Chiral Br?nsted Acid Catalyzed Enantioselective aza-Friedel-Crafts Reaction of Cyclic α-Diaryl N-Acyl Imines with Indoles

Article abstract of DOI:10.1021/acs.joc.7b01420

Asymmetric addition of indoles to cyclic α-diaryl-substituted N-acyl imines, which are generated in situ from 3-aryl 3-hydroxyisoindolinones, is described. The transformation proceeds smoothly with a broad range of indoles and isoindolinone alcohols using

Full text of DOI:10.1021/acs.joc.7b01420

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Note
Chiral Brønsted Acid-Catalyzed Enantioselective aza-Friedel-
Crafts Reaction of Cyclic #-Diaryl N-Acyl Imines With Indoles
Danijel Glava#, Chao Zheng, Irena Dokli, Shu-Li You, and Matija Gredi#ak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01420 • Publication Date (Web): 25 Jul 2017
Downloaded from http://pubs.acs.org on July 25, 2017
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Chiral Brønsted Acid-Catalyzed Enantioselective aza-Friedel-Crafts
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Reaction of Cyclic α-Diaryl N-Acyl Imines With Indoles
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Danijel Glavač,a Chao Zheng,b Irena Dokli,a ShuꢀLi Youb* and Matija Gredičaka*
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a Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54,
10 000 Zagreb, Croatia. Email: matija.gredicak@irb.hr
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China. Email:
slyou@sioc.ac.cn
Abstract
Asymmetric addition of indoles to cyclic αꢀdiarylꢀsubstituted Nꢀacyl imines, which are
generated in situ from 3ꢀaryl 3ꢀhydroxyisoindolinones, is described. The transformation
proceeds smoothly with a broad range of indoles and isoindolinone alcohols using a SPINOLꢀ
derived
chiral
Brønsted
acid
catalyst
to
afford
αꢀtetrasubstituted
(3ꢀ
indolyl)(diaryl)methanamines in excellent yields and enantioselectivities (up to 98 % yield, up
to >99:1 e.r.). The origin of stereochemical induction is supported by DFT calculations and
experimental data.
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The asymmetric addition of indoles to imines is the most straightforward synthetic approach
for the preparation of 3ꢀindolyl methanamines, structural motifs embedded in numerous
indole alkaloids and synthetic indole derivatives.1 The most common strategies for the
construction of such optically active stereocentres employ organocatalytic asymmetric azaꢀ
FriedelꢀCrafts reactions.2 In Lewis acid catalyzed protocols, Cu(I) complexes are usually
employed for the generation of chiral 3ꢀindolyl methanamines in high yields and
enantioselectivities,3 though their efficiency depends on the electronic properties of the
indoles.4 Due to the ability to activate a large spectrum of substrates, asymmetric Brønsted
acid catalysis has become a method of choice for this transformation. In 2004, Terada
reported first chiral phosphoric acidꢀcatalyzed azaꢀFriedelꢀCrafts reaction of furan with
imines.5 Terada's seminal work gave raise to the development of numerous protocols for the
preparation of chiral 3ꢀindolyl methanamines using chiral Brønsted acid catalysts.6
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However, these methodologies result in methanamines with chiral αꢀtertiary centres, and in
recent years significant, progress has been made in the construction of chiral αꢀ
tetrasubstituted methanamines. Nishibayashi6 and Watson7 groups reported asymmetric
copperꢀcatalyzed alkynylation of ketimines to deliver αꢀdiaryl quaternary stereogenic centres.
Chiral phosphoric acidꢀcatalyzed asymmetric azaꢀFriedelꢀCrafts reactions developed by
Nakamura,9 Rueping,10 Wang11 and Maruoka12 furnished tetrasubstituted αꢀketo(diaryl)
methanamines. Although elegant and versatile, these protocols result in products in the form
of chiral αꢀ(diaryl)alkylꢀ, rather than chiral αꢀ(triaryl)ꢀsubstituted methanamines. Only a
handful of reports tackled the organocatalytic asymmetric catalytic azaꢀFriedelꢀCrafts addition
for the generation of αꢀtriaryl methanamines. In 2011, Wang and Zhou reported an
enantioselective azaꢀFriedelꢀCrafts reaction of indoles with Nꢀacyl imines, affording
isoindolinones with quaternary stereogenic centres in high yields, but moderate
enantioselectivities.13 Among a range of obtained (diaryl)methanamines, the substrate scope
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included only one example of chiral αꢀ(3ꢀindolyl)(diaryl)methanamine product. In 2012, Lete
et al reported an asymmetric addition of indoles to isoindoloquinolines.14 The authors
obtained desired products in very good yields, but low enantiomeric ratios. To the best of our
knowledge, there are currently no effective protocols for the organocatalytic asymmetric azaꢀ
FriedelꢀCrafts reaction for the preparation of chiral αꢀ(3ꢀindolyl)(diaryl) methanamines.
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Herein, we report a chiral phosphoric acidꢀcatalyzed enantioselective addition of indoles to
cyclic αꢀdiarylꢀsubstituted Nꢀacyl imines, generated in situ from 3ꢀaryl 3ꢀ
hydroxyisoindolinones. These heterocycles have recently been succesfully employed as
substrates in various asymmetric metalloꢀ and organocatalytic transformations. Nishimura and
Hayashi developed rhodiumꢀcatalyzed asymmetric FriedelꢀCrafts additions to N(sulfonyl)ꢀ
imines15 and N(acyl)ꢀimines,16 resulting in αꢀ(triaryl)ꢀsubstituted methanamines. Nishimura
expanded this protocol to iridiumꢀcatalyzed arylations of N(acyl)ꢀketimines,17 while Hayashi
successfully employed modified amino acidꢀderived phosphineꢀimine ligands for palladiumꢀ
catalyzed asymmetric arylations of N(sulfonyl)ꢀimines.18 Along with aforementioned azaꢀ
FriedelꢀCrafts reaction described by Wang and Zhou,13 various organocatalytic
transformations of 3ꢀhydroxyisoindolinones have also been developed. In 2012, Zhou et al
reported asymmetric hydrogenolysis of racemic tertiary alcohols, 3ꢀsubstituted 3ꢀ
hydroxyisoindolinones with Hantzsch's esters.19 The following year, Jia et al reported the
same transformation by employing benzothiazolines as hydrogen source.20 Recently, Singh et
al developed enantioselective hydrophosphonylation of αꢀ(diaryl)ꢀsubstituted 3ꢀ
hydroxyisoindolinones,21 while the Singh group22 and our group23 independently reported
asymmetric addition of thiols to form N(acyl),Sꢀacetals derived from these heterocycles
comprising newlyꢀformed quaternary stereogenic centres.
Since our preliminary results showed that BINOLꢀderived chiral phosphoric acids are not
appropriate catalysts for these transformations (see Supporting Information), we turned our
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attention to SPINOLꢀderived catalysts.6e,24 We started our investigations by combining 3ꢀ
phenyl 3ꢀhydroxyisoindolinone with indole in the presence of various chiral Brønsted acids
(BA*) (Table 1).
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Table 1. Enantioselective reaction optimization[a]
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Time Yield
Entry Cat.
Solvent
e.r.
(h)
(%)
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Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
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16
168
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95
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87:13
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79:21
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BA1
BA2
BA3
BA4
BA5
BA6
BA7
6
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BA5 Fluorobenzene
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pꢀXylene
Chloroform
DCM
Toluene
Toluene
Toluene
92:8
95:5
BA5
BA5
BA5
BA5
BA5
BA5
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14
93:7
97:3[b]
96:4[c]
96:4[d]
[a] Reactions performed on 0.2 mmol scale. e.r. determined by the chiral HPLC. [b] BA5 (5 mol%). [c] –10 °C.
[d] Additive: MgSO4.
