Simple and Efficient Ruthenium-Catalyzed Oxidation of Primary Alcohols with Molecular Oxygen

Article abstract of DOI:10.1002/chem.201601800

Oxidative transformations utilizing molecular oxygen (O₂) as the stoichiometric oxidant are of paramount importance in organic synthesis from ecological and economical perspectives. Alcohol oxidation reactions that employ O₂are scarce in homogeneous catalysis and the efficacy of such systems has been constrained by limited substrate scope (most involve secondary alcohol oxidation) or practical factors, such as the need for an excess of base or an additive. Catalytic systems employing O₂as the “primary” oxidant, in the absence of any additive, are rare. A solution to this longstanding issue is offered by the development of an efficient ruthenium-catalyzed oxidation protocol, which enables smooth oxidation of a wide variety of primary, as well as secondary benzylic, allylic, heterocyclic, and aliphatic, alcohols with molecular oxygen as the primary oxidant and without any base or hydrogen- or electron-transfer agents. Most importantly, a high degree of selectivity during alcohol oxidation has been predicted for complex settings. Preliminary mechanistic studies including¹⁸O labeling established the in situ formation of an oxo–ruthenium intermediate as the active catalytic species in the cycle and involvement of a two-electron hydride transfer in the rate-limiting step.

Full text of DOI:10.1002/chem.201601800

DOI: 10.1002/chem.201601800
Full Paper
&
Aerobic Oxidation |Hot Paper|
Simple and Efficient Ruthenium-Catalyzed Oxidation of Primary
Alcohols with Molecular Oxygen
[
a]
Ritwika Ray,* Shubhadeep Chandra, Debabrata Maiti,* and Goutam Kumar Lahiri*
Chem. Eur. J. 2016, 22, 8814 – 8822
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Abstract: Oxidative transformations utilizing molecular
an efficient ruthenium-catalyzed oxidation protocol, which
enables smooth oxidation of a wide variety of primary, as
well as secondary benzylic, allylic, heterocyclic, and aliphatic,
alcohols with molecular oxygen as the primary oxidant and
without any base or hydrogen- or electron-transfer agents.
Most importantly, a high degree of selectivity during alcohol
oxidation has been predicted for complex settings. Prelimi-
oxygen (O ) as the stoichiometric oxidant are of paramount
2
importance in organic synthesis from ecological and eco-
nomical perspectives. Alcohol oxidation reactions that
employ O are scarce in homogeneous catalysis and the effi-
2
cacy of such systems has been constrained by limited sub-
strate scope (most involve secondary alcohol oxidation) or
practical factors, such as the need for an excess of base or
18
nary mechanistic studies including O labeling established
the in situ formation of an oxo–ruthenium intermediate as
the active catalytic species in the cycle and involvement of
a two-electron hydride transfer in the rate-limiting step.
an additive. Catalytic systems employing O as the “primary”
2
oxidant, in the absence of any additive, are rare. A solution
to this longstanding issue is offered by the development of
Introduction
catalytic system involving Shvo’s catalyst for alcohol oxidation
[
11e]
but substrates were mainly limited to secondary alcohols.
Furthermore, these systems (see above) required hydrogen- or
The oxidation of alcohols to aldehydes or ketones constitutes
[
1–3]
[11c]
one of the pivotal transformations in organic synthesis.
Tra-
electron-transfer agents, such as TEMPO
or benzoquino-
[
11e]
ditionally, alcohol oxidations involve the use of stoichiometric
amounts of strong oxidants and thereby generate large
ne
(Scheme 1).
Therefore, development of an atom-efficient transition
[
4]
amount of deleterious byproducts. As an alternative to such
metal-catalyzed system for alcohol oxidation utilizing molecu-
lar oxygen as the primary oxidant, in the absence of exoge-
nous additives, is highly demanding from a practical viewpoint.
Katsuki and co-workers reported an additive-free chemoselec-
tive oxidation of unprotected diols in the presence of a rutheni-
traditional procedures, the use of O as a stoichiometric oxi-
2
dant is desirable, since it produces water as the sole byproduct
[
5]
without generation of copious waste. Various transition
[6–11]
metal-catalyzed systems
have been implemented in combi-
[
11g]
nation with O2 for alcohol oxidation. Among them, recent
um salen complex, albeit with limited substrate scope.
