Voituriez, A.; Betzer, J.-F.; Marinetti, A. Silyl-Substituted
Planar Chiral Phosphoric Acids with Ferrocene-Bridged Paracyclophane Frameworks: Synthesis, Characterization, and Uses in
Enantioselective Aza-Friedel-Crafts Reactions. Adv. Synth. Catal. 2017, 359, 519–526. [CrossRef]
73. Cheng, H.-G.; Miguélez, J.; Miyamura, H.; Yoo, W.-J.; Kobayashi, S. Integration of Aerobic Oxidation and Intramolecular
Asymmetric Aza-Friedel-Crafts Reactions with a Chiral Bifunctional Heterogeneous Catalyst. Chem. Sci. 2017, 8, 1356–1359.
[CrossRef] [PubMed]
74. Wang, L.; Rahman, A.; Lin, X. Enantioselective Synthesis of Cyclic Quaternary α-Amino Acid Derivatives by Chiral Phosphoric
Acid Catalysis. Org. Biomol. Chem. 2017, 15, 6033–6041. [CrossRef] [PubMed]
75. Fan, Y.; Kass, S.R. Enantioselective Friedel-Crafts Alkylation between Nitroalkenes and Indoles Catalyzed by Charge Activated
Thiourea Organocatalysts. J. Org. Chem. 2017, 82, 13288–13296. [CrossRef]
76. Xu, W.; Shen, X.; Ma, Q.; Gong, L.; Meggers, E. Restricted Conformation of a Hydrogen Bond Mediated Catalyst Enables
the Highly Efficient Enantioselective Construction of an All-Carbon Quaternary Stereocenter. ACS Catal. 2016, 6, 7641–7646.
[CrossRef]
77. Chang, C.-H.; Han, J.-L. Organocatalytic Enantioselective Friedel-Crafts Reaction of Sesamol and Electron-Rich Phenols with
Alkylideneindolenine Intermediates Generated from Arylsulfonyl Indoles. ChemistrySelect 2016, 1, 5628–5632. [CrossRef]
78. Lou, H.; Wang, Y.; Jin, E.; Lin, X. Organocatalytic Asymmetric Synthesis of Dihydrobenzoxazinones Bearing Trifluoromethylated
Quaternary Stereocenters. J. Org. Chem. 2016, 81, 2019–2026. [CrossRef]
79. Weng, J.-Q.; Fan, R.-J.; Deng, Q.-M.; Liu, R.-R.; Gao, J.-R.; Jia, Y.-X. Enantioselective Friedel–Crafts Alkylation Reactions of
3-Substituted Indoles with Electron-Deficient Alkenes. J. Org. Chem. 2016, 81, 3023–3030. [CrossRef] [PubMed]
80. Ge, C.; Liu, R.-R.; Gao, J.-R.; Jia, Y.-X. Cu(I)-Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with 2-Aryl- N
-Sulfonylaziridines as Alkylating Agents. Org. Lett. 2016, 18, 3122–3125. [CrossRef]
81. Yang, G.-J.; Du, W.; Chen, Y.-C. Construction of Furan Derivatives with a Trifluoromethyl Stereogenic Center: Enantioselective
Friedel–Crafts Alkylations via Formal Trienamine Catalysis. J. Org. Chem. 2016, 81, 10056–10061. [CrossRef] [PubMed]
82. Zheng, J.; Lin, L.; Dai, L.; Yuan, X.; Liu, X.; Feng, X. Chiral N,N’-Dioxide–Scandium(III) Complex-Catalyzed Asymmetric
Friedel–Crafts Alkylation Reaction of Ortho-Hydroxybenzyl Alcohols with C3-Substituted N-Protected Indoles. Chem. Eur. J.
