Asymmetric Organocatalytic Synthesis of 4-Aminoisochromanones via a Direct One-Pot Intramolecular Mannich Reaction

Article abstract of DOI:10.1055/s-0035-1562522

A highly stereoselective one-pot intramolecular Mannich reaction using 2-oxopropyl-2-formylbenzoates and anilines as substrates, catalyzed by a secondary amine, has been developed. The procedure leads to a new class of 4-aminoisochromanones bearing two ad

Full text of DOI:10.1055/s-0035-1562522

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
F. Vetica et al.
Paper
Synthesis
Asymmetric Organocatalytic Synthesis of 4-Aminoisochromanones
via a Direct One-Pot Intramolecular Mannich Reaction
Fabrizio Veticaa
Jeanne Fronerta
Rakesh Puttreddyb
Kari Rissanenb
Dieter Enders*a
N
N
N
H
R2
O
N N
H
NH
O
R2
(20 mol%)
O
R1
Me
O
R1
DMSO, r.t.
one-pot
intramolecular
Mannich reaction
69–85%
Me
NH2
O
O
a Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
enders@rwth-aachen.de
b Department of Chemistry, Nanoscience Center, University of
Jyväskylä, 40014 Jyväskylä, Finland
O
9 examples
up to 99:1 dr
92–99% ee
Received: 01.07.2016
Accepted: 05.07.2016
Published online: 16.08.2016
OH
Cl
Me
DOI: 10.1055/s-0035-1562522; Art ID: ss-2016-z0472-op
H
Bn
N
O
O
Abstract A highly stereoselective one-pot intramolecular Mannich re-
action using 2-oxopropyl-2-formylbenzoates and anilines as substrates,
catalyzed by a secondary amine, has been developed. The procedure
leads to a new class of 4-aminoisochromanones bearing two adjacent
stereocentres in good yields (up to 85%) with excellent cis-stereoselec-
tivities (dr up to 99:1) and ee values of 92–99%.
CO2H O
OH
O
OH
O
ochratoxin A (I)
mycotoxin
(–)-hydrangenol (II)
antidiabetic
N
N
MeO
MeO
Me
Key words organocatalysis, one-pot reaction, asymmetric synthesis,
isochromanones, Mannich reaction
O
OH
O
O
OH
O
aldosterone synthase
fusarentin (IV)
natural insecticide
The isochroman-1-one framework is a common scaffold
of a variety of natural and synthetic compounds showing
inhibitor (III)
Figure 1 Natural 3,4-disubstituted isochromanones with remarkable
biological activities
notable biological activities, such as ochtratoxin A (I),1
a
powerful mycotoxin isolated from Aspergillus ochraceus, the
antidiabetic (–)-hydrangenol (II),2 the aldosterone synthase
inhibitor (III),3 and fusarentin (IV),4 a natural insecticide
(Figure 1). Due to their interesting chemical and medicinal
properties, these compounds have been widely studied in
recent years.5
in total synthesis.6a,h,7b,c,9 However, the application of this
protocol has been mainly focused on intermolecular ap-
proaches and less attention has been given to intramolecu-
lar direct Mannich reaction.7b,9a,b,10
Asymmetric organocatalytic methodologies are becom-
ing an increasingly efficient alternative to the well-estab-
lished metal-based and enzymatic procedures for the con-
struction of new stereogenic centers.6 In the vast field of
asymmetric synthesis, organocatalytic Mannich reactions
have proven to be a powerful and highly selective tool for
the synthesis of β-aminocarbonyl compounds under mild
conditions.7 Particularly, after the pioneering work of List in
2000,8 the direct Mannich reaction between unmodified
ketones and in situ generated imines has been widely inves-
tigated, because basically this one-pot sequence avoids the
time-consuming and costly preparation/purification of the
imine intermediate and represents an outstanding resource
Mannich-type cyclizations have been involved as key
step in numerous total syntheses of complex natural prod-
ucts, but it often required functional group protections as
well as the isolation/purification of the intermediates.11
Nevertheless, in the last decade some examples of organo-
catalytic intramolecular Mannich and aza-Mannich meth-
odologies have been reported, employing pyrrolidine deriv-
atives,12 cinchona alkaloids,13 amino acids,14 and cyclodex-
trins as catalysts,15 as well as under an oxidative coupling.16
In 2013, we reported a secondary amine-catalyzed aldol
addition reaction for the trans-selective synthesis of 3,4-di-
functionalized isochroman-1-one derivatives (Scheme 1).17
We envisaged the possibility to employ the 2-oxopropyl-2-
formylbenzoate substrates 1 in an intramolecular direct
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
F. Vetica et al.
Paper
Synthesis
Mannich reaction to achieve a new class of 3-acetyl-4-ami-
noisochroman-1-ones bearing two contiguous stereogenic
centers. This particular 4-aminoisochromanone scaffold
has never been achieved nor studied, although related 3,4-
diaminoisochromen-1-ones have been synthesized utiliz-
ing multicomponent Strecker or Ugi reactions.18 In view of
the previously discussed importance of this particular class
of heterocycles, the development of a facile access to a vari-
ety of these molecules is of high interest.
OMe
MeO
O
N
O
NH
O
O
cat.* (20 mol%)
Me
O
O
Me
solvent, r.t.
O
O
Me
O
4
3a
5
HO
Ph
N
N
Ph
H
N
N
CO2H
N
H
N
Previous work (2013)17
N
CO2H
H
H
N
N
N
OTMS
H
H
N
N
N
H
E
A
B
C
D
HO R2
O
O
O
N
N
H
DMSO
DMSO
47% yield
99% ee
95% de
CH2Cl2
only 5
DMSO
no reaction
CH2Cl2
no reaction
R2
O
O
Me
(30 mol%)
70% yield
99% ee
95% de
R1
R1
O
Me
O
Scheme 2 Catalyst screening for the direct intramolecular Mannich re-
action
This work:
N
N
N
H
R2
O
N
N
H
NH
O
of the catalyst loading led to the identification of the best
reaction conditions using 20 mol% of A to provide 72% yield,
97:3 dr, and 99% ee (entries 8–10).