[
6d–h,j]
[7a–k]
II
studies by the groups of Sigman
and Stahl
on Pd -
I
and Cu /TEMPO catalyzed systems (TEMPO=2,2’,6,6’-tetrame-
thylpiperidine N-oxyl), respectively, received much attention
owing to the simplicity of the reaction protocols and broad
functional group compatibilities. Although, the palladium-
based coordination complexes developed for aerobic oxidation
of alcohols were effective for primary (18) and secondary (28)
allylic and benzylic substrates, those containing N-, O-, and S-
[6]
heterocycles were often inhibited by them. Furthermore, in
all cases additives and/or bases played a vital role for the effec-
tive oxidation of the substrates and the role of O was restrict-
2
[6–11]
ed to that of a terminal oxidant.
In this regard, reports on aerobic oxidation of alcohols cata-
lyzed by ruthenium are mostly limited to heterogeneous sys-
[
10]
tems. Precedents for Ru-catalyzed aerobic alcohol oxidation
under homogeneous condition exist but are scarce and ex-
[11]
tremely substrate-specific. For example, the seminal report
by Sheldon and co-workers revealed that [Ru(PPh ) Cl ] is
3
3
2
highly efficient in the oxidation of 18 and 28 allylic, benzylic,
and aliphatic substrates, but is somewhat hindered in the pres-
[11c]
ence of substrates containing various heterocycles.
Alterna-
tively, Bäckvall and co-workers reported a biomimetic coupled
[
a] R. Ray, S. Chandra, Prof. D. Maiti, Prof. G. K. Lahiri
Department of Chemistry, Indian Institute of Technology Bombay
Mumbai 400 076 (India)
Scheme 1. A brief outline of previous and present work. a) previous work:
Ru-catalyzed aerobic alcohol oxidation “with hydrogen and electron transfer
agents”; b) previous work: “acceptorless” and “base-free” dehydrogenation
of “secondary” alcohols using Ru-hydride complexes as precatalysts; c) pres-
ent work: Ru-catalyzed aerobic oxidation of both “primary” and “secondary”
alcohols using O2 as the primary oxidant (additive-free).
E-mail: ritwika@chem.iitb.ac.in
dmaiti@chem.iitb.ac.in
lahiri@chem.iitb.ac.in
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/chem.201601800.
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Recently, Muthaiah and Hong reported Ru-catalyzed accept-
orless dehydrogenation of secondary alcohols to ketones by
using readily available ruthenium hydride complexes as preca-
entry 6). Furthermore, neither GC nor GC-MS showed evidence
of overoxidized byproduct formation, thereby insinuating the
high selectivity of the present strategy.
[
12a]
talysts (Scheme 1).
Unfortunately, primary aliphatic alcohols
Screening of various Ru complexes as potential catalysts es-
tablished the superiority of phosphine-based complexes, in
comparison to [Ru (CO) ] and RuCl ·3H O. This superiority can
yielded homocoupled esters instead of the desired aldehydes.
Indeed, this report was the genesis of the present work, dem-
onstrating an efficient and mild oxidation protocol for primary
and secondary alcohols by using [RuH(CO)Cl(PPh ) ] as the pre-
3
12
3
2
be attributed to the probable involvement of an in situ-gener-
ated (oxo)(phosphine)ruthenium(IV) species as the active cata-
3
3
[
13b–e]
catalyst and O as the primary oxidant (Scheme 1).
lyst for alcohol oxidation
(Table 2).
2
Herein, the oxidation of an exemplary set of 42 substrates
showcases tolerance of a wide variety of functional groups
under the present conditions. Notably, successful oxidation of
alcohols containing N-, O-, or S-heterocyclic substituents em-
phasizes the broad applicability of this protocol. To our knowl-
edge, this study demonstrates the first homogeneous “addi-
tive-free” ruthenium-catalyzed oxidation of primary alcohols
that displays tolerance towards heterocyclic substrates with
molecular oxygen as the primary oxidant. Moreover, the pres-
ent work established a mechanistic pathway involving an oxo–
ruthenium intermediate.
Additionally, systematic screening of solvents revealed tolu-
ene to be ideal for the desired transformation (Table 3).