Our initial attempt with phenylꢀsubstituted chiral phosphoric acid BA1 in toluene led to the
complete conversion to the desired product 1 within 5 hours at room temperature, and with
the observed enantioselectivity of 87:13 e.r. (Entry 1). Introduction of the TMS group on the
phenyl ring of the acid (BA2) lead to the increase of the enantiomeric purity in the product
(Entry 2). When electronꢀwithdrawing (BA3) and electronꢀdonating (BA4) groups were
placed on the catalyst, the reaction maintained its level of enantioselectivity (Entries 3 and 4).
However, the introduction of pꢀchlorophenyl substitutent on the SPINOL backbone resulted
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in substantially higher enantiomeric ratio in the product (97:3 e.r., Entry 5). On the other
hand, introduction of bulkier substituents on the flanking aromatic rings of the catalyst
resulted in significant drop in the enantioselectivities (Entries 6 and 7).
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After identifying BA5 catalyst as the optimal catalyst for the transformation, the influence of
solvent, temperature, catalyst loading, and the addition of additives was investigated. By
conducting the reaction in other common solvents, the product was obtained with slightly
lower enantioselectivities (Entries 8–11). Next, we examined the chiral catalyst loading.
5 mol% of the catalyst led to the same enantioselectivity as with 10 mol% loading, though the
reaction time was prolonged to 16 hours (Entry 12). Cooling the reaction to –10 °C led to an
incomplete conversion after 7 days, but the enantioselectivity of the reaction was not
improved (Entry 13). Lastly, we investigated the addition of a drying agent, but the
enantiomeric ratio remained the same (Entry 14). Hence, the optimized procedure employed
5 mol% of BA5 catalyst in toluene at room temperature.
With optimized reaction conditions in hand, we turned our attention to investigate the
substrate scope and reaction limitations. Initially, we examined asymmetric (3ꢀ
indolyl)(diaryl)methanamine formation with various 3ꢀaryl 3ꢀhydroxyisoindolinones23
(Table 2). Indole reacted efficiently with a range of different 3ꢀaryl 3ꢀhydroxyisoindolinones
and provided high yields and enantioselectivities. When alkyl groups were placed around the
3ꢀaryl substituent, a small drop in enantiomeric ratios was observed, and products 2 and 3
were furnished in very good yields and enantioselectivities. By introducing electronꢀdonating
groups on the meta and para positions of the 3ꢀaryl ring, the reaction maintained its
effectiveness, and no significant change in enantiomeric ratios was observed (4, 98% yield,
91:9 e.r., and 5, 93% yield, 92:8 e.r.). However, when methoxy substitutents were placed in
both meta positions of the 3ꢀaryl, the enantioselectivity of the reaction was dramatically
improved (6, 92% yield, 99:1 e.r.). Trifluoromethyl groups on the 3ꢀaryl substituent were also
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well tolerated, furnishing products 7 and 8 in high yields and enantioselectivities, though the
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reactions had to be performed at elevated temperatures.
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Table 2. Substrate scope: isoindolinone alcohols[a]
[a] Isolated yields. Reactions performed on 0.2 mmol scale. [b] 40 °C. [c] 50 °C. [d] 60 °C. [e] 96 h. [f] 40
°C, 60 h. [g] 6 days.
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When orthoꢀmethyl and orthoꢀtrifluoromethyl substituents were introduced, the reaction times
were significantly prolonged, and moderate enantioselectivities were observed (9, 86% yield,
80:20 e.r., and 10, 93% yield, 70:30 e.r.). The most probable explanation for this observation
is that the increased steric hidrance around the reaction centre overrides the steric influence of
the chiral phosphoric acid catalyst. Introduction of the halogenꢀcontaining 3ꢀaryl substituent
(11 and 12), 3ꢀnaphtyl substituent (13), and phthalimide aromatic ring substitutions (14) did
not change the efficiency of the reaction. When smaller aromatic systems were employed as
3ꢀaryl groups, a significant drop in enantioselectivity was observed (15, 77% yield, 80:20 e.r.,
and 16, 70% yield, 82:18 e.r.).
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Although the aim of this study was the preparation of (3ꢀindolyl)(diaryl)methanamines, we
investigated whether 3ꢀalkyl substituents were also tolerated. Submitting 3ꢀbutyl 3ꢀ
hydroxyisoindolinone substrate to the optimized reaction conditions resulted in product 17 in
high yield, but poor enantioselectivity (98% yield, 60:40 e.r.). By utilizing 3ꢀbenzyl
substituent on the isoindolinone alcohol, the enantiomeric ratio in the product was
substantially higher, though still moderate (18, 84:16 e.r.). Poor or moderate
enantioselectivities in examples with smaller aromatic rings and alkyl chains as 3ꢀsubstituents
are most likely due to their size; these groups are probably not big enough to successfully
create a differentiation between the enantiotopic faces of the Nꢀacyl iminium intermediate
when binding to the catalyst.
Furthermore, we turned our attention to investigating the scope and limitations of the reaction
with various indoles (Table 3).
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Table 3. Substrate scope: indoles[a]
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[a] Isolated yields. Reactions performed at 0.2 mmol scale. [b] 80 °C. [c] 50 °C. [d] 36 h. [e] 50 °C, 72 h.
Initially, we chose 3ꢀphenyl and 3ꢀ(mꢀmethoxy)phenyl 3ꢀhydroxyisoindolinones as model
alcohols for the investigation of the influence of indole substituents on the reaction outcome
(entries 19–25). In general, enantioselectivities slightly dropped regardless of the position and
nature of the substituent on the indole. αꢀChiral methanamine products were isolated in
excellent yields and in enantioselectivities ranging from 85:15 e.r. to 92:8 e.r. The reaction
maintained moderate effectiveness when 3ꢀhydroxyisoindolinone with substituted phthalimide
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ring was reacted with 5ꢀchloroindole (26, 97% yield, 87:13 e.r.). Better level of
enantioselectivity was obtained when 3ꢀ(3,5ꢀditrifluoromethyl)phenyl 3ꢀhydroxyisoindolinone
was combined with 6ꢀfluoroindole (27, 76% yield, 96:4 e.r.). Next, we screened 3ꢀ(3,5ꢀ
dimethoxy)phenyl 3ꢀhydroxyisoindolinone, the alcohol that yielded the best enantiomeric
ratio in the reaction with unsubstituted indole. Corresponding products 28–33 were isolated in
very good yields and excellent enantioselectivities (>99:1 e.r.), regardless of the position and
nature of the substituents on indole. This result indicates that 3,5ꢀdimethoxy substitution on 3ꢀ
phenyl ring is alone responsible for the extraordinary high enenatiomeric ratios in products, as
observed in metalꢀcatalyzed reactions investigated by Nishimura et al.17
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By comparing HPLC traces of product 1 with HPLC traces of a known compound (see
Supporting information),13 the absolute configuration was assigned to be (S), and the absolute
configurations of the remaining products were assigned by analogy. In order to investigate the
origin of the observed enantioselectivity, we performed mechanistic investigation
experiments. First, DFT calculations were performed at B3LYPꢀD3(BJ)/6ꢀ311+G** level of
theory on a model reaction. Two transition states (TS-R and TS-S) leading to the products in
(R) and (S) configurations, respectively were located (Figure 1).
Figure 1. The optimized structures and the relative Gibbs free energies (in kcal/mol) of the two key
transition states. The catalyst BA5 is represented with VDW model. The indole and isoindolinone Nꢀ
acyl iminium ion are represented with stick models in pink and purple, respectively. The yellow
dashlines show the forming C–C bonds.
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The calculated Gibbs free energy of TS-
the product in (S) configuration should be formed predominantly, which is consistent with the
experimental results. In the unfavorable TS- , significant steric repulsion is established
R is 2 kcal/mol higher than that of TS-S, indicating
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R
between the phenyl group of the isoindolinone and the lower 4ꢀClC6H4 group on the chiral
phosphoric acid catalyst, which is the main reason that accounts for the higher energetic
barrier of this transition state.
In order to further elucidate stereochemical induction of the reaction, experiments with Nꢀ
protected isoindolinone alcohol and Nꢀprotected indole were performed, respectively
(Scheme 1).
