Novel chiral C2-symmetric bisimidazole-N-oxides as promising organocatalysts for enantioselective allylation of aromatic aldehydes

Article abstract of DOI:10.1055/s-0029-1217365

A series of new, chiral Lewis bases containing imidazole-N-oxide moiety were tested for purposes of asymmetric catalysis. Bisimidazole-N-oxides derived from (1R,2R)- and (1S,2S)-trans-1,2-diaminocyclohexane were used as catalysts in the allylation reactio

Full text of DOI:10.1055/s-0029-1217365

LETTER
1757
Novel Chiral C2-Symmetric Bisimidazole-N-Oxides as Promising Organo-
catalysts for Enantioselective Allylation of Aromatic Aldehydes
C
hira
l
C
2-Symimetric
o
Bisimidazol
t
N
-O
x
r
ides Kwiatkowski,a,b Paulina Mucha,c Grzegorz Mlostoń,*c Janusz Jurczak*a,b
a
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: jurczak@icho.edu.pl
b
c
Department of Organic and Applied Chemistry, Łódź University, Narutowicza 68, 90-136 Łódź, Poland
Fax +48(42)6655162; E-mail: gmloston@uni.lodz.pl
Received 17 February 2009
Dedicated to Prof. Dr. Hans-Ulrich Reißig (Berlin) on the occasion of his 60th birthday.
condensation of (1R,2R)- or (1S,2S)-trans-cyclohexane-
1,2-bis(methylidenamine) (2a) with a-hydroxy-iminoke-
tones 3a–d in boiling EtOH or in glacial acetic acid at
room temperature (Scheme 1).8 In solution, the monomer-
Abstract: A series of new, chiral Lewis bases containing imida-
zole-N-oxide moiety were tested for purposes of asymmetric catal-
ysis. Bisimidazole-N-oxides derived from (1R,2R)- and (1S,2S)-
trans-1,2-diaminocyclohexane were used as catalysts in the allyla-
tion reaction of aromatic aldehydes with allyltrichlorosilane, which ic form 2a exists in an equilibrium with the dimer identi-
fied as the eicosan derivative 2b.9 In average, yields of the
isolated products were good or very good (62–85%) and
yielded homoallyl alcohols in good yields and with enantioselectiv-
ity up to 80% ee. Screening of catalysts revealed that the type of
substituents and their location in imidazole ring has a crucial influ-
could be reproduced with no problem. The optically ac-
ence on enantioselectivity of the addition process.
tive substrate 2 was easily obtained from the correspond-
Key words: allylation, asymmetric catalysis, chiral imidazole-N-
ing, enantiomerically pure trans-1,2-diaminocyclohexane
oxides, nucleophilic addition, organocatalysis
and paraformalehyde.7,8
One of the most important tasks of the modern asymmet-
1a R1 = R2 = Me
R1
ric synthesis is the quest for novel catalysts useful for
preparation of chiral compounds in high enantiomeric pu-
rity. In recent years, we observe rapidly growing interest
in the development of asymmetric organocatalytic reac-
tions,1 including catalysis with organic Lewis bases.2
Amine N-oxides and azaheterocyclic N-oxides are recog-
nized as a group of very promising catalysts of this type,
well documented by growing number of original papers3,4
and review articles.5 Diverse N-oxides were reported as
more or less efficient catalysts for such reactions as asym-
metric allylation of aldehydes, cyanosilylation of carbon-
yl and imine compounds, aldol-type reactions, and
desymmetryzation of meso-epoxides.5 To the best of our
knowledge, chiral N-oxides derived from pyridine (and
related heterocycles, e.g., quinoline)3,5 or from tertiary
amines (e.g., N-alkyl proline)4,5 are only representatives
reported, which found application in asymmetric catalysis
until the present time. Herein, we report for the first time
application of a new type of chiral catalysts based on the
novel, 2-unsubstituted bisimidazole-N-oxides derived
from trans-1,2-diaminocyclohexane.
