Chiral Bis(imidazolidine)iodobenzene (I-Bidine) Organocatalyst for Thiochromane Synthesis Using an Asymmetric Michael/Henry Reaction

Article abstract of DOI:10.1055/s-0036-1588614

Bis(imidazolidine)iodobenzene (I-Bidine) was designed as an organocatalyst based on previously reported imidazolidine- or oxazolidine-containing chiral metal catalysts. I-Bidine showed catalytic activity for the Michael/Henry reaction of thiosalicyl aldeh

Full text of DOI:10.1055/s-0036-1588614

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
T. Arai et al.
Letter
Synlett
Chiral Bis(imidazolidine)iodobenzene (I-Bidine) Organocatalyst
for Thiochromane Synthesis Using an Asymmetric Michael/Henry
Reaction
Takayoshi Arai*
Takumi Suzuki
Takahiro Inoue
Satoru Kuwano
Ph
Ph
NH
I
HN
Ph
Ph
N
N
Molecular Chirality Research Center, and Department of
Chemistry, Graduate School of Science, Chiba University,
1-33 Yayoi, Inage, Chiba 263-8522, Japan
tarai@faculty.chiba-u.jp
OH
I-Bidine-9-anthracenyl
(10 mol%)
CHO
SH
NO2
Ar
NO2
+
Ar
toluene, –40 °C
S
anti major
1 equiv
1.5 equiv
slow addition over 15 h
99% yield
65% ee
up to
Received: 27.07.2016
Accepted after revision: 11.09.2016
Published online: 05.10.2016
selective reactions, the metal center must cooperate with
the hydrogen bonding from the NH of the imidazolidine (or
oxazolidine), as suggested by structural analysis of the cata-
lyst, experimental studies on the reaction mechanism, and
density functional theory (DFT) studies.5–7 Based on these
results, a new bis(imidazolidine)-containing organocatalyst
was designed (Figure 1). For this catalyst, the metal center
of PyBidine-metal and the NCN pincer complex was re-
placed by iodine because of the potential use of the halogen
bonding facilitated by the Lewis acidity of the iodine.8,9
DOI: 10.1055/s-0036-1588614; Art ID: st-2016-u0488-l
Abstract Bis(imidazolidine)iodobenzene (I-Bidine) was designed as an
organocatalyst based on previously reported imidazolidine- or oxazoli-
dine-containing chiral metal catalysts. I-Bidine showed catalytic activity
for the Michael/Henry reaction of thiosalicyl aldehydes with ni-
troalkenes to give optically active thiochromanes with moderate enan-
tiomeric excesses.
Key words organocatalyst, thiochromane, tandem reaction, asym-
metric synthesis
Ph
Ph
H
N
X
H
N
Ph
Ph
H
N
X
Mtl
N
H
N
Mtl
Ph
Ph
The chemistry of asymmetric organocatalysis has devel-
oped rapidly to become a fundamentally important process
for providing optically active compounds.1 The successful
development of organocatalysis depends on optimizing cat-
alyst–substrate interactions, especially the hydrogen bond-
ing network and steric effects. This report describes a new
approach to designing imidazolidine-containing iodoben-
zene organocatalyst based on the parent chiral imidazoli-
dine-metal catalyst.
N
N
Ph
Ph
Y
Y
Bn
Bn
tBu
PyBidine: Y = NBn
PyBodine: Y = O
Imidazolidine-NCN-Pd Pincer
Imidazolidine-NCN-Rh Pincer
H...Hydrogen-bonding donor
Mtl...Lewis acid
Ph
Ph
H
H
For the development of novel asymmetric catalysts, a
series of imidazolidine- and oxazolidine-containing chiral
ligands have been developed, such as bis(imidazoli-
dine)pyridine (PyBidine)2 and bis(oxazolidine)pyridine (Py-
Bodine),3 which enabled various metal-catalyzed asymmet-
ric reactions. Bis(imidazolidine)-containing NCN-pincer Pd
and Rh complexes also have been developed.4 These imid-
azolidine- and oxazolidine-containing catalysts possess
unique catalytic activities that cannot be explained by the
activity of the simple metal center. To provide highly stereo-
N
I
N
Ph
Ph
N
N
R
R
I-Bidine = Bis(imidazolidine)Iodobenzene
Potential:
H...Hydrogen-bonding donor
I...Soft Lewis acid
R...Steric effect
Figure 1 Design of bis(imidazolidine) iodobenzene (I-Bidine) from im-
idazolidine (or oxazolidine)-containing chiral metal catalysts
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
T. Arai et al.
Letter
Synlett
The synthesis of bis(imidazolidine) iodobenzene (I-
Bidine) is shown in Scheme 1.10 After iodination of phthalo-
nitrile, the nitrile was reduced by DIBAL-H to give the alde-
hyde. Condensation with monobenzyl diphenylethylenedi-
amine using acetic acid in dichloromethane gave I-Bidine
(1a). I-Bidine analogues 1b–f were prepared by following
the same procedure.11
ond and fourth quadrants, although the imidazolidine rings
do not appear to have any direct interaction with iodine.
