Cascade reaction of β,γ-unsaturated α-ketoesters with phenols in trityl chloride/TFA system. Highly selective synthesis of 4-aryl-2H-chromenes and their applications

Article abstract of DOI:10.1039/c0ob01143f

The treatment of β,γ-unsaturated α-ketoesters with phenols in the presence of trityl chloride and 4 A molecular sieves in refluxing trifluoroacetic acid afforded 4-aryl-2H-chromenes in high yields, in which a reverse of the regiochemistry of Jorgensen-Rut

Full text of DOI:10.1039/c0ob01143f

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PAPER
Cascade reaction of b,c-unsaturated a-ketoesters with phenols in trityl
chloride/TFA system. Highly selective synthesis of 4-aryl-2H-chromenes and
their applications†
Yan-Chao Wu,* Hui-Jing Li, Li Liu, Zhe Liu, Dong Wang and Yong-Jun Chen*
Received 9th December 2010, Accepted 3rd February 2011
DOI: 10.1039/c0ob01143f
˚
The treatment of b,g-unsaturated a-ketoesters with phenols in the presence of trityl chloride and 4 A
molecular sieves in refluxing trifluoroacetic acid afforded 4-aryl-2H-chromenes in high yields, in which
a reverse of the regiochemistry of Jørgensen–Rutjes chromane synthesis was observed. The isolation of
4H-chromene intermediates, confirmed by single-crystal X-ray analysis, indicates that the early stage of
the reaction involves a Friedel–Crafts alkylation/cyclodehydration processes. Stirring of the
4H-chromene intermediate with trityl chloride in deuterotrifluoroacetic acid under reflux afforded the
2H-chromene and triphenylmethane in high yields, which implies the late stage of the reaction involves
a hydrogen transfer process. Highly selective derivation of the hydroxyl esters to the corresponding
hydroxyl amides, amino acids, amino esters and Friedel–Crafts adducts was further accomplished. Our
endeavors will lead to a better understanding of the controlling elements behind their structural motifs.
The products were confirmed unambiguously from their spectra and by single-crystal X-ray analysis.
Introduction
Selectivity continues to be a major area of focus in organic
chemistry. The obtention of high selectivity in a cascade reaction is
a long-standing challenge for organic chemists. Another challenge
is to perform the reaction using substrates bearing multiple
functional groups that could lead to many possible transforma-
tions. Thanks to their versatile functional groups of unsaturated
double bonds, ketones and esters, b,g-unsaturated a-ketoesters
2 (Scheme 1) are attractive substrates for the development of
selective cascade reactions. 2 can react with phenols through
Friedel–Crafts alkylation,1,2 Friedel–Crafts hydroxyalkylation,1a
oxa-Michael addition,1a,3 transesterification,4 hemiacetalization,
acetalization and so on.5,6 For example, Jørgensen and Rutjes
reported an elegant Lewis acid-catalyzed [Mg(OTf)2 or Cu(OTf)2
in combination with bisoxazoline ligands in toluene] oxa-Michael
addition/Friedel–Crafts hydroxyalkylation of b,g-unsaturated a-
ketoesters 2 with phenols 1 for the selective synthesis of optically
active chromanes 8A–B (Scheme 1, Route I).1a They noted that
the above reaction and Friedel–Crafts alkylation of 2 with 1
concurrently occurred in some cases to result in side products
9 together with the desired products 8 (Scheme 1, Route II).1a
Scheme 1 Reaction of b,g-unsaturated a-ketoesters 2 with phenols 1.
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS
Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail:
ycwu@iccas.ac.cn, yjchen@iccas.ac.cn
Since the seminal work reported by Jørgensen and Rutjes, Luo
(Scheme 1, Route II),1c Zhao and Yang (Scheme 1, Route III)
have also developed selective Friedel–Crafts alkylation of b,g-
unsaturated a-ketoesters 2 with phenols 1 to afford Friedel–Crafts
adducts 9–10. Subsequent dehydration of 10 in dichloromethane
† Electronic supplementary information (ESI) available: Copies of 1H
NMR and 13C NMR spectra, and crystallographic data. CCDC reference
numbers 791782–791784. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob01143f
1b
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Table 1 A survey of the reaction conditionsa
process. Therefore, the addition of a dehydrating agent to the
reaction mixture would absorb the water produced, and thereby
facilitate the reaction (entries 1 and 6–7). The yield of 3a was
˚
increased up to 81% by simply adding 4 A molecular sieves as
dehydrating agent (entry 7).
The formation of 13a (2% yield) and 3a (Table 1, entry 5) also
indicates that the transformation of 1a and 2a into 4H-chromene
intermediate 13a was not completely finished when the oxidation
process of 13a to 3a took place. Herein, 2a appeared to serve
the dual role of the substrate and oxidation agent (entries 1–7).
