Ti(iv)-catalyzed cascade synthesis of tetrahydrofuro[3,2-d]oxazole from arene-1,4-diones

Article abstract of DOI:10.1039/c5ob00174a

A tetrahydrofuro[3,2-d]oxazole scaffold was synthesized efficiently and stereoselectively. The tandem ionic hydrogenation, ketalization, and intramolecular cyclization of arene-1,4-diones with a combination of TiCl₄/Et₃SiH give facile access to tetrahydrofuro[3,2-d]oxazole derivatives in good yields at room temperature.

Full text of DOI:10.1039/c5ob00174a

Organic &
Biomolecular Chemistry
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COMMUNICATION
Ti(IV)-catalyzed cascade synthesis of
tetrahydrofuro[3,2-d]oxazole from
arene-1,4-diones†
Cite this: Org. Biomol. Chem., 2015,
13, 4418
Received 29th January 2015,
Accepted 9th March 2015
Gang Li, Li Li, Haihong Huang* and Dali Yin*
DOI: 10.1039/c5ob00174a
www.rsc.org/obc
A tetrahydrofuro[3,2-d]oxazole scaffold was synthesized efficiently were from D-glucosamine. Therefore, the search for new
and stereoselectively. The tandem ionic hydrogenation, ketaliza- synthetic strategies leading to these scaffolds from simple
tion, and intramolecular cyclization of arene-1,4-diones with a starting materials in a sustainable and atom-economical
combination of TiCl4/Et3SiH give facile access to tetrahydrofuro- fashion is of continued interest of our group.
[3,2-d]oxazole derivatives in good yields at room temperature.
Recently, we developed a mild and efficient method for the
synthesis of tetralins via sequential ionic hydrogenation and
cyclization in the presence of TiCl4 and Et3SiH from the substi-
tuted phenylpentane-1,4-dione substrates.6 We believe that the
same concept can be applied to the synthesis of other hetero-
cycles. However, when NHAc and COOEt were incorporated
into the C(3) position of 1-(4-phenoxyphenyl)pentane-1,4-
dione (3), the treatment of substrate 1k with titanium chloride
and triethylsilane only afforded tetrahydrofuro[3,2-d]oxazole
racemate 2k, instead of the attempted product 5 (Scheme 1).
We did not find any other diastereomers except one pair of
enantiomers indicated as 2k. In order to confirm the relative
configuration, molecule 2k was converted into 6 which is a
solid by NaBH4/K2HPO4 reduction (Scheme 2). The configur-
Fused bicyclic oxygen-containing heterocycles are embodied in
a wide range of natural products, modified sugar derivatives,
and important bioactive molecules.1 Among these hetero-
cycles, the tetrahydrofuro[3,2-d]oxazole motif has been
exploited as a versatile biomimetic synthetic precursor for the
chemical syntheses of some rare sugars and antisense oligo-
nucleotides.2,3 It is reported that important groups of com-
pounds with the tetrahydrofuro[3,2-d]oxazole skeleton are
prodrugs of caspase inhibitors with apoptosis-regulating
activity (Fig. 1).4 However, there are very limited methods
available to stereoselectively synthesize such scaffolds.5 Most
methodologies for the construction of this type of heterocycles
Fig. 1 Representative examples of tetrahydrofuro[3,2-d]oxazole
derivatives.
Scheme 1 Strategy for the synthesis of tetrahydrofuro[3,2-d]oxazole
derivatives.
State Key Laboratory of Bioactive Substances and Function of Natural Medicine and
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation,
Institute of Materia Medica, Peking Union Medical College & Chinese Academy of
Medical Sciences, Beijing 100050, P. R. China. E-mail: yindali@imm.ac.cn,
joyce@imm.ac.cn; Fax: +86 10 63165244
†Electronic supplementary information (ESI) available: Experimental details,
compound characterization data and X-ray crystal structure data (CIF) for com-
pound 6. CCDC 978589. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c5ob00174a
Scheme 2 Reduction of 2k in the presence of NaBH4/K2HPO4 buffer.
4418 | Org. Biomol. Chem., 2015, 13, 4418–4421
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ation of the tetrahydrofuro[3,2-d]oxazole motif was confirmed due to the over reduction of other functional groups (Table 1,
by an X-ray crystal structure of 6 (CCDC 978589, Fig. 2). The entries 4–6).
X-ray analysis data demonstrate the exclusive formation of cis-
Encouraged by this promising result, a series of arene-1,4-
fused bicycles. The ring conjunction methyl and hydroxy- dione substrates, prepared by the method described in
methyl substituents were syn, as expected, and they were anti Scheme 3, were used to investigate the scope of the method for
to the benzyl hydrogen. So we can draw the conclusion that tetrahydrofuro[3,2-d]oxazole skeleton formation. Intermediate
compound 2k also has the same relative configuration. This 8 was prepared from ethyl acetoacetate/propionylacetate 7 via
interesting result encouraged us to explore the conditions, nitrosation, reduction and acylation. However, the reaction of
scope and mechanism of this novel reaction.
aroylation did not occur when R1 groups were aryl or aromatic
We initiated our studies by choosing 1k as the model sub- heterocyclic substituents. Subsequent replacement of the
strate. First, we screened various Lewis acids, Brønsted acids, bromide group of 9 with 8 gave substrate 1.
and solvents that might promote the heterocyclization. The
To our delight, the arene-1,4-dione substrate 1 smoothly
results indicated that only TiCl4 could promote the reaction to underwent heterocyclization to afford tetrahydrofuro[3,2-d]-
give racemate 2k. The choice of solvents was also crucial for oxazole racemate 2 in good yields and a series of functional
