Direct Aerobic Oxidative Reactions of 2-Hydroxyacetophenones

Article abstract of DOI:10.1002/ejoc.201700909

Valuable and direct aerobic oxidation reactions of 2-hydroxyacetophenones were explored. The concept was based on the in situ treatment of small quantities of aerobically formed α-keto aldehydes that drove the reactions to the corresponding products. This new strategy was applied for a variety of oxidative reactions of 2-hydroxyacetophenones, and valuable products such as phthalides, quinoxalines, and α-keto amides were obtained in good to high yields.

Full text of DOI:10.1002/ejoc.201700909

A Journal of
Accepted Article
Title: Direct Aerial Oxidative Reactions of 2-Hydroxyacetophenones
Authors: Subhas Chandra Pan, Subas Chandra Sahoo, and Utpal Nath
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700909
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700909
Supported by

10.1002/ejoc.201700909
European Journal of Organic Chemistry
COMMUNICATION
Direct Aerial Oxidative Reactions of 2-Hydroxyacetophenones
Subas Chandra Sahoo, Utpal Nath and Subhas Chandra Pan*[a]
Dedication ((optional))
Abstract:
A
valuable direct aerial oxidative reactions of 2-
oxygen has emerged as the most abundant terminal oxidant with
important advantages of atom economy, cost efficiency etc.[3] For
catalytic aerial oxidation reactions, mostly substrate selective
transition metal catalysts were employed[4a-j] and the elegant
contributions from Stahl, Sigman, Stoltz, Bäckvall and Katsuki are
noteworthy. In contrast, metal-free aerial oxidative approaches
have been much less developed.[4k-l]
hydroxyacetophenones is described. The concept is based on the in
situ treatment of small quantities of aerially formed α-ketoaldehydes
that drives the reaction to the corresponding product side. This new
strategy was applied for a variety of oxidative reactions of 2-
hydroxyacetophenones and valuable products such as phthalides,
quinoxalines and α-ketoamides were obtained in good to high yields.
However the direct oxidation of alcohols with molecular oxygen
is rare due to the high energy barrier involved in the electron
transfer from alcohol to oxygen and vice versa.[2] On the other
hand, aldehydes, on exposure to oxygen or air, is slowly
converted to the corresponding peracid, which further reacts with
the aldehyde to form the normal acid.[5] To overcome the direct
aerial oxidation of alcohols to aldehydes, we envisioned a
postulate. We presumed that activated alcohols like α-
hydroxyketones might be aerially converted to the correspond-ing
aldehydes i.e 2-ketoaldehydes in small equilibrium quantities. If
this in situ formed aldehyde could be trapped by other reagents
or reacted with other compounds in catalytic condition, then this
equilibrium could be shifted and overall high yield of the final
product could be attained (eq. 1). To this end, the work by Taylor
et al on manganese oxide mediated oxidation of unactivated
alcohols under in situ oxidation-Wittig reaction is noteworthy.[6]
We were particularly interested in the oxidation of 2-
hydroxyacetophenones (1) as the resulting products 2-
ketoaldehydes (2) are potentially valuable synthetic intermediates
as reflected in the synthesis of crotonates,[7-9] quinoxalines,[9]
dihydropyrazines,[9] imidazoles,[10] pteridines,[11] furans,[12] α-
ketoimines,[9] α-ketoamides[13] and many other important class of
compounds.