R1
1b R1 = Me, R2 = Ph
1c R1 = Ph, R2 = Me
1d R1 = R2 = Ph
N
N
R2
R2
N +
O–
+ N
–O
(1R,2R)-trans-1a–d
Figure 1 Chiral bisimidazole-N-oxides 1a–d
The allylation of aromatic aldehydes 4 with allyltrichlo-
rosilane was selected as a test reaction for the screening of
catalysts of type 1.10 It is well known that highly nucleo-
philic amine N-oxides can act as efficient activators of or-
ganosilicon reagents.5,11
In the model reaction of benzaldehyde (4a) with allyl-
trichlorosilane (Scheme 2), the activities of four N-oxides
1a–d, bearing Me and/or Ph substituents at C(4) and C(5)
in imidazole ring, were compared. It turned out that the
type of substituents and their positions in the imidazole
ring have a crucial influence on enantioselectivities and
the sense of asymmetric induction (Table 1). The pres-
ence of catalytic amount of 1a with two Me groups at C(4)
and C(5) resulted in the formation of product 5a in mod-
erate chemical yield and low enantioselectivity (entry 1).
On the other hand, replacement of one Me group at C(4)
with Ph substituent (catalyst 1b) led to improvement of
the yield of 5a and better enantioselectivity (entry 2). The
reaction carried out in the presence of the catalyst 1c with
reversed arrangement of Me and Ph substituents led to
Recently, we described a simple and efficient method for
the preparation of diverse chiral imidazole N-oxides6,7 in-
cluding bisimidazole-N-oxides of type 17 (Figure 1).
Enantiomerically pure trans-1,10-(cyclohexane-1,2-
diyl)bis(imidazole-N-oxides) 1a–d were prepared via
SYNLETT 2009, No. 11, pp 1757–1760
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217365; Art ID: G07009ST
© Georg Thieme Verlag Stuttgart · New York

1758
P. Kwiatkowski et al.
LETTER
The optimization study was performed using the most
promising catalyst 1d. The influence of the type of sol-
vents, catalyst loading, and temperature were also investi-
gated. Among typical solvents used in the study (THF,
MeCN, DMF, toluene, CH2Cl2), dichloromethane turned
out to be the best in terms of enantioselectivity and chem-
ical yields. Experiments showed that the mode of loading
of the catalyst 1d has also a significant influence on asym-
metric induction (Table 2, entries 1–3). Moreover, lower
temperature of the reaction mixture led to substantial in-
crease of enantioselectivity up to 72%. However, in these
cases the yield remarkably dropped. The reaction condi-
tions with 10 mol% concentration of 1d and temperature
kept at 0 °C during the addition of allyltrichlorosilane
seem to be optimal in terms of the yield of 5a and enanti-
omeric excess (entry 3).12
CH2 CH2
H2N
NH2
H
H
N
N
H
N
N
(CH2O)n
N
2
MeOH
r.t.
N
H
2a
2b
R1
R2
O
2b
R1
R1
(0.5 equiv)
N
N
EtOH, reflux, 3 h
or
1. AcOH, 16 h, r.t.
2. HCl gas
R2
N
+
R2
N
+
N
OH
O–
–O
3. NaHCO3, MeOH, r.t.
3a–d
trans-1a–d
Scheme 1 Short synthesis of chiral bisimidazole-N-oxides
Table 2 Optimization of the Model Reaction with the Catalyst 1da
Entry
Catalyst 1d
Temp (°C)
Yield of 5a ee (%)
(mol%)
(%)
CHO
OH
OH
1
2
3
4
5
2
0 to 20
0 to 20
0
70
86
90
65
34
35
53
64
68
72
4a
cat. 1a–d
+
Ph
Ph
+
DIPEA
CH2Cl2
5
SiCl3
10
10
5
(S)-5a
(R)-5a
–10
Scheme 2 The model reaction
–78 to –25
Table 1 Screening of Catalyst in the Reaction of Benzaldehyde and
a Reactions were performed using 2–10 mol% of catalyst 1d, 0.5
mmol of 4a, 1.5 mmol of DIPEA, and 0.6 mmol of allyltrichlorosilane
in 1.0 mL of CH2Cl2, 20 h.
