Chiral N,N'-Dioxide Organocatalyzed Asymmetric Electrophilic α-Cyanation of β-Keto Esters and β-Keto Amides

Article abstract of DOI:10.1021/acs.joc.6b02726

An enantioselective electrophilic α-cyanation of 1-indanone-derived β-keto esters and β-keto amides using a hypervalent iodine as the cyanide-transfer reagent was realized. A chiral N,N'-dioxide was used as the efficient bifunctional organocatalyst in the presence of inorganic base, which gave the corresponding α-cyano dicarbonyl compounds in yields of 50-99% with good enantioselectivities (87-97% ee).

Full text of DOI:10.1021/acs.joc.6b02726

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Article
Chiral N,N'-Dioxide Organocatalyzed Asymmetric Electrophilic
alpha-Cyanation of beta-Keto Esters and beta-Keto Amides
Baiwei Ma, Xiaobin Lin, Lili Lin, Xiaoming Feng, and Xiaohua Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02726 • Publication Date (Web): 12 Dec 2016
Downloaded from http://pubs.acs.org on December 13, 2016
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Chiral N,N'-Dioxide Organocatalyzed Asymmetric Electrophilic α-Cyanation of
β-Keto Esters and β-Keto Amides
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Baiwei Ma, Xiaobin Lin, Lili Lin, Xiaoming Feng* and Xiaohua Liu*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, P. R. China
*E-mail: xmfeng@scu.edu.cn; liuxh@scu.edu.cn
Abstract: An enantioselective electrophilic α-cyanation of 1-indanone-derived β-keto esters and
β-keto amides using a hypervalent iodine as the cyanide-transfer reagent was realized. A chiral
N,N'-dioxide was used as the efficient bifunctional organocatalyst in the presence of inorganic base,
which gave the corresponding α-cyano dicarbonyl compounds in yields of 50–99% with good
enantioselectivities (87–97% ee).
INTRODUCTION
The enantioselective introduction of a cyano group into molecules is vital to research in organic
chemistry.1 There are several successful examples of asymmetric nucleophilic addition of cyano
reagents to electrophiles including C=O, C=N and C=C bonds (Scheme 1, eq. a).2 Nonetheless, as an
alternative method, catalytic enantioselective electrophilic cyanation reaction is less explored. Until
very recently, asymmetric electrophilic α-cyanations of β-keto esters3 were reported by Waser4a and
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Zheng4b, respectively (Scheme 1, eq. b). The use of cinchona alkaloids allows the enantioselective
α-cyanation reaction of 1-indanone derived β-keto esters in 20–52% ee4a. And in the presence of
cinchona alkaloid-based chiral quaternary ammonium salt and using tert-butyl substituted cyano
benziodoxole as the cyanide transfer reagent, up to 93% ee was obtained for the reaction, but organic
base was found crucial to both the yield and the enantioselectivity.4b In addition, previous synthesis of
racemic α-cyanation products reported by the Chen group could be performed without additional
catalyst in DMF.4c We propose that a proper chiral Brønsted base would enable the formation of enol
or enolate intermediate from the β-keto ester, which undergoes electrophilic addition of hypervalent
iodine reagent5 and cyano group rearrangement, generating the α-cyanation β-keto ester product6 in an
enantioselective manner.
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Scheme 1. Asymmetric nucleophilic and electrophilic cyanations and the possible bifunctional catalytic
models of chiral N,N'-dioxides catalysts
Acting as a bifunctional organocatalyst, chiral N,N'-dioxides7 has been proven useful for the
asymmetric cyanosilylation of carbonyl compounds and imines.7b In these cases, O-amine units of the
catalysts act as Lewis base for activation of silicon-based cyanide and the amide units act as
hydrogen-bond donor to activate the electrophiles (Scheme 1, lower-left model). We envision that
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chiral N,N'-dioxides could also work as an efficient bifunctional catalyst for the asymmetric
electrophilic cyanation reaction of the β-keto esters, in view of the fact that the asymmetric
α-functionalization reaction of β-keto esters has been realized by such chiral catalyst.8 N,N'-dioxides
could act as Brønsted base catalysts to activate the enol of β-keto carbonyl compounds, and the
amide-NH as a hydrogen-bond donor to bind the cyano benziodoxole (Scheme 1, lower-right model).
Herein, we expand chiral N,N'-dioxides in asymmetric electrophilic cyanation of both β-keto esters and
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β-keto amides. Unlike earlier study,4b an inorganic base Na3PO4 12H2O instead of DMAP, and an
unsubstituted cyano benziodoxole as the cyanide reagent9 are involved. Excellent enantioselectivities
(87-97% ee) are achieved for 1-indanone-derived β-keto esters and β-keto amides regardless of the
nature of the substituents.
RESULTS AND DISSCUSION
Table 1. Optimization of the Reaction Conditions[a]
entry
cat.
additive
solvent
yield (%)[b]
ee (%)[c]
56
1
1
2
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7
─
─
─
─
─
─
─
CH2Cl2 35
CH2Cl2 40
CH2Cl2 48
CH2Cl2 27
1a
1a
1a
1a
1a
1a
1a
C2-PrmMe2
C2-PrMe3
C2-PrEt2
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28
25
C3-PrmMe2
C2-PrmMe2
C2-PrmMe2
C2-PrmMe2
TCE
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80
74
66
THF
32
EtOAc
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8[d]
9[e]
─
TCE
TCE
TCE
TCE
TCE
TCE
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23
85
88
64
88
85
99
69
55
62
82
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91
79
80
0
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1q
1r
C2-PrmMe2
C2-PrmMe2
C2-PrmMe2
C2-PrmMe2
─
─
10[e]
11[e]
12[f]
13[f]
14[e]
15[g]
16[g]
17[g]
18[g]
19[g]
K2CO3
DMAP
K2CO3
DMAP
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─
0
[Na3PO4] TCE
[Na3PO4] TCE
[Na3PO4] TCE
[Na3PO4] TCE
[Na3PO4] TCE
[Na3PO4] TCE
90
93
0
C2-PrmMe2
C2-PrmMe2
C-2
9
C-3
65
89
C2-PrmMe2
C2-PrmMe2
[a] Unless otherwise noted, the reactions were performed with 1 (0.1 mmol), 2 (1.2 equiv), catalyst (10
mol %) in solvent (1.0 mL) at 35 oC (entries 1–7 and entries 12, 13, 24 h; entries 8–11 and entries 14–19, 96 h).
o
[b] Isolated yield. [c] Determined by HPLC analysis on a chiral stationary phase. [d] At 0 C. [e] Catalyst
(20 mol %) and additive (1.5 equiv) at −30 oC. [f] Without catalyst. [g] Catalyst (20 mol %), NaI (15 mol %)
and Na3PO4.12H2O (2.0 equiv) at −30 oC. TCE = CHCl2CHCl2. [Na3PO4] = Na3PO4.12H2O.