The selective oxidation of alcohols to the subsequent carbonyl
compounds is considered as one of the important organic
transformations and extensively performed in laboratory as well
was on industrial scale.[1] Traditionally, stoichiometric amounts of
toxic organic or inorganic reagents such as dimethyl sulfoxide,
lead acetates, chromium and manganese oxides have been used
for such transformations.[1] Many of these processes suffer from
high reagent cost, operational complexity and production of
harmful bi-products. During the last two decades there has been
a tremendous development in the field and consequently catalytic
versions of the reaction using environmentally friendly oxidants
such as H2O2 and molecular oxygen have been identified.[2] Aerial
O
O
O
O2/air
O2/air
R
OH
R
OH
R
H
R
H
Direct aerial oxidation
of aldehydes = common
Direct aerial oxidation
of alchols elusive
New concept for oxidation of activated alcohols: High conversion by in-situ trapping
O
O
In-situ trapping
by futher reaction
O2/air
(Eq 1)
R
P
R
OH
O
To test the proposed concept, we initially heated 2-
hydroxyacetophenone at 80 oC in toluene for 30 hours.
Interestingly, traces of benzaldehyde (~10%) was detected by
TLC and GC which could be explained by the formation of
phenylglyoxal by oxidation followed by its conversion to
benzaldehyde.[14] Encouraged by this outcome, we planned to
perform reactions of 2-hydroxyacetophenone with other
compounds under this condition. Initially homophthalic anhydride
was chosen as the reaction partner because so far no reports of
its reaction with phenyl glyoxal are available, though a reaction
with benzaldehyde was recently published.[15] Since homophthalic
anhydride needed to be activated with base, we screened a
variety of bases for the reaction (Table 1). Alhough there was no
Application of the concept: Direct oxidative reaction of 2-hydroxyacetophenones
O
O
O
phthalide
O
O
O
Ar
base catalyst, O2/air
O
Ar
NH2
(Eq 2)
OH
N
NH2
quinoxaline
acid catalyst, O2/air
N
Ar
conversion
with
potassium
carbonate,
1,8-
[a]
S. C. Sahoo, Utpal Nath and Prof. Dr. S. C. Pan
Department of Chemistry
Indian Institute of Technology Guwahati
Assam, 781039, India
E-mail: span@iitg.ernet.in
Webpage: www.iitg.ac.in/span
diazabicyclo[5.4.0]undec-7-ene (DBU) indeed provided 20% yield
of the biologically important phthalide[16] 3a whose structure was
unambiguously confirmed by X-ray crystallography (CCDC
1518677, entry 2).[17] 1,4-Diazabicyclo[2.2.2]octane (DABCO) as
catalyst provided moderate yield (40%) of the product (entry 3).
Also similar yield was observed with 1,1,3,3 tetramethylguanidine
(TMG) (entry 4). Slightly higher yields were obtained with 4-
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700909
European Journal of Organic Chemistry
COMMUNICATION
dimethylaminopyridine (DMAP) and diisobutylamine (entries 5-6).
Interestingly, triethylamine was found to be a better catalyst
providing 60% yield of the product (entry 7). Finally the best
catalyst turned out to be diisopropylethylamine (DIPEA) which
afforded 70% yield of the product (entry 8). Higher catalyst loading
was not beneficial for the improvement of the yield of the reaction
(entry 9). Surprisingly the yield decreased by increasing the
reaction temperature to 100 oC (entry 10). The yield was also not
improved by using oxygen balloon for the reaction (entry 11).
Other solvents were also screened but toluene was found to be
the best solvent (see supporting information for details). Thus we
decided to carry out further reactions with 10 mol% DIPEA in
toluene.
interestingly the highest yield of 84% was obtained with 2-thieyl
containing hydroxyketone 1v. Then we focused on the
employment of other substituted homophthalic anhydrides.
Though different substitutions on the aryl group were tested, only
7-methoxy substituted anhydride 3b delivered the corresponding
product 4w in 65% yield.
