Aerobic oxidation of secondary benzylic alcohols and direct oxidative amidation of aryl aldehydes promoted by sodium hydride

Article abstract of DOI:10.1016/j.tet.2011.03.052

We reported herein new reactivities and possible mechanistic implications of a simplest oxidant (NaH/air) uncovered on a broad range of useful transformations, including aerobic alcohol oxidations, allylic alcohol isomerizations and oxidations, cyclopropyl alcohol fragmentations, and direct aryl aldehyde oxidative amidations. These readily implementable transition-metal-free processes feature exceptional material accessibility, operational simplicity, and environmental compatibility, and add new dimensions to its synthetic utilities that are fairly robust yet had not previously been fully realized and systematically explored.

Full text of DOI:10.1016/j.tet.2011.03.052

Tetrahedron 67 (2011) 3406e3411
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Tetrahedron
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Aerobic oxidation of secondary benzylic alcohols and direct oxidative amidation
of aryl aldehydes promoted by sodium hydride
*
Xinbo Wang, David Zhigang Wang
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen University Town,
Shenzhen 518055, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We reported herein new reactivities and possible mechanistic implications of a simplest oxidant (NaH/air)
uncovered on a broad range of useful transformations, including aerobic alcohol oxidations, allylic alcohol
isomerizations and oxidations, cyclopropyl alcohol fragmentations, and direct aryl aldehyde oxidative
amidations. These readily implementable transition-metal-free processes feature exceptional material
accessibility, operational simplicity, and environmental compatibility, and add new dimensions to its
synthetic utilities that are fairly robust yet had not previously been fully realized and systematically
explored.
Received 24 December 2010
Received in revised form 10 March 2011
Accepted 17 March 2011
Available online 12 April 2011
Keywords:
Sodium hydride
Aerobic oxidation
Oxidative amidation
Benzylic alcohol
Ó 2011 Elsevier Ltd. All rights reserved.
Sodium hydrogen peroxide
1. Introduction
metal catalysts (such as Pd, Ru, Fe, Cu, Pt, Au, Ir, Rh, Co, Mn, Mo, etc.)
and dioxygen gas as the terminal oxidant.2,3 Despite these im-
The oxidation of alcohols into their corresponding carbonyl
compounds represents fundamentally important functional
pressive advances, very few of the available methods are capable of
offering truly economic and practical oxidation transformations
across a broad spectrum of alcohol substrates. Many of these sys-
tems also suffer from high reagent cost, air-instability, employment
of heavy metals or organic oxidants, stringent reaction conditions,
operational complexity, functional group incompatibility, or pro-
duction of wastes in their related processes. Thus, there is a con-
tinuing demand for new reagents that could help address the
above-mentioned challenges. We herein report on an exceedingly
simple secondary alcohols aerobic oxidation protocol and related
direct aryl aldehydes oxidative amidation processes promoted by
the widely available sodium hydride (NaH) reagent.
While pursuing another synthesis project, we lately had pre-
pared a DMAP-derived benzylic alcohol 1 and desired to use its
sodium alkoxide ion for an intended nucleophilic substitution event.
However, upon treatment of 1 with NaH in freshly distilled THF at
room temperature for 10 h, it was found that the reaction surpris-
ingly gave ketone 2 cleanly in 95% isolated yield (Scheme 1). When
a
group transformation and occupies a prominent position in mod-
ern synthetic organic chemistry. Advances in the development of
new oxidation reagents and methodologies and their applications
in both target- and diversity-oriented synthesis have been regularly
surveyed, and constituted one of the most extensively and actively
investigated areas of current organic synthesis.1 In this context, an
extensive range of classical oxidants, including those small organic
molecule-based reagents (such as DesseMartin periodinane, Swern
oxidation, Moffatt oxidation, CoreyeKim oxidation, and SO3/pyri-
dine) and metal-based systems (such as Jones reagent, Collins
reagent, pyridinium chloro-chromate, pyridinium dichromate,
barium permanganate, manganese dioxide, ruthenium tetroxide,
silver carbonate, and Oppenauer oxidation), have been known to be
powerful tools for converting alcohols into their corresponding
aldehydes or ketones, thus evolved as a most important class of
tools in synthetic chemists’ arsenal. A recent conceptually novel
approach in this area, driven by the increasingly significant con-
cerns of process environmental compatibility and sustainability,
has been exploring aerobic oxidations with highly active transition-
* Corresponding author. Tel.: þ86 755 26032702; fax: þ86 755 26035307; e-mail
Scheme 1. Aerobic oxidation of DMAP-derived benzylic alcohol promoted by NaH.