Subsequently, the scope and limitations of the present pro-
tocol was evaluated by using a variety of primary alcohols
(Table 4). Benzyl alcohol smoothly afforded benzaldehyde (2a)
in high yield. Excellent yields of the respective para- and meta-
alkyl- or para-phenyl-substituted aldehydes (2b–d, 2w) were
also obtained. Sterically encumbered trimethyl benzyl alcohol
afforded the desired aldehyde 2e in good yield. Alcohols sub-
stituted with the strongly electron-donating methoxy group at
the para and meta positions underwent clean conversion with
high yields (2 f and 2g). Notably, ortho-methoxybenzyl alcohol,
Results and Discussion
Table 2. Screening of various ruthenium complexes for aerobic oxidation
of alcohols.
In an attempt to identify an efficient catalyst capable of aero-
bic oxidation of alcohols in the absence of any additives,
[a]
[
RuH(CO)Cl(PPh ) ] was initially chosen as a suitable catalyst for
3 3
the oxidation of functionalized p-methylbenzyl alcohol as the
model substrate (Table 1). Initial optimization under N atmos-
2
phere afforded p-tolualdehyde in only 20% yield (Table 1,
entry 1). Even addition of a base could not improve the yield
of the product. However, a significant increase in the yield in
[b]
Entry
Catalyst
t [h]
Yield [%]
1
2
3
4
5
6
[Ru (CO) ]
3
12
12
12
12
12
18
12
37
45
88
96
RuCl
3
.3H
2
O
air atmosphere indicated a crucial role of O in the oxidation
2
[RuCl
2
3 3
(PPh ) ]
process (Table 1, entry 3). Finally, an efficient Ru-catalyzed oxi-
dation protocol was realized with a catalyst loading of 2 mol%
[RuH(CO)Cl(PPh
[RuH(CO)Cl(PPh
[RuHCl(PPh ) ]
3
3
)
)
3
]
]
[c]
3
98 (94)
under O balloon pressure, resulting in p-tolualdehyde in 96%
90
2
3 3
yield (GC) after 12 h (Table 1, entry 5). Presence of activated
molecular sieves (4 Š) was also critical, since the same reaction
in their absence afforded the aldehyde in only 56% yield, im-
[
(
a] Reaction conditions: catalyst (2 mol%), 4-methylbenzyl alcohol
0.75 mmol), molecular sieves (4 Š, 200 mg) in toluene (3 mL) at 908C
under O
2
(1 atm, balloon); [b] determined by GC using n-decane as an in-
[5e,6e]
ternal standard; [c] yield of isolated product given in parentheses.
plying the formation of water as a byproduct
(Table 1,
[a]
Table 1. Optimization by varying atmosphere for alcohol oxidation.
[a]
Table 3. Screening of solvents for aerobic oxidation of alcohols.
[
b]
Entry
Atmosphere
Yield [%]
1
2
3
4
5
6
N
N
air
O
O
O
2
2
20
15
68
–
96 (94)
56
[b]
Entry
Solvent
Conversion [%]
Yield [%]
[
c]
1.
2.
3.
4.
acetonitrile
10
89
>99
25
8
[
[
[
d,e]
PhCF
3
88
96 (94)
2
2
2
d]
[f]
[c]
toluene
d,g]
1,2-dichloroethane
22
22
[d]
5.
THF
23
[
(
[
a] Reaction conditions: catalyst (2 mol%), 4-methylbenzyl alcohol
0.75 mmol), molecular sieves (4 Š, 200 mg) in toluene (3 mL), 12 h;
b] determined by GC using n-decane as an internal standard; [c] reflux in
[a] Reaction conditions: catalyst (2 mol%), 4-methylbenzyl alcohol
(0.75 mmol), molecular sieves (4 Š, 200 mg) in solvent (3 mL) at 908C
toluene; [d] O
lyst; [f] yield of isolated product given in parentheses for reaction after
8 h; [g] no molecular sieves.
2
balloon pressure; [e] reaction in the absence of any cata-
2
under O (1 atm, balloon); [b] determined by GC using n-decane as an in-
ternal standard; [c] yield of isolated product given in parentheses for the
reaction after 18 h; [d] T=608C.
1
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Table 4. Aerobic oxidation of 18 benzylic and aliphatic alcohols.
