Asymmetric henry reactions of aldehydes using chiral biaryl-based bis(thiourea) organocatalysts

Article abstract of DOI:10.1055/s-0032-1318490

Biaryl-based bis(thiourea) was found to be an efficient organocatalyst for the asymmetric Henry reaction. High enantioselectivity of up to 93% ee was obtained for the reaction of nitromethane with aryl aldehydes when the combination of N,O-bis(trimethylsi

Full text of DOI:10.1055/s-0032-1318490

LETTER
▌883
lAettserymmetric Henry Reactions of Aldehydes Using Chiral Biaryl-Based
Bis(thiourea) Organocatalysts
Asymmetric Henry Reaction
Yuki Nakayama,1 Yusaku Hidaka, Katsuji Ito*
Department of Chemistry, Fukuoka University of Education, Akama, Munakata, Fukuoka 811-4192, Japan
Fax +81(940)351711; E-mail: itokat@fukuoka-edu.ac.jp
Received: 23.01.2013; Accepted after revision: 28.02.2013
tivity of 54% ee was obtained.5 Ooi and Maruoka et al. re-
ported that a Henry reaction of aldehydes with silyl
nitronates that used chiral quaternary ammonium bifluo-
rides was highly enantioselective.6 Significant progress in
Abstract: Biaryl-based bis(thiourea) was found to be an efficient
organocatalyst for the asymmetric Henry reaction. High enantiose-
lectivity of up to 93% ee was obtained for the reaction of nitrometh-
ane with aryl aldehydes when the combination of N,O-
bis(trimethylsilyl)trifluoroacetoamide (BSTFA) with a catalytic the development of the asymmetric direct Henry reaction
amount of potassium acetate was used as the base.
using organocatalyst was made with the introduction of
Nagasawa’s guanidine–thiourea bifunctional organocata-
lyst (up to 92% ee).7 Other organocatalysts, including cin-
chona alkaloid based aminothioureas,8 axially chiral
bisarylthioureas,9 axially chiral guanidines,10 tetraamino-
phosphonium salts,11 and polymeric cinchona alkaloids,12
have all exhibited good to high enantioselectivities in re-
actions of aldehydes with nitromethane or nitroethane.
Quite recently, Hong et al. developed [(bisurea-salen)Co]
complexes, which are combined metallic and organocata-
lysts, for the asymmetric Henry reaction. These catalysts
led to high enantioselectivities in reactions of both ali-
phatic and aromatic aldehydes.13
Key words: asymmetric catalysis, bis(thiourea), Henry reaction,
nucleophilic addition, enantioselectivity
The Henry (or nitroaldol) reaction is one of the most use-
ful carbon–carbon bond-forming reactions because the re-
action proceeds smoothly with high atom efficiency under
mild conditions to yield β-nitro alcohols, which are key
building blocks. In the field of organic synthesis, the
asymmetric version of the Henry reaction has therefore re-
ceived considerable interest.2 In 1992, Shibasaki et al. re-
ported the first example of a catalytic asymmetric Henry
reaction, which used a chiral La–BINOL catalyst.3 Subse-
quently, various chiral metal complexes have been exten-
sively evaluated as catalysts.4 In parallel with these
approaches, methods using organocatalysts have also
been developed. In 1994, Nájera et al. reported the first or-
ganocatalytic asymmetric Henry reaction using a chiral
guanidine catalyst; however, only moderate enantioselec-
To achieve high enantioselectivity in the Henry reaction,
the aldehyde and nitronate ion should both be captured in
an appropriate chiral environment on the catalyst. Previ-
ously, we reported that the newly designed biaryl-based
bis(thiourea) 1 is an effective organocatalyst for the asym-
metric Morita–Baylis–Hillman reaction.14 This reaction
Morita–Baylis–Hillman reaction
Ar
N+R3
R
S
N
RCHO
2-cyclohexen-1-one
R3N
OH
O
H
re-face attack
N
O
O-
S
R
H
H
N
H
H
S
N
R = aryl: 62–84% ee
R = alkyl: 84–96% ee
S
H
H
Ar
N
N
Ar
Ar
N
N
H
H
S
Ar
S
N
H
1: Ar = 3,5-(CF3)2C6H3
OH
O-
N
N+
re-face attack
RCHO
MeNO2
base
H
H
NO2
O
S
R
R
N
O–
H
H
S
N
this work: Henry reaction
Ar
Scheme 1
SYNLETT 2013, 24, 0883–0885
Advanced online publication: 11.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318490; Art ID: ST-2013-U0077-L
© Georg Thieme Verlag Stuttgart · New York