Initially, we chose the asymmetric cyanation of 1-indanone-derived β-keto ester 1a and cyano
benziodoxole 2 as the model reaction to optimize the chiral catalysts (Table 1). Chiral N,N'-dioxides
o
with variable amide substituents and amino acid backbone are investigated in CH2Cl2 at 35 C.
Assessment of the amino acid backbone of N,N'-dioxides shows that L-proline derived ones give better
outcomes in terms of enantioselectivity than other amino acid derived ones (see SI for details). Aniline
subunits of the catalysts with substituents at meta-positions are superior in enantioselectivity than
substituents at ortho-positions (entry 1 vs entries 2 and 3). N,N'-dioxide C2-PrmMe2 bearing a two
carbon linkage shows better enantiocontrol than 3C-linked C3-PrmMe2 (35% yield and 56% ee; entry 1
vs entry 4). Next, a series of solvents are screened when C2-PrmMe2 is employed as the catalyst of the
reaction. It is found that the yield and the enantioselectivity improved to 50% and 66% ee, respectively,
when TCE is used as the reaction solvent (entries 5–7). The reactions in THF and EtOAc led to a
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significant improvement in the yields (up to 80%) but afforded the products in sharply decreased
enantiomeric excess (entries 6 and 7). It is possible that oxygen-containing solvent might interfere with
the hydrogen-bond network between the catalyst and the reactants. Thus, TCE is chosen as the best
solvent to investigate the effect of reaction temperature. The enantioselectivity increases to 91% ee
upon decreasing the reaction temperature to −30 oC and increasing the catalyst loading, but the yield is
extremely low (23% yield; entries 8 and 9). To improve the reactivity, basic additives, such as K2CO3,
and DMAP, are included in the reaction, and almost in all cases the yields increase a lot but the
enantioselectivity reduce a little (entries 10 and 11). These bases brought more or less background
reaction (64% and 88% yield, respectively; entries 12 and 13), which made the enantioselectivity
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slightly lower. While Na3PO4 12H2O is used as an additive, high yield (85%) and 90% ee are obtained
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(entry 14). Moreover, increasing the amount of Na3PO4 12H2O and adding NaI yields a further
increased outcome (99% yield and 93% ee; entry 15). In addition, replacing the chiral N,N′-dioxide
catalyst with the bisaminoamide C-2, the precursor of C2-PrmMe2, affords the desired product 3a in 69%
yield as a racemate (entry 16). It indicates that the N-oxide units of the catalyst are crucial for the
enantiocontrol. Racemic cyanation reaction performs well in DMF,4c which might act as both a
Brønsted base catalyst and reaction solvent. Therefore, a chiral bisformamide C-3, which included a
formamide structure similar to DMF, was tested in the presence of additives. Although a moderate
yield of 55% was given, the enantioselectivity was poor (entry 17). Moreover, it is found that the steric
hindrance of the ester unit on the substrate 1 greatly affects the enantioselectivity. Bulky protecting
groups, such as 1-adamantoyl and tert-butyl protection groups are important to afford higher
enantioselectivity, and methyl-substituted one gives sharply decreased enantioselectivity (entries 18
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and 19). Therefore, chiral N,N'-dioxide C2-PrmMe2 and Na3PO4 12H2O/NaI are used as the optimal
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catalysts for the reaction of various 1-adamantyl substituted β-keto carbonyl compounds.
Table 2. Substrate scope for β-keto esters[a]
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[a] Unless otherwise noted, the reactions were performed with 1 (0.1 mmol), 2 (1.2 equiv), C2-PrmMe2
(20 mol %) and Na3PO4.12H2O (2.0 equiv), NaI (15 mol %) in TCE (1.0 mL) at −30 oC for 96 h. Isolated yield,
and ee values were determined by HPLC analysis on a chiral stationary phase. [b] The reaction was carried
out with 1a (3.0 mmol) and Na3PO4.12H2O (3.0 equiv) in TCE (30 mL) instead. [c] NaI (20 mol %). [d]
Na3PO4.12H2O (1.5 equiv). Ad = 1-adamantyl. TCE = CHCl2CHCl2.
In the effort to explore the scope of the cyanation reaction, the standard conditions identified in
Table 1, entry 15 are tested with a range of substituted 1-indanone-derived β-keto esters. As show in
Table 2, a wide range of β-keto esters 1a–1l bearing different substituents at variable positons
participated in the asymmetric cyanation reactions with cyano benziodoxole 2 well, affording the
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corresponding cyano-substituted β-keto esters 3a–3l in excellent yields (66–99%) and
enantioselectivities (88–95% ee). It is obvious that the electronic nature and position of the substituents
on the indanone unit have a slight effect on the enantioselectivity but a significant effect on the yield.
This trend is different from chiral quaternary ammonium salt/DMAP system in which
electron-donating groups gave obviously higher enantioselectivity than electron-withdrawing ones.4b In
the current system, comparatively, electron-donating substituted substrates give higher yields than the
electron-withdrawing substituted ones. Substituents at C6-position afford slightly higher
enantioselectivities than these at C5-position. Phenyl and alkynyl substituents are also tolerable, and
the desired cyanation products 3k and 3l could be obtained in 75% and 70% yield, as well as 94% and
92% ee, respectively. We also attempts α-cyanation reaction of the dihydronaphthalen-1(2H)-one
derived β-keto ester 1m, only trace amount of the product 3m is observed. Unfortunately, other
substrates with varied skeleton, such as 3,3’-dimethyl substituted one 1n, acyclic substrate 1o, and
2-oxocyclopentanecarboxylate 1p do not react in the standard condition. In addition, the reaction
between β-keto ester 1a and 2 at a gram-scale performed well, giving the cyanation product 3a in 88%
yield and 92% ee. The absolute configuration of the product 3a was determined to be R according to
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specific optical rotation of the known compound.4b
Table 3. Substrate scope for β-keto amides[a]
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[a] Unless otherwise noted, the reactions were performed with 4 (0.1 mmol), 2 (1.2 equiv), C2-PrmMe2
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(20 mol %), NaI (15 mol %), and Na3PO4 12H2O (2.0 equiv) in TCE (1.0 mL) at −30 oC for 96 h. Isolated yield,
.