Table 5. Aerobic oxidation of 18 heterocyclic alcohols.
Unless otherwise stated, yields refer to isolated products. [a] GC yield
with n-decane as an internal standard.
However, the poor yields observed in some cases (particularly
in 4b and 4h) could be attributed to partial coordination of
the heterocyclic heteroatoms to the ruthenium center.
As anticipated, a broad range of aromatic, heterocyclic and
aliphatic secondary alcohols also underwent oxidation, afford-
ing ketones 6a–i in good to excellent yields (Table 6).
Unless otherwise stated, yields refer to isolated products. [a] GC yield
with n-decane as an internal standard.
Table 6. Aerobic oxidation of 28 alcohols.
which was hindered in earlier Pd-catalyzed oxidations by chela-
tion of the substrate or product to the metal center, was con-
verted into the desired aldehyde 2h in preparatively useful
[
6e]
yield. A similar chelation might be the reason that no prod-
uct was formed with NH -substituted benzyl alcohol substrates
2
in the present case (not shown). However, with Boc-protected
amines as substrates, high yields of aldehydes 2r and 2s were
obtained. A range of halogenated benzylic alcohols consistent-
ly afforded the respective aldehydes 2j–m in good yields with-
out any dehalogenation process. Successful implementation of
this protocol was further evident through the excellent yields
3
of aldehydes with strongly electron-withdrawing CF or NO2
Unless otherwise stated, yields refer to isolated products. [a] Substrate is
substituents (2n–q), as well as those with unfunctionalized
1,2-diphenylethane-1,2-diol, GC yield with n-decane as internal standard;
[
b] 5 mol% catalyst.
fused-ring aryl systems (2t–v). The smooth oxidation of cin-
namyl alcohol to cinnamaldehyde (2i) without any intramolec-
ular hydrogen transfer further emphasized the excellent func-
tional group compatibility of the present strategy, since similar
oxidation was reported to be less effective in an earlier Pd-cat-
Mechanistic studies
[
6e]
alyzed system. However, although the present protocol was
also amenable towards the oxidation of 3-phenylpropanol to
Based on experimental observations, including kinetic studies
18
and an O labeling study, we have proposed two mechanistic
pathways for ruthenium catalyzed alcohol oxidation with mo-
lecular oxygen (Scheme 2).
3
-phenylpropanal (2x), other primary aliphatic alcohols yielded
homocoupled esters as the major products instead of alde-
[
12a]
hydes (not shown).
Both pathways involve the initial dissociation of one PPh3
ligand, analogous to earlier reported alcohol dehydrogenation
Another intriguing feature of this methodology is its toler-
ance to a variety of alcohol substrates incorporating N-, O-, or
S-heterocyclic groups, affording aldehydes 4a–i in moderate to
good yields (Table 5). Oxidation of such substrates was inhibit-
ed in the [RuCl (PPh) ]/TEMPO-catalyzed system reported by
[
14]
processes, to form a coordinatively unsaturated complex I.
This was substantiated through detection of free PPh3 or
PPh =O by GC-MS within 5 mins of the reaction before any sig-
3
nificant production of aldehyde or ketone. The coordinatively
2
3
[11c]
Sheldon and co-workers,
as a result of catalyst inactivation.
unsaturated complex I then reacted with oxygen to generate
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Scheme 3. Deuterium labeling experiments.
4
-MeC H CH OH and isotopically labeled 4-MeC H CD OH re-
6 4 2 6 4 2
vealed an intermolecular kinetic isotope effect (KIE) of k /k =
H
D
6
.73 (Scheme 3; see the Supporting Information for details).
Such a large KIE value gives indirect evidence in support of an
oxo–ruthenium intermediate, as was reported earlier with
ruthenium–oxo complexes in the presence of tertiary phos-
phine ligands being effective catalysts in selective alcohol oxi-
[
13]
dation processes.
