9-Amino-(9-deoxy)cinchona alkaloid-derived new chiral phase-transfer catalysts

Article abstract of DOI:10.1039/c4ob01648c

A new class of 9-amino-(9-deoxy)cinchona alkaloid-derived chiral phase-transfer catalysts bearing amino groups was developed by using known cinchona alkaloids as the starting materials. Due to the transformation of the 9-hydroxyl group into a 9-amino functional group, the catalytic performances were significantly improved in comparison with the corresponding first generation phase-transfer catalysts, and excellent yields (92-99%) and high enantioselectivities (87-96% ee) were achieved in the benchmark asymmetric α-alkylation of glycine Schiff base. Based on the special contribution of the amino group to the high yield and enantioselectivity, the possible catalytic mechanism was conjectured. This journal is

Full text of DOI:10.1039/c4ob01648c

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
9-Amino-(9-deoxy)cinchona alkaloid-derived
new chiral phase-transfer catalysts†
Wenwen Peng,a Jingwei Wan,a Bing Xie*b and Xuebing Ma*a
Cite this: Org. Biomol. Chem., 2014,
12, 8336
A new class of 9-amino-(9-deoxy)cinchona alkaloid-derived chiral phase-transfer catalysts bearing amino
groups was developed by using known cinchona alkaloids as the starting materials. Due to the transform-
ation of the 9-hydroxyl group into a 9-amino functional group, the catalytic performances were signifi-
cantly improved in comparison with the corresponding first generation phase-transfer catalysts, and
excellent yields (92–99%) and high enantioselectivities (87–96% ee) were achieved in the benchmark
asymmetric α-alkylation of glycine Schiff base. Based on the special contribution of the amino group to
the high yield and enantioselectivity, the possible catalytic mechanism was conjectured.
Received 3rd August 2014,
Accepted 18th August 2014
DOI: 10.1039/c4ob01648c
www.rsc.org/obc
Finally, the most efficient third generation of N-9-anthracenyl-
methyl-O-allyl quaternary ammonium salts was developed
Introduction
Phase-transfer (PT) catalysis has long been recognized as a independently by Lygo and Corey.6 These salts achieved a
practical and versatile methodology for organic synthesis in breakthrough in their high enantioselectivity in alkylation
both industry and academia, owing to its operational simpli- and conjugate addition, owing to the steric effects of the bulky
city, mild reaction conditions, environmentally benign nature, 9-methylanthryl group.7
and suitability for large-scale synthesis.1 Recently, various
Despite all these successful results, there is always a need
natural and non-natural asymmetric phase-transfer catalysts for new catalyst structures. Due to the available access to the
with excellent catalytic performances, such as cinchona alkal- first generation, the structural modification only at the quinucli-
oid-derived quaternary ammonium salts2 and chiral N-spiro dine nitrogen atom was expected to accomplish a high and
ammonium salts,3 have been developed, particularly in the satisfactory catalytic performance. Fortunately, two successful
last 20 years. In particular, the numerous structural modifi- examples achieved considerably improved enantioselecti-
cations of cinchona alkaloid-derived quaternary ammonium vity in the asymmetric benzylation of N-(diphenylmethylene)
salts that concentrated on the quinuclidine nitrogen atom and glycine tert-butyl ester, by using an aryl ketone and a benzo-
9-hydroxy group achieved excellent catalytic performances. Up triazole moiety in substitution for the N-benzyl substituent.8
to now, three successful generations of cinchona alkaloid- Recently, Dixon reported bifunctional 9-amino-(9-deoxy)-
derived quaternary ammonium salts have been reported. The epi-cinchona-derived PT catalysts bearing phase-transfer com-
simple N-benzyl cinchona alkaloid ammonium salts, intro- ponents (ammonium salts) and H-bond donor components
duced by O’Donnell in 1989, were recognized as the first gene- (urea, amide and sulphonamide) through the structural
ration.4 Later, the same group reported that the second modification of the 9-amino group.9 In the enantioselective
generation of N-alkyl-O-alkyl cinchona alkaloid derivatives nitro-Mannich reaction of amidosulfones, good reactivity
could lead to a remarkably higher enantiomeric excess.5 and high stereoselectivities (up to 24 : 1 dr and 95% ee)
were obtained under optimal conditions. In this paper, we
describe our efforts toward the design of a family of new
9-amino-(9-deoxy)cinchona alkaloid-derived PT catalysts bearing
a primary amino group with different configurations at the
9-position and N-benzyl substituents (Scheme 1), which could
achieve efficient catalytic performances (92–99% and 87–96%
ee) similar to the third generation of N-9-anthracenylmethyl-
O-allyl quaternary ammonium salts in the benchmark enantio-
selective benzylation of N-(diphenylmethylene)glycine tert-
butyl ester.
aCollege of Chemistry and Chemical Engineering, Southwest University, Chongqing,
400715, P. R. China. E-mail: zcj123@swu.edu.cn; Fax: (+86)23-68253237;
Tel: (+86)23-68253237
bSchool of Chemistry and environmental science, Guizhou Minzhu University,
Guiyang, 550025, P. R. China. E-mail: bing_xie1963@hotmail.com;
Fax: (+86)851-3610278; Tel: (+86)851-3610278
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of various catalysts and products; HPLC spectra of products and the data of
optimization procedure. See DOI: 10.1039/c4ob01648c
8336 | Org. Biomol. Chem., 2014, 12, 8336–8345
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
selective benzylation of N-(diphenylmethylene)glycine tert-
butyl ester.
From Table 1, it was found that the PT catalysts b1, b2, d1
and d2 with (8S,9S)-configurations gave the better catalytic per-
formances, including yields of 42–97% and enantioselectivities
of 50–91% ee in an ether–water biphasic system, than the cata-
lysts a1, a2, c1 and c2 with (8R,9R)-configurations. It was worth
noting that the catalysts c1, c2, d1 and d2 (R1 = OCH3) produced
lower yields and enantioselectivities owing to their poor organo-
solubilities in ether, compared with the catalysts a1, b1, a2
and b2 (R1 = H). In addition, all the catalysts a1–d1 and a2–d2
afforded good to excellent yields in a toluene–water biphasic
system (79–98%). In particular, the catalysts c1, c2, d1 and d2
(R1 = OCH3) afforded improved enantioselectivities (65–79% ee)
in the toluene–water biphasic system owing to their good
organosolubilities in toluene (entries 5–8). Unfortunately, it
was found that the catalysts a1, a2, b1 and b2 (R1 = H) gave
relatively lower enantioselectivities in toluene, although good
to excellent yields (80–98%) could be achieved. On the other
hand, the modifications at the quinuclidine nitrogen atom
were effective in improving the enantioselectivity. The PT
catalysts a2–d2 (R1 = OCH3) bearing 3,5-bis(trifluoromethyl)-
benzyl moieties gave better yields and enantioselectivities
than the PT catalysts a1–d1 (R1 = H) with a 4-(trifluoro-
methyl)benzyl group, both in toluene–water and ether–water
biphasic systems.
Scheme 1 The synthetic route to 9-amino-(9-deoxy)cinchona alkal-
oid-derived N-benzyl ammonium salts.
Taking into account the above mentioned considerations of
the substituents attached to aromatic rings (R1, R2, R3 and R4)
and the spatial configurations at the 8 and 9-positions,
the (8S,9S)-9-amino-(9-deoxy)cinchonidine-derived ammonium
salt (b2) bearing 3,5-bis(trifluoromethyl)benzyl moieties pro-
duced the enantiomeric product tert-butyl 3-phenyl-2-(diphenyl-
methyleneamino)propanoate in an ether–water biphasic
system with the highest enantioselectivity (91% ee) in 97%
yield (entry 4).
Results and discussion
Synthesis of the PT catalysts
Four 9-amino-(9-deoxy)cinchona alkaloids, 1a–d, bearing
different substituent groups (R1, R2, R3 and R4) and possessing
(8R,9R), (8S,9S)-configurations were prepared in 75–81% yields
by the Mitsunobu reaction, according to the references.10 After
the primary amino group at the 9-position was protected by
using Boc2O, the N-Boc-protected 9-amino-(9-deoxy)cinchona
alkaloid-derived ammonium salts 3a1–d1 and 3a2–d2 could be
precipitated out and filtered from the reaction mixture in
60–80% yields upon the quaternization of the quinuclidine
nitrogen atom using 4-(trifluoromethyl) or 3,5-bis(trifluoro-
methyl)benzyl bromides, respectively, in toluene at 65 °C for
12 h. Finally, the target PT catalysts a1–d1 and a2–d2 bear-
ing different substituents and (8R,9R), (8S,9S)-configurations
were prepared in 90–95% yields by the deprotection of the
N-Boc-amino group using TFA at room temperature for 3 h
(Scheme 1).