and ee values were determined by HPLC analysis on a chiral stationary phase. [b] Na3PO4 12H2O (3.0
equiv). Ad = 1-adamantyl. TCE = CHCl2CHCl2
Subsequently, we examine the scope of β-keto amides in this α-cyanation reaction with the
identified reaction conditions (Table 3). It is clear that a range of 1-indanone-derived β-keto amides 4
can be successfully employed in this electrophilic cyanation reaction without loss of
enantioselectivities (87–97% ee). Similar to the situation of β-keto esters, both the electronic nature and
position of the substituents on the indanone unit of β-keto amides have a slight effect on the
enantioselectivity but a remarkable influence on the yield. Up to 92% yield and 97% ee are achieved
when 6-chloro-substiuted β-keto amide 4f is used. However, 5,6-dimethyl substituted β-keto amide 4c
gave the lowest yield (50%) with 92% ee. These two examples are just to make up for the
corresponding substituted β-keto esters 1c and 1h. Again, phenyl and alkynyl substituted β-keto amide
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4k and 4l react efficiently, affording 69% and 76% yields, as well as 95% and 94% ee, respectively.
4-Substituted β-keto amides 4n–4q are also readily employed to create the corresponding products.
β-Keto amide 4m incorporating a naphthyl group is applied to the reaction, giving 78% yield with 97%
ee. Finally, tert-butyl substituted amide 4r is tolerated in the process, and a slightly reduced yield and
enantioselectivity are obtained.
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We have suggested that chiral N,N’-dioxides may act as a bifunctional catalyst. We determine that
no reaction occurred if additional 2-iodobenzoic acid (0.5 equiv) was added in the presence of 20 mol %
.
of C2-PrmMe2 without Na3PO4 12H2O. It indicates that 2-iodobenzoic acid caused the deactivation of
the chiral catalyst, which might occur through the hydrogen bonding between the carboxylic acid and
N-oxide unit of the catalyst. The inorganic base additive should benefit the recovery of the chiral
catalyst by neutralizing 2-iodobenzoic acid generated from the cyanation of cyano benziodoxole 2.
Therefore, the yield of the reaction was greatly improved without the loss of the enantioselectivity after
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Na3PO4 12H2O was added. These experiment results support our hypothesis that the reaction goes
through an enol intermediate of the β-keto esters or amides rather than an enolate assisted by an
inorganic base. N-oxide units of the catalyst will activate the enol intermediate as a H-bond acceptor,
on the other hand, the amide units will act as a H-bond donor to activate the cyano benziodoxole 2.
Such a bifunctional catalytic model makes the two reactants closer together with proper orientation,
thus a high enantioselective cyanation occurs smoothly (Scheme 1).
SUMMARY
In summary, asymmetric electrophilic organocatalyzed α-cyanation reactions of
1-indanone-derived β-keto esters and β-keto amides have been realized with good to high yields and
excellent enantioselectivities. An easily accessible and efficient chiral N,N′-dioxide catalyst exhibits its
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unique advantages in this asymmetric electrophilic cyanation reaction via a bifunctional catalytic
model. In addition, developing asymmetric electrophilic cyanation reactions of simple carbonyl
compounds is still a challenge. Further studies, regarding the catalytic performance of chiral
N,N′-dioxide organocatalysts and ligands in other catalytic asymmetric transformations, are underway
in our group.
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EXPERIMENTAL SECTION
General remarks: Reactions were carried out using commercial available reagents in oven-dried
1
apparatus. CHCl2CHCl2 was dried over powdered CaH2 and distilled under nitrogen. H NMR spectra
were recorded at 400 MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and
with the solvent resonance as the internal standard. Data were reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constants (Hz), integration.
13C NMR data were collected at 100 MHz with complete proton decoupling. Chemical shifts were
reported in ppm from the tetramethylsilane with the solvent resonance as internal standard. The
preparation of β-keto esters, β-keto amides and cyano benziodoxole followed the literature.4b
Enantiomeric excesses were determined by chiral HPLC analysis on Daicel Chiralcel IA/IE in
comparison with the authentic racemates. Optical rotations were reported as follows: [α]T = (c: g/100
λ
mL, in CH2Cl2, D: 589 nm). HRMS was recorded on a commercial apparatus (ESI Source, TOF), and
3a, 3b, 3d, 3e, 3g-3j, 3l and 3q compounds had been reported.4b Cyano benziodoxole 2 was prepared
according to the methods of the literature.4b
Typical procedure for the synthesis of β-keto esters and β-keto amides
To a stirred suspension of NaH (20 mmol, 60% in mineral oil) in dimethyl carbonate (5 mL) was added
dropwise a solution of indanone (10.0 mmol) in dimethyl carbonate (15 mL). The mixture was refluxed
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at 80 °C for 1 h. After cooling to room temperature, HCl (2 mol/L, 20 mL) aqueous solution was added.
The aqueous phase was separated and extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts were dried (Na2SO4) and concentrated under reduced pressure. The crude product thus
obtained was subjected to column chromatography.
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To a flask equipped with reflux condenser was added β-keto methyl ester (3.0 mmol), the
corresponding alcohol or amine (6.0 mmol), the transesterification catalyst ZnO (20 mol %), toluene
(10 mL) and 4 Å MS (1.0 g). The mixture was refluxed under N2 until complete conversion was
observed by TLC, then concentrated under reduced pressure and the crude residue was purified by
column chromatography. Then the pure β-keto ester or β-keto amide was obtained after
recrystallization.
General procedure for asymmetric electrophilic α-cyanation reaction
Chiral catalyst C2-PrmMe2 (20 mol %), NaI (15 mol %), β-keto esters or β-keto amides (0.1 mmol),
cyano benziodoxole
2
(1.2 equiv) and Na3PO4∙12H2O (2.0 equiv) were stirred in
1,1,2,2-tetrachloroethane (1.0 mL) at −30 oC under N2 atmosphere for 96 h. The reaction mixtures were
purified by flash chromatography on silica gel (ethyl acetate /petroleum ether = 1:10) to afford the
desired products.