Table 2. Substrate Scope for the Phthalide Synthesis
Entry[a]
1
R1
3
Time (h) Product
Yield[b]
70
Table 1. Catalyst Evaluation for the Phthalide Synthesis
Ph
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
30
30
36
30
30
30
30
42
36
34
38
34
30
38
42
30
30
30
42
4a
4b
4c
4d
4e
4f
2
4-MeC6H4
4-OMeC6H4
4-FC6H4
55
50
50
45
55
40
74
50
55
40
70
50
60
72
35
32
56
82
3
4
Entry[a]
Catalyst
Mol%
Temp (°C) Time (h) Yield[b]
5
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-PhC6H4
2-MeC6H4
2-ClC6H4
2-BrC6H4
2-IC6H4
1
2
K2CO3
DBU
10
10
80
80
30
30
0
6
20
7
4g
4h
4i
3
4
5
6
7
DABCO
TMG
10
10
10
10
10
80
80
80
80
80
30
30
30
30
30
40
40
50
50
60
8
9
DMAP
10
11
12
13
14
15
16
17
18
19
4j
Diisobutylamine
Et3N
4k
4l
8
9
DIPEA
DIPEA
10
20
80
80
30
22
70
70
4m
4n
4o
4p
4q
4r
10
DIPEA
DIPEA
10
10
100
80
18
18
60
70
3-MeC6H4
3-OMeC6H4
3-BrC6H4
3-CF3C6H4
3,4-Cl2C6H3
11[c]
[a] Reactions were carried out with 0.025 mmol of 1a and 0.025 mmol of 3a in
0.25 mL toluene. [b] Isolated yield after silica gel column chromatography. [c]
Reaction under oxygen atmosphere.
With the optimized condition in hand, the scope and
generality of the reaction was explored. Initially a variety of
4s
electron-poor
and
electron-rich
aryl-substituted
2-
hydroxyacetopheones was evaluated and the reaction proceeded
well (Table 2). At first, 2-hydroxyacetophenones having para-
substitutions on the phenyl group were engaged in the reaction.
To our delight, moderate to good yields were achieved with most
of the substrates. In particular, 4-halo substituted
hydroxyacetophenones delivered the corresponding products in
good yields. Also, a good yield of 74% was attained with
hydroxyacetophenone 1h having 4-nitro group. Incorporation of
biphenyl group did not change the outcome of the reaction.
Different ortho-and meta-substituted hydroxyacetophenones
were studied and here too, good yields were obtained.
Disubstituted hydroxyacetophenones such as 1r and 1s could
also be employed and the products 4r-s were isolated in
acceptable yields. The reaction also worked well with
hydroxyketone 1t having 2-naphthyl group. Gratifyingly, our
reaction was also suitable for heteroaryl hydroxyketones and
20
21
22
23
2-naphthyl
2-furyl
3a
3a
3a
3b
30
36
36
36
4t
50
50
84
65
4u
4v
4w
2-thienyl
Ph
[a] Reactions were carried out with 0.1 mmol of 1 and 0.1 mmol of 3 in 1 mL
toluene. [b] Isolated yield after silica gel column chromatography.
Then we became curious about the direct synthesis of
quinoxalines 6 by the reaction of 2-hydroxyacetophenone (1a)
with o-phenylenediamine (5a) (Table 3). Quinoxaline derivatives
are present in a broad range of bioactive compounds and
frequently used as insecticides, fungicides, herbicides and
anthelminitics, as well as receptor antagonists.[18] Though
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700909
European Journal of Organic Chemistry
COMMUNICATION
previous reports on quinoxalines synthesis include oxidative
reaction of 2-hydroxyacetophenones with o-phenylenediamine
but either a metal catalyst in the presence of air[19] or a
stoichiometric oxidant such as MnO2[20] had been used. Based on
our preceding discovery, we predicted that direct synthesis of
quinoxaline might be possible utilizing 2-hydroxyacetophenone
and the reaction could be accelerated using acid catalyst. After
some optimization, it was found that infact 62% yield of the
quinoxaline 6a was achieved using diphenyl phosphate as the
catalyst in toluene solvent (Table 3). The generality of the reaction
was then explored and gratifyingly different substitutions at the
ortho-, meta- and para- positions of the phenyl group of 2-
hydroxyacetophenone was tolerated. Biphenyland 2-napthyl
containing hydroxyketones 1i and 1t provided the corresponding
products 6f and 6g in good yields. For heteroaromatic
hydroxyketone 1u, having 2-furyl moiety, a high yield of product
6j was obtained (Table 3). Then different o-phenylenediamines
were screened and here also good yields of the corresponding
products 6k-l were observed.