The comparative kinetics of catalyst b2 with the 3rd generation
PT catalyst
To assess the comparative catalytic performances of the
9-amino-(9-deoxy)cinchona alkaloid-derived catalysts and the
3rd generation of N-9-anthracenylmethyl-O-allyl quaternary
ammonium salts, the stereoselectivities and yields during the
course of the catalytic reaction were monitored by using HPLC.
The famous O-allyl-N-(9-anthracenylmethyl)cinchonidinium
bromide (1) and the as-synthesized (8S,9S)-9-amino-(9-deoxy)
cinchonidine-derived ammonium salt b2 were selected as
representative samples. Under the same catalytic reaction con-
ditions (−40 °C, ether, 50% aq. KOH, 10 mol% catalyst, 12 h),
The effect of an aromatic substituent and configuration on the
catalytic performance
Using PT catalyst b2 as an example, the effects of the solvent, the yield and enantioselectivity profiles of tert-butyl 3-phenyl-
temperature, amount of the catalyst used and base species on 2-(diphenylmethyleneamino)propanoate plotted versus time
the catalytic performances were investigated in detail and the during the whole process are shown in Fig. 1. As shown in
following optimum conditions were established: 10 mol% b2, Fig. 1, the (8S,9S)-9-amino-(9-deoxy)cinchonidine-derived PT
−40 °C, 50% KOH and 12 h (ESI†). Thus, under these catalyst b2 gave better yields (up to 98%) and somewhat
optimum conditions, the PT catalysts a1–d1 and a2–d2 with lower enantioselectivities (91% ee) than O-allyl-N-(9-anthracenyl-
different structures, including substituent groups and con- methyl)cinchonidinium bromide (1) during the whole
figurations at 8,9-positions, were evaluated in the enantio- process.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8336–8345 | 8337

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 The benchmark enantioselective benzylation of N-(diphenyl-
a
methylene)glycine tert-butyl ester catalyzed by a1–d1 and a2–d2
Entry
1
Catalyst
Yieldb (%)
% eec
76
23 (S)
30 (S)
80d
2
3
85
71 (S)
67 (S)
88d
Fig. 1 The yield and enantioselectivity profiles of the catalysts b2 and 1
plotted versus time during the experiment.
94
50 (R)
43 (R)
91d
Application in α-alkylation using different electrophiles
With the optimum conditions in hand, the scope of the cata-
lyst b2 with respect to various electrophiles was surveyed in the
enantioselective α-alkylation of N-(diphenylmethylene)glycine
tert-butyl ester.
4
97
91 (R)
85 (R)
98d
As shown in Table 2, it was found that the various substi-
tuted aromatic aldehydes, both with electron-withdrawing
(–CF3 and –F) and electron-donating (–CH3) substituents, could
produce the corresponding α-alkylation products with high
enantioselectivities (90–96% ee) in 92–99% yields (entries
1–11). In particular, when the aromatic aldehydes bearing
o-CF3, o-F and o-CH3 were employed as electrophiles, slightly
lower yields and higher enantioselectivities were observed
owing to the sterically hindered and confined interactions
between the o-substituents of the electrophiles and the catalyst
(entries 3, 6 and 10).8 Furthermore, good enantioselectivities
in the enantioselective alkylation of N-(diphenylmethylene)
glycine tert-butyl ester with allyl bromides (89% ee and
87% ee) were also achieved in the presence of the catalyst b2
(entries 12 and 13).
5
6
37
5 (S)
30 (S)
79d
43
31 (S)
77 (S)
87d
Mechanism investigation
7
8
42
51 (R)
65 (R)
83d
It is generally accepted that the enantioselective α-alkylation of
N-(diphenylmethylene)glycine tert-butyl ester under basic con-
ditions follows an interfacial mechanism.1a The first step is
the interfacial deprotonation of the α-proton of N-(diphenyl-
methylene) glycine tert-butyl ester with bases such as KOH to
give the corresponding metal enolate. Subsequently, the ion-
exchange between the enolate anion and the PT catalyst
(Q*+X−) generates a lipophilic chiral onium enolate. Finally,
nucleophilic substitution with an alkyl halide affords the opti-
cally active monoalkylation product with the concomitant
regeneration of the catalyst. Of particular importance to
enantioselective α-alkylation is the generation of the highly
reactive chiral onium enolate through sufficiently fast ion-
exchange and the effective shielding of one of the two enantio-
topic faces of the enolate anion.
48
63 (R)
79 (R)
89d
a Reaction conditions: N-(diphenylmethylene)glycine tert-butyl ester
(0.1 mmol), −40 °C, 2 mL ether, 0.4 mL 50% aq. KOH, 10 mol% PT
catalyst, 12 h. b Isolated yield. c Determined by chiral HPLC with Daicel
Chiralpak OD-H column. d Toluene as the solvent.
8338 | Org. Biomol. Chem., 2014, 12, 8336–8345
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 The scope of the enantioselective α-alkylation of N-(diphenyl-
methylene)glycine tert-butyl ester using different electrophilesa
Table 2 (Contd.)
Entry
10
Product
Time (h)
5
Yieldb (%)
% eec
Entry
1
Product
Time (h)
5
Yieldb (%)
99
% eec
92
92 (R)
90 (R)
11
12
8
5
99
99
96 (R)
89 (R)
2
3
5
5
99
93
95 (R)
96 (R)
13
10
93
87 (R)
4
5
6
5
5
5
97
94
92
90 (R)
90 (R)
91 (R)
a Reaction conditions: N-(diphenylmethylene)glycine tert-butyl ester
(0.1 mmol), −40 °C, 2 mL ether, 0.4 mL 50% aq. KOH, 10 mol%
catalyst b2. b Isolated yield. c Determined by chiral HPLC with Daicel
Chiralpak OD-H column.
In order to elucidate the mechanism of the enantioselective
α-alkylation of N-(diphenylmethylene)glycine tert-butyl ester
catalyzed by the catalyst b2, the corresponding first generation
PT catalysts b1′ and b2′, with the same (8S,9S)-configurations
as b1 and b2 (Table 3), were synthesized and selected as a com-
parative trial (see ESI†). As shown in Table 3 (entries 1 and 2),
it was found that the catalysts b1′ and b2′ afforded the various
α-alkylation products with disappointing enantioselectivities
(14–54% ee) in moderate to good yields (62–86%). Further-
more, when the amino functional group (–NH2) in b2 was
replaced by aminomethyl (–NHCH3) and carbamate (–NCO2C
(CH3)3), the catalyst e bearing a secondary amine moiety only
produced tert-butyl 3-phenyl-2-(diphenylmethyleneamino)pro-
panoate with low enantioselectivity (56% ee) in 45% yield
(entry 3), and 2b2 with a carbamate moiety (NHCO2C(CH3)3)
exhibited no catalytic activity, owing to the acidity of the
remaining hydrogen on the nitrogen atom (entry 4). Therefore,
it was confirmed that the primary amino functional group
(–NH2) in b2 at the 9-position played a key role in controlling
the stereochemical course and the yield of the reaction.
7
8
9
4
5
8
99
96
95
90 (R)
92 (R)
91 (R)
Based on the prominent role of the primary amino group in
controlling the catalytic process and the mechanism never
having been reported, a possible catalytic mechanism of
the (8S,9S)-9-amino-(9-deoxy)cinchonidine-derived ammonium
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8336–8345 | 8339

View Article Online
Paper
Organic & Biomolecular Chemistry
the corresponding metal enolate. Subsequently, a chiral lipo-
philic onium enolate m with an –N–H⋯N intramolecular
hydrogen bond was generated through the fast ion-exchange of
the enolate anion with the catalyst b2. The intermediate m
could go deep into the organic phase and result in the
improved yield for α-alkylation. Meanwhile, the intermediate
m could shield one of the two enantiotopic faces of the
enolate anion and thus achieve the aim of controlling the
stereochemical course. With the hydroxyl (–OH), secondary
amino (–NHCH3) and carbamate (–NCO2C(CH3)3) groups,
instead of the primary amino group (–NH2), the formation of
an intramolecular hydrogen bond in the intermediate m could
be retarded and result in a weakened enantioselectivity and
yield. Finally, the nucleophilic substitution with an alkyl
halide afforded the optically active α-alkylation product with
the concomitant regeneration of the catalyst b2 (H2N-Q*+X−).
Table 3 The enantioselective benzylation of N-(diphenylmethylene)
glycine tert-butyl ester catalyzed by b1’, b2’, e and 2b2
a
Yieldb
(%)
%
Entry
1
Product
Catalyst
eec
3
4
10
11
68
69
62
65
26
14
22
20
2
3
4
10
11
86
85
83
81
54
53
45
45
3
4
45
56.2
Conclusion
—
—
In summary, we developed a family of novel 9-amino-(9-deoxy)
cinchona alkaloid-derived N-benzyl ammonium salts with
different substituents and configurations by the transform-
ation of the 9-hydroxyl into a 9-amino functional group.