(R)-1-adamantyl-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3a): Purified by flash chromatography (petroleum
ether: EtOAc = 10:1) to afford a white solid (m.p. 90 – 92 oC); 33.2 mg, 99% yield, 93% ee; [α]26.4D = −27.0 (c 0.48, CH2Cl2); the
ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) =
1
16.03 min, t (minor) = 22.32 min; H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.7 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.54 (d, J = 7.8
Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.65 (d, J = 17.2 Hz, 1H), 2.18 (s, 3H), 2.12 (d, J = 3.0 Hz, 6H), 1.65
(d, J = 2.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 191.3, 162.3, 151.6, 136.7, 132.3, 128.8, 126.4, 126.1, 116.1, 85.8, 55.3, 40.8,
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37.5, 35.8, 30.9.
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(−)-1-adamantyl-2-cyano-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3b): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 102 – 104 oC); 33.5 mg, 96% yield, 95% ee; [α]26.1D = −25.5 (c 0.65,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t
(major) = 17.02 min, t (minor) = 22.49 min; 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9
Hz, 1H), 3.82 (d, J = 17.1 Hz, 1H), 3.58 (d, J = 17.1 Hz, 1H), 2.42 (s, 3H), 2.17 (s, 3H), 2.11 (d, J = 2.6 Hz, 6H), 1.64 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 191.3, 162.4, 149.1, 139.0, 138.0, 132.5, 126.0, 125.9, 116.2, 85.7, 55.6, 40.8, 37.2, 35.8, 30.9,
21.0.
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(−)-1-adamantyl-2-cyano-5,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3c): Purified by flash chromatography
(petroleum ether: EtOAc = 12:1) to afford a colorless oil; 34.4 mg, 95% yield, 95% ee; [α]26.5D = −28.8 (c 0.33, CH2Cl2); the ee
was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) = 26.05
min, t (minor) = 34.77 min; 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.29 (s, 1H), 3.78 (d, J = 17.0 Hz, 1H), 3.54 (d, J = 17.0
Hz, 1H), 2.38 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.12 (d, J = 2.8 Hz, 6H), 1.64 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 190.8,
162.7, 149.9, 147.7, 138.0, 130.4, 127.0, 126.2, 116.4, 85.6, 55.6, 40.8, 37.1, 35.8, 30.9, 21.0, 19.8; HRMS (ESI-TOF): Calcd for
C23H25NO3Na+ [M+Na]+ 386.1727, Found 386.1731.
(−)-1-adamantyl-2-cyano-6-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3d): Purified by flash chromatography
(petroleum ether: EtOAc = 6:1) to afford a colorless oil; 30.3 mg, 83% yield, 92% ee; [α]25.9 = −21.5 (c 0.54, CH2Cl2); the ee
D
was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) = 17.55
min, t (minor) = 24.76 min; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.4, 2.5 Hz, 1H), 7.22 (d, J =
2.5 Hz, 1H), 3.85 (s, 3H), 3.78 (d, J = 16.9 Hz, 1H), 3.57 (d, J = 16.9 Hz, 1H), 2.18 (s, 3H), 2.12 (d, J = 2.9 Hz, 6H), 1.64 (t, J =
2.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 191.3, 162.4, 160.3, 144.6, 133.6, 127.0, 126.4, 116.1, 106.7, 85.8, 56.0, 55.7, 40.8,
36.9, 35.8, 30.9.
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(−)-1-adamantyl-2-cyano-5-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3e): Purified by flash chromatography
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(petroleum ether: EtOAc = 6:1) to afford a colorless oil; 27.0 mg, 74% yield, 93% ee; [α]25.9 = −62.4 (c 0.49, CH2Cl2); the ee
D
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was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) = 25.44
min, t (minor) = 33.77 min; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 8.6, 2.1 Hz, 1H), 6.92 (d, J =
1.7 Hz, 1H), 3.92 (s, 3H), 3.81 (d, J = 17.2 Hz, 1H), 3.56 (d, J = 17.2 Hz, 1H), 2.18 (s, 3H), 2.13 (d, J = 2.8 Hz, 6H), 1.64 (t, J =
2.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 189.1, 166.8, 162.7, 154.9, 127.8, 125.2, 117.0, 116.4, 109.4, 85.6, 55.9, 55.6, 40.8,
37.4, 35.8, 30.9.
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(−)-1-adamantyl-2-cyano-6-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3f): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 80 – 82 oC); 31.7 mg, 90% yield, 91% ee; [α]26.2D = −13.0 (c 1.00,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
1
(major) = 11.87 min, t (minor) = 16.12 min; H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.4, 4.4 Hz, 1H), 7.53 – 7.41 (m, 2H),
3.84 (d, J = 17.0 Hz, 1H), 3.61 (d, J = 17.0 Hz, 1H), 2.19 (s, 3H), 2.11 (d, J = 2.9 Hz, 6H), 1.64 (t, J = 2.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 190.4 (d, J = 3.4 Hz), 162.8 (d, J = 249 Hz), 161.9, 147.1 (d, J = 2.1 Hz), 134.2 (d, J = 8.1 Hz), 127.9 (d, J
= 8.1 Hz), 124.6 (d, J = 23.7 Hz), 115.8, 111.94 (d, J = 22.6 Hz), 86.2, 56.0, 40.8, 37.0, 35.8, 30.9; HRMS (ESI-TOF): Calcd for
C21H20FNO3Na+ [M+Na]+ 376.1321, Found 376.1319.
(−)-1-adamantyl-5-bromo-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3g): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 115 – 117 oC ); 28.9 mg, 70% yield, 88% ee; [α]26.4 = −37.9 (c
D
0.53, CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254
nm), t (major) = 15.70 min, t (minor) = 18.62 min; 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.62 (d,
J = 8.2 Hz, 1H), 3.86 (d, J = 17.4 Hz, 1H), 3.61 (d, J = 17.4 Hz, 1H), 2.18 (s, 3H), 2.11 (s, 6H), 1.64 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 190.1, 161.9, 153.0, 132.6, 132.5, 131.2, 129.7, 127.1, 115.7, 86.2, 55.3, 40.8, 37.0, 35.8, 30.9.
