A mild method for synthesizing carboxylic acids by oxidation of aldoximes using hypervalent iodine reagents

Article abstract of DOI:10.1039/c7ob02858j

A mild oxidation method for the conversion of aldoximes to carboxylic acids was developed mediated by hypervalent iodine reagents. This method covers a wide range of functionalized aldoximes and proceeds under mild conditions, utilizing PhI(OH)OTs as an oxidant.

Full text of DOI:10.1039/c7ob02858j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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A mild method for synthesizing carboxylic acids by oxidation of
aldoximes using hypervalent iodine reagents
Akira Nakamura,a Hodaka Kanou,a Junki Tanaka,a Akira Imamiya,a Tomohiro Maegawa*a and
Yasuyoshi Miki*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mild oxidation method for the conversion of aldoximes to
carboxylic acids was developed mediated by hypervalent
iodine reagents. This method covers
a wide range of
functionalized aldoximes and proceeds under mild
conditions, utilizing PhI(OH)OTs as an oxidant.
Oxidation is one of the fundamental reactions in organic
synthesis, particularly the oxidative synthesis of carboxylic
acids. Pinnick oxidation is a well-known and widely utilized
method for the preparation of carboxylic acids from
aldehydes.1 However, aldoximes, which act as protecting
groups to certain aldehydes,2 are less reactive than the parent
aldehyde and few methods have been reported for their
oxidation to carboxylic acids. The oxidation of aldoximes with
sodium hypochlorite is a cheap and simple method but suffers
from substrate limitation.3 Another method for the oxidation
of aldoximes utilizes transition metals as catalysts; however,
these reactions require elevated thermal conditions.4-6
Therefore, the development of a mild oxidation method for
the conversion of aldoximes to carboxylic acids is desirable.
Hypervalent iodine reagents are readily available,
environmentally benign, and have unique reactivity.7 Several
oxidation reaction methods for the conversion of aldoximes
mediated by hypervalent iodine reagents are reported herein
course of our recent research on the utilization of nitrile oxide,
we reacted aldoximes with PhI(OAc)2. Surprisingly, the major
product was the corresponding carboxylic acid, and not
oxadiazole N-oxide or hydroxamic acid. We investigated the
reaction in detail and report herein the novel transformation
of aldoximes to their carboxylic acids using hypervalent iodine
reagents under mild conditions.
8b
(Scheme 1).8a The reaction of aldoximes using PhICl2 or
8c
PhI(OAc)2 generated nitrile oxides in situ and oxadiazole N-
oxides were formed by dimerization of nitrile oxides. Patel and
co-workers reported that both aromatic and aliphatic
aldoximes, with the hypervalent iodine reagents PhI(OAc)2 or
PhI(OH)OTs (Koser’s reagent), yielded the corresponding
hydroxamic esters and hydroxamic acids, respectively, and
nitrile oxides were proposed as reactive intermediates.9 We
are interested in hypervalent iodine-mediated reactions, and
as such have developed new synthetic methods.10 During the
We employed 4-methoxybenzaldehyde oxime 1a as a
substrate, and conducted the reaction using two equivalents
of PhI(OAc)2 at room temperature. The carboxylic acid 2a was
isolated in 47% yield and the aldehyde in 25% yield (entry 1).
Other hypervalent iodine reagents were also examined and
two equivalents of PhI(OH)OTs gave acid 2a in 63% yield,
slightly better than that with use of PhI(OCOCF3)2 (entries 2
and 3). Next, various solvents were studied and reactions in
tetrahydrofuran (THF), N,N-dimethylformamide (DMF) and N-
methylpyrrolidone (NMP) gave moderate yields (entries 4–6).
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OH
H
PhI(OH)OTs (2.2 eq.)
O
OH
H
N
O
N
DMSO-H2O (50:1)
rt, 24 h
R
O
OH
Reagent
Solvent
rt, 24 h
R
OH
2
1
O
O
MeO
O
MeO
MeO
MeO
1a
2a
OH
OH
OH
OH
OMe
OMe
2c 80%
MeO
Entry
Reagent
Eq.
2
Solvent
MeCN
MeCN
MeCN
THF
Yield (%)b
47 (25)c
OMe
OMe
1
2
PhI(OAc)2
PhI(OCOCF3)2
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
PhI(OH)OTs
2b 92%
2d 95%
2e 92%
2
60
O
O
O
O
3
2
63
OH
OH
OH
OH
4
2
43
HO
Br
Cl
5
2
DMF
57
2f 82%
2g 89%
2h 89%
2i 88%
6
2
NMP
18
7
2
CH2Cl2
DMSO
DMSO
72
O
O
OH
O
O
8
2
75
OH
OH
OH
9
1
23
O2N
NC
10
11
12
2
DMSO-H2O (50:1)
85
2j
2k
2l
2m
82%
41%
87%
O
84%
O
2.2 DMSO-H2O (50:1)
2.2 DMSO-H2O (1:1)
94
74 (10)c
O
OH
O
OH
S
OH
OH
AcO
N
Ts
c
2n
2o
2p
2q
89%
63%
95%
92%
OH
The yield was increased in CH2Cl2 and the best result was
obtained in dimethyl sulfoxide (DMSO) (entries 7 and 8). One
equivalent of PhI(OH)OTs resulted in a decrease in yield (23%)
(entry 9). It was found that the addition of water had a
significant effect, and the reaction with a 50:1 ratio of DMSO-
H2O improved the yield to 85% (entry 10). Finally, the acid 2a
was obtained at 94% yield by the use of 2.2 equivalents of
PhI(OH)OTs (entry 11).11 When the reaction was performed in
a 1:1 ratio of DMSO-H2O, the yield of 2a was decreased to 74%
and the aldehyde was isolated at 10% (entry 12).