Among them, (8S,9S)-9-amino-(9-deoxy)cinchonidine-derived
ammonium salts with a (8S,9S)-configuration and N-[3,5-bis
a Reaction conditions: N-(diphenylmethylene)glycine tert-butyl ester
(0.1 mmol), −40 °C, 2 mL ether, 0.4 mL 50% aq. KOH, 10 mol%
catalyst, 12 h. b Isolated yield. c Determined by chiral HPLC with Daicel (trifluoromethyl)benzyl] group could achieve the same excel-
Chiralpak OD-H column.
lent yields and enantioselectivities as the third generation of
cinchona alkaloid-derived phase-transfer catalysts in the
enantioselective alkylation of N-(diphenylmethylene)glycine
tert-butyl ester. Furthermore, it was confirmed that the
primary amino functional group (–NH2) played a key role in
controlling the stereochemistry of the catalytic reaction and
the yield.
Experimental
General methods
All commercially available chemicals were used without
further purification. Four 9-amino-(9-deoxy)-epi-cinchona alkal-
oids 1a–d were synthesized according to the references and
their identities were ascertained by 1H and 13C NMR.10
TLC, where applicable, was performed on pre-coated alu-
minium-backed plates and spots were made visible by using
UV fluorescence (λ = 254 nm). The melting points were deter-
mined with an X-4 binocular microscope melting-point appar-
atus (Beijing Tech Instruments Co., Beijing, China) and the
thermometer was not calibrated. Fourier transform infrared
spectra were recorded on a Perkin-Elmer Model GX Spectro-
Scheme 2 The possible catalytic mechanism of the (8S,9S)-9-amino-
meter using a KBr pellet method with polystyrene as a stan-
(9-deoxy)cinchona alkaloid-derived N-benzyl ammonium salt b2.
dard. Low-resolution mass spectrometry (MS) was performed
on a mass spectrometer (Brucker Daltonics, USA, Brucker Co.)
salt b2 was conjectured, which is depicted in Scheme 2. The with a HCT ultra ion trap. High resolution mass spectra
first step was the interfacial deprotonation of N-(diphenyl- (HRMS) were recorded on a Bruker Apex IV FTMS spectrometer
methylene)glycine tert-butyl ester with base (KOH) to produce using electrospray ionization (ESI). 1H and 13C NMR spectra
8340 | Org. Biomol. Chem., 2014, 12, 8336–8345
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
were obtained using a Bruker AV-300 NMR instrument at 300.1 (d, 3J = 2.4, 1H), 7.35 (d, 3J = 2.6 Hz, 1H), 5.94 (s, 1H),
and 75.0 MHz respectively, in which all of the chemical shifts 5.74–5.63 (m, 1H), 4.98–4.90 (m, 3H), 3.96 (s, 3H), 3.29–2.52
were reported downfield in ppm relative to the hydrogen and (m, 7H), 2.28 (s, 1 H), 1.64–1.60 (m, 2 H), 1.34–1.26 (m, 9H),
carbon resonances of TMS and chloroform-d1, respectively. 0.98–0.91 (m, 2H); 13C NMR (75.0 MHz, CDCl3, TMS) δ 157.5,
Optical rotations were measured on a Perkin-Elmer 343plus 155.4, 147.5, 147.2, 144.6, 141.2, 131.7, 131.3, 121.3, 120.4,
polarimeter, concentrations (c) were given in g per 100 mL of 114.5, 101.8, 79.5, 77.2, 55.9, 55.5, 49.4, 40.8, 39.5, 28.1, 27.9,
solution. The enantioselectivities were determined by chiral 27.3, 25.9.
HPLC analysis (Daicel Chiralpak OD-H or Phenomenex Lux 5u
General procedure for synthesizing the N-Boc-9-amino-(9-
deoxy)-epi-cinchona alkaloid-derived ammonium salts 3a1–d1
and 3a2–d2
Amylose-2; hexane–dioxane = 95 : 5; flow rate: 0.5 mL min−1
;
25 °C; 254 nm). The absolute configuration was determined by
the comparison of the HPLC retention time with the reported
samples. C, H and N elemental analysis was performed using A toluene solution (4 mL) containing the N-Boc-9-amino-
a FLASHEA1112 automatic elemental analyzer instrument (9-deoxy)-epi-cinchona alkaloid 2a (0.20 g, 0.51 mmol) and
(Italy).
4-trifluoromethyl benzyl bromide (0.12 g, 0.51 mmol) or 3,5-
bis(trifluoromethyl)benzyl bromide (0.16 g, 0.51 mmol) was
added to a 50 mL round-bottom flask and stirred at 65 °C for
12 h. During this process, a white solid gradually separated
General procedure for synthesizing the N-Boc-9-amino-(9-
deoxy)-epi-cinchona alkaloids 2a–d
A THF solution (20 mL) containing the 9-amino-(9-deoxy)-epi- out. The white precipitate was filtered, washed with toluene
cinchona alkaloid 1a (1.47 g, 5.0 mmol) was added to a (3 mL × 2) and dried under reduced pressure to afford the pure
100 mL round-bottom flask and cooled to 0–5 °C. Sub- N-Boc-9-amino-(9-deoxy)-epi-cinchona alkaloid-derived ammonium
sequently, the THF solution (20 mL) containing Boc2O (1.31 g, salt 3a1 or 3a2.
6.0 mmol) was added dropwise and stirred at 0–5 °C for 6 h.
After the solvent was evaporated under reduced pressure, the CD3OD, TMS) δ 8.82 (d, J = 4.0 Hz, 1H), 8.48 (d, J = 6.7 Hz,
3a1: 0.19 g, 58%, mp 154–156 °C; 1H NMR (300.1 MHz,
3
3
3
3
residue was subjected to flash column chromatography by gra- 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.84–7.67 (m, 7H), 6.24 (d, J =
dient elution with CHCl3–CH3OH (v/v = 60/1→30/1→15/1→5/1) 8.5 Hz, 1H), 5.63–5.48 (m, 1H), 5.19–4.96 (m, 3H), 4.78–4.64
to obtain the pale yellow and oily liquid 2a.
(m, 2H), 3.93–3.72 (m, 2H), 3.72–3.55 (m, 1H), 3.42–3.15 (m,
2a: 1.7 g, 86%; 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.88 2H), 2.67 (s, 1H), 2.04–1.71 (m, 3H), 1.48 (s, 1H), 1.17 (s, 10H);
3
3
(d, J = 4.5 Hz, 1H), 8.33 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.71 13C NMR (75.0 MHz, CD3OD, TMS) δ 153.7, 148.3, 146.1, 144.6,
3
3
(t, J = 7.1 Hz, 1H), 7.58 (t, J = 7.1 Hz, 1H), 7.51 (s, 1H), 6.18 134.1, 132.5, 130.6 (q, 1JC–F = 32.9 Hz, CF3), 130.0, 128.5, 127.5,
2
(s, 1H), 5.97–5.86 (m, 1H), 5.19–5.10 (m, 3H), 3.18–2.87 (m, 126.2, 124.0, 124.3 (q, JC–F = 3.7 Hz), 124.0, 121.6, 120.4,
5H), 2.36–2.28 (m, 1H), 1.64 (s, 1H), 1.56–1.47 (m, 2H), 118.1, 115.1, 78.9, 76.4, 67.9, 61.8, 55.0, 50.7, 35.0, 27.7, 25.4,
1.34–1.11 (m, 9H), 0.93–0.84 (m, 2H); 13C NMR (75.0 MHz, 24.5, 21.3; FT-IR (cm−1): 3446 (N–H), 2929 (C–H), 1707 (CvO),
CDCl3, TMS) δ 155.2, 149.7, 148.2, 147.2, 139.9, 130.0, 128.6, 1570 (CvC).
127.1, 126.0, 123.0, 118.9, 114.5, 79.2, 60.1, 55.2, 48.8, 46.8,
3a2: 0.16 g, 46%, mp 202–204 °C; 1H NMR (300.1 MHz,
CDCl3, TMS) δ 8.94 (d, 3J = 4.4 Hz, 1H), 8.48 (d, 3J = 7.7 Hz,
38.9, 27.8, 27.1, 26.2, 24.7.