R2
(20 mol%)
O
R1
Me
O
R1
Me
NH2
O
O
O
3
Table 1 Optimization of the Reaction Conditionsa
1
2
Scheme 1 Asymmetric organocatalytic syntheses of 3,4-disubstituted
isochromanones
N
OMe
MeO
N
N
H
N
N
H
By taking advantage of the well-demonstrated applica-
tion of pyrrolidine derivatives in organocatalytic asymmet-
ric Mannich reactions, a number of differently substituted
prolines were first tested, which can interact with the pre-
formed imine 4 (Scheme 2). Considering that Mannich and
aldol reactions are competing transformations, it was not
surprising to isolate the isocumarin 5 as a single product
when catalyst C was applied. This outcome could be ratio-
nalized by hydrolysis of the imine 4 to form the 2-oxopro-
pyl-2-formylbenzoate 1, which reacts with the catalyst to
give 5 or by p-methoxyaniline elimination from 3a. In con-
trast, no products could be detected when the Jørgensen–
Hayashi catalyst E as well as the hydroxyproline D were
employed. However, (S)-proline (B) and the tetrazole-sub-
stituted catalyst A showed moderate to good reactivity
(47% and 70% yield, respectively) accompanied with an ex-
cellent stereoselectivity (dr 97:3 and 99% ee in both cases).
Further optimization involving catalyst A has been car-
ried out by analyzing the effect of both solvents and catalyst
loading on the reaction outcome (Table 1). By changing
from the initially used DMSO to DMF, no significant chang-
es in the stereoselectivity were observed (dr 96:4, 99% ee).
However, the reaction time was prolonged from 24 to 72
hours (Table 1, entry 2). Subsequently we tested the effects
of less polar solvents, but in almost all cases product forma-
tion could not be observed (entries 3–7). Further screening
N
O
NH
O
O
A (X mol%)
O
Me
solvent, r.t.
O
O
Me
4
3a
Entry
Solvent
Catalyst A Time
Yield
(%)b
drc
ee
(mol%)
(d)
(%)d
1
2
DMSO
DMF
20
20
20
20
20
20
20
5
1
3
3
3
3
3
3
1
1
1
70
70
nr
97:3
96:4
–
99
99
–
3
CH2Cl2
CHCl3
MeCN
Et2O
4
12
22
nr
nd
nd
nd
–
5
nd
6
–
7
THF
nr
–
–
8
DMSO
DMSO
DMSO
35
50
72
97:3
97:3
97:3
99
99
99
9
10
30
10
a Unless otherwise stated, the reaction conditions were: 0.2 mmol of 4 and
0.4 mL of solvent (0.5 M); nr = no reaction, nd = not determined.
b Yield of the isolated product 3a after flash chromatography.
c Determined via HPLC analysis on a chiral stationary phase.
d Determined via HPLC analysis on a chiral stationary phase.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
F. Vetica et al.
Paper
Synthesis
In all the above-mentioned cases, the condensation
product 5 has been detected in non-negligible amounts,
caused by the previously discussed side reaction. In order
to avoid this complication, we subsequently tested unmodi-
fied 2-oxopropyl-2-formylbenzoate (1a) and p-anisidine
(2a) as substrates under the optimized reaction conditions
to perform a one-pot intramolecular Mannich reaction. To
our delight, the isochroman-1-one 3a was obtained in bet-
ter yield (85%) as compared to the former procedure (70%
yield), with no loss in either diastereo- or enantioselectivity
(dr 98:2, 99% ee) (Scheme 3).
Table 2 Investigation of the Substrate Scopea
N
N
N
H
R2
N
N
O
O
H
NH
O
R2
A (20 mol%)
O
R1
Me
O
R1
DMSO, r.t.
Me
NH2
O
O
1
2
3
3
R1
R2
Time
(d)
Yield
(%)b
drc
ee
(%)d
MeO
a
b
c
d
e
f
H
4-OMe
4-Cl
1
85
70
81
81
72
84
69
83
75
98:2
99
99
99
99
99
92
99
98
99
O
OMe
H
H
H
H
H
1.7
1.7
1.7
1.7
1.7
1
99:1
98:2
95:5
99:1
97:3
79:21
94:6
98:2
A (20 mol%)
NH
O
O
O
4-F
DMSO, r.t.
Me
Me
O
O
NH2
4-CF3
4-Me
4-Br
O
1a
2a
3a
99% ee
dr 98:2
85% yield
g
h
i
6-Br
4-OMe
4-Cl
Scheme 3 Asymmetric organocatalytic synthesis of 3a
7,8-(OMe)2
6-Cl
1
4-Cl
1
Due to the intramolecular character of our transforma-
tion and to avoid the possible condensation product under
the one-pot condition, it was necessary to push the equilib-
rium towards the imine formation by using 1.5 equivalents
of aniline, as well as a more concentrated solution. Indeed
the condensation product 5 could then be detected in only
trace amount.
a Unless otherwise stated, the reaction conditions were: 0.2 mmol of 1, 0.3
mmol of 2 (1.5 equiv) in 0.4 mL of solvent (0.5 M), and 0.04 mmol of cata-
lyst A (20 mol%).
b Yield of the isolated product 3 after flash chromatography.
c Determined via HPLC analysis on a chiral stationary phase.
d Determined via HPLC analysis on a chiral stationary phase.
With the optimized reaction conditions in hand, we fo-
cused on the general applicability of the developed new
protocol by using variously substituted substrates (Table 2).
A broad scope of anilines 2a–f was tested and the corre-
sponding isochromanones 3a–f were obtained in good
yields (70–85%) and with very high diatereo- and enantio-
selectivities (dr up to 99:1 and 99 ee in almost all cases), ir-
respective of the steric and electronic nature of the substit-
uents. Similar results have been observed after the intro-
duction of different functional groups on the substrates 1.
However, the presence of a bulky substituent R1 on the 6-
position of the aromatic ring led to a decrease of the dia-
stereoselectivity to 79:21 (3g). The presence of strongly
electron-donating groups on positions 7 and 8 [7,8-(OMe)2]
did not influence the reaction outcome and the corre-
sponding product 3h was obtained with high stereoselec-
tivity (dr 94:6, 98% ee).
aldol and Mannich reaction usually show an opposite rela-
tive topicity in intermolecular reactions, and this stereo-
chemical outcome may also be reflected in intramolecular
reactions.