2016, 22, 18254–18258. [CrossRef]
83. Wu, Q.; Ma, C.; Du, X.; Chen, Y.; Huang, T.; Shi, X.; Tu, S.; Cai, P. Chiral Brønsted Acid-Catalyzed Alkylation of C3-Substituted
Indoles with o-Hydroxybenzyl Alcohols: Highly Enantioselective Synthesis of Diarylindol-2-Ylmethanes and Evaluation on
Their Cytotoxicity. Tetrahedron Asymmetry 2016, 27, 307–316. [CrossRef]
84. Huang, K.; Ma, Q.; Shen, X.; Gong, L.; Meggers, E. Metal-Templated Asymmetric Catalysis: (Z)-1-Bromo-1-Nitrostyrenes as
Versatile Substrates for Friedel-Crafts Alkylation of Indoles. Asian J. Org. Chem. 2016, 5, 1198–1203. [CrossRef]
85. Li, N.-K.; Kong, L.-P.; Qi, Z.-H.; Yin, S.-J.; Zhang, J.-Q.; Wu, B.; Wang, X.-W. Friedel-Crafts Reaction of Indoles with Isatin-Derived
β,γ-Unsaturated α-Keto Esters Using a BINOL-Derived Bisoxazoline (BOX)/Copper(II) Complex as Catalyst. Adv. Synth. Catal.
2016, 358, 3100–3112. [CrossRef]
86. Zhuo, M.-H.; Liu, G.-F.; Song, S.-L.; An, D.; Gao, J.; Zheng, L.; Zhang, S. Chiral Imidodiphosphoric Acids-Catalyzed Friedel-
Crafts Reactions of Indoles/Pyrroles with 3-Hydroxy-Indolyloxindoles: Enantioselective Synthesis of 3,3-Diaryloxindoles.
Adv. Synth. Catal. 2016, 358, 808–815. [CrossRef]
87. Le, P.Q.; Nguyen, T.S.; May, J.A. A General Method for the Enantioselective Synthesis of α-Chiral Heterocycles. Org. Lett. 2012,
14, 6104–6107. [CrossRef] [PubMed]
88. Vallakati, R.; Lundy, B.J.; Jansone-Popova, S.; May, J.A. Biomimetic Synthesis and Studies Toward Enantioselective Synthesis of
Flindersial Alkaloids. Chirality 2015, 27, 14–17. [CrossRef] [PubMed]
89. Shih, J.-L.; Nguyen, T.S.; May, J.A. Organocatalyzed Asymmetric Conjugate Addition of Heteroaryl and Aryl Trifluoroborates:
A Synthetic Strategy for Discoipyrrole, D. Angew. Chem. Int. Ed. 2015, 54, 9931–9935. [CrossRef] [PubMed]
90. Xing, J.; Chen, G.; Cao, P.; Liao, J. Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to Indolylnitroalkenes. Eur. J.
Org. Chem. 2012, 2012, 1230–1236. [CrossRef]
91. Dabrowski, J.A.; Villaume, M.T.; Hoveyda, A.H. Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers through
Copper-Catalyzed Conjugate Additions of Aryl- and Alkylaluminum Reagents to Acyclic Trisubstituted Enones. Angew. Chem.
Int. Ed. 2013, 52, 8156–8159. [CrossRef] [PubMed]
92. Huo, H.; Fu, C.; Harms, K.; Meggers, E. Asymmetric Catalysis with Substitutionally Labile yet Stereochemically Stable Chiral-at-
Metal Iridium(III) Complex. J. Am. Chem. Soc. 2014, 136, 2990–2993. [CrossRef]
93. Austin, J.F.; MacMillan, D.W.C. Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective
Chiral Amine for Iminium Catalysis. J. Am. Chem. Soc. 2002, 124, 1172–1173. [CrossRef] [PubMed]
94. Lee, S.; MacMillan, D.W.C. Organocatalytic Vinyl and Friedel-Crafts Alkylations with Trifluoroborate Salts. J. Am. Chem. Soc.
2007, 129, 15438–15439. [CrossRef] [PubMed]
95. Ganesh, M.; Seidel, D. Catalytic Enantioselective Additions of Indoles to Nitroalkenes. J. Am. Chem. Soc. 2008, 130, 16464–16465.
[CrossRef]
96. Dobish, M.C.; Johnston, J.N. Chiral Brønsted Base-Promoted Nitroalkane Alkylation: Enantioselective Synthesis of Sec.-Alkyl-3-
Substituted Indoles. Org. Lett. 2010, 12, 5744–5747. [CrossRef]

Molecules 2021, 26, 1615
17 of 17
97. Luan, Y.; Schaus, S.E. Enantioselective Addition of Boronates to o-Quinone Methides Catalyzed by Chiral Biphenols. J. Am.