(−)-1-adamantyl-6-chloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3h): Purified by flash chromatography
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(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 88 – 90 oC); 24.4 mg, 66% yield, 94% ee; [α]26.4D = −12.1 (c 0.42,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
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(major) = 12.94 min, t (minor) = 19.08 min; H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 8.2, 2.0 Hz,
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1H), 7.49 – 7.47 (m, 1H), 3.84 (d, J = 17.3 Hz, 1H), 3.60 (d, J = 17.4 Hz, 1H), 2.18 (s, 3H), 2.11 (d, J = 3.0 Hz, 6H), 1.64 (t, J =
2.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 190.1, 161.8, 149.7, 136.8, 135.3, 133.9, 127.5, 125.7, 115.6, 86.2, 55.7, 40.8, 37.1,
35.8, 30.9; HRMS (ESI-TOF): Calcd for C21H2034.9689ClNO3Na+ [M+Na]+ 392.1024, Found 392.1028; Calcd for
C21H2036.9659ClNO3Na+ [M+Na]+ 394.0994, Found 394.1006.
(−)-1-adamantyl-5-chloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3i): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 126 – 128 oC); 27.0 mg, 73% yield, 90% ee; [α]26.1D = −47.6 (c 0.42,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
(major) = 14.79 min, t (minor) = 18.47 min; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 8.3
Hz, 1H), 3.85 (d, J = 17.4 Hz, 1H), 3.61 (d, J = 17.4 Hz, 1H), 2.18 (s, 3H), 2.11 (d, J = 2.4 Hz, 6H), 1.64 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 189.8, 161.9, 153.0, 143.6, 130.8, 129.7, 127.1, 126.7, 115.7, 86.2, 55.4, 40.8, 37.1, 35.8, 30.9.
(−)-1-adamantyl-2-cyano-5-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3j): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a light yellow soid (120 – 122 oC ); 26.1 mg, 74% yield, 90% ee; [α]26.3 = −77.8 (c
D
0.50, CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254
nm), t (major) = 13.15 min, t (minor) = 17.54 min; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 8.3, 5.2 Hz, 1H), 7.21 – 7.16 (m,
2H), 3.87 (d, J = 17.4 Hz, 1H), 3.62 (d, J = 17.5 Hz, 1H), 2.19 (s, 3H), 2.12 (d, J = 3.0 Hz, 6H), 1.64 (t, J = 2.9 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 189.3, 168.1(d, J = 259.2 Hz), 162.0, 154.7 (d, J = 10.7 Hz), 128.7 (d, J = 1.8 Hz), 128.6 (d, J = 10.9
Hz), 117.40 (d, J = 23.8 Hz), 115.8, 113.3 (d, J = 23.0 Hz), 86.1, 55.5, 40.8, 37.2, 35.8, 30.9.
(−)-1-adamantyl--2-cyano-5-phenyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3k): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 110 – 112 oC); 30.8 mg, 75% yield, 94% ee; [α]27.0D = −64.5 (c 0.22,
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CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t
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(major) = 22.02 min, t (minor) = 26.12 min; H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H),
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(s, 6H); 13C NMR (100 MHz, CDCl3) δ 190.7, 162.4, 152.3, 149.9, 139.3, 131.1,129.1, 129.0, 128.1, 127.5, 126.4, 124.7, 116.1,
85.8, 55.6, 40.8, 37.5, 35.9, 30.9; HRMS (ESI-TOF): Calcd for C27H25NO3Na+ [M+Na]+ 434.1734, Found 434.1727.
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(−)-1-adamantayl-2-cyano-5-phenylethynyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(3l):
Purified
by
flash
chromatography (petroleum ether: EtOAc = 10:1) to afford a light yellow oil; 30.5 mg, 70% yield, 92% ee; [α]26.1 = −60.9 (c
D
0.22, CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254
1
nm), t (major) = 13.32 min, t (minor) = 15.86 min; H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.66 –
7.55 (m, 3H), 7.40 (s, 3H), 3.87 (d, J = 17.2 Hz, 1H), 3.63 (d, J = 17.2 Hz, 1H), 2.19 (s, 3H), 2.12 (s, 6H), 1.65 (s, 6H);13C NMR
(100 MHz, CDCl3) δ 190.3, 162.2, 151.4,132.1, 132.0, 131.9, 131.5, 129.3, 129.0, 128.5, 125.9, 122.1, 115.9, 94.9, 88.2, 85.9,
55.4, 40.8, 37.2, 35.8, 30.9.
(−)-methyl-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3q): Purified by flash chromatography (petroleum ether:
EtOAc = 10:1) to afford a colorless oil ; 13.3 mg, 62% yield, 65% ee; [α]26.4D = −31.7 (c 0.23, CH2Cl2); the ee was determined by
HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) = 20.23 min, t (minor) =
23.47 min; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.51 (t, J =
7.5 Hz, 1H), 3.96 (d, J = 17.3 Hz, 1H), 3.89 (s, 3H), 3.71 (d, J = 17.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 190.6, 164.6,
151.5, 137.0, 132.0, 129.0, 126.5, 126.4, 115.7, 54.7, 54.2, 37.5.
(−)-tert-butyl-5-chloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3r): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 74 – 76 oC); 23.8 mg, 82% yield, 89% ee; [α]26.1D = −30.1 (c 0.77,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
(major) = 9.68 min, t (minor) = 12.17 min; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 0.9 Hz, 1H), 7.47
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– 7.44 (m, 1H), 3.86 (d, J = 17.4 Hz, 1H), 3.62 (d, J = 17.4 Hz, 1H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 189.8, 162.4,
153.0, 143.7, 130.7, 129.7, 127.1, 126.7, 115.7, 86.2, 55.2, 37.0, 27.6; HRMS (ESI-TOF): Calcd for C15H1434.9689ClNO3Na+
[M+Na]+ 314.0554, Found 314.0558; Calcd for C15H1436.9659ClNO3Na+ [M+Na]+ 316.0525, Found 316.0533.