Thus, one equivalent of 2a might be saved with another agent
as the oxidant. On the other hand, the dual role of 2a as the
substrate and oxidation agent would affect the application scope
of the protocol. Moreover, the potential reducing products were
unstable under the harsh conditions and were not isolated from
the reaction, which was not in accordance with the standpoint of
atom economy. Therefore, a series of other oxidation agents was
examined for the reaction (entries 8–12). Iron chloride (FeCl3, 1.1
equiv.), DDQ (1.1 equiv.) and chloranil (1.1 equiv.) didn’t provide
any better results (entries 8–10). Gratifyingly, 3a (90%) along with
triphenylmethane (Ph3CH, 14, 81% yield) were isolated by simply
adding trityl chloride (Ph3CCl, 1.1 equiv.) as an oxidation agent
(entries 7–12), in which nearly one equivalent of 2a was saved. The
formation of 14 indicates that the reaction involves a hydrogen
transfer process.12
With the optimized reaction conditions in hand, the scope of
the reaction with respect to b,g-unsaturated a-ketoesters 2 and
(thio)phenols 1 was subsequently investigated (Table 2). With
weak electron-donating groups, tert-butyl, phenyl and methyl, at
the para position of phenols, the cascade reaction of phenols
1a–c with (3E)-2-oxo-4-phenylbut-3-enoate methyl ester (2a)
under standard conditions afforded 2H-chromenes 3a–c in high
yields (entries 1–3). With the para position of phenols bearing
electron-withdrawing groups such as fluoro, chloro and bromo,
phenols 1d–f reacted equally well with 2a to afford 2H-chromenes
3d–f in excellent yields (entries 4–6). With a strong electron-
donating group such as a methoxy group at the para position of the
phenol, phenol 1g reacted with 2a to afford 2H-chromene 3g with a
slightly decreased yield (78%, entry 7). Besides phenols, 1-naphthol
(1h) and 2-naphthol (1i) were also reacted with 2a to afford
2H-benzo[h]chromenes 3h–i in 81% and 84% yields, respectively
(entries 8–9). b,g-Unsaturated a-ketoesters 2 with either electron-
withdrawing or electron-donating groups have also been investi-
gated, which reacted with phenols 1 uneventfully under standard
conditions to afford the desired 2H-chromenes 3j–o in 83–89%
yields (entries 10–15). The cascade reaction of 2a with thiophenol
1j under standard conditions afforded 2H-thiochromene 3p in
72% yield (entry 16), demonstrating similar selectivity as for
2H-chromenes. Highly deactivated 4-nitrophenol (1k) prevented
any reaction (entry 17). b,g-Unsaturated a-ketoesters 2f–h were
found to be quite unstable under the standard reaction conditions
and therefore were incompatible substrates (entries 18–20). The
structures of 2H-chromenes were confirmed from their spectra
and supported by the X-ray crystallographic analysis of 3a (see
the ESI†).13
Entry Conditions
Time Yields
1
2
3
4
5
6
7
8
2a (2.0 equiv.), TFA, reflux
48 h
48 h
48 h
48 h
48 h
12 h
12 h
12 h
12 h
73%
< 5%
< 5%
71%
36%
77%
81%
46%
65%
72%
88%
90%
2a (2.0 equiv.), 3 N HCl in MeOH, reflux
2a (2.0 equiv.), AcOH, reflux
2a (2.0 equiv.), HCO2H, reflux
2a (1.1 equiv.), TFA, reflux
2a (2.0 equiv.), TFA, Na2SO4, reflux
˚
2a (2.0 equiv.), TFA, 4 A MS, reflux
˚
2a (1.1 equiv.), TFA, FeCl3, 4 A MS, reflux
˚
2a (1.1 equiv.), TFA, DDQ, 4 A MS, reflux
9
˚
˚
10
11
12
2a (1.1 equiv.), TFA, chloranil, 4 A MS, reflux 12 h
2a (1.1 equiv.), TFA, Ph3CBF4, 4 A MS, reflux 12 h
˚
2a (1.1 equiv.), TFA, Ph3CCl, 4 A MS, reflux
12 h
a c = 0.1 M. MS = molecular sieves; DDQ = 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone.
with concentrated sulfuric acid afforded naphthopyran derivatives
11 (Scheme 1, Routes III–IV).1b In connection with our ongoing
projects aiming for the development of selective strategies for the
synthesis of various functional heterocycles,7 herein we would like
to report a cascade reaction of b,g-unsaturated a-ketoesters 2 with
phenols 1 for the selective synthesis of 4-aryl-2H-chromenes 3 in
a one-pot fashion (Scheme 1). The tandem reaction likely involves
processes of Friedel–Crafts alkylation (Route II), cyclodehydra-
tion (Route V), in situ oxidation and hydration (Route VI). As
the ketone functionalities of 2 are activated by the ester groups,
another possibility for the formation of potential intermediates 13
involves processes of hemiacetalization (Route VII), intramolecu-
lar Friedel–Crafts alkylation and cyclodehydration (Route VIII).
This synthesis and Jørgensen–Rutjes chromane synthesis would
complement each other to enrich the reaction diversity. Moreover,
from the resulting hydroxyl esters 3 were derived, in a highly
selective manner, the corresponding hydroxyl amides 4, amino
acids 5, amino esters 6 and Friedel–Crafts adducts 7 (Scheme 1).
Results and discussion
The reaction of (3E)-2-oxo-4-phenylbut-3-enoate methyl ester (2a)
with 4-tert-butylphenol (1a) was used as a probe for evaluating the
reaction conditions, and several representative results are summa-
rized in Table 1. Optimization of standard reaction parameters
identified TFA as the most effective catalyst and solvent (entries
1–3).8,9 Formic acid was also an effective solvent for this reaction
(entry 4) and might be useful for a large scale process. However,
TFA was chosen in our investigations because it led to the best
yield.
The desired 4-aryl-2H-chromene 3a was isolated in only 36%
yield when the molar ratio of 1a to 2a was changed from 1 : 2
to 1 : 1.1 under otherwise the same conditions (Table 1, entry
5), in which 4H-chromene intermediate 13a (2% yield) and 1a
(43% of the starting material) were isolated. The isolation of
13a, confirmed by single-crystal X-ray analysis (see the ESI†),10,11
indicates that the early stage of the reaction involves a dehydration
A proposed mechanistic model for this cascade reaction is
outlined in Scheme 2. It is anticipated that the Friedel–Crafts
alkylation/cyclodehydration of b,g-unsaturated a-ketoesters 2
with phenols 1 formed the 4H-chromenes 13 (also see Scheme 1),
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Table 2 Cascade reaction of b,g-unsaturated a-ketoesters
(thio)phenols 1a
2
with
Table 2 (Contd.)
Entry
12
1
2
Yields of 3
Entry
1
1
2
Yields of 3
1a
2
3
4
2a
2a
2a
13
14
1a
1h
1i
2c
2c
5
6
7
2a
2a
2a
15
16
2a
2a
8
2a
2a
17
18
—
—
1a
1a
1a
9
19
20
—
—
10
1a
1a
11
a Conditions: 1 (1.0 equiv.), 2 (1.1 equiv.), Ph3CCl (1.1 equiv.), c = 0.1 M,
˚
4 A MS.
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On the other hand, 2H-chromenes 3 are also among the
challenging substrates for developing selective reactions due
to their versatile functionalities of hemiacetal, hydroxyl and
ester. The equilibrium between 2-hydroxy-2H-chromenes and
benzopyrylium salts has long been a subject of extensive inves-
tigations in the overlapping areas of chemistry and biology due
to their relevant importance in the plant kingdom and human
beings.20 In neutral or basic solutions, benzopyrylium salts are
easily converted to the corresponding 2-hydroxy-2H-chromenes
by hydration with water.21 Accordingly, benzopyrylium species
20 in a neutral solution should be less stable than 2-hydroxy-
2H-chromene 3a, a normal representative of our synthesized
2H-chromenes 3 (Scheme 4). However, we believed that further
reaction of 20 with some nucleophiles would drive the equilibrium
toward the desired side. To our delight, by treating different types
of amino-containing nucleophiles with hydroxyl ester 3a in a
dichloromethane refluxing system without the presence of any
catalyst, various interesting functional compounds were obtained
in high selectivity. Listed in Table 3 (entries 1–13) are representative
results.