corresponding products were obtained in acceptable yields. A
naphthyl group was also tolerated and product 8e was isolated in
an acceptable yield. Then we performed a Wittig reaction with
stabilized ylide 9 and here also moderate yield (40%) of the
product 10 was achieved.
Table 4. Synthesis of α-Ketoamides and Wittig Reaction[a],[b]
[a] Reactions were carried out on a 0.2 mmol of 1 and 0.2 mmol of 7/9 in 2 mL
toluene. [b] Yields correspond to the isolated yield of the product after column
chromatography.
Table 3. Scope for the Quinoxaline Synthesis[a],[b]
To further investigate the aerial oxidation of 2-
hydroxyacetopheone (1a), we performed few experiments
(Scheme 1). After carrying out the reaction of 2-
hydroxyacetopheone (1a) and homophthalic anhydride (3a) in
inert atmosphere for 30 hours, no product was detected. To clarify
the requirement of air environment, same reaction between 1a
and 3a in the presence of oxygen atmosphere was conducted.
Interestingly, reaction rate was remarkably enhanced and 70%
yield of 4a was observed in only 18 hours. Thus it proves that
oxygen in air is the actual oxidant. To check whether secondary
alcohol can also be oxidized, hydroxyl ketone 1x was employed
in the reaction of 3a with DIPEA catalyst; however no reaction
occurred. To confirm that 2-phenylglyoxal (2a) is the actual
reactant in the phthalide formation, we carried out a reaction
between 2a and 3a and product 4a was formed in 72% yield. Also,
we observed that DIPEA does not participate in the oxidation
process.
[a] Reactions were carried out on a 0.2 mmol of 1 and 0.2 mmol of 5 in 2 mL
toluene. [b] Yields correspond to the isolated yield of the product after column
chromatography.
We further explored the possibility of uncatalyzed aerial
oxidative reactions of 2-hydroxyacetophenones (Table 4). To our
delight, when the reaction of 2-hydroxyacetophenone (1a) and
pyrrolidine (7) was carried out at 80 oC in toluene, the desired α-
ketoamide[13] product 8a was isolated in 52% yield (Table 4).
Scheme 1. Controlled Experiments and Screening of 1x, 2a
To further check whether moisture in the air also plays
Inspired
by
this
result,
we
further
screened
a role in the phthalide (
3) formation, a reaction in the
hydroxyacetophenones 1h, 1k and 1o having substitutions at the
para-, ortho-, and meta-positions respectively and gratifyingly the
presence of H2O18 (2.5 equiv) was performed (Scheme 2).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700909
European Journal of Organic Chemistry
COMMUNICATION
Indeed, in the product 4a, O18 incorporation was found that
was confirmed by mass spectrometry. Thus the possibility for
We gratefully acknowledge financial support from DST-SERB
(EMR/2015/001034). We also thank CIF, Indian Institute of
Technology Guwahati for the instrument facility.
the formation of an intermediate
A was envisaged that could
be generated via aldol reaction between homophthalic acid
11 (formed by hydrolysis of homophthalic anhydride) and 2-
Keywords: 2-hydroxyacetophenone • aerial oxidation •
phthalides• quinoxalines • α-ketoamides
phenylglyoxal
.
[1]
[2]
[3]
[4]
M. Hudlicky, Oxidation in Organic Chemistry (ACS Monograph Series),
American Chemical Society, Washington, DC, 1990.