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(−)-N-1-adamantyl-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5a): Purified by flash chromatography (petroleum
ether: EtOAc = 10:1) to afford a light yellow oil; 25.4 mg, 76% yield, 93% ee; [α]26.4 = −43.1 (c 0.59, CH2Cl2); the ee was
D
determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) = 11.43 min,
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t (minor) = 22.39 min; H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.8 Hz, 1H), 7.78 – 7.63 (m, 1H), 7.54 (d, J = 7.8 Hz, 1H),
7.46 (t, J = 7.4 Hz, 1H), 6.39 (s, 1H), 4.19 (d, J = 17.2 Hz, 1H), 3.51 (d, J = 17.2 Hz, 1H), 2.09 (s, 3H), 2.01 (d, J = 2.6 Hz,
6H),1.66 (d, J = 3.2, 6H); 13C NMR (100 MHz, CDCl3) δ 194.1, 158.9, 152.8, 137.0, 132.0, 128.6, 126.5, 125.9, 117.6, 54.3, 53.6,
40.9, 36.1, 35.4, 29.3; HRMS (ESI-TOF): Calcd for C21H22N2O2Na+ [M+Na]+ 357.1573, Found 357.1577.
(−)-N-1-adamantyl-2-cyano-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5b): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 150 – 152 oC); 27.5 mg, 79% yield, 95% ee; [α]27.4D = −84.6 (c 0.30,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
(major) = 12.57 min, t (minor) = 24.52 min; 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9
Hz, 1H), 6.38 (s, 1H), 4.12 (d, J = 17.2 Hz, 1H), 3.44 (d, J = 17.2 Hz, 1H), 2.41 (s, 3H), 2.08 (s, 3H), 2.00 (d, J = 2.6 Hz, 6H),
1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.1, 159.0, 150.3, 138.8, 138.4, 132.2, 126.1, 125.7, 117.7, 54.6, 53.5, 40.9, 36.1,
35.1, 29.3, 21.0; HRMS (ESI-TOF): Calcd for C22H24N2O2Na+ [M+Na]+ 371.1730, Found 371.1737.
(−)-N-1-adamantyl--2-cyano-5,6-dimethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide
(5c):
Purified
by
flash
chromatography (petroleum ether: EtOAc = 10:1) to afford a colorless oil; 18.1 mg, 50% yield, 92% ee; [α]26.4D = −47.8 (c 0.32,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
1
(major) = 17.55 min, t (minor) = 34.55 min; H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.29 (s, 1H), 6.40 (s, 1H), 4.08 (d, J =
17.2 Hz, 1H), 3.40 (d, J = 17.2 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.08 (s, 3H), 2.00 (s, 6H), 1.66 (s, 6H); 13C NMR (100 MHz,
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CDCl3) δ 193.6, 159.2, 151.0, 148.1, 137.9, 130.1, 127.1, 126.0, 117.9, 54.5, 53.5, 40.9, 36.1, 35.0, 29.3, 21.0, 19.7; HRMS
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(ESI-TOF): Calcd for C23H26N2O2Na+ [M+Na]+ 385.1886, Found 385.1895.
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(−)-N-1-adamantyl-2-cyano-6-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxamide
(5d):
Purified
by
flash
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chromatography (petroleum ether: EtOAc = 8:1) to afford a light yellow oil; 28.0 mg, 77% yield, 95% ee; [α]26.3D = −34.0 (c 0.40,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t
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(major) = 17.45 min, t (minor) = 41.48 min; H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.5, 2.5 Hz,
1H), 7.19 (d, J = 2.4 Hz, 1H), 6.38 (s, 1H), 4.09 (d, J = 17.1 Hz, 1H), 3.84 (s, 3H), 3.43 (d, J = 17.1 Hz, 1H), 2.09 (s, 3H), 2.01 (d,
J = 2.2 Hz, 6H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.0, 160.2, 159.0, 145.9, 133.2, 127.1, 126.7, 117.6, 106.5, 55.7,
55.0, 53.6, 40.9, 36.1, 34.8, 29.3; HRMS (ESI-TOF): Calcd for C22H24N2O3Na+ [M+Na]+ 387.1679, Found 387.1684.
(−)-N-1-adamantyl-2-cyano-5-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5e): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 122 – 124 oC); 22.2 mg, 63% yield, 90% ee; [α]25.8D = −48.3 (c 0.53,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
1
(major) = 9.11 min, t (minor) = 14.43 min; H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 8.5, 5.2 Hz, 1H), 7.21 – 7.14 (m,2H),
6.36 (s, 1H), 4.18 (d, J = 17.6 Hz, 1H), 3.49 (d, J = 17.6 Hz, 1H), 2.10 (s, 3H), 2.01 (d, J = 2.6 Hz, 6H), 1.67 (d, J = 2.8 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 192.1, 168.4 (d, J = 259.6Hz), 158.7, 155.8 (d, J = 10.9 Hz), 128.5 (d, J = 10.8 Hz),128.4, 117.3
(d, J = 23.9 Hz), 117.2, 113.4 (d, J = 23.0 Hz) , 54.6, 53.7, 40.9, 36.1, 35.2, 29.3; HRMS (ESI-TOF): Calcd for C21H21FN2O2Na+
[M+Na]+ 375.1479, Found 375.1482.
(−)-N-1-adamantyl-6-chloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5f): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 148 – 150 oC); 33.9 mg, 92% yield, 97% ee; [α]26.5D = −83.3 (c 0.45,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
1
(major) = 10.37 min, t (minor) = 27.88 min; H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.2, 1.9 Hz,
1H), 7.48 (d, J = 8.2 Hz, 1H), 6.30 (s, 1H), 4.14 (d, J = 17.4 Hz, 1H), 3.46 (d, J = 17.4 Hz, 1H), 2.09 (s, 3H), 1.99 (d, J = 2.4 Hz,
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6H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 192.9, 158.5, 150.8, 137.0, 135.1, 133.5, 127.6, 125.5, 117.1, 54.9, 53.7, 40.9,
36.0, 35.1, 29.3; HRMS (ESI-TOF): Calcd for C22H2534.9689ClN2O3Na+ [M+Na+CH3OH]+ 423.1446, Found 423.1449; Calcd for
C22H2536.9659ClN2O3Na+ [M+Na+CH3OH]+ 425.1416, Found 425.1416.