O
O
O
8
OH
(
)
Cl
OH
2t 99%
2s 89%
2r
87%
HO
O
O
OH
OH
HO
2v
2u 86%
79%
After optimizing the reaction conditions, the substrate
scope was explored (Table 2). Electron-rich benzaldehyde
oximes were successfully converted to the corresponding
alcohols. The oxidation of aldoximes proceeded in the
presence of primary and secondary benzylic alcohols, which
remained intact, and the acids 2u and 2v were obtained in 86%
and 79% yields, respectively.
carboxylic acids in good yields (2b–2f). In the presence of the
phenolic hydroxy group, the reaction provided the acid 2g in
89% yield without dearomatization of the phenol moiety.12
The reaction of the substrate with electron-withdrawing
substituents at the para-position proceeded well and the
To elucidate the reaction mechanism, we explored the
possible reaction pathways and intermediates (Scheme 2). In
accordance with previous reports, the first step would be the
formation of nitrile oxide, and then the hydroxamic acid could
be formed by the nucleophilic addition of water.9 The
improvement in yield of carboxylic acid in aqueous solvent
tends to support this pathway, although there is an excess of
water involved in the generation of the aldehyde. Then, the
hydroxamic acid seems to react with PhI(OH)OTs to afford the
carboxylic acid. The reaction of benzohydroxamic acid with 1
equivalent of PhI(OH)OTs provided benzoic acid in 86% yield
(eq. 1), and no reaction occurred with p-TsOH (eq. 2). This
result is consistent with the previous report about oxidative
cleavage of a rhodamine-hydroxamic acid by hypervalent
iodine reagents,13 and the conversion of hydroxamic acid to
the corresponding carboxylic acid was confirmed by
demonstrating a follow-up experiment using PhI(OH)OTs (see
corresponding acids were obtained in good yields (2h–2j). The
different reactivities of 1-naphthaldehyde oxime and 2-
naphthaldehyde oxime were observed under these conditions,
and 1-naphthoic acid 2k was isolated at 41% yield, whereas 2-
naphthoic acid 2l was obtained at 87% yield. The aldoximes
with the nitrile group (1m) and ester group (1n) successfully
converted to acids 2m and 2n in yields of 84% and 89%,
respectively. The yield of 2-thiophenecarboxylic acid (2o) was
decreased to 63% due to the partial decomposition. The Ts-
protected indole moiety endured these conditions and the
acid 2p was obtained in 95% yield. The oxidation proceeded in
the presence of conjugated double bonds and produced
cinnamic acid 2q in 92% yield. Aliphatic aldoximes were also
oxidized to carboxylic acids in high yields (2r–2t). We next
examined selective oxidation in the presence of benzyl
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reactivity. Further investigations concerning the catalytic use
of hypervalent iodine reagents with an oxidant are currently
under way.
Acknowledgements
This work was generously supported by Grant-in-Aid for Young
Scientists (B) (15K18840) from the Japan Society for the
Promotion of Science (JSPS) and also by the MEXT-Supported
Program for the Strategic Research Foundation at Private
Universities, 2014–2018 (S1411037). We thank Kindai
University Joint Research Center for use of facilities. We also
thank reviewers for insightful comments.
Notes and references
1
(a) J. R. McNesby and C. A. Heller, Chem. Rev. 1954, 54, 325;
(b) J. E. Backvall, Modern Oxidation Methods, Wiley,
Weinheim, 2004; (c) G. Tojo and M. Fernández, Oxidation of
Primary Alcohols to Carboxylic Acids, Springer, New York,
2010.
supporting information). Furthermore, the acid could be
obtained by another pathway, via the aldehyde generated by
the hydrolysis of the aldoxime. The oxidation of benzaldehyde
was examined with one equivalent of PhI(OH)OTs, but no
reaction was observed (eq. 3). Hence, this method is a
characteristic transformation of aldoximes, not via aldehydes.
Another possible intermediate, oxadiazole N-oxides generated
by dimerization of nitrile oxides, was also applied to the
conditions and all of the oxadiazole N-oxide was recovered
after the reaction (eq. 4). On the basis of control experiments,
a possible reaction mechanism was described in Scheme 3. As
reported by Patel’s work, one equivalent of PhI(OH)OTs was
consumed by the transformation of the hydroxamic acid. Then,
ligand exchange between hydroxamic acid and tosylate on
PhI(OH)OTs was occurred. Elimination of PhI and H2O from the
intermediate afforded the acyl-nitroso compound, which
giving the carboxylic acid by hydrolysis.
