3-methyl-4-oxa-5-azahomoadamantane: Alkoxyamine-type organocatalyst for alcohol oxidation

Article abstract of DOI:10.1002/anie.201307144

Strong, silent type: A novel alkoxyamine-type organocatalyst has been discovered for alcohol oxidation (see scheme). The alkoxyamine exhibits a high catalytic activity for the oxidation of alcohols to afford the corresponding carbonyl compounds in high yield by oxidative transformation into an oxoammonium ion, which is proposed to serve as an active species. Copyright

Full text of DOI:10.1002/anie.201307144

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Communications
DOI: 10.1002/anie.201307144
Synthetic Methods
3-Methyl-4-oxa-5-azahomoadamantane: Alkoxyamine-Type
Organocatalyst for Alcohol Oxidation**
Yusuke Sasano, Keiichi Murakami, Tomohiro Nishiyama, Eunsang Kwon, and
Yoshiharu Iwabuchi*
The unique behavior and eminent reactivity of organic/
inorganic nitrogen oxides have continuously attracted the
attention of chemists not only because of their profound
chemistry, but also because of their use in various fields of
material and life sciences.[1] Herein, we report the discovery of
a novel alkoxyamine-type organocatalyst, 3-methyl-4-oxa-5-
azahomoadamantane (1), which enables highly efficient
oxidation of primary and secondary alcohols into their
corresponding carbonyl compounds using NaOCl as the
terminal oxidant. The present work first shows a useful
pathway from an alkoxyamine/alkoxyaminyl radical to
a nitroxyl radical/oxoammonium ion under oxidative condi-
tions (Figure 1).[2,3]
(5), a highly active catalyst for alcohol oxidation.[4] Thus, we
envisaged that 1-Me-AZADOL (4) could be obtained from
hydroxylamine (3) by an intramolecular Cope-type hydro-
amination (Scheme 1).[5–7]
Scheme 1. Synthetic plan of 1-Me-AZADOL (4).
Although the intended cyclization reaction of 3 did not
proceed even in boiling xylene, the treatment of 3 with
5 equivalents of TfOH in CH2Cl2 at 08C induced a rapid and
clean reaction to give the polar product 1, for which spectral
data were not consistent with those of 4 (Scheme 2).[8,9] After
detailed spectral analysis and single-crystal X-ray crystallog-
raphy, we concluded that the structure of 1 is that of 3-methyl-
4-oxa-5-azahomoadamantane (Figure 2). It was concluded
that, upon treatment with TfOH, 3 did not undergo the
intended Cope-type hydroamination, but instead reacted
Figure 1. Redox properties of nitroxyl radicals and alkoxyaminyl
radicals.
The synthesis of a homoadamantane-embedded alkoxy-
amine and its use as a catalyst for alcohol oxidation were
unexpectedly discovered during our attempts to develop 1-
methyl-2-azaadamantan-2-ol (1-Me-AZADOL; 4), which is
a functional equivalent of the nitroxyl radical 1-Me-AZADO
Scheme 2. Discovery of the alkoxyamine 1. Tf=trifluoromethanesul-
[*] Y. Sasano, K. Murakami, T. Nishiyama, Prof. Dr. Y. Iwabuchi
Department of Organic Chemistry
fonyl.
Graduate School of Pharmaceutical Sciences, Tohoku University
6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: y-iwabuchi@m.tohoku.ac.jp
Dr. E. Kwon
Research and Analytical Center for Giant Molecules, Graduate
School of Science, Tohoku University, Sendai 980-8578 (Japan)
[**] This work was partly supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysis” from the Ministry of Education, Culture,
Sports, Science and Technology (Japan), by a Grant-in-Aid for
Scientific Research (B) (No. 24390001), and by a Grant-in-Aid for
Young Scientists (B) (No. 25860001) from the Japan Society for the
Promotion of Science (JSPS).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307144.
Figure 2. ORTEP drawing of 1 with probability ellipsoids drawn at the
50% level.
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through hydroetherification to form a less stable seven-
membered ring.[10]
Our curiosity urged us to examine the catalytic activity of
1 in connection with 4. We surprisingly found that 1 exhibited
exceptionally high catalytic efficiency in the presence of
NaOCl to oxidize menthol in quantitative conversion
(Scheme 3).[11]
Scheme 3. Catalytic activity of 1 for alcohol oxidation.
Encouraged by the excellent catalytic activity of 1, we
evaluated the scope of the alcohol oxidation catalyzed by
1 using NaOCl as the bulk oxidant (Table 1). Various alcohols,
Table 1: Scope of the 1-catalyzed oxidation.
Scheme 4. Experiments for determination of active species. a) Isola-
tion of products derived from 1. b) Structure elucidation of 8-Br-1-Me-
AZADO (8). c) Catalytic activities of isolated compounds.
residue after extraction and evaporation. Chromatographic
purification of the residue gave products derived from
1 (Scheme 4a). The 8-Br-1-Me-AZADO (8) and dimeric
diazo compound 9 were isolated as the major products.
Notably, 1 and related homoadamantane skeletal compounds
were not isolated. The structure of 8 was determined by the
spectral analysis of the corresponding hydroxylamine 10, and
that of the diazo compound 9 was determined by single-
crystal X-ray crystallography (Scheme 4b). The isolated 9 and
