Novel structure-defined chiral bis(oxazolinyl)thiophenes for Ru-catalyzed asymmetric cyclopropanation

Article abstract of DOI:10.1016/j.tetlet.2004.05.120

The novel structures of sulfur-containing chiral bis(oxazoline) compounds which have been synthesized have been determined by X-ray crystal diffraction analyses. A high enantioselectivity (ee>99%) in the asymmetric cyclopropanation of diphenylethene with

Full text of DOI:10.1016/j.tetlet.2004.05.120

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5649–5652
Novel structure-defined chiral bis(oxazolinyl)thiophenes for
Ru-catalyzed asymmetric cyclopropanationq
Ming Z. Gao, Deyuan Kong, Abraham Clearfield and Ralph A. Zingaro*
Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA
Received 18 April 2004; accepted 21 May 2004
Available online 15 June 2004
Abstract—The novel structures of sulfur-containing chiral bis(oxazoline) compounds which have been synthesized have been
determined by X-ray crystal diffraction analyses. A high enantioselectivity (ee >99%) in the asymmetric cyclopropanation of
diphenylethene with diazoester using the bis(oxazoline)-Ru(II) catalyst was obtained.
Ó 2004 Elsevier Ltd. All rights reserved.
The catalytic enantioselective synthesis of cyclopropanes
has received great attention because of their frequent
occurrence in biological compounds and their use as
valuable synthetic intermediates.1 Since the introduction
of chiral cyclopropanation catalysts by Noyori and
co-workers and Pfaltz and co-workers,2 the catalyzed
asymmetric cyclopropanation by transition-metal com-
plex catalysts has been one of the most efficient synthetic
methods for the formation of optically pure cyclopro-
pane compounds.3 Catalysts containing several metals
and various chiral ligands, such as Schiff base–Cu,4
salen–Co,5 Rh2(5S-MEPY),6 porphyrin–Ru,7 and espe-
cially over the last decade, the C2-symmetric chiral
oxazoline metal complexes have shown desirable enan-
tioselective catalytic effects.8 They have been successfully
employed in asymmetric cyclopropanation.
reported.12 Recently, we reported the synthesis of the
new chiral bis(oxazolinyl)thiophenes 4.13 X-ray struc-
tures of these chiral bis(oxazolinyl)thiophenes are herein
reported together with their application for catalytic
asymmetric cyclopropanation reactions of alkenes with
ethyl diazoacetate (EDA) using the Ru(II) complex.
O
O
O
O
N
N
N
N
N
R
R
R
2
R
1
R
N
O
O
S
O
N
N
O
N
*
Currently, several kinds of C2-symmetric chiral oxazo-
lines, for example, ligand 1 with one carbon spacer,9 2
with pyridine nitrogen atom spacer,10 and 3 with a rigid
chiral biaryl skeleton11 has been synthesized and high
enantioselectivity for cyclopropanations has been
obtained. The sulfur-containing chiral bis(oxazoline) for
the asymmetric cyclopropanation has not yet been
described, although sulfur-containing chiral ligands in
the other asymmetric catalytic reactions have been
*
R
R
R
4
3
The chiral bis(oxazolines) 4 (thiobox) have been pre-
pared using two methods (Scheme 1):8;13 The reaction of
a diacid chloride with chiral b-amino alcohols to form
dihydroxy diamide compounds, which are subsequently
treated with thionyl chloride to afford dichloride di-
amide compounds. The above compounds are trans-
formed into 4 by treatment with a base. The improved
route includes one step (e) instead of two steps (c) and
(d). This results not only in a simplification of the pro-
cedure, but also in an improved the yield of the
bis(oxazoline). These new ligands were characterized by
IR, NMR, MS, and elemental analysis.14
Keywords: Asymmetric cyclopropanation; Bis(oxazoline); Bis(oxazo-
linyl)thiophene; Ruthenium.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.05.120
* Corresponding author. Tel.: +1-409-8452731; fax: +1-979-8454719;
e-mail: zingaro@mail.chem.tamu.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.120