Allyltrichlorosilanea
Entry Catalyst
R1
R2
Yield of 5a ee (%)c Config.d
(%)b
1
2
3
4
5
(1R,2R)-1a Me Me 55
(1R,2R)-1b Me Ph 85
Me 54
18
43
5
R
R
S
Finally, in order to estimate the scope of aldehyde sub-
strates, which can be applied in the enantioselective allyl-
ation reactions catalyzed by 1d, differently substituted
aromatic aldehydes were examined as substrates
(Table 3).12
(1R,2R)-1c Ph
(1R,2R)-1d Ph
(1S,2S)-1d Ph
Ph
Ph
86
84
53
52
S
The reaction occurred efficiently with different aromatic
aldehydes 4, and the enantiomeric excesses were deter-
mined, ranging from 39–80% (Table 3). Application of
the catalyst (1R,2R)-1d led to the formation of S-config-
ured homoallyl alcohols 5. The best enantioselectivities
(76–80%) were observed in the case of furan-2-carbalde-
hyde (4k) and thiophen-2-carbaldehyde (4l). On the other
hand, lower enantioselectivities were determined for
products obtained in reactions with para-substituted benz-
aldehydes 4b, 4d, and 4f (57–72% ee). The presence of
electron-withdrawing substituents, such as Cl attached to
aromatic ring (in 4f–h), seems to contribute to the drop of
enantioselectivity (57–39% ee). Finally, ortho-substituted
analogues gave substantially lower ee (below 51%). All
these observations lead to the conclusion that the substitu-
tion pattern in the molecule of aldehydes 4 strongly influ-
ences the enantioselectivity of formation of the
corresponding alcohols 5.
R
a Reactions were performed using 5 mol% of catalyst 1a–d, 0.5 mmol
of benzaldehyde, 1.5 mmol of DIPEA, and 0.6 mmol of allyltrichlo-
rosilane in 1.0 mL of CH2Cl2 initially at 0 °C (ca. 10 min) and then at
20 °C (20 h).
b Yields of isolated product by column chromatography on silica gel.
c The ee were determined by HPLC on chiral stationary phases (OD-
H).
d Absolute configuration assigned by measurement of optical rotation
and comparison with the literature data.
formation of 5a via opposite sense of induction and with
clear drop of efficiency (entry 3). Finally, the best enanti-
oselectivity (53% ee) was achieved using the catalytic
amount of 1d bearing two phenyl groups at C(4) at C(5),
respectively (entries 4 and 5). The comparison of the re-
sults summarized in Table 1 leads to the conclusion, that
the best results in terms of both, yield and enantioselectiv-
ity, were achieved using (1R,2R)-1b and (1R,2R)-1d as
the catalysts. Interestingly to note, that the sense of asym-
metric induction was in these two entries just the opposite.
In summary, preliminary results presented in the paper
showed, that the novel, easy in handling, and readily
Synlett 2009, No. 11, 1757–1760 © Thieme Stuttgart · New York

LETTER
Chiral C2-Symmetric Bisimidazole-N-Oxides
1759
Table 3 Scope of Aromatic Aldehydes 4 in the Allylation Reaction Catalyzed by (1R,2R)-1da,12
OH
OH
cat. (1R,2R)-1d
(10 mol%)
+
SiCl3
+
ArCHO
Ar
Ar
DIPEA, CH2Cl2
0 °C, 20 h
4a–l
(R)-5a–l
(S)-5a–l
Entry
1
Products 5a–l (Ar =)
Yield (%)b
ee (%)c
64
Config.d
(–)-S
(–)-S
(–)-S
(–)-S
(–)-S
(–)-S
(–)
5a
5b
5c
5d
5e
5f
Ph
90
78
76
72
85
76
82
81
75
69
50
64
2
4-MeC6H4
2-MeC6H4
70
3
51
4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
72
5
48
6
57
7
5g
5h
5i
2-ClC6H4
40
8
3-ClC6H4
39
(–)-S
(–)-S
(–)-S
(–)-S
(–)-S
9
b-naphthyl
a-naphthyl
furan-2-yl
thien-2-yl
62
10
11
12
5j
39
5k
5l
76
80
a Reactions were performed using 10 mol% of catalyst 1a–d, 0.5 mmol of 4, 1.5 mmol of DIPEA, and 0.6 mmol of allyltrichlorosilane in 1.0
mL of CH2Cl2 at 0 °C, 20 h (see ref. 12).