Chem. Soc. 2012, 134, 19965–19968. [CrossRef]
98. Hara, S.; Hyuga, S.; Aoyama, M.; Sato, M.; Suzuki, A. Bf3 Etherate Mediated 1,4-Addition of 1-Alkenyldialkoxyboranes to
α,β-Unsaturated Ketones. A Stereoselective Synthesis of γ, δ-Unsaturated Ketones. Tetrahedron Lett. 1990, 31, 247–250. [CrossRef]
99. Zhu, H.; Yin, L.; Chang, Z.; Wang, Y.; Dou, X. Rhodium-Catalyzed Asymmetric Conjugate Addition of Organoboronic Acids to
Carbonyl-Activated Alkenyl Azaarenes. Adv. Synth. Catal. 2020, 362, 3142–3147. [CrossRef]
100. Han, J.-L.; Liao, Y.-T.; Chang, C.-H. Asymmetric Organocatalytic Conjugate Addition of Electron-Rich Phenols and 1,3-Dicarbonyls
to Arylsulfonyl Indoles in an Oil-Water Biphasic System. Eur. J. Org. Chem. 2019, 2019, 5815–5823. [CrossRef]
101. Wang, J.-R.; Jiang, X.-L.; Hang, Q.-Q.; Zhang, S.; Mei, G.-J.; Shi, F. Catalytic Asymmetric Conjugate Addition of Indoles to Para
-Quinone Methide Derivatives. J. Org. Chem. 2019, 84, 7829–7839. [CrossRef]
102. Li, S.-W.; Wan, Q.; Kang, Q. Chiral-at-Metal Rh(III) Complex-Catalyzed Michael Addition of Pyrazolones with α,β-Unsaturated
2-Acyl Imidazoles. Org. Lett. 2018, 20, 1312–1315. [CrossRef]
103. Liang, W.; Yin, W.; Wang, T.; Qiu, F.G.; Zhao, J. Organocatalytic Stereoselective Conjugate Addition of 3-Substituted Oxindoles
with in Situ Generated Ortho-Quinone Methides. Tetrahedron Lett. 2018, 59, 1742–1747. [CrossRef]
104. Correia, J.T.M.; List, B.; Coelho, F. Catalytic Asymmetric Conjugate Addition of Indolizines to
Angew. Chem. Int. Ed. 2017, 56, 7967–7970. [CrossRef]
α
,β-Unsaturated Ketones.
105. Metz, T.L.; Evans, J.; Stanley, L.M. Catalytic Conjugate Addition of Electron-Rich Heteroarenes to
Org. Lett. 2017, 19, 3442–3445. [CrossRef]
β,β-Disubstituted Enones.
106. Ma, H.-L.; Xie, L.; Zhang, Z.; Li, J.-Q.; Qin, Z.-H.; Fu, B. Enantioselective Copper(II)-Catalyzed Conjugate Addition of Indoles to
β-Substituted Unsaturated Acyl Phosphonates. Adv. Synth. Catal. 2016, 358, 1011–1016. [CrossRef]
107. Fujishima, H.; Takada, E.; Kara, S.; Suzuki, A. Boron Trifluoride Etherate Mediated 1,4-Addition of (1-Alkynyl)Diisopropoxyboranes
to α,β-Unsaturated Ketones. A Convenient New Route to 3-Alkynyl Ketone Synthesis. Chem. Lett. 2006, 21. [CrossRef]
108. Takada, E.; Hara, S.; Suzuki, A. A Stereoselective Synthesis of Γδ-Unsaturated Ketones Possessing Perfluoroalkyl Groups
by Trifluoroborane Etherate Mediated 1,4-Addition Reaction of Alkenyldiisopropoxyboranes to
α,β-Unsaturated Ketones.
Tetrahedron Lett. 1993, 34, 7067–7070. [CrossRef]
109. Hara, S.; Ishimura, S.; Suzuki, A. Cyanuric Fluoride-Induced 1,4-Addition Reaction of Alkenylboronic Acids to
α
,
β-Unsaturated
Ketones. Stereoselective Synthesis of γ,δ-Unsaturated Ketones Having Functionalities. Synlett 1996, 1996, 993–994. [CrossRef]
110. Hara, S.; Shudoh, H.; Ishimura, S.; Suzuki, A. The Regioselective 1,4-Addition Reaction of Alkenylboronic Acids to α,β
,A0,B0-
Unsaturated Ketones. Bull. Chem. Soc. Jpn. 1998, 71, 2403–2408. [CrossRef]
111. Yoshida, K.; Hayashi, T. Rhodium-Catalyzed additions of boronic acids to Alkenes and Carbonyl compounds. In Boronic Acids;
John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2006; pp. 171–203. ISBN 978-3-527-60654-2.