Based on the magnitude of k /k , two mechanisms for the
H
D
rate-determining step seem reasonable. One possible pathway
is hydride transfer from the alcohol in the slow step, resulting
À
IV
II
in a 2e reduction at the metal center (Ru !Ru ) to form an
intermediate A, followed by a fast proton transfer in the subse-
quent step (Scheme 2, pathway 1). An alternative pathway is
a hydrogen atom transfer (HAT) in the slow step, leading to
III
Ru ÀOH intermediate B, and a sequential rapid outer-sphere
electron and proton transfer in the next step (Scheme 2, path-
À
way 2). However, the involvement of a 2 e reduction at the
IV
II
metal center (Ru !Ru ; Scheme 2, pathway 1) seems logical
in the slow step since the use of radical clock substrate cyclo-
Scheme 2. Proposed mechanistic pathways for ruthenium-catalyzed alcohol
oxidation.
À
butanol as a mechanistic probe yielded the 2e oxidation
product cyclobutanone exclusively, without any of the ring-
opening product 4-hydroxybutanal (Scheme 4; see the Sup-
porting Information for details), thereby suggesting that a free
IV
a Ru =O complex II (Scheme 2). ESI-MS of the reaction mix-
[
13,16]
ture in the presence of O after 5 h detected a peak at m/z=
radical pathway is less likely.
As expected, a radical scav-
2
+
6
69.08 [MÀH ] in CH CN (Figure 1a), corresponding to
enger such as TEMPO did not affect the reaction rate or the
product selectivity for the oxidation of 4-methylbenzyl alco-
3
16
C H ( O) P Ru which was shifted to m/z=671.09 (Figure 1b)
37
30
2 2
18
[16]
in the presence of O , thereby establishing the in situ forma-
hol. Also, a role of the metal hydride cannot be completely
2
tion of complex II, in which the oxo moiety originated from
ruled out under the present reaction conditions.
O .
2
Kinetic investigation indicated a pseudo-first-order (1.6) reac-
tion, since alcohol was present in a large excess with respect
to II (oxidant) in the catalytic cycle (Scheme 2). Deuterium la-
beling studies conducted for ruthenium-catalyzed oxidation of
Scheme 4. Radical clock substrate oxidation.
Furthermore, the relationship between log(k /k ) and the
X
H
Brown–Okamoto s values for the oxidation of differently sub-
stituted benzyl alcohols gave a linear plot with a Hammett
2
1
value of À0.815 (r =0.96; Figure 2). The moderately negative
Figure 1. Positive-ion ESI mass spectra (experimental and simulated isotope
value of 1 can be interpreted in terms of a positively charged
transition state at the a-carbon atom adjacent to the phenyl
ring.
3
patterns) of II in CH CN after 5 h: a) peak cluster at m/z=669.08 assigned
1
6
+
to C37
H
30( O)
2
P
2
Ru [MÀH ]; b) peak cluster at m/z=671.09 assigned to
1
6
18
+
C
37
H
30( O)( O)P
2
Ru [MÀH ].
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18
of 50% O incorporated aldehyde, also seems unlikely in this
[
15]
case (Scheme 5).
A probable dehydrogenation pathway under the present re-
action conditions could be excluded since similar reaction
under N atmosphere and in the presence of a hydrogen ac-
2
ceptor, p-bromoacetophenone (a), resulted in poor yield of the
desired aldehyde and no trace of 1-(4-bromophenyl)ethanol
[
17]
(
a’) could be detected by either GC or GC-MS (Scheme 6).
A set of intermolecular competition experiments shed fur-
ther light on the predictable selectivity of the various alcohols
towards oxidation under the present reaction conditions
(
Scheme 7). A competition experiment between 18 benzylic
and 18 aliphatic substrates clearly showed the greater rate of
oxidation for benzylic substrates compared to aliphatic. Simi-
larly, greater reactivity was obtained for 28 benzylic substrates
relative to 28 aliphatic substrates. Competition between the
same classes of compounds, that is, between 18 and 28 ana-
logues of either benzylic or allylic substrates showcased the
greater rate of reactivity for 18 than for 28 analogues. Further-
more, a direct contrast between the 18/28 benzylic with the 28/
18 aliphatic substrates confirmed the greater reactivity of the
benzylic substrates in every case. This positional selectivity can
clearly be attributed to the stability of the transient positive
charge generated as shown in the present mechanism. From
these competitive studies, it can be concluded that the rate of
alcohol oxidation decreases in the following order: 18 benzylic
2
X H
Figure 2. Hammett plot [log(k /k ) versus s (R =0.96)] for competitive oxi-
dation of benzyl alcohol and p-substituted benzyl alcohols. Reaction condi-
tions: benzyl alcohol (0.25 mmol), p-substituted benzyl alcohol (0.25 mmol),
catalyst (1 mol%), toluene (1 mL), 908C under O (1 atm, balloon).