Scheme 1. Reactions with Nꢀprotected isoindolinone alcohol, and Nꢀprotected indole.
When Nꢀmethylated 3ꢀhydroxyisoindolinone 55 was submitted to azaꢀFriedelꢀCrafts reaction
with indole, the product 34 was obtained in high yield and low enantioselectivity (88% yield,
63:37 e.r.) after performing the reaction at 60 °C for 4 days. Similarly, in the reaction of
isoindolinone alcohol 36 and Nꢀbenzylated indole under optimized reaction conditions,
product 35 was obtained practically as a racemate (81% yield, 53:47 e.r.). These experiments
indicate that chiral phosphoric acid binds to both substrates in the transition state via their
respective NH atoms, which is in accordance with the generally accepted mechanism.6e
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In conclusion, we have developed a chiral Brønsted acidꢀcatalyzed asymmetric azaꢀFriedelꢀ
Crafts reaction between indoles and in situ generated cyclic αꢀdiarylꢀsubstituted Nꢀacyl
imines. The reaction proceeds smoothly with a broad range of indoles and isoindolinone
alcohols to afford chiral αꢀtetrasubstituted (3ꢀindolyl)(diaryl)methanamines in high yields and
enantioselectivities. The origin of the enantioselectivity was supported by DFT calculations
and experimental data. We anticipate that the utility of the developed asymmetric azaꢀFriedelꢀ
Crafts reaction as a central component in the construction of complex heterocyclic cores will
be further explored.
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Experimental Section
General Information
Chemicals and solvents were purchased from commercial suppliers and used as received.
Flash column chromatography was carried out using silica gel (Merck, 40−63 ꢁm particle
size). NMR spectra were recorded on Bruker Avance 600 MHz and 300 MHz spectrometers,
operating at 150.92 or 75.47 MHz for 13C and 600.13 or 300.13 MHz for 1H nuclei. Chemical
shifts are quoted in ppm, and are referenced to the residual nonꢀdeuterated solvent peak.
Spectra were acquired at 298 K. Infraꢀred spectra were recorded on a Varian Uv/Vis Cary
4000 spectrometer equipped with an attenuated total reflectance attachment with internal
calibration. Absorbtion maxima (νmax) are reported in wavenumbers (cmꢀ1). Mass
spectrometry measurements were performed on HPLC system coupled with triple quadrupole
mass spectrometer, operating in a positive electrospray ionization (ESI) mode. High
resolution mass spectrometry (HRMS) was performed on a 4800 Plus MALDI TOF/TOF
Analyzer. Mps were determined using an Electrothermal 9100 apparatus in open capillaries
and are uncorrected. Substrates, 3ꢀaryl 3ꢀhydroxyisoindolinones, (36–55 in SI) were
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synthesized in high yields from readily available starting materials, by employing addition of
Grignard or organolithium reagent to phthalimide.25 Chiral phosphoric acids BA1–BA7 have
been prepared according to known procedures, and obtained data corresponds to data reported
therein.26 Racemic standards were prepared by using pꢀtoluenesulfonic acid (10 mol%)
instead of a chiral catalyst.
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General Procedure
To a flameꢀdried Schlenk tube containing a solution of 3–aryl 3–hydroxyisoindolinone (0.2
mmol) in toluene (2 mL) was added indole (0.22 mmol) and chiral phosphoric acid BA5 (5
mol%). The reaction mixture was stirred at room temperature until substrate was fully
consumed according to HPLC. The crude reaction mixture was directly purified by column
chromatography on silica gel.
(S
)-3-(1H-indol-3-yl)-3-phenylisoindolin-1-one (1).13 White solid. Yield: 70 mg (97 %),
1
97:3 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR (600
MHz, DMSO) δ 11.04 (s, 1H), 9.59 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H),
7.58 (dd, J = 10.6, 4.1 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.37 (d, J =
8.2 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.07 – 7.00 (m, 1H), 6.87 (d, J
= 2.5 Hz, 1H), 6.84 – 6.73 (m, 2H). 13C NMR (75 MHz, DMSO) δ 168.9, 151.3, 143.3, 137.5,
132.3, 131.6, 128.7, 127.9, 126.9, 125.6, 124.7, 124.6, 123.6, 121.7, 120.3, 119.1, 117.2,
112.2, 66.7. ESI–MS: 325 [M+H]+. tR1 = 11.6 min (major), tR2 = 19.6 min (minor) (Daicel
Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
(S
)-3-(1H-indol-3-yl)-3-(
p
-tolyl)isoindolin-1-one (2). White solid. Yield: 69 mg (98 %), 93:7
1
e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR (600 MHz,
DMSO) δ 11.00 (s, 1H), 9.52 (s, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.50 –
7.46 (m, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 9.0 Hz, 2H), 7.04
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– 6.97 (m, 1H), 6.88 – 6.71 (m, 3H), 2.25 (s, 3H). 13C NMR (75 MHz, DMSO) δ 168.9,
151.5, 140.3, 137.5, 136.9, 132.3, 131.5, 129.30, 128.6, 126.8, 125.6, 124.6, 123.6, 121.7,
120.4, 119.1, 117.3, 112.2, 66.5, 21.0. mp 265.9–267.3 °C. νmax (neat): 3289, 1676, 1352,
1107, 812, 736, 541 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H19N2O 339.1497;
Found 339.1486. tR1 = 12.2 min (major), tR2 = 22.6 min (minor) (Daicel Chiralpack ICꢀ3, 20%
IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(3,5-dimethylphenyl)-3-(1H-indol-3-yl)isoindolin-1-one (3). White solid. Yield: 66
1
mg (95 %), 93:7 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H
NMR (300 MHz, DMSO) δ 11.03 (s, 1H), 9.52 (s, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.64 – 7.46
(m, 3H), 7.36 (d, J = 8.2 Hz, 1H), 7.08 (s, 2H), 7.06 – 6.99 (m, 1H), 6.95 – 6.75 (m, 4H), 2.20
(s, 6H). 13C NMR (151 MHz, DMSO) δ 168.9, 151.4, 143.2, 137.6, 137.5, 132.2, 131.5,
129.3, 128.6, 125.6, 124.7, 124.6, 123.6, 121.7, 120.4, 119.1, 117.3, 112.2, 66.6, 21.6. mp
181.3–186.0 °C. νmax (neat): 3233, 2918, 1681, 1465, 1245, 1014, 739 cm–1. HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C24H21N2O 353.1654; Found 353.1671. tR1 = 11.1 min (major),
tR2 = 17.1 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-3-(1H-indol-3-yl)-3-(3-methoxyphenyl)isoindolin-1-one (4). White solid. Yield: 68 mg
1
(98 %), 91:9 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR
(300 MHz, DMSO) δ 11.07 (s, 1H), 9.61 (s, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.66 – 7.49 (m,
3H), 7.38 (d, J = 8.2 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.10 – 7.00 (m, 3H), 6.93 – 6.76 (m,
4H), 3.70 (s, 3H). 13C NMR (75 MHz, DMSO) δ 168.9, 159.5, 151.1, 144.9, 137.5, 132.3,
131.5, 129.9, 128.8, 125.5, 124.7, 123.6, 121.7, 120.3, 119.3, 119.1, 117.1, 113.3, 112.6,
112.2, 66.6, 55.5. mp 144.1–145.5 °C. νmax (neat): 3273, 1677, 1289, 1246, 1037, 703 cm–1.
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H19N2O2 355.1447; Found 355.1433. tR1 = 15.8
min (major), tR2 = 24.5 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0
mL/min, 220 nm).