10 were employed in the catalytic oxidation of menthol
(Scheme 4c). Although 9 did not oxidize menthol, 10
smoothly oxidized the alcohol to afford menthone in 94%
yield. Notably, a similar oxidative transformation of 1 into the
oxoammonium salt 11 proceeded in 67% yield using NaOCl
in the presence of HClO4 (Scheme 5a).[12] In contrast, the
oxidative dimerization and spontaneous isomerization pro-
ceeded under one-electron oxidation conditions to give the
diazo compound 9 in high yield (Scheme 5b).
Entry
1
Substrate
Product
Yield [%][a]
90
2
3
93
99
4
92
5
6
98
90
7
100
8
99
87
Considering the above results, we propose a possible
reaction mechanism (Scheme 6). First, 1 is brominated by
9[b]
10[c]
84
[a] Yield is that of the isolated product. [b] Used 1.2 equiv of NaOCl.
[c] Used 2.5 equiv of NaOCl. Cbz=benzyloxycarbonyl.
including the sugar derivative 6g and the N-protected amino
alcohol 6h, were efficiently oxidized to the corresponding
carbonyl compounds with 1 mol% catalyst in high yield.
To gain mechanistic insight into the 1-catalyzed oxidation,
we attempted to identify active species generated in situ. We
conducted a large-scale oxidation of isopropyl alcohol
(20 mmol) with 0.6 equivalent of NaOCl and obtained the
Scheme 5. Oxidative transformation of the alkoxyamine 1. a) Isolation
of the oxoammonium salt 11. b) One-electron oxidation of catalyst 1.
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combined, washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (Et2O/n-hexane) to give the corresponding carbonyl
compound 7 in 84–100% yield.
Received: August 14, 2013
Published online: October 11, 2013
Keywords: alcohols · N-oxides · organocatalysis · oxidation ·
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synthetic methods
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Scheme 6. Possible reaction mechanism of the 1-catalyzed oxidation.
NaOCl and KBr to give the bromoamine 13. Unstable 13 is
degraded by either heterolytic (path a) or homolytic (path b)
cleavage. The heterolytic cleavage of 13 gives the nitro-
soalkene 14 as a transient intermediate,[13] which immediately
undergoes bromoamination to give the oxoammonium spe-
cies 15.[14] The oxoammonium species plays the same role as
this species in TEMPO/AZADO oxidation.[4] It oxidizes an
alcohol to give the corresponding carbonyl compound and 10,
which is then converted into 15 by NaOCl and KBr to
establish the catalytic cycle. In contrast, an alkoxyaminyl
radical generated by the homolytic cleavage of 13 immedi-
ately dimerizes,[15] then isomerization proceeds to afford the
diazo compound 9, which does not function as a catalyst.[16]
In summary, we have discovered an alkoxyamine-type
organocatalyst (1) for alcohol oxidation. The alkoxyamine is
readily accessed and efficiently oxidizes various primary and
secondary alcohols to give their corresponding carbonyl
compounds in high yield. The novel oxidative pathway
involving transformation of an alkoxyamine into an oxoam-
monium ion plays a key role. The novel oxidative pathway
disclosed in this study should inspire new avenues for the
design of redox catalysts as well as of organic paramagnetic
compounds.
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Experimental Section
General procedure for alcohol oxidation: A 20 mL round-bottomed
flask equipped with a magnetic stirring bar was charged with
a solution of the alcohol 6 (1.00 mmol), the alkoxyamine 1 (1.67 mg,
10 mmol), and KBr (11.9 mg, 0.100 mmol) in CH2Cl2 (2.7 mL) and sat.
NaHCO3 (1 mL). To this cooled (08C, ice water bath) and well-stirred
(800 rpm) mixture was added dropwise a premixed solution of
aqueous NaOCl (1.0 mL, 1.5 mmol: 1.45m, purchased from Junsei
Chemical Co., Ltd. and titrated) and sat. NaHCO3 (1.7 mL) over
5 min. The reaction mixture was stirred for 20 min at 08C, then
quenched with 20% aqueous Na2S2O3 (3 mL). The aqueous layer was
separated and extracted with CH2Cl2. The organic layers were
[8] We have constructed the azaadamantane skeleton by intra-
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buya, Y. Sasano, M. Tomizawa, T. Hamada, M. Kozawa, N.
Nagahama, Y. Iwabuchi, Synthesis 2011, 3418 – 3425.
[9] 1-Me-AZADOL (4) was prepared by the reduction of 1-Me-
AZADO (5); see the Supporting Information.
[10] R. N. Farr, Tetrahedron Lett. 1998, 39, 195 – 196.
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339.
[14] The density functional theory (DFT) calculations at the B3LYP/
6-311 + G(2d,p) level show that the hydroxylamine 4 is thermo-
dynamically more stable than the alkoxyamine
1 by ca.
12 kcalmolÀ1 in the gas phase. See the Supporting Information.
[15] R. G. Kostyanovsky, V. F. Rudchenko, V. G. Shtamburg, I. I.
Chervin, S. S. Nasibov, Tetrahedron 1981, 37, 4245 – 4254.
[16] The DFT calculations at the B3LYP/6-311 ++ G(d,p) level show
that 9 is thermodynamically more stable than 12 by ca. 62 kcal
molÀ1 in the gas phase. See the Supporting Information.
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