Transition-metal-free and chemoselective NaOtBu-O 2-mediated oxidative cleavage reactions of vic-1,2-diols to carboxylic acids and mechanistic insight into the reaction pathways

Article abstract of DOI:10.1021/ol501012f

A method for efficient oxidative cleavage of vic-1,2-diols using a NaO ^tBu-O₂ system resulted in the formation of carboxylic acids in high yields. The present protocol is an eco-friendly alternative to a conventional transition-metal-based method. This new strategy allows large-scale production with nonchromatographic purification while also suppressing competitive reaction pathway such as benzilic acid rearrangement.

Full text of DOI:10.1021/ol501012f

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free and Chemoselective NaOtBu−O2‑Mediated
Oxidative Cleavage Reactions of vic-1,2-Diols to Carboxylic Acids and
Mechanistic Insight into the Reaction Pathways
Sun Min Kim,† Dong Wan Kim,† and Jung Woon Yang*
Department of Energy Science, Sungkyunkwan University, Suwon 440-746, Republic of Korea
S
* Supporting Information
ABSTRACT: A method for efficient oxidative cleavage of vic-
1,2-diols using a NaOtBu−O2 system resulted in the formation
of carboxylic acids in high yields. The present protocol is an
eco-friendly alternative to a conventional transition-metal-
based method. This new strategy allows large-scale production
with nonchromatographic purification while also suppressing competitive reaction pathway such as benzilic acid rearrangement.
he development of transition-metal-free, chemoselective
reactions is one of the most important and fundamental
catalysts also facilitate the direct conversion of vic-1,2-diols to
carboxylic acids (Scheme 1, eq 2).5 For such reactions, either a
high oxidation metal−oxo catalyst (i.e., Cr, V, Mn, Ru, W) or a
transition metal (Pt) catalyst is still accompanied by high
temperature (∼70 °C).6 In some cases, low product selectivity
between aldehydes and carboxylic acids is also observed.6b−d
Recently, a transition-metal-free version of oxidative cleavage
of vic-1,2-diols to carboxylic acids was reported by utilizing
T
tasks in organic synthesis, as it contributes significantly to green
chemistry practices.1 To keep pace with scientific advancement
on green processes, we recently reported the transition-metal-
free oxidation of primary allylic alcohol to α,β-unsaturated
carboxylic acids utilizing NaOtBu under oxygen atmosphere.2a,2
This protocol has distinctive advantages over existing method-
ologies because it replaces precious transition-metal catalysts
(e.g., Au, Pt, Ru, Cu, or Pd), has a lower reaction temperature,
and has a shorter reaction time. Transition-metal-free
oxidations of a variety of allylic alcohols with high chemo-
selectivities were fully investigated for the first time.
a
Table 1. Optimization of Reaction Conditions
As part of a wider research program aimed at designing and
developing transition-metal-free processes, we became inter-
ested in the oxidative cleavage reaction of vic-1,2-diol in
combination with alkali metal tert-butoxide and oxygen.3 In
general, the most common oxidizing agents for oxidative
cleavage of vic-1,2-diols are sodium periodate (NaIO4), periodic
acid (HIO4), and lead tetraacetate [Pb(OAc)4], which lead to
aldehydes or ketones as major products (Scheme 1, eq 1).4
Several different types of oxidants including transition-metal
b
entry
base (equiv)
solvent
THF
time (h)
yield (%)
1
24
24
24
24
3
ND
42
2
KOtBu (2)
NaOtBu (2)
NaOtBu (3)
NaOtBu (4)
NaOiPr (4)
NaOMe (4)
NaH (4)
THF
3
THF
50
4
THF
56
5
THF
75
6
THF
24
24
24
24
24
3
42
7
THF
34
Scheme 1. Utility of NaOtBu-O2 System for Oxidative
Cleavage of vic-1,2-Diol
8
THF
71
9
KHMDS (4)
Cs2CO3 (4)
NaOtBu (4)
NaOtBu (4)
NaOtBu (4)
NaOtBu (4)
NaOtBu (4)
NaOtBu (4)
THF
<5
ND
ND
55
10
11
12
13
14
15
THF
CH2Cl2
toluene
1,4-dioxane
Et2O
3
3
54
3
64
DMSO
THF
3
67
c
16
3
ND
a
General conditions: 1a (0.5 mmol), base (2−4 equiv), solvent (3
b
c
mL), O2 (1 atm), rt. Isolated yield. Anaerobic conditions.