address: dzw@szpku.edu.cn (D.Z. Wang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.052

X. Wang, D.Z. Wang / Tetrahedron 67 (2011) 3406e3411
3407
NaH was repeatedly washed with freshly distilled THF to remove
possible air oxygen that might had been pre-absorbed on the com-
mercial reagent (NaH from Aldrich), 2 was consistently obtained
albeit with lower and varying yields (10e51%); but when dry air
oxygen was purposefully introduced into the reaction system, the
yield was essentially quantitative, demonstrating a remarkable level
of oxidation efficiency.
Historically, an earliest significant documentation of alkaline aer-
obicoxidationofanarylalcoholmaybetracedbacktotheautoxidation
of quinine and quininone under the action of KOtBu/O2 reported by
Doering and Woodward in their studies on the racemization and
synthesis of quinine.4 They proposed an Oppenauer-type oxidation
pathway (initiated by self-generated quininone or externally added
benzophenone) and addition of O2 to the enolate ion from quininone
to account for the observed establishment of quinineequininone
equilibrium and formation of quininic acid, respectively (Scheme 2).
were conducted without strict exclusion of air oxygen contaminant.
Yet despite these recorded observations and empirical appreciations,
this type of reactivities has usually been viewed as bypass culprits
leading to side-reactions rather than methodology of constructive
usefulness. The fact thus firmly remains that the scope and synthetic
utilities of such a simple aerobic oxidation protocol as NaH/air have
never before been fully realized and systematically explored, and
consequently, this simple oxidant had not yet emerged as a viable
methodology in synthetic chemists’ toolbox. Intrigued by this ob-
servation of aerobic oxidation of 1 into 2 promoted by NaH/air, we
embarked on an investigation on its reactivities in the general context
of alcohol oxidation chemistry. The findings summarized here over
a number of synthetically significant contexts surprisingly uncovered
new dimensions of reactivities of this arguably simplest oxidant.
2. Results and discussion
2.1. NaH-promoted aerobic oxidation of secondary aryl
alcohols
Mechanistically, it may be envisioned that the formation of so-
dium alkoxide ion 3 during the transformation of 1 into 2 under
aerobic conditions would either stimulate the ejection of a hydride
from the intermediate 3a that subsequently could be captured by
O2 to form sodium hydrogen peroxide (NaOOH), or the ejection of
a hydrogen radical from the species 3b that could be formed from
the homolytic cleavage of the benzylic CeH bond (Scheme 4). The
resulted benzylic radical is structurally analogous to the well-
established benzophenone ketyl. The hydrogen radical released
would then add to O2 to yield a hydrogen peroxide radical in 4 that
recombines with the benzylic radical to yield the intermediate 5.
Collapse of this tetrahedron species should produce ketone product
2 with concomitant release of NaOOH. Indeed, NaOOH solid pow-
der generated in this process could be easily recovered through
a repeated centrifugation-THF washing procedure. Moreover, sub-
sequent literature searching identified that, as a matter of fact,
Berre had reported in 1961 a highly practical and large scale an-
hydrous NaOOH preparation procedure that actually takes advan-
tage of alkaline oxidation of benzhydrol under oxygen atmosphere
with NaOtBu.7 NaOOH could also be generally formed and re-
covered from aerobic oxidation of other substrates under similar
conditions (vide infra, such as alcohol oxidation on 19 and 20 in
Scheme 5, and direct aldehyde amidation of 70 in Scheme 11).