2
1
8
Interestingly, labeling study showed only 8% O incorpora-
tion into p-tolualdehyde (Scheme 5). A possible explanation for
1
8
the minor formation of O-incorporated aldehyde is that the
water generated in the aerobic oxidation process is not cap-
tured fast enough by the molecular sieves but has time to un-
dergo exchange with the aldehyde molecule. An alternate pos-
sibility of a “radical rebound” pathway involving the formation
>
28 benzylic >18 aliphatic >28 aliphatic.
Conclusions
In conclusion, the present article demonstrates for the first
time a simple and sustainable Ru-catalyzed oxidation protocol
for alcohols with the aid of O as the primary oxidant in the
2
absence of excess base or hydrogen or electron transfer
agents. The reaction proceeds with 100% selectivity with a low
catalyst loading, does not require expensive ligands, and
avoids the formation of any byproducts by overoxidation. Se-
lective oxidation of allylic alcohols without intramolecular hy-
drogen transfer, along with tolerance of substrates containing
N-, O-, or S-heterocycles, leading to aldehydes in moderate to
good yields make the present protocol unique. Mechanistic in-
IV
vestigations established the in situ formation of a Ru =O com-
plex as the active catalytic species and the possible involve-
À
ment of a 2e hydride transfer in the redox step to afford alde-
hydes or ketones in good to excellent yields. The substrate se-
lectivities under competitive reaction environments further un-
derscores the utility of this procedure.
18
Scheme 5. Product study by O labeling experiment.
Overall, this catalytic system provides an excellent
alternative to traditional procedures for alcohol oxi-
dation and the mechanistic insights might further
be useful for the development of more efficient Ru
precursors by fine tuning of the coordinated ligands,
which would help to overcome the difficulties inher-
ent in selective oxidation of more challenging ali-
phatic alcohols confronted in the present case. Aero-
bic oxidation of other organic scaffolds with similar
metal precursors might also be investigated.
Scheme 6. Experiment to test for possible dehydrogenation of primary alcohol.
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Experimental Section
General considerations
Unless otherwise stated, all reactions were carried out under
oxygen atmosphere in screw cap reaction tubes. All solids were
weighed in air. All solvents were purchased from Merck, India and
were used as received without using any drying agents. All primary
and secondary alcohols were bought from Aldrich. [RuH(-
CO)Cl(PPh ) ] was synthesized according to the literature proce-
3
3
[18]
dure. All other ruthenium catalysts were bought from Aldrich
and Alfa Aesar. Molecular sieves (4 Š; particle size 2–3 mm) were
bought from Aldrich. Molecular sieves were kept in oven in small
amount before use. For column chromatography, silica gel (100–
2
00 mesh) from SRL Co. was used. A gradient elution using pet
ether and ethyl acetate was performed based on Merck aluminium
TLC sheets (silica gel 60F254) and visualized by UV (254 nm) lamp.
Analytical methods
1
13
All isolated compounds were characterized by H and C NMR
spectroscopy and gas chromatography mass spectrometry (GC-
MS). NMR spectra were recorded on Bruker 400 and 500 MHz in-
1
13
struments. Copies of the H and C NMR spectra can be found in
the Supporting Information. Chemical shifts d are reported in parts
per million (ppm) and were measured relative to the signals for re-
1
13
sidual chloroform (d=7.26 and 77.23 ppm for H and C NMR, re-
spectively) in the deuterated solvent, unless otherwise stated.
13
1
C NMR spectra were obtained with H decoupling. GC analyses
were performed on Shimadzu GC-2014 gas chromatograph with
a FID detector using a J&W HP-5 column (length 50 m, inner diam-
eter 0.320 mm, film 0.52 mm) with n-decane as the internal stan-
dard. GC-MS analyses were done by an Agilent 7890A GC system
connected with 5975C inert XL EI/CI MSD (with triple axis detector).
