Oxidative transformation of cyclic ethers/amines to lactones/lactams using a DIB/TBHP protocol

Article abstract of DOI:10.1039/c3ra44184a

A novel C-H oxidation of cyclic ethers and amines to the corresponding lactones and lactams was developed using a DIB/TBHP protocol. The reaction is mild and no metallic reagent is involved. In addition, study shows that the electronic properties of the substituents could affect the selectivity of oxidation. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra44184a

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Communication
Oxidative Transformation of Cyclic Ethers/Amines to Lactones/Lactams
Using DIB/TBHP Protocol †
Yi Zhao,a Jascelyn Qian Lin Ang,a Angela Wan Ting Ng,a Ying-Yeung Yeung*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel C-H oxidation of cyclic ethers and amines to the 45 insertion products were obtained when alkyl and aryl α-
corresponding lactones and lactams was developed using a
DIB/TBHP protocol. The reaction is mild and no metallic
reagent is involved. In addition, study shows that the
substituents were used.
10 electronic properties of the substituents could affect the
selectivity of oxidation.
Lactones and lactams are common structural elements present
in numerous biologically activate naturally occurring molecules,
for example lignans and rebeccamycin.1 Owing to their
15 prevalence in natural products, there have been a number of
synthetic methods devised to construct these motifs. One of the
most straightforward syntheses is through the oxidation of cyclic
ethers/amines, readily available substrates already possessing the
carbon backbone of the desired lactones and lactams. Benzylic
20 heterocycles (e.g. Isocoumaran) can readily be oxidized to the
corresponding products (e.g. Phtoalide). However, the oxidation
of cyclic, non-benzylic ethers/amines remains a challenging task
and a high-energy process, partly due to the relatively inert
property of such α-C-Hs. Efforts have involved the use of
25 metallic reagents/catalysts such as Ru,2 Cr,3 Cu,4 Fe,5 and Ir6 in
the non-benzylic cyclic ether/amine oxidation.7 In contrast,
sporadic studies have been reported on nonmetallic-based
methods.8
Scheme 1 Summary of the oxidation reactions in this manuscript.
An initial experiment was performed using (tetrahydrofuran-2-
50 yl)methyl acetate (1a) together with DIB/TBHP in CH2Cl2. After
12 h, the reaction was quenched with sodium sulfite to afford a
29% isolated yield of the desired product (5-oxotetrahydrofuran-
2-yl)methyl acetate (2a) (Table 1, entry 1). Encouraged by this
Table 1. Optimization of the oxidation of 1a.
55
Entrya
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeNO2
CHCl3
H2O
DIB (eqiv)TBHP (eqiv)Yieldb
1
2
2
3
4
3
3
3
3
3
3
3
3
3
3
3
4
3
3
3
3
3
3
4
4
4
4
4
4
4
29
33
31
26
28
33
21
65
38
55
23
35
28
39
3
We have recently established a DIB/TBHP oxidation protocol
30 which was applied to the allylic oxidation,9a the oxidation of
unactivated and remote methylene sp3 C-Hs to ketones,9b and the
transformation of azides to aryl nitriles.9c In these studies,
bis(tert-butylperoxy)iodobenzene, which was generated in situ by
the reaction between diacetoxyiodobenzene (DIB) and tert-butyl
35 hydroperoxide (TBHP), is believed to be the active species which
can provide a reactive but controllable tBuOO• for the methylene
proton abstraction.10 We rationalized that the DIB/TBHP protocol
can also activate the inert methylene C-H bonds adjacent to
oxygen/nitrogen in cyclic ethers/amines, which can offer the
40 corresponding lactone/lactam products.11 Herein, we are pleased
to disclose our recent development of a new synthetic method for
the construction of non-benzylic lactones/lactams employing
simple reaction setup and readily available reagents, and under
mild conditions. In addition, unexpected ring-opeing/oxygen
4
5
6
7
8
9
10
11
toluene
12 1:1 MeCN : H2O
13
14
EtOAc
nBuOAc
a Reactions were carried out with 1a (0.5 mmol) in solvent (1 mL) for 12
h. b Isolated yield.