5650
M. Z. Gao et al. / Tetrahedron Letters 45 (2004) 5649–5652
R
*
OH
(b)
(a) SOCl2
NH2
HOOC
O
COOH
ClOC
COCl
S
S
Et3N, CH2Cl2
5
6
O
(c) SOCl2
(d) Base
4a R1 = Et (S)
S
O
O
S
4b R2 = iso-Pr (S)
4c R3 = Benzy l (S)
4d R4 = tert-Bu (S)
HN
NH
or (e) BF3.Et2O or DAST
*
*
R
N
N
R
R
R
OH
HO
4
7
Scheme 1.
These ligands were successfully utilized for Ru-catalyzed
cyclopropanation of alkenes with ethyl diazoacetate.
This is the commonly investigated model reaction with
chiral ligands.10;16 The asymmetric cyclopropanation
was carried out in CH2Cl2 in the presence of 4 mol % of
ruthenium(II) catalyst by mixing [RuCl2(p-cymene)]2
and the bis(oxazoline) ligands 4 to give cyclopropane-
carboxylate as a mixture of trans and cis isomers
(Scheme 2).
1
The ratio of trans to cis isomers was determined by H
4a
NMR analysis, and enantiomeric excess of these mix-
tures was determined by HPLC analysis using a chiral
column (Chiralcel OD-H or OJ). The results are sum-
marized in Table 1. Using ligand 4a and substrate 1,1-
diphenylethene, studies were carried out to determine
the optimum reaction conditions. The choice of the
solvents has a significant effect on both the enantio-
selectivity and the yield. Dichloromethane was found to
give the best results. Slightly lower enantioselectivities
were obtained in chloroform and dichloroethane, and
the enantioselectivity and yield decreased in THF (entry
1). Reduction of the reaction temperature from 40 to
0 °C, did not noticeably affect the reaction, but increased
enantioselectivity from 92% ee (entry 4) to >99% ee
(entry 6) and lowered the yield from 91% to 70%.
Changing the ligand (4b,c,d) has a little effect on the
enantioselectivity of 2,2-phenyl-cyclopropanecarboxyl-
ate.à
4d
Figure 1. Molecular structures of 4 with atom labeling.
In order to obtain a direct understanding of the struc-
ture of the new chiral bis(oxazoline) ligands 4, the
structures of the ligands 4a,d were determined by X-ray
crystallography. Compounds 4a and 4d were obtained
as air-stable, colorless crystals by slow evaporation from
solutions of 4 in acetone–hexane (v/v 1:3). The per-
spective views of compounds 4a and 4d are shown in
Figure 1.
Variation of the ligand on the cyclopropanation of other
alkenes has a great effect on the trans/cis diastereo-
The ligand 4 (0.21 mmol) and [RuCl2(p-cymene)]2 (0.1 mmol) were
mixed in 4 mL CH2Cl2 and refluxed for 40 min, cooled to rt, 1,1-
ꢀ
diphenylethene or other alkenes (10.0 mmol, excess) and 4 A molec-
From the view of the crystal structures of 4a and 4d, the
thiophene unit with two oxazolines moieties possesses a
twist angle and they do not lie in the same plane, and
it is found that the N–S–N bond angle is quite large.
This differs from the structure of previously reported
pybox.10;15 In 4, the thiophene functions as a backbone,
where the sulfur atom is part of strong p-donor system.
The chirality has been introduced by two oxazoline
moieties near the sulfur. These C2-symmetric bis(oxaz-
olines) offer the possibility for a new group of N–S–N
chelating tridentate ligands.
ular sieves (MS) were added to the above mixture. Then, a solution of
the diazoester (5.0 mmol) in 3 mL CH2Cl2 was slowly added at rt over
4 h. The reaction was stirred for another 16 h. The solvent was
removed and the crude product was separated by flash chromato-
graphy over silica gel to give cyclopropyl ester products in 63–91%
isolated yield.
à
Single crystals of 4a and 4d were scanned at 110 K on a Bruker Smart
ꢀ
CCD-1000 diffractometer (Mo-Ka, k ¼ 0:71069 A). The structures
were solved using direct methods and refined with full-matrix least-
squares (SHELX-97) with atomic coordinates and anisotropic thermal
parameters for all nonhydrogen atoms.18 CCDC reference number
232493 and 232495.