ESI HRMS was carried out on a BRUKER Maxis Impact mass spec-
trometer. The yields of non-isolated products were determined by
GC. Response factors for the alcohols and aldehydes were deter-
mined with respect to the internal standard n-decane (0.513 mmol)
for the GC yield analysis. A 2.0 mL aliquot was used for the analysis
by GC-FID in each case.
General procedure for the oxidation of primary benzylic al-
cohols
To an oven-dried screw cap reaction tube charged with a magnetic
stir-bar and molecular sieves (4 Š, 200 mg), ruthenium catalyst
(
2 mol%, 0.015 mmol) was added. Depending on the physical state
of the primary alcohols (0.75 mmol), solid compounds were weigh-
ed along with the other reagents, whereas liquid alcohols were
added by microliter syringe under air atmosphere. Toluene (3 mL)
was then added and the reaction tube was closed with a screw
cap and heated with vigorous stirring in a preheated oil bath at
9
08C for 18 h under oxygen balloon pressure. Concentration was
maintained at 0.25m. After completion, the reaction mixture was
cooled to room temperature, diluted with water (10 mL) and ex-
tracted with ethyl acetate (3”10 mL). The combined organic ex-
tracts were dried over anhydrous Na SO and concentrated under
Scheme 7. Intermolecular competition experiments to predict selectivity
2
4
reduced pressure. The crude product was purified by column chro-
matography using a mixture of petroleum ether and ethyl acetate
as the eluent.
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General procedure for the oxidation of primary heterocyclic
alcohols
[6] For Pd catalysis, see: a) T. Nishimura, T. Onoue, K. Ohe, S. Uemura, J.
Org. Chem. 1999, 64, 6750; b) T. Nishimura, T. Onoue, K. Ohe, S. Uemura,
Tetrahedron Lett. 1998, 39, 6011; c) X. Ye, M. D. Johnson, T. Diao, M. H.
Yates, S. S. Stahl, Green Chem. 2010, 12, 1180; d) D. R. Jensen, M. J.
Schultz, J. A. Mueller, M. S. Sigman, Angew. Chem. Int. Ed. 2003, 42,
To an oven-dried screw cap reaction tube charged with a magnetic
stir-bar and molecular sieves (4 Š, 200 mg), ruthenium catalyst
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state of primary heterocyclic alcohols (0.75 mmol), solid com-
pounds were weighed along with the other reagents, whereas
liquid alcohols were added by microliter syringe under air atmos-
phere. Toluene (3 mL) was then added and the reaction tube was
closed with a screw cap and heated with vigorous stirring in a pre-
heated oil bath at 110 8C for 24 h under oxygen balloon pressure.
Concentration was maintained at 0.25m. After completion, the re-
action mixture was cooled to room temperature, diluted with
water (10 mL) and extracted with ethyl acetate (3”10 mL). The
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To an oven-dried screw cap reaction tube charged with a magnetic
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1
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2 mol%, 0.015 mmol) was added. Depending on the physical state
2
of secondary alcohols (0.75 mmol), solid compounds were weighed
along with the other reagents, whereas liquid alcohols were added
by microliter syringe under air atmosphere. Toluene (3 mL) was
then added and the reaction tube was closed with a screw cap
and heated with vigorous stirring in a preheated oil bath at 908C
for 18 h under oxygen balloon pressure. Concentration was main-
tained at 0.25 M. After completion, the reaction mixture was
cooled to room temperature, diluted with water (10 mL) and ex-
tracted with ethyl acetate (3”10 mL). The combined organic ex-
tracts were dried over anhydrous Na SO and concentrated under
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[
2
4
[
reduced pressure. The crude product was purified by column chro-
matography using a mixture of petroleum ether and ethyl acetate
as the eluent.
Mizuno, Angew. Chem. Int. Ed. 2002, 41, 4538; Angew. Chem. 2002, 114,
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Acknowledgements
1
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The authors acknowledge DST, New Delhi, India for financial
support. R.R. thanks UGC (Govt. of India) for a fellowship. The
authors sincerely thank Dr. Sayam Sengupta (NCL Pune, India)
for lab facilities and experimental support.
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Keywords: alcohols
mechanisms · ruthenium
·
aldehydes
·
oxidation
· reaction
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Received: April 17, 2016
Published online on June 3, 2016
Chem. Eur. J. 2016, 22, 8814 – 8822
www.chemeurj.org
8822
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim