Chiral Phosphoric Acid-Catalyzed Synthesis of Fluorinated 5,6-Dihydroindolo[1,2- c]quinazolines with Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.joc.9b00985

A chiral phosphoric acid-catalyzed enantioselective synthesis of fluorinated 5,6-dihydroindolo[1,2-c]quinazolines has been developed by a condensation/amine addition cascade from 2-(1H-indolyl)anilines and fluorinated ketones, giving the fluorinated aminals with quaternary stereogenic centers with excellent yields and up to 97% ee. A series of the fluorinated aromatic, aliphatic ketones, and ethyl trifluoropyruvate are suitable.

Full text of DOI:10.1021/acs.joc.9b00985

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Note
Chiral Phosphoric Acid-Catalyzed Synthesis of Fluorinated 5,6-
Dihydroindolo[1,2-c]quinazolines with Quaternary Stereocenters
Xin-Wei Wang, Mu-Wang Chen, Bo Wu, Baomin Wang, and Yong-Gui Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00985 • Publication Date (Web): 27 May 2019
Downloaded from http://pubs.acs.org on May 28, 2019
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Chiral Phosphoric Acid-Catalyzed Synthesis of Fluorinated 5,6-
8
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Dihydroindolo[1,2-c]quinazolines
Stereocenters
with
Quaternary
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Xin-Wei Wang,a,b,c Mu-Wang Chen,a Bo Wu,a Baomin Wang,c and Yong-Gui
Zhoua,b*
a
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China
b University of Chinese Academy of Sciences, Beijing 100049, P. R. China
c State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116024, P. R. China
*E-mail: ygzhou@dicp.ac.cn.
ABSTRACT
R'
R'
O
(R)-TRIP
N
+
toluene, 5 Å MS
R
CF3
N
NH
H
R
H2N
CF3
20 Examples, up to 97% ee
Quaternary Stereocenters
A chiral phosphoric acid-catalyzed enantioselective synthesis of fluorinated 5,6-dihydroindolo[1,2-
c]quinazolines has been developed by condensation/amine addition cascade from 2-(1H-indolyl)anilines and
fluorinated ketones, giving the fluorinated aminals with quaternary stereogenic centers with excellent yields
and up to 97% ee. A series of the fluorinated aromatic, aliphatic ketones and ethyl trifluoropyruvate are
suitable.
Chiral aminal moieties are common structural unit in myriad natural products, synthetic pharmaceutical
molecules and chiral catalysts.1 Among them, the optically active 5,6-dihydroindolo[1,2-c]quinazolines
could be also found in natural products and pharmaceutical molecules.2 For instance, (-)-goniomitine is a
natural occurring alkaloid,2a and compound A is an original semi-synthetic cytotoxic bisindole alkaloid2b
(Figure 1).
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OH
CO2Me
N
HN
HO
N
Me
H
N
N
H
N
HO
H
N
HO
CO2Me
Me
(-)-Goniomitine
Me
A
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Figure 1. The selected bioactive 5,6-dihydroindolo[1,2-c]quinazolines .
Owing to the importance of chiral aminals, continuous efforts have been devoted to synthesize these
compounds. In 2003, Ramsden’s group reported the first enantioselective synthesis of the chiral aminal by
asymmetric hydrogenation of dihydropyrrolobenzothiadiazine dioxide using a diphosphine ruthenium
diamine catalyst with 87% ee.3 Since then, some efficient methods have been successfully developed for
synthesis of chiral aminals. Enantioselective amidations of imines catalyzed by VAPOL-derived phosphoric
acid were developed by Antilla’s group.4 Asymmetric cyclization of aldehydes or aldimines with 2-
aminobenzamides, 2-amino-benzenesulfona-mides, N-(2,6-diisopropylbenzyl)ethane-1,2-diamine and 2-(1H-
pyrrol-2-yl)aniline could be catalyzed by Brønsted acids,5 Lewis acids6 and organocatalysts,7 respectively.
Diastereo- and enantioselective [3+2],8 [3+3],9 and [4+2]10 cycloadditions were also established. Antilla’s,
You’s and Ma’s groups demonstrated asymmetric cascade dearomatization procedures for formation of
pyrroloindolines.11 Chiral phosphoric acid catalyzed asymmetric tandem 1,5-hydride transfer/ring closing to
give cyclic aminals was disclosed by Gong’s group.12 Li and co-workers described a novel approach to
aminals via palladium-catalyzed C−N coupling with chiral bisphosphine monooxides.13 Enantioselective N–
H functionalizations of indoles catalyzed by chiral phosphoric acids or dinuclear zinc-ProPhenol were
realized.14
Compared to chiral aminals containing tertiary stereocenters, asymmetric synthesis of chiral aminals
bearing quaternary stereocenters have been relatively less studied owing to low activity of ketones and
ketimines. Consequently, the reactions of highly reactive cyclic isatins were investigated by List,5a Shi9,15
and Wang16 to give spirocyclic aminals using chiral phosphoric acids as catalysts. Another approach to chiral
aminals containing quaternary stereocenters is enantioselective hydrazination of -aminocarbonyl
compounds by organocatalysis.17 Recently, Zhong and co-workers demonstrated a chiral SPINOL-derived
phosphoric acid-catalyzed asymmetric N-alkylation reaction of indoles and 3-aryl 3-hydroxyisoin-dolinones
with excellent enantioselectivities.14d
The chemistry of organofluorine compounds has been of great importance, since the incorporation of
fluorine into organic molecules can modify their physical, chemical, and biological properties.18 However,
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asymmetric synthesis of fluorinated aminals has been rarely explored. Wang group developed Cu(I)-
catalyzed 1,3-dipolar cycloaddition of azomethine ylides with fluorinated imines for synthesis of fluorinated
imidazolidines (Scheme 1a).8b Toste and co-workers demonstrated enantioselective synthesis of
fluoro−dihydroquinazolones by fluorination-initiated asymmetric cyclization (Scheme 1b).19 Cation-directed
highly enantioselective N-functionalization of pyrroles was developed by Smith group, which was the only
enantioselective synthesis of chiral aminals with quaternary stereogenic centers from linear aliphatic ketones
(Scheme 1c).7a The method acquired pre-preparation of ketimines by condensation of 2-(1H-pyrrol-2-
yl)aniline and excess trifluoromethyl ketones with moderate yields. Due to relatively lower reactivity of
linear aromatic ketones, to the best of our knowledge, the use of linear aromatic ketones for enantioselective
synthesis of aminals has not been documented. Herein, we reported a chiral phosphoric acid-catalyzed direct
enantioselective synthesis of fluorinated 5,6-dihydroindolo[1,2-c]quinazolines with quaternary stereocenters
from linear fluorinated ketones and 2-(1H-indolyl)anilines with excellent yields and up to 97% ee (Scheme
1d).
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Scheme 1. Synthesis of chiral fluorinated aminals
Cu(I)-catalyzed Asymmetric 1,3-Dipolar Cycloaddition by Wang (2013)
Rf
PMP
Cu(I)/L
N
PMP
+
R
N
CO2Me
N
Rf
(a)
CO2Me
R
N
H
Fluorination-initiated Asymmetric Cyclization Reactions by Toste (2016)
O
O
R
Chiral PTC
N
NH
Ar
Ar
H
(b)
(c)
Selectfluor, Na2CO3
NHR'
N
F
R'
R
Asymmetric Phase-transfer Catalysis by Smith Group (2016)
RCOCF3
Chiral PTC
KOH (aq.)