Scheme 2 Proposed mechanism for the cascade reaction of phenols 1
with b,g-unsaturated a-ketoesters 2.
and the intermolecular hydrogen transfer from 13 to trityl
chloride formed triphenylmethane (14) and benzopyrylium
ions 15. Subsequent hydration of 15 with water afforded
4-aryl-2H-chromenes 3.14
The reversible oxa-Michael addition of phenols 1 to b,g-
unsaturated a-ketoesters 2, accomplished in Jørgensen–Rutjes
chromane synthesis,1a was reported to be suppressed when some
Brønsted acids were used.1c Accordingly, in our case, Brønsted
acid TFA should also suppress the reversible process of oxa-
Michael addition. Moreover, the facile and irreversible Friedel–
Crafts alkylation of 2 with 1 in our reaction system should further
obviate the reversible oxa-Michael addition, and thus cause a
reverse of the regiochemistry of the Jørgensen–Rutjes chromane
process.
The intermolecular hydrogen transfer process was further con-
firmed by a hydrogen/deuterium exchange experiment (Scheme 3).
In this case, the reaction of the isolated 4H-chromene intermediate
13a with trityl chloride in deuterotrifluoroacetic acid (CF3CO2D,
TFA-d) under reflux for 12 h, followed by hydration with water
afforded 4-aryl-2H-chromene 3a and triphenylmethane (14) in
91% and 83% yields, respectively. The transformation of trityl
chloride to the non-deuterated 14 in a deuterated atmosphere im-
plies a hydrogen transfer process, in which hydrogen is selectively
transferred from the 4-position of 13a to the quaternary carbon
of trityl chloride.
Scheme 4 Possible structural transformations.
By treating hydroxyl ester 3a with heptylamine (16a) in
dichloromethane under reflux for 24 h, hydroxyl amide 4a was
obtained in 83% yield (Table 3, entry 1). Decreasing yields were
observed with primary amines 16b–c in comparison to 16a (entries
1–3), indicating that the steric factor affects the amide formation.
Indeed, when sterically hindered amines such as cyclohexylamine
(16d) and a-methylbenzylamine (16e) were used, no reaction took
place and the starting materials were recovered (entries 4–5). It is
noteworthy that the amination of the hemiacetal function of 3a
was not detected in these reactions (entries 1–5) even with an excess
of amines 16 as nucleophiles. Indeed, the potential amino esters 21
(Scheme 4), supposed to be formed from the amination of hemi-
acetal 3a with 16, are probably unstable in the dichloromethane
refluxing system. Nitrogen’s lone pair of electrons, in aliphatic
amines 21, is likely to cause the transformation of N,O-acetals 21
into a-ketoesters 23, which underwent intramolecular cyclization
to convert back to the hemiacetal 3a. The irreversible amidation
of ester 3a with active aliphatic amines 16 furthermore facilitated
the reaction with a high selectivity.
Scheme 3 A hydrogen/deuterium exchange experiment.
2H-Chromenes have been a subject of consistent interest due to
the presence of their structural motifs in a large number of natural
products,15 pharmaceuticals16 and functional materials.17 The
multistate/multifunctional chemical system existing in 2-hydroxy-
2H-chromenes has attracted increasing attention in molecular
information processing, optical memories and logic gates.18 The
significance and prevalence of this class of compounds has served
to stimulate continual interest in their diversity-oriented structural
modification,19 which triggered us to further study the derivation
of our synthesized 2H-chromenes.
Treatment of hydroxyl ester 3a with aqueous ammonia (17)
in dichloromethane under reflux for 6 h afforded amino acid
5 in 71% yield (Table 3, entry 6), in which conversion of a
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Table 3 Highly selective reactions of hydroxyl ester 3a with various
Table 3 (Contd.)
amino-containing nucleophilesa
Entry
13
Nucleophiles
Time
72 h
Yields of products 4–7
Entry
1
Nucleophiles
Time
24 h
Yields of products 4–7
c
—
a Conditions: 3a (1.0 equiv.), nucleophiles (1.1 equiv.), CH2Cl2, reflux.
2
3
36 h
48 h
b 5.0 M aqueous ammonia (5.0 equiv.) was used. c No reaction.
hydroxyl group to an amino group as well as the hydroxylation
were efficiently achieved in a one-pot fashion. In contrast to the
potential N,O-acetals 21 (Scheme 4), N,O-acetal 5 was stable
because the intramolecular reaction between the amine and acid
moiety, formed by aqueous hydrolysis, led to an ammonium salt
c
4
5
72 h
72 h
—
1
(Scheme 4), supported by its H NMR spectra (see the ESI†),
which dispersed nitrogen’s lone pair of electrons and thereby
avoided the deamination process mentioned before.
c
—
Anilines 18a–c are weaker nucleophiles than aliphatic amines
16a–c since the orbital containing the nitrogen’s lone pair of elec-
trons overlaps with the p system of the aromatic ring. Accordingly,
condensation of anilines 18a–c with ester 3a in dichloromethane
under reflux did not afford the corresponding amides. Instead,
amino esters 6a–c were isolated in excellent yields (Table 3,
entries 7–9). In contrast to N,O-acetals 21, N,O-acetals 6a–c were
relatively stable because the nitrogen’s lone pair of electrons was
delocalized in the aromatic ring and thereby obviated the process
of deamination mentioned previously, which was supported by the
result that transamination of N,O-acetals 6 with another aromatic
amine was not detected in refluxing dichloromethane. As in the
case of 13a and 3a, the structure of 6a was assigned from spectra
and single crystal data (see the ESI†).22
In contrast to simple anilines 18a–c, condensation of highly ster-
ically hindered anilines with hydroxyl ester 3a in dichloromethane
under reflux did not afford amino esters. Instead, some Friedel–
Crafts adducts were obtained (Table 3, entries 10–12). Treatment
of 2,6-diisopropylaniline (19a) and 2,6-dimethylbenzenamine
(19b) with 3a in the dichloromethane refluxing system for 72 h
afforded Friedel–Crafts adducts 7a–b in 82% and 80% yields,
respectively (entries 10–11). There was an obvious decrease
in yields with the less activated 2-chloro-6-methylaniline (19c)
in comparison to 2,6-dimethylbenzenamine (19b) (entries 11–
12), reflecting the electronic factor effect on the Friedel–Crafts
reaction. When 2,6-dichloroaniline (19d) was subjected to this
procedure, the starting materials were recovered and no reaction
took place (entry 13), confirming the importance of electronic
effects in this catalyst-free Friedel–Crafts reaction.