884
Y. Nakayama et al.
LETTER
was thought to proceed through a transition-state model as 52% ee; dichloromethane: 96 h, 26% yield, 68% ee). This
described in Scheme 1: two thiourea groups capture the may be partially due to the low solubility of bis(thiourea)
carbonyl group of aldehyde and enolate. Therefore, it was 1 in less polar solvent. Fortunately, we found that the
expected that the Henry reaction would also proceed effi- combination of N,O-bis(trimethylsilyl)acetoamide (BSA)
ciently through the capture of both the aldehyde and nitro- with a catalytic amount of potassium acetate, which is a
nate ion by the two thiourea groups. To examine this widely used base for palladium-catalyzed allylic substitu-
possibility, we examined the asymmetric Henry reaction tions,15 led to a greatly increased reaction rate without a
of aldehydes using bis(thiourea) 1.
decrease in enantioselectivity (Table 1, entry 7). The reac-
tion rate was further increased by using N,O-bis(trimeth-
ylsilyl)trifluoroacetoamide (BSTFA)16 (Table 1, entry 8),
which allowed the reaction to be carried out at low tem-
peratures. As expected, enantioselectivity was increased
with decreased reaction temperatures. A high enantiose-
lectivity of 89% ee was obtained when the reaction was
carried out at –40 °C (Table 1, entry 10).17,18
We first examined the reaction of 4-nitrobenzaldehyde
with nitromethane in tetrahydrofuran (THF) performed at
room temperature in the presence of a base (20 mol%) and
catalyst 1 (10 mol%, Table 1). Both the reaction rate and
enantioselectivity were largely dependent on the type of
base. The reaction proceeded smoothly with 1,4-diazabi-
cyclo[2.2.2]octane (DABCO) as the base; however, the
reaction yielded low enantioselectivity (Table 1, entry 1). Under the optimized reaction conditions, we next exam-
Other tertiary amines, including 1,8-diazabicyc- ined asymmetric Henry reactions of several other alde-
lo[5.4.0]undec-7-ene (DBU), i-Pr2NEt, and 4-(dimethyl- hydes (Table 2).19 A similarly high enantioselectivity of
amino)pyridine (DMAP), also resulted in low 92% ee was obtained for the reaction of 4-chlorobenzal-
enantioselectivities (Table 1, entries 2–4).
dehyde, although the reaction proceeded somewhat slow-
ly (Table 2, entry 1). The reactions of benzaldehyde and
aryl aldehydes bearing an electron-donating group also
exhibited high enantioselectivities (88–92% ee), but pro-
ceeded slowly and were not completed after 96 hours (Ta-
ble 2, entries 2–4). On the other hand, the reactions of 2-
naphthaldehyde and 4-biphenylcarboxaldehyde were
completed within 47 hours and yielded the corresponding
products with high enantioselectivities (Table 2, entries 5
and 6). In contrast, reactions of aliphatic aldehydes pro-
ceeded smoothly; however, their enantioselectivities were
moderate (Table 2, entries 7 and 8).
Table 1 Asymmetric Henry Reaction of 4-Nitrobenzaldehyde and
Nitromethane Using 1 as the Catalysta
OH
1 (10 mol%)
base (20 mol%)
CHO
+
NO2
MeNO2
r.t.