N
H
N
N
toluene, MgSO4
N
H
N
H2N
F3C
H
R
F3C
R
Two examples: R = Me, Et
This work: Brønsted Acid-Catalyzed Synthesis of Chiral Aminals
R'
R'
O
(R)-TRIP
(d)
N
+
toluene, 5 Å MS
R
Rf
R = Ar, Alkyl, CO2Et
Quaternary Stereocenters
N
NH
H
R
H2N
Rf
20 Examples, up to 97% ee
Initially, we chose 5 mol% of chiral phosphoric acid (R)-4a as catalyst to test the reaction of 2-(1H-
indolyl)aniline 1a and simple trifluoromethyl phenyl ketone 2a in toluene at room temperature, but no
reaction was observed. To our delight, the desired product 3aa could be obtained in 61% yield and 92% ee
o
when the reaction was performed at 80 C for 48 h (Table 1, entry 1). Subsequently, different solvents
including 1,2-dichloroethane, acetonitrile and 1,4-dioxane were examined (Table 1, entries 2-4). The results
revealed that solvents effect played a crucial role; toluene is the best in term of yield and enantioselectivity.
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Further screening of aromatic solvents, toluene was more suitable than the others (Table 1, entries 5-7).
Subsequently, some commercially available chiral phosphoric acids were evaluated using toluene as solvent
(Table 1, entries 8-14). It should be noteworthy that steric hindrance of the substituted groups at the 3,3′-
positions of chiral phosphoric acids displayed a profound influence on enantioselectivity and reactivity. The
sterically congested catalysts furnished the reaction in higher yields (Table 1, entries 10-13 vs 8-9). However,
catalyst (R)-4h bearing a triphenylsilyl group at 3,3’-positions of the binaphthyl unit was not effective (Table
1, entry 14). In the presence of 50 mg 5 Å MS as dehydrating agent, the reaction proceeded smoothly, giving
3aa in 71% yield without influence of enantisoselectivity (Table 1, entry 15). Increasing the ratio of 2a to
1.5 equiv., the yield can improved to 95% with slightly lower ee (Table 1, entry 16). When reaction
temperature was decreased to 70 oC, 94% ee could be obtained (Table 1, entry 17) albeit with low reactivity.
Raising the temperature to 90 oC, the ee value dropped to 85% (Table 1, entry 18). Additionally, the reaction
concentrations had remarkable influences on reactivity (Table 1, entries 19 and 20). Prolong reaction time to
72 h using 1.0 mL toluene, 94% yield and 92% ee could be gained (Table 1, entry 21). Finally, the optimized
reaction condition was established: 5 mol% (R)-4a as catalyst, 1.5 equiv. of 2a to 1a in the presence of 50
mg 5 Å MS in toluene (0.1 M) for 72 h.
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Table 1. Optimization of the reaction conditions a
Me
Me
O
4
5 mol%
+
Ph
CF3
solvent, 80 oC, 48 h
N
N
H
NH
CF3
3aa
NH2
Ph
1a
2a
4a
(R)- Ar = 2,4,6-(i-Pr)3C6H2
4b
(S)- Ar = Ph
Ar
4c
(S)- Ar = Ph [H8]
O
O
O
4d
(S)- Ar = 3,5-(CF3)2C6H3 [H8]
4e
(R)- Ar = 2,4,6-Me3C6H2 [H8]
P
OH
4f
(S)- Ar = 9-Anthracenyl [H8]
4g
(S)- Ar = 9-Phenanthryl [H8]
Ar
4h
(R)- Ar = SiPh3
Entry
1
CPA
Solvent
toluene
DCE
T (oC)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
Yield (%)b
ee (%)c
92 (R)
87 (R)
89 (R)
-
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(S)-4b
(S)-4c
(S)-4d
(R)-4e
(S)-4f
(S)-4g
(R)-4h
(R)-4a
(R)-4a
61
80
13
< 5
35
50
79
36
31
70
59
92
91
< 5
71
95
2
3
MeCN
4
1,4-dioxane
benzene
o-xylene
PhCl
5
93 (R)
92 (R)
87 (R)
15 (S)
10 (S)
50 (S)
40 (R)
75 (S)
73 (S)
-
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15d
16e
92 (R)
90 (R)
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17e
18e
19e,f
20e,g
21e,,j
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
toluene
toluene
toluene
toluene
toluene
70
90
70
70
70
81
97
97
45
94
94 (R)
85 (R)
90 (R)
94 (R)
92 (R)
a
Conditions: 1a (0.10 mmol) and 2a (0.10 mmol) in toluene (1.0 mL)
using 5 mol% 4 as catalyst at 80 oC for 48 h. b Determined by 1H NMR. c
Determined by HPLC. 50 mg 5 Å MS was used. e 50 mg 5 Å MS and
d
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2a (0.15 mmol) were used. 0.5 mL toluene was used. g 2.0 mL toluene
f
was used. j 72 h.
Under the optimal condition, a series of substrates were explored to determine the generality of this
method, and the results are summarized in Scheme 2. Most of substrates performed well under the standard
reaction conditions. Aromatic trifluoromethyl ketones bearing electron-withdrawing groups and weak
electron-donating groups delivered the corresponding products in high yields with excellent
enantioselectivities (Scheme 2, 3aa-3ad, 3af-3ag). The 4-methoxyl substituted ketone 2e afforded expected
3ae with moderate 60% yield and 89% ee after prolonged time. In addition, 2-naphthyl trifluoromethyl
ketone 2h gave 95% ee. Next, the reaction of various 2-(1H-indolyl)anilines and ketone 2a were investigated
(Scheme 2, 3ba-3ga). No substituent at 3-position of indole, the N-functionalization of 1b was predominant
in 74% yield with 88% ee and C3-alkylation side-product was isolated (see Experimental Section). 3-
Ethylindole 1c underwent smoothly and gave 3ca in 90% yield and 92% ee (Scheme 2, 3ca). The substituted
groups at meta-position of aniline moiety increased enantioselectivities (Scheme 2, 3da and 3ea). With an
electron-withdrawing group, aniline 1d gave product 3da with 28% yield and 96% ee (Scheme 2, 3da).
o
When reaction temperature was raised to 90 C for 120 h, a limited influence of yield and stereoselectivity
was observed. The best enantioselectivity was given with m-methyl substituted anline 1e (Scheme 2, 3ea).
The 5-bromo substituted indole 1f gave product with relatively higher ee than 5-methoxyl substituted indole
1g (Scheme 2, 3fa vs 3ga). The pentafluoroethyl ketone 2i gave poor reactivity (Scheme 2, 3ai), the reason
is not clear. The difluoromethyl ketone 2j afforded 3aj in quantitative yield but poor 25% ee. Furthermore,
alphatic trifluoromethyl ketone 2k furnished the reaction with good yield and enantioselectivity (Scheme 2,
3ak). The absolute configuration of product 3aa was assigned as R based on the X-ray diffraction analysis
after recrystallization from mixed solvents methanol/ethyl acetate/hexanes to upgrade ee to > 99%.
Scheme 2. Substrate scope a
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R1
N
R1
O
Ar2
NH
4a
5 mol% (R)-
Ar1
Ar1
Ar2
+
R2
Rf toluene, 5 Å MS
70 oC, 72 h
N
H
R2
H2N
6
Rf
7
1
2
3
8
Me
Me
Me
9
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N
N
N
NH
CF3
NH
NH
CF3
CF3
Cl
F
3aa
3ab
3ac
94% yield, 93% ee
86% yield, 91% ee
93% yield, 91% ee
Me
Me
Me
N
N
N
NH
NH
NH
CF3
CF3
CF3
Br
Me
MeO
3ad
3af
3ae
91% yield, 92% ee
88% yield, 92% ee
60% yield, 89% eeb
Me
Me
N
N
N
NH
NH
NH
CF3
CF3
CF3
Me
3ag
3ah
3ba
85% yield, 93% ee
79% yield, 95% ee
74% yield, 88% ee
Et
Me
Me
Br
Me
N
N
N
NH
NH
NH
CF3
CF3
CF3
3ca
3ea
3da
90% yield, 92% ee
73% yield, 97% ee
28% yield, 96% eeb
42% yield, 95% eec
Me
Me
Me
Br
MeO
N
N
N
NH
NH
NH
CF3
CF3
C2F5
3fa
3ga
3ai
< 5% yieldb
77% yield, 95% ee
84% yield, 90% ee
Me
Me
Me
N
N
N
NH
NH
NH
Bn
CHF2
CF3
Me
3aj
3ak
3al
99% yield, 25% eed
89% yield, 84% eed
94% yield, < 1% ee
a Conditions: 1 (0.20 mmol) and 2 (0.3 mmol) in toluene (2.0 mL) using 5 mol% (R)-4a as catalyst in the presence
of 100 mg 5 Å MS at 70 oC for 72 h. b 70 oC for 120 h. c 90 oC for 120 h. d 70 oC for 12 h.
