Catalytic hetero-ene reactions of 5-methyleneoxazolines: Highly enantioselective synthesis of 2,5-disubstituted oxazole derivatives

Article abstract of DOI:10.1039/c4cc02809k

An efficient catalytic asymmetric hetero-ene reaction of 5-methyleneoxazolines with 1,2-dicarbonyl compounds (including α-ketoesters and glyoxal derivatives) was realized using Ni(ii)-N,N′-dioxide complexes as the catalysts. It provides a rapid, high yielding (up to 99%) route for the preparation of 2,5-disubstituted oxazole derivatives in a highly enantioenriched form (up to >99% ee) under mild conditions. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02809k

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Catalytic hetero-ene reactions of
5-methyleneoxazolines: highly enantioselective
synthesis of 2,5-disubstituted oxazole derivatives†
Cite this: Chem. Commun., 2014,
50, 7524
Received 16th April 2014,
Accepted 21st May 2014
Weiwei Luo, Jiannan Zhao, Chengkai Yin, Xiaohua Liu, Lili Lin and Xiaoming Feng*
DOI: 10.1039/c4cc02809k
www.rsc.org/chemcomm
An efficient catalytic asymmetric hetero-ene reaction of 5-methyl- components has been less studied. The hetero-ene reaction using
eneoxazolines with 1,2-dicarbonyl compounds (including a-ketoesters 2-methylene-2,3-dihydrofuran8h and 2-methylene-tetrahydropyrans8i
and glyoxal derivatives) was realized using Ni(II)–N,N0-dioxide complexes as the nucleophiles was reported by Miles and Totah, respectively.
as the catalysts. It provides a rapid, high yielding (up to 99%) route for However, a comprehensive study on the asymmetric hetero-ene
the preparation of 2,5-disubstituted oxazole derivatives in a highly reaction of exocyclic enol ethers has not been carried out. Along these
enantioenriched form (up to 499% ee) under mild conditions.
lines, we report the realization of such a method that a number of
a-ketoesters and glyoxal derivatives were employed in the catalytic
Oxazoles are very important structural motifs towards a wide enantioselective hetero-ene reaction with 5-methyleneoxazoline. The
variety of natural products, pharmaceuticals, and synthetic chiral N,N0-dioxide complex9 of Ni(BF4)2ꢀ6H2O afforded the desired
intermediates.1 Specifically, 2- and 5-substituted oxazoles exist in a products with excellent outcomes (up to 99% yield, 499% ee) under
wide range of compounds that show potent antibacterial, antiviral, mild reaction conditions.
and antitumor activity.2 Traditional methodologies for the formation
Our preliminary experiment surveyed the asymmetric reaction
of substituted oxazole derivatives mainly include cyclization of between 5-methyleneoxazoline 2a and methyl 2-oxo-2-phenylacetate
acyclic precursors,3 oxidation of oxazolines,4 and functionalization 1a considering that the resulting product contains two privileged
of the parent oxazole ring.5 In recent years, the cyclization of moieties: a-hydroxyl esters with a quaternary carbon center10 and
acetylenic amides to the corresponding oxazole derivatives has been 2,5-disubstituted oxazole. Initial observations revealed that both the
a focus of interest.6a,b In some cases, the synthesis of oxazoles from metal precursor and the chiral ligands were crucial to the yields and
N-propargylcarboxamides stopped at the alkylideneoxazoline stage, enantioselectivities (Table 1, entries 1–5). Using N,N0-dioxide L1 as the
which provides an alternative route to synthesis of 5-functionalized chiral ligand, the reaction proceeded sluggishly in the presence of
oxazoles.6c–e A one-pot combination of alkylideneoxazoline synthesis metal salts such as Sc(OTf)3 and Zn(OTf)2 (Table 1, entries 1 and 2);
with an Alder-ene reaction of azodicarboxylates was designed to however, the L1–Yb(OTf)3 complex gave the desired product in 29%
form oxazolemethylhydrazinedicarboxylates by Hashmi and yield and 83% ee (Table 1, entry 3); and better outcomes were
coworkers.6f We envision that using methyleneoxazolines as obtained when Y(OTf)3 was used as the metal precursor (69% yield
the ene analogues and with the assistance of chiral catalysts, a and 87% ee; entry 4). It was gratifying to find that the L1–Ni(BF4)2ꢀ
variety of carbonyl compounds as the enophiles could be 6H2O complex furnished the products with excellent enantioselectivity
coupled. Thus, optically active alcohol derivatives with pendant although the yield was low (16% yield and 499% ee; entry 5).