Received: April 7, 2014
Published: May 15, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
equiv), 80 °C], and sodium perborate [NaBO3·4H2O (10
equiv) as oxidant in AcOH (2−3 mL per oxidant) under reflux
conditions].7 Therefore, multifarious ways to accomplish
oxidative cleavage of vic-1,2-diols into carboxylic acids without
the need for transition-metal catalysts, costly oxidants, and
power supply instruments are highly desirable.
Table 2. Reaction Scope
Herein, we report a scalable, transition-metal-free, and
chemoselective cascade of reactions utilizing NaOtBu and O2
as oxidant, which are both readily available and inexpensive.
This could potentially address the shortcomings of the
aforementioned transition metal-based methodologies (Scheme
1, eq 3). The labeling experiment with 18O2 was performed to
elucidate the pathway for the preferential mechanism.
b
entry substrate
product
time (h)
yield (%)
To investigate the viability of the envisioned direct oxidative
cleavage reaction of vic-1,2-diol, hydrobenzoin 1a was selected
as a model substrate. First, various bases and solvents were
screened. The results are summarized in Table 1. In a
controlled experiment it was found that the reaction did not
proceed in the absence of either base or oxygen as oxidant
(Table 1, entries 1 and 16).
1
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
3
75
91
96
70
70
75
89
91
96
60
60
2
5
3
5
4
7
5
3
6
6
7
1g
1h
1i
2g
2h
2i
3.5
2.5
2
The use of NaOtBu gave a slightly better chemical yield than
the use of KOtBu (Table 1, entries 2 and 3). Product yield was
significantly influenced by varying the equivalents of NaOtBu
(Table 1, entries 3−5). The influence of the alkoxide nature
was also examined. For instance, sodium isopropoxide and
sodium methoxide gave low product yield (Table 1, entries 6−
7). Interestingly, the chemical yield of product increased in the
following order of alkoxide ion basicity: tert-butoxide >
isopropoxide > methoxide. NaH gave results comparable to
those obtained from reaction mediated by NaOtBu, but a much
longer reaction time (24 h) was required (Table 1, entry 8).
However, KHMDS and Cs2CO3 showed negligible conversion.
A number of other solvents, including CH2Cl2, toluene, 1,4-
dioxane, Et2O, and DMSO, were subsequently investigated, but
they were inferior to THF in terms of yield (Table 1, entries
11−15).
8
9
10
11
12
13
14
15
1j
2j
5
1k
1l
2k
5
1/2 2b + 1/2 2h
1/2 2i + 1/2 2m′
1/2 2b
2
45 (2b) + 44 (2h)
39 (2i) + 39 (2m′)
44 (2b)
c
e
d
1m
1n
1o
8
2
f
2o
6
40
a
General conditions: 1 (0.5 mmol), NaOtBu (4 equiv), solvent (3
b
c
d
mL), O2 (1 atm), rt. Isolated yield. Using NaOtBu (6 equiv). 2m′ is
e
f
n-hexanoic acid. Using NaOtBu (6 equiv). Determination of the yield
by Fisher esterification with H2SO4−MeOH.
organocatalysis [nitroxyl radical as organocatalyst and PhI-
(OAc)2 (5 equiv)/or NaClO2 (3 equiv) as oxidants],
photooxidation [2-chloroanthraquinone as catalyst, O2, hν
(400-W Hg lamp)], aqueous sodium hypochlorite (10 equiv),
hydroperoxide [tert-butyl hydroperoxide (4 equiv), KOtBu (3
We next explored the scope of this reaction of vic-1,2-diols
with NaOtBu under optimized conditions [NaOtBu (4 equiv),
O2 (1 atm), THF, rt]. The results are summarized in Table 2. A
Figure 1. Proposed mechanism for the oxidative cleavage of vic-1,2-diols to carboxylic acids.