b Yields of isolated product by column chromatography on silica gel.
c The ee were determined by HPLC on chiral stationary phases (OD-H or AS-H).
d Absolute configuration assigned by measurement of optical rotation and comparison with the literature data.
KBN-126/T09/12 (M. G.), PBZ-KBN-126/T09/06 (J. J.) and the
Foundation for Polish Science for support to P. K.
available chiral bisimidazole-N-oxides of type 1, derived
from trans-1,2-diaminocyclohexane, can be considered as
promising organocatalysts for enantioselective allylation
of aromatic aldehydes 4 and, very likely, also for other
stereocontrolled reactions. The chiral bisimidazole N-ox-
ide 1d turned out to be the most efficient catalyst; the ex-
pected alcohols 5 were obtained in good chemical yields
References and Notes
(1) For reviews on asymmetric organocatalysis, see:
(a) Enantioselective Organocatalysis; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, 2007. (b) List, B., Ed. Chem. Rev.
2007, 107, 5413–5883. (c) Gaunt, M. J.; Johansson, C. C.
and in fair enantioselectivities up to 80% ee. The obvious
advantage of the catalysis with imidazole-N-oxides of
type 1 is their straightforward synthesis and possible mod-
ification of the substitution pattern within the imidazole
ring. However, further studies are needed to determine the
scope and limitation for the possible exploration of imida-
zole-N-oxides of type 1 as catalysts for purposes of enan-
tio- and diastereoselective synthesis.
C.; McNally, A.; Vo, N. C. Drug Discov. Today 2007, 12, 8.
(d) Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis;
Berkessel, A.; Gröger, H., Eds.; Wiley-VCH: Weinheim,
2004. (e) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138.
(2) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed.
2008, 47, 1560. (b) Gawronski, J.; Wascinska, N.; Gajewy,
J. Chem. Rev. 2008, 108, 5227. (c) Kizirian, J.-C. Chem.
Rev. 2008, 108, 140. (d) France, S.; Guerin, D. J.; Miller,
S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985.
Acknowledgment
(3) For recent examples of asymmetric reactions catalyzed by
chiral pyridine-derived N-oxides, see: (a) Malkov, A. V.;
Westwater, M.-M.; Gutnov, A.; Ramírez-López, P.;
Authors thank the Polish Ministry for Science and Higher Educati-
on for financial support in framework of research grants ## PBZ-
Synlett 2009, No. 11, 1757–1760 © Thieme Stuttgart · New York

1760
P. Kwiatkowski et al.
LETTER
Friscourt, F.; Kadlčíková, A.; Hodačová, J.; Rankovic, Z.;
Kotora, M.; Kočovský, P. Tetrahedron 2008, 64, 11335.
(b) Malkov, A. V.; Ramírez-López, P.; Biedermannová, L.
(née Bendová); Rulíek, L.; Dufková, L.; Kotora, M.; Zhu, F.;
Kočovský, P. J. Am. Chem. Soc. 2008, 130, 5341.
(c) Hrdina, R.; Boyd, T.; Valterova, I.; Hodacova, J.; Kotora,
M. Synlett 2008, 3141. (d) Hrdina, R.; Dracinsky, M.;
Valterova, I.; Hodacova, J.; Cisarova, I.; Kotora, M. Adv.