Modern Oxidation Methods (Ed.: J.-E. Bäckvall), Wiley-VCH: Weinheim,
2004.
a) J. Piera, J.-E. Bäckvall, Angew. Chem. Int. Ed. 2008, 47, 3506; b) G.
Stavber, Synlett 2007, 3224.
Scheme 2. Phthalide Formation in the Presence of H2O18
For selected examples, see: a) B. A. Steinhoff, S. S. Stahl, J. Am. Chem.
Soc. 2006, 128, 4348, and references cited therein. b) B. A. Steinhoff, S.
R. Fix, S. S. Stahl, J. Am. Chem. Soc. 2002, 124, 766. c) D. R. Jensen,
J. S. Pugsley, M. S. Sigman, J. Am. Chem. Soc. 2001, 123, 7475. d) J.
T. Bagdanoff, B. M. Stoltz, Angew. Chem. Int. Ed. 2004, 43, 353. e) G.
Csjernyik, A. H. Ell, L. Fadini, B. Pugin, J.-E. Bäckvall, J. Org. Chem.
2002, 67, 1657. f) N.-W. Wang, R.-H. Liu, J.-P. Chen, X.-M. Liang, Chem.
Commun. 2005, 42, 5322. g) T. Kunisu, T. Oguma, T. Katsuki, J. Am.
Chem. Soc. 2011, 133, 12937. h) S. D. McCann, S. S. Stahl, J. Am.
Chem. Soc. 2016, 138, 199. i) G. Li, L. Tang, H. Liu, Y. Wang, G. Zhao,
Z. Tang, Org. Lett. 2016, 18, 4526. j) M. R. Nabid, Y. Bide, E.
Aghaghafari, S. J. T. Rezaei, Catal. Lett. 2014, 144, 355. For metal-free
systems: k) A. Rahimi, A. Azapira, H. Kim, J. Ralph, S. S. Stahl, J. Am.
Chem. Soc. 2013, 135, 6415. l) R. Prebil, G. Stavber, S. Stavber, Eur. J.
Org. Chem. 2014, 395.
Based on the experiments, a plausible mechanism for
the formation of phthalides has been depicted in Scheme 3
which reveals that DIPEA catalyzes the reaction either
between homophthalic anhydride (3a) and small equilibrium
quantities of 2-phenylglyoxal (2a) (path a) or between
homophthalic acid (11) and 2a (path b) that provides 13 on
decarboxylation. Similarly, intermediate 12, obtained via path
a, delivers 13 after decarboxylation and this process could
also be catalyzed by DIPEA. Finally DIPEA facilitates the
conjugate addition of carboxylic acid functionality to enone
moiety in 13 to afford phthalide 4.
[5]
For reviews, see: a) L. Vanoye, A. Favre-Réguillon, A. Aloui, R. Philippe,
C. de Bellefon, RSC Adv. 2013, 3, 18931. b) J. R. McNesby, C. A. Heller,
Chem. Rev. 1954, 54, 325.
[6]
[7]
[8]
K. A. Runcie, R. J. K. Taylor, Chem. Commun. 2002, 38, 974.
R. E. Ireland, D. W. Norbeck, J. Org. Chem. 1985, 50, 2198.
W. Kroutil, M. E. Lasterra-Sánchez, S. J. Maddrell, P. Mayon, P. Morgan,
S. M. Roberts, S. R. Thornton, C. J. Todd, M. Tüter, J. Chem. Soc. Perkin
Trans 1, 1996, 2837.
[9]
P. Darkins, N. McCarthy, M. A. McKervey, T. Ye, Chem. Commun. 1993,
29, 1222.
[10] B. H. Lipshutz, M. C. Morey, J. Org. Chem. 1983, 48, 3745.
[11] A. Rosowsky, K. K. N. Chen, J. Org. Chem. 1973, 38, 2073.
[12] J. Li, L. Liu, D. Ding, J. Sun, Y. Ji, J. Dong, Org. Lett. 2013, 15, 2884.