M. Z. Gao et al. / Tetrahedron Letters 45 (2004) 5649–5652
5651
COOEt
R1
R2
R1
R2
Ru-ligand 4a-d
H
R1
R2
+
CO2Et
N2
+
CH2Cl2, 4A MS
H
COOEt
Scheme 2.
Table 1. Enantioselective cyclopropanation catalyzed by the Ru-bis(oxazolines)
Entry
Ligand
R1
R2
T (°C)
Solvent
trans:cisa
%Ee (trans)b
%Ee (cis)
Yield%c
1
4a
4a
4a
4a
4a
4a
4b
4c
4d
4a
4b
4c
4d
4d
4d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph
Ph
rt
rt
rt
40
rt
0
THF
ClCH2CH2Cl
CHCl3
––
––
81
96
81
96
95
66
82
83
2
3
Ph
Ph
––
––
95
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
929912
99
5
Ph
Ph
––
––
99
>99
98
85
70
77
72
63
6
>99
98
7
Ph
Ph
rt
rt
rt
rt
rt
rt
rt
rt
rt
––
––
8
96
98
96
98
9
Ph
Ph
––
10
11
12
13
14
15
67:33
76:24
72:28
79:21
82:18
80:20
6266
81
90
H
Ph
Ph
84
79
83
80
79
78
82
H
75
89
H
Ph
4-MeO-Ph
4-Cl-Ph
82
85
H
91
87
H
83
a The ratio of trans and cis was determined by 1H NMR.
b Ee values were determined by chiral HPLC analysis(Chiralcel OD-H or OJ column).
c Isolated yield of a mixture of trans and cis based on EDA.
selectivity and enantioselectivity. As can be seen from
entries 10–15 in Table 1, when the R groups of the
ligand are changed from ethyl to bulkier groups (iso-Pr;
benzyl; tert-butyl), all reaction give higher trans:cis
ratios for the cyclopropanation products of styrene,
p-chlorostyrene and 4-vinylanisole. The best results were
obtained with the tert-butyl group, where a trans:cis
ratio of 82:18 (entry 14) and 91% ee of trans product
were obtained. This is consistent with the results previ-
ously reported.17 Apart from styrene substrate, p-chloro-
styrene and 4-vinylanisole were also selected as substrates.
There was no obvious improvement on the enantioselec-
tivity of the cyclopropyl ester product.
synthesized and some structures have been determined
by X-ray crystal diffraction analyses. Preliminary results
in the asymmetric cyclopropanation of alkenes with
diazoacetate have been obtained. A high enantioselec-
tivity has been obtained in the cyclopropanation of
diphenylethene using the Ru(II)-bis(oxazoline) catalyst,
the trans:cis stereoselectivity and enantioselectivity are
also good. The preliminary results suggest that these
novel bis(oxazolines) posses potential as new catalysts
for asymmetric reactions. Further studies on the asym-
metric reactions are currently being investigated.
See Supplemental materials for crystallographic data in
CIF or other electronic format.
Compared with results reported for the catalyst Ru-
pybox,10 with respect to ee values and yield of cyclo-
propanation of 1,1-diphenylethene, better results are
reported herein by the use of the catalyst Ru-thiobox. In
the case of styrene and substituent styrenes, the ee values
of the cyclopropanation product are similar, but the
trans/cis stereoselectivity is somewhat lower with Ru-
thiobox. These differences may result from the different
catalyst structure. With respect to the structure of the
catalyst, it is expected that the N–S–N bonds coordi-
nated to Ru have a larger and longer angle than that of
N–N–N bonds coordinated to Ru. This may result in
easier access of the reactive substrate and is favorable
for a larger sterically bulky substrate. In addition, Ru–S
coordination is much stronger than Ru–N coordination,
because sulfur and ruthenium are both soft centers. The
Ru–N coordination represents a soft to hard interaction,
and a soft–soft interaction is expected to be much
stronger.
Acknowledgements
The authors acknowledge the assistance of the Robert
A. Welch Foundation and the Department of Energy,
Basic Sciences Division (DE-FG03-00ER 15806) for
financial support. We also thank Dr. G. A. Sulikowski
and Dr. K. Burgess for equipment assistance in the use
of chiral HPLC.
References and notes
1. Meier, W. Chem. Soc. Rev. 2000, 29, 295; Suckling, C. J.
Angew. Chem., Int. Ed. Engl. 1988, 27, 537.
2. Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Tetra-
hedron Lett. 1966, 7, 5239; Nozaki, H.; Takaya, H.;
Moriuti, S.; Noyori, R. Tetrahedron 1968, 24, 3655;
In conclusion, a series of new chiral sulfur-containing
bis(oxazolines) with thiophene as the backbone has been