O2N
O2N
Entry Base
Solvent
Time (h) Yield (%) ee (%)b
1
2
DABCO
DBU
THF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
2
69
69
29
2
1
Table 2 Asymmetric Henry Reaction of Aldehydes and Nitrometh-
ane Using 1 as the Catalysta
3
i-Pr2NEt
DMAP
1
95
20
18
68
69
68
75
88
89
4
0.5
79
OH
1 (10 mol%)
+
MeNO2
RCHO
NO2
5
imidazole
imidazole
BSA
16
12
3.5
0.25
11
23
98
R
BSTFA (20 mol%)
KOAc (cat.)
–40 °C
6
100
91
92
7c
8c
9c,d
10c,e
Entry
R in RCHO
Time (h) Yield (%) ee (%)b
BSTFA
BSTFA
BSTFA
1
2
3
4
5
6
7
8
4-ClC6H4
Ph
96
96
96
96
47
47
19
96
70
50
51
47
76
70
99
85
92
92
88
91
93
91
58
64
82
91
4-MeC6H4
4-MeOC6H4
2-naphthyl
4-PhC6H4
c-Hex
a All reactions were carried out at r.t. with molar ratios of
aldehyde/nitromethane/1/base = 1:10:0.1:0.2, unless otherwise indi-
cated.
b Determined by HPLC analysis using chiral stationary phase column
(Daicel Chiralpak AD-H; hexane–i-PrOH = 70:30).
c Catalytic amount of KOAc was added.
d Reaction was performed at –20 °C.
e Reaction was performed at –40 °C.
PhCH2CH2
a All reactions were carried out at –40 °C with molar ratios of
aldehyde/nitromethane/1/BSTFA = 1:10:0.1:0.2, unless otherwise in-
dicated.
Enantioselectivity was improved to 68% ee when imidaz-
ole was used as a base, though the reaction rate was de-
creased (Table 1, entry 5). However, the reaction rate was
improved to some extent by the change of solvent to DMF
(Table 1, entry 6). The results of reactions in less polar
solvents were unsatisfactory (toluene: 96 h, 13% yield,
b Determined by HPLC analysis using chiral stationary-phase column
according to the literature.4b,g,j,9
Synlett 2013, 24, 883–885
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Henry Reaction
885
Shaw, S. Org. Lett. 2012, 14, 6270. (u) Angulo, B.; García,
I. J.; Herrerías, I. C.; Mayoral, A. J.; Miñana, C. A. J. Org.
Chem. 2012, 77, 5525.
The absolute configuration of each product was deter-
mined to be S.20 The observed stereochemistry was con-
sistent with the postulated transition-state model depicted
in Scheme 1, in which the re face of the aldehyde was
preferentially attacked by the nitronate ion.21
(5) Chinchilla, R.; Nájera, C.; Sánchez-Agulló, P. Tetrahedron:
Asymmetry 1994, 5, 1393.
(6) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 2054.
(7) (a) Sohtome, Y.; Hashimoto, Y.; Nawasaga, K. Adv. Synth.
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Hiemstra, H. Angew. Chem. Int. Ed. 2006, 45, 929.
(9) Liu, X.; Jiang, J.; Shi, M. Tetrahedron: Asymmetry 2007, 18,
2773.
In conclusion, we have demonstrated that biaryl-based
bis(thiourea) 1 is an efficient chiral organocatalyst for the
asymmetric Henry reaction. Further studies to expand the
substrate scope and elucidate the reaction mechanism are
under way in our laboratory.
Acknowledgment
(10) Ube, H.; Terada, M. Bioorg. Med. Chem. Lett. 2009, 19,
3895.
(11) Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007,
129, 12392.
(12) Tang, Z.; Iida, H.; Hu, H.-Y.; Yashima, E. ACS Macro Lett.
2012, 1, 261.
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1620.