112. Chong, J.M.; Shen, L.; Taylor, N.J. Asymmetric Conjugate Addition of Alkynylboronates to Enones. J. Am. Chem. Soc. 2000
122, 1822–1823. [CrossRef]
,
113. Wu, T.R.; Chong, J.M. Ligand-Catalyzed Asymmetric Alkynylboration of Enones: A New Paradigm for Asymmetric Synthesis
Using Organoboranes. J. Am. Chem. Soc. 2005, 127, 3244–3245. [CrossRef]
114. Wu, T.R.; Chong, J.M. Asymmetric Conjugate Alkenylation of Enones Catalyzed by Chiral Diols. J. Am. Chem. Soc. 2007
129, 4908–4909. [CrossRef]
,
115. Turner, H.M.; Patel, J.; Niljianskul, N.; Chong, J.M. Binaphthol-Catalyzed Asymmetric Conjugate Arylboration of Enones.
Org. Lett. 2011, 13, 5796–5799. [CrossRef]
116. Sugiura, M.; Tokudomi, M.; Nakajima, M. Enantioselective Conjugate Addition of Boronic Acids to Enones Catalyzed by
O-Monoacyltartaric Acids. Chem. Commun. 2010, 46, 7799–7800. [CrossRef] [PubMed]
117. Kotani, S.; Osakama, K.; Sugiura, M.; Nakajima, M. A Tertiary Amine as A Hydride Donor: Trichlorosilyl Triflate-Mediated
Conjugate Reduction of Unsaturated Ketones. Org. Lett. 2011, 13, 3968–3971. [CrossRef] [PubMed]
118. Grimblat, N.; Sugiura, M.; Pellegrinet, S.C. A Hydrogen Bond Rationale for the Enantioselective β-Alkenylboration of Enones
Catalyzed by O-Monoacyltartaric Acids. J. Org. Chem. 2014, 79, 6754–6758. [CrossRef] [PubMed]
119. Sugiura, M.; Kinoshita, R.; Nakajima, M. O-Monoacyltartaric Acid Catalyzed Enantioselective Conjugate Addition of a Boronic
Acid to Dienones: Application to the Synthesis of Optically Active Cyclopentenones. Org. Lett. 2014, 16, 5172–5175. [CrossRef]
120. Inokuma, T.; Takasu, K.; Sakaeda, T.; Takemoto, Y. Hydroxyl Group-Directed Organocatalytic Asymmetric Michael Addition of
α,β-Unsaturated Ketones with Alkenylboronic Acids. Org. Lett. 2009, 11, 2425–2428. [CrossRef]
121. Pellegrinet, S.C.; Goodman, J.M. Asymmetric Conjugate Addition of Alkynylboronates to Enones: Rationale for the Intriguing
Catalysis Exerted by Binaphthols. J. Am. Chem. Soc. 2006, 128, 3116–3117. [CrossRef]
122. Paton, R.S.; Goodman, J.M.; Pellegrinet, S.C. Theoretical Study of the Asymmetric Conjugate Alkenylation of Enones Catalyzed
by Binaphthols. J. Org. Chem. 2008, 73, 5078–5089. [CrossRef]
123. Nguyen, T.S.; Yang, M.S.; May, J.A. Experimental Mechanistic Insight into the BINOL-Catalyzed Enantioselective Conjugate
Addition of Boronates to Enones. Tetrahedron Lett. 2015, 56, 3337–3341. [CrossRef]
124. We Also Examined the Use of an Additional Lewis Acid as Reported by Yu and Mao.
125. Wang, J.-F.; Meng, X.; Zhang, C.-H.; Yu, C.-M.; Mao, B. Organocatalytic Enantioselective Conjugate Alkynylation of
β-
Aminoenones: Access to Chiral -Alkynyl- -Amino Carbonyl Derivatives. Org. Lett. 2020, 22, 7427–7432. [CrossRef] [PubMed]
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