Figure 2 X-ray crystal structure of compound 3b19 and proposed tran-
sition state for the intramolecular direct one-pot Mannich reaction
The absolute configuration was unambiguously deter-
mined by X-ray crystal structure analysis of compound
3b,19 and by analogy the configuration of all other products
was assigned accordingly (Figure 2). The cis-configuration
of the 3,4-disubstituted δ-lactone ring, different as com-
pared to our previously developed trans-selective 6-enolexo
aldolization on the same substrates, is in accordance with
literature reports.9c Indeed, it has been demonstrated that
The proposed reaction mechanism for the direct one-
pot intramolecular Mannich reaction involves the forma-
tion of the corresponding imine 4, which is attacked on its
Re-face by the Re-face of the E-enamine, formed from the
organocatalyst A and the ketone moiety, explaining the ob-
served cis-diastereo- and enantioselectivity.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
F. Vetica et al.
Paper
Synthesis
In summary, we have developed an efficient asymmet-
ric synthesis for the new class of 4-aminoisochromanones
via an organocatalytic direct intramolecular Mannich reac-
tion. The one-pot sequence involves an initial imine forma-
tion followed by a cis-selective 6-enolexo-exo-trig Mannich
reaction catalyzed by a tetrazole analogue of proline to pro-
vide the potentially bioactive title heterocycles in good
yields (up to 85%) with excellent stereoselectivities (dr up
to 99:1, up to 99% ee).
1H NMR (600 MHz, CDCl3): δ = 10.63 (s, 1 H, CHO), 8.07–8.04 (m, 1 H,
CHar), 7.98–7.95 (m, 1 H, CHar), 7.71–7.65 (m, 2 H, CHar), 4.97 (s, 2 H,
CH2), 2.25 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 200.52, 192.18, 165.67, 137.28,
133.17, 132.93, 131.34, 130.76, 128.62, 69.37, 26.23.
MS (EI+, 70 eV): m/z (%) = 206.0 (4, [M]+ = [C11H10O4]+), 205.1 (27),
149.1 (97), 133.0 (51), 120.1 (14), 104.1 (100), 93.1 (12), 83.0 (18),
76.1 (98).
MS (CI+, methane): m/z (%) = 207 (28, [M + H]+ = [C11H11O4]+).
HRMS (ESI+): m/z [M + Na]+ calcd for [C11H10O4Na]+: 229.0471; found:
229.0471.
Unless otherwise noted, all commercially available compounds were
used without further purification. For preparative column chroma-
tography SIL G-25 UV252 from Macherey-Nagel, particle size 0.040–
0.063 nm (230–240 mesh. flash) was used. Visualization of the devel-
oped TLC plates was performed with UV irradiation (254 nm) or by
staining with ninhydrin stain (0.5% EtOH solution); P = n-pentane.
Optical rotations were measured on a PerkinElmer 241 polarimeter.
Mass spectra were recorded on a Finnigan SSQ7000 (EI 70 eV) spec-
trometer and high-resolution mass spectra on a Thermo Fisher Scien-
tific Orbitrap XL spectrometer. IR spectra were recorded on a Perkin-
Elmer FT-IR Spectrum 100 using ATR-Unit. 1H and 13C spectra were
recorded at ambient temperature on Varian Mercury 300, Inova 400,
Varian VNMRS-400, or Varian VNMRS-600 spectrometers with TMS
as an internal standard. Analytical HPLC was performed on a Hewlett-
Packard 1100 Series instrument using chiral stationary phases (Daicel
AD, Daicel AS, Daicel IA, Daicel OD, Daicel OJ, Chiralpak IC, or Whelk M
columns).
2-Oxopropyl 4-Bromo-2-formylbenzoate (1b)
Yield: 280 mg (20%, after 3 reaction steps); pale yellow solid; mp 58–
59 °C; Rf = 0.23 (P/Et2O, 4:6).
IR (ATR): 3436, 3345, 3100, 3036, 2980, 2942, 2851, 1716, 1680, 1580,
1562, 1473, 1426, 1377, 1271, 1179, 1136, 1088, 1010, 957, 878 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.60 (s, 1 H, CHO), 8.08 (d, J = 2.0 Hz, 1
H, CHar), 7.94 (d, J = 8.3 Hz, 1 H, CHar), 7.79 (dd, J = 8.3, 2.1 Hz, 1 H,
CHar), 4.97 (s, 2 H, CH2), 2.25 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 200.10, 190.74, 164.92, 138.66,
136.04, 132.42, 131.61, 129.81, 128.31, 69.44, 26.16.
MS (EI+, 70 eV): m/z (%) = 386.1 (6, [M + H]+ = [C11H10BrO4]+), 229.1
(19), 227.1 (22), 213.0 (17), 210.9 (11), 184.0 (11), 183.1 (9), 75 (41),
58 (100).
MS (CI+, methane): m/z (%)
= 315.1 (3, [M + =
C2H5, 81Br]+
[C13H14BrO4]+), 313.1 (3, [M + C2H5, 79Br]+ = [C13H14BrO4]+), 287.0 (12,
[M, 81Br]+ = [C11H9BrO4]+), 284.9 (13, [M, 79Br]+ = [C11H9BrO4]+), 228.9
(18), 226.9 (21), 213.9 (12), 212.9 (95), 211.9 (13), 210.9 (100).
The catalyst A was prepared according to the previously described
procedure.20
HRMS (ESI+): m/z [M + Na]+ calcd for [C11H9BrO4Na]+: 306.9574;
found: 306.9576.
2-Oxopropyl 2-Formylbenzoates 1; General Procedure
Under argon atmosphere, the respective phthalide (7 mmol, 1.0
equiv) was dissolved in CCl4 (35 mL, 0.2 M). NBS (7.7 mmol, 1.1 equiv)
and AIBN (0.7 mmol, 0.1 equiv) were added and the reaction mixture
was refluxed for 3 h. After stirring for another 1 h at 0 °C, the mixture
was filtered, and the filtrate was concentrated under reduced pres-
sure. H2O (25 mL) was then added and the suspension was refluxed 2
h. After cooling to r.t., EtOAc was added and the phases were separat-
ed. The aqueous phase was extracted with EtOAc (3 × 10 mL), the
combined organic phases were dried (anhyd MgSO4), filtered, and
concentrated under reduced pressure to give the crude corresponding
2-formylbenzoic acid. The crude product was dissolved in acetone (14
mL, 0.5 M) and Et3N (7 mmol, 1.0 equiv), and chloroacetone (7.35
mmol, 1.5 equiv) was added to the suspension. The mixture was re-
fluxed for 2 h, then H2O was added, the phases were separated, and
the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic phases were dried (anhyd MgSO4), filtered, and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography to give the desired 2-oxopropyl 2-formylben-
zoate 1.