1
2b: 1.8 g, 91%, mp 181–183 °C; H NMR (300.1 MHz, 1H), 8.22 (s, 2H), 8.12 (d, 3J = 4.6 Hz, 1H), 8.03 (s, 1 H),
CDCl3, TMS) δ 8.88 (d, 3J = 4.1 Hz, 1H), 8.37 (d, 3J = 6.8 Hz, 7.79–7.67 (m, 3H), 6.47–6.18 (m, 3H), 5.69–5.57 (m, 1H),
1H), 8.12 (d, 3J = 8.3 Hz, 1H), 7.70 (t, 3J = 7.0 Hz, 1H), 7.58 5.35–5.18 (m, 2H), 4.96–4.86 (m, 2H), 4.09–4.03 (m, 1H),
(t, 3J = 7.6 Hz, 1H), 7.48 (d, 3J = 3.6 Hz, 1H), 6.09 (s, 1H), 3.51–3.43 (m, 1H), 3.06–2.99 (m, 2H), 2.60–2.55 (m, 1H),
5.72–5.60 (m, 1H), 5.12–4.88 (m, 3H), 3.28–2.64 (m, 5H), 2.27 2.24–2.14 (m, 1H), 1.86 (s, 2H), 1.52–1.43 (m, 1H), 1.28 (s, 9H);
(s, 1H), 1.63 (s, 3H), 1.40–1.27 (m, 9H), 0.97–0.91 (m, 2H); 13C NMR (75.0 MHz, CDCl3, TMS) δ 155.4, 150.9, 148.2, 144.9,
13C NMR (75.0 MHz, CDCl3, TMS) δ 155.5, 150.0, 148.4, 141.6, 134.5, 133.6, 132.8 (q, 1J = 33.9 Hz, CF3), 130.6, 130.3, 129.5,
2
141.2, 130.3, 128.9, 127.4, 126.4, 123.2, 118.3, 114.4, 79.5, 59.7, 127.5, 126.6, 126.2, 124.7 (q, J = 2.1 Hz), 124.3, 122.6, 120.3,
55.8, 42.5, 40.7, 39.5, 28.1, 27.8, 27.3, 25.6; FT-IR (KBr) cm−1
3447, 2975, 1717, 1630, 1172.
:
118.8, 81.0, 67.5, 62.5, 55.4, 52.5, 48.6, 37.4, 28.0, 27.3, 26.3,
23.6; FT-IR (cm−1): 3452 (N–H), 1711 (CvO), 1628 (CvC).
3b1: 0.20 g, 62%, mp 168–170 °C; 1H NMR (300.1 MHz,
2c: 1.6 g, 83%; 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.60
3
3
(d, J = 4.3 Hz, 1H), 7.90 (d, J = 7.1 Hz, 1H), 7.44 (s, 1H), 7.33 CDCl3, TMS) δ 8.89 (d, 3J = 4.5 Hz, 1H), 8.17 (d, 3J = 8.3 Hz,
(d, 3J = 3.5, 1H), 7.26–7.22 (m, 2H), 5.95 (s, 1H), 5.86–5.75 1H), 8.09–8.05 (m, 2H), 7.69–7.58 (m, 6H), 6.88 (d, J = 9.4 Hz,
3
(m, 1H), 5.04–4.85 (m, 3H), 3.84 (s, 3H), 2.99–2.76 (m, 5H), 1H), 6.23–5.99 (m, 3H), 5.82–5.71 (m, 1H), 5.21–5.10 (m, 2H),
2.33–2.28 (m, 1H), 1.53 (s, 1H), 1.41–1.30 (m, 2H), 1.24–1.14 4.89 (d, 3J = 12.9 Hz, 1H), 4.35–4.25 (m, 2H), 3.35–3.16 (m, 2H),
(m, 9H), 0.94–0.78 (m, 2H); 13C NMR (75.0 MHz, CDCl3, TMS) 2.48–2.42 (m, 1H), 2.18 (s, 2H), 2.02–1.87 (m, 3H), 1.23 (s, 9H);
δ 157.5, 155.4, 147.5, 144.5, 140.3, 131.6, 128.2, 121.7, 119.0, 13C NMR (75.0 MHz, CDCl3, TMS) δ 155.4, 151.1, 148.6, 143.9,
114.7, 111.4, 101.1, 79.5, 77.2, 60.3, 55.4, 49.1, 46.9, 39.0, 28.1, 134.8, 134.0, 132.7 (q, 1JC–F = 33.1 Hz, CF3), 131.5, 130.9, 129.7,
2
27.2, 26.4, 25.1.
127.9, 126.2 (q, JC–F = 3.5 Hz), 125.7, 125.1, 122.2, 120.1,
2d: 1.8 g, 87%; 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.72 119.1, 81.4, 67.5, 64.5, 59.1, 50.3, 49.1, 37.6, 28.1, 27.4, 26.7,
(d, J = 4.5 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.63 (s, 1H), 7.38 24.8; FT-IR (cm−1): 3447 (N–H), 1713 (CvO), 1567 (CvC).
3
3
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8336–8345 | 8341

View Article Online
Paper
Organic & Biomolecular Chemistry
13
3b2: 0.19 g, 52%, mp 168–170 °C; 1H NMR (300.1 MHz, (s, 9H);
C NMR (75.0 MHz, CDCl3, TMS) δ 158.7, 155.4,
CDCl3, TMS) δ 8.98 (d, 3J = 4.5 Hz, 1H), 8.31 (d, 3J = 8.2 Hz, 148.2, 144.6, 141.6, 134.1, 133.3, 132.8 (q, 1JC–F = 33.9 Hz, CF3),
1H), 8.21 (d, 3J = 4.5 Hz, 1H), 8.15 (d, 3J = 8.5 Hz, 1H), 8.10 132.0, 130.1, 126.5, 124.4 (q, JC–F = 3.0 Hz), 124.1, 122.1,
2
(s, 2H), 8.03 (s, 1H), 7.79–7.67 (m, 2H), 7.08 (d, 3J = 8.7 Hz, 120.4, 119.7, 119.2, 100.0, 81.6, 67.2, 63.3, 59.1, 55.5, 50.9,
1H), 6.45–6.40 (m, 1H), 6.32–6.18 (m, 2H), 5.94–5.83 (m, 1H), 49.0, 37.3, 29.4, 27.8, 26.6, 24.5; FT-IR (cm−1): 3447 (N–H),
5.34–5.23 (m, 3H), 4.54–4.43 (m, 1H), 3.45 (t, 3J = 10.5 Hz, 1H), 1719 (CvO), 1589 (CvC).
3.19–3.09 (m, 1H), 2.63–2.58 (m, 1H), 2.27 (s, 2H), 2.15–2.02
General procedure of 9-amino-(9-deoxy)-epi-cinchona alkaloid-
derived ammonium salts a1–d1 and a2–d2
(m, 1H), 1.35 (s, 9H); 13C NMR (75.0 MHz, CDCl3, TMS)
1
δ 155.5, 151.1, 148.5, 143.9, 134.6, 133.6, 132.9 (q, JC–F
=
=
33.8 Hz, CF3), 130.9, 130.3, 129.6, 127.8, 125.7, 124.5 (q, 2JC–F
The CH2Cl2 solution (4 mL) containing N-Boc-9-amino-
3.4 Hz), 122.2, 120.7, 120.1, 119.3, 81.6, 67.6, 63.5, 59.4, 50.6, (9-deoxy)-epi-cinchona alkaloid 3a1 (98.0 mg, 0.16 mmol) and
49.1, 37.6, 28.0, 27.1, 26.8, 24.7; FT-IR (cm−1): 3445 (N–H), TFA (0.36 g, 3.2 mmol) was added to a 50 mL round-bottom
1712 (CvO), 1628 (CvC).
flask and stirred at room temperature for 3 h. The organic sol-
3c1: 0.17 g, 53%, mp 172–174 °C; 1H NMR (300.1 MHz, vents were removed under reduced pressure. The residues were
3
3
CD3OD, TMS) δ 8.66 (d, J = 4.3 Hz, 1H), 7.91 (d, J = 9.2 Hz, adjusted to pH = 8–9 by aqueous ammonia and extracted by
1H), 7.81 (s, 4H), 7.63 (s, 1H), 7.59 (d, 3J = 4.5 Hz, 1H), 7.42 CH2Cl2 (2 mL × 3). After the combined organic phases were
(d, 3J = 9.2 Hz, 1H), 6.12 (d, 3J = 9.6 Hz, 1H), 5.72–5.63 (m, 1H), evaporated under reduced pressure, the residue was subjected
5.27–5.12 (m, 2H), 4.98–4.94 (m, 1H), 4.80–4.71 (m, 2H), 4.00 to flash silica column chromatography with CHCl3–CH3OH
(s, 4H), 3.84–3.69 (m, 2H), 3.31–3.27 (m, 1H), 2.63 (s, 1H), (v/v = 60/1→30/1→15/1→5/1) mixtures as the eluents to afford
2.00–1.94 (m, 1H), 1.82 (s, 2H), 1.67–1.60 (m, 1H), 1.24 (s, 9H), the pale yellow solid a1 (75 mg, 93%).