Moreover, when a portion of this recovered NaOOH powder was
dissolved in water and made acidic with HCl, H2O2 was readily
generated and detected positively by the potassium iodide/starch
test. It should be noted that NaOOH itself did not promote the above
oxidation under otherwise identical conditions.8 A number of other
bases (Na, MeONa, tBuONa) and solvents (Et2O, toluene, DMF,
DMSO, 1,4-dioxane) were surveyed (with product yields ranging
from 15 to 80%) and the NaH/THF combination was found to be
Scheme 2. Alkaline autoxidation of quinine and quininone observed by Doering and
Woodward.
Sincethese initialobservations, afewother scatteredexamplesof
alkaline autoxidations had appeared during a considerably long
course of time, and these were summarized in Scheme 3. Doering
disclosed alkoxide-catalyzed autoxidative cleavage of ketones and
esters in 1954;5 Lewis reported on aerobic oxidation of p-nitro-
benzylic alcohol into its carboxylic acid under NaH/air/THF condi-
tions in 1965;6a Ohta and co-workers further showed in 1983 that
aerobic oxidation of a range of benzylic alcohols or aryl aldehydes
could be effectively promoted by sodium pyrazolide and trans-
formed these substrates into their corresponding carboxylic acids;6b
Morzycki and co-workers uncovered a striking example of aerobic
oxidation of a purely aliphatic triol to form a lactol ring in a steroid
synthesis in 2006;6c finally, conceptually relevant, the Danishefsky
group recorded a remarkable ‘chance observation’ of conversion of
an aryl diol to its hydroxyketone by simple exposure to Et3N/air in
2001 that proved to be critical for the subsequent spirocyclization
event in their total synthesis of heliquinomycinone.6d
Scheme 3. Scattered literature on alkaline aerobic oxidations.
The feasibility of these alkaline alcohol autoxidations has also
occasionally been manifested by the formation of varying amounts of
ketone by-products during etherification of aryl alcohols with the
conventional NaH/benzyl halide protocol when the manipulations
Scheme 4. Possible hydride and radical pathways in NaH-promoted aerobic oxidations.

3408
X. Wang, D.Z. Wang / Tetrahedron 67 (2011) 3406e3411
of several important pharmaceutical and fine chemical compounds
(Scheme 7). An intermediate (29) in the synthesis of TianeptineÒ,10a
a drug used for treating major depressive episodes; 30, a key pre-
cursor to the structure of sertraline (ZoloftÒ), a selective serotonin
reuptake inhibitor;10b can both be easily prepared in high yields at
multi-gram scales. A photo-initiator (31) widely used in the coating
material UV-curing processes,10c was produced in moderate yield
(with the unreacted substrate quantitatively recovered) but with
higher separation efficiency and compound purity as compared to
the
tionehalogenationeepoxide-opening technology. Particularly no-
table is the production of proprietary new-generation
conventional
AlCl3-promoted
FriedeleCraft
acyla-
a
environmentally friendly UV photo-initiator 32, which has now
been advanced to commercial bulk scales with an overall economic
and environmental benefit well comparable to the low-yielding
and massively waste-generating FriedeleCraft process.10d
Scheme 7. Economic preparations of some important pharmaceutical and fine
chemical compounds through NaH-promoted aerobic oxidation technology.
Scheme 5. NaH-promoted aerobic oxidation of secondary aryl alcohols.
2.3. Mechanism of radical-triggered cyclopropane ring
fragmentation in NaH-promoted aerobic oxidations
most effective in terms of isolated yield, reaction time, and solvent
recycling and compound purification easiness.
In attempts to mechanistically differentiate the radical-versus-
hydride ejection pathway illustrated in Scheme 4 and further probe
the structures of the intermediates involved in the aerobic oxida-
tion pathway, some cyclopropane-containing radical clock sub-
strates structured as 33 were prepared and subjected to the NaH/
O2/THF conditions (Scheme 8). Surprisingly, no formal ring-open-
ing ketone product was obtained in each case examined, even with
substrates bearing strong electron-withdrawing thus radical-sta-
bilizing substituents (such as NO2 in 41 and 45). The reactions in-
stead gave cyclopropyl ketone 34, equal amount of carboxylic acids
Among many secondary alcohols randomly surveyed under
these aerobic oxidation conditions, aryl and hetero-aryl alcohols
summarized as structure 6 (Scheme 5) were found to be substrates
of choice, while alkyl alcohols and propargyl alcohols gave either no
reaction or complicated decomposed mixtures.