the reaction. The use of 1,2-dichloroethane resulted in a mode- groups including fluoro, chloro, bromo, methoxyl, trifluoro-
rate yield of products (Table 1, entry 7) and toluene gave a methyl, and phenoxyl on the aryl ring were well tolerated
much lower yield (Table 1, entry 8). Dichloromethane was under the optimal reaction conditions (2a–2t in Table 2). It
proved to be a good solvent for this reaction (Table 1, entry 4). was noticed that the substrates containing electron-donating
To further optimize the reaction parameters, the combination groups, such as alkyl, methoxy, and phenoxy, in general gave
of catalyst and reducing agent loading was screened. It was higher yields (2b–2d, 2h, 2k–2o, 2q–2t), while electron
found that the increased ratio of TiCl4 to Et3SiH resulted in deficient substrates with trifluoromethyl and halogen substitu-
higher yields of the product (Table 1, entries 1–4) while more ents gave lower yields (2e–2g, 2i). Moreover, heterocyclic sub-
than one equivalent of Et3SiH decreased the yield presumably strates could also react with TiCl4 and Et3SiH to smoothly
afford the expected products in good yields (2j, 2p). However,
for substrates bearing strong electron-withdrawing groups,
such as nitro, cyano, and pyridyl, no reaction occurred in the
presence of TiCl4 and Et3SiH under the optimized conditions.
Furthermore, we examined the heterocyclization of arene-1,4-
dione containing substitutions on alkyl counterparts (R1, R2).
Various substrates containing an ethyl group reacted smoothly
to provide the desired tetrahydrofuro[3,2-d]oxazoles (2n–2t,
respectively) in good yields. The above results indicate the gen-
Fig. 2 X-ray crystal structure of 6.
erality of the method in preparing tetrahydrofuro[3,2-d]oxa-
zoles in this new and highly efficient way.
To further study the substrate-controlled stereoselectivity of
this reaction, chiral separation of racemate 1k on a Chiralcel
AD-H column was employed to provide the chiral starting
Table 1 Optimization of reaction conditionsa
material (S)- and (R)-1k. The absolute configuration was con-
firmed by circular dichroism spectra. Both (S)-1k and (R)-1k
could be smoothly converted to the corresponding chiral 2k,
respectively, with over 99% ee and dr > 99 : 1 (Scheme 4).
A plausible mechanism to rationalize this transformation is
illustrated in Scheme 5. There are four carbonyls in the sub-
Catalyst
(equiv.)
Reductant
(equiv.)
Entry
Solvent
Yieldb (%)
strate (S)-1a. The real catalyst–reactant complex is not easy to
be captured. The complexation of benzyl carbonyl and acetyl-
1
2
3
4
5
6
7
8
9
TiCl4 (1.1)
TiCl4 (2.1)
TiCl4 (3.1)
TiCl4 (3.8)
TiCl4 (3.8)
TiCl4 (3.8)
TiCl4 (3.8)
TiCl4 (3.8)
TiCl4 (3.8)
TiCl4 (3.8)
Et3SiH (1.1)
Et3SiH (1.1)
Et3SiH (1.1)
Et3SiH (1.1)
Et3SiH (2.1)
Et3SiH (3.8)
Et3SiH (1.1)
Et3SiH (1.1)
Et3SiH (1.1)
Et3SiH (1.1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
Toluene
CH3CN
THF
NRc
65
74
81
52
45
68
15
NR
NR
10
a All reactions were performed at room temperature under an argon
atmosphere for 4 h with 0.5 mmol of 1k, the indicated amount of
TiCl4 and Et3SiH in 5.0 mL of the indicated solvent. b Isolated yields.
c No reaction.
Scheme 3 Synthesis of arene-1,4-dione substrates 1.
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Table 2 Heterocyclization from arene-1,4-dionea,b
Scheme 4 Substrate-controlled stereoselective synthesis of chiral 2k.
Scheme 5 Proposed mechanism for the formation of (+)-2a.
carbonyl of (S)-1a was firstly stereoselectively reduced to afford
intermediate A, promoted by TiCl4 using ionic hydrogenation.
Then the ketalization intramolecularly led to the formation of
intermediate B, whereas intermediate B could be easily con-
verted to intermediate C by strong Lewis acid according to the
literature.7 Finally, the neighboring acetamido group led to a
protonated oxazoline which could be deprotonated by the tri-
ethylsilanolate anion to afford the desired product (+)-2a.
Conclusions
In conclusion, an efficient and versatile method for the con-
struction of a tetrahydrofuro[3,2-d]oxazole scaffold has been
developed. Starting from easily accessible arene-1,4-diones,
these heterocycles are stereoselectively formed in a cascade of
ionic hydrogenation, ketalization, and intramolecular cycliza-
tion at room temperature. The efficiency and substrate scope
of this reaction have been demonstrated by the formation of a
wide range of functionalized tetrahydrofuro[3,2-d]oxazoles.
Mild conditions, high efficiency, and simple procedure render
this cascade reaction an attractive method in preparing tetra-
hydrofuro[3,2-d]oxazoles. Extension of the present reaction
toward the synthesis of related heterocyclic moieties and
detailed mechanistic investigations are currently in progress in
our laboratory.
a Reaction conditions: arene-1,4-dione
1
(0.5 mmol), TiCl4
(1.91 mmol), Et3SiH (0.55 mmol), CH2Cl2 (5 mL) at room temperature
under an argon atmosphere for 4 h. b Isolated yield.
amino with titanium was finally proposed to form a stable six-
membered cyclic half-chair intermediate. Large group COOEt
and Ac(NH) were more stable in equatorial orientation. The
Acknowledgements
reductant Et3SiH preferentially attacked on the less-encum- We thank the National Research Center for Analysis of Drugs
bered side of the plane. According to this proposal, the benzyl and Metabolites for NMR and IR analysis. We thank the
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