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(−)-N-1-adamantyl-5-bromo-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5g): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 168 – 170 oC); 33.4 mg, 81% yield, 91% ee; [α]26.8D = −68.2 (c 0.41,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
(major) = 10.86 min, t (minor) = 16.26 min; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.61 – 7.56 (m,
1H), 6.32 (s, 1H), 4.16 (d, J = 17.5 Hz, 1H), 3.48 (d, J = 17.5 Hz, 1H), 2.09 (s, 3H), 2.00 (d, J = 2.6 Hz, 6H), 1.67 (s, 6H);13
C
NMR (100 MHz, CDCl3) δ 192.8, 158.6, 154.1, 132.9, 132.4, 130.9, 129.9, 126.9, 117.1, 54.5, 53.7, 40.9, 36.0, 35.0, 29.3;
HRMS (ESI-TOF): Calcd for C22H2578.9183BrN2O3H+ [M+H+CH3OH]+ 445.1127, Found 445.1124; Calcd for
C22H2580.9163BrN2O3H+ [M+H+CH3OH]+ 447.1106, Found 447.1109.
(−)-N-1-adamantyl-6-bromo-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5h): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 124 – 126 oC); 32.2 mg, 78% yield, 96% ee; [α]25.9D = −29.0 (c 0.63,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
1
(major) = 13.16 min, t (minor) = 37.83 min; H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 1.7 Hz, 1H), 7.80 (dd, J = 8.2, 1.8 Hz,
1H), 7.42 (d, J = 8.2 Hz, 1H), 6.30 (s, 1H), 4.12 (d, J = 17.5 Hz, 1H), 3.43 (d, J = 17.5 Hz, 1H), 2.09 (s, 3H), 1.99 (d, J = 2.6 Hz,
6H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 192.7, 158.5, 151.3, 139.7, 133.8, 128.6, 127.9, 122.8, 117.1, 54.8, 53.8, 40.9,
36.0, 35.2, 29.3; HRMS (ESI-TOF): Calcd for C21H2178.9183BrN2O2Na+ [M+Na]+ 435.0679, Found 435.0684; Calcd for
C21H2180.9163BrN2O2Na+ [M+Na]+ 437.0658, Found 437.0661.
(−)-N-1-adamantyl-5-chloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5i): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 168 – 170 oC); 32.4 mg, 88% yield, 90% ee; [α]26.4D = −76.1 (c 0.38,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
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(major) = 9.71 min, t (minor) = 14.76 min; 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H),
7.54 (s, 1H), 7.44 (dd, J = 8.3, 0.9 Hz, 1H), 6.32 (s, 1H), 4.16 (d, J = 17.5 Hz, 1H), 3.47 (d, J = 17.5 Hz, 1H), 2.09 (s, 3H), 2.00
(d, J = 2.5 Hz, 6H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 192.6, 158.6, 154.1, 144.0, 130.5, 129.6, 126.8, 126.9, 117.2,
54.5, 53.7, 40.9, 36.0, 35.1, 29.3; HRMS (ESI-TOF): Calcd for C21H2134.9689ClN2O2Na+ [M+Na]+ 391.1184, Found 391.1187;
Calcd for C21H2136.9659ClN2O2Na+ [M+Na]+ 393.1154, Found 393.1186.
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(−)-N-1-adamantyl-5,6-dichloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide
(5j):
Purified
by
flash
chromatography (petroleum ether: EtOAc = 10:1) to afford a light yellow solid (m.p. 182 – 184 oC); 35.1 mg, 87% yield, 93% ee;
[α]27.0D = −48.7 (c 0.46, CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0
mL/min, λ = 254 nm), t (major) = 9.36 min, t (minor) = 16.90 min; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.67 (s, 1H), 6.27
(s, 1H), 4.13 (d, J = 17.5 Hz, 1H), 3.45 (d, J = 17.5 Hz, 1H), 2.10 (s, 3H), 1.99 (s, 6H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 191.8, 158.3, 151.2, 142.0, 134.0, 131.5, 128.3, 127.0, 116.8, 54.9, 53.8, 40.9, 36.0, 34.8, 29.3; HRMS (ESI-TOF): Calcd for
C22H2434.9689Cl2N2O3Na+ [M+Na+CH3OH]+ 457.1056, Found 457.1058; Calcd for C22H2436.9659Cl2N2O3Na+ [M+Na+CH3OH]+
459.1027, Found 459.1034.
(−)-N-1-adamantyl--2-cyano-5-phenyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5k): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a light yellow oil; 28.3 mg, 69% yield, 95% ee; [α]26.5D = −69.4 (c 0.68, CH2Cl2); the
ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) =
15.84 min, t (minor) = 23.18 min; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H),
7.62 (d, J = 7.4 Hz, 2H), 7.51 – 7.42 (m, 3H), 6.42 (s, 1H), 4.24 (d, J = 17.3 Hz, 1H), 3.54 (d, J = 17.3 Hz, 1H), 2.10 (s, 3H), 2.02
(s, 6H), 1.68 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 193.5, 159.1, 153.4, 150.3, 139.3, 130.8, 129.1, 129.0, 128.0, 127.5, 126.2,
124.8, 117.6, 54.6, 53.6, 41.0, 36.1, 35.5, 29.3; HRMS (ESI-TOF): Calcd for C27H26N2O2Na+ [M+Na]+ 433.1886, Found
433.1894.
(−)-N-1-adamantayl-2-cyano-5-phenylethynyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5l): Purified by flash
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chromatography (petroleum ether: EtOAc = 10:1) to afford a colorless oil; 33.1 mg, 76% yield, 94% ee; [α]26.7D = −28.5 (c 0.35,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
(major) = 16.97 min, t (minor) = 20.59 min; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.58 – 7.56 (m
3H), 7.40 – 7.38 (m, 3H), 6.38 (s, 1H), 4.19 (d, J = 17.4 Hz, 1H), 3.49 (d, J = 17.4 Hz, 1H), 2.10 (s, 3H), 2.02 (s, 6H), 1.68 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 193.1, 158.8, 152.5, 132.4, 131.9, 131.8, 131.1, 129.3, 129.2, 128.5, 125.7, 122.1, 117.4,
95.0, 88.3, 54.4, 53.6, 40.9, 36.1, 35.1, 29.3; HRMS (ESI-TOF): Calcd for C29H27N2O2+ [M+H]+ 435.2067, Found 435.2065.