The oxidation occurred effectively at room temperature and went
to completion usually within just a few hours (1e10 h). The isolated
yields of ketone products 7 are generally high (with several of them
being essentially quantitative), except in the cases of substrates
bearing an electron-withdrawing substituent (24e26), in which
a large amount of their corresponding carboxylic acid 8 was also
obtained. Given the specific reaction conditions employed here and
the observation that the formation of acid 8 is directly accompanied
by the consumption of initially formed ketone 7, this side-reaction is
best explained by Doering’s autoxidative cleavage mechanism5
(Scheme 6), rather than a Dakin-type oxidation pathway.9 As com-
pared to transition metal complexes-promoted processes, these re-
actions are particularly operationally simple, product separation and
organicwasterecyclingcouldbereadilyachieved,andthereisnosuch
issue asmetal residuecontaminantsincurredduringtheprocess, thus
offering a significant environmental and pharmaceutical advantage.
Scheme 6. Doering mechanism for autoxidative cleavage of ketone 7 bearing electron-
withdrawing aryl substituent.
2.2. Applications of NaH-promoted aerobic oxidation in
practical synthesis of some important fine chemical and
pharmaceutical compounds
The value of this new oxidation methodology was further
highlighted in the economic and environmentally benign synthesis
Scheme 8. NaH-promoted aerobic oxidative cyclopropyl ring cleavages. The ratio of
the four products in each case is listed in the sequence of 34:35:36:37.

X. Wang, D.Z. Wang / Tetrahedron 67 (2011) 3406e3411
3409
35 and 36, and diene 37 with concomitant release of ethylene.
These results clearly dispelled the possibility of participation of
a hydride ejection pathway, under which ketone 34 would be ex-
clusively formed.
A radical-triggered fragmentation mechanistic scenario may
thus be advanced (Scheme 9) to account for these fascinating oxi-
dative cleavage processes. The cyclopropyl-carbinyl radical 47 ini-
tially formed under NaH/O2 condition could either proceed through
the pathway A (in blue) to yield ketone 34, or, alternatively, undergo
a ring-opening-radical recombination event as summarized in
pathway B (in red) to give an enolate-hydroperoxide intermediate
48. This species would then engage itself in a tandem intramolecular
proton transferecarbonyl nucleophilic additionefragmentation
process to produce the observed products 35 and 36. The crucial
fragmentation event may be initiated through either the homolytic
cleavage of the weak OeO bond (in 49) or collapse of the crowded
tetrahedron peroxide intermediate (in 50). The formation of diene
37 (when X¼Cl, Y¼OMe in structure 33, i.e., substrate 38), as
summarized in the minor pathway C, may be attributed to a tandem
aryl cyclopropyl ring fragmentationeproton releasing event, or al-
ternatively, a NaOOH-triggered cyclopropyl ring openingeHOOH
elimination cascade.
Scheme 10. NaH-promoted isomerization of allylic alcohols.
The reactions gave ketones smoothly and showed an interesting
dependence on both the substrate concentration and the amount of
oxygen introduced: higher concentrations led to the formation of
more dimeric ketones (in 54 such a dimeric ketone became the
major product), and excessive air or pure oxygen gas resulted in
complicated mixture. The employment of commercially available
NaH powder (i.e., not pre-treated through THF-washing O2-removal
procedure as described earlier) under nitrogen atmosphere is suf-
ficient to bring about the observed reactivities. Mechanistically,
a pathway involving the formation of an enolate intermediate from
anionically accelerated [1,5] hydrogen shiftdan event that was
previously shown by Giomi and co-workers11 to thermally operate
only at high temperatures in closely related molecular con-
textsdrepresents an attractive possibility, while it is also likely that
the process involves the deprotonation at the benzylic position byan
external pre-formed sodium alkoxide species and subsequent allylic
shift and protonation. These scenarios require no participation of air
oxygen, but allylic alcohol oxidation may competitively operate as
neither of them could economically accommodate the observed
enone formations and isomerizations (see 28 in Scheme 5).
