Oxidative cyclization of alkenols with Oxone using a miniflow reactor

Article abstract of DOI:10.3762/bjoc.5.18

A miniflow system for oxidative cyclization of alkenols with Oxone was developed. Thus, the oxidative cyclization of (Z)- and (E)- alkenols in i-PrOH with an aqueous solution of Oxone proceeded smoothly and safely in a PTFE tube without any exogenous catalytic species, and was subsequently quenched in a flow-reaction manner to afford the corresponding furanyl and pyranyl carbinols quantitatively within 5 or 10 min of residence time.

Full text of DOI:10.3762/bjoc.5.18

Oxidative cyclization of alkenols with
Oxone using a miniflow reactor
Yoichi M. A. Yamada1,2, Kaoru Torii2 and Yasuhiro Uozumi*,1,2
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 18.
1RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan and 2Institute for
Molecular Science (IMS), Myodaiji, Okazaki, Aichi 444-8787, Japan
doi:10.3762/bjoc.5.18
Received: 13 March 2009
Accepted: 27 April 2009
Published: 29 April 2009
Email:
Yasuhiro Uozumi* - uo@ims.ac.jp
* Corresponding author
Guest Editor: A. Kirschning
Keywords:
© 2009 Yamada et al; licensee Beilstein-Institut.
License and terms: see end of document.
alkenols; cyclic ethers; miniflow reaction; oxidative cyclization; Oxone
Abstract
A miniflow system for oxidative cyclization of alkenols with Oxone was developed. Thus, the oxidative cyclization of (Z)- and (E)-
alkenols in i-PrOH with an aqueous solution of Oxone proceeded smoothly and safely in a PTFE tube without any exogenous cata-
lytic species, and was subsequently quenched in a flow-reaction manner to afford the corresponding furanyl and pyranyl carbinols
quantitatively within 5 or 10 min of residence time.
Introduction
The development of flow-reaction systems for molecular trans- time) via a palladium-catalyzed Suzuki-Miyaura reaction under
formations is an important goal in organic syntheses. Recently, microflow conditions. An additional advantage of micro- and
innovative devices such as micro- and miniflow reactors that minireactors is the small heat capacity of the micro- and mini-
offer many fundamental as well as practical advantages for effi- flow systems thus rendering exothermic and/or potentially
cient organic transformations have been gaining ground in explosive reactions safe and practical. Consequently, oxidative
chemical experimentation [1-15]. Extensive investigations have transformations with potentially explosive oxidants would be
revealed that the large interfacial area and the short molecular ideal target reactions for miniflow systems. We wish to report
diffusion path in narrow space reactors often drastically the oxidative construction of furanyl and pyranyl alkyl carbinols
improve the efficiency of a given chemical reaction. As a case with Oxone via a miniflow reaction system.
in point, we have previously developed a catalyst-installed
microflow reactor where a membranous polymeric palladium Results and Discussion
catalyst was deposited inside a micro-channel reactor at the Furanyl and pyranyl carbinols have generated considerable
laminar flow interface [16], resulting in the instantaneous interest due to their presence in a number of therapeutically and
production of biaryls (quantitative yield within 4 s of residence biologically active compounds [17-31]. We therefore decided to
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Beilstein Journal of Organic Chemistry 2009, 5, No. 18.
Table 1: The oxidative cyclization of an alkenol 1a with Oxone under batch conditions.
oxidant
conditions
80 °C, 5 min
yield of 2a (%)
aq Oxone
99
30% aq H2O2
80 °C, 60 min
50 °C, 24 h
no reaction
99
polymeric PW12O403− (cat) with 30% aq H2O2 (see [32])
turn our attention to developing an oxidative cyclization of large-scale use impractical. To avoid these potentially
alkenols [32,33] for the preparation of furanyl and pyranyl alkyl dangerous and hazardous conditions in a large-scale batch oxid-
carbinols. During our investigation, we found that the oxidative ation, we switched the conventional batch system to a miniflow
cyclization of (Z)-4-decen-1-ol (1a) with Oxone system.
(2KHSO5·KHSO4·K2SO4) proceeded at 80 °C without any
exogenous catalysts under small-scale batch conditions (up to The miniflow reaction system is composed of poly(tetrafluoro-
50 mmol of 1a) to give threo-1-(2-tetrahydrofuranyl)hexan-1-ol ethylene) (PTFE) tubes of ø = 1 mm, T-shaped connectors, and
(2a) in 99% yield within 5 min (Table 1) [34]. When a mixture syringes with syringe pumps as shown in Figure 1. When the