(−)-N-1-adamantyl-2-cyano-1-oxo-2,3-dihydro-1H-cyclopenta[b]naphthalene-2-carboxamide (5m): Purified by flash
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chromatography (petroleum ether: EtOAc = 8:1) to afford a white solid (m.p. 178 – 180 oC); 30.0 mg, 78% yield, 97% ee; [α]26.8
D
= −38.1 (c 0.52, CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min,
λ = 254 nm), t (major) = 18.14 min, t (minor) = 35.54 min; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H),
7.92 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 6.42 (s, 1H), 4.35 (d, J = 17.1 Hz, 1H),
3.66 (d, J = 17.2 Hz, 1H), 2.09 (s, 3H), 2.02 (s, 6H), 1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.3, 159.1, 144.0, 138.1,
132.5, 130.5, 130.1, 129.5, 128.0, 127.8, 126.9, 124.9, 117.7, 55.2, 53.6, 40.1, 40.9, 36.1, 35.0, 29.3; HRMS (ESI-TOF): Calcd
for C25H24N2O2Na+ [M+Na]+ 407.1730, Found 407.1731.
(−)-N-1-adamantyl-4-bromo-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5n): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a colorless oil; 39.2 mg, 95% yield, 92% ee; [α]26.4D = −54.2 (c 0.66, CH2Cl2); the ee
was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 10/90, 1.0 mL/min, λ = 254 nm), t (major) = 20.42
min, t (minor) = 18.64 min; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.7 Hz,
1H), 6.32 (s, 1H), 4.13 (d, J = 17.9 Hz, 1H), 3.44 (d, J = 17.8 Hz, 1H), 2.10 (s, 3H), 2.02 (s, 6H), 1.68 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 193.3, 158.6, 152.4, 139.7, 134.0, 130.3, 124.7, 121.8, 117.1, 54.4, 53.8, 40.9, 36.6, 36.1, 29.3; HRMS
(ESI-TOF): Calcd for C21H2178.9183BrN2O2Na+ [M+Na]+ 435.0679, Found 435.0684; Calcd for C21H2180.9163BrN2O2Na+ [M+Na]+
437.0658, Found 437.0666.
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(−)-N-1-adamantyl-2-cyano-4-iodo-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5o): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a light yellow oil; 33.6 mg, 73% yield, 88% ee; [α]25.8D = −39.3 (c 0.57, CH2Cl2); the
ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) =
11.68 min, t (minor) = 12.80min; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6
Hz, 1H), 6.33 (s, 1H), 4.02 (d, J = 17.7 Hz, 1H), 3.35 (d, J = 17.7 Hz, 1H), 2.10 (s, 3H), 2.01 (s, 6H), 1.68 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 193.7, 158.6, 156.4, 145.9, 133.6, 130.3, 125.4, 117.1, 95.5, 54.6, 53.8, 40.9, 40.4, 36.1, 29.3; HRMS (ESI-TOF):
Calcd for C21H22IN2O2+ [M+H]+ 461.0720, Found 461.0725.
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(−)-N-1-adamantyl-4-chloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5p): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a light yellow oil; 33.2 mg, 90% yield, 91% ee; [α]26.4D = −51.0 (c 0.57, CH2Cl2); the
ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ = 254 nm), t (major) =
13.47 min, t (minor) = 11.84 min; 1H NMR (400 MHz, CDCl3) δ 7.72 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.7 Hz, 1H), 6.33 (s, 1H),
4.18 (d, J = 17.9 Hz, 1H), 3.48 (d, J = 17.9 Hz, 1H), 2.10 (s, 3H), 2.02 (s, 6H), 1.68 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 193.2,
158.6, 150.3, 136.6, 133.9, 132.8, 130.1, 124.1, 117.1, 54.3, 53.8, 40.9, 36.0, 34.6, 29.3; HRMS (ESI-TOF): Calcd for
C21H2134.9689ClN2O2Na+ [M+Na]+ 391.1184, Found 391.1190; Calcd for C21H2136.9659ClN2O2Na+ [M+Na]+ 393.1154, Found
393.1169.
(−)-N-1-adamantyl--2-cyano-4-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5q): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 146 – 148 oC); 25.0 mg, 72% yield, 92% ee; [α]27.1D = −61.0 (c 0.46,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
1
(major) = 11.75 min, t (minor) = 13.71 min; H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H),
7.37 (t, J = 7.5 Hz, 1H), 6.42 (s, 1H), 4.10 (d, J = 17.4 Hz, 1H), 3.37 (d, J = 17.4 Hz, 1H), 2.39 (s, 3H), 2.09 (s, 3H), 2.01 (s, 6H),
1.67 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.4, 159.0, 151.7, 137.5, 136.1, 131.8, 128.8, 123.3, 117.7, 54.2, 53.6, 40.9, 36.1,
34.4, 29.3, 17.7; HRMS (ESI-TOF): Calcd for C22H24N2O2Na+ [M+Na]+ 371.1730, Found 371.1737.
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(−)-N-tert-butyl-5-chloro-2-cyano-1-oxo-2,3-dihydro-1H-indene-2-carboxamide (5r): Purified by flash chromatography
(petroleum ether: EtOAc = 10:1) to afford a white solid (m.p. 68 – 70 oC ); 20.9 mg, 72% yield, 87% ee; [α]26.5D = −59.1 (c 0.67,
CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (iPrOH/hexane = 20/80, 1.0 mL/min, λ= 254 nm), t
(major) = 6.54 min, t (minor) = 8.16 min; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.45 (dd, J = 8.3,
1.0 Hz, 1H), 6.48 (s, 1H), 4.18 (d, J = 17.6 Hz, 1H), 3.49 (d, J = 17.6 Hz, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 192.5,
159.0, 154.1, 144.0, 130.4, 129.6, 126.9, 126.8, 117.1, 54.4, 53.1, 35.1, 28.2; HRMS (ESI-TOF): Calcd for
C15H1534.9689ClN2O2Na+ [M+Na]+ 313.0714, Found 313.0719; Calcd for C15H1536.9659ClN2O2Na+ [M+Na]+ 315.0685, Found
315.0697.
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ACKNOWLEDGMENTS
We appreciate the National Natural Science Foundation of China (Nos. 21222206, 21332003, 21321061), the Fok Ying Tung
Education Foundation (141115), and National Program for Support of Top-notch Young Professionals for financial support.
Supporting Information
Optimization detail, 1H and 13C NMR spectra, and HPLC data are available. This material is available
free of charge via the Internet at http://pubs.acs.org.
REFERENCES
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