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Letter
series of symmetrical and unsymmetrical vic-1,2-diols were
examined. In general, the symmetrical vic-1,2-diols bearing
electron-withdrawing substituents smoothly transformed to
corresponding products in high yields ranging from 70% to
96%. However, those with electron-donating substituents
resulted in relatively lower yields (60%). Interestingly, unsym-
metrical vic-1,2-diols (1l and 1m) can be oxidatively cleaved
with NaOtBu-O2 to form two different acids (Table 2, entries
12 and 13). Specifically, 4-chlorobenzoic acid 2b and 4-
cyanobenzoic acid 2h were obtained in virtually identical yields
(∼45%) when hydrobenzoin derivative 1l was employed.
Unsymmetrical vic-1,2-diol bearing both aryl and alkyl
substituents also gave the corresponding products (2i and
2m′).
Figure 2. Isotopic labeling results from the oxidative cleavage of vic-
1,2-diol utilizing a NaOtBu-18O2 system.
Styrene-derived terminal 1,2-diol 1n gave one-half the
product 2b with 44% yield (Table 2, entry 14). Aliphatic
internal 1,2-diol 1o proved suitable candidate for this
transformation. The yield of actual product 2o was determined
by Fischer esterification of the resulting 5-phenylpentanoic acid
with MeOH in the presence of catalytic amounts of H2SO4
(Table 2, entry 15). During the oxidative cleavage reaction of
vic-1,2-diol, small amounts of benzilic acid (10%) were detected
in most cases.
Scheme 2. Large-Scale Production of 2a
Scheme 3. Transition-Metal-Free, Oxidation/Oxidative
Cleavage Reaction in a One-Pot Manner Utilizing a NaOtBu-
O2 System
To ascertain mechanistic insights into the nature of oxidant,
an 18O isotopic labeling experiment was conducted with 18O2
gas (Figure 1).
Double deprotonation of the hydroxyl group in vic-1,2-diol
with 2 equiv of NaOtBu presumably generated 1,2-diketone 3
and 18O-labeled hydroperoxide anion 4 via hydride transfer
from the α-carbon of alcohol to the 18O-labeled oxygen. The
subsequent nucleophilic attack of 18O-labeled hydroperoxide
anion 4 to the carbonyl group of 1,2-diketone would form two
different 18O-labeled anhydride 5 and 5′ as transient
intermediate and 18O-labeled hydroxide ion 6 via epoxidation
mechanism (pathway A) or Baeyer−Villiger mechanism with
acyl group migration (pathway B), leading to three main
categories of carboxylic acids 7 after simple acid-workup.8 The
resulting products were subjected to GC/MS analysis (Hewlett-
Packard Agilent 6890, 5973 MSD). The 16O and 18O
compositions of individual carboxylic acids were determined
by the relative abundances of mass peaks at m/z = 122 for
16O16O, m/z = 124 for 16O18O, and m/z = 126 for 18O18O.
As shown in Figure 2 and proposed in Figure 1, it was
revealed that the relative abundances of isotopic masses for
each product 7 are identical to those of isotopic masses
( t h e o r e t i c a l r a t i o o f b e n z o i c a c i d i s o t o p e s
[16O16O:16O18O:18O18O] = 1:6:1, experimental ratio of
[16O16O:16O18O:18O18O] = 1:6.2:1.3).
During the reaction course, small amounts of benzilic acid
derivative 8 were observed. This indicates that the released
hydroxide ion 6 serves as a formidable competitor to the
formation of carboxylic acid 7 and α-hydroxy acid 8. Namely,
the benzilic acid rearrangement had clearly occurred, in which
1,2-diketone 3 was converted to α-hydroxy acid 8 upon
treatment with hydroxide ion 6. This information provides
crucial evidence of the existence of 1,2-diketone and hydroxide
ion while allowing a better understanding of the reaction
mechanism.
parasitic pathways, such as benzilic acid rearrangement, the
desired carboxylic acid was almost selectively formed. The
existence of reactive intermediate such as anhydride 5 or 5′,
which are not easily isolable from reaction mixture in the
presence of strong nucleophile (such as hydroxide ion9), offers
the possibility to suppress competing parasitic reactions
(benzilic acid rearrangement). The ability to control selectivity
while avoiding the use of transition-metal catalyst is one of the
most distinctive features of the oxidative cleavage of vic-1,2-
diols. The presence of trace transition metal elements in
NaOtBu was also examined by ICP-ACE, and the results are
shown in ref 10.