2-Oxopropyl 6-Formyl-2,3-dimethoxybenzoate (1c)
Prepared from commercially available 2,3-dimethoxy-6-formylben-
zoic acid; yield: 2.369 g (89%); colorless solid; mp 93–95 °C; Rf = 0.5
(P/EtOAc, 4:6).
IR (ATR): 2930, 2853, 1722, 1679, 1572, 1458, 1429, 1372, 1273, 1150,
1049, 962, 908, 828, 791, 743 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 9.90 (s, 1 H, CHO), 7.64 (d, J = 8.5 Hz, 1
H, CHar), 7.09 (d, J = 8.5 Hz, 1 H, CHar), 4.92 (s, 2 H, CH2), 3.98 (s, 3 H,
OCH3), 3.92 (s, 3 H, OCH3), 2.27 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 202.38, 189.29, 165.91, 157.99,
146.83, 129.50, 128.32, 126.98, 112.81, 69.72, 62.06, 56.39, 26.63.
MS (EI+, 70 eV): m/z (%) = 266.3 (1, [M]+ = [C13H14O6]+), 209.1 (23),
194.1 (12), 193.1 (100), 165.1 (32), 163.1 (12), 150.1 (12), 149.1 (12),
135.1 (14), 122.1 (23), 121.1 (14), 119.1 (13), 107.2 (27), 106.1 (12),
105.1 (16), 104.1 (16), 79.2 (31), 78.2 (19), 77.2 (36), 76.2 (17), 65.3
(13), 63.3 (18), 58.4 (14), 53.4 (12), 51.3 (35), 50.3 (18).
HRMS (ESI+): m/z [M + Na]+ calcd for [C13H14O6Na]+: 289.0683; found:
289.0683.
2-Oxopropyl 2-Formylbenzoate (1a)
Prepared from commercially available 2-formylbenzoic acid; yield:
1.227 g (85%); yellow oil; Rf = 0.26 (P/Et2O, 1:1).
2-Oxopropyl 4-Chloro-2-formylbenzoate (1d)
Prepared from commercially available 4-chloro-2-formylbenzoic
acid; yield: 430 mg (44%); yellow oil; Rf = 0.51 (P/Et2O, 1:2).
IR (ATR): 3450, 2933, 1788, 1725, 1593, 1420, 1367, 1280, 1191, 1128,
1086, 1011, 961, 920, 828, 793, 753, 698, 641 cm–1
.
IR (ATR): 3851, 3743, 3673, 3451, 3081, 2928, 1727, 1587, 1420, 1371,
1276, 1187, 1105, 899, 844, 774 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
F. Vetica et al.
Paper
Synthesis
1H NMR (600 MHz, CDCl3): δ = 10.59 (s, 1 H, CHO), 8.03 (d, J = 2.1 Hz, 1
H, CHar), 7.94 (d, J = 8.3 Hz, 1 H, CHar), 7.65 (d, J = 10.4 Hz, 1 H, CHar),
4.98 (s, 2 H, CH2), 2.26 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 199.97, 190.86, 164.52, 139.81,
135.38, 133.06, 132.82, 130.88, 130.13, 69.55, 26.17.
(3R,4S)-3-Acetyl-4-[(4-chlorophenyl)amino]isochroman-1-one
(3b)
Yield: 44 mg (70%); colorless solid; after measuring the HPLC data,
the product was recrystallized from a mixture of PE/Et2O (1:1); the
crystals were filtered and washed with the same solvent mixture; mp
20
150–151 °C; Rf = 0.46 (P/Et2O 4:6); [α]D +162.4 (c 0.50, CHCl3, 99%
MS (EI+, 70 eV): m/z (%) = 241.0 (3, [M + H]+ = [C11H10ClO4]+), 182.9
(53), 166.9 (63), 138.9 (31), 111.0 (24), 75.1 (38), 58.1 (100).
ee).
HPLC: Whelk M, n-heptane/i-PrOH (7:3), 0.7 mL/min, λ = 254.4 nm,
tR = 28.7 min (minor), tR = 11.9 min (major); 99:1 dr, 99% ee.
HRMS (ESI+): m/z [M + Na]+ calcd for [C11H9ClO4Na]+: 263.0082;
found: 263.0082.
IR (ATR): 3374, 3057, 2925, 2312m 2089, 1870, 1712, 1596, 1495,
1246, 1093, 765, 692 cm–1
.
Direct Organocatalytic Mannich Reaction; General Procedure
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 7.5 Hz, 1 H, CHar), 7.57 (t, J =
7.5 Hz, 1 H, CHar), 7.50 (t, J = 7.6 Hz, 1 H, CHar), 7.28 (d, J = 7.6 Hz, 1 H,
CHar), 7.15 [d, J = 8.7 Hz, 2 H, CHar (aniline)], 6.67 [d, J = 8.8 Hz, 2 H,
CHar (aniline)], 5.10 (dd, J = 10.1, 3.0 Hz, 1 H, NHCH), 5.00 (d, J = 3.2
Hz, 1 H, CH), 4.00 (d, J = 10.4 Hz, 1 H, NH), 2.39 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 206.17, 163.35, 144.30, 139.25,
135.03, 130.92, 129.48, 129.39, 126.41, 124.57, 123.00, 116.07, 83.56,
53.18, 28.53.
MS (EI+, 70 eV): m/z (%) = 317.0 (14, [M, 37Cl]+ = [C17H14ClNO3]+), 315.0
(44, [M, 35Cl]+ = [C17H14ClNO3]+), 244.0 (32), 242.0 (100), 217.0 (20),
216.0 (24), 215.0 (65), 214.0 (49), 147.0 (12), 127.0 (27), 118.0 (12),
111.0 (14), 90.2 (11), 89.1 (16), 77.2 (11), 75.1 (11).
To a solution of the appropriate 2-oxopropyl 2-formylbenzoate 1 (0.2
mmol, 1.0 equiv) in DMSO (0.4 mL, 0.5 M) was added the respective
aniline 2 (0.3 mmol, 1.5 equiv) and the mixture was stirred for 2 h.
