Anaerobic nitroxide-catalyzed oxidation of alcohols using the NO +/NO· redox pair

Article abstract of DOI:10.1021/ol403016p

A new method for alcohol oxidation using TEMPO or AZADO in conjunction with BF₃·OEt₂ or LiBF₄ as precatalysts and tert-butyl nitrite as a stoichiometric oxidant has been developed. The system is based on a NO⁺/NO· pair for nitroxide reoxidation under anaerobic conditions. This allows the simple, high-yielding conversion of various achiral and chiral alcohols to carbonyl compounds without epimerization and no formation of nonvolatile byproducts.

Full text of DOI:10.1021/ol403016p

Letter
pubs.acs.org/OrgLett
Anaerobic Nitroxide-Catalyzed Oxidation of Alcohols Using the
NO+/NO· Redox Pair
Martin Holan and Ullrich Jahn*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam
́ ̌
estí 2, 166 10 Prague
6, Czech Republic
S
* Supporting Information
ABSTRACT: A new method for alcohol oxidation using TEMPO or AZADO
in conjunction with BF3·OEt2 or LiBF4 as precatalysts and tert-butyl nitrite as a
stoichiometric oxidant has been developed. The system is based on a NO+/NO·
pair for nitroxide reoxidation under anaerobic conditions. This allows the simple,
high-yielding conversion of various achiral and chiral alcohols to carbonyl
compounds without epimerization and no formation of nonvolatile byproducts.
he oxidation of alcohols catalyzed by nitroxides is a widely
used methodology in organic synthesis.1 Usually 2,2,6,6-
Alkyl nitrites are a source of the nitrosonium ion, a strong
oxidizing agent with a redox potential of 1.0 V vs ferrocene.9
Some time ago, we used the NO+/NO· pair as stoichiometric
SET oxidants.10 This triggered our interest to apply it for
TEMPO reoxidation.11
We report here that tert-butyl nitrite (TBN) as a convenient
and cheap NO+ precursor efficiently mediates alcohol
oxidations catalyzed by 1 or 2 in the presence of BF3·OEt2
or LiBF4 providing aldehydes and ketones in high yield without
compromising resident stereocenters.
T
tetramethylpiperidin-1-oxyl (TEMPO) 1 is used as the catalyst
with stoichiometric oxidants such as bleach, tert-butyl
hypochlorite, elemental halogens, bis(acetoxy)iodobenzene
(BAIB), or trichloroisocyanuric acid. Catalysis based on
azaadamantane- (AZADO) 2 and azabicyclo[3.3.1]nonane-
(ABNO) 3 type nitroxyl radicals has been more recently
developed (Figure 1).2 A common disadvantage of many of
The investigation began with finding conditions for the
stoichiometric oxidation of 1 to N-oxopiperidinium salt 4
(Table 1). When 1 was added to an ethereal solution of TBN
and BF3·OEt2, salt 4 precipitated in 67% yield (entry 1).
Figure 1. Types of nitroxyl radicals used in alcohol oxidations.
Table 1. Screening of the Oxidation Conditions for TEMPO
a
1
these catalytic systems is the formation of nonvolatile reduced
species, resulting from the consumption of the stoichiometric
oxidant, such as iodobenzene, isocyanuric acid, or inorganic
salts. Oxygen has been used as the stoichiometric oxidant in
TEMPO catalyzed alcohol oxidations based on the catalytic use
of transition metal compounds.3
The first transition-metal-free aerobic oxidation process using
TEMPO/Br2/NaNO2 was reported in 2004.4 Other TEMPO/
nitrite-based systems followed shortly after,5 and versions with
supported catalysts were also developed.6 Besides metal nitrites,
NH2OH and HNO3 were also applied.7 A common feature of
these catalytic systems is the operation of the NO·/NO2· pair as
mediator between O2 and the TEMPOH/TEMPO/TEMPO+
manifold. Even though these conditions are environmentally
friendly, the use of O2 often requires work in autoclaves, which
makes them impractical and potentially hazardous. Moreover
NO2 that is formed in situ may interfere with some functional
groups, such as alkenes.8
−
entry
1
solvent
BF4 source
yield (%)
Et2O
BF3·OEt2
BF3·OEt2
BF3·OEt2
HBF4
67
79
70
79
b
2
Et2O
bc
,
3
4
5
CH2Cl2
Et2O
d
c
Et2O
LiBF4
65
−
a
Conditions: 1 (1 mmol) added to a solution (4 mL) of BF4 source
(1 mmol) and TBN (1 mmol). BF3·OEt2 (1.35 mmol) used. TBN
(1.5 mmol) used. TBN (1 mmol) added to 1 (1 mmol) and HBF4 (1
b
c
d
mmol).
Received: October 21, 2013
© XXXX American Chemical Society
A
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Letter
Increasing the amount of BF3·OEt2 to 1.35 equiv improved the
yield of 4 to 79% (entry 2). n-Butyl nitrite was similarly
effective. The oxidation in CH2Cl2 also proceeded in 70% yield
(entry 3). HBF4 and LiBF4 provided 4 in good yields, although
the reaction with LiBF4 was considerably slower (entries 4, 5).