Acetophenone was also tested under the above standard condition. To our surprise, the corresponding
aminal could be isolated with 94% yield but poor enantioselectivity (Scheme 2, 3al). Changing reaction
conditions could not obviously improve the enantioselectivity. The above experimental results show the
trifluoromethyl group plays a vital role in enantiocontrol. The experimental results show the trifluoromethyl
group plays a vital role in enantiocontrol. In recent years, fluorine effect was observed in asymmetric
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organocatalysis by many groups.20 For example, Lin Group observed a remarkable fluorine effect in chiral
phosphoric acid-catalyzed asymmetric synthesis of bihydrobenzoxazinones, mechanistic studies through
combination theory calculations with the experimental suggested the CF3 moiety serving as an attractive
hydrogen-bond acceptor.20c Based on the previous reports, we speculated the reactivity trends may also owe
to fluorine effect or possible H···F hydrogen bond between fluorine and N-H of indole or chiral phosphoric
acid.
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-Diamino acids and derivatives were valuable and unusual substructures with important biological and
pharmacological properties, such as anticonvulsant activity.21 To the best of our knowledge, catalytic
enantioselective synthesis of chiral -diamino acids have not been reported. Then, we expanded the reaction
of ethyl trifluoropyruvate 2m. 2-(1H-indolyl)aniline 1a reacted with 2m to afford the desired 3am with 75%
yield and 89% ee after lowering temperature to 50 oC for 42 h (Scheme 3, 3am). Other two anilines (1e & 1f)
were used, moderate yields, 91% and 89% ee were observed (Scheme 3, 3em and 3fm).
Scheme 3. Substrate scope: ethyl trifluoropyruvate
Me
Me
O
Ar'
4a
5 mol% (R)-
toluene, 5 Å MS
50 o
Ar
EtO2C
Ar'
+
Ar
N
F3C
CO2Et
N
NH
H
C
H2N
CF3
1
2m
3
Me
N
Me
Me
Br
Me
N
N
NH
CF3
3em
59% yield, 91% ee
NH
CF3
3fm
52% yield, 89% ee
NH
CF3
3am
75% yield, 89% ee
EtO2C
EtO2C
EtO2C
The product transformation was conducted (Scheme 4). The -diamino ester 3am could be converted to
the corresponding -diaminoalcohol 5 with sodium borohydride in methanol without loss of optical purity.
Scheme 4. Product transformation
Me
Me
NaBH4, MeOH
0 oC to rt
N
N
NH
CF3
NH
CF3
, 94% yield, 88% ee
EtO2C
3am
HOH2C
5
, 88% ee
In conclusion, we have developed a chiral phosphoric acid-catalyzed condensation/amine addition cascade
for synthesis of chiral fluorinated aminals with quaternary stereocenters, giving the chiral dihydroindolo[1,2-
c]quinazolines with good yields and up to 97% ee. The substrate scope could be extended to aromatic,
aliphatic trifluoromethyl ketones and ethyl trifluoropyruvate. Detailed mechanistic studies and further
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expanding the scope of this chemistry are currently ongoing in our laboratory.
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EXPERIMENTAL SECTION
8
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Commercially All reactions were carried out under an atmosphere of nitrogen using the standard Schlenk
techniques, unless otherwise noted. Commercially available reagents were used without further purification.
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Solvents were treated prior to use according to the standard methods. H NMR, 13C NMR spectra were
recorded at 400 MHz and 100 MHz with the Brucker spectrometer. 19F was recorded at 376 MHz with
Brucker spectrometer. Chemical shifts are reported in ppm using tetramethylsilane as internal standard when
using CDCl3, CD2Cl2 and CD3OD as solvent for 1H NMR spectra. The following abbreviations were used to
symbolize the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Flash
column chromatography was performed on silica gel (200-300 mesh). All reactions were monitored by TLC
analysis. Optical rotations were measured by the polarimeter. Enantiomeric excess was determined by HPLC
analysis using chiral column described below in detail. High-resolution mass spectrometry (HRMS) was
measured on an electrospray ionization (ESI) apparatus using time-of-flight (TOF) mass spectrometry.
Procedures for Synthesis of 2-(1H-Indolyl)anilines 1. 2-(1H-Indolyl)aniline derivatives 1a and 1c-1g
could be conveniently synthesized from the indoles and 2-nitrobromobenzenes in two steps according to the
known literature procedures with minor modification.22-23 1b was prepared by Fisher indole synthesis
according to a reported method.24 Among them, compound 1b is the known compound.24
General Procedure A for Synthesis of 2-(1H-Indolyl)anilines 1a, 1c, 1e and 1g. 2-(2-Nitrophenyl)-1H-
indoles were prepared from indoles and 1-bromo-2-nitrobenzenes in the presence of cesium carbonate under
reflux with acetonitrile as solvent. The corresponding 2-(1H-indolyl)anilines could be obtained after
reduction of above nitro-compounds using Pd/C as catalyst under hydrogen gas.
In a dried round bottomed flask was added indoles (0.20 mol), 1-bromo-2-nitrobenzenes (0.10 mol),
cesium carbonate (0.20 mol, 65.16 g) and anhydrous acetonitrile (500 mL). The resulting suspension was
stirred for 24 h under inert atmosphere under reflux. The solvent was evaporated under vacuum and water
was added. The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were
washed with water and brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure.
The crude product was purified by flash column chromatography to give the crude product.
The above crude product (28.1 mmol) was dissolved in ethanol (250 mL) and dichloromethane (5 mL),
Pd/C (1.200 g, 10 wt. %) was added, and the mixture was stirred under hydrogen gas (balloon pressure)
overnight. The mixture was filtered through celite, the solvent was evaporated under the reduced pressure.
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The residue was purified by column chromatography on silica gel using hexanes and ethyl acetate as eluent
to give the desired compouds 1.
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General Procedure B for Synthesis of 2-(1H-Indolyl)anilines 1d and 1f. 2-(2-Nitrophenyl)-1H-indoles
could be synthesized from indoles and 1-bromo-2-nitrobenzenes. Reduction of them by employing iron
powder and concentrated hydrochloric acid gave 2-(1H-indolyl)anilines 1d and 1f.
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In a dried round bottomed flask was added indoles (0.20 mol), 1-bromo-2-nitrobenzenes (0.10 mol),
cesium carbonate (0.20 mol, 65.16 g) and anhydrous acetonitrile (500 mL). The resulting suspension was
stirred for 24 h under inert atmosphere under reflux. The solvent was evaporated under vacuum and water
was added. The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were
washed with water and brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure.
The crude product was purified by flash column chromatography to give the crude product.