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(S)-3-(1H-indol-3-yl)-3-(4-methoxyphenyl)isoindolin-1-one (5). White solid. Yield: 65 mg
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5
1
(94 %), 92:8 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR
(600 MHz, DMSO) δ 11.01 (s, 1H), 9.52 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.60 – 7.54 (m,
2H), 7.52 – 7.47 (m, 1H), 7.35 (t, J = 7.5 Hz, 3H), 7.03 (t, J = 7.5 Hz, 1H), 6.92 – 6.82 (m,
4H), 6.79 (t, J = 7.4 Hz, 1H), 3.73 (s, 3H). 13C NMR (151 MHz, DMSO) δ 168.8, 158.9,
151.7, 137.5, 135.1, 132.2, 131.5, 128.6, 128.1, 125.6, 124.6, 124.5, 123.5, 121.7, 120.4,
119.1, 117.5, 114.0, 112.2, 66.3, 55.5. mp 208.7–213.4 °C. νmax (neat): 3250, 1671, 1509,
1248, 1033, 740, 542 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H19N2O2 355.1447;
Found 355.1456. tR1 = 20.2 min (major), tR2 = 35.0 min (minor) (Daicel Chiralpack ICꢀ3, 20%
IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(3,5-dimethoxyphenyl)-3-(1H-indol-3-yl)isoindolin-1-one (6). White solid. Yield: 62
1
mg (92 %), 99:1 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H
NMR (300 MHz, DMSO) δ 11.04 (s, 1H), 9.55 (s, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.65 – 7.49
(m, 3H), 7.36 (d, J = 8.1 Hz, 1H), 7.06 – 6.99 (m, 1H), 6.88 (d, J = 2.5 Hz, 1H), 6.87 – 6.74
(m, J = 13.1, 6.4 Hz, 2H), 6.60 (d, J = 2.2 Hz, 2H), 6.45 (t, J = 2.1 Hz, 1H), 3.69 (s, 6H). 13C
NMR (151 MHz, DMSO) δ 168.9, 160.8, 150.9, 145.7, 137.5, 132.3, 131.6, 128.8, 125.6,
124.7, 124.7, 123.6, 121.7, 120.3, 119.1, 116.9, 112.2, 105.7, 98.9, 66.7, 55.6. mp 162.1–
166.4 °C. [α]D= +222° (c 0.5, MeOH). νmax (neat): 3233, 1683, 1591, 1456, 1152, 739 cm–1.
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C24H21N2O3 385.1552; Found 385.1534. tR1 = 17.8
min (major), tR2 = 24.2 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0
mL/min, 220 nm).
(S)-3-(1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)isoindolin-1-one (7). White solid.
Yield: 61 mg (90 %), 92:8 e.r. Column chromatography eluents: dichloromethaneꢀmethanol
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40:1. H NMR (600 MHz, DMSO) δ 11.16 (s, 1H), 9.77 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H),
7.73 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.63 – 7.59 (m,
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1H), 7.55 (t, J = 7.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.08 – 7.03 (m, 1H), 6.92 (d, J = 2.5
Hz, 1H), 6.85 – 6.81 (m, 2H). 13C NMR (151 MHz, DMSO) δ 168.9, 150.6, 148.0, 137.6,
132.6, 131.5, 129.1, 128.5 (q, J = 31.8 Hz), 127.7, 125.8 (q, J = 3.7 Hz), 125.4, 124.9, 124.7
(q, J = 271.9 Hz), 124.6, 123.8, 121.9, 120.2, 119.3, 116.4, 112.3, 66.5. mp 285.9–288.6 °C.
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ν
max (neat): 3292, 1674, 1325, 1132, 1068, 737, 595 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C23H16F3N2O 393.1215; Found 393.1215. tR1 = 7.8 min (major), tR2 = 13.2 min
(minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(1H-indol-3-yl)isoindolin-1-one (8). White solid.
Yield: 57 mg (90 %), 95:5 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate
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2:1. H NMR (600 MHz, DMSO) δ 11.23 (s, 1H), 9.85 (s, 1H), 8.15 – 8.09 (m, J = 17.3 Hz,
3H), 7.80 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.60 – 7.57 (m,
1H), 7.40 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.96 – 6.89 (m, J = 9.7 Hz, 1H), 6.83
(t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 168.8, 149.7,
146.7, 137.5, 133.0, 131.4, 130.9 (q, J = 32.9 Hz), 129.5, 127.5 (q, J = 3.2 Hz), 125.5, 125.0,
124.6, 124.0, 123.6 (q, J = 273.0 Hz), 122.3, 122.1, 119.6, 119.5, 115.7, 112.5, 66.2. mp
259.5–263.4 °C. νmax (neat): 3337, 1676, 1278, 1171, 1117, 743, 702, 680 cm–1. HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C24H15F6N2O 461.1089; Found 461.1106. tR1 = 6.9 min (major),
tR2 = 9.6 min (minor) (Daicel Chiralpack ICꢀ3, 10% IPA in hexane, 1.0 mL/min, 220 nm).
(S
)-3-(1H-indol-3-yl)-3-(
o
-tolyl)isoindolin-1-one (9). White solid. Yield: 61 mg (86 %),
1
80:20 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR (600
MHz, DMSO) δ 11.03 (s, 1H), 9.46 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.60 – 7.56 (m, J = 10.8,
4.0 Hz, 1H), 7.54 – 7.47 (m, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.17 –
7.10 (m, 4H), 7.08 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 1.95
(s, 3H). 13C NMR (151 MHz, DMSO) δ 169.4, 151.6, 139.7, 137.6, 133.0, 132.2, 131.5,
128.6, 128.5, 128.4, 126.2, 125.5, 124.6, 123.6, 122.9, 121.8, 120.4, 119.1, 118.4, 112.3, 67.5,
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21.4. mp 186.8–190.1 °C. νmax (neat): 3222, 1666, 1343, 1105, 732 cm–1. HRMS (ESIꢀTOF)
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m/z: [M+H]+ Calcd for C23H19N2O 339.1497; Found 339.1497. tR1 = 9.3 min (major), tR2
11.7 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
=
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(S)-3-(1H-indol-3-yl)-3-(2-(trifluoromethyl)phenyl)isoindolin-1-one (10). White solid.