b
6
7
NH3 (17)
6 h
24 h
8
24 h
48 h
72 h
9
10
11
12
72 h
72 h
Conclusions
In summary, we have detailed the cascade reaction of
b,g-unsaturated a-ketoesters with phenols, naphthols and
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thiophenols in a trityl chloride/TFA refluxing system to afford
4-aryl-2H-chromenes, 4-aryl-2H-benzo[h]chromenes and 4-aryl-
2H-thiochromenes with excellent yields and high selectivity, in
which a reverse of the regiochemistry of the Jørgensen–Rutjes
chromane synthesis was observed. One representative of our syn-
thesized 4-aryl-2H-chromenes, possessing hemiacetal, hydroxyl
and ester functionalities, was selected to react with various amino-
containing nucleophiles, which afforded hydroxyl amides, amino
acids, amino esters and Friedel–Crafts adducts under catalyst-
free conditions with high selectivity. Cytotoxicity tests (in vitro)
indicated that hydroxyl amide 4b is cytotoxic against a human
colon tumor cell line HCT-116 (IC50 = 1.3 mM), which would
widen the structural diversity of this antitumor target and confirm
the perspectives of further investigations in this area. We believe
that our controlling elements behind their structural motifs would
be useful in the synthesis of complex molecules because of the
significance and prevalence of these functionalities in modern
organic synthesis.
126.1, 125.9, 124.1, 117.5, 114.7, 114.4, 90.8, 51.5, 18.4; FTIR
(KBr) 3443, 2954, 2928, 2855, 1753, 1489, 1242, 1124, 1046, 822,
761, 703 cm-1; HRMS (FAB) Calcd. For [M+Na]+ C18H16NaO4:
319.0941, Found: 319.0942; Anal. Calcd. For C18H16O4: C, 72.96;
H, 5.44. Found: C, 72.89; H, 5.51.
4-Aryl-2H-chromene 3d. 83% yield; foam; 1H NMR
(300 MHz, CDCl3) d 7.43 (m, 5H), 7.04–6.94 (m, 2H), 6.89 (d,
J = 9.0 Hz, 1H), 5.89 (s, 1H), 4.51 (s, 1H), 3.91 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 169.6, 159.2, 156.1, 146.3, 146.3, 138.6, 138.6,
136.5, 128.7, 128.7, 128.7, 121.4, 121.3, 118.2, 118.1, 118.1, 116.6,
116.3, 112.7, 112.4, 93.3, 54.0; FTIR (KBr) 3060, 2955, 1754, 1484,
1248, 1193, 1044, 825, 765, 704 cm-1; HRMS (FAB) Calcd. For
[M+Na]+ C17H13FNaO4: 323.0690, Found: 323.0692; Anal. Calcd.
For C17H13FO4: C, 68.00; H, 4.36. Found: C, 68.11; H, 4.53.
4-Aryl-2H-chromene 3e. 86% yield; foam; 1H NMR
(300 MHz, CDCl3) d 7.47–7.39 (m, 5H), 7.23 (dd, J = 8.7, 2.4 Hz,
1H), 7.14 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 5.87
(s, 1H), 4.52 (s, 1H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 169.5, 149.0, 138.4, 136.3, 129.7, 128.7, 128.7, 127.0, 125.9,
121.6, 118.4, 118.1, 93.3, 54.0; FTIR (KBr) 3446, 3029, 2954,
1755, 1475, 1253, 1046, 936, 821, 764, 702 cm-1; HRMS (FAB)
Calcd. For [M+Na]+ C17H13ClNaO4: 339.0395, Found: 339.0397;
Anal. Calcd. For C17H13ClO4: C, 64.46; H, 4.14. Found: C, 64.34;
H, 4.39.
Experimental
General procedure for the synthesis of 4-aryl-2H-chromenes
A mixture of (thio)phenol 1 (0.10 mmol), b,g-unsaturated a-
˚
ketoester 2 (0.11 mmol), trityl chloride (0.11 mmol) and 4 A molec-
ular sieves (0.10 g) in TFA (1 mL) under a nitrogen atmosphere
was stirred at reflux for 12 h, and concentrated. To the residue
were added ethyl acetate (20 mL) and saturated aqueous sodium
hydrogen carbonate (10 mL). The two layers were separated, and
the aqueous layer was extracted with ethyl acetate (3 ¥ 20 mL).
The combined organic extracts were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by column chromatography over silica gel to afford
4-aryl-2H-(thio)chromenes 3a–p (Table 2).
4-Ar◦yl-2H-chromene 3f. 88% yield; pale yellow solid; mp =
1
92–93 C; H NMR (300 MHz, CDCl3) d 7.46–7.35 (m, 6H),
7.27 (dd, J = 6.3, 1.2 Hz, 1H), 6.94 (dd, J = 8.7, 1.2 Hz, 1H),
5.86 (d, J = 0.9 Hz, 1H), 4.52 (s, 1H), 3.91 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 169.5, 149.5, 138.3, 136.3, 132.6, 128.8, 128.7,
122.1, 118.9, 118.1, 114.4, 93.3, 77.2, 54.0; FTIR (KBr) 3411, 3057,
2958, 1757, 1475, 1259, 1165, 1123, 1026, 820, 762, 701 cm-1; Anal.
Calcd. For C17H13BrO4: C, 56.53; H, 3.63. Found: C, 56.62; H, 3.73.