To a solution of 2-(2-nitrophenyl)-1H-indoles (5.62 mmol) in ethanol (24 mL) was added iron powder
(33.72 mmol, 1.888 g) and concentrated hydrogen chloride (6.0 mL) under nitrogen. The mixture was stirred
under reflux for 4 h. After cooled to room temperature, excess sodium hydroxide solution was added. The
mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water
and brine, dried over anhydrous sodium sulfate. After concentrated under the reduced pressure, the residue
was purified by flash column chromatography to afford the pure products 1.
o
2-(3-Methyl-1H-indol-2-yl)aniline (1a). 5.340 g, 24% yield in 2 steps, yellow solid, m.p. = 105-107 C,
new compound, Rf = 0.35 (hexanes/ethyl acetate 10:1); 1H NMR (400 MHz, CDCl3) δ 7.99 (brs, 1H), 7.60 (d,
J = 7.6 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.26–7.11 (m, 4H), 6.90–6.70 (m, 2H), 3.82 (brs, 2H), 2.28 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 145.0, 136.0, 131.8, 131.2, 129.5, 129.4, 122.1, 119.4, 118.8, 118.39,
118.36, 115.7, 110.7, 109.8, 9.4. HRMS (ESI-TOF) m/z Calculated for C15H15N2 [M+H]+ 223.1230, found
223.1235.
2-(3-Ethyl-1H-indol-2-yl)aniline (1c). 0.831 g, 18% yield in 2 steps, yellow oil, new compound, Rf =
0.30 (hexanes/ethyl acetate 10:1); 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0
Hz, 1H), 7.22–7.14 (m, 2H), 7.13–7.07 (m, 1H), 7.06–7.00 (m, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.81–6.74 (m,
1H), 2.72 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz, CD3OD) δ 145.8, 136.7,
131.7, 130.8, 128.8, 128.1, 120.9, 118.9, 118.19, 118.18 117.3, 115.3, 114.8, 110.6, 17.5, 14.5. HRMS (ESI-
TOF) m/z Calculated for C16H17N2 [M+H]+ 237.1386, found 237.1390.
5-Bromo-2-(3-methyl-1H-indol-2-yl)aniline (1d). 1.072 g, 18% yield in 2 steps, yellow solid, m.p. =
163-164 oC, new compound, Rf = 0.30 (hexanes/ethyl acetate 10:1); 1H NMR (400 MHz, CD3OD) δ 7.41 (d,
J = 7.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.04–6.98 (m, 1H), 6.97–6.88 (m, 3H), 6.75 (dd, J = 8.1, 2.0 Hz,
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1H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CD3OD) δ 147.5, 136.6, 132.1, 131.1, 129.1, 122.3, 121.2,
119.5, 118.4, 117.9, 117.3, 110.5, 108.2, 8.1. HRMS (ESI-TOF) m/z Calculated for C15H14BrN2 [M+H]+
301.0335, found 301.0331.
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5-Methyl-2-(3-methyl-1H-indol-2-yl)aniline (1e). 1.034 g, 22% yield in 2 steps, yellow oil, new
compound, Rf = 0.35 (hexanes/ethyl acetate 10:1); 1H NMR (400 MHz, CD3OD) δ 7.51 (d, J = 7.8 Hz, 1H),
7.33 (d, J = 8.0 Hz, 1H), 7.13–7.06 (m, 2H), 7.06–7.01 (m, 1H), 6.69 (s, 1H), 6.62 (d, J = 7.7 Hz, 1H), 2.30
(s, 3H), 2.22 (s, 3H). 13C{1H} NMR (100 MHz, CD3OD) δ 145.3, 138.7, 136.5, 132.4, 130.6, 129.2, 120.9,
118.5, 118.2, 117.8, 116.2, 116.0, 110.4, 107.7, 20.1, 8.1. HRMS (ESI-TOF) m/z Calculated for C16H17N2
[M+H]+ 237.1386, found 237.1402.
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2-(5-Bromo-3-methyl-1H-indol-2-yl)aniline (1f). 1.059 g, 23% yield in 2 steps, yellow oil, new
compound, Rf = 0.20 (hexanes/ethyl acetate 10:1); 1H NMR (400 MHz, CD3OD) δ 7.54 (d, J = 1.6 Hz, 1H),
7.18–7.03 (m, 1H), 7.11–7.04 (m, 3H), 6.79–6.73 (m, 1H), 6.70–6.64 (m, 1H), 2.09 (s, 3H). 13C{1H} NMR
(100 MHz, CD3OD) δ 145.7, 135.1, 134.0, 131.0, 130.6, 129.0, 123.5, 120.4, 118.0, 117.3, 115.4, 112.0,
111.4, 107.6, 7.9. HRMS (ESI-TOF) m/z Calculated for C15H14BrN2 [M+H]+ 301.0335, found 301.0334.
Procedures for Enantioselective Synthesis of Chiral 5,6-Dihydroindolo[1,2-c]quinazolines. To a 25
ml sealed tube charged with 2-(1H-indolyl)anilines 1 (0.20 mmol), chiral phosphoric acid TRIP (R)-4a (7.5
mg, 0.01 mmol), dry toluene (2.0 mL) and 5 Å MS (100 mg) was added ketones 2 (0.3 mmol ) under
nitrogen. The mixture was kept stirring at 70 oC for 72 h. The solvent was evaporated under reduced pressure
and the residue was purified by flash column chromatography on a silica gel using hexanes/ethyl acetate as
the eluent to give the desirable products 3.
(R)-(+)-12-Methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3aa). 71 mg, 94%
yield, white solid, m.p. = 96-97 oC, new compound, Rf = 0.65 (hexanes/ethyl acetate 10:1), 93% ee, [α]20
=
D
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+61.54 (c 1.42, EtOAc); H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.6 Hz, 2H),
7.62 (d, J = 7.9 Hz, 1H), 7.58–7.43 (m, 3H), 7.20 (t, J = 7.2 Hz, 1H), 7.14–7.00 (m, 2H), 6.86 (t, J = 7.7 Hz,
1H), 6.77 (d, J = 7.8 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 4.67 (brs, 1H), 2.74 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 138.1, 136.4, 134.7, 130.7, 130.1, 129.6, 128.9, 128.4, 127.8, 125.6 (q, J = 296.0 Hz), 125.1,
122.1, 120.3, 120.0, 118.4, 117.1, 113.7, 112.8, 108.5, 75.4 (q, J = 30 Hz), 11.1; 19F{1H} NMR (376 MHz,
CDCl3) δ -72.0. Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 98/2,
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detector: 254 nm, flow rate: 1.0 mL/min, 30 C), retention time 7.2 min (major) and 9.5 min. HRMS (ESI-
TOF) m/z Calculated for C23H18F3N2 [M+H]+ 379.1417, found 379.1421.
(+)-6-(4-Fluorophenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ab). 68
mg, 86% yield, colorless oil, new compound, Rf = 0.70 (hexanes/ethyl acetate 10:1), 91% ee, [α]20D = +48.23
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(c 1.36, EtOAc); H NMR (400 MHz, CD3OD) δ 7.75 (d, J = 7.8 Hz, 1H), 7.66–7.52 (m, 2H), 7.42 (d, J =
7.9 Hz, 1H), 7.14–6.97 (m, 3H), 6.87 (t, J = 7.5 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H),
6.66 (t, J = 7.5 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H) 2.52 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 163.2 (d,
J = 247.0 Hz), 139.4, 134.5, 133.0 (d, J = 3.0 Hz), 130.7, 130.6 (dq, J = 8.0 Hz, J = 1.0 Hz), 129.8, 127.6,
125.8 (q, J = 296.0 Hz), 124.4, 121.4, 119.6, 118.9, 117.8, 116.2, 115.1 (d, J = 22.0 Hz), 113.3, 112.3, 107.2,
75.0 (q, J = 30.0 Hz), 9.7; 19F{1H} NMR (376 MHz, CD3OD) δ -73.3 (s, 3F), -113.3 (s, 1F). Enantiomeric
excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 95/5, detector: 254 nm, flow rate:
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1.0 mL/min, 30 C), retention time 5.9 min (major) and 6.9 min. HRMS (ESI-TOF) m/z Calculated for
C23H17F4N2 [M+H]+ 397.1322, found 397.1350.