oxazole units could be afforded readily from such an enantio- Inspired by these results, the efficiency of other N,N0-dioxide ligands
selective hetero-ene reaction, which has not yet been reported. with Ni(BF4)2ꢀ6H2O was explored. The observations suggested that
An asymmetric hetero-ene reaction is useful in carbon–carbon L-pipecolic-acid derived L2 exhibited superior reactivity compared with
bond forming processes which has received remarkable progress in L-proline derived ligand L1 and L-ramipril derived L3 (Table 1, entry 6
the past decade.7,8 While the addition of acyclic enol ethers has been versus entries 5 and 7). Steric hindrance on the phenyl ring of the
widely applied,8a–g the use of exocyclic enol ethers as the ene ligand plays a key role in promoting both the enantioselectivity and
reactivity. Poor results were observed by using the aniline-derived
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
ligand L4 (Table 1, entry 8 versus entry 6). Further attempts to improve
the yield were focused on the reaction temperature and the additives.
Fortunately, elevating the reaction temperature from 30 1C to 40 1C
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: xmfeng@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
† Electronic supplementary information (ESI) available: Additional experimental
benefited the yield (Table 1, entry 9 versus entry 6). Moreover, addition
of 4 Å molecular sieves (MS) to the system could improve the yield to
and spectroscopic data. CCDC 991898 and 994240. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4cc02809k
7524 | Chem. Commun., 2014, 50, 7524--7526
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Table 1 Optimization of the reaction conditions
Table 2 Substrate scope for the catalytic asymmetric hetero-ene reaction
of a-ketoesters
Entrya 1, R1, R2
2, R3
Yieldb (%) eec (%)
1
2
3
4
1a, C6H5, Me
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
97 (3a)
99 (3a2)
98 (3a3)
98 (3a4)
95 (3b)
77 (3c)
42 (3d)
97 (3e)
63 (3f)
66 (3g)
499
499
499
499
499
499
99
1a2, C6H5, Et
1a3, C6H5, iPr
Entrya
L
Metal
T (1C)
Yieldb (%)
eec (%)
1a4, C6H5, tBu
5
1b, 3-MeC6H4, Me
1c, 4-MeC6H4, Me
1d, 2-MeOC6H4, Me
1e, 3-MeOC6H4, Me
1f, 4-MeOC6H4, Me
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L2
L3
L3
L3
L3
L3
Sc(OTf)3
Zn(OTf)2
Yb(OTf)3
Y(OTf)3
Ni(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
30
30
30
30
30
30
30
30
40
40
40
40
0
Trace
29
69
16
59
31
7
64
86
95
97
—
—
6
7d
8
83
87
499 (S)e
499
499
9
10
499
499
97
1g,
, Me
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1h, 3-FC6H4, Me
1i, 4-FC6H4, Me
1j, 3-ClC6H4, Me
1k, 4-ClC6H4, Me
1l, 3-F3CC6H4, Me
1m, 4-F3CC6H4, Me
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
99 (3h)
95 (3i)
98 (3j)
99 (3k)
99 (3l)
97 (3m)
97 (3n)
95 (3o)
93 (3p)
95 (3q)
96 (3r)
95 (3s)
98 (3t)
98 (3u)
96 (3v)
40 (3w)
84 (3x)
75 (3y)
499
499
499
499
499
99
499
499
499
499
499
499
499
99
92
9
499
499
499
499
10d
11d,e
12d–f
a
1n, 3-CH2QCHC6H4, Me 2a, C6H5
1o, 4-CH2QCHC6H4, Me 2a, C6H5
Unless otherwise noted, all reactions were carried out with 1a
(0.1 mmol) and 1.1 equiv. of 2a in CH2Cl2 (1.0 mL) at 30 1C for 48 h.
1p, 3,5-Me2C6H3, Me
1q, 3-iPrC6H4, Me
1r, 4-tBuC6H4, Me
1s, 4-phC6H4, Me
1t, 2-naphthyl, Me
1u, 2-thienyl, Et
1v, 2-furyl, Me
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
b
c
Isolated yield. Determined by HPLC analysis using a Chiralcel IB
d
e
column. 4 Å MS (20 mg) was added. 2.0 equiv. of 2a was used.
f
Reactions were carried out with 1a (0.2 mmol) in CH2Cl2 (1.0 mL).
86% with the ee being maintained (Table 1, entry 10). Pleasingly,
when the ratio of a-ketoester 1a and methyleneoxazoline 2a was fixed
to 1 : 2, the desired product 3a was generated in 95% yield and
499% ee (Table 1, entry 11). Furthermore, increasing the reaction
concentration also favoured the improvement of the yield (Table 1,
entry 12). Remarkably, we found that the catalytic system was
insensitive to both atmospheric oxygen and moisture, thus making
the catalytic system practical.
