Novel cinchona-aminobenzimidazole bifunctional organocatalysts

Article abstract of DOI:10.1002/adsc.200900787

Efficient Cinchona-derived chiral 2-aminobenzimidazole catalysts were prepared by the coupling of 5,7-bis(trifluoromethyl)-2-chlorobenzimidazole with C(9S)-aminodihydroquinine or C(9R)-aminodihydroquinidine and successively applied to the Michael addition

Full text of DOI:10.1002/adsc.200900787

COMMUNICATIONS
DOI: 10.1002/adsc.200900787
Novel Cinchona-Aminobenzimidazole Bifunctional
Organocatalysts
Lei Zhang,a Myoung-Mo Lee,b Soo-Mi Lee,b Jihye Lee,b Maosheng Cheng,a
Byeong-Seon Jeong,c Hyeung-geun Park,b,* and Sang-sup Jewb,*
a
Shenyang Pharmaceutical University, Shenyang Wenhua Road 103, Shenyang, Liaoning 110016, Peopleꢀs Republic of
China
b
Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742,
Republic of Korea
fax: (+82)-2-872-9129, (+82)-2-888-7621; phone: (+82)-2-880-7871, (+82)-2-880-7872
E-mail: hgpk@snu.ac.kr or ssjew@snu.ac.kr
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea
c
Received: October 18, 2009; Revised: November 11, 2009; Published online: December 8, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900787.
Abstract: Efficient Cinchona-derived chiral 2-ami-
nobenzimidazole catalysts were prepared by the
coupling of 5,7-bis(trifluoromethyl)-2-chlorobenzi-
midazole with C(9S)-aminodihydroquinine or
C(9R)-aminodihydroquinidine and successively ap-
plied to the Michael addition of dimethyl malonate
to nitroolefins as very efficient chiral Lewis acid bi-
functional organocatalysts (up to >99% ee).
Figure 1. Thiourea-based bifunctional organocatalysts.
Keywords: 2-aminobenzimidazoles; bifunctional
catalysts; Cinchona alkaloids; enantioselectivity; or-
ganocatalysts
cilitates a hydrogen bonding interaction with the
sulfur atom in the thioureas.[3] The N-3,5-bis(trifluoro-
methyl)phenyl group, introduced by Schreinerꢀs group
in 2002, has been popularly employed in the design of
thiourea-based organocatalysts thus far.[4]
In 2005, Gçbelꢀs group introduced metal-free cata-
Since Jacobsenꢀs group first disclosed thiourea-based lysts derived from 2-aminobenzimidazoles for the
chiral ligands for the metal-free Strecker reaction in cleavage of RNA (Scheme 1).[5] The guanidine moiety
1998, thioureas have been extensively studied as in tris[2-(benzimidazol-2-ylamino)ethyl]amine (1) effi-
Lewis acid organocatalysts given their functionality as ciently activated phosphates by hydrogen bonding,
hydrogen bond donors, and successfully applied to which could facilitate the cleavage of phosphate
various useful organic reactions.[1] Especially, thiour- esters to cyclic phosphate 3 under neutral conditions
eas conjugated with chiral amines have been devel- (pH 7.0). Since the 2-aminobenzimidazole group is
oped as chiral bifunctional catalysts capable of simul- conformationally more rigid and bears a more acidic
À
taneously activating both nucleophiles and electro- N H compared to the corresponding thiourea group
philes in a reaction by their Brønsted/Lewis acidic as in Figure 1, N-substituted-2-aminobenzimidazoles
(thiourea moiety) and basic (chiral amine moiety) could serve as new Lewis acid organocatalysts.[6] In
functionalities. As such, they have successfully been this paper, we report new Cinchona alkaloid-derived
applied to various asymmetric syntheses (Figure 1).[2]
2-aminobenzimidazole catalysts and their application
The cumulative results reveal that the electron- in enantioselective Michael additions.[7]
withdrawing moiety, for instance, trifluoromethyl
group not only increases N H acidity, but also con- zole-containing compound in a Brønsted acid-cata-
First, the catalytic activity of a 2-aminobenzimida-
À
tributes to the conformational rigidity of the catalyst lyzed reaction was examined. Model compound 5 was
by polarizing the adjacent H atoms, which in turn fa- prepared according to a known synthetic method[8]
Adv. Synth. Catal. 2009, 351, 3063 – 3066
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3063