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cyclic ether oxidation, the oxidation of cyclic amines (5- and 6-
40 membered rings) returned with good conversions and functional
groups compatibility. More importantly, the L-proline-derived
substrate 3e gave the desired product 4e with retention of
enantiomeric purity, which suggests that the C-H abstraction did
not take place at the more substituted carbon.14
preliminary study, further optimizations were carried out. The
ratio of DIB/TBHP was firstly varied and the reaction was found
to give an isolated yield up to 33% when the ratio was 3:4 (Table
1, entries 2–6). Having identified the appropriate ratio of DIB and
TBHP, various solvents were screened and nitromethane was
found to afford 65% of the lactone product (Table 1, entries 7–
14). It is noteworthy that the reaction proceeded smoothly even
when using pure water as the solvent (Table 1, entry 10).
5
45
Towards the understanding of mechanism, a plausible pathway
is proposed and illustrated in Scheme 1. The tert-butylperoxy
radical may abstract the α-heteroatom proton of A to generate the
α-heteroatom radical B, potentially stabilized by the heteroatom.
Coupling of tBuOO• with species B can produce the peroxy ether
With the optimized conditions identified, some cyclic ether
10 substrates were examined and the results are summarized in
Table 2.12 In general, the reaction selectivity of cyclic ethers
proceeded smoothly to yield the corresponding lactones with
good conversions. Moreover, excellent chemo- and
regioselectivities were observed, wherein the reaction occurred
15 on the less sterically-hindered side of the cyclic ether systems.
We attempted to subject the lactone product 2a under the
optimized conditions. After 72 h, 2a was recovered quantitatively
and no over-oxidized product was detected. The oxidation
protocol is also highly compatible with various protecting and
20 functional groups including tert-butyldimethylsilyl (TBS), acetyl,
benzoyl, and tosyl groups (Table 2, entries 1–5). In addition,
other than five member ring system, six member ring system also
returned with good reaction yield (Table 2, entry 7).
50 intermediate C, which was evidenced by the successful isolation
Table 3. Oxidation of Cyclic Amines 3 to Lactams 4.
Table 2. Oxidation of Cyclic Ethers 1 to Lactones 2.
a
Reactions were carried out with 3 (0.5 mmol), DBH (0.12 mmol) in
b
solvent (5 mL) at –60 oC. The reaction was conducted at –50 oC.
55 Isolated yield.
c
of species C (X = O, R = H).15 Subsequent oxidation of C can
provide the desired lactone or lactam product D. Moreover, the
reaction was terminated immediately upon the addition of
butylated hydroxytoluene (BHT), which indicated the radical
60 nature of the reaction.
25
a
Reactions were carried out with 1 (0.5 mmol), DIB (1.5 mmol), TBHP
(2.0 mmol), in MeNO2 (1.0 mL) for 12 h. b Isolated yield. The amount of
unreacted starting material 1 was determined by 1H NMR and indicated in
the parentheses. c DIB (3.0 mmol) and TBHP (4.0 mmol) were used.
30
Other than the oxidation of cyclic ethers, we have also
examined the oxidation of cyclic amines to lactams (Table 3).
Under the optimized conditions, N-Boc and N-Ac pyrrolidines 3a
and 3b returned with good conversions. In fact, we have also
examined N-methyl pyrrolidine and no desired lactam was
35 detected.13 It appears that the electronic demand at the nitrogen
plays a crucial role in the reactivity; an electron-rich pyrrolidine
gave a direct N-oxidation product, while a relatively electron-
deficient system suffered from lower reactivity. Similar to the
Scheme 1 Proposed Mechsnism of the oxidation reaction resulting in the
formation of lactones and lactams.
2
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DOI: 10.1039/C3RA44184A
50
S. V. Pitre, M. V. Ram Reddy, R. Kumareswaran, Y. D. Vankar, J.
Org. Chem., 1999, 64, 4509–4511.
We attempted to further explore the substrate scope.