2.5. Direct oxidative amidation of aryl aldehydes
These novel reactivities of this simple aerobic oxidation system
prompted us to explore further its potential in oxidizing hydroxyl
groups in labile N,O-hemiacetal species thereby yielding directly
oxidative amidation products (Scheme 11). Indeed, using picoli-
nealdehyde as a model substrate, it was found that the corre-
sponding amide 70 was readily obtained in 55% yield under
standard NaH/O2 conditions. The detection of pyridin-2-ylmetha-
nol as the major reduction by-product inspired the employment of
the bulkier and hydride-free base NaHMDS at a lower temperature
to suppress the competing aldehyde reduction pathway. Indeed,
a much higher yield of 93% was obtained. The yield of 70 was fur-
ther improved to 95% when KHMDS was used. With this optimal
KHMDS/O2 condition, a variety of aromatic and hetero-aromatic
aldehydes 67 readily coupled with their secondary amine partners
68 to give the desired amides 69, i.e., products 70e86, in usually
good-to-high yields and within just a few hours, demonstrating an
impressive level of efficiency and simplicity.12 This simple yet un-
usual direct amide synthesis protocol constitutes a very useful and
appealing complement to various transition metal complexes-cat-
alyzed oxidative amidation technologies.13
Scheme 9. Mechanistic proposals.
2.4. NaH-promoted isomerization of allylic alcohols
Under these aerobic oxidation conditions, the formation of
isomeric imidazole-derived
a,
b-unsaturated ketone 28 (E/Z¼3:1,
Scheme 5) from its (E)-allylic alcohol precursor caught our atten-
tion as this implied formally a reversible hydride or radical (hy-
drogen radical or hydrogen peroxide radical) conjugate reduction
event following the initial allylic alcohol oxidation. The nitrogen
atoms in the imidazole ring, as was the case of oxidation of DMAP-
derived alcohol 1 under air-free conditions, seemed to be beneficial
for reactivity, and phenyl-substituted allylic alcohols were found to
yield no oxidation product but their corresponding alkoxide spe-
cies. Encouraged by these observations, we set out to explore the
reactivities of several other heterocyclic allylic alcohol systems
represented by structure 51 (Scheme 10).

3410
X. Wang, D.Z. Wang / Tetrahedron 67 (2011) 3406e3411
was allowed to warm to room temperature. The reaction was
quenched by addition of saturated NH4Cl (2 mL) after the indicated
time, extracted with EtOAc (10 mLꢁ2), and washed by brine (15 mL).
The combined organic phase was dried over MgSO4, the solvent was
removed under vacuum, and the residue was purified by flash chro-
matography on silica gel to give the desired ketone product 7 and 34.
For isolations of acids 8 and 35/36: the combined aqueous phase
was acidified with 2 M HCl, and then extracted with EtOAc
(10 mLꢁ2) and washed by brine (15 mL). The combined organic
phase was dried over Na2SO4, the solvent was removed under
vacuum to give acid product that can be further purified by flash
chromatography on silica gel.
4.3. Conversion of allylic alcohols to saturated ketones
To a round-bottom flask that was flame-dried and cooled under
nitrogen were added allylic alcohol 51 (0.5 mmol) and THF (2.5 mL).
After stirring at 0 ꢀC for 5 min, NaH powder (1 mmol, 2 equiv) was
added in one portion, the mixture was then allowed to warm to
room temperature. The reaction was quenched by addition of sat-
urated NH4Cl (2 mL) after the indicated time, extracted with EtOAc
(10 mLꢁ2), and washed by brine (15 mL). The combined organic
phase was dried over MgSO4, the solvent was removed under
vacuum, and the residue was purified by flash chromatography on
silica gel to give the desired ketone product 52.
Scheme 11. Direct oxidative amidation of aryl aldehydes.