A 23-fold scale-up was also demonstrated with substrate 1a
compared to the currently approved reaction under the
NaOtBu−O2 system. The detailed experimental procedure is
described in the Supporting Information. Organic and aqueous
layers were clearly separated by salting-out, eliminating the
need for additional organic extraction. Moreover, the desired
product 2a was easily isolated from residues due to the
insolubility of resulting side product benzilic acid 8 in EtOAc/
hexanes (Scheme 2).
To verify the existence of 1,2-diketone, a reaction of 4,4′-
methoxyhydrobenzoin 1k was carried out with 4 equiv of
NaOtBu under oxygen atmosphere at −20 °C to produce 4,4′-
methoxybenzil 3k in 11% yield. The product was identified by
1H and 13C NMR spectroscopy. Despite being hampered by
Finally, the oxidation/oxidative cleavage reaction of 9 was
performed in a one-pot manner. For example, a simple primary
allylic alcohol moiety was oxidized to α,β-unsaturated
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Letter
Steele, A. M.; Meric, P. J. Catal. 2004, 226, 435. (d) Barroso, S.; Blay,
carboxylic acid, and a 1,2-diol moiety was oxidatively cleaved to
carboxylic acid (Scheme 3).
G.; Fernan
́
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Munoz, M. C. J. Mol. Catal. A.: Chem. 2006, 243, 214. (e) Che, C.-M.;
̃
In summary, we have developed a transition-metal-free,
oxidative cleavage reaction of vic-1,2-diols to carboxylic acids
with NaOtBu under oxygen atmosphere. We also demonstrated
how to scale-up experiments without organic extraction and
chromatographic technique. This protocol was used to perform
an oxidation/oxidative cleavage reaction in a one-pot fashion.
Yip, W.-P.; Yu, W.-Y. Chem.Asian J. 2006, 1, 453. (f) Fujitani, K.;
Mizutani, T.; Oida, T.; Kawase, T. J. Oleo Sci. 2009, 58, 323.
(g) Alagiri, K.; Prabhu, K. R. Tetrahedron 2011, 67, 8544. (h) Schmidt,
A.-K. C.; Stark, C. B. W. Org. Lett. 2011, 13, 5788.
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Org. Lett. 2012, 14, 5006. (b) Shibuya, M.; Shibuta, T.; Fukuda, H.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedure and characterization of all
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) Cullis, P. M.; Arnold, J. R. P.; Clarke, M.; Howell, R.; DeMira,
M.; Naylor, M.; Nicholls, D. J. Chem. Soc., Chem. Commun. 1987, 1088.
(9) The reaction of 1a was performed in the presence of TEMPO
(1−3 equiv) as radical scavenger under optimal conditions, resulted in
the formation of the desired product 2a in high yield. It is crucial
evidence to support the involvement of non-free-radical species (e.g.,
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jwyang@skku.edu.
Author Contributions
¯
¯OH, O2H) in this transformation.
(10) In order to eliminate the possibility of the presence of trace
transition-metal elements in NaOtBu that would potentially affect our
results, we purified the NaOtBu by sublimation and also examined by
inductively coupled plasma-atomic emission spectrometry (ICP-ACE)
prior to our investigation. These results clearly show that the contents
of transition metals (Pd, Fe, and Cu) were in the range of 0.2−0.5
ppm. After identifying negligible transition metal contents, we carried
out the reaction of 1a with the purified NaOtBu under oxygen
atmosphere to produce the desired product 2a in a yield similar to that
obtained in Table 2.
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NRF Nano·Material
Technology Development Program (2012M3A7B4049652)
and the KETEP Human Resources Development Program
(20124010203270).
NOTE ADDED AFTER ASAP PUBLICATION
■
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A partially corrected version of this article published May 15,
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2014.
■
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