Single-chiral bis(oxazolinyl)pyridine (pybox). Efficiency in asymmetric catalytic cyclopropanation

Article abstract of DOI:10.1016/S0957-4166(98)00303-6

Single-chiral bis(oxazolinyl)pyridine ligands were examined as ligands for ruthenium-catalyzed asymmetric catalytic cyclopropanation of olefins: enantioselectivities up to 94% for the trans-cyclopropane were observed.

Full text of DOI:10.1016/S0957-4166(98)00303-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2865–2869
Single-chiral bis(oxazolinyl)pyridine (pybox). Efficiency in
asymmetric catalytic cyclopropanation
Hisao Nishiyama,∗ Norikazu Soeda, Tomonari Naito and Yukihiro Motoyama
School of Materials Science, Toyohashi University of Technology, Tempaku-cho, Toyohashi 441-8580, Japan
Received 24 June 1998; accepted 29 July 1998
Abstract
Single-chiral bis(oxazolinyl)pyridine ligands were examined as ligands for ruthenium-catalyzed asymmetric
catalytic cyclopropanation of olefins: enantioselectivities up to 94% for the trans-cyclopropane were observed.
© 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Two-fold axial (C2) symmetry in the shape of chiral ligands has been utilized in preference to obtain
excellent results in asymmetric catalysis.1,2 We have also perceived efficiency of C2-symmetry in ligand
design through our investigation of optically active bis(oxazolinyl)pyridine (pybox), whose potential has
been revealed in the asymmetric cyclopropanation (ACP) of olefins and diazoacetates with ruthenium
catalysts.3–5 Whilst reviewing the features of our ACP, we arrived at the following interesting reasoning:
in order to obtain high ees and trans:cis ratio of the products, single-chirality in pybox is presumably
sufficient in place of the C2-symmetry in pybox. The illustrative detail of our rationalization is described
in Fig. 1. If the single-chiral pybox with only one substituent R is adopted, the resultant intermediate A
may be selectively attacked by olefins from the third quadrant at the re-face of the carbene moiety. Even
though the rotational isomer B might be formed as a possible minor intermediate, it may rotate back to A
in an equilibrium. Therefore, we reasoned that the single-chirality in pybox is sufficient to a large extent
for the high stereoselectivities in the ruthenium-catalyzed ACP.
∗
Corresponding author. E-mail: hnishi@tutms.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00303-6

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Fig. 1.
2. Results and discussion
The single-chiral pybox-(H,R)-(S) 1a and 1b [R=i-Pr (ip) for a, R=t-Bu (tb) for b] were synthesized
by stepwise introduction of different amino alcohols into dimethyl pyridine-2,6-dicarboxylate. The
asymmetric cyclopropanation of styrene (10 mmol) and diazoacetate 3a–g (2 mmol) [ester group: a=Me,
b=Et, c=i-Pr, d=t-Bu, e=d-menthyl, f=l-menthyl, g=2,6-di-i-propyl-phenyl] was carried out using the in
situ catalyst of pybox-ip 1a (7 mol%) and [Ru(p-cymene)Cl2]2 (2) (5 mol% of Ru to diazoacetate) as a
standard condition (Scheme 1, Table 1). A reaction of pybox-ip 1a with methyl diazoacetate 3a resulted
in 71% and 48% ees for the trans-cyclopropane 4t and the cis-cyclopropane 4c, respectively, in a ratio
of 89:11 (entry 1). Pybox-tb 1b increased the ees up to 86% for 4t and 63% for 4c (entry 2). All the
products in entries 1 and 2 have a 1R-absolute configuration, the same as those previously reported by us
with pybox-(i-Pr,i-Pr)-(S,S) 5a.3 This fact, giving the same absolute configuration with high ees for the
trans-product, is consistent with the reaction course of styrene in both the C2-symmetric ligand and the
single-chiral one being similar; styrene attacks at the β-carbon atom to the re-face of the carbene moiety
followed by cyclopropane formation.
Scheme 1. Asymmetric cyclopropanation of styrene
Under the same reaction conditions using pybox-tb 1b, changing the ester groups of diazoacetate
increased the trans:cis ratio from 89:11 to 99:1 due to the bulkiness of the d- and l-menthyl group (entries
3–7). The highest ee of 94% for the trans-product 4t was eventually obtained with l-methyl diazoacetate
3f (entry 7), but the ees of the cis-product 4c settled in the middle range, 69% ee being the highest
with d-menthyl ester (entry 6). 2,6-Di-i-propylphenyl diazoacetate 3g in benzene at 60°C exclusively
gave the trans-product with 90% ee (entry 8). The unexpected decrease of the ees for the trans-product
with t-butyl ester and d-menthyl ester in entries 5 and 6 (68% and 55%, respectively) may be explained
by a mismatching of the stereotopic situation. As a comparison, the reaction of methyl diazoacetate with