(+)-6-(4-Chlorophenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ac). 77
mg, 93% yield, colorless oil, new compound, Rf = 0.80 (hexanes/ethyl acetate 10:1), 91% ee, [α]20D = +64.67
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(c 1.54, EtOAc); H NMR (400 MHz, CD3OD) δ 7.71 (dd, J = 7.9, 0.9 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H),
7.37 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.01–6.94 (m, , 1H), 6.87–6.80 (m, 1H), 6.80–6.69 (m,
2H), 6.67–6.59 (m, 1H), 6.09 (d, J = 8.4 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 139.3,
135.6, 135.4, 134.4, 130.7, 129.9, 129.7, 128.4, 127.6, 125.7 (q, J = 295.0 Hz), 124.4 121.4, 119.7, 118.9,
117.9, 116.2, 113.3, 112.3, 107.3, 75.0 (q, J = 30.0 Hz), 9.7; 19F{1H} NMR (376 MHz, CD3OD) δ -73.2.
Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 95/5, detector: 254
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nm, flow rate: 1.0 mL/min, 30 C), retention time 6.0 min (major) and 7.4 min. HRMS (ESI-TOF) m/z
Calculated for C23H17ClF3N2 [M+H]+ 413.1027, found 413.1041.
(+)-6-(4-Bromophenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ad). 84
mg, 91% yield, colorless oil, new compound, Rf = 0.70 (hexanes/ethyl acetate 10:1), 92% ee, [α]20D = +58.26
(c 1.67, EtOAc); 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J = 7.7 Hz, 1H), 7.55–7.37 (m, 5H), 7.06–6.96 (m,
1H), 6.88 (t, J = 7.3 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.71–6.62 (m, 1H), 6.12 (d, J
= 8.4 Hz, 1H), 2.52 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 139.2, 136.1, 134.4, 131.5, 130.7, 130.1,
129.7, 127.6, 125.7 (q, J = 295.0 Hz), 124.4, 123.6, 121.5, 119.7, 119.0, 117.9, 116.2, 113.4, 112.3, 107.4,
75.1 (q, J = 30.0 Hz), 9.8; 19F{1H} NMR (376 MHz, CD3OD) δ -73.3 (s, 3F). Enantiomeric excess was
determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 95/5, detector: 254 nm, flow rate: 1.0 mL/min,
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30 C), retention time 6.5 min (major) and 7.9 min. HRMS (ESI-TOF) m/z Calculated for C23H17BrF3N2
[M+H]+ 457.0522, found 457.0517.
(+)-6-(4-Methoxyphenyl)-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ae).
49 mg, 60% yield, colorless oil, new compound, Rf = 0.25 (hexanes/ethyl acetate 20:1), 89% ee, [α]20
=
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+45.30 (c 0.98, EtOAc); 1H NMR (400 MHz, CD3OD) δ 7.74 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H),
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7.40 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.89–6.81 (m, 3H), 6.81–6.75 (m, 1H), 6.72 (d, J = 8.0 Hz,
1H), 6.66–6.59 (m, 1H), 6.13 (d, J = 8.5 Hz, 1H), 3.68 (s, 3H), 2.51 (s, 3H); 13C{1H} NMR (100 MHz,
CD3OD) δ 160.6, 139.6, 134.7, 130.6, 129.8, 129.6, 128.6, 127.5, 126.0 (q, J = 295.0 Hz), 124.3, 121.2,
119.4, 118.7, 117.6, 116.3, 113.5, 113.3, 112.6, 107.0, 75.1 (q, J = 30.0 Hz), 54.4, 9.7; 19F{1H} NMR (376
MHz, CD3OD) δ -73.4. Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH
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= 95/5, detector: 254 nm, flow rate: 1.0 mL/min, 30 C), retention time 8.6 min (major) and 10.7 min.
HRMS (ESI-TOF) m/z Calculated for C24H20F3N2O [M+H]+ 409.1522, found 409.1533.
(+)-12-Methyl-6-(p-tolyl)-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3af). 69 mg, 88%
yield, colorless oil, new compound, Rf = 0.30 (hexanes/ethyl acetate 50:1), 92% ee, [α]20D = +54.85 (c 1.38,
EtOAc); 1H NMR (400 MHz, CD3OD) δ 7.72 (d, J = 7.8, 1H), 6.47–6.33 (m, 3H), 7.10 (d, J = 8.1 Hz, 2H),
6.97 (t, J = 7.4 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.57 (t, J
= 7.6 Hz, 1H) 6.09 (d, J = 8.4 Hz, 1H), 2.49 (s, 3H), 2.23 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ
139.7, 139.5, 134.6, 133.9, 130.6, 129.8, 128.8, 128.1, 127.5, 126.0 (q, J = 295.0 Hz), 124.3, 121.2, 119.4,
118.7, 117.6, 116.2, 113.3, 112.6, 107.0, 75.2 (q, J = 30.0 Hz), 19.8, 9.8; 19F{1H} NMR (376 MHz, CD3OD)
δ -73.2. Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 98/2, detector:
254 nm, flow rate: 1.0 mL/min, 30 oC), retention time 7.2 min (major) and 11.0 min. HRMS (ESI-TOF) m/z
Calculated for C24H20F3N2 [M+H]+ 393.1573, found 393.1608.
(+)-12-Methyl-6-(m-tolyl)-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ag). 67 mg, 85%
yield, white solid, m.p. = 150-151 oC, new compound, Rf = 0.30 (hexanes/ethyl acetate 50:1), 93% ee, [α]20
D
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= +60.67 (c 1.34, EtOAc); H NMR (400 MHz, CD3OD) δ 7.73 (d, J = 7.8, 1H), 7.44–7.31 (m, 3H), 7.23–
7.11 (m, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.9 Hz,
1H), 6.58 (t, J = 7.7 Hz, 1H), 6.09 (d, J = 8.4 Hz, 1H), 2.49 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR (100 MHz,
CH3OD) δ 139.5, 138.3, 136.8, 134.6, 130.6, 130.1, 129.8, 128.9, 128.0, 127.5, 126.0 (q, J = 295.0 Hz),
125.0, 124.4, 121.2, 119.5, 118.7, 117.7, 116.2, 113.3, 112.6, 107.0, 75.3 (q, J = 29.0 Hz), 20.2, 9.8; 19F{1H}
NMR (376 MHz, CH3OD) δ -73.1. Enantiomeric excess was determined by HPLC (IA column, elute: n-
Hexane/i-PrOH = 95/5, detector: 254 nm, flow rate: 1.0 mL/min, 30 oC), retention time 4.8 min (major) and
6.2 min. HRMS (ESI-TOF) m/z Calculated for C24H20F3N2 [M+H]+ 393.1573, found 393.1608.
(+)-12-Methyl-6-(naphthalen-2-yl)-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ah). 68
mg, 79% yield, white solid, m.p. = 214-215 oC, new compound, Rf = 0.30 (hexanes /ethyl acetate 100:1), 95%
ee, [α]20D = +20.85 (c 1.18, EtOAc); 1H NMR (400 MHz, CD2Cl2) δ 8.28 (s, 1H), 7.94–7.85 (m, 2H), 7.84–
7.73 (m, 2H), 7.59–7.41 (m, 4H), 7.13–7.05 (m, 1H), 6.70–6.88 (m, 2H), 6.72–6.57 (m, 2H), 6.18 (d, J = 8.5
Hz, 1H), 4.71 (brs, 1H), 2.63 (s, 3H); 13C{1H} NMR (100 MHz, CD2Cl2) δ 138.1, 134.7, 133.6, 133.4, 132.4,
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130.7, 129.5, 129.1, 129.0, 127.9, 127.8, 127.6, 127.0, 126.9 (q, J = 3.0 Hz), 125.77, 125.76 (q, J = 295.0
Hz), 125.0, 122.1, 120.2, 120.1, 118.4, 116.8, 113.8, 112.6, 108.6, 75.6 (q, J = 30.0 Hz), 10.8; 19F{1H} NMR
(376 MHz, CD2Cl2) δ -72.1. Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-
PrOH = 95/5, detector: 254 nm, flow rate: 1.0 mL/min, 30 oC), retention time 7.3 min (major) and 10.5 min.