5652
M. Z. Gao et al. / Tetrahedron Letters 45 (2004) 5649–5652
ꢁ
Fritschi, H.; Leutenegger, U.; Pfaltz, A. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 1005.
3. Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54,
7919; Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98,
911; Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette,
A. B. Chem. Rev. 2003, 103, 977.
4. Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett.
1975, 16, 1707; Aratani, T.; Yoneyoshi, Y.; Nagase, T.
Tetrahedron Lett. 1982, 23, 685.
5. Fukuda, T.; Katsuki, T. Tetrahedron 1997, 53, 7201;
Ikeno, T.; Sato, M.; Yamada, T. Chem. Lett. 1999, 1345.
6. Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.;
Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897.
7. Lo, W.-C.; Che, C.-M.; Cheng, K.-F.; Mark, T. C. W.
J. Chem. Soc., Chem. Commun. 1997, 1205; Zhang, J.-L.;
Che, C.-M. Org. Lett. 2002, 4, 1911.
8. (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahe-
dron: Asymmetry 1998, 9, 1; (b) Gao, M. Z.; Wang, B.
Prog. Chem. 2002, 14(5), 347.
12. Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.;
Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J.
Org. Chem. 1996, 61, 6244; Voituriez, A.; Schulz, E.
Tetrahedron: Asymmetry 2003, 14, 339.
13. Gao, M. Z.; Wang, B.; Liu, H. B.; Xu, Z. L. Chin. J.
Chem. 2002, 20(1), 85.
14. Selected data for 4d, (þ)-2,5-bis[40(S)-tert-butyloxazolin-
22
20-yl]thiophene: mp, 120–121 °C. ½aꢀ þ5.44 (c 0.55,
D
acetone). IR: 2958, 2903, 2875, 1945, 1534, 1479, 1362,
1305, 1252, 1212, 1066, 1014, 949, 831, 748, 675 cmꢁ1. H
1
NMR (CDCl3), dH: 0.97 [s, 18H, 2 ꢂ C(CH3)], 4.03 (dd,
J ¼ 7:5, 10.0 Hz, 2H, 2 ꢂ OCHH), 4.23 (dd, J ¼ 8:0,
8.5 Hz, 2H, 2 ꢂ NCH), 4.34 (dd, J ¼ 8:5, 10.0 Hz, 2H,
2 ꢂ OCHH), 7.52(s, H2 , thiophene-H);
13C NMR, dc:
25.79, 34.05, 53.79, 69.25, 129.91, 133.80, 158.39. MS
(FAB): 335 (Mþ1, 100%), 277, 223, 221, 179, 165, 95, 69;
Anal. Calcd for C18H24N2O2S: C, 64.64; H, 7.83; N, 8.37;
S, 9.58. Found: C, 64.97; H, 8.08; N, 8.14; S, 9.13.
15. Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H.
W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780.
16. Boulch, R.; Scheurer, A.; Mosset, P.; Saalfrank, R. W.
Tetrahedron Lett. 2000, 41, 1023.
9. Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul,
M. M. J. Am. Chem. Soc. 1991, 113, 726.
10. Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.;
Itoh, K. J. Am. Chem. Soc. 1994, 116, 2223; Nishiyama,
H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Aoki, K.;
Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1247; Gupta, A.
D.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994, 50,
13725.
17. Kim, S.-G.; Cho, C.-W.; Ahn, K. H. Tetrahedron:
Asymmetry 1997, 8, 1023; Glos, M.; Reiser, O. Org. Lett.
2000, 2, 2045.
18. Sheldrick, G. M.; SHELXTL, version 5.03; Siemens Ana-
lytical X-ray Instruments: Madison, WI, 1995;
11. Uozurui, Y.; Kyota, H.; Kishi, E.; Kitayama, K.;
Hoyashi, T. Tetrahedron: Asymmmetry 1996, 7, 1603.
Sheldrick, G. M.; SHELX-96 Program for Crystal Structure
Determination; Bruker-AXS: Madison, WI, 1996.