Benzyl alcohol 5a served to optimize the catalytic oxidations
(Table 2). Using diethyl ether as the solvent gave 6a only in
Attempts to apply identical conditions to aliphatic aldehydes
gave only moderate results. Dodecanol 5h converted only to a
50% yield after 3 h, and the catalytic process stopped after some
time (Table 3, entry 1). Addition of a new batch of 1 induced
a
Table 3. Oxidation of Dodecan-1-ol 5h
a
Table 2. Oxidation of Benzyl Alcohol 5a Catalyzed by 1
b
−
entry
BF4 source (mol %)
time (h)
1 (mol %)
conv. (%)
1
2
3
4
5
BF3·OEt2 (6.75)
BF3·OEt2 (6.75)
BF3·OEt2 (5)
BF3·OEt2 (5)
LiBF4 (5)
3
5
50
98
92
88
92
5.5
5
5 + 5
5 + 5
5
entry
solvent
temp
time (h)
1 (mol %)
yield (%)
b
1
2
3
4
5
6
Et2O
rt
5
10
10
10
5
30
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
4
94
95
97
82
73
5
5
a
reflux
reflux
reflux
reflux
0.75
1.5
5
Conditions: 5h (1 mmol), CH2Cl2 (5 mL), BF3·OEt2, TBN (3
mmol), 1, stirring under reflux. Determined by GC.
b
1
c
5.5
−
complete conversion after 5.5 h (entry 2). Addition of further
BF3·OEt2 led to a deterioration of the reaction mixture as
indicated by GC analysis, whereas a decrease in the BF3·OEt2
amount was beneficial (entry 3). A high conversion was
observed with only 5 mol % of BF3·OEt2, even if the second
batch of 1 was not added (entry 4). Thus, it was important to
use a maximum of 1 equiv of BF3·OEt2 and 1 or even a slight
excess of 1 over BF3·OEt2 for the oxidation of aliphatic
aldehydes. LiBF4 could also be used as the anion source (entry
5).
a
Conditions: 5a (2 mmol), solvent (10 mL), BF3·OEt2 (1.35 times the
amount of 1), TBN (4 mmol), 1, added and stirred at the indicated
b
c
temperature. Determined by 1H NMR. BF3·OEt2 (6.75 mol %) used.
30% yield, probably due to precipitation of the active oxidant.
Switching to CH2Cl2 at a 10 mol % loading of 1 at room
temperature provided 6a in a very good 94% yield after 4 h
(entry 2). Heating the reaction mixture to reflux and reduction
of the catalyst loading to 5 mol % led to similar yields (entries
3, 4). However, when the amount of catalyst 1 was further
decreased to 1 mol %, a drop in the yield to 82% was observed
(entry 5). A reaction in the absence of TEMPO under
otherwise identical conditions also gave 6a, however in a lower
yield after a considerably longer reaction time (entry 6; see the
Supporting Information for further details).12
The reason for the lower reactivity of aliphatic alcohols was
traced to a competing nitroso group transfer forming aliphatic
nitrites and tert-butanol (Scheme 2). Indeed, when TBN was
Scheme 2. NMR Study of Alcohol/Nitrite Equilibria
With optimal conditions in hand, the scope of the oxidation
of aromatic and allylic alcohols was studied (Scheme 1).
Electronically diverse benzylic alcohols 5b−e were converted to
the corresponding carbonyl compounds 6b−e in good yields.
Cinnamic aldehyde 6f was similarly obtained in high yield. 2,4-
Decadienol 5g gave dienal 6g in 60% yield using LiBF4 instead
of BF3·OEt2, provided it was added as the last component to
the reaction mixture.
mixed with an equimolar amount of 3-phenylpropanol in
CDCl3 the equilibrium established quickly to a 3:1 ratio of 3-
phenylpropyl nitrite and 3-phenylpropanol (K = 9), with no
further change. Similarly, when equimolar amounts of n-
BuONO and t-BuOH were mixed, a 3:1 ratio of n-BuONO and
n-BuOH was established (K = 0.11). Therefore only relatively
small amounts of free 5 are present under the reaction
conditions thus reducing the rate of oxidation.
Scheme 1. Oxidation of Benzylic and Allylic Alcohols 5b−
a
,b
g
Based on these results, the scope for oxidation of aliphatic
alcohols was determined using 5 mol % of 1 and BF3·OEt2 in
the presence of 3 equiv of TBN. It proved to be useful to add 5
mol % of catalyst 1 after 1 h at reflux (Scheme 3). Aldehydes or
ketones 6h−6j were oxidized in high yields. 5-Hexynal 6k was
obtained in a slightly lower yield, probably due to its volatility.