3. Conclusion
In summary, the novel reactivities and mechanisms uncovered
here on a broad range of aerobic alcohol oxidations, allylic alcohol
isomerizations and oxidations, cyclopropyl alcohol fragmentations,
and direct aldehyde oxidative amidations collectively add new di-
mensions of synthetic utilities of this simplest oxidation system, they
are proven to be very robust yet had not previously been fully realized
and systematically explored. The advantages of these transition
metal-free methodologies, as already highlighted in the preparations
ofsome important pharmaceutical and fine chemical compounds, are
very significant in terms of material accessibility, operational sim-
plicity, and environmental and pharmaceutical compatibility. It
therefore might well be anticipated that these findings will invite
favorable consideration from the synthetic community and thus
stimulate their wide-spreading applications in appropriate synthetic
contexts, particularly in the economic and sustainable preparation of
pharmaceutically meaningful compounds.14
4.4. Direct oxidative amidation of aryl aldehydes
Procedure A: To a round-bottom flask that was flame-dried and
cooled under nitrogen were added THF (3 mL), aromatic aldehyde 67
(0.5 mmol), and amine 68 (2 mmol, 4 equiv). After stirring for 30 min
at room temperature, the reaction system was cooled to ꢂ78 ꢀC and
after another 10 min, the flask was collected to an oxygen balloon,
NaHMDS (2 M inTHF, 0.75 mL,1.5 mmol, 3 equiv) or KHMDS (0.5 M in
toluene, 3 mL, 1.5 mmol, 3 equiv) was added dropwise via a syringe.
The reaction mixture was then allowed to warm slowly to an in-
dicated temperature. Upon completion at the indicated time, the re-
action was quenched by addition of saturated NH4Cl (3 mL) and
extracted with EtOAc (15 mLꢁ2). The combined organic layer was
washed by brine (15 mL) and dried over MgSO4. The solvent was re-
moved under vacuum, and the residue was purified by flash chro-
matography on silica gel to give the amide product 69.
4. Experimental
Procedure B: To a round-bottom flask that was flame-dried and
cooled under oxygen were added THF (2 mL), amine 68 (2 mmol,
4 equiv), and KHMDS (0.5 M in toluene, 3 mL, 1.5 mmol, 3 equiv).
After stirring at room temperature for 1 h, aldehyde 67 (0.5 mmol)
in THF (1 mL) was added dropwise. The reaction was monitored by
TLC until the aldehyde was completely consumed. The reaction was
quenched by addition of saturated NH4Cl (3 mL), extracted with
EtOAc (15 mLꢁ2), and washed by brine (15 mL). The combined
organic phase was dried over MgSO4. The solvent was removed
under vacuum, and the residue was purified by flash chromatog-
raphy on silica gel to give the amide product 69.
4.1. General experimental
Reagents were purchased at the highest commercial quality
from Acros and Aldrich and used without further purification un-
less otherwise noted. Sodium hydride was purchased from Aldrich,
60% dispersion in mineral oil and used without further purification
unless otherwise noted. Anhydrous THF was freshly distilled from
a benzophenone ketyl still. Yields refer to chromatographically
purified compounds, unless otherwise stated. Silica gel (ZCX-II,
200e300 mesh) used for flash column chromatography was pur-
chased from Qing Dao Ocean Chemical Industry Co. 1H NMR and 13
C
1
€
NMR spectra were recorded on either a Bruker Advance 300 ( H:
Acknowledgements
13
1
€
300 MHz, C: 75.5 MHz), or Bruker Advance 500 ( H: 500 MHz,
13C: 125 MHz) spectrometer. Mass spectrometric data were
obtained using ABI-Q Star Elite high resolution mass spectrometer.
Financial support was provided by the National Science Foun-
dation of China (grants 20872004 and 20972008), the Shenzhen
Municipal ‘Shuang Bai Project’, and the Shenzhen Bureau of Science,
Technology and Information to D.Z.W.
4.2. Aerobic oxidation of secondary aryl alcohols
A round-bottom flask that was flame-dried and cooled under dry
air or oxygen atmosphere was charged with alcohol 6 or 33
(0.5 mmol) and THF (2.5 mL). After stirring at 0 ꢀC for 5 min, NaH
powder (1 mmol, 2 equiv) was added in one portion, and the mixture
Supplementary data
Detailed experimental procedures, compound characterization
data, and copies of 1H and 13C NMR spectra. Supplementary data

X. Wang, D.Z. Wang / Tetrahedron 67 (2011) 3406e3411
3411
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