Then the catalyst A was added to the solution (5.6 mg, 0.04 mmol, 20
mol%) and the reaction mixture was stirred at r.t. After completion of
the reaction, H2O (3 mL) was added, and the mixture was extracted
with Et2O (3 × 2 mL). The combined organic phases were dried (anhyd
MgSO4), filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography to give the desired cis-
(3R,4S)-3-acetyl-4-aminoisochromanone 3a–i.
(3R,4S)-3-Acetyl-4-[(4-methoxyphenyl)amino]isochroman-1-one
(3a)
MS (CI+, methane): m/z (%) = 344.0 (7, [M + C2H5, 35Cl]+ = [C19H19ClNO3]+),
Yield: 53 mg (85%); colorless solid; mp 158–159 °C; Rf = 0.46 (P/Et2O,
1:2); [α]D20 +88.2 (c 1.00, CHCl3, 99% ee).
317.9 (23, [M + H, 37Cl]+ = [C17H15ClNO3]+), 317.0 (13, [M, 37Cl]+
=
[C17H14ClNO3]+), 316.0 (67), 314.9 (35, [M, 35Cl]+ = [C17H14ClNO3]+),
271.9 (12), 258.2 (14), 257.4 (18), 242.0 (24), 216.3 (11), 214.0 (15),
190.1 (11), 188.9 (99), 187.9 (36), 156.0 (17), 149.0 (16), 147.1 (2),
145.4 (13), 130.1 (28), 129.1 (33), 128.0 (100), 127.0 (81), 75.2, (12).
HPLC: Whelk M, n-heptane/EtOH (8:2), 0.5 mL/min, λ = 230.4 nm;
major diastereomer: tR = 43.0 min (minor), tR = 21.4 min (major); mi-
nor diastereomer: tR = 28.2 min (minor), tR = 24.0 min (major); 98:2
dr, 99% ee.
HRMS (ESI+): m/z [M + H]+ calcd for [C17H15ClNO3]+: 316.0735; found:
IR (ATR): 3364, 2956, 2833, 2289, 2185, 2063, 1887, 1717, 1603, 1513,
316.0735.
1457, 1357, 1243, 1113, 1033, 824, 766, 696 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.15 (dd, J = 7.7, 1.1 Hz, 1 H, CHar), 7.51
(dtd, J = 30.7, 7.5, 1.2 Hz, 2 H, CHar), 7.20 (d, J = 7.5 Hz, 1 H, CHar), 6.77
[d, J = 8.9 Hz, 2 H, CHar (aniline)], 6.66 [d, J = 8.9 Hz, 2 H, CHar (ani-
line)], 5.00 (d, J = 3.2 Hz, 1 H, CH), 4.97 (dd, J = 10.5, 3.2 Hz, 1 H,
NHCH), 3.75 (s, 3 H, OCH3), 3.56 (d, J = 10.4 Hz, 1 H, NH), 2.42 (s, 3 H,
CH3).
13C NMR (151 MHz, CDCl3): δ = 206.44, 163.77, 154.09, 139.77,
139.54, 134.94, 131.04, 129.43, 126.73, 123.05, 117.61, 115.02, 84.20,
55.77, 55.11, 28.76.
MS (EI+, 70 eV): m/z (%) = 312.1 (23, [M + H]+ = [C18H18NO4]+), 311.1
([M]+, 100), 239.1 (15), 138.2 (67), 211.1 (40), 210.1 (12), 196.1 (38),
167.1 (19), 147.1 (9), 123.1 (22), 122.1 (40), 118.1 (12), 108.1 (26),
90.2 (12), 89.2 (23), 77.2 (11), 48.5 (61).
MS (CI+, methane): m/z (%) = 340.1 (16, [M + C2H5]+ = [C20H22NO4]+),
313.1 (33), 312.0 (100, [M + H]+ = [C18H18NO4]+), 311.0 ([M]+, 58.3),
328.0 (9).
(3R,4S)-3-Acetyl-4-[(4-fluorophenyl)amino]isochroman-1-one
(3c)
Yield: 48 mg (81%); colorless solid; mp 166–167 °C; Rf = 0.66 (P/Et2O,
4:6); [α]D20 +151.3 (c 0.40, CHCl3, 99% ee).
HPLC: IB, n-heptane/EtOH (9:1), 0.7 mL/min, λ = 230.16 nm; major
diastereomer: tR = 18.8 min (minor), tR = 17.1 min (major); minor dia-
stereomer: tR = 22.1 min (minor), tR = 19.8 min (major); 98:2 dr, 99%
ee.
IR (ATR): 3782, 3360, 3047, 2870, 2635, 2454, 2285, 2167, 2050, 1863,
1717, 1603, 1511, 1415, 1362, 1272, 1216, 1109, 811, 696 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.15 (dd, J = 7.8, 1.4 Hz, 1 H, CHar), 7.56
(td, J = 7.5, 1.4 Hz, 1 H, CHar), 7.49 (td, J = 7.6, 1.2 Hz, 1 H, CHar), 7.24–
7.21 (m, 1 H, CHar), 6.93–6.87 [m, 2 H, CHar (aniline)], 6.69–6.63 [m, 2
H, CHar (aniline)], 5.02 (dd, J = 10.3, 3.2 Hz, 1 H, NHCH), 5.00 (d, J = 3.3
Hz, 1 H, CH), 3.78 (d, J = 10.3 Hz, 1 H, NH), 2.42 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 206.28, 163.48, 157.97, 156.39,
141.93, 139.35, 134.93, 130.94, 129.44, 126.48, 122.94, 116.73,
116.68, 116.11, 115.96, 83.83, 54.33, 30.94.
HRMS (ESI+): m/z [M + H]+ calcd for [C18H18NO4]+: 312.1230; found:
312.1230.
MS (EI+, 70 eV): m/z (%) = 300.1 (17), 299.1 (73, [M]+ = [C17H14FNO3]+),
227.1 (23), 226.1 (100), 200.1 (9), 199.1 (69), 198.1 (67), 111.1 (12).
Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.13;
H, 5.42; N, 4.42.
MS (CI+, methane): m/z (%) = 378.2 (4, [M + C2H5]+ = [C20H19F3NO3]+),
350.1 (48), 349.1 (35, [M]+ = [C18H14F3NO3]+), 331.1 (13), 330 (61),
277.1 (23), 276.1 (100), 249.1 (24).