1.18 (s, 1H); 13C NMR (75.0 MHz, CD3OD, TMS) δ 159.1, 155.7,
a1: 75.1 mg, 93%, mp 153–155 °C; [α]2D0 = +16.2 (c = 1.16,
147.0, 144.3, 143.8, 136.2, 134.1, 132.1 (q, 1JC–F = 32.7 Hz, CF3), CHCl3); 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.80 (d, 3J =
2
3
3
131.6, 130.4, 127.5, 125.8 (q, JC–F = 3.8 Hz), 122.7, 121.9, 4.6 Hz, 1H), 8.48 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H),
119.6, 116.5, 101.1, 80.6, 69.0, 63.8, 56.6, 55.1, 52.5, 48.9, 36.5, 7.87–7.67 (m, 7H), 5.63–5.49 (m, 2H), 5.28–5.03 (m, 3H), 4.81
27.5, 27.0, 25.7, 23.1; FT-IR (cm−1): 3453 (N–H), 1710 (CvO), (s, 2H), 4.52–4.49 (m, 1H), 3.95–3.76 (m, 3H), 3.66–3.58
1621 (CvC).
(m, 1H), 3.16–3.13 (m, 2H), 2.57–2.50 (m, 1H), 1.95–1.76 (m,
3c2: 0.15 g, 43%, mp 175–177 °C; 1H NMR (300.1 MHz, 2H), 1.68 (s, 1H), 1.51–1.42 (m, 1H), 1.22–1.11 (m, 1H);
CD3OD, TMS) δ 8.66 (d, 3J = 4.5 Hz, 1H), 8.31 (s, 2H), 8.15 13C NMR (75.0 MHz, CDCl3, TMS) δ 150.3, 148.2, 147.6, 134.8,
(s, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 4.8 Hz, 2H), 7.42 134.1, 132.7, 131.7 (q, 1JC–F = 33.1 Hz, CF3), 130.5, 129.5, 127.5,
(d, 3J = 7.8 Hz, 1 H), 6.12 (d, 3J = 9.4 Hz, 1H), 5.70–5.60 125.3, 124.7, 124.0, 121.1, 119.3, 118.3, 71.9, 64.4, 55.4, 51.7,
(m, 1H), 5.25–5.10 (m, 3H), 4.92–4.87 (m, 1H), 4.00 (s, 5H), 49.0, 37.5, 27.5, 26.8, 23.6; FT-IR (cm−1): 3444, 3384 (N–H),
3.70–3.61 (m, 1H), 3.35–3.29 (m, 1H), 2.63 (s, 1H), 2.07–1.63 1571 (CvC); Mass (MS): m/z 532.4 [M + H]+; Anal. calcd for
(m, 4H), 1.22 (s, 10H); 13C NMR (75.0 MHz, CD3OD, TMS) C27H29BrF3N3: C 60.91, H 5.49, N 7.89; Found: C 60.89, H 5.42,
δ 159.0, 155.7, 147.1, 144.2, 143.8, 136.0, 133.8, 132.3 (q, N 7.82%.
3
3
1JC–F = 33.7 Hz, CF3), 130.5, 128.4, 127.4, 124.8, 124.3 (q,
a2: 72.0 mg, 86%, mp 132–134 °C; [α]2D0 = +9.2 (c = 0.84,
2JC–F = 4.1 Hz), 122.6, 121.2, 119.9, 116.6, 101.0, 80.6, 69.4, CHCl3); 1H NMR (300.1 MHz, CD3OD, TMS) δ 8.81 (d, 3J =
62.8, 56.3, 55.1, 52.5, 48.7, 36.5, 27.4, 27.0, 25.7, 23.0; FT-IR 4.7 Hz, 1H), δ 8.42 (d, 3J = 8.2 Hz, 1H), 8.30 (s, 2H), 8.10
(cm−1): 3449 (N–H), 1715 (CvO), 1622 (CvC).
(s, 1H), 8.02 (d, J = 7.7 Hz, 3H), 7.79–7.65 (m, 3H), 5.64–5.53
3
3d1: 0.19 g, 60%, mp 182–184 °C; 1H NMR (300.1 MHz, (m, 1H), 5.47–5.33 (m, 2H), 5.21–5.04 (m, 2H), 4.46–4.41
CDCl3, TMS) δ 8.72 (d, 3J = 4.4 Hz, 1H), 7.99–7.96 (m, 2H), 7.72 (m, 1H), 3.93–3.79 (m, 2H), 3.58–3.50 (m, 1H), 3.29–3.19
(s, 4H), 7.51 (s, 1H), 7.36 (d, 3J = 7.1 Hz, 1H), 6.95 (d, 3J = (m, 2H), 2.58–2.54 (m, 1H), 1.97–1.83 (m, 2H), 1.68 (s, 1H),
8.3 Hz, 1H), 6.20–6.18 (m, 1H), 6.12–6.02 (m, 1H), 5.30–5.18 1.55–1.45 (m, 1H), 1.25–1.17 (m, 1H); 13C NMR (75.0 MHz,
(m, 2H), 4.39–4.19 (m, 3H), 3.99 (s, 3H, OCH3), 3.49–3.09 CD3OD, TMS) δ 148.4, 147.8, 146.2, 134.2, 132.3, 130.5 (q,
(m, 3H), 2.84 (s, 1H), 2.58–2.51 (m, 1H), 2.21–1.88 (m, 5H), 1JC–F = 33.5 Hz, CF3), 129.9, 128.3, 127.5, 126.9, 126.0, 124.3,
2
1.33 (s, 9H); 13C NMR (75.0 MHz, CDCl3, TMS) δ 158.6, 155.3, 123.3, 122.3 (q, JC–F = 3.6 Hz), 121.6, 119.7, 114.9, 71.0, 63.2,
147.9, 144.5, 141.8, 134.5, 133.7, 132.4 (q, 1JC–F = 32.3 Hz, CF3), 59.4, 54.7, 50.4, 35.2, 25.7, 24.8, 21.4; FT-IR (cm−1): 3444, 3358
2
131.8, 131.3, 126.7, 126.0 (q, JC–F = 3.7 Hz), 122.1, 121.3, (N–H), 1571 (CvC); Mass (MS): m/z 602.1 [M + H]+; Anal. calcd
119.7, 118.8, 100.2, 81.1, 67.3, 64.5, 59.0, 55.5, 50.8, 49.0, 37.3, for C28H28BrF6N3: C 56.01, H 4.70, N 7.00; Found: C 55.89,
27.9, 27.3, 26.5, 24.5; FT-IR (cm−1): 3442 (N–H), 1692 (CvO), H 4.54, N 6.92%.
1590 (CvC).
3d2: 0.17 g, 49%, mp 215–217 °C; H NMR (300.1 MHz, CHCl3); 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.81 (d, 3J =
b1: 73.8 mg, 92%, mp 142–144 °C; [α]2D0 = +37.4 (c = 0.92,
1
3
3
CDCl3, TMS) δ 8.82 (d, 3J = 4.3 Hz, 1H), 8.08–8.04 (m, 5H), 7.49 4.5 Hz, 1H), 8.74 (s, 1H), 8.11 (d, J = 9.5 Hz, 1H), 8.01 (d, J =
3
3
3
3
(s, 1H), 7.41 (d, J = 7.0 Hz, 1H), 6.73 (d, J = 9.1 Hz, 1H), 6.50 6.9 Hz, 2H), 7.73 (d, J = 4.4 Hz, 2H), 7.57 (s, 1H), 7.41 (d, J =
(s, 1H), 6.16–6.09 (m, 1H), 5.94–5.82 (m, 1H), 5.36–5.25 (m, 8.0 Hz, 2H), 5.97–5.86 (m, 1H), 5.82–5.66 (m, 3H), 5.20–5.12
3H), 4.51 (s, 2H), 4.01 (s, 3H, OCH3), 3.50–3.43 (m, 1H), (m, 2H), 5.00 (s, 1H), 4.77 (s, 1H), 3.75–3.45 (m, 3H), 2.61
3.20–3.10 (m, 1H), 2.65–2.57 (m, 1H), 2.28–1.94 (m, 5H), 1.38 (s, 3H), 1.06 (s, 1H), 1.89–1.77 (m, 3H); 13C NMR (75.0 MHz,
8342 | Org. Biomol. Chem., 2014, 12, 8336–8345
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
CDCl3, TMS) δ 150.5, 149.7, 148.6, 135.6, 134.2, 132.6, 131.9 5.82–5.77 (m, 1H), 5.69–5.65 (m, 1H), 5.18–5.11 (m, 3H), 4.53
1
(q, JC–F = 32.6 Hz, CF3), 130.6, 129.7, 128.7, 127.8, 125.5 (s, 1H), 4.18 (s, 3H, OCH3), 3.85 (s, 1H), 3.70 (s, 1H), 3.33
2
(q, JC–F = 3.7 Hz), 125.1, 123.6, 121.5, 118.3, 68.9, 64.5, 60.3, (s, 1H), 2.84 (s, 3H), 2.68 (s, 1H), 2.11 (s, 1H), 1.92 (s, 1H),
51.5, 49.7, 37.5, 28.1, 27.0, 26.8, 24.9; FT-IR (cm−1): 3447, 3387 1.81–1.74 (m, 2H); 13C NMR (75.0 MHz, CDCl3, TMS) δ 159.0,
+
1
(N–H), 1571 (CvC); HRMS: m/z calcd for C27H29F3N3
147.6, 144.8, 135.5, 134.1, 132.6, 132.2, 132.0 (q, JC–F
=
2
452.2308; found: 452.2308; Anal. calcd for C27H29BrF3N3: 29.2 Hz), 131.8, 126.8, 125.6 (q, JC–F = 3.5 Hz), 125.1, 122.8,
C 60.91, H 5.49, N 7.89; Found: C 60.88, H 5.46, N 7.86%.