4-Aryl-2H-chromene 3g. 78% yield; foam; 1H NMR
(300 MHz, CDCl3) d 7.45–7.41 (m, 5H), 7.01 (d, J = 8.7 Hz, 1H),
6.85 (dd, J = 8.7, 3.0 Hz, 1H), 6.72 (d, J = 3.0 Hz, 1H), 5.88 (s, 1H),
4.33 (s, 1H), 3.91 (s, 3H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 169.8, 154.4, 139.1, 137.0, 128.8, 128.7, 128.5, 128.5, 120.8,
117.8, 117.7, 115.5, 111.4, 93.2, 55.8, 53.9; FTIR (KBr) 3440, 2952,
1755, 1488, 1260, 1219, 1048, 829, 762, 703 cm-1; HRMS (FAB)
Calcd. For [M+Na]+ C18H16NaO5: 335.0890, Found: 335.0886;
Anal. Calcd. For C18H16O5: C, 69.22; H, 5.16. Found: C, 69.07; H,
5.39.
4-◦Aryl-2H-chromene 3a. 90% yield; white solid; mp = 115–
1
116 C; H NMR (300 MHz, CDCl3) d 7.49–7.45 (m, 5H), 7.35
(dd, J = 8.4, 2.4 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.04 (d, J =
8.4 Hz, 1H), 5.88 (s, 1H), 4.48 (s, 1H), 3.92 (s, 3H), 1.25 (s, 9H); 13
C
NMR (75 MHz, CDCl3) d 169.8, 148.2, 144.6, 139.4, 137.1, 128.8,
128.4, 128.3, 127.0, 123.1, 119.3, 117.0, 116.4, 93.2, 53.7, 34.3,
31.3; FTIR (KBr) 3467, 2960, 1743, 1489, 1287, 1236, 1149, 1026,
768, 698 cm-1; HRMS (FAB) Calcd. For [M+Na]+ C21H22NaO4:
361.1410, Found: 361.1407; Anal. Calcd. For C21H22O4: C, 74.54;
H, 6.55. Found: C, 74.77; H, 6.74.
4-Aryl-2H-chromene 3h. 81% yield; pale yellow solid; mp =
◦
1
4-Ar◦yl-2H-chromene 3b. 87% yield; pale yellow solid; mp =
116–117 C; H NMR (300 MHz, CDCl3) d 8.34 (t, J = 4.5 Hz,
1H), 7.76 (t, J = 4.5 Hz, 1H), 7.52–7.41 (m, 8H), 7.27 (dd, J =
4.5, 1.3 Hz, 1H), 5.91 (s, 1H), 4.55 (s, 1H), 3.96 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 169.8, 146.1, 139.6, 137.3, 134.5, 128.9,
128.5, 128.4, 127.6, 127.0, 125.9, 124.7, 123.2, 122.2, 121.2, 115.8,
114.6, 93.8, 53.9; FTIR (KBr) 3439, 3063, 2952, 1733, 1297, 1262,
1145, 1091, 985, 818, 753, 700 cm-1; HRMS (FAB) Calcd. For
[M+Na]+ C21H16NaO4: 355.0941, Found: 355.0942; Anal. Calcd.
For C21H16O4: C, 75.89; H, 4.85. Found: C, 75.77; H, 4.98.
1
63–64 C; H NMR (300 MHz, CDCl3) d 7.52–7.28 (m, 12H),
7.14 (d, J = 8.4 Hz, 1H), 5.89 (s, 1H), 4.52 (s, 1H), 3.93 (s, 3H);
13C NMR (75 MHz, CDCl3) d 169.7, 150.0, 140.6, 139.2, 136.9,
135.3, 128.9, 128.8, 128.7, 128.6, 128.5, 127.0, 126.9, 124.9, 120.4,
117.5, 117.4, 93.4, 53.9; FTIR (KBr) 3436, 1749, 1480, 1253, 1237,
1157, 1140, 1123, 1050, 1022, 826, 761, 700 cm-1; Anal. Calcd. For
C23H18O4: C, 77.08; H, 5.06. Found: C, 76.91; H, 5.18.
4-Aryl-2H-chromene 3c. 85% yield; foam; 1H NMR
(300 MHz, CDCl3) d 7.45–7.41 (m, 5H), 7.09 (dd, J = 7.8,
1.8 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 1.7 Hz, 1H),
5.83 (s, 1H), 4.37 (s, 1H), 3.91 (s, 3H), 2.23 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 167.4, 145.8, 136.8, 134.7, 128.9, 128.2, 126.5,
4-Aryl-2H-chromene 3i. 84% yield; pale yellow solid; mp =
58–60 ◦C; 1H NMR (400 MHz, CDCl3) d 7.82 (d, J = 8.8 Hz, 1H),
7.75 (d, J = 8.0 Hz, 1H), 7.40–7.38 (m, 5H), 7.32 (d, J = 8.8 Hz,
1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.06
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(td, J = 7.6, 1.6 Hz, 1H), 6.02 (s, 1H), 4.30 (s, 1H), 3.92 (s, 3H);
13C NMR (100 MHz, CDCl3) d 169.6, 149.7, 140.5, 139.4, 131.3,
130.7, 129.8, 128.5, 128.4, 128.0, 126.5, 125.4, 123.8, 118.5, 118.2,
114.4, 92.7, 53.8; FTIR (KBr) 3444, 3057, 2954, 1748, 1630, 1257,
1232, 1159, 1019, 821, 760, 700 cm-1; HRMS (FAB) Calcd. For
[M+Na]+ C21H16NaO4: 355.0941, Found: 355.0942; Anal. Calcd.
For C21H16O4: C, 75.89; H, 4.85. Found: C, 75.79; H, 4.87.
1512, 1271, 1038, 821, 754 cm-1; Anal. Calcd. For C22H18O4: C,
76.29; H, 5.24. Found: C, 76.21; H, 5.40.
4-Aryl-2H-thiochromene 3p. 72% yield; pale yellow oil; 1H
NMR (300 MHz, CDCl3) d 7.33–7.07 (m, 9H), 3.80 (s, 3H), 3.13
(s, 3H), 2.26 (s, 3H); 13C NMR (75 MHz, CDCl3) d 164.6, 146.1,
137.3, 135.3, 129.5, 129.4, 129.1, 128.4, 128.4, 127.5, 125.7, 125.6,
123.8, 73.5, 52.9, 21.2; FTIR (film) 3478, 2951, 1724, 1483, 1440,
1256, 1228, 1068, 812, 744, 702 cm-1; HRMS (FAB) Calcd. For
[M+Na]+ C18H16NaO3S: 335.0712, Found: 335.0708; Anal. Calcd.