Synth. Catal. 2008, 350, 1449. (e) Takenaka, N.;
Sarangthem, S. R.; Captain, B. Angew. Chem. Int. Ed. 2008,
47, 9708. (f) Chelucci, G.; Baldino, S.; Pinna, G. A.;
Benaglia, M.; Buffa, L.; Guizzetti, S. Tetrahedron 2008, 64,
7574. (g) Hrdina, R.; Valterova, I.; Hodacova, J.; Cisarova,
I.; Kotora, M. Adv. Synth. Catal. 2007, 349, 822.
(h) Chelucci, G.; Belmonte, N.; Benaglia, M.; Pignataro, L.
Tetrahedron Lett. 2007, 48, 4037. (i) Pignataro, L.;
Benaglia, M.; Annunziata, R.; Cinquini, M.; Cozzi, F.
J. Org. Chem. 2006, 71, 1458. (j) Chai, Q.; Song, C.; Sun,
Z.; Ma, Y.; Ma, C.; Dai, Y.; Andrus, M. B. Tetrahedron Lett.
2006, 47, 8611. (k) Denmark, S. E.; Yu, F. Tetrahedron:
Asymmetry 2006, 17, 687.
soln for ca. 1.5 h, and the separated colorless bisimidazole N-
oxide hydrochloride was filtered off and dried in vacuum
exsiccator. The crude hydrochloride was suspended in
MeOH (ca 25 mL) and 1 g of the solid NaHCO3 was added;
stirring was continued for ca.1.5 h until evolution of CO2
was complete. Precipitated solid of inorganic salts was
filtered off, and the filtrate was evaporated to dryness. The
colorless solid material was triturated with a little portion
(ca. 5 mL) of a CHCl3–MeOH (2:1) mixture. Suspended,
solid material was separated, and the filtrate was evaporated
to dryness. Crude product was washed with little amount of
dry acetone to yield analytically pure sample of (1R,2R)-
trans-1,1¢-(cyclohexane-1,2-diyl)bis(4,5-diphenylimida-
zole)-3,3¢-dioxide [(R,R)-1d]; yield 342 mg (62%); colorless
crystals; mp(dec) 208–210 °C. IR (KBr): n = 3424–2867 (vs,
br), 1635 (m), 1570 (m), 1506 (m), 1484 (m), 1446 (m), 1405
(m), 1339 (s), 1222 (m), 1193 (m), 767 (s), 711 (s), 658 (m),
636 (m) cm–1. 1H NMR (CD3OD): d = 8.08 [s, 2 H, HC(2),
HC(2¢) imidazole], 7.65–7.50 (m, 4 H, 4 arom. H), 7.38–7.23
(m, 12 H, 12 arom. H), 7.18–7.07 (m, 4 H, 4 arom. H), 4.37–
4.26 (m, 2 H, 2CH, cHex), 2.38–1.40 (m, 8 H, 4CH2, cHex).
13C NMR (CD3OD): d = 131.8, 131.4, 131.2, 130.8, 129.9,
129.7 [6 d, 20 arom. CH, C(2), C(2¢) imidazole], 131.0,
129.6, 127.3 [3 s, 4 arom. C, C(4), C(4¢), C(5), C(5¢)
imidazole], 61.4 (d, 2 CH, cHex), 34.0, 25.3 (2 t, 4 CH2,
cHex). ESI-MS: m/z = 575 (100) [M + Na]+. ESI-HRMS:
m/z calcd for C36H32N4O2Na [M + Na]+: 575.2423; found:
575.2422. [a]D20 +6.0 (c 1.02; MeOH). For X-ray structure
determination of (1R,2R)- and (1S,2S)-1d, see: Mloston G.,
Mucha P., Tarka R., Urbaniak K., Linden A., Heimgartner
H.; Polish J. Chem.; 2009, 83, 1105.
(4) For recent examples of asymmetric reactions catalyzed by
chiral N-oxides derived from tertiary amines, see:
(a) Simonini, V.; Benaglia, M.; Pignataro, L.; Guizzetti, S.;
Celentano, G. Synlett 2008, 1061. (b) Wen, Y.; Gao, B.; Fu,
Y.; Dong, S.; Liu, X.; Feng, X. Chem. Eur. J. 2008, 14,
6789. (c) Qin, B.; Liu, X.; Shi, J.; Zheng, K.; Zhao, H.; Feng,
F. J. Org. Chem. 2007, 72, 2374.
(5) For reviews on application of chiral N-oxides in asymmetric
catalysis, see: (a) Benaglia, M.; Guizzetti, S.; Pignataro, L.