Yield: 62 mg (93 %), 70:30 e.r. Column chromatography eluents: dichloromethaneꢀmethanol
1
40:1. H NMR (300 MHz, DMSO) δ 11.05 (s, 1H), 9.22 (s, 1H), 7.89 – 7.70 (m, 2H), 7.63 –
7.32 (m, 7H), 7.06 (t, J = 7.4 Hz, 1H), 7.00 – 6.80 (m, 2H), 6.71 (d, J = 1.9 Hz, 1H). 13C
NMR (151 MHz, DMSO) δ 169.6, 150.5, 141.1, 137.6, 132.7, 132.4, 132.2, 131.8, 128.9,
128.8, 128.4 (q, J = 6.8 Hz), 127.0 (q, J = 31.0 Hz), 125.2, 124.5 (q J = 274.1 Hz), 124.4,
123.7, 123.4, 121.9, 120.8, 119.5, 119.1, 112.2, 67.0. mp 274.7–278.0 °C. νmax (neat): 3292,
1679, 1308, 1152, 1128, 1111, 1037, 789, 739, 694 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C23H16F3N2O 393.1215; Found 393.1200. tR1 = 31.2 min (major), tR2 = 35.3 min
(minor) (Daicel Chiralpack ICꢀ3, 10% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-3-(4-fluorophenyl)-3-(1H-indol-3-yl)isoindolin-1-one (11). White solid. Yield: 68 mg
1
(97 %), 92:8 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR
(600 MHz, DMSO) δ 11.06 (s, 1H), 9.61 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.64 – 7.56 (m, J =
7.7 Hz, 2H), 7.55 – 7.51 (m, 1H), 7.48 (dd, J = 8.8, 5.4 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.16
(t, J = 8.8 Hz, 2H), 7.07 – 7.01 (m, J = 8.2, 5.7, 2.5 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 6.85 –
6.76 (m, 2H). 13C NMR (151 MHz, DMSO) δ 168.9, 161.9 (d, J = 243.8 Hz), 151.2, 139.5 (d,
J = 2.9 Hz), 137.5, 132.4, 131.5, 129.0 (d, J = 8.2 Hz), 128.8, 125.4, 124.7, 124.5, 123.7,
121.8, 120.3, 119.2, 117.1, 115.5 (d, J = 21.4 Hz), 112.3, 66.2. mp 216.3–219.9 °C. νmax
(neat): 3293, 1673, 1505, 1226, 739, 586 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C22H16FN2O 343.1247; Found 343.1237. tR1 = 11.8 min (major), tR2 = 18.4 min (minor)
(Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(4-chlorophenyl)-3-(1H-indol-3-yl)isoindolin-1-one (12). White solid. Yield: 40 mg
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5
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(58 %), 91:9 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR
(300 MHz, DMSO) δ 11.08 (s, 1H), 9.62 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.65 – 7.57 (m,
2H), 7.53 – 7.33 (m, 6H), 7.09 – 6.99 (m, 1H), 6.93 – 6.78 (m, 3H). 13C NMR (75 MHz,
DMSO) δ 168.9, 150.9, 142.4, 137.6, 132.6, 132.5, 131.5, 128.9, 128.8, 128.7, 125.4, 124.7,
124.5, 123.7, 121.8, 120.3, 119.2, 116.7, 112.3, 66.2. mp 256.3–259.9 °C. νmax (neat): 3273,
1670, 1333, 1013, 740, 539 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C22H16ClN2O
359.0951; Found 359.0963. tR1 = 32.0 min (major), tR2 = 61.4 min (minor) (Daicel Chiralpack
ICꢀ3, 10% IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(1H-indol-3-yl)-3-(naphthalen-2-yl)isoindolin-1-one (13). White solid. Yield: 40 mg
(59 %), 94:6 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. 1H NMR
(600 MHz, DMSO) δ 11.10 (s, 1H), 9.71 (s, 1H), 7.97 (s, 1H), 7.91 – 7.86 (m, 2H), 7.86 –
7.81 (m, 1H), 7.78 (d, J = 10.4 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.56 –
7.46 (m, 3H), 7.39 (d, J = 8.1 Hz, 1H), 7.07 – 7.00 (m, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.83 (d,
J = 8.0 Hz, 1H), 6.79 – 6.73 (m, 1H). 13C NMR (151 MHz, DMSO) δ 169.0, 151.2, 140.8,
137.5, 132.9, 132.7, 132.4, 131.6, 128.8, 128.5, 128.4, 127.9, 126.8, 126.7, 125.9, 125.6,
124.8, 124.7, 124.6, 123.7, 121.8, 120.3, 119.1, 117.1, 112.2, 66.8. mp 299.3–302.1 °C. νmax
(neat): 3180, 3053, 1671, 1242, 1107, 742, 478 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd
for C26H19N2O 375.1497; Found 375.1515. tR1 = 8.8 min (major), tR2 = 12.8 min (minor)
(Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-5,6-dichloro-3-(1H-indol-3-yl)-3-phenylisoindolin-1-one (14). White solid. Yield: 66
1
mg (90 %), 93:7 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H
NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 9.88 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.52 – 7.48
(m, 2H), 7.40 – 7.32 (m, 4H), 7.05 (ddd, J = 8.2, 6.2, 1.9 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H),
6.87 – 6.76 (m, 2H). 13C NMR (75 MHz, DMSO) δ 166.7, 151.2, 142.2, 137.5, 135.3, 132.3,
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132.1, 128.9, 128.2, 126.9, 126.7, 125.5, 125.4, 125.2, 121.9, 120.1, 119.3, 116.0, 112.3, 66.6.
mp 268.0–269.7 °C. νmax (neat): 3249, 1683, 1398, 1101, 782, 740 cm–1. HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C22H15Cl2N2O 393.0561; Found 393.0542. tR1 = 16.6 min (major), tR2
= 21.6 min (minor) (Daicel Chiralpack ICꢀ3, 30% IPA in hexane, 1.0 mL/min, 220 nm).
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(
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)-3-(furan-2-yl)-3-(1H-indol-3-yl)isoindolin-1-one (15). Brown solid. Yield: 56 mg (77
1
%), 80:20 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H NMR
(600 MHz, DMSO) δ 11.07 (s, 1H), 9.59 (s, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.68 – 7.61 (m,
1H), 7.61 – 7.54 (m, 2H), 7.54 – 7.49 (m, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.06 – 6.97 (m, J =
8.1, 6.2, 1.9 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.85 – 6.74 (m, 2H), 6.43 (dd, J = 3.2, 1.8 Hz,
1H), 6.32 (d, J = 3.0 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 168.9, 155.2, 149.4, 143.6,
137.2, 132.5, 131.6, 129.2, 125.2, 124.5, 124.4, 123.5, 121.7, 119.5, 119.3, 114.9, 112.3,
110.7, 107.3, 62.6. mp 237.2–240.4 °C. νmax (neat): 3187, 1670, 1352, 1011, 736 cm–1. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C20H15N2O2 315.1134; Found 315.1127. tR1 = 11.7 min
(major), tR2 = 23.8 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min,
220 nm).
(S
)-3-(1H-indol-3-yl)-3-(thiophen-2-yl)isoindolin-1-one (16). White solid. Yield: 50 mg (70
1
%), 82:18 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H NMR
(600 MHz, DMSO) δ 11.13 (s, 1H), 9.74 (s, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.65 – 7.60 (m, J =
7.6 Hz, 2H), 7.58 – 7.53 (m, J = 10.3, 3.9 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 8.1
13
Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H), 7.08 – 7.01 (m, 3H), 6.87 – 6.82 (m, J = 8.3 Hz, 2H). C
NMR (75 MHz, DMSO) δ 168.7, 151.4, 147.9, 137.4, 132.6, 131.1, 129.1, 127.5, 126.1,
125.6, 125.4, 124.8, 124.3, 123.6, 121.8, 120.1, 119.3, 116.6, 112.3, 64.3. mp 285.6–289.4
°C. νmax (neat): 3182, 1679, 1339, 1077, 740, 596 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C20H15N2OS 331.0905; Found 331.0908. tR1 = 12.3 min (major), tR2 = 23.5 min
(minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
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(S
)-3-butyl-3-(1H-indol-3-yl)isoindolin-1-one (17).13 White solid. Yield: 73 mg (98 %),
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60:40 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H NMR (600
MHz, DMSO) δ 11.04 (s, 1H), 8.86 (s, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.50 – 7.41 (m, J = 14.7,
7.4, 0.9 Hz, 3H), 7.33 (dd, J = 12.1, 7.9 Hz, 2H), 7.02 – 6.94 (m, 2H), 6.81 – 6.76 (m, 1H),
2.47 – 2.41 (m, 1H), 2.34 – 2.27 (m, J = 13.5, 4.5 Hz, 1H), 1.30 – 1.16 (m, J = 18.5, 12.5, 6.6
Hz, 4H), 0.80 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, DMSO) δ 169.4, 152.1, 137.2, 132.4,
132.2, 128.2, 125.2, 123.5, 123.0, 122.8, 121.4, 119.7, 118.9, 116.5, 112.1, 63.6, 37.9, 25.7,
22.7, 14.4. ESI–MS: 305 [M+H+]. tR1 = 8.2 min (major), tR2 = 17.0 min (minor) (Daicel
Chiralpack AD, 20% IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-benzyl-3-(1H-indol-3-yl)isoindolin-1-one (18). White solid. Yield: 47 mg (66 %),
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84:16 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H NMR (600
MHz, DMSO) δ 11.13 (s, 1H), 8.92 (s, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.52 – 7.45 (m, J = 14.6,
7.5 Hz, 2H), 7.37 (dd, J = 19.9, 7.8 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.01 (dd, J = 8.7, 3.9
Hz, 4H), 6.94 – 6.87 (m, 3H), 6.78 (t, J = 7.5 Hz, 1H), 3.86 (d, J = 13.2 Hz, 1H), 3.67 (d, J =
13
13.1 Hz, 1H) C NMR (75 MHz, DMSO) δ 169.0, 150.6, 137.2, 135.8, 132.8, 131.6, 131.1,
128.1, 127.5, 126.5, 125.3, 123.7, 123.6, 122.6, 121.5, 119.7, 119.0, 116.7, 112.1, 63.9, 43.5.