I
NC
CN
LDA (1.1 equiv)
THF, –78 °C, 1 h
NC
CN
I2 (1.1 equiv)
THF, –78 °C, 1 h
then rt, 20 h
58%
Ph
Ph
NH
R
NH2
(2.2 equiv)
O
I
O
Figure 3 X-ray crystal structure of 1a
DIBAL-H (2.2 equiv)
CH2Cl2, –78 °C, 2 h
AcOH (2.2 equiv)
H
H
CH2Cl2, rt, 15 h
Considering the soft Lewis acidity of iodine in I-Bidine,
the synthesis of thiochromane using nitroalkene (2) and
thiosalicyl aldehyde (3) was selected as a target reaction.13
Using 10 mol% I-Bidine (1a), the reaction of nitrostyrene
(2a) with thiosalicyl aldehyde (3) gave syn-nitroaldol (syn-
4a) with 13% ee and racemic anti-nitroaldol (anti-4a) in
toluene at –40 °C (Table 1, entry 1). Addition of a thiosalicyl
aldehyde using a syringe pump improved the enantiomeric
excess of syn-4a to 40% ee, although racemic anti-4a was
also obtained (entry 2). The different enantiomeric excess
values for syn- and anti-4a suggest that I-Bidine catalyst
also affects asymmetric induction in the Henry reaction,
not only the first step of the Michael reaction.
The use of catalyst 5 without iodine and bis(imidazo-
line)iodobenzene 6 resulted in lower enantiomeric excesses
for syn-4a (Table 1, entries 3 and 4), though some asym-
metric inductions were observed on anti-4a using 5 and 6.
Using a syringe pump technique, catalyst screening was
conducted in order to evaluate the steric effects of N-alkyl
substituents in I-Bidines (Table 2).
81%
Ph
Ph
Ph
R
R = phenyl (1a), y. 87%
NH
I
HN
R = cyclohexyl (1b), y. <85%
R = mesityl (1c), y. <99%
R = 1-naphthyl (1d), y. <94%
R = 2,4,6-triisopropylphenyl (1e), y. <52%
R = 9-anthracenyl (1f), y. 53%
Ph
N
N
R
I-Bidine
Scheme 1 Synthesis of bis(imidazolidine) iodobenzene (I-Bidine)
Highly stereoselective imidazolidine ring formation was
confirmed from the 1H NMR spectrum of 1a (Figure 2). The
1H NMR data for the analogues are provided in the Support-
ing Information.
In all cases, anti-4a was the major isomer formed. The
sterically hindered I-Bidines (1b–f) underwent asymmetric
induction to form the major isomer anti-4a. For both dia-
stereomers and catalytic activity, I-Bidine 1f was selected to
examine the generality of the thiochromane synthesis
(Scheme 2).
Because the obtained thiochromanes epimerized par-
tially during silica gel column chromatography, the yields
1
and dr determined by H NMR analysis of the crude prod-
ucts are provided with the isolated values after the silica gel
column chromatography. Various nitrostyrenes with elec-
tron-donating and -withdrawing substituents were suc-
cessfully employed for the I-Bidine (1f)-catalyzed Mi-
chael/Henry reaction with thiosalicyl aldehyde to give chi-
Figure 2 1H NMR spectrum of I-Bidine (1a)
X-ray crystallographic analysis of 1a revealed an all-
trans configuration of the imidazolidine ring (Figure 3).12 In
the structure of 1a, derived from (R,R)-diphenylethylenedi-
amine, the NH protons of imidazolidine appear in the sec-
ral thiochromanes with moderate enantiomeric excess.14
A
thiophenyl nitroalkene also was transformed to thiochro-
mane 4f. For the p-methoxy nitrostyrene, syn-4h with 63%
ee was obtained along with anti-4h with 65% ee. The abso-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
T. Arai et al.
Letter
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Table 1 Reaction Optimization of I-Bidine (1a)-Catalyzed Michael/Henry Reaction of Nitroalkene (2) and Thiosalicyl Aldehyde (3)
OH
OH
CHO
SH
NO2
Ph
NO2
Ph
catalyst (10 mol%)
+
+
NO2
Ph
toluene, –40 °C, time
S
S
2a
3
syn-4a
anti-4a
Ph
Ph
Ph
Ph
NH
H
HN
N
I
N
Ph
Ph
Ph
Ph
N
N
N
N
Ph
Ph
Ph
Ph
5
6
Entry
Catalyst
Time (h)
Yielda (%)
syn/antia
ee of syn (%)
ee of anti (%)
1b
2
1a
1a
5
0.5
15c
15c
15c
99
99
93
94
52:48
48:52
23:77
23:77
13
40
14
9
rac
rac
–15
27
3
4
6
a Yields and diastereomeric ratios (dr) were determined by the 1H NMR analysis of the crude product.
b Compound 3 was added in one portion.
c Compound 3 was added using a syringe pump over 15 h.