HRMS (ESI+): m/z [M + H]+ calcd for [C18H15F3NO3]+: 350.0999; found:
350.0999.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
F. Vetica et al.
Paper
Synthesis
(3R,4S)-3-Acetyl-4-{[4-(trifluoromethyl)phenyl]amino}isochro-
man-1-one (3d)
IR (ATR): 3379, 3050, 2319, 2083, 1885, 1713, 1592, 1497, 1254, 1081,
778 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.14 (dd, J = 7.8, 1.1 Hz, 1 H, CHar), 7.58
(td, J = 7.6, 1.4 Hz, 1 H, CHar), 7.50 (td, J = 7.6, 1.1 Hz, 1 H, CHar), 7.31–
7.26 [m, 3 H, CHarom and 2 × CHar (aniline)], 6.64–6.59 [m, 2 H, CHar
(aniline)], 5.11 (br s, 1 H, NHCH), 5.00 (d, J = 3.3 Hz, 1 H, CH), 4.01 (br
s, 1 H, NH), 2.39 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 206.36, 163.51, 144.92, 1f39.38,
135.24, 132.47, 131.11, 129.68, 126.59, 123.16, 116.60, 111.84, 83.70,
53.15, 28.73.
MS (EI+, 70 eV): m/z (%) = 362.0 (4, [M, 81Br]+ = [C17H14BrNO3]+), 360.8
(4, [M, 79Br]+ = [C17H14BrNO3]+), 287.9 (29), 185.9 (29), 261 (39), 260.0
(35), 259.0 (42), 258.9 (43), 219.2 (10), 209.2 (23), 207.1 (27), 198.1
(11), 196.1 (12), 193.2 (14), 180.1 (52), 178.1 (27), 173.0 (58), 171.0
(58), 157.1 (31), 155.0 (30), 153.2 (15), 152.0 (30), 151.1 (16), 147.1
(100), 145.0 (30), 118.1 (57), 104.1 (20), 91.2 (32).
Yield: 49 mg (81%); colorless solid; mp 168–169 °C; Rf = 0.46 (P/Et2O
4:6); [α]D20 +150.3 (c 0.40, CHCl3, 99% ee).
HPLC: OD, n-heptane/i-PrOH (9:1), 1.0 mL/min, λ = 254.16 nm; major
diastereomer: tR = 20.7 min (minor), tR = 17.4 min (major); minor dia-
stereomer: tR = 10.4 min (minor), tR = 14.8 min (major); 95:5 dr, 99%
ee.
IR (ATR): 3390, 3069, 2925, 2851, 2159, 2077, 2044, 1981, 2894, 1718,
1611, 1535, 1461, 1417, 1323, 1263, 1215, 1157, 1093, 1061, 911,
854, 820, 767, 729, 695 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.13 (dd, J = 7.8, 1.0 Hz, 1 H, CHar), 7.60
(td, J = 7.6, 1.3 Hz, 1 H, CHar), 7.51 (td, J = 7.7, 1.1 Hz, 1 H, CHar), 7.45 [d,
J = 8.6 Hz, 2 H, CHar (aniline)], 7.34 (d, J = 7.6 Hz, 1 H, CHar), 6.79 [d, J =
8.6 Hz, 2 H, CHar (aniline)], 5.26 (dd, J = 10.2, 3.3 Hz, 1 H, NHCH), 5.02
(d, J = 3.3 Hz, 1 H, CH), 4.48 (d, J = 10.1 Hz, 1 H, NH), 2.39 (s, 3 H, CH3).
MS (CI+, methane): m/z (%) = 362.0 (17, [M, 81Br]+ = [C17H14BrNO3]+),
360.0 (18, [M, 79Br]+ = [C17H14BrNO3]+), 267.1 (9), 207.1 (22), 190.1
(12), 189.0 (100), 174.0 (64), 173.0 (16), 172.0 (64), 171.0 (13), 147.1
(9), 121.1 (16), 93.1 (26), 79.1 (17), 75.2 (44).
HRMS (ESI+): m/z [M + Na]+ calcd for [C17H14BrNO3Na]+: 382.0049;
found: 382.0047.
13C NMR (151 MHz, CDCl3): δ = 206.32, 163.43, 148.53, 139.16,
135.39, 131.11, 129.80, 127.09 (q, JC,F = 3.7 Hz), 126.57, 123.25, 121.38
(q, JC,F = 32.8 Hz), 113.65, 83.48, 52.02, 28.71.
MS (EI+, 70 eV): m/z (%) = 349.1 (8, [M]+ = [C18H14F3NO3]+), 277.1 (19),
276.1 (100), 250.1 (13), 249.1 (84), 248.1 (85), 208.1 (11), 180.1 (9),
145.0 (25), 118.1 (10), 89.1 (12), 69.2 (11), 48.4 (28).
HRMS (ESI+): m/z [M + Na]+ calcd for [C17H14FNO3Na]+: 322.0850;
found: 322.0846.
(3R,4S)-3-Acetyl-6-bromo-4-[(4-methoxyphenyl)amino]isochro-
man-1-one (3g)
Yield: 54 mg (69%); yellow solid; the two diastereomers were sepa-
rated by preparative TLC with hexane/i-PrOH (8:2); mp 151–152 °C;
Rf = 0.6 (P/Et2O, 1:2); [α]D20 +90.2 (c 0.25, CHCl3, 99% ee).
(3R,4S)-3-Acetyl-4-(p-tolylamino)isochroman-1-one (3e)
Yield: 43 mg (72%); pale yellow solid; mp 139–140 °C; Rf = 0.51
(P/Et2O, 4:6); [α]D20 +156.6 (c 0.35, CHCl3, 99% ee).
HPLC: IC, n-heptane/EtOH (9:1), 1.0 mL/min, λ = 254.4 nm; major dia-
stereomer: tR = 13.0 min (minor) tR = 11.4 min (major); minor diaste-
reomer: tR = 24.2 min (minor), tR = 15.8 min (major); 79:21 dr, 99% ee.
HPLC: IA, n-heptane/i-PrOH (9:1), 0.7 mL/min, λ = 230.4 nm, tR = 17.2
min (minor), tR = 18.7 min (major); 99:1 dr, 99% ee.