mp 211.0–213.0 °C. νmax (neat): 3192, 1673, 1455, 1120, 739, 697 cm–1. HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C23H19N2O 338.1419; Found 338.1426. tR1 = 12.2 min (minor), tR2
39.7 min (major) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
=
(S)-3-(5-nitro-1H-indol-3-yl)-3-phenylisoindolin-1-one (19). Yellow solid. Yield: 79 mg
1
(96 %), 85:15 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H
NMR (300 MHz, DMSO) δ 11.81 (s, 1H), 9.82 (s, 1H), 7.96 (dd, J = 9.0, 2.2 Hz, 1H), 7.83 –
7.73 (m, 2H), 7.66 – 7.59 (m, 2H), 7.59 – 7.52 (m, 2H), 7.52 – 7.44 (m, J = 8.1, 1.4 Hz, 2H),
13
7.42 – 7.28 (m, 3H), 7.16 (d, J = 2.2 Hz, 1H). C NMR (151 MHz, DMSO) δ 169.0, 150.7,
142.8, 140.8, 140.7, 132.6, 131.4, 129.1, 129.0, 128.6, 128.2, 126.7, 124.8, 124.6, 123.8,
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120.1, 117.6, 117.2, 112.8, 66.1. mp 318.8–323.1 °C. νmax (neat): 3203, 1667, 1332, 1254,
1048, 738, 692 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C22H16N3O3 370.1192; Found
370.1193. tR1 = 59.8 min (major), tR2 = 72.0 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in
hexane, 1.0 mL/min, 220 nm).
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(
S
)-3-(5-methyl-1H-indol-3-yl)-3-phenylisoindolin-1-one (20). White solid. Yield: 67 mg
1
(89 %), 92:8 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H NMR
(300 MHz, DMSO) δ 10.92 (s, 1H), 9.57 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.63 – 7.39 (m,
5H), 7.38 – 7.20 (m, J = 22.1, 9.2, 5.4 Hz, 4H), 6.86 (dd, J = 8.3, 1.2 Hz, 1H), 6.81 (d, J = 2.6
Hz, 1H), 6.65 (s, 1H), 2.16 (s, 3H). 13C NMR (151 MHz, DMSO) δ 169.0, 151.4, 143.3,
135.9, 132.3, 131.5, 128.7, 128.7, 127.8, 127.4, 126.9, 125.8, 124.7, 124.6, 123.6, 123.4,
120.1, 116.6, 111.9, 66.7, 21.8. mp 239.1–240.3 °C. νmax (neat): 3272, 1669, 1315, 1030, 697,
539 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H19N2O 339.1497; Found 339.1497.
tR1 = 10.3 min (major), tR2 = 21.2 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane,
1.0 mL/min, 220 nm).
(S)-3-phenyl-3-(5-(trifluoromethyl)-1H-indol-3-yl)isoindolin-1-one (21). White solid.
Yield: 62 mg (71 %), 89:11 e.r. Column chromatography eluents: dichloromethaneꢀmethanol
1
40:1. H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 9.79 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H),
7.64 – 7.43 (m, 6H), 7.40 – 7.27 (m, 4H), 7.13 (s, 1H), 7.05 (s, 1H). 13C NMR (151 MHz,
DMSO) δ 169.0, 150.9, 142.9, 139.0, 132.5, 131.4, 128.9, 128.9, 128.1, 127.1, 126.7, 125.8
(q, J = 271.4 Hz), 124.8, 124.6, 123.7, 119.9 (q, J = 30.9 Hz), 118.2 (q, J = 3.2 Hz), 113.1,
66.3. mp 275.3–277.5 °C. νmax (neat): 3270, 1670, 1329, 1108, 746, 699, 589 cm–1. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C23H16F3N2O 393.1215; Found 393.1216. tR1 = 13.2 min
(major), tR2 = 19.2 min (minor) (Daicel Chiralpack ICꢀ3, 10% IPA in hexane, 1.0 mL/min,
220 nm).
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(S)-3-(7-fluoro-1H-indol-3-yl)-3-phenylisoindolin-1-one (22). White solid. Yield: 65 mg
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(86 %), 85:15 e.r. Column chromatography eluents: dichloromethaneꢀmethanol 40:1. H
NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 9.66 (s, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.65 – 7.44
(m, 5H), 7.39 – 7.27 (m, 3H), 6.94 – 6.84 (m, 2H), 6.82 – 6.73 (m, 1H), 6.63 (d, J = 8.0 Hz,
1H). 13C NMR (151 MHz, DMSO) δ 168.9, 151.0, 149.6 (d, J = 243.3 Hz), 142.9, 132.4,
131.5, 129.5 (d, J = 5.6 Hz), 128.9, 128.8, 127.9, 126.8, 125.7, 125.4 (d, J = 13.5 Hz), 124.6,
123.7, 119.5 (d, J = 6.0 Hz), 118.6, 116.6 (d, J = 3.1 Hz), 106.6 (d, J = 15.7 Hz), 66.4. mp
261.6–264.6 °C. νmax (neat): 3254, 1670, 1321, 1235, 1031, 696 cm–1. HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C22H16FN2O 343.1260; Found 343.1247. tR1 = 9.8 min (major), tR2 = 16.2
min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(5-methoxy-1H-indol-3-yl)-3-(3-methoxyphenyl)isoindolin-1-one (23). White solid.
Yield: 68 mg (90 %), 89:11 e.r. Column chromatography eluents: dichloromethaneꢀmethanol
1
40:1. H NMR (600 MHz, DMSO) δ 10.87 (s, 1H), 9.60 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H),
7.62 (d, J = 7.6 Hz, 1H), 7.59 – 7.55 (m, 1H), 7.51 (dd, J = 10.8, 4.0 Hz, 1H), 7.27 – 7.23 (m,
2H), 7.04 – 7.01 (m, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.2, 2.0 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H),
13
6.69 (dd, J = 8.8, 2.4 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 3.68 (s, 3H), 3.48 (s, 3H). C NMR
(75 MHz, DMSO) δ 169.0, 159.6, 153.2, 151.1, 144.8, 132.6, 132.3, 131.6, 129.8, 128.8,
126.0, 125.3, 124.7, 123.5, 119.2, 116.6, 113.3, 112.7, 112.6, 111.5, 102.7, 66.6, 55.5, 55.4.
mp 203.4–207.8 °C. νmax (neat): 3233, 1681, 1465, 1215, 1034, 740 cm–1. HRMS (ESIꢀTOF)
m/z: [M+H]+ Calcd for C24H20F3N2O3 385.1552; Found 385.1550. tR1 = 13.5 min (major), tR2
= 31.1 min (minor) (Daicel Chiralpack ICꢀ3, 30% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-3-(5-(benzyloxy)-1H-indol-3-yl)-3-(3-methoxyphenyl)isoindolin-1-one (24). White
solid. Yield: 78 mg (87 %), 88:12 e.r. Column chromatography eluents: dichloromethaneꢀ
1
methanol 40:1. H NMR (300 MHz, DMSO) δ 10.90 (s, 1H), 9.62 (s, 1H), 7.74 (dd, J = 6.1,
1.9 Hz, 1H), 7.58 – 7.48 (m, 3H), 7.37 – 7.23 (m, 7H), 7.04 – 6.96 (m, 2H), 6.88 (dd, J = 9.3,
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2.3 Hz, 2H), 6.77 (dd, J = 8.8, 2.4 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 4.84 (dd, J = 27.7, 12.2
Hz, 2H), 3.69 (s, 3H). 13C NMR (151 MHz, DMSO) δ 169.0, 159.6, 152.1, 151.1, 144.8,
137.9, 132.8, 132.3, 131.5, 129.9, 128.8, 128.7, 128.0, 125.9, 125.1, 124.6, 123.6, 119.2,
116.7, 113.3, 112.8, 112.7, 112.4, 104.3, 70.1, 66.6, 55.5. mp 129.1–133.1 °C. νmax (neat):
3225, 1683, 1465, 1254, 1038, 782, 737, 696, 593 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C30H25F3N2O3 461.1865; Found 461.1846. tR1 = 10.3 min (major), tR2 = 22.1 min
(minor) (Daicel Chiralpack ICꢀ3, 30% IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(1-(3-methoxyphenyl)-3-oxoisoindolin-1-yl)-1H-indol-4-yl acetate (25). White solid.