Coord. Chem. Rev. 2008, 252, 492. (b) Malkov, A. V.;
Kočovský, P. Eur. J. Org. Chem. 2007, 29. (c) Chelucci,
G.; Marineddu, G.; Pinna, G. A. Tetrahedron: Asymmetry
2004, 15, 1373. (d) Malkov, A. V.; Kočovský, P. Curr. Org.
Chem. 2003, 7, 1737. (e) Nakajima, M. J. Synth. Org. Chem.
Jpn. 2003, 61, 1081.
(6) (a) Jasinski, M.; Mloston, G.; Mucha, P.; Linden, A.;
Heimgartner, H. Helv. Chim. Acta 2007, 90, 1765.
(b) Mloston, G.; Mucha, P.; Urbaniak, K.; Broda, K.;
Heimgartner, H. Helv. Chim. Acta 2008, 91, 232.
(c) Jasinski, M.; Mloston, G.; Linden, A.; Heimgartner, H.
Helv. Chim. Acta 2008, 91, 1916. (d) Mloston G.,
Romanski J., Jasinski M., Heimgartner H.; Tetrahedron:
Asymmetry; 2009, 20, 1073.
(7) Mucha, P.; Mloston, G.; Jasinski, M.; Linden, A.;
Heimgartner, H. Tetrahedron: Asymmetry 2008, 19, 1600.
(8) Typical Procedure for the Preparation of Bisimidazole
N-Oxides – Synthesis of (1R,2R)-1d
(9) Edward, J. T.; Chubb, F. L.; Gilson, D. F. R.; Hynes, R. C.;
Sauriol, F.; Wisenthal, A. Can. J. Chem. 1999, 77, 1057.
(10) For reviews on asymmetric allylation of carbonyl
compounds, see: (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003,
103, 2763. (b) Denmark, S. E.; Fu, J. Chem. Commun. 2003,
167.
(11) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.-I. J. Am.
Chem. Soc. 1998, 120, 6419.
(12) General Allylation Procedure
To a stirred soln of the catalyst 1d (27.7 mg, 0.05 mmol) in
dry CH2Cl2 (1 mL) the corresponding aldehyde 4 (0.5 mmol)
and dry diisopropylethylamine (260 mL, 1.5 mmol) were
added. After 5 min. magnetic stirring at 0 °C, allyltrichloro-
silane (90–95 mL, 0.6 mmol) was added to the reaction
mixture. Stirring was continued at 0 °C for another 20 h, and
after this time the mixture was firstly diluted with Et2O,
quenched with aq NaHCO3 (1 mL) and next shaken with
H2O. Organic layer was separated and the aqueous soln was
extracted again with Et2O (2 × 10 mL); combined ethereal
soln were dried over MgSO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography.
Yields refer to the isolated amount of alcohol 5. The ee was
determined using HPLC technique with chiral column
(Chiralcel OD-H or Chiralpak AS-H); mixture of 2-PrOH–
hexane was applied as an eluent.
To a stirred soln of (1R,2R)-trans-1,2-diamonocyclohexane
(114.0 mg, 1.0 mmol) in MeOH (3 mL), a portion of
paraformaldehyde (63.0 mg, 2.1 mmol) was added and the
soln was stirred overnight at ambient temperature. After
evaporation of the solvent in vacuum, the resulting, viscous
oil was dissolved in glacial acid (7 mL) containing 473 mg
(2.1 mmol) a-benzil monoxime 3d and the soln obtained
thereby was stirred overnight at ambient temperature. Next
day, a gentle stream of gaseous HCl was bubbled through the
Synlett 2009, No. 11, 1757–1760 © Thieme Stuttgart · New York