HRMS (ESI-TOF) m/z Calculated for C27H20F3N2 [M+H]+ 429.1573, found 429.1571.
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(+)-6-Phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ba). 54 mg, 74% yield,
colorless oil, new compound, Rf = 0.60 (hexanes/ethyl acetate 20:1), 88% ee, [α]20 = +97.40 (c 1.08,
D
1
EtOAc); H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.7 Hz, 3H), 7.44–7.28 (m, 4H), 7.05–6.96 (m, 1H),
6.90–6.79 (m, 2H), 6.78–6.66 (m, 2H), 6.63–6.54 (m, 1H), 6.10 (d, J = 8.5 Hz, 1H); 13C{1H} NMR (100
MHz, CD3OD) δ 138.7, 136.6, 135.7, 135.1, 129.9, 129.5, 128.43, 128.38, 128.1 (q, J = 2.0 Hz), 125.9 (q, J
= 295.0 Hz), 123.2, 120.9, 120.1, 119.8, 118.8, 114.4, 113.3, 112.7, 96.3, 75.7 (q, J = 30.0 Hz); 19F{1H}
NMR (376 MHz, CD3OD) δ -73.5. Enantiomeric excess was determined by HPLC (IA column, elute: n-
Hexane/i-PrOH = 90/10, detector: 254 nm, flow rate: 1.0 mL/min, 30 oC), retention time 6.7 min (major) and
10.2 min. HRMS (ESI-TOF) m/z Calculated for C22H16F3N2 [M+H]+ 365.1260, found 365.1258.
(+)-6-Phenyl-6-(trifluoromethyl)-6,11-dihydro-5H-indolo[3,2-c]quinoline (3ba'). 4 mg, 5% yield, pale
yellow oil, new compound, Rf = 0.35 (hexanes/ethyl acetate 20:1), 35% ee, [α]20 = +2.50 (c 0.08, EtOAc);
D
1H NMR (400 MHz, CD2Cl2) δ 8.48 (brs, 1H), 7.73–7.59 (m, 2H), 7.34–7.21 (m, 5H), 7.07–6.95 (m, 2H),
6.81–6.67 (m, 3H), 6.56 (d, J = 8.0 Hz, 1H), 4.56 (brs, 1H); 13C{1H} NMR (100 MHz, CD2Cl2) δ 141.2,
140.3, 137.1, 132.7, 129.3, 128.31, 128.28, 127.9 (q, J = 2.0 Hz), 126.7 (q, J = 289.0 Hz), 125.8, 122.5,
120.50, 119.6 (q, J = 2.0 Hz), 118.3, 113.1, 112.3, 111.1, 104.5, 66.0 (q, J = 29.0 Hz); 19F{1H} NMR (376
MHz, CD2Cl2) δ -74.9. Enantiomeric excess was determined by HPLC (IB column, elute: n-Hexane/i-PrOH
o
= 90/10, detector: 254 nm, flow rate: 0.8 mL/min, 30 C), retention time 11.1 min (major) and 12.6 min.
HRMS (ESI-TOF) m/z Calculated for C22H16F3N2 [M+H]+ 365.1260, found 365.1264.
(+)-12-Ethyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ca). 71 mg, 90%
yield, colorless oil, new compound, Rf = 0.50 (hexanes/ethyl acetate 20:1), 92% ee, [α]20D = +38.73 (c 1.42,
EtOAc); 1H NMR (400 MHz, CD3OD) δ 7.71 (dd, J = 7.9, 0.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.41 (d, J =
7.9 Hz, 1H), 7.37–7.26 (m, 3H), 6.99 (d, J = 6.8 Hz, 1H), 6.89–6.69 (m, 3H), 6.64–6.53 (m, 1H), 6.07 (d, J =
8.5 Hz, 1H), 3.12–2.95 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 139.5, 136.9,
134.7, 129.8, 129.4, 129.2, 128.3, 128.2, 127.6, 125.9 (q, J = 295.0 Hz), 124.1, 121.3, 119.5, 118.9, 117.6,
115.9, 114.1, 113.5, 112.6, 75.3 (q, J = 30.0 Hz), 17.8, 13.5; 19F{1H} NMR (376 MHz, CD3OD) δ -73.0.
Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 95/5, detector: 254
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nm, flow rate: 1.0 mL/min, 30 C), retention time 5.1 min (major) and 6.5 min. HRMS (ESI-TOF) m/z
Calculated for C24H20F3N2 [M+H]+ 393.1573, found 393.1592.
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(+)-3-Bromo-12-methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3da). 26
mg, 28% yield, colorless oil, new compound, Rf = 0.70 (hexanes/ethyl acetate 10:1), 96% ee, [α]20D = +8.65
(c 0.52, EtOAc); 1H NMR (400 MHz, CD3OD) δ 7.68–7.53 (m, 3H), 7.46–7.31 (m, 4H), 6.96–6.90 (m, 2H),
6.96–6.84 (m, 1H), 6.67–6.58 (m, 1H), 6.07 (d, J = 8.5 Hz, 1H), 2.50 (s, 3H); 13C{1H} NMR (100 MHz,
CD3OD) δ 140.7, 136.4, 134.6, 130.5, 129.6, 128.9, 128.4, 128.1, 125.8 (q, J = 295.0 Hz), 125.7, 121.6,
121.5, 120.7, 119.7, 117.9, 115.8, 115.3, 112.5, 107.8, 75.2 (q, J = 30.0 Hz), 9.7; 19F{1H} NMR (376 MHz,
CD3OD) δ -73.4. Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 95/5,
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detector: 254 nm, flow rate: 1.0 mL/min, 30 C), retention time 6.1 min (major) and 7.2 min. HRMS (ESI-
TOF) m/z Calculated for C23H17BrF3N2 [M+H]+ 457.0522, found 457.0532.
(+)-3,12-Dimethyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ea). 57 mg, 73%
yield, pink solid, m.p. = 190-191 oC, new compound, Rf = 0.55 (hexanes/ethyl acetate 20:1), 97% ee, [α]20
=
D
+39.38 (c 1.14, EtOAc); 1H NMR (400 MHz, CD2Cl2) δ 7.70 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H),
7.48–7.30 (m, 4H), 6.95–6.86 (m, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.69–6.61 (m, 1H), 6.46 (s, 1H), 6.07 (d, J =
8.5 Hz, 1H), 4.59 (brs, 1H), 2.55 (s, 3H), 2.21 (s, 3H); 13C{1H} NMR (100 MHz, CD2Cl2) δ 138.3, 138.1,
136.5, 134.6, 130.8, 130.1, 129.8, 128.8, 128.2 (q, J = 2.0 Hz), 125.7 (q, J = 295.0 Hz), 124.9, 121.7, 121.2,
120.0, 118.2, 114.2, 112.5, 107.6, 75.4 (q, J = 30.0 Hz), 21.1, 10.7; 19F{1H} NMR (376 MHz, CD2Cl2) δ -
72.3. Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 95/5, detector:
o
254 nm, flow rate: 1.0 mL/min, 30 C), retention time 5.6 min (major) and 8.1 min. HRMS (ESI-TOF) m/z
Calculated for C24H20F3N2 [M+H]+ 393.1573, found 393.1581.