Yield: 79 mg (98 %), 87:13 e.r. Column chromatography eluents: dichloromethaneꢀmethanol
1
40:1. H NMR (300 MHz, DMSO) δ 11.33 (s, 1H), 8.49 (s, 1H), 7.75 (d, J = 7.3 Hz, 1H),
7.65 – 7.47 (m, 3H), 7.32 (d, J = 8.1 Hz, 1H), 7.21 – 7.06 (m, 3H), 6.99 – 6.88 (m, 1H), 6.77
– 6.64 (m, 3H), 3.61 (s, 3H), 1.67 (s, 3H). 13C NMR (75 MHz, DMSO) δ 169.0, 168.7, 159.7,
151.6, 145.8, 143.2, 140.3, 132.6, 130.9, 130.2, 128.8, 125.7, 124.7, 123.9, 122.4, 118.6,
117.9, 114.4, 113.2, 112.7, 112.5, 109.8, 66.7, 55.4, 21.0. mp 252.7–256.2 °C. νmax (neat):
3324, 1681, 1323, 1195, 1040, 750, 583 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C25H21F3N2O4 413.1501; Found 413.1490. tR1 = 21.4 min (major), tR2 = 25.0 min (minor)
(Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-5,6-dichloro-3-(5-chloro-1H-indol-3-yl)-3-(3-methoxyphenyl)isoindolin-1-one
(26).
White solid. Yield: 68 mg (97 %), 87:13 e.r. Column chromatography eluents: petroleum
etherꢀethyl acetate 2:1. 1H NMR (300 MHz, DMSO) δ 11.37 (s, 1H), 9.99 (s, 1H), 7.96 (d, J =
3.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.11 – 6.99 (m, 4H), 6.97 –
6.86 (m, 2H), 3.74 (s, 3H). 13C NMR (75 MHz, DMSO) δ 166.7, 159.7, 150.6, 143.6, 136.0,
135.5, 132.4, 131.9, 130.3, 126.9, 126.8, 126.4, 125.6, 123.9, 122.0, 119.4, 119.1, 115.8,
113.9, 113.1, 66.2, 55.6. mp 165.8–169.3 °C. νmax (neat): 3177, 1693, 1239, 893, 773, 466 cm–
1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H16N2O2 457.0277; Found 457.0269. tR1
=
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12.3 min (major), tR2 = 14.2 min (minor) (Daicel Chiralpack ICꢀ3, 10% IPA in hexane, 1.0
mL/min, 220 nm).
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(S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(6-fluoro-1H-indol-3-yl)isoindolin-1-one
(27).
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White solid. Yield: 50 mg (76 %), 96:4 e.r. Column chromatography eluents: petroleum etherꢀ
ethyl acetate 2:1. 1H NMR (300 MHz, DMSO) δ 11.28 (s, 1H), 9.86 (s, 1H), 8.15 – 8.05 (m, J
= 12.8 Hz, 3H), 7.83 – 7.57 (m, 4H), 7.18 (dd, J = 9.9, 2.0 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H),
6.80 – 6.60 (m, 2H). 13C NMR (151 MHz, DMSO) δ 168.8, 159.3 (d, J = 235.6 Hz), 149.5,
146.5, 137.5 (d, J = 12.7 Hz), 133.1, 131.3, 130.9 (q, J = 32.8 Hz), 129.6, 127.5 (q, J = 3.0
Hz), 124.1, 123.6 (q, J = 273.0 Hz), 121.9, 120.7 (d, J = 10.1 Hz), 116.0, 108.2 (d, J = 24.4
Hz), 98.4 (d, J = 25.4 Hz), 66.1. mp 316.4–318.9 °C. [α]D= +125° (c 1, MeOH). νmax (neat):
3329, 1674, 1278, 1121, 807, 699 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C24H14F7N2O 479.0994; Found 479.1001. tR1 = 6.9 min (major), tR2 = 9.0 min (minor) (Daicel
Chiralpack ICꢀ3, 10% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-3-(3,5-dimethoxyphenyl)-3-(7-fluoro-1H-indol-3-yl)isoindolin-1-one (28). White solid.
Yield: 50 mg (71 %), 98:2 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate
2:1. 1H NMR (600 MHz, DMSO) δ 11.56 (s, 1H), 9.57 (s, 1H), 7.75 – 7.70 (m, 1H), 7.63 (d, J
= 7.7 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.54 – 7.49 (m, 1H), 6.92 – 6.84 (m, 2H), 6.81 – 6.75 (m,
1H), 6.66 (d, J = 8.0 Hz, 1H), 6.60 – 6.56 (m, 2H), 6.47 – 6.42 (m, 1H), 3.66 (s, 6H). 13C
NMR (151 MHz, DMSO) δ 168.9, 160.8, 150.7, 149.6 (d, J = 243.2 Hz), 145.4, 132.4, 131.5,
129.4 (d, J = 5.5 Hz), 128.9, 125.7, 125.3 (d, J = 13.4 Hz), 124.7, 123.6, 119.6 (d, J = 5.9 Hz),
118.3, 116.5 (d, J = 2.8 Hz), 106.6 (d, J = 15.8 Hz), 105.6, 99.0, 66.4, 55.6. mp 222.1–226.8
°C. [α]D= +159° (c 1, MeOH). νmax (neat): 3259, 1676, 1422, 1154, 697, 537 cm–1. HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C24H20FN2O3 403.1458; Found 403.1454. tR1 = 13.8 min
(major), tR2 = 20.4 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min,
220 nm).
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solid. Yield: 60 mg (86 %), 99:1 e.r. Column chromatography eluents: petroleum etherꢀethyl
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acetate 2:1. H NMR (300 MHz, DMSO) δ 10.89 (s, 1H), 9.51 (s, 1H), 7.73 (d, J = 7.3 Hz,
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1H), 7.63 – 7.48 (m, 3H), 7.25 (d, J = 8.3 Hz, 1H), 6.92 – 6.80 (m, 2H), 6.71 (s, 1H), 6.59 (d,
J = 2.1 Hz, 2H), 6.49 – 6.41 (m, 1H), 3.69 (s, 6H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO)
δ 169.0, 160.7, 151.0, 145.8, 135.8, 132.2, 131.5, 128.7, 127.4, 125.8, 124.8, 124.7, 123.6,
123.4, 119.9, 116.3, 111.9, 105.7, 98.9, 66.7, 55.6, 21.8. mp 142.4–145.7 °C. [α]D= +170° (c
1, MeOH). νmax (neat): 3235, 2929, 1683, 1423, 1154, 724, 593 cm–1. HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C25H23N2O3 399.1709; Found 399.1727. tR1 = 16.4 min (major), tR2 = 26.0
min (minor) (Daicel Chiralpack ICꢀ3, 10% IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(6-chloro-1H-indol-3-yl)-3-(3,5-dimethoxyphenyl)isoindolin-1-one (30). White solid.