Lei Zhang et al.
COMMUNICATIONS
Scheme 1. Cleavage of RNA by tris[2-(benzimidazol-2-ylamino)ethyl]amine.
and its catalytic efficiency compared with that of the Table 1. Screening and optimization.[a]
corresponding thiourea analogue 4 (Figure 2) in the
Michael addition of dimethyl malonate to nitroolefin
10a (Table 1). The reaction was performed with di-
methyl
malonate
(2.0
equiv.),
triethylamine
(10 mol%), and catalysts (10 mol%) in toluene at
08C. As shown in Table 1, the 2-aminobenzimidazole
catalyst 5 (entry 2, 85%) afforded adduct 11a in
higher chemical yield than the thiourea catalyst 4
(entry 1, 71%), which could prove the potentiality of
a 2-aminobenzimidazole group as a Brønsted acid or-
ganocatalyst.
Entry Cat. Solvent Temp. Time Yield ee
[8C]
[h]
[%][b] [%][c]
1[d]
2[d]
3
4
5
6
7
8
9
4
5
6
7
8
7
7
7
7
7
7
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2 r.t.
THF
PhMe
CH2Cl2
CH2Cl2 -20
CH2Cl2 -40
r.t.
r.t.
r.t.
r.t.
r.t.
24
24
24
7
7
7
24
24
24
40
144
71
85
98
99
99
99
99
89
98
98
95
–
–
83 (S)[e]
91 (S)
93 (R)
91 (S)
91 (S)
94 (S)
94 (S)
95 (S)
95 (S)
The successful model study with the simple achiral
2-aminobenzimidazole organocatalyst 5 prompted the
preparation of chiral bifunctional organocatalysts by
conjugation of a chiral amine to the 2-aminobenzimi-
dazoles. There have been many chiral amines em-
ployed for the design and preparation of thiourea-
r.t.
0
0
10
based chiral bifunctional catalysts.[2] In 2005, Con- 11
nonꢀs group reported Cinchona alkaloid-derived thio-
[a]
Reaction was performed with 2 equivalents of of dimeth-
yl malonate and 2 mol% of catalyst under the given con-
ditions.
Isolated yields.
Determined by chiral HPLC.
urea catalysts as highly efficient chiral bifunctional or-
ganocatalysts[2i] and demonstrated that the C(9)-NH2
[b]
epimer of Cinchona alkaloids is an excellent chiral
amine resource. This approach was adopted herein by
employing C(9S)-aminodihydroquinine and C(9R)-
aminodihydroquinidine as chiral amines to prepare
[c]
[d]
10 mol% of triethylamine and 10 mol% of catalyst were
used.
[e]
Absolute configurations were determined by comparison
novel “Cinchona-aminobenzimidazole” chiral bifunc-
of the optical rotation of 11a with reported values.[9]
tional organocatalysts. Three benzimidazole deriva-
tives 6–8 (Figure 2) were prepared by coupling 2-
chlorobenzimidazoles (9) with the corresponding
amines under microwave irradiation at 1708C (6,
42%; 7, 47%; 8, 40%) (Scheme 2).[8]
Catalytic efficiencies were evaluated by the Michael
addition of dimethyl malonate to 10a in toluene at
room temperature. As shown in Table 1, both 5,7-bis-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
methyl)benzimidazole-2-aminodihydroquinidine (8)
(entry 5, 99%, 93% ee) afforded the adducts (S)-11a
and (R)-11a in high enantioselectivity with high chem-
ical yields, respectively. The lower catalytic efficiency
of benzimidazole-2-aminodihydroquinine (6) (entry 3,
98%, 83% ee), relative to its trifluoromethyl analogue
Figure 2. 2-Aminobenzimidazole-containing organocatalysts.
3064
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3063 – 3066