For C18H16O3S: C, 69.21; H, 5.16. Found: C, 69.02; H, 5.39.
4-Aryl-2H-chromene 3j. 86% yield; foam; 1H NMR (300 MHz,
CDCl3) d 7.43 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.32
(dd, J = 8.4, 2.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.00 (d, J =
8.4 Hz, 1H), 5.82 (s, 1H), 4.40 (s, 1H), 3.91 (s, 3H), 1.22 (s, 9H);
13C NMR (75 MHz, CDCl3) d 169.7, 148.1, 144.8, 138.5, 135.6,
134.4, 130.2, 128.7, 127.3, 122.9, 119.0, 117.2, 116.5, 93.1, 53.9,
34.3, 31.4; FTIR (KBr) 3439, 2961, 1751, 1489, 1243, 1130, 826,
754 cm-1; Anal. Calcd. For C21H21ClO4: C, 67.65; H, 5.68. Found:
C, 67.52; H, 5.91.
◦
1
4-Aryl-4H-chromene 13a. white solid; mp = 176–177 C; H
NMR (300 MHz, CDCl3) d 7.34 (d, J = 6.8 Hz, 2H), 7.29 (d, J =
6.8 Hz, 1H), 7.26–7.20 (m, 4H), 7.09 (dd, J = 8.6, 1.31 Hz, 1H), 6.93
(d, J = 2.2 Hz, 1H), 6.27 (d, J = 4.5 Hz, 1H), 4.82 (d, J = 4.4 Hz,
1H), 3.85 (s, 3H), 1.20 (s, 9H); 13C NMR (75 MHz, CDCl3) d
162.4, 148.3, 147.2, 145.0, 140.1, 128.8, 128.3, 127.0, 126.3, 125.3,
120.9, 116.5, 114.0, 52.4, 41.3, 34.3, 31.3; FTIR (KBr) 3028, 2961,
1738, 1665, 1497, 1286, 1233, 1137, 1083, 700 cm-1; HRMS (FAB)
Calcd. For [M+H]+ C21H23O3: 323.1642, Found: 323.1636; Anal.
Calcd. For C21H22O3: C, 78.23; H, 6.88. Found: C, 78.14; H, 6.97.
4-◦Aryl-2H-chromene 3k. 89% yield; white solid; mp = 126–
1
127 C; H NMR (300 MHz, CDCl3) d 7.39–7.26 (m, 6H), 7.03
(d, J = 8.4 Hz, 1H), 5.87 (s, 1H), 4.54 (s, br, 1H), 3.90 (s, 3H), 2.45
(s, 3H), 1.26 (s, 9H); 13C NMR (75 MHz, CDCl3) d 169.9, 148.3,
144.6, 139.4, 138.2, 134.3, 129.2, 128.8, 126.9, 123.3, 119.5, 116.8,
116.5, 93.4, 53.8, 34.4, 31.5, 21.3; FTIR (KBr) 3468, 2959, 1739,
1489, 1285, 1258, 1237, 1145, 1032, 808 cm-1; Anal. Calcd. For
C22H24O4: C, 74.98; H, 6.86. Found: C, 74.85; H, 7.01.
The hydrogen/deuterium exchange experiment (Scheme 3)
A mixture of 4-aryl-4H-chromene 13a (16.1 mg, 50.0 mmol) and
trityl chloride (15.3 mg, 55.0 mmol) in deuterotrifluoroacetic acid
(0.5 mL) under a nitrogen atmosphere was stirred at reflux for 12 h,
and concentrated. To the residue were added ethyl acetate (20 mL)
and saturated aqueous sodium hydrogen carbonate (10 mL). The
two layers were separated, and the aqueous layer was extracted
with ethyl acetate (3 ¥ 20 mL). The combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by column
chromatography over silica gel to afford 4-aryl-2H-chromene 3a
(15.4 mg, 91% yield) and triphenylmethane (14, 10.1 mg, 83%
yield).
4-Aryl-2H-chromene 3l. 85% yield; pale yellow solid; mp = 55–
◦
1
57 C; H NMR (300 MHz, CDCl3) d 7.39 (dd, J = 8.7, 2.1 Hz,
2H), 7.32 (dd, J = 8.7, 2.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.03–
6.97 (m, 3H), 5.83 (s, 1H), 4.51 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H),
1.24 (s, 9H); 13C NMR (75 MHz, CDCl3) d 169.9, 159.7, 148.3,
144.6, 139.0, 130.1, 129.5, 126.9, 123.2, 119.6, 116.5, 113.9, 93.4,
55.3, 53.7, 34.3, 31.4; FTIR (KBr) 3436, 2959, 1749, 1512, 1287,
1249, 1130, 1032, 830 cm-1; Anal. Calcd. For C22H24O5: C, 71.72;
H, 6.57. Found: C, 71.61; H, 6.58.
4-Aryl-2H-chromene 3m. 86% yield; foam; 1H NMR
(300 MHz, CDCl3) d 7.43 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz,
2H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.00 (d,
J = 8.4 Hz, 1H), 5.81 (s, 1H), 4.44 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H),
1.34 (t, J = 7.2 Hz, 3H), 1.22 (s, 9H); 13C NMR (75 MHz, CDCl3) d
169.3, 148.2, 144.8, 138.4, 135.7, 134.4, 130.2, 128.7, 127.2, 122.9,
119.1, 117.3, 116.6, 93.0, 63.4, 34.3, 31.4, 14.1; FTIR (KBr) 3440,
2962, 1750, 1490, 1244, 1129, 1054, 827, 755 cm-1; HRMS (FAB)
Calcd. For [M+Na]+ C22H23ClNaO4: 409.1177, Found: 409.1173.
Triphenylmethane (14). Brown solid; mp = 93–94 ◦C; 1H NMR
(300 MHz, CDClB3B) d 7.23–7.03 (m, 15H), 5.47 (s, 1H); 13C NMR
(75 MHz, CDClB3B) d 143.9, 129.5, 128.3, 126.3, 56.8; FTIR (KBr)
3019, 1595, 1492, 1443, 1077, 1029, 914, 755, 731, 696, 658 cm-1;
Anal. Calcd. For C19H16: C, 93.40; H, 6.60. Found: C, 93.38; H,
6.69.