For one of the most Lewis acid sensitive substrates, 6-
triethylsilyloxy-1-hexanol 5l, LiBF4 proved to be the better
anion source providing aldehyde 6l in 73% yield. The rate of
oxidation of cyclic alcohols depended on their configuration.
cis-4-tert-Butylcyclohexanol with an axial hydroxy group was
oxidized in essentially quantitative yield in 3 h, whereas
a
Conditions: 5b−f (2 mmol), CH2Cl2 (10 mL), BF3·OEt2 (6.75 mol
%), TBN (6 mmol), 1 (5 mol %), reflux. bIsolated yields. cConditions:
CH2Cl2 (5 mL), LiBF4 (5 mol %), TBN (3 mmol), 1 (5 mol %), 5g (1
mmol), reflux.
B
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Letter
a
,b
promote concomitant oxidation and N-nitrosation using 10
equiv of TBN gave 7r as the main product in 47% yield.
The mechanism of this oxidation can be proposed as follows
(Scheme 4). First TBN reacts with the catalytic amount of
Scheme 3. Oxidation of Aliphatic Alcohols
Scheme 4. Proposed Mechanism of Alcohol Oxidation with
TBN
BF3·OEt2 to generate nitrosonium tetrafluoroborate 8 and the
borate ester.16 The nitrosonium salt 8 oxidizes 1 to the N-
oxopiperidinium salt 4 as shown in the stoichiometric
experiments. The alcohols 5 are subsequently oxidized by salt
4 to the corresponding aldehydes or ketones 6 resulting in
hydroxylamine 9 and tetrafluoroboric acid, which is in
equilibrium with its salt 10. Another equivalent of TBN
subsequently reoxidizes 9 to 1 thus closing the catalytic cycle.
In conclusion, we reported a convenient nitroxide-catalyzed
alcohol oxidation, using TEMPO or AZADO and BF3·OEt2 or
LiBF4 as precatalysts and TBN as the stoichiometric oxidant.
The catalytic system based on the NO+/NO· pair differs
significantly from the aerobic NO·/NO2· pair for catalyst
reoxidation. The mild oxidation conditions allow oxidation of
enantiomerically pure substrates without racemization. A
limitation is the competing nitrosation of acidic N−H-
containing amides or carbamates. The use of TBN, a low
molecular weight organic oxidant, enables simple and fast
purification by chromatography, since all side products are
volatile. However, the crude aldehydes may also be used
directly in further reaction steps.
a
Conditions: 5h−k,m−r (2 mmol), CH2Cl2 (10 mL), BF3·OEt2 (5
b
mol %), TBN (6 mmol), 1 (5 + 5 mol %), reflux. Isolated yields.
cTBN (8 mmol) used. dConditions: CH2Cl2 (5 mL), LiBF4 (5 mol %),
TBN (3 mmol), 1 (5 + 5 mol %), 5l (1 mmol), reflux. eAZADO 2 (5 +
5 mol %) used instead of 1. f5q (25%) recovered. g5r (10%) recovered,
7r (14%) isolated. hAlso 6r (14%) isolated. iCAUTION: N-
Nitrosamines are potentially carcinogenic; proper care should be
taken when working with them.
diequatorial trans-4-tert-butylcyclohexanol required a much
longer reaction time for completion. Commercial 5n having a
cis-configuration at the methyl groups but existing as a 66:34
mixture of cis/trans-isomers at the hydroxy group gave ketone
6n in 75% yield under standard conditions. However when the
conditions for the oxidation of benzylic alcohols were applied,
the cis,trans-isomer was oxidized in 46% yield, whereas 30% of
the all-cis isomer of 5n was recovered. Thus, the former
conditions can be applied for separating mixtures or oxidizing
cyclic alcohols with a defined configuration selectively. L-
Menthol 5o, a recognized difficult substrate for TEMPO-
catalyzed oxidations, did not react under the standard
conditions, but provided nitrite 7o in 81% yield. However,
replacing 1 with AZADO 22 under otherwise identical
conditions afforded L-menthone 6o in high yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Enantiomerically pure alcohols 5p−r with potentially labile
stereocenters at the α-position were applicable under the
reaction conditions without compromising the optical purity of
the products 6p−r. The integrity of the stereocenters in the
products was proven by reducing aldehydes 6p−r back to the
starting alcohol and analysis of the corresponding Mosher
esters of 5p and 5r13,14 or the benzoate of 5q15 (see the
Supporting Information). However, amino alcohols, such as N-
Boc-prolinol 5q or phenylalaninol 5r, reacted slowly and the
conversion stopped after some time, even though they were
oxidized previously by 1.1d N-Boc-Prolinal 6q was obtained in
40% yield; the remainder of the mass balance was recovered 5q.
For amino alcohols bearing acidic NH functions, the method is
not suitable, since N-nitrosation competed. An attempt to
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jahn@uochb.cas.cz.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the grant agency of the Czech
Republic (13-40188S), the Institute of Organic Chemistry and
Biochemistry, Academy of Sciences of the Czech Republic
(RVO: 61388963), and the Gilead Sciences & IOCB research
center is gratefully acknowledged.
C
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