121.5, 118.2, 118.1, 101.4, 68.3, 64.2, 60.6, 57.0, 51.6, 50.3,
b2: 74.9 mg, 89%, mp 144–146 °C; [α]2D0 = +79.1 (c = 0.54, 37.4, 29.6, 26.8, 25.0; FT-IR (cm−1): 3445, 3386 (N–H), 1559
CHCl3); 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.80 (d, 3J = (CvC); HRMS: m/z calcd for C28H31F3N3O+ 482.2414; found:
3
4.3 Hz, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 482.2414; Anal. calcd for C28H31BrF3N3O: C 59.79, H 5.56,
7.86 (s, 1H), 7.71–7.66 (m, 2H), 7.35 (s, 1H), 6.13 (s, 1H), 5.91 N 7.47; Found: C 59.77, H 5.54, N 7.44%.
(d, 3J = 11.2 Hz, 1H), 5.69 (s, 1H), 5.57–5.46 (m, 1H), 5.16
d2: 74.1 mg, 87%, mp 158–160 °C; [α]2D0 = +82.0 (c = 0.40,
(s, 1H), 5.03–4.97 (m, 2H), 4.23–4.05 (m, 3H), 2.93–2.73 CHCl3); 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.71 (d, 3J =
(m, 5H), 2.18–1.84 (m, 3H), 1.77–1.66 (m, 2H); 13C NMR 4.1 Hz, 1H), 8.99 (d, 3J = 9.0 Hz, 1H), 7.91 (d, 3J = 10.4 Hz, 2H),
(75.0 MHz, CDCl3, TMS) δ 150.5, 148.8, 148.3, 135.1, 134.1, 7.38 (d, 3J = 9.0 Hz, 1H), 7.29 (s, 1H), 6.18 (d, 3J = 12.5 Hz, 1H),
132.2 (q, 1JC–F = 33.6 Hz, CF3), 131.6, 131.5, 130.5, 129.9, 128.0, 5.95 (d, J = 12.7 Hz, 1H), 5.77 (d, J = 10.2 Hz, 1H), 5.66–5.52
3
3
2
125.6, 124.5, 123.9 (q, JC–F = 3.5 Hz), 123.1, 120.9, 118.3, (m, 1H), 5.41–5.32 (m, 1H), 5.11–5.04 (m, 2H), 4.24–4.21
117.7, 67.3, 63.0, 61.3, 51.9, 51.3, 37.1, 26.7, 26.3, 25.0; FT-IR (m, 2H), 4.10 (m, 4H), 3.18 (s, 3H), 2.98–2.86 (m, 2H),
(cm−1): 3446, 3369 (N–H), 1571 (CvC); HRMS: m/z calcd for 2.20–2.10 (m, 2H), 1.86–1.72 (m, 2H); 13C NMR (75.0 MHz,
+
C28H28F6N3 520.2200; found: 520.2182; Anal. calcd for CDCl3, TMS) δ 159.1, 147.5, 146.7, 144.9, 135.1, 133.9, 132.2
1
C28H28BrF6N3: C 56.01, H 4.70, N 7.00; Found: C 55.87, H 4.64, (q, JC–F = 33.6 Hz, CF3), 131.8, 131.6, 126.9, 124.5, 123.9 (q,
N 6.90%.
2JC–F = 3.5 Hz), 122.8, 120.9, 118.3, 117.6, 101.3, 67.1, 62.7,
c1: 79.3 mg, 95%, mp 155–157 °C; [α]2D0 = +4.5 (c = 0.92, 61.4, 56.7, 51.9, 51.6, 37.1, 26.8, 26.4, 25.1; FT-IR (cm−1): 3450,
CHCl3); 1H NMR (300.1 MHz, CD3OD, TMS) δ 8.64 (d, 3J = 3369 (N–H), 1540 (CvC); HRMS: m/z calcd for C29H30F6N3O+
3
4.7 Hz, 1H), 7.90–7.76 (m, 5H), 7.63 (d, J = 4.7 Hz, 1H), 7.42 550.2288; found: 550.2288; Anal. calcd for C29H30BrF6N3O:
(d, 3J = 9.2 Hz, 1H) 5.68–5.57 (m, 1H), 5.47 (d, 3J = 8.7 Hz, 1H), C 55.25, H 4.80, N 6.66; Found: C 55.19, H 4.72, N 6.59%.
5.33 (d, 3J = 13.3 Hz, 1H), 5.18–5.06 (m, 3H), 4.45–4.37 (m, 1H),
Enantioselective phase-transfer alkylation
4.01 (s, 3H, OCH3), 3.96–3.61 (m, 3H), 3.16–3.13 (m, 3H),
2.58–2.51 (m, 1H), 1.98–1.76 (m, 2H), 1.71 (s, 1H), 1.52–1.43
A mixture of N-(diphenylmethylene)glycine-tert-butyl ester
(m, 1H), 1.25–1.18 (m, 1H); 13C NMR (75.0 MHz, CD3OD, (30 mg, 0.1 mmol) and the catalyst b2 (6 mg, 0.01 mmol) in
TMS) δ 157.4, 147.7, 145.7, 142.3, 134.6, 132.7, 131.1, 130.2 ether (2 mL) was cooled to −40 °C and then 50% aqueous
1
2
(q, JC–F = 32.4 Hz, CF3), 128.9, 125.6, 124.0 (q, JC–F = 3.7 Hz), KOH (0.4 mL, 3.6 mmol) and benzyl bromide (20 mg,
120.9, 120.5, 118.4, 114.9, 99.8, 70.9, 64.1, 54.9, 54.0, 50.5, 0.12 mmol) were added. The reaction mixture was stirred at
48.9, 35.2, 25.8, 24.7, 21.5; FT-IR (cm−1): 3444, 3354 (N–H), −40 °C for 12 h, extracted by ethyl acetate (10 mL × 3) and
1540 (CvC); Mass (MS): m/z 561.2 [M + H]+; Anal. calcd evaporated under reduced pressure. The crude product was
for C28H31BrF3N3O: C 59.79, H 5.56, N 7.47; Found: C 59.67, purified by column chromatography using hexane–EtOAc (v/v
H 4.51, N 7.36%.
= 50 : 1) as the eluent to afford the pure α-alkylation product,
c2: 76.0 mg, 89%, mp 161–163 °C; [α]2D0 = +4.1 (c = 1.12, which was identified using NMR spectra. The data of the new
CH3OH); 1H NMR (300.1 MHz, CD3OD, TMS) δ 8.71 (d, 3J = α-alkylation products are shown as follows and the others are
3
4.7 Hz, 1H), 8.38 (s, 2H), 8.18 (s, 1H), 7.90 (d, J = 9.2 Hz, 1H), listed in the ESI.†
7.63 (d, 3J = 4.8 Hz, 2H), 7.42 (d, 3J = 6.8 Hz, 1H), 5.69–5.57
tert-Butyl 3-(3-trifluoromethylphenyl)-2-(diphenylmethylene-
(m, 1H), 5.49–5.44 (m, 2H), 5.22–5.07 (m, 3H), 4.46–4.37 amino)propanoate (2). 45.1 mg, 99%; 1H NMR (300.1 MHz,
(m, 1H), 4.08 (s, 3H, OCH3), 3.88–3.81 (m, 1H), 3.61–3.49 CDCl3, TMS) δ 7.52 (d, 3J = 7.0 Hz, 2H, Ph–H), 7.40–7.21
3
3
(m, 1H), 3.29–3.27 (m, 3H), 2.62–2.56 (m, 1H), 1.97–1.78 (m, 10H, Ph–H), 6.57 (d, J = 6.6 Hz, 2H, Ph–H), 4.09 (dd, J =
(m, 2H), 1.55 (s, 1H), 1.50–1.46 (m, 1H), 1.25–1.19 (m, 1H); 5.6 Hz, 5.6 Hz, 1H, NCH), 3.23–3.21 (m, 2H, CH2), 1.41 (s, 9 H,
13C NMR (75.0 MHz, CD3OD, TMS) δ 158.9, 149.0, 147.2, 143.9, CH3); 13C NMR (75.0 MHz, CDCl3, TMS) δ 170.8, 170.3 (CvN,
136.0, 133.9, 132.1 (q, 1JC–F = 33.5 Hz, CF3), 131.4, 130.5, 127.0, CvO), 139.3, 139.2, 136.1, 133.4, 133.4, 132.4, 130.5, 130.2,
2
124.9, 123.8 (q, JC–F = 3.7 Hz), 122.4, 121.2, 119.8, 116.4, 130.1, 130.0, 128.6, 128.4, 128.3, 128.2, 128.1, 127.9,
101.2, 72.6, 64.8, 56.8, 56.2, 55.4, 52.1, 36.7, 27.3, 26.2, 23.0; 127.4, 126.4 (q, 2JC–F = 3.7 Hz, CF3), 125.9 (Ph), 123.0 (q, 1JC–F
=
FT-IR (cm−1): 3446, 3381 (N–H), 1540 (CvC); Mass (MS): m/z 3.8 Hz, CF3), 81.4 (O–C), 67.3 (NCH), 39.2 (CH2), 27.9 (CH3);
631.2 [M + H]+; Anal. calcd for C29H30BrF6N3O: C 55.25, Mass (MS): m/z 454.2 [M + H]+; HPLC analysis: Daicel
H 4.80, N 6.66; Found: C 55.17, H 4.75, N 6.60%.