Novel Cinchona-Aminobenzimidazole Bifunctional Organocatalysts
Table 2. Scope and limitations.[a]
COMMUNICATIONS
Entry
R
Cat. Time Yield ee
[h]
[%][b] [%][c]
95 (S)[d]
1
Ph (10a)
7
8
7
8
7
8
7
8
7
8
7
8
7
8
7
8
7
8
7
8
7
8
7
8
40
40
40
40
40
40
40
40
40
40
40
40
40
40
60
60
40
40
60
60
40
40
96
96
98
99
98
98
97
94
97
95
91
86
90
85
93
95
94
95
99
99
96
97
93
91
70
67
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23[e]
24[e]
97 (R)
96 (S)
97 (R)
92 (S)
95 (R)
95 (S)
94 (R)
97 (S)
95 (R)
>99 (S)
>99 (R)
98 (S)
92 (R)
>99 (S)
97 (R)
97 (S)
>99 (R)
92 (S)
94 (R)
94 (S)
94 (R)
94 (R)
91 (S)
4-Me-C6H4 (10b)
4-CN-C6H4 (10c)
4-Cl-C6H4 (10d)
4-Br-C6H4 (10e)
3-Br-C6H4 (10f)
2-Br-C6H4 (10g)
4-MeO-C6H4 (10h)
3-MeO-C6H4 (10i)
2-MeO-C6H4 (10j)
2-Naphthyl (10k)
n-Hexyl (10l)
Scheme 2. Preparation of novel Cinchona-aminobenzimida-
zole bifunctional organocatalysts.
7, implies that the trifluoromethyl group plays an im-
portant role in enantioselectivity, which is in accord
with previous results.[2i] Enantioselectivity seemed in-
sensitive to the nature of the reaction solvent at room
temperature (entries 4, 6, 7), but lower temperature
provided increased enantioselectivities. Notably, the
chemical yield was preserved with reaction tempera-
ture only in dichloromethane as solvent (entries 8, 9).
The highest enantioselectivity was observed in di-
chloromethane at À208C, however, a lower reaction
temperature (À408C) gave a reaction time three
times longer with comparable enantioselectivity (en-
tries 10, 11).
Further investigation into the scope and limitations
was performed with various nitroolefins 10b–10l
under optimal reaction conditions (entry 10 in
Table 1). Very high chemical yields (S-11, up to 99%;
R-11, up to 99%) and enantioselectivities (S-11, up to
>99% ee; R-11, up to >99% ee) were obtained
(Table 2), which were slightly higher than those of thi-
ourea-based catalysts.[2i]
[a]
Reaction was carried out with 2 equivalents of dimethyl
malonate and 2 mol% of catalyst under the given condi-
tions.
[b]
[c]
Isolated yields.
Enantiopurity was determined by HPLC analysis of the
corresponding addition adducts (11) on chiral columns
with hexanes/2-propanol as an eluent.
[d]
[e]
A
plausible transition state is proposed in
Absolute configurations were determined by comparison
of the optical rotation of 11.[9]
Figure 3.[10] The nitro group of substrate 10a forms hy-
Reaction was performed with 5 mol% of catalyst.
À
drogen bonds with two N H moieties from the cata-
lyst 7 while the bridgehead nitrogen of the Cinchona
moiety abstracts an a-proton from dimethyl malonate
to form an ion-pair located downside to 10a. As a
consequence, the malonate anion can only approach
the b-carbon of the nitroolefin from the downside
during the 1,4-nucleophilic addition, affording the S
isomer (11a). This is in agreement with the results.
In conclusion, chiral “Cinchona-aminobenzimida-
zole” catalysts 6–8 were designed, prepared and veri-
fied as efficient chiral Brønsted acid-base bifunctional
organocatalysts in the Michael addition of dimethyl
malonate to nitroolefins. The facile preparation and
high enantioselective efficiency make these catalysts
very efficient bifunctional organocatalysts. Further ap-
plications of these new catalysts are currently under
investigation.
Figure 3. A plausible transition state between the catalyst 7,
an anion of dimethyl malonate, and (E)-(2-nitrovinyl)ben-
zene 10a.
Adv. Synth. Catal. 2009, 351, 3063 – 3066
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3065