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Table 1
Asymmetric cyclopropanation of styrene and diazoacetates with chiral pybox 1 and 5 and
[RuCl2(p-cymene)]2 (2)a
pybox-(i-Pr,i-Pr)-(S,S) 5a and non-chiral pybox-(H,H) 5b was reexamined by using 5 mol% of ruthenium
under the same reaction conditions applied above to show similar trans:cis ratios (89:11), 92% ee for the
trans-product 4t and 97% ee for the cis-product 4c (entries 9 and 10).
1,1-Diphenylethylene 6 was also cyclopropanated to give (1R)-product 7 in 68% ee with d-menthyl
ester. However, 1,2-disubstituted olefins such as trans-PhCH_CHPh, trans-EtCH_CHEt and dihydro-
naphthalene gave no cyclopropane derivatives, similar to our previous results with pybox 5a.
In order to confirm an intermediate complex, 2,6-di-t-butyltolyl diazoacetate 3h was subjected to a
reaction with [Ru(p-cymene)Cl2]2 2 and the single-chiral pybox-ip in dichloromethane at 20°C.6 After
stirring for 2 h, addition of hexane to the mixture produced a dark red product, which was defined as a
single isomer of the corresponding carbene complex 8 on the basis of an NMR study; in CD2Cl2 (TMS),
δ 21.68 (s, 1H) ppm for the carbene’s proton and δ 304.8 for the carbene’s carbon. In particular, 5% of
the NOE between the carbene proton H1 and the isopropyl proton H2 was observed, whilst only a 1%
NOE was observed for H1 and the oxazoline proton H3. We can conclude that the intermediate type A
predominately forms in the reaction solution rather than intermediate type B, presumably in equilibrium
due to free rotation at higher temperatures.7

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3. Experimental section
3.1. General
All reactions were carried out under nitrogen. Dichloromethane was distilled under nitrogen from
1
phosphorus pentoxide. H and 13C NMR spectra were recorded at 270 and 67.8 MHz, respectively, on
a JEOL JNM-GX 270 spectrometer using tetramethylsilane as the internal reference in CDCl3. Infrared
spectra were recorded on a JASCO A-3 spectrometer. Column chromatography was performed with silica
gel (Merck, Art 7734). Analytical TLC was performed on Merck (Art 5715) precoated silica gel plates
(0.25 mm). Optical purity was determined on a Shimadzu capillary gas chromatograph 14A with a chiral
capillary column (Astec Chiraldex B-DA, 30 m). Optical rotation was measured on a JASCO DIP-140
polarimeter.
3.2. Preparation of 1a and 1b
A solution of pyridine-2,6-dicarboxylic acid dimethyl ester (1.95 g, 10 mmol) and 2-aminoethanol
(0.6 ml, 10 mmol) in toluene (30 ml) was heated at 100°C for 30 min. The corresponding monoamide
methyl ester 9 (1.24 g, 55%) was obtained after silica gel chromatography. Then, the monoamide 9 (1.8
g, 8.0 mmol) and (S)-valinol (1 g, 10 mmol) in xylene (15 ml) was heated at 120°C for ca. 1 day. At
65°C, SOCl2 (3.4 ml) was added to the mixture, which was stirred for a further 16 h. Hydrolysis and
chromatography gave the bis-amide chloride 10 (2.46 g) in ca. 93%. Finally, the bis-amide 10 (1.83 g,
5.5 mmol) was treated with NaH (ca. 16 mmol) in THF (40 ml) at 35°C for 30 min to produce the desired
pybox 1a (1.33 g, 5.1 mmol, 93%). Compound 1b was prepared by the same procedure with (S)-2-t-
butyl-2-aminoethanol. 1a: m.p. 149–150°C; [α]D22=−65.1 (c=1.01, CH2Cl2); 1H NMR (CDCl3) δ=0.94
(d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.88 (m, 1H), 4.09–4.26 (m, 4H), 4.50–4.57 (m, 3H), 7.84
(t, J=7.8 Hz, 1H), 8.15 (dd, J=7.8 Hz and 1.0 Hz, 1H), 8.21 (dd, J=7.8 Hz and 1.0 Hz, 1H). 1b: m.p.
173–174°C; [α]D22=−58.0 (c=1.00, CH2Cl2); H NMR (CDCl3) δ=0.97 (s, 9H), 4.08–4.16 (m, 3H),
1
4.33 (t, J=8.9 Hz, 1H), 4.44–4.58 (m, 3H), 7.86 (t, J=7.8 Hz, 1H), 8.16 (dd, J=7.8 Hz, and 1.6 Hz, 1H),
8.26 (dd, J=7.8 Hz and 1.6 Hz, 1H).