We would like to thank Dr. Hiroshi Furuno, Institute for Materials
Chemistry and Engineering (IMCE), Kyushu University, for the
measurement of HRMS spectra and X-ray crystal structure analysis.
We would also like to thank Ms. Keiko Ideta, Ms. Yasuko Tanaka,
and Mr. Taisuke Matsumoto (Evaluation Center of Materials Pro-
perties and Function, IMCE, Kyushu University) for the measure-
ment of NMR and HRMS spectra and X-ray analysis. This work
was partially supported by JSPS KAKENHI Grant Number
24650532 and by the Cooperative Research Program of the ‘Net-
work Joint Research Center for Materials and Devices (IMCE,
Kyushu University)’.
(14) Nakayama, Y.; Gotanda, T.; Ito, K. Tetrahedron Lett. 2011,
52, 6234.
(15) (a) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.;
Pfaltz, A. Tetrahedron 1992, 48, 2143. (b) For a review, see:
Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(16) Use of the combination of BSTFA and KOAc as a base for
palladium-catalyzed asymmetric allylic substitution: Ito, K.;
Kashiwagi, R.; Hayashi, S.; Uchida, T.; Katsuki, T. Synlett
2001, 284.
(17) Typical Experimental Procedure is Exemplified by
Henry Reaction of 4-Nitrobenzaldehyde with
Nitromethane
References and Notes
(1) Present address: Institute for Materials Chemistry and
Engineering (IMCE), Kyushu University, Hakozaki,
Higashi-ku, Fukuoka 812-8581, Japan.
(2) For reviews on the catalytic asymmetric Henry reaction, see:
(a) Boura, J.; Gogoi, N.; Saikia, P. P.; Barua, C. N.
Tetrahedron: Asymmetry 2006, 17, 3315. (b) Palomo, C.;
Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561.
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Chem. Soc. 1992, 114, 4418.
Catalyst 1 (8.1 mg, 10.0 μmol) was placed in microtube
under nitrogen and to this tube was added BSTFA (5.5 μL,
20.0 μmol) in DMF (100 μL), a catalytic amount of KOAc
(0.4–0.5 mg, 4.1–5.1 μmol), and 4-nitrobenzaldehyde (16.1
mg, 0.1 mmol). After the mixture was cooled to –40 °C,
MeNO2 (55 μL, 1.0 mmol) was added at that temperature.
After being stirred for 23 h at –40 °C, the mixture was
quenched with H2O and extracted with EtOAc. The organic
extract was dried over anhyd MgSO4 and concentrated.
Silica gel chromatography of the residue (hexane–
Et2O = 6:4) gave the desired product (19.3 mg, 91%). The ee
of the product was determined to be 91% by HPLC using
chiral stationary-phase column as described in the footnote
of Table 1.
(4) Some selected examples: (a) Trost, B. M.; Yeh, V. S. C.
Angew. Chem. Int. Ed. 2002, 41, 861. (b) Evans, D. A.;
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(18) Time-course studies suggested that the retro process is not
involved in the reaction (3 h: 15% yield, 89% ee, 6 h: 35%
yield, 88% ee, 12 h: 47% yield, 88% ee, 24 h: 90% yield,
89% ee). For the retro process in the asymmetric Henry
reaction using organocatalyst, see ref. 7b.
(19) We also examined the reaction of aldehydes and EtNO2, but
the reaction did not proceed.
(20) Absolute configuration of all nitro alcohols were determined
by comparison of elution order of HPLC and specific
rotation with the reported value.4b,g,j,9
(21) (a) At the moment, we have no evidence that the nitronate
anion is generated under the optimized conditions. However,
we believe that the nitronate anion from MeNO2
(pKa = 10.2) is generated, because the imidate anion
generated from BSA or BSTFA and KOAc can deprotonate
dimethyl malonate (pKa = 13). (b) For a review on the use of
BSA in organic synthesis, see: El Gihani, M. T.; Heaney, H.
Synthesis 1998, 357.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 883–885

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