499
499
499
499
1w, c-hexyl, Me
1x, Me, Me
1y,
, Et
29
30
1a, C6H5, Me
1a, C6H5, Me
2b, 3-MeOC6H4 91 (3ba)
2c, 4-MeC6H4 98 (3ca)
499
499
a
Unless otherwise noted, all reactions were carried out with 10 mol%
of L2–Ni(BF4)2ꢀ6H2O, 0.2 mmol of a-ketoester 1, 2.0 equiv. of 2, and
b
20 mg of 4 Å MS in CH2Cl2 (1.0 mL) at 40 1C for 48 h. Isolated yield.
With the optimized reaction conditions identified, the substrate
scope was investigated by using a series of a-ketoesters. It seemed that
methyl, ethyl, isopropyl and tert-butyl esters gave identical excellent
c
d
Determined by HPLC analysis. The reaction was carried out for 96 h.
The absolute configuration was determined by X-ray analysis.
e
results (Table 2, entries 1–4). Generally, the reactions were remarkably phenylglyoxal 4a was expanded to a gram scale, and the desired
tolerant of functional groups in terms of enantioselectivity regardless product 5a was accomplished in 93% yield with 99% ee (Scheme 1b).
of the electronic properties and steric hindrance of the substituents Notably, the reduction of the carbonyl group in 5a by using KBH4
on the a-aryl group of the a-ketoesters (Table 2, entries 5–23). The afforded the 1,2-diol 6 in quantitative yield with the maintained
catalyst system was also applicable to heteroaryl a-ketoesters, which enantioselectivity, which is a valuable intermediate in the synthesis
delivered the related adducts in excellent outcomes (Table 2, entries of drugs and natural products (Scheme 1c).12
24 and 25). The aliphatic a-ketoesters also reacted with 2a in excellent
Based on the X-ray crystal structure of the catalyst,9a as well as the
enantioselectivity even though the yield decreased a little (Table 2, absolute configuration of the products,13 a possible transition state
entries 26–28). Moreover, when nucleophiles, like 2b and 2c, were was proposed (Scheme 2). The a-ketoester or glyoxal derivative tended
subjected to the reaction, the desired products with up to 98% yield to coordinate to nickel(II) in a bidentate fashion by the dicarbonyl
and 499% ee were achieved (Table 2, entries 29 and 30).
group. The Si face of the a-ketoester was shielded by the neighboring
Encouraged by the above results, glyoxal derivatives were 2,6-diisopropylphenyl group of the ligand, and the nucleophile
tested in the reaction with 5-methyleneoxazoline. Pleasingly, the attacked from the Re face predominantly to give the S-configured
L2–Ni(BF4)2ꢀ6H2O complex was more suitable for such kinds of product 3h. In a similar manner, the 5-methyleneoxazoline would
substrates even at 0.5 mol% catalyst loading, and the desired attack from the Si face of the glyoxal derivative to give the S-configured
products were obtained in excellent yields (60–99% yields) with product 5m.
excellent ee values in the range of 95–499% (Scheme 1a).11 To
show the utility of the current method, the hetero-ene reaction of asymmetric hetero-ene reaction that involves methyleneoxazoline
In conclusion, we have developed a highly efficient catalytic
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Notes and references
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Scheme 1 (a) Substrate scope for the catalytic asymmetric hetero-ene
reaction of glyoxal derivatives (see ESI† for full lists); (b) scaled-up version
of the asymmetric hetero-ene reaction; (c) transformation of product 5a.
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Scheme 2 Proposed transition-state and the X-ray crystallographic
structure of (S)-product 3h and (S)-product 5m.
as the reaction partner for the enantioselective synthesis of
2,5-disubstituted oxazole derivatives. In the presence of the
N,N0-dioxide–Ni(BF4)2ꢀ6H2O catalysts, both a-ketoesters and glyoxal
derivatives underwent the reaction smoothly, thus providing
the corresponding products in excellent yields (up to 99%) and
extremely high enantioselectivities (up to 499% ee). In particular,
this new process proceeds under mild conditions, exhibits a broad
substrate scope and functional-group tolerance, and features good
air and moisture tolerance. Application of this chemistry to natural
product synthesis and additional studies of alkylideneoxazolines is
currently ongoing.
9 For selected examples using chiral N,N0-dioxide metal complexes,
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We appreciate the National Natural Science Foundation of 11 See ESI† for details.
12 (a) S. D. Rychnovsky, Chem. Rev., 1995, 95, 2021; (b) K. Murata,
China (No. 21321061 and 21172151), the National Basic Research
Program of China (973 Program: No. 2011CB808600), and the
Ministry of Education (NCET-11-0345) for financial support.
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13 CCDC 991898 (3h) and 994240 (5m).
7526 | Chem. Commun., 2014, 50, 7524--7526
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