Chiralpak OD-H, hexane–dioxane = 95 : 5, 254 nm, flow rate =
d1: 73.4 mg, 88%, mp 146–148 °C; [α]2D0 = +48.5 (c = 0.74, 0.5 ml min−1, retention time: 9.4 min (R), 10.9 min (S).
CHCl3); 1H NMR (300.1 MHz, CDCl3, TMS) δ 8.62 (d, 3J =
tert-Butyl 3-(2-trifluoromethylphenyl)-2-(diphenylmethyle-
4.1 Hz, 1H), 8.04 (d, 3J = 7.1 Hz, 2H), 7.97 (d, 3J = 8.8, 2H), 7.44 neamino)propanoate (3). 42.0 mg, 93%; 1H NMR (300.1 MHz,
(d, 3J = 6.4 Hz, 2H), 7.38 (d, 3J = 9.2, 2H), 5.91 (s, 2H), CDCl3, TMS) δ 7.76 (d, 3J = 7.1 Hz, 1H, Ph–H), 7.57–7.41
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8336–8345 | 8343

View Article Online
Paper
Organic & Biomolecular Chemistry
3
(m, 4H, Ph–H), 7.35–7.15 (m, 7H, Ph–H), 6.43 (d, J = 6.4 Hz, Ph–H), 7.39–7.25 (m, 6H, Ph–H), 6.96 (q, 3J = 7.9 Hz, 4H,
3
3
3
2H, Ph–H), 4.13 (dd, J = 3.5 Hz, 1H, 3.5 Hz, NCH), 3.50–3.22 Ph–H), 6.62 (d, J = 6.6 Hz, 2H, Ph–H), 4.09 (dd, J = 4.4 Hz,
(m, 2H, CH2), 1.39 (s, 9H, CH3); 13C NMR (75.0 MHz, CDCl3, 4.4 Hz, 1 H, NCH), 3.23–3.07 (m, 2H, CH2), 2.28 (s, 3H, CH3),
TMS) δ 170.7, 170.5 (CvN, CvO), 139.2, 136.8 (q, JC–F
2
=
1.44 (s, 9H, CH3); 13C NMR (75.0 MHz, CDCl3, TMS) δ 170.9,
1.6 Hz), 136.0, 133.3, 132.4, 131.1, 130.2, 131.0, 129.6, 128.7, 170.1 (CvN, CvO), 139.5, 137.5, 136.3, 135.5, 135.1, 132.4,
128.2, 128.1, 127.9, 127.9, 127.3, 126.3, 126.0 (Ph), 125.7 130.0, 129.6, 128.7, 128.2, 128.1, 128.0, 127.9, 127.6 (Ar and
1
(q, JC–F = 5.7 Hz, CF3), 81.2 (O–C), 66.5 (NCH), 36.0 (CH2), Ph), 81.0 (O–C), 68.0 (NCH), 39.1 (CH2), 28.0 (CH3), 21.0 (CH3);
27.9 (CH3); Mass (MS): m/z 454.2 [M + H]+; HPLC analysis: Mass (MS): m/z 400.2 [M + H]+; HPLC analysis: Daicel
Daicel Chiralpak OD-H, hexane–dioxane = 95 : 5, 254 nm, flow Chiralpak OD-H, hexane–dioxane = 95 : 5, 254 nm, flow rate =
rate = 0.5 ml min−1, retention time: 10.8 min (R), 13.5 min (S).
tert-Butyl 3-(3-fluorophenyl)-2-(diphenylmethyleneamino)-
0.5 ml min−1, retention time: 10.7 min (R), 13.1 min (S).
tert-Butyl 3-(3-methylphenyl)-2-(diphenylmethyleneamino)-
propanoate (5). 37.9 mg, 94%; 1H NMR (300.1 MHz, CDCl3, propanoate (9). 37.9 mg, 95%; 1H NMR (300.1 MHz, CDCl3,
TMS) δ 7.49 (d, 3J = 6.7 Hz, 2H, Ph–H), 7.26–7.19 (m, 7H, TMS) δ 7.81 (d, 3J = 7.2 Hz, 1H, Ph–H), 7.62–7.46 (m, 4H,
Ph–H), 7.08 (q, 3J = 6.6 Hz, 1H, Ph–H), 6.79–6.62 (m, 4H, Ph–H), 7.38–7.26 (m, 7H, Ph–H), 6.59 (d, 3J = 6.5 Hz, 2H,
3
3
Ph–H), 6.66 (d, J = 6.6 Hz, 2H, Ph–H), 4.04 (dd, J = 3.8 Hz, Ph–H), 4.09 (dd, 3J = 4.5 Hz, 4.3 Hz, 1H, NCH), 3.23–3.08
3.8 Hz, 1H, NCH), 3.17–3.04 (m, 2H, CH2), 1.37 (s, 9H, CH3); (m, 2H, CH2), 2.22 (s, 3H, CH3), 1.45 (s, 9H, CH3); 13C NMR
13C NMR (75.0 MHz, CDCl3, TMS) δ 170.5, 170.4 (CvN, CvO), (75.0 MHz, CDCl3, TMS) δ 170.8, 170.2 (CvN, CvO), 139.5,
3
164.2, 160.9, 140.8 (d, JC–F = 7.4 Hz), 139.3, 136.2, 132.3, 138.1, 137.4, 136.3, 132.4, 132.3, 130.6, 130.0, 130.0, 128.6,
130.1, 130.0, 128.6, 128.3, 128.2, 128.1, 127.9, 127.5, 125.5, 128.2, 128.2, 128.1, 127.9, 127.8, 127.7, 126.8, 126.7 (Ar and
2
1
125.4 (Ar and Ph), 116.4 (d, JC–F = 20.9 Hz), 112.9 (d, JC–F
=
Ph), 81.0 (O–C), 67.8 (NCH), 39.4 (CH3), 28.0 (CH2), 21.1 (CH3);
20.9 Hz), 81.2 (O–C), 67.4 (NCH), 39.2 (CH2), 27.9 (CH3); Mass Mass (MS): m/z 400.2 [M + H]+; HPLC analysis: Daicel
(MS): m/z 404.2 [M + H]+; HPLC analysis: Daicel Chiralpak Chiralpak OD-H, hexane–dioxane = 95 : 5, 254 nm, flow rate =
OD-H, hexane–dioxane = 95 : 5, 254 nm, flow rate = 0.5 ml min−1
retention time: 9.8 min (R), 12.1 min (S).