Table 2 Catalyst Screening for the Catalytic Asymmetric Synthesis of Thiochromanea
OH
OH
CHO
1 (10 mol%)
NO2
Ph
NO2
Ph
NO2
+
Ph
toluene, –40 °C, 15 h
SH
S
S
2a
1 equiv
3
syn-4a
anti-4a
1.5 equiv
slow addition over 15 h
Entry
Catalyst
Yieldb (%)
syn/antib
ee of syn (%)
ee of anti (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
99
68
84
75
99
99
48:52
40:60
32:68
31:69
39:61
44:56
40
21
64
33
67
69
rac
16
59
8
63
53
a Compound 3 was added using a syringe pump over 15 h.
b Yields and dr were determined by the 1H NMR analysis of the crude product.
lute structure of thiochromane 4d was determined by com-
parison of the HPLC retention time with that reported pre-
viously.13e,m Using (R,R)-diphenylethylenediamine-derived
1f, (2R,3S,4R)-4d was obtained as the major anti-isomer
and (2R,3S,4S)-4d was obtained as the syn-isomer.
In conclusion, bis(imidazolidine)iodobenzene (I-Bidine)
was developed as an organocatalyst based on imidazoli-
dine- or oxazolidine-containing chiral metal catalysts. The
I-Bidine possessed catalytic activity for the Michael/Henry
reaction of thiosalicyl aldehydes with nitroalkenes to give
optically active thiochromanes. The development of more
efficient organocatalysts based on cooperative function is
ongoing.
Acknowledgment
This research was supported by JSPS KAKENHI Grant Number
26105706 in Advanced Molecular Transformations by Organocata-
lysts, and by the Workshop on Chirality at Chiba University (WCCU).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
T. Arai et al.
Letter
Synlett
OH
OH
I-Bidine (1f)
(10 mol%)
CHO
SH
NO2
Ar
NO2
Ar
NO2 +
Ar
toluene, –40 °C, 15 h
S
S
2
syn-4
anti-4
3
1 equiv
1.5 equiv
slow addition over 15 h
OH
OH
S
OH
S
NO2
NO2
NO2
Cl
S
Cl
Br
4b: 99 (99)% yield
4c: 99 (99)% yield
4d: 99 (99)% yield
syn/anti = 23:77 (25:75)
syn/anti = 30:70 (31:69)
syn/anti = 13:87 (28:72)
syn 53% ee, anti 39% ee
syn 54% ee, anti 31% ee
syn 55% ee, anti 52% ee
OH
OH
OH
NO2
NO2
NO2
Br
S
S
S
S
F
4g: 99 (99)% yield
syn/anti = 45:55 (42:58)
syn 69% ee, anti 52% ee
4e: 97 (96)% yield
syn/anti = 33:67 (31:69)
syn 49% ee, anti 44% ee
4f: 99 (99)% yield
syn/anti = 35:65 (29:71)
syn 33% ee, anti 19% ee
OH
OH
OH
NO2
NO2
NO2
OMe
S
S
S
OMe
4h: 99 (99)% yield
4i: 99 (99)% yield
4j: 99 (99)% yield
syn/anti = 41:59 (40:60)
syn/anti = 40:60 (40:60)
syn/anti = 43:57 (44:56)
syn 63% ee, anti 65% ee
syn 34% ee, anti 19% ee
syn 50% ee, anti 30% ee
Scheme 2 Catalytic asymmetric synthesis of thiochromane.a a) Yields and dr were determined by 1H NMR analysis of the crude product. Values in
parentheses represent yields and dr after silica gel column chromatography.
Supporting Information
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M. Angew. Chem. Int. Ed. 2015, 54, 1595.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588614.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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(14) General Procedure for Asymmetric Michael/Henry Reaction:
To a two-necked round-bottomed flask were added I-Bidine
(0.015 mmol), nitrostyrene (0.15 mmol), and anhyd toluene (1
mL) under argon, and the mixture was cooled to –40 °C. Slow
addition of 2-mercaptobenzaldehyde (0.225 mmol, ca. 75%
purity) in anhyd toluene (5 mL) using syringe pump was con-
ducted for 15 h. Then the completion of the reaction was
checked by TLC and the solvent was removed under reduced
pressure. Yield and diastereomeric ratio of the product were
1
determined by crude H NMR. The crude mixture was purified
by silica gel column chromatography to afford the 2-aryl-3-
nitrothiochroman-4-ol. The enantiomeric excesses of the
product were determined by chiral stationary phase HPLC using
a Daicel Chiralpak AD-H, AS-H, and Chiralcel OD-H column.