Lei Zhang et al.
COMMUNICATIONS
X. Yu, L. Zu, W. Wang, Org. Lett. 2005, 7, 4293; d) Y.
Sohtome, A. Tanatani, Y. Hashimoto, K. Nagasawa,
Tetrahedron Lett. 2004, 45, 5589; e) T. Marcelli, R. N. S.
van der Haas, J. H. van Maarseveen, H. Hiemstra,
Angew. Chem. 2006, 118, 943; Angew. Chem. Int. Ed.
2006, 45, 929; f) Y. Sohtome, Y. Hashimoto, K. Nagasa-
wa, Adv. Synth. Catal. 2005, 347, 1643; g) D. E. Fuerst,
E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 8964;
h) A. Berkessel, F. Cleemann, S. Mukherjee, T. N.
Mꢂller, J. Lex, Angew. Chem. 2005, 117, 817; Angew.
Chem. Int. Ed. 2005, 44, 807; i) S. H. McCooey, S. J.
Connon, Angew. Chem. 2005, 117, 6525; Angew. Chem.
Int. Ed. 2005, 44, 6367; j) J. Ye, D. J. Dixon, P. S. Hynes,
Chem. Commun. 2005, 4481; k) S. B. Tsogoeva, S. Wei,
Chem. Commun. 2006, 1451; l) H. Huang, E. N. Jacob-
sen, J. Am. Chem. Soc. 2006, 128, 7170; m) M. S.
Taylor, N. Tokunaga, E. N. Jacobsen, Angew. Chem.
2005, 117, 6858; Angew. Chem. Int. Ed. 2005, 44, 6700;
n) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc.
2004, 126, 10558.
Experimental Section
Typical Procedure
To a cooled solution (À208C) of (E)-(2-nitrovinyl)benzene
(10a) (50.0 mg, 0.335 mmol) and catalyst 8 (3.87 mg, 6.7
mmol) in anhydrous CH2Cl2 (0.67 mL) was added dimethyl
malonate (76.6 mL, 0.67 mmol). After stirring for 40 h at
À208C under an argon atmosphere, the reaction mixture
was concentrated under vacuum. The residue was purified
by silica gel column chromatography (hexanes:EtOAc=7:1)
to afford the Michael adduct (R)-11a as a white solid; yield:
93.0 mg (98%). The enantiomeric excess was determined by
chiral HPLC analysis [Chiral Technologies Inc., Chiralcel
AD-H column, hexanes:2-propanol=90:10, flow rate=
1.0 mLminÀ1, 238C, l=254 nm]: retention times: 16.4 min
(major), 26.3 min (minor), 97% ee. The absolute configura-
tion of (À)-11a was determined to be R by comparing the
specific optical rotation with the literature value, [a]2D3:
À6.02 (c 1.0, CHCl3) 97% ee, {lit (S)-(+), [a]2D5: +5.9 (c 1.0,
CHCl3) 96% ee}.[9]
[3] D. P. Curran, L. H. Kuo, J. Org. Chem. 1994, 59, 3259.
[4] P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217.
[5] U. Scheffer, A. Strick, V. Ludwig, S. Peter, E. Kalden,
M. W. Gçbel, J. Am. Chem. Soc. 2005, 127, 2211.
[6] a) F. G. Bordwell, G. Z. Ji, J. Am. Chem. Soc. 1991,
113, 8398; b) T. N. Brown, N. Mora-Diez, J. Phys.
Chem. B. 2006, 110, 20546.
[7] During the preparation of this manuscript, Nꢃjeraꢀs
group independently reported chiral trans-cyclohexane-
diamine-benzimidazole organocatalysts and their appli-
cations to the conjugate addition of 1,3-dicarbonyl
compounds to nitroolefins; D. Almas¸i, D. A. Alonso, E.
Gꢄmez-Bengoa, C. Nꢃjera, J. Org. Chem. 2009, 74,
6163.
Acknowledgements
This work was supported by the SRC/ERC program of
MOST/KOSEF (R11-2007-107-02001-0) and the Mid-career
Researcher Support Programs of National Research Founda-
tion of Korea (2009-0078814).
References
[1] For the reviews, see: a) P. R. Schreiner, Chem. Soc.
Rev. 2003, 32, 289; b) Y. Takemoto, Org. Biomol.
Chem. 2005, 3, 4299; c) A. G. Doyle, E. N. Jacobsen,
Chem. Rev. 2007, 107, 5713; d) X. Yu, W. Wang, Chem.
Asian J. 2008, 3, 516; e) S. J. Connon, Synlett 2009, 3,
0354.
[8] U. S. Soerensen, L. Teuber, D. Peters, D. Stroebaek,
T. H. Johansen, K. S. Nielsen, P. Christophersen, PCT
Int. Appl. WO 2006136580A2, 2006.
[9] H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem. Soc.
2004, 126, 9906.
[10] Recrystallization of the catalysts was unsuccessful. The
conformation of catalyst 7 was calculated by MM2
energy-minimization using PCModel v9.1.
[2] a) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc.
1998, 120, 4901; b) T. Okino, Y. Hoashi, Y. Takemoto,
J. Am. Chem. Soc. 2003, 125, 12672; c) J. Wang, H. Li,
3066
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 3063 – 3066