IR (ATR): 3352, 2925, 2302, 2084, 1881, 1717, 1614, 1514, 1359, 1260,
IR (ATR): 3344, 3003, 2932, 2835, 2254, 2068, 1724, 1590, 1509, 1465,
1096, 804, 696 cm–1
.
1409, 1360, 1233, 1095, 1035, 907, 826, 782, 727, 690 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.14 (dd, J = 7.8, 1.3 Hz, 1 H, CHarom),
7.55 (td, J = 7.5, 1.4 Hz, 1 H, CHarom), 7.48 (td, J = 7.6, 1.2 Hz, 1 H,
CHarom), 7.30–7.27 (m, 1 H, CHarom), 7.01 [d, J = 8.0 Hz, 2 H, CHarom (an-
iline)], 6.63 [d, J = 8.4 Hz, 2 H, CHarom (aniline)], 5.12–5.08 (m, 1 H,
CHNH), 5.00 (d, J = 3.3 Hz, 1 H, CH), 3.77 (d, J = 8.0 Hz, 1 H, NH), 2.40
(s, 3 H, CH3), 2.25 (s, 3 H, ArCH3).
13C NMR (151 MHz, CDCl3): δ = 206.36, 163.74, 143.40, 139.86,
135.06, 130.98, 130.16, 129.50, 129.42, 126.65, 123.12, 115.43, 84.02,
53.71, 28.74, 20.61.
1H NMR (600 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 0.3 H, CHar, minor),
7.99 (d, J = 8.3 Hz, 1 H, CHar, major), 7.65 (dd, J = 8.4, 1.9 Hz, 0.4 H,
CHar, minor), 7.62 (dd, J = 8.4, 1.9 Hz, 1 H, CHar, major and 0.22 H, CHar,
minor), 7.41 (d, J = 1.9 Hz, 1 H, CHar, major), 6.87–6.83 (m, 0.6 H, CHar,
minor), 6.82–6.77 (m, 2 H, CHar, major), 6.76–6.72 (m, 1 H, CHar, mi-
nor), 6.70–6.63 (m, 2 H, CHar, major), 5.18 (d, J = 2.7 Hz, 0.5 H, CH, mi-
nor), 4.96 (m, 2 H 2 × CH, major and 0.5 H, CH, minor), 3.78 (d, J = 3.5
Hz, 1.5 H, OCH3, minor), 3.77 (d, J = 3.5 Hz, 3 H, OCH3, major), 3.70–
3.61 (m, 1.4 H, 2 × NH), 2.39 (s, 3 H, CH3, major), 2.22 (s, 1.3 H, CH3,
minor).
13C NMR (151 MHz, CDCl3): δ = 205.87, 204.27, 162.89, 162.15,
154.09, 141.32, 138.96, 133.19, 132.68, 132.37, 131.81, 131.61,
130.05, 129.47, 121.82, 117.19, 116.39, 116.14, 115.26, 115.03,
114.19, 83.51, 83.29, 65.83, 55.63, 54.40, 53.39, 51.62, 34.11, 28.60.
MS (EI+, 70 eV): m/z (%) = 295.0 (12, [M]+ = [C18H17NO3]+), 223.1 (18),
222.1 (93), 196.1 (15), 195.1 (100), 194.1 (69), 118.1 (12), 107.2 (23),
106.1 (20), 91.2 (24), 89.2 (13), 77.2 (12), 65.3 (10).
MS (CI+, methane): m/z (%) = 297.2 (8), 296.2 (46, [M + H]+ = [C18H18
-
NO3]+), 295.1 (8, [M]+ = [C18H17NO3]+), 189.0 (84), 149.1 (22), 108.2
(100), 107.3 (14).
MS (EI+, 70 eV): m/z (%) = 391.0 (15, [M, 81Br]+ = [C18H16BrNO4]+), 389.0
(15, [M, 79Br]+ = [C18H16BrNO4]+), 335.0 (15), 334.0 (96), 333.0 (20),
332.0 (100), 318 (16), 316 (16), 255.1 (10), 247.0 (11), 246.0 (11),
245.0 (9), 244.0 (10), 210.0 (19), 207.9 (19), 166.0 (10).
HRMS (ESI+): m/z [M + H]+ calcd for [C18H18NO3]+: 296.1281; found:
296.1279.
(3R,4S)-3-Acetyl-4-[(4-bromophenyl)amino]isochroman-1-one
(3f)
MS (CI+, methane): m/z (%) = 392.2 (5), 391.3 (5, [M, 81Br]+ = [C18H16Br-
NO4]+), 390.1 (6), 389.1 (6, [M, 79Br]+ = [C18H16BrNO4]+), 269.0 (29),
268.1 (13), 267.0 (19), 266.0 (6), 125.2 (7), 124.2 (89), 123.1 (100),
109.2 (10), 108.1 (44), 80.2 (6).
HRMS (ESI+): m/z [M + H]+ calcd for [C18H17BrNO4]+: 390.0341; found:
390.0340.
Yield: 43 mg (84%); colorless solid; mp 175–176 °C; Rf = 0.66 (P/Et2O,
4:6); [α]D20 +164.1 (c 0.50, CHCl3, 92% ee).
HPLC: AD, n-heptane/EtOH (7:3), 1.0 mL/min, λ = 230.16 nm; major
diastereomer: tR = 11.7 min (minor), tR = 9.3 min (major); minor dia-
stereomer: tR = 8.5 min (minor), tR = 5.1 min (major); 97:3 dr, 92% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
F. Vetica et al.
Paper
Synthesis
(3R,4S)-3-Acetyl-4-[(4-chlorophenyl)amino]-7,8-dimethoxyiso-
chroman-1-one (3h)
MS (CI+, methane): m/z (%) = 354.1 (2, [M, 2 × 37Cl]+ = [C17H13Cl2NO3]+),
353.1 (3), 352.0 (15, [M, 37Cl and 35Cl]+ = [C17H13Cl2NO3]+), 351.1 (6),
350.0 (23, [M, 2 × 35Cl]+ = [C17H13Cl2NO3]+), 241.0 (16), 225.0 (35),
224.0 (17), 223.0 (100), 222.0 (13), 168.9 (19), 166.9 (57), 130.0 (14),
129.0 (14), 128.0 (46), 127.0 (40), 85.0 (35), 83.0 (53).