General procedure for reactions of 2H-chromene 3a with various
amino-containing nucleophiles
4-Aryl-2H-chromene 3n. 83% yield; white solid; mp = 137–
138 ◦C; 1H NMR (300 MHz, CDCl3) d 8.40 (m, 1H), 7.78 (m, 1H),
7.52–7.26 (m, 8H), 5.91 (s, 1H), 4.56 (s, br, 1H), 3.95 (s, 3H), 2.44
(s, 3H); 13C NMR (75 MHz, CDCl3) d 169.9, 146.1, 139.5, 138.3,
134.5, 129.2, 128.8, 127.6, 127.0, 125.9, 124.8, 123.3, 122.2, 121.1,
115.5, 114.7, 93.8, 53.9, 21.3; FTIR (KBr) 3440, 2956, 1733, 1378,
1295, 1262, 1146, 1090, 985, 815 cm-1; Anal. Calcd. For C22H18O4:
C, 76.29; H, 5.24. Found: C, 76.17; H, 5.38.
A mixture of 4-aryl-2H-chromene 3a (0.10 mmol) and amino-
containing nucleophiles 16–19 (0.11 mmol) in dichloromethane
(1 mL) under a nitrogen atmosphere was stirred at reflux for
6–72 h, and concentrated. The residue was purified by column
chromatography over silica gel to afford the corresponding
products 4–7 (Table 3).
Hydroxyl amide 4a. 83% yield; pale yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.46–7.42 (m, 5H), 7.34 (dd, J = 8.4, 2.4 Hz,
1H), 7.24 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.27 (t,
J = 5.1 Hz, 1H), 5.83 (s, 1H), 3.38–3.31 (m, 2H), 1.59–1.50 (m,
4-◦Aryl-2H-chromene 3o. 84% yield; white solid; mp = 135–
136 C; 1H NMR (300 MHz, CDCl3) d 7.83–7.73 (m, 2H), 7.35–
7.19 (m, 8H), 6.01 (s, 1H), 4.29 (s, br, 1H), 3.93 (s, 3H), 2.41 (s, 3H);
13C NMR (75 MHz, CDCl3) d 169.7, 149.7, 139.3, 138.0, 137.6,
131.2, 130.7, 129.9, 129.3, 128.5, 128.0, 126.7, 125.4, 123.8, 118.3,
118.1, 114.6, 92.8, 53.9, 21.3; FTIR (KBr) 3448, 2955, 1749, 1627,
2H), 1.31–1.23 (m, 8H), 1.22 (s, 9H), 0.86 (t, J = 6.6 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) d 169.8, 148.5, 144.9, 139.5, 137.0, 128.8,
128.5, 127.1, 123.2, 119.5, 118.5, 116.7, 93.3, 40.4, 34.3, 31.6, 31.4,
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29.3, 28.8, 26.7, 22.5, 14.0; FTIR (KBr) 3321, 2956, 2928, 2858,
1669, 1538, 1491, 1466, 1446, 1365, 1243, 1130, 1037, 945, 895,
827, 701 cm-1; Anal. Calcd. For C27H35NO3: C, 76.92; H, 8.37; N,
3.32. Found: C, 76.99; H, 8.42; N, 3.36.
(d, J = 8.1 Hz, 1H), 6.29 (s, 1H), 4.06 (q, J = 6.9 Hz, 2H),
3.86 (s, 1H), 3.76 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H), 1.18 (s,
9H); 13C NMR (75 MHz, CDCl3) d 171.7, 150.2, 146.3, 144.1,
138.0, 137.9, 136.7, 129.7, 128.8, 128.4, 128.1, 126.7, 123.0, 122.4,
121.2, 119.2, 116.6, 114.2, 109.5, 81.2, 63.8, 52.9, 34.2, 31.4, 14.9;
FTIR (KBr) 3483, 3384, 3058, 2958, 1750, 1620, 1517, 1430,
1364, 1236, 1129, 1046, 828, 738, 703 cm-1; Anal. Calcd. For
C29H31NO4: C, 76.12; H, 6.83; N, 3.06. Found: C, 75.99; H, 6.89;
N, 3.12.
Hydroxyl amide 4b. 79% yield; pale yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.45–7.41 (m, 5H), 7.33 (dd, J = 8.4, 2.4 Hz,
1H), 7.22 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.26 (t,
J = 5.4 Hz, 1H), 5.79 (s, 1H), 5.41 (s, br, 1H), 3.43–3.38 (m, 2H),
2.19–2.13 (m, 2H), 1.91–1.83 (m, 4H), 1.61–1.43 (m, 4H), 1.22 (s,
9H); 13C NMR (75 MHz, CDCl3) d 169.6, 148.5, 144.8, 139.6,
137.0, 134.0, 128.7, 128.5, 128.4, 127.1, 124.3, 123.1, 119.3, 118.6,
116.6, 93.4, 37.9, 37.3, 34.3, 31.4, 27.8, 25.1, 22.7, 22.2; FTIR
(KBr) 3321, 2928, 1676, 1534, 1491, 1446, 1365, 1243, 1130, 1039,
828, 701 cm-1; Anal. Calcd. For C28H33NO3: C, 77.93; H, 7.71; N,
3.25. Found: C, 77.89; H, 7.70; N, 3.21.
Friedel–Crafts adduct 7a. 82% yield; white solid; mp = 75–
◦
1
76 C; H NMR (300 MHz, CDCl3) d 7.48–7.41 (m, 5H), 7.29
(s, 2H), 7.24 (dd, J = 8.4, 2.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H),
7.05 (d, J = 2.4 Hz, 1H), 6.30 (s, 1H), 3.79 (s, 3H), 2.96–2.83 (m,
2H), 1.27 (d, J = 6.6 Hz, 12H), 1.20 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 171.9, 150.3, 143.8, 140.6, 138.1, 137.4, 132.0, 129.3,
128.8, 128.3, 128.0, 126.6, 122.9, 121.12, 121.10, 116.5, 81.6, 52.7,
34.2, 31.3, 28.1, 22.32, 22.28; FTIR (KBr) 2962, 2870, 1745, 1624,
1490, 1465, 1445, 1365, 1290, 1270, 1235, 1175, 1128, 1051, 906,
824, 727, 700 cm-1; Anal. Calcd. For C33H39NO3: C, 79.64; H, 7.90;
N, 2.81. Found: C, 79.76; H, 7.98; N, 2.89.