H. Nishiyama et al. / Tetrahedron: Asymmetry 9 (1998) 2865–2869
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3.3. Isolation of 8
A solution of 2,6-di-t-butyltolyl diazoacetate 3h (52 mg, 0.2 mmol) in CH2Cl2 (1 ml) was added to
the solution of the pybox 1a and [RuCl2(p-cymene)]2 (61 mg, 0.1 mmol) in CH2Cl2 (4 ml) under cis-2-
butene atmosphere. The mixture was stirred at 20°C for 2 h. After concentration, the residue was charged
onto a silica gel column at 0°C with CH2Cl2:acetone (10:1–5:1) as eluent. The dark brown band was
collected and the eluent was concentrated to give brown solids of 8 (92 mg, 0.13 mmol) in 67% yield:
1
m.p. 119–120°C (dec): H NMR (CD2Cl2): δ=0.69 (d, J=7.3 Hz, 3H), 0.78 (d, J=7.3 Hz, 3H), 1.43 (s,
9H), 1.47 (s, 9H), 1.94 (m, 1H), 2.36 (s, 3H), 3.83 (dd, J=10.8 Hz, 2H), 4.05 (m, 2H), 4.77 (m, 1H),
4.86–5.00 (m, 3H), 7.20 (s, 2H), 8.02 (d, J=7.7 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 8.23 (t, J=7.7 Hz, 1H),
21.68 (s, 1H); 13C NMR (CD2Cl2): δ=15.0, 19.3, 21.6, 28.8, 31.1, 32.2, 32.4, 36.1, 36.2, 57.2, 71.4, 73.0,
73.5, 123.7, 123.9, 127.5, 134.8, 140.0, 141.6, 142.0, 143.7, 146.1, 163.4, 182.8, 304.8; IR (KBr disk):
1717 cm−1
.
3.4. Cyclopropanation of styrene and diazoacetate with 1 and 3
To a solution of 1 (0.14 mmol), 2 (0.05 mmol), and styrene (10 mmol) in dichloromethane (1 ml)
was added a dichloromethane solution of diazoacetate 3 (2.0 mmol, ca. 1 N) through a microsyringe
controlled by mechanical feeder (ca. 4 ml/drop, ca. 0.4 ml/h) for 5 h at 30–35°C under an argon
atmosphere. After stirring for an additional 5 h, the mixture was concentrated under reduced pressure.
The residual oil was subjected to silica gel column chromatography with hexane–ether as eluent to give
an oily mixture of trans-2-phenylcyclopropane-1-carboxylate 4t and the cis-isomer 4c. After the products
were converted to the corresponding methyl ester, their enantiomeric purities were measured by GLPC
(Astec, Chiraldex B-DA, 30 m×0.25 mm). See the detail in the literature.3b
References
1. (a) I. Ojima, Catalytic Asymmetric Synthesis, VCH, New York, 1993. (b) R. Noyori, Asymmetric Catalysis in Organic
Synthesis, John Wiley and Sons, Inc., New York, 1994, p. 199. (c) L. Seyden-Penne, Chiral Auxiliaries and Ligands in
Asymmetric Synthesis, John Wiley & Sons, Inc., New York, 1995. (d) M. P. Doyle, Advances in Catalytic Processes, Vol.
2, JAI Press, London, 1997. (e) A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron: Asymmetry, 1998, 9, 1.
2. (a) J. K. Whitesell, Chem. Rev., 1989, 89, 1581. (b) S. L. Blystone, Chem. Rev., 1989, 89, 1663.
3. (a) H. Nishiyama, Y. Itoh, H. Matsumoto, S.-B. Park, K. Itoh, J. Am. Chem. Soc., 1994, 116, 2223. (b) H. Nishiyama, Y.
Itoh, Y. Sugawara, H. Matsumoto, K. Aoki, K. Itoh, Bull. Chem. Soc. Jpn, 1995, 68, 1247 and references cited therein.
4. (a) S.-B. Park, N. Sakata, H. Nishiyama, Chem. Eur. J., 1996, 2, 303. (b) H. Nishiyama, K. Aoki, H. Itoh, T. Iwamura, N.
Sakata, O. Kurihara, Y. Motoyama, Chem. Lett., 1996, 1071.
5. In Ref. 1d (p. 180), we described the molecular orbital calculation of RuCl2(pybox)(CH2); the conformational isomer,
having a 0° dihedral angle between the plane of Cl–Ru–Cl and CH2, is a more stable isomer than the other isomer having
a 90° angle on the basis of extended Hückel calculation.
6. The cyclopropanation with the diazoacetate 3h and styrene did not proceed under the same condition at 60°C for entry 8.
7. We also confirmed that complex 8 acts as a catalyst of the cyclopropanation described above.