Yield: 61 mg (83 %), 99.5:0.5 e.r. Column chromatography eluents: petroleum etherꢀethyl
1
acetate 2:1. H NMR (300 MHz, DMSO) δ 11.19 (s, 1H), 9.62 (s, 1H), 7.74 (d, J = 7.2 Hz,
1H), 7.66 – 7.49 (m, 3H), 7.42 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.85 (s, 2H), 6.58 (d, J = 2.1
13
Hz, 2H), 6.47 (d, J = 2.0 Hz, 1H), 3.70 (s, 6H). C NMR (75 MHz, DMSO) δ 168.9, 160.8,
150.7, 145.4, 137.9, 132.4, 131.4, 128.9, 126.6, 125.9, 124.6, 124.4, 123.7, 121.6, 119.5,
117.3, 111.8, 105.6, 99.0, 66.4, 55.6. mp 334.8–338.4 °C. [α]D= +169° (c 1, MeOH). νmax
(neat): 3262, 1680, 1455, 1154, 699, 582 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C24H20ClN2O3 419.1162; Found 419.1181. tR1 = 43.8 min (major), tR2 = 55.7 min (minor)
(Daicel Chiralpack ICꢀ3, 10% IPA in hexane, 1.0 mL/min, 220 nm).
(S)-3-(5-bromo-1H-indol-3-yl)-3-(3,5-dimethoxyphenyl)isoindolin-1-one (31). White
solid. Yield: 60 mg (74 %), 98:2 e.r. Column chromatography eluents: petroleum etherꢀethyl
1
acetate 2:1. H NMR (600 MHz, DMSO) δ 11.26 (s, 1H), 9.65 (s, 1H), 7.74 (d, J = 7.4 Hz,
1H), 7.65 – 7.58 (m, 2H), 7.57 – 7.50 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.17 (dd, J = 8.6, 1.8
Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 2.2 Hz, 2H), 6.47 (t, J
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= 2.1 Hz, 1H), 3.69 (s, 6H). 13C NMR (151 MHz, DMSO) δ 169.0, 160.8, 150.7, 145.4, 136.1,
132.4, 131.4, 129.0, 127.3, 126.4, 124.7, 124.4, 123.7, 122.4, 116.7, 114.3, 111.9, 105.6, 99.0,
66.3, 55.7. mp 303.2–305.9 °C. Solution of the sample is too opaque for [α]D measurement.
νmax (neat): 3287, 1677, 1315, 1158, 697, 590 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C24H20BrN2O3 463.0657; Found 463.0640. tR1 = 11.8 min (major), tR2 = 18.2 min (minor)
(Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
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(S)-3-(3,5-dimethoxyphenyl)-3-(5-nitro-1H-indol-3-yl)isoindolin-1-one (32). Yellow solid.
Yield: 30 mg (40 %), >99.5:0.5 e.r. Column chromatography eluents: petroleum etherꢀethyl
1
acetate 2:1. H NMR (600 MHz, DMSO) δ 11.80 (s, 1H), 9.77 (s, 1H), 7.96 (dd, J = 9.0, 2.3
Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.79 – 7.75 (m, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.62 (td, J =
7.5, 1.2 Hz, 1H), 7.59 – 7.54 (m, 2H), 7.18 (s, 1H), 6.61 (d, J = 2.2 Hz, 2H), 6.49 (t, J = 2.2
Hz, 1H), 3.69 (s, 6H). 13C NMR (75 MHz, DMSO) δ 169.0, 160.9, 150.4, 145.1, 140.8, 140.6,
132.6, 131.3, 129.2, 128.7, 124.7, 123.8, 119.7, 117.4, 117.3, 112.8, 105.5, 99.2, 66.1, 55.7.
mp 134.5–138.7 °C. [α]D= –27° (c 1, MeOH). νmax (neat): 3208, 2931, 1687, 1332, 1052, 742,
598 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C24H20N3O5 430.1403; Found 430.1382.
tR1 = 33.5 min (major), tR2 = 61.6 min (minor) (Daicel Chiralpack ICꢀ3, 30% IPA in hexane,
1.0 mL/min, 220 nm).
(S)-3-(3,5-dimethoxyphenyl)-3-(6-fluoro-1H-indol-3-yl)isoindolin-1-one (33). White solid.
Yield: 66 mg (94 %), 99.5:0.5 e.r. Column chromatography eluents: petroleum etherꢀethyl
1
acetate 2:1. H NMR (300 MHz, DMSO) δ 11.09 (s, 1H), 9.58 (s, 1H), 7.74 (d, J = 7.3 Hz,
1H), 7.65 – 7.49 (m, 3H), 7.14 (dd, J = 10.0, 2.2 Hz, 1H), 6.93 – 6.78 (m, 2H), 6.71 (td, J =
9.5, 2.3 Hz, 1H), 6.59 (d, J = 2.1 Hz, 2H), 6.51 – 6.41 (m, 1H), 3.68 (s, 6H). 13C NMR (75
MHz, DMSO) δ 168.9, 159.2 (d, J = 235.9 Hz), 150.8, 145.5, 137.4 (d, J = 12.6 Hz), 132.3,
131.5, 128.9, 125.4, 124.6, 123.6, 122.4, 121.3 (d, J = 10.0 Hz), 117.2, 107.7 (d, J = 24.2 Hz),
105.6, 99.0, 98.1 (d, J = 25.4 Hz), 66.5, 55.6. mp 244.5–247.0 °C. Solution of the sample is
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too opaque for [α]D measurement. νmax (neat): 3321, 1677, 1589, 1312, 1157, 800, 697 cm–1.
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HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C24H20FN2O3 403.1458; Found 403.1475. tR1
=
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42.8min (major), tR2 = 50.3 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0
mL/min, 220 nm).
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(
S
)-3-(1H-indol-3-yl)-2-methyl-3-phenylisoindolin-1-one (34). White solid. Yield: 62 mg
1
(88 %), 63:37 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H
NMR (300 MHz, DMSO) δ 11.29 (s, 1H), 7.83 – 7.77 (m, 1H), 7.54 – 7.48 (m, 3H), 7.44 –
7.34 (m, 6H), 7.09 – 7.01 (m, 2H), 6.83 – 6.75 (m, 1H), 6.45 (d, J = 8.1 Hz, 1H), 2.79 (s, 3H).
13C NMR (75 MHz, DMSO) δ 167.4, 151.3, 140.7, 137.4, 132.5, 130.6, 129.2, 128.8, 128.3,
127.3, 126.7, 125.8, 124.1, 123.4, 121.7, 119.9, 119.5, 113.2, 112.6, 71.5, 26.3. mp 244.5–
247.0 °C. νmax (neat): 3260, 1671, 1380, 818, 759 cm–1. HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C23H19N2O 339.1497; Found 339.1501. tR1 = 21.4 min (major), tR2 = 29.5 min
(minor) (AD, 10% EtOH in hexane, 1.0 mL/min, 220 nm).
(S
)-3-(1-benzyl-1H-indol-3-yl)-3-phenylisoindolin-1-one (35). White solid. Yield: 75 mg
1
(81 %), 47:53 e.r. Column chromatography eluents: petroleum etherꢀethyl acetate 2:1. H
NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.69 – 7.45 (m, 5H), 7.43 –
7.20 (m, 7H), 7.20 – 7.10 (m, 3H), 7.09 – 6.99 (m, 1H), 6.87 – 6.74 (m, 2H), 5.39 (s, 2H). 13C
NMR (75 MHz, DMSO) δ 168.9, 151.2, 143.2, 138.6, 137.3, 132.4, 131.5, 129.0, 128.8,
128.6, 127.9, 127.8, 127.4, 126.8, 126.3, 124.6, 123.7, 122.0, 120.8, 119.4, 117.0, 110.9, 66.6,
49.5. mp 244.5 – 247.0 °C. νmax (neat): 3058, 1684, 1351, 1175, 739, 690 cm–1. HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C29H23N2O 415.1810; Found 415.1805. tR1 = 16.6 min (major),
tR2 = 17.0 min (minor) (Daicel Chiralpack ICꢀ3, 20% IPA in hexane, 1.0 mL/min, 220 nm).
Acknowledgements
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This work was supported by the AbbvieꢀCroatian Science Foundation Young Researcher
Grant 2015 and Science and Technology Commission of Shanghai Municipality
(16490712200). We are grateful to the Croatian Academy of Sciences and Arts, and to the
Chinese Academy of Sciences.
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Supporting Information: 1H and 13C NMR spectra, HPLC traces, the assignation of absolute
stereochemistry, complete catalyst screening, and DFT calculation parameters.
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