,
0.5 ml min−1, retention time: 10.0 min (R), 12.3 min (S).
tert-Butyl 3-(2-methylphenyl)-2-(diphenylmethyleneamino)-
1
tert-Butyl 3-(2-fluorophenyl)-2-(diphenylmethyleneamino)- propanoate (10). 36.7 mg, 92%; H NMR (300.1 MHz, CDCl3,
propanoate (6). 37.1 mg, 92%; 1H NMR (300.1 MHz, CDCl3, TMS) δ 7.60 (d, 3J = 7.2 Hz, 2H, Ph–H), 7.35–7.23 (m, 6H,
TMS) δ 7.56 (d, 3J = 7.1 Hz, 2H, Ph–H), 7.37–7.25 (m, 6H, Ph–H), 7.09–7.04 (m, 4H, Ph–H), 6.52 (d, 3J = 4.1 Hz, 2H,
Ph–H), 7.16–7.11 (m, 2H, Ph–H), 6.98–6.87 (m, 2H, Ph–H), 6.66 Ph–H), 4.15 (dd, 3J = 3.9 Hz, 3.9 Hz, 1 H, NCH), 3.33–3.15
(d, 3J = 6.6 Hz, 2H, Ph–H), 4.19 (dd, J = 4.4 Hz, 4.4 Hz, 1H, (m, 2H, CH2), 2.06 (s, 3H, CH3), 1.39 (s, 9H, CH3); 13C NMR
3
NCH), 3.36–3.12 (m, 2H, CH2), 1.44 (s, 9H, CH3); 13C NMR (75.0 MHz, CDCl3, TMS): δ 171.0, 170.1 (CvN, CvO), 139.3,
(75.0 MHz, CDCl3, TMS): δ 170.6, 170.5 (CvN, CvO), 162.9, 136.9, 136.3, 136.2, 132.4, 131.0, 130.0, 130.0, 129.9, 128.7,
159.7, 139.4, 136.1, 132.3, 130.1, 130.0, 128.7, 128.2, 128.2, 128.2, 128.1, 127.9, 127.8, 127.6, 126.3, 125.9, 125.5 (Ar and
3
128.0, 128.0, 127.9, 127.9, 127.6 (C–Ph), 125.2 (d, JC–F
=
Ph), 81.0 (O–C), 66.4 (NCH), 36.7 (CH3), 28.0 (CH2), 19.2 (CH3);
15.5 Hz), 123.5 (d, JC–F = 3.5 Hz), 114.9 (d, JC–F = 21.9 Hz), Mass (MS): m/z 400.2 [M + H]+; HPLC analysis: Daicel
81.2 (O–C), 66.0 (NCH), 32.6 (CH2), 27.9 (CH3); Mass (MS): m/z Chiralpak OD-H, hexane–dioxane = 95 : 5, 254 nm, flow rate =
404.2 [M + H]+; HPLC analysis: Daicel Chiralpak OD-H, 0.5 ml min−1, retention time: 10.1 min (R), 12.3 min (S).
2
1
hexane–dioxane = 95 : 5, 254 nm, flow rate = 0.5 ml min−1
retention time: 11.0 min (R), 13.7 min (S).
,
tert-Butyl 3-(3, 4-difluorophenyl)-2-(diphenylmethylene-
amino)propanoate (7). 41.7 mg, 99%; 1H NMR (300.1 MHz,
Acknowledgements
CDCl3, TMS) δ 7.57 (d, 3J = 7.0 Hz, 2H, Ph–H), 7.40–7.25 We are grateful to the National Science Foundation of China
3
(m, 6H, Ph–H), 7.02–6.73 (m, 5H, Ph–H), 4.10 (dd, J = 4.7 Hz, (21362005, 21071116) and Chongqing Scientific Foundation
4.7 Hz, 1H, NCH), 3.21–3.07 (m, 2H, CH2), 1.44 (s, 9H, CH3); (CSTC, 2010BB4126).
13C NMR (75.0 MHz, CDCl3, TMS) δ 170.7, 170.3 (CvN, CvO),
3
3
148.1 (d, JC–F = 12.5 Hz), 147.3 (d, JC–F = 12.5 Hz), 139.2,
1
2
136.1, 135.3 (dd, JC–F = 5.7 Hz, F, JC–F = 3.9 Hz, F), 132.3,
Notes and references
130.3, 130.0, 128.6, 128.4, 128.2, 128.1, 127.9, 127.5, 125.6 (dd,
2
2
1JC–F = 6.0 Hz, F, JC–F = 3.6 Hz, F), 118.4 (d, JC–F = 16.8 Hz),
1 (a) T. Ooi and K. Maruoka, Angew. Chem., Int. Ed., 2007, 46,
4222; (b) S. Shirakawa and K. Maruoka, Angew. Chem., Int.
Ed., 2013, 52, 4312; (c) T. Hashimoto and K. Maruoka,
Chem. Rev., 2007, 107, 5656.
2 (a) T. Marcelli and H. Hiemstra, Synthesis, 2010, 1229;
(b) K. Kacprzak and J. Gawroński, Synthesis, 2001, 961.
3 (a) T. Kano, Q. Lan, X. Wang and K. Maruoka, Adv. Synth.
Catal., 2007, 349, 556; (b) S. Shirakawa, M. Ueda,
Y. Tanaka, T. Hashimoto and K. Maruoka, Chem. – Asian J.,
2
116.6 (d, JC–F = 16.8 Hz), 114.4 (Ar and Ph), 81.4 (O–C), 67.3
(NCH), 38.7 (CH2), 27.9 (CH3); Mass (MS): m/z 422.2 [M + H]+;
HPLC analysis: Daicel Chiralpak OD-H, hexane–dioxane =
95 : 5, 254 nm, flow rate = 0.5 ml min−1, retention time:
10.3 min (R), 12.3 min (S).
tert-Butyl 3-(4-methylphenyl)-2-(diphenylmethyleneamino)-
propanoate (8). 37.8 mg, 95%; 1H NMR (300.1 MHz, CDCl3,
TMS) δ 7.81 (d, 3J = 7.2 Hz, 1H, Ph–H), 7.58 (d, 3J = 7.1 Hz, 2H,
8344 | Org. Biomol. Chem., 2014, 12, 8336–8345
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
2007, 2, 1276; (c) T. Ooi, Y. Uematsu, M. Kameda and
K. Maruoka, Angew. Chem., Int. Ed., 2002, 41, 1551;
(d) T. Ooi, Y. Uematsu, M. Kameda and K. Maruoka, Tetra-
hedron, 2006, 62, 11425; (e) M. Waser, K. Gratzer, R. Herchl
and N. Müller, Org. Biomol. Chem., 2012, 10, 251;
(f) M. Kitamura, Y. Arimura, S. Shirakawa and K. Maruoka,
Tetrahedron Lett., 2008, 49, 2026; (g) M. Kitamura,
S. Shirakawa, Y. Arimura, X. Wang and K. Maruoka, Chem.
– Asian J., 2008, 3, 1702; (h) Y. Wang and K. Maruoka, Org.
Process Res. Dev., 2007, 11, 628; (i) Y. Wang, M. Ueda,
X. Wang, Z. Han and K. Maruoka, Tetrahedron, 2007, 63,
6042; ( j) B. Lygo, B. Allbutt, D. J. Beaumont, U. Butt and
J. A. R. Gilks, Synlett, 2009, 675; (k) B. Lygo, U. Butt and
M. Cormack, Org. Biomol. Chem., 2012, 10, 4968.
7 (a) Y. Lee, Y. Park, M. Kim, S. Jew and H. Park, J. Org.
Chem., 2011, 76, 740; (b) B. Lygo, C. Beynon, M. C. McLeod,
C. Roy and C. E. Wade, Tetrahedron, 2010, 66, 8832;
(c) P. Nun, V. Pérez, M. Calmès, J. Martinez and F. Lamaty,
Chem. – Eur. J., 2012, 18, 3773; (d) M. B. Andrus and Z. Ye,
Tetrahedron Lett., 2008, 49, 53.
8 (a) J. Lv, L. Zhang, L. Liu and Y. Wang, Chem. Lett., 2007,
36, 1354; (b) X. Wang, J. Lv, L. Liu, Y. Wang and Y. Wu,
J. Mol. Catal. A: Chem., 2007, 276, 102; (c) W. He, Q. Wang,
Q. Wang, B. Zhang, X. Sun and S. Zhang, Synlett, 2009,
1311.
9 K. M. Johnson, M. S. Rattley, F. Sladojevich, D. M. Barber,
M. G. Nuñez, A. M. Goldys and D. J. Dixon, Org. Lett., 2012,
14, 2492.
4 M. J. O’Donnell, W. D. Bennett and S. Wu, J. Am. Chem. 10 (a) H. Brunner, J. Bügler and B. Nuber, Tetrahedron: Asym-
Soc., 1989, 111, 2353.
5 M. J. O’Donnell, S. Wu and J. C. Huffman, Tetrahedron,
1994, 50, 4507.
6 (a) B. Lygo and P. G. Wainwright, Tetrahedron Lett., 1997,
38, 8595; (b) E. J. Corey, F. Xu and M. C. Noe, J. Am. Chem.
Soc., 1997, 119, 12414.
metry, 1995, 6, 1699; (b) J. Wan, X. Ma, R. He and M. Li,
Chin. Chem. Lett., 2014, 25, 557–560; (c) W. Wang, X. Ma,
J. Wan, J. Cao and Q. Tang, Dalton Trans., 2012, 41, 5715–
5726; (d) J. Zhou, J. Wan, X. Ma and W. Wang, Org. Biomol.
Chem., 2012, 10, 4179; (e) B. Zheng, Q. Liu, C. Guo,
X. Wang and L. He, Org. Biomol. Chem., 2007, 5, 2913–2915.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8336–8345 | 8345