(2R,3S,4R)-3-Nitro-2-phenylthiochroman-4-ol (anti-4a): 1H
NMR (400 MHz, acetone-d6): δ = 7.72–7.74 (m, 1 H), 7.53 (dd, J =
1.6, 8.5 Hz, 2 H), 7.36–7.43 (m, 3 H), 7.22–7.29 (m, 2 H), 7.11–
7.14 (m, 1 H), 5.69 (d, J = 8.3 Hz, 1 H), 5.36–5.45 (m, 2 H), 5.15
(d, J = 10.8 Hz, 1 H). 13C NMR (125 MHz, acetone-d6): δ = 136.4,
135.9, 132.5, 130.0, 129.8, 129.3, 129.1, 128.6, 126.0, 125.4,
94.1, 72.3, 47.4. HRMS: m/z [M + NH4]+ calcd for C15H17N2O3S:
(10) Braddock, D. C.; Cailleau, T.; Cansell, G.; Hermitage, S. A.;
Pouwer, R. H.; Redmond, J. M.; White, A. J. P. Tetrahedron: Asym-
metry 2010, 21, 2911.
(11) Synthesis of I-Bidines (1); General Procedure: To a stirred
solution of 2-iodoisophthalaldehyde (1 equiv) in CH2Cl2 (0.067
M) were added monoarylmethyl-(1R,2R)-1,2-diphenylethane-
1,2-diamine (2.2 equiv), and AcOH (2.2 equiv) at rt. After being
stirred for appropriate time, the reaction mixture was
quenched by H2O, and extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography to afford the
product.
305.0954; found: 305.0954. IR (neat): 3380, 3062, 3024, 1587,
26 5
1555, 1037, 753, 741, 702 cm–1. [α]D
. +7.0 (c = 0.05, MeOH,
53% ee); enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column [hexane–2-propanol (85:15), flow rate:
0.7 mL/min, λ = 254 nm]; tR (minor enantiomer) = 16.4 min, tR
(major enantiomer) = 17.7 min; 53% ee.
I-Bidine (1a): 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.2 Hz,
2 H), 7.21–7.43 (m, 21 H), 7.00–7.08 (m, 6 H), 6.94 (d, J = 7.4 Hz,
4 H), 5.31 (s, 2 H), 4.29 (d, J = 7.9 Hz, 2 H), 3.77 (d, J = 8.1 Hz, 2
H), 3.70 (d, J = 13.7 Hz, 2 H), 3.62 (d, J = 13.9 Hz, 2 H), 2.27 (br s,
(2R,3S,4S)-3-Nitro-2-phenylthiochroman-4-ol (syn-4a): 1H
NMR (400 MHz, acetone-d6): δ = 7.59–7.62 (m, 2 H), 7.49 (dd, J =
1.6, 7.6 Hz, 1 H), 7.33–7.43 (m, 3 H), 7.30 (dt, J = 1.5, 7.6 Hz, 1 H),
7.20 (dt, J = 1.4, 7.5 Hz, 1 H), 7.15 (dd, J = 1.4, 7.9 Hz, 1 H), 5.71
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
T. Arai et al.
Letter
Synlett
25 9
(dd, J = 2.9, 11.7 Hz, 1 H), 5.48 (d, J = 5.8 Hz, 1 H), 5.41 (dd, J =
2.9, 5.6 Hz, 1 H), 5.28 (d, J = 11.7 Hz, 1 H). 13C NMR (100 MHz,
acetone-d6): δ = 137.7, 134.5, 133.5, 132.0, 129.9, 129.6, 129.22,
129.19, 125.7, 125.4, 90.1, 70.6, 41.4. HRMS: m/z [M + NH4]+
calcd for C15H17N2O3S: 305.0954; found: 305.0957. IR (neat):
3389, 3061, 2925, 2853, 1702, 1644, 1586, 1555, 1520, 1439,
1316, 1036, 762 cm–1. [α]D
.
+78.9 (c = 0.05, MeOH, 69% ee);
enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column [hexane:2-propanol (85:15), flow rate: 0.7
mL/min, λ = 254 nm]; tR (minor enantiomer) = 21.4 min; tR
(major enantiomer) = 14.2 min; 69% ee.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F