(+)-10-Bromo-12-methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3fa). 70
mg, 77% yield, colorless oil, new compound, Rf = 0.55 (hexanes/ethyl acetate 10:1), 95% ee, [α]20D = +66.28
1
(c 1.40, EtOAc); H NMR (400 MHz, CD3OD) δ 7.73 (dd, J = 7.9, 0.9 Hz, 1H), 7.59–7.51 (m, 3H), 7.39–
7.26 (m, 3H), 7.06–6.99 (m, 1H), 6.82–6.72 (m, 2H), 6.67 (dd, J = 8.9, 2.0 Hz, 1H), 5.95 (d, J = 8.9 Hz, 1H),
2.45 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 139.6, 136.4, 133.2, 132.5, 131.3, 129.6, 128.4, 128.12,
128.08, 125.9 (q, J = 295.0 Hz), 124.6, 123.8, 120.3, 118.9, 115.7, 114.0, 113.5, 112.9, 106.5, 75.4 (q, J =
30.0 Hz), 9.7; 19F{1H} NMR (376 MHz, CD3OD) δ -73.2. Enantiomeric excess was determined by HPLC
(IA column, elute: n-Hexane/i-PrOH = 95/5, detector: 254 nm, flow rate: 1.0 mL/min, 30 oC), retention time
6.1 min (major) and 7.7 min. HRMS (ESI-TOF) m/z Calculated for C23H17BrF3N2 [M+H]+ 457.0522, found
457.0546.
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(+)-10-Methoxy-12-methyl-6-phenyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ga).
69 mg, 84% yield, pink oil, new compound, Rf = 0.65 (hexanes/ethyl acetate 10:1), 90% ee, [α]20D = +48.37
6
7
1
(c 0.86, EtOAc); H NMR (400 MHz, CD3OD) δ 7.74 (dd, J = 7.9, 1.0 Hz, 1H), 7.62–7.54 (m, 2H), 7.41–
8
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7.29 (m, 3H), 7.02–6.97 (m, 1H) 6.89 (d, J = 2.5 Hz, 1H), 6.82–6.76 (m, 1H), 6.73 (dd, J = 8.0, 0.8 Hz, 1H),
6.26 (dd, J = 9.1, 2.5 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 3.66 (s, 3H), 2.50 (s, 3H); 13C{1H} NMR (100 MHz,
CD3OD) δ 154.2, 139.4, 136.9, 131.2, 130.5, 129.7, 129.4, 128.3, 128.2, 127.4, 125.9 (q, J = 296.0 Hz),
124.2, 118.7, 116.2, 113.3, 113.2, 111.0, 106.8, 99.6, 75.3 (q, J = 30.0 Hz), 54.7, 9.8; 19F{1H} NMR (376
MHz, CD3OD) δ -73.2. Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/ i-PrOH
= 95/5, detector: 254 nm, flow rate: 1.0 mL/min, 30 oC), retention time 7.0 min (major) and 8.2 min. HRMS
(ESI-TOF) m/z Calculated for C24H20F3N2O [M+H]+ 409.1522, found 409.1530.
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(+)-6-(Difluoromethyl)-12-methyl-6-phenyl-5,6-dihydroindolo[1,2-c]quinazoline (3aj). 72 mg, 99%
yield, colorless oil, new compound, Rf = 0.55 (hexanes/ethyl acetate 10:1), 25% ee, [α]20D = +15.94 (c 1.38,
EtOAc); 1H NMR (400 MHz, CD2Cl2) δ 7.79 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.45 (d, J = 7.9
Hz, 1H), 7.43–7.32 (m, 3H), 7.08–7.00 (m, 1H), 6.94–6.84 (m, 2H), 6.70–6.62 (m, 2H), 6.24 (t, J = 54.5 Hz,
1H), 6.04 (d, J = 8.5 Hz, 1H), 4.63 (brs, 1H), 2.56 (s, 3H); 13C{1H} NMR (100 MHz, CD2Cl2) δ 138.6, 137.0,
134.9, 130.7, 129.9, 129.3, 128.8, 128.6 (t, J = 2.0 Hz), 128.0, 125.1, 121.9, 120.1, 119.8, 118.4, 117.0,
115.1 (t, J = 254.0 Hz), 114.3, 112.2, 108.3, 74.1 (t, J = 23. 0 Hz), 10.8; 19F{1H} NMR (376 MHz, CD2Cl2) δ
-123.6 (d, J = 276.8 Hz, 1F), -128.4 (d, J = 276.8 Hz, 1F). Enantiomeric excess was determined by HPLC
(IA column, elute: n-Hexane/i-PrOH = 95/5, detector: 254 nm, flow rate: 1.0 mL/min, 30 oC), retention time
6.7 min (major) and 8.1 min. HRMS (ESI-TOF) m/z Calculated for C23H19F2N2 [M+H]+ 361.1511, found
361.1543.
(+)-6-Benzyl-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline (3ak). 70 mg, 89%
yield, white solid, m.p. = 145-146 oC, new compound, Rf = 0.75 (hexanes/ethyl acetate 10:1), 84% ee, [α]20
D
= +94.28 (c 1.40, EtOAc); 1H NMR (400 MHz, CD2Cl2) δ 7.68 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H),
7.51 (d, J = 7.8 Hz, 1H), 7.15–6.95 (m, 8H), 6.81 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 4.32–4.19 (m,
2H), 3.60 (d, J = 15.4 Hz, 1H), 2.48 (s, 3H); 13C{1H} NMR (100 MHz, CD2Cl2) δ 137.6, 134.7, 132.6, 131.1,
130.4, 129.2, 128.4, 128.0, 125.7 (q, J = 295.0 Hz), 127.6, 125.0, 122.6, 120.27, 120.26, 118.9, 116.6, 114.1,
113.2 (q, J = 2.0 Hz), 108.9, 73.8 (q, J = 29.0 Hz), 38.5, 10.9; 19F{1H} NMR (376 MHz, CD2Cl2) δ -78.2.
Enantiomeric excess was determined by HPLC (IA column, elute: n-Hexane/i-PrOH = 95/5, detector: 254
o
nm, flow rate: 1.0 mL/min, 30 C), retention time 6.3 min (major) and 7.1 min. HRMS (ESI-TOF) m/z
Calculated for C24H20F3N2 [M+H]+ 393.1573, found 393.1573.
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6,12-Dimethyl-6-phenyl-5,6-dihydroindolo[1,2-c]quinazoline (3al). 61 mg, 94% yield, white solid,
known compound,25 Rf = 0.50 (hexanes/ethyl acetate 10:1), < 1% ee; 1H NMR (400 MHz, CDCl3) δ 7.88 (dd,
J = 7.9, 1.0 Hz, 1H), 7.66–7.59 (m, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.42–7.34 (m, 3H), 7.14–7.06 (m, 1H),
7.05–6.98 (m, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.85–6.76 (m, 1H), 6.68 (dd, J = 7.9, 0.7 Hz, 1H), 6.22 (d, J =
8.4 Hz, 1H), 4.24 (brs, 1H), 2.66 (, 3H), 2.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.4, 140.0,
134.1, 130.5, 129.9, 129.0, 128.7, 127.6, 127.5, 125.2, 121.5, 119.8, 119.1, 118.4, 117.9, 115.2, 111.7, 107.3,
73.5, 24.9, 11.1. Enantiomeric excess was determined by HPLC (IB column, elute: n-Hexane/i-PrOH =
70/30, detector: 254 nm, flow rate: 0.7 mL/min, 30 oC), retention time 7.1 min and 7.6 min (major).
(+)-Ethyl 12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline-6-carboxylate (3am).