of an aqueous solution of Oxone (100 mM, 1 mL, 2 equiv vs miniflow reaction of the alkenols 1 in i-PrOH with an aqueous
1a) and a 2-propanol solution of 1a (50 mM, 1 mL) was stirred solution of Oxone was carried out in the miniflow reactor with
at 80 °C for 5 min, the cyclization took place very smoothly to 5 min of residence time at 80 °C, we were pleased to see that
afford threo-1-(2-tetrahydrofuranyl)hexan-1-ol (2a) in 99% the reaction proceeded smoothly to afford the corresponding
yield as a single racemic diastereoisomer. Yet when 30% aq cyclic ethers 2 in high conversion. Thus, a solution of an
H2O2 was used as the oxidant at 80 °C, the cyclization hardly alkenol 1 in i-PrOH (50 mM) and Oxone in water (100 mM)
proceeded at all, even with a longer reaction time [32]. We had were oppositely injected with a flow rate of 4.0 μl/min each by
previously found that a polymeric phosphotungstate catalyst using syringe pumps from the individual inlets. The mixed solu-
promoted the cyclization of 1a with 30% aq H2O2 at 50 °C with tion passed through a PTFE tube reactor (length = 50 mm) at
a much longer reaction time (24 h). Thus, Oxone was found to 80 °C, and then was quenched with 30% aq Na2S2O3 solution
be the most efficient oxidant to promote the cyclization of (Z)- injected into the flow tube with a flow rate of 4.0 μl/min. The
4-decen-1-ol (1a). Although a powerful and inexpensive resulting organic/aqueous outflow was collected in a glass vial.
oxidant for this transformation [35-42], Oxone however is also The chemical conversion and structure of the products were
a known fire and explosion hazard [43] essentially rendering its determined by GC and 1H NMR analysis. As shown in Table 2,
Figure 1: Miniflow reaction system of oxidative cyclization.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 18.
Table 2: Oxidative cyclization of alkenols with Oxone through a miniflow reactor.a
Entry
1
Substrate
Product
Conversion (%)
99
1a
1b
2a
2b
2
90
3
88
90
1c
1d
2c
2d
4b
5b
70
1e
2e
aalkenol (50 mM in i-PrOH), Oxone (2KHSO5·KHSO4·K2SO4) (100 mM in H2O), flow rate: 4.0 μL/min each, 80 °C, residence time = 5 min; several frac-
tions were collected for each reaction shown to demonstrate the stable and high reactive performance of the miniflow reactor; the product 2a was
obtained in 0.12 mmol/h. bflow rate: 2.0 μL/min each, 80 °C, residence time = 10 min.
entry 1, the oxidative cyclization of (Z)-4-decen-1-ol (1a) with the product 2 stereospecifically [44,45]. It should be noted that
Oxone was performed within 5 min of residence time to afford the miniflow cyclization of 1a was continuously carried out to
threo-1-(2-tetrahydrofuranyl)hexan-1-ol (2a) in 99% conver- give a quantitative conversion of 2a over 2 h.
sion. The cyclization of (Z)-4-hexen-1-ol (1b) and (Z)-4-hepten-
1-ol (1c) proceeded smoothly to give the threo-tetrahydrofur- Conclusion
anyl alcohols 2b and 2c in 90% and 88% conversion, respect- In conclusion, we have developed a miniflow reaction system
ively (entries 2 and 3). This flow reaction system was also util- for the oxidative cyclization of alkenols with Oxone, affording
ized for the formation of six-membered cyclic ethers. Thus, the the corresponding cyclic ethers in high conversion, where
oxidation of (Z)-5-octen-1-ol (1d) was carried out with a flow potentially explosive Oxone was used and quenched safely.
rate of 2.0 μL/min (residence time: 10 min) to give 90% conver- Development of instantaneous flow reaction systems for the
sion of the threo-tetrahydropyranyl alcohol 2d (entry 4). (E)-4- oxidation reactions with a retention time of several seconds is
Decen-1-ol (1e) underwent oxidative cyclization with 10 min currently in progress.
residence time to afford the erythro-product 2e in 70% conver-
sion (entry 5). These stereochemical observations indicate that Acknowledgments
the cyclization involves a stereospecific reaction pathway. The This work was supported by the GSC project, sponsored by the
reaction pathway of the present oxidative cyclization should METI. We thank the JSPS (Grant-in-Aid for Scientific
proceed via the epoxidation of the alkene 1 with Oxone and Research, no.15205015, no. 16790025, no.18065019 and
subsequent oxirane ring opening with the intramolecular no. 20655035), and the MEXT (Scientific Research on Priority
oxygen nucleophile (an intramolecular SN2 reaction) to afford Areas, no. 460) for partial financial support of this work.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 18.
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