2
3
4
5
T. W. Greene and P. G. M. Wuts, Protective groups in organic
synthesis, 5th ed., John Wiley, New York, 2007, 515–527.
J. M. Khurana, A. Ray and P. K. Sahoo, Bull. Chem. Soc. Jpn.,
1994, 67, 1091.
J. G. Handique, L. Borah, J. Sarma and J. B. Baruah, J. Mol.
Catal. A: Chem., 2002, 188, 63.
M. Giurg, S. B. Said, L. Syper and J. Mlochowski, Synth.
Commun., 2001, 31, 3151.
6
7
K. Alagiri and K. R. Prabhu, Tetrahedron, 2011, 67, 8544.
For recent reviews see: (a) T. Wirth, Top. Curr. Chem.,:
Hypervalent Iodine Chemistry Modern Developments in
Organic Synthesis, Springer, Berlin, 2003; (b) H. Tohma and Y.
Kita, Adv. Synth. Catal., 2004, 346, 111; (c) R. M. Moriarty, J.
Org. Chem., 2005, 70, 2893; (d) T. Wirth, Angew. Chem., Int.
Ed., 2005, 44, 3656; (e) V. V. Zhdankin and P. J. Stang, Chem.
Rev., 2008, 108, 5299; (f) M. Ochiai, Synlett, 2009, 159; (g) T.
Dohi and Y Kita, Chem. Commun., 2009, 2073; (h) A. Duschek
and S. F. Kirsch, Angew. Chem., Int. Ed., 2011, 50, 1524; (i) E.
A. Merritt and B. Olofsson, Synthesis, 2011, 517; (j) D. F.
Gonzalez, F. Benfatti and J. Waser, ChemCatChem, 2012, 4,
955; (k) Y. Kita, and T. Dohi, Chem. Rec., 2015, 15, 837; (l) A.
Yoshimura and V. V. Zhdankin, Chem. Rev., 2016, 116, 3328.
(a) A. Yoshimura and V. V. Zhdankin, ARKIVOC, 2017, 99; (b)
A. S. Radhakrishna, K. Sivaprakash and B. B. Singh, Synth.
Commun., 1991, 21, 1625; (c) O. Prakash and K. Pannu,
ARKIVOC, 2007, 28.
Conclusions
8
9
In conclusion, we have developed a novel method for oxidative
conversion of aldoximes to carboxylic acids using the
hypervalent iodide reagent, PhI(OH)OTs. The reaction
parameters were examined in detail and a variety of aldoximes
were successfully transformed into their corresponding
carboxylic acids, in good to high yields. This procedure is
characterized by its mild reaction conditions and distinctive
H. Ghosh and B. K. Patel, Org. Biomol. Chem., 2010, 8, 384.
10 (a) H. Hamamoto, H. Umemoto, M. Umemoto, C. Ohta, M.
Dohshita and Y. Miki, Synlett, 2010, 17 2593; (b) H.
Hamamoto, H. Umemoto, M. Umemoto, C. Ohta, E. Fujita, A.
Nakamura, T. Maegawa and Y. Miki, Heterocycles, 2015, 91
,
,
561; (c) A. Nakamura, S. Tanaka, A. Imamiya, R. Takane, C.
Ohta, K. Fujimura, T. Maegawa and Y. Miki, Org. Biomol.
Chem., 2017, 15, 6702.
11 The other solvent systems were also examined (DMSO-H2O
10:1 and 4:1) and the acid 2a was obtained in 94% in both
cases. Finally, 50:1 ratio was found to be better solvent
system as a result of the substrate screening. For example,
the yield of 2h was decreased to 77% when 10:1 ratio of
solvent was used.
12 (a) Y. Tamura, T. Yakura, J. Haruta and Y. Kita, J. Org. Chem.
1987, 52, 3927; (b) L. Pouysegu, D. Deffieux and S. Quideau,
Tetrahedron, 2010, 66, 2235.
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13 T. Sun, J. O. Moon, M. G. Choi, Y. Cho, S. W. Ham and S. K.
Chang, Sensors Actuators B Chem., 2013, 182, 755.
14 General Oxidation Procedure: To a DMSO-H2O (50:1, 2 mL)
solution of aldoxime
1 (0.2 mmol) was added PhI(OH)OTs
(0.21 mmol) at room temperature, and another amount of
PhI(OH)OTs (0.21 mmol) was added in 30 min. After
completion of the reaction as indicated by TLC monitoring,
the reaction mixture was poured into 10% aq. Na2CO3 and
then EtOAc was added. The organic layer was extracted with
10% aq. Na2CO3. The combined aqueous layers were
acidified by addition of aq. HCl, and then extracted with
EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4 and then concentrated in
vacuo to afford pure carboxylic acid
further purification.
2
with no need for
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