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56 mg, 75% yield, pale yellow solid, m.p. = 156-158 C, new compound, Rf = 0.40 (hexanes/ ethyl acetate
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10:1), 89% ee, [α]20 = +69.10 (c 1.12, EtOAc); H NMR (400 MHz, CD3OD) δ 7.70 (d, J = 7.9 Hz, 1H),
D
7.53–7.43 (m, 1H), 7.10–6.98 (m, 4H), 6.86–6.73 (m, 2H), 4.31–4.14 (m, 2H), 2.49 (s, 3H), 1.07 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 164.9, 137.8, 134.0, 130.5, 127.8, 124.4, 124.2 (q, J = 294.0
Hz), 122.0, 120.2, 119.2, 118.2, 115.5, 113.6, 110.1 (q, J = 3.0 Hz), 107.4, 73.7 (q, J = 30.0 Hz), 63.1, 12.7,
9.5; 19F{1H} NMR (376 MHz, CD3OD) δ -77.3. Enantiomeric excess was determined by HPLC (IA column,
elute: n-Hexane/i-PrOH = 80/20, detector: 254 nm, flow rate: 0.8 mL/min, 30 oC), retention time 5.4 min and
5.9 min (major). HRMS (ESI-TOF) m/z Calculated for C20H18F3N2O2 [M+H]+ 375.1315, found 375.1319.
(+)-Ethyl
3,12-dimethyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline-6-carboxylate
o
(3em). 46 mg, 59% yield, pink solid, m.p. = 137-138 C, new compound, Rf = 0.40 (hexanes /ethyl acetate
10:1), 91% ee, [α]20 = +58.80 (c 0.92, EtOAc); H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 8.5 Hz, 1H),
1
D
7.50–7.44 (m, 1H), 7.05–6.98 (m, 3H), 6.67–6.59 (m, 2H), 4.30–4.16 (m, 2H), 2.46 (s, 3H), 2.20 (s, 3H),
1.07 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 165.0, 138.1, 137.8, 133.9, 130.6, 128.1,
124.4, 124.3 (q, J = 294.0 Hz), 121.7, 120.2, 120.1, 118.0, 114.0, 112.9, 110.1 (q, J = 2.0 Hz), 106.6, 73.7 (q,
J = 30.0 Hz), 63.0, 20.1, 12.7, 9.4; 19F{1H} NMR (376 MHz, CD3OD) δ -77.2. Enantiomeric excess was
determined by HPLC (OD-H column, elute: n-Hexane/i-PrOH = 70/30, detector: 254 nm, flow rate: 0.7
mL/min, 30 oC), retention time 5.5 min and 5.9 min (major). HRMS (ESI-TOF) m/z Calculated for
C21H20F3N2O2 [M+H]+ 389.1471, found 389.1475.
(+)-Ethyl
10-bromo-12-methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazoline-6-
o
carboxylate (3fm). 47 mg, 52% yield, pale yellow solid, m.p. = 203-204 C, new compound, Rf = 0.45
(hexanes/ethyl acetate 10:1), 89% ee, [α]20D = +50.95 (c 0.94, EtOAc); 1H NMR (400 MHz, CD2Cl2) δ 7.75
(d, J = 7.8 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.8, 1.9 Hz, 1H), 7.15–7.08 (m, 1H), 6.99–6.88 (m,
2H), 6.77 (d, J = 8.0 Hz, 1H), 4.94 (brs, 1H), 4.38–4.19 (m, 2H), 2.50 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H);
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13C{1H} NMR (100 MHz, CD2Cl2) δ 164.3, 136.3, 132.8, 132.5, 128.8, 128.7, 125.4, 125.2, 123.7 (q, J =
293 Hz), 121.5, 121.3, 116.0, 114.8, 114.0, 112.3 (q, J = 2.0 Hz), 108.5, 73.9 (q, J = 30.0 Hz), 64.2, 13.6,
10.6; 19F{1H} NMR (376 MHz, CD2Cl2) δ -75.8. Enantiomeric excess was determined by HPLC (IA column,
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elute: n-Hexane/i-PrOH = 70/30, detector: 254 nm, flow rate: 0.7 mL/min, 30 C), retention time 5.5 min
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(major) and 6.7 min. HRMS (ESI-TOF) m/z Calculated for C20H17BrF3N2O2 [M+H]+ 453.0420, found
453.0420.
General Procedure for the Scale-up Reaction. To a 25 ml sealed tube charged with 2-(1H-
indolyl)aniline 1a (222 mg, 1.0 mmol), chiral phosphoric acid TRIP (R)-4a (37.6 mg, 0.05 mmol), dry
toluene (10.0 mL) and 5 Å MS (500 mg) was added ketone 2a (211 µL, 1.5 mmol) under nitrogen. The
o
mixture was kept stirring at 70 C for 72 h. The solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on a silica gel using hexanes/ethyl acetate (30:1) as
the eluent to give the desirable product 3aa (363 mg, 96% yield, 94% ee) as white solid.
Determination of the Absolute Configuration. The absolute configuration of 12-methyl-6-phenyl-6-
(trifluoromethyl)-5,6-dihydroindolo[1,2-c] quinazoline (+)-(3aa) was assigned as (R) based on the X-ray
diffraction analysis after recrystallization from mixture solvents methanol/ethyl acetate/hexanes to upgrade
ee to > 99%. The absolute configurations of the other chiral products are assigned by analogy. The CCDC
number is 1873205. These details can be obtained free of charge via www.ccdc.com.ac.uk/data_request/cif
from the Cambridge Crystallographic Data Centre.
Product Elaboration. To a solution of (R)-(+)-3am (56 mg, 0.15 mmol, 88% ee) in anhydrous methanol
(3 mL) was added sodium borohydride (114 mg, 3.0 mmol) at 0 oC under nitrogen. After stirring for 30 min,
the suspension was warmed to room temperature and stirred overnight. TLC showed 3am was not consumed
completely; sodium borohydride (114 mg, 3.0 mmol) was added in portions until disappearance by TLC.
The solvent was evaporated in vacuo and the residue was dissolved by saturated ammonium solvent and
ethyl acetate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate. After concentrated under the reduced pressure, the residue was
purified by flash column chromatography using hexanes/ethyl acetate (4:1) as the eluent to afford the pure
product (R)-(-)-5 (47 mg, 94%) as white solid.
(-)-(R)-(12-Methyl-6-(trifluoromethyl)-5,6-dihydroindolo[1,2-c]quinazolin-6-yl)methanol (5). 47 mg,
o
94% yield, white solid, m.p. = 165-167 C, new compound, Rf = 0.30 (hexanes/ethyl acetate 2:1), 88% ee,
[α]20D = -10.53 (c 0.94, EtOAc); 1H NMR (400 MHz, CD3OD) δ 7.68 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz,
2H), 7.11–6.95 (m, 3H), 6.88–6.74 (m, 2H), 4.67 (d, J = 12.2 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 2.48 (s,
3H). 13C{1H} NMR (100 MHz, CD3OD) δ 139.2, 134.5, 130.8, 129.3, 127.6, 125.6 (q, J = 296 Hz), 124.4,
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122.1, 119.6, 118.9, 118.0, 116.5, 113.8, 112.2 (q, J = 1.0 Hz), 107.3, 74.1 (q, J = 28.0 Hz), 61.3, 9.7. 19F{1H}
NMR (376 MHz, CD3OD) δ -78.7. Enantio- meric excess was determined by HPLC (IA column, elute: n-
Hexane/i-PrOH = 70/30, detector: 254 nm, flow rate: 0.7 mL/min, 30 oC), retention time 6.2 min (major) and
6.8 min. HRMS (ESI-TOF) m/z Calculated for C18H16F3N2O [M+H]+ 333.1209, found 333.1221.
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ASSOCIATED CONTENT
Supporting information
NMR spectra of products, and HPLC for racemic and chiral products of all compounds. This material is
available free of charge via the internet at http://pubs.acs.org.
Copies of 1H, 13C{1H}and 19F{1H} spectra of all new compounds (PDF)
X-ray crystallography data and CIF file for 3aa (CCDC 1873205)
AUTHOR INFORMATION
Corresponding author
*E-mail: ygzhou@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Natural Science Foundation of China (21532006, 21690074) and
Chinese Academy of Sciences (XDB17020300, QYZDJ-SSW-SLH035) is acknowledged.
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