Surprisingly, when 2-methyltetrahydrofuran (5) and 2-
phenyltetrahydrofuran (7) were oxidized using the DIB/TBHP
protocol, no lactone was detected. Instead, unusual ring-opening
hydroxyl-esters 6 and 8 were isolated as the sole products,
respectively (Scheme 2, eq 1 and 2). When the chlorinated ether
was used as the substrate, a mixture of ring-opening product and
lactone (5:7, ratio determined by 1H NMR) was detected (Scheme
2, eq 3). Although the mechanistic pathway that leads to such
4
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10 ring-opening products remains unclear, these results suggest that
the electronic properties of the substituents can affect the
oxidation’s positional selectivity.16
65
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80
10 For some recent examples of oxidative reactions using hypervalent
iodine reagents, see: (a) T. Dohi, N. Takenaga, T. Nakae, Y.
Toyoda, M. Yamasaki, M. Shiro, H. Fujioka, A. Maruyama, Y.
Kita, Y. J. Am. Chem. Soc., 2013, 135, 4558–4566; (b) T. Dohi, T.
Nakae, N. Takenaga, T. Uchiyama, K. Fukushima, H. Fujioka, Y.
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11 In 1968, Plensicar reported that preparation of bis(tert-
butylperoxy)iodobenzene in diethyl ether solvent gave appreciable
amount of ethyl acetate, which should be a result of C-H oxidaiton
of ether. For ref, see: N. A. Milas, B. Plesnicar, J. Am. Chem. Soc.,
1968, 90, 4450–4453.
12 Representative procedure for the oxidation: To a solution of
(tetrahydrofuran-2-yl)methyl acetate (1a) (72 mg, 0.50 mmol) in
nitromethane (1 mL) was added diacetoxyiodobenzene (484 mg,
1.5 mmol) at 0 oC. The resultant suspension was vigorously stirred
and a solution of tert-butylhydroperoxide (5.0 M in decane, 400
µL, 2.0 mmol) was added dropwise over 30 min. After 12 hours,
the reaction was quenched with Na2SO3 (5 mL). The organic layer
was separated and the aqueous layer was extracted with
dichloromethane (4 x 5 mL). The combined extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography eluted with n-
hexanes/EtOAc (2:1) to yield (5-oxotetrahydrofuran-2-yl)methyl
acetate (2a) as a yellow oil (51 mg, 65%).
15
Scheme 2 Examination on Other Substrates.
In summary, we have developed a novel C-H oxidation of
cyclic ethers and amines to the corresponding lactones and
lactams using a DIB/TBHP protocol. The reaction is mild and no
metallic reagent is involved. Further investigation on the
85
20 mechanism is underway.
90
We thank the financial support from Agency for Science,
Technology and Research, Public Sector Funding (A*STAR-
PSF) (Grant No. 143-000-536-305) and National Environmental
Agency (NEA-ETRP) (Grant No. 143-000-547-490). We also
25 thank Professor Y. Kita (Retsumeikan University) for his advice
and encouragement. Yi Zhao would like to thank National
University of Singapore for sponsoring his PhD scholarship.
95
100
Notes and references
a Department of Chemistry, NUS, 3 Science Drive 3, Singapore 11754 .
30 Fax: (65)-6779-1691; Tel: (65)-6516-7760; E-mail: chmyyy@nus.edu.sg
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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35
40
45
110 13 A very polar product was detected in the reaction which is believed
to be the N-oxide compound.
14 J. Sperry, Synthesis, 2011, 3569–3580 and references cited therein.
15 It was evidenced by the successful isolation of peroxy ether C (X =
O, R = H, n = 1) when the reaction of THF with DIB/TBHP was
2
o
115
quenched at 0 C. Subjecting the intermediate C (X = O, R = H, n
= 1) under standard oxidation condition gave the desired lactone D
(X = O, R = H, n = 1).
16 We speculate that the key step involves the proton abstraction of 5
(or 7) may occur at the tertiary carbon to yield the corresponding
tertiary radical species, followed by the coupling of tert-
butylperoxy radical. However, this remains unclear and is
subjected to further investigation.
120
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