Hydroxyl amide 4c. 77% yield; white solid; mp = 90–92 ◦C;
1H NMR (300 MHz, CDCl3) d 7.45–7.42 (m, 5H), 7.35–7.22 (m,
7H), 7.04 (d, J = 8.4 Hz, 1H), 6.65 (s, br, 1H), 5.89 (s, 1H), 4.55
(t, J = 6.9 Hz, 1H), 1.22 (s, 9H); 13C NMR (75 MHz, CDCl3) d
169.8, 148.4, 145.0, 139.8, 137.1, 137.0, 128.9, 128.8, 128.5, 127.8,
127.8, 127.2, 123.2, 119.5, 118.3, 116.7, 93.4, 44.3, 34.4, 31.4; FTIR
(KBr) 3422, 1676, 1536, 1491, 1364, 1255, 700 cm-1; Anal. Calcd.
For C27H27NO3: C, 78.42; H, 6.58; N, 3.39. Found: C, 78.39; H,
6.72; N, 3.38.
Friedel–Crafts adduct 7b. 80% yield; white solid; mp = 116–
117 ◦C; 1H NMR (300 MHz, CDCl3) d 7.46–7.42 (m, 5H), 7.25–
7.19 (m, 3H), 7.06 (s, 2H), 6.25 (s, 1H), 3.76 (s, 3H), 3.61 (s, br, 2H),
2.17 (s, 6H), 1.18 (s, 9H); 13C NMR (75 MHz, CDCl3) d 172.0,
150.4, 143.9, 143.2, 138.0, 137.5, 129.0, 128.8, 128.4, 128.1, 126.7,
126.3, 122.9, 122.5, 121.5, 120.9, 116.5, 81.2, 52.9, 34.2, 31.4, 17.9;
FTIR (KBr) 3485, 3396, 3060, 3027, 1735, 1628, 1491, 1365, 1246,
907, 827, 733, 699 cm-1; Anal. Calcd. For C29H31NO3: C, 78.88; H,
7.08; N, 3.17. Found: C, 78.91; H, 7.22; N, 3.09.
Amino acid 5. 71% yield; white solid; mp = 53–54 ◦C;1H NMR
(300 MHz, CDCl3) d 7.45–7.41 (m, 5H), 7.34 (dd, J = 8.4, 2.4 Hz,
1H), 7.24 (d, J = 2.4 Hz, 1H), 7.04 (s, J = 8.4 Hz, 1H), 6.36 (s, br,
1H), 6.10 (s, br, 1H), 5.89 (s, 1H), 4.92 (s, br, 1H), 1.22 (s, 9H);
13C NMR (75 MHz, CDCl3) d 172.0, 148.3, 145.0, 139.7, 136.9,
128.8, 128.5, 127.2, 123.2, 119.5, 118.2, 116.7, 93.3, 77.2, 34.4,
31.4; FTIR (KBr) 3476, 3318, 2961, 1693, 1490, 1365, 1257, 1130,
1038, 759 cm-1; HRMS (FAB) Calcd. For [M+Na]+ C20H21NNaO3:
346.1414, Found: 346.1410; Anal. Calcd. For C20H21NO3: C, 74.28;
H, 6.55. Found: C, 74.19; H, 6.71.
Friedel–Crafts adduct 7c
◦
1
51% yield; white solid; mp = 81–82 C; H NMR (300 MHz,
CDCl3) d 7.39–7.30 (m, 6H), 7.16 (s, 1H), 7.14 (dd, J = 8.4, 2.4 Hz,
1H), 6.98 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.13 (s,
1H), 3.96 (s, br, 2H), 3.68 (s, 3H), 2.09 (s, 3H), 1.10 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 171.4, 150.0, 144.1, 141.4, 138.0, 137.7,
129.7, 128.7, 128.4, 128.2, 126.9, 126.6, 125.2, 123.2, 123.0, 121.7,
120.8, 118.8, 116.5, 80.6, 53.0, 34.2, 31.3, 18.1; FTIR (KBr) 3489,
3393, 3057, 2954, 1738, 1622, 1487, 1445, 1365, 1304, 1231, 1126,
1050, 1026, 899, 873, 802, 779, 731, 699 cm-1; Anal. Calcd. For
C28H28ClNO3: C, 72.80; H, 6.11; N, 3.03. Found: C, 72.82; H, 6.10;
N, 3.07.
Amino ester 6a. 89% yield; white solid; mp = 175–171 ◦C; 1H
NMR (300 MHz, CDCl3) d 7.43–7.25 (m, 7H), 7.15 (d, J = 2.1 Hz,
1H), 6.99 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.84 (s,
1H), 4.73 (s, br, 1H), 3.79 (s, 3H), 2.24 (s, br, 3H), 1.20 (s, 9H);
13C NMR (75 MHz, CDCl3) d 170.0, 149.7, 144.2, 141.0, 140.6,
137.2, 129. 8, 129.6, 128.7, 128.5, 127.2, 123.1, 120.2, 119.1, 117.1,
116.8, 86.9, 77.2, 53.4, 34.3, 31.4, 20.6; FTIR (KBr) 3384, 2956,
1743, 1521, 1491, 1254, 1135, 1048, 814 cm-1; Anal. Calcd. For
C28H29NO3: C, 78.66; H, 6.84; N, 3.28. Found: C, 78.52; H, 6.91;
N, 3.20.
Acknowledgements
Amino ester 6b. 93% yield; white solid; mp = 162–163 ◦C; 1H
NMR (300 MHz, CDCl3) d 7.45–7.41 (m, 5H), 7.29–7.27 (m, 1H),
7.16–7.12 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 9.0 Hz,
1H), 5.80 (s, 1H), 4.86 (s, br 1H), 3.80 (s, 3H), 1.25 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 169.6, 149.5, 144.5, 141.8, 141.4, 137.0,
129.0, 128.7, 128.6, 128.5, 127.4, 125.3, 123.2, 120.0, 118.6, 117.6,
116.9, 86.6, 53.6, 34.3, 31.4; FTIR (KBr) 3381, 2956, 1739, 1600,
1496, 1292, 1253, 1134, 1048, 824, 694 cm-1; Anal. Calcd. For
C27H26ClNO3: C, 72.39; H, 5.85; N, 3.13. Found: C, 72.22; H,
5.90; N, 3.07.
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology (No. 2009ZX09501-006) and
the Chinese Academy of Sciences for the financial support.
Notes and references
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