HRMS (ESI+): m/z [M + Na]+ calcd for [C17H13Cl2NO3Na]+: 372.0165;
found: 372.0164.
Yield: 62 mg (83%); pale yellow solid; mp 107–108 °C; Rf = 0.64
(P/EtOAc, 4:6); [α]D20 +165.3 (c 0.50, CHCl3, 98% ee).
HPLC: IC, n-heptane/EtOH (9:1), 1.0 mL/min, λ = 230.4 nm; major dia-
stereomer: tR = 14.8 min (minor) tR = 15.9 min (major); minor diaste-
reomer: tR = 37.7 min (minor), tR = 31.2 min (major); 94:6 dr, 98% ee.
IR (ATR): 3358, 2940, 2844, 2325, 2099, 1925, 1726, 1582, 1489, 1417,
1363, 1269, 1198, 1133, 1051, 956, 901, 821, 736, 675 cm–1
.
Acknowledgment
1H NMR (600 MHz, CDCl3): δ = 7.13 (dd, J = 12.3, 8.2 Hz, 2 H, CHar),
7.07 (dd, J = 16.0, 8.6 Hz, 2 H, CHar), 6.98 (d, J = 8.4 Hz, 1 H, CHar), 6.67
(dd, J = 13.4, 8.8 Hz, 2 H, CHar), 6.60 (d, J = 8.7 Hz, 1 H, CHar), 5.05 (d, J =
2.06 Hz, 0.21 H, NHCH, minor), 5.01–4.96 (m, 1 H, NHCH, major),
4.88–4.85 (m, 1.13 H, CH, major and minor), 4.14 (d, J = 9.5 Hz, 1.25 H,
NH, major and minor), 3.96 (d, J = 4.8 Hz, 3.82 H, OCH3, major and mi-
nor), 3.89 (s, 0,67 H, OCH3, minor), 3.86 (s, 3 H, OCH3, major), 2.36 (s,
3 H, CH3, major), 2.19 (s, 0.72 H, CH3, minor).
Support from the European Research Council (ERC Advanced Grant
320493 ‘DOMINOCAT’) is gratefully acknowledged.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562522.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C NMR (151 MHz, CDCl3): δ = 206.80, 205.38, 160.25, 159.80,
154.22, 151.79, 144.63, 132.00, 129.68, 129.47, 129.22, 124.33,
124.08, 121.88, 118.01, 117.94, 117.35, 116.34, 116.07, 115.00, 83.27,
82.97, 61.76, 61.72, 56.35, 56.32, 53.50, 51.37, 28.76, 27.21.
References
MS (EI+, 70 eV): m/z (%) = 377.5 (16, [M, 37Cl]+ = [C19H18ClNO5]+), 376.5
(25), 375.5 (35, [M, 35Cl]+ = [C19H18ClNO5]+), 320.5 (29), 319.5 (15),
318.5 (100), 304.5 (25), 303.5 (14), 302.5 (71), 258.4 (12), 207.5 (33),
192.4 (10), 150.7 (12), 149.3 (13), 127.3 (13), 111.2 (17).
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MS (CI+, methane): m/z (%) = 404.5 (11, [M + C2H5, 35Cl]+ = [C21H23ClNO5]+),
378.5 (36, [M + H, 37Cl]+ = [C19H19ClNO5]+), 377.5 (26, [M, 37Cl]+
=
[C19H18ClNO5]+), 376.5 (100, [M + H, 35Cl]+ = [C19H19ClNO5]+), 375.5 (24,
[M, 35Cl]+ = [C19H18ClNO5]+), 304.4 (15), 302.4 (47).
HRMS (ESI+): m/z [M + H]+ calcd for [C19H19ClNO5]+: 376.0946; found:
376.0954.
(3R,4S)-3-Acetyl-6-chloro-4-[(4-chlorophenyl)amino]isochroman-
1-one (3i)
Yield: 53 mg (75%); colorless solid; mp 168–169 °C; Rf = 0.6 (P/Et2O,
4:6); [α]D20 +160.4 (c 0.50, CHCl3, 99% ee).
(6) For selected reviews on asymmetric organocatalysis, see:
(a) Vetica, F.; de Figueiredo, R. M.; Orsini, M.; Tofani, D.; Gasperi,
T. Synthesis 2015, 47, 2139. (b) Comprehensive Enantioselective
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HPLC: IA, n-heptane/EtOH (7:3), 0.7 mL/min, λ = 254.4 nm, tR = 19.8
min (minor), tR = 13.4 min (major); 98:2 dr, 99% ee.
IR (ATR): 3366, 3080, 2962, 2852, 2261, 2086, 1993, 1887, 1729, 1597,
1488, 1414, 1362, 1241, 1188, 1087, 1013, 970, 823, 782, 728, 682
cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.11 (d, J = 2.1 Hz, 1 H, CHar), 7.53 (dd,
J = 8.2, 2.2 Hz, 1 H, CHar), 7.24 (d, J = 8.2 Hz, 1 H, CHar), 7.18–7.14 [m, 2
H, CHar (aniline)], 6.68–6.64 [m, 2 H, CHar (aniline)], 5.08 (s, 1 H,
NHCH), 4.98 (d, J = 3.3 Hz, 1 H, CH), 3.96 (s, 1 H, NH), 2.39 (s, 3 H, CH3).
13C NMR (151 MHz, CDCl3): δ = 205.89, 162.38, 144.17, 137.72,
135.87, 135.26, 130.87, 129.66, 128.09, 125.09, 124.64, 116.34, 83.61,
52.92, 28.72.
MS (EI+, 70 eV): m/z (%) = 354.1 (1, [M, 2 × 37Cl]+ = [C17H13Cl2NO3]+),
353.1 (7) 352.1 (9, [M, 37Cl and 35Cl]+ = [C17H13Cl2NO3]+), 351.0 (38),
350.1 (15, [M, 2 × 35Cl]+ = [C17H13Cl2NO3]+), 349.0 (57), 294.0 (15),
292.0 (24), 280.0 (11), 279.0 (11), 278.0 (62), 277.0 (18), 275.9 (100),
51.0 (27), 250.0 (22), 249.0 (42), 248.0 (28), 181.0 (10), 127.0 (19),
111.0 (11).
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(19) CCDC-1482605 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
the
Cambridge
Crystallographic
Data
Centre
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H