[13] a) N. Mupparapu, N. Battini, S. Battula, S. Khan, R. A. Vishwakarma, Q.
N. Ahmed, Chem. Eur. J. 2015, 21, 2954. b) N. Mupparapu, S. Khan, S.
Battula, M. Kushwaha, A. P. Gupta, Q. N. Ahmed, R. A. Vishwakarma,
Org. Lett. 2014, 16, 1152. b) C. Zhang, X. Zong, L. Zhang, N. Jiao, Org.
Lett. 2012, 14, 3280. d) S. S. Kotha, S. Chandrasekhar, S. Sahu, G.
Sekar, Eur. J. Org. Chem. 2014, 7451. e) S. Mutara, K. Suzuki, M. Miura,
M. Nomura, J. Chem. Soc. Perkin Trans. 1 1990, 361.
Scheme 3. Proposed Mechanism for the Phthalide Formation
In summary, we have disclosed an unprecedented oxidative
reaction of 2-hydroxyacetophenones using air as the sole oxidant
and without any need of redox catalyst system. The finding of
aerial oxidation of alcohols was remarkable and also the in situ
trapping concept was not exploited previously in the aerial
oxidation reaction. The aerial oxidative reactions of 2-
hydroxyacetophenones allow for the synthesis of diverse
compounds such as phthalides, quinoxalines, α-ketoamides
under mild catalytic or catalyst-free condition. We believe these
findings will have tremendous impact in the oxidation chemistry
and could be applied in academia and industry.
[14] For
a copper catalyzed oxidation of 2-hydroxyacetophenone to
benzaldehyde, see: L. Zhang, X. Bi, X. Guan, X. Li, Q. Liu, B-D. Barry,
P. Liao, Angew. Chem. Int. Ed. 2013, 52, 11303.
[15] C. Cornaggia, F. Manoni, E. Torrente, S. Tallon, S. J. Connon, Org. Lett.
2012, 14, 1850.
[16] For selected recent syntheses of phthalides, see: a) S. Sueki, Z. Wang,
Y. Kuninobu, Org. Lett. 2016. 18, 304. b) S. Warratz, C. Kornhaaβ, A.
Cajaraville, B. Niepötter, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed.
2015, 54, 5513. c) H. Miura, K. Tsutsui, K. Wada, T. Shishido, Chem.
Commun. 2015, 51, 1654. d) R. Karmakar, P. Pahari, D. Mal, Chem. Rev.
2014, 114, 6213. e) A. Clerici, O. Porta, J. Org. Chem. 1989,54, 3872.
[17] CCDC 1518677 contains the crystallographic data for 4a.
[18] For selected reviews on the synthesis and bioactivities of quinoxalines,
see: a) A. Husain, D. Madhesia, J. Pharm. Res. 2011, 4, 924. b) D. F.
Saifina, V. A. Mamedov, Russ. Chem. Rev. 2010, 79, 351. c) S. Gobec,
U. Urleb, In Science of Synthesis; 2004; Vol. 16, p 845. d) S. Khaksar,
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700909
European Journal of Organic Chemistry
COMMUNICATION
M. Tajbakhsh, M. Gholami, F. Rostamnezhad, Chin. Chem. Lett. 2014,
25, 1287.
[20] a) S. Y. Kim, K. H. Park, Y. K. Chung, Chem. Commun. 2005, 1321. b)
S. A. Raw, C. D. Wilfred, R. J. K. Taylor, Chem. Commun. 2003, 2286.
[19] For selected examples, see: a) M. M. Heravi, S. Taheri, K. Bakhtiari, H.
A. Oskooie, Catal. Commun. 2007, 8, 211. d) R. S. Robinson, R. J. K.
Taylor, Synlett 2005, 1003.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700909
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Page No. – Page No.
Title
((Insert TOC Graphic her))
Layout 2:
COMMUNICATION
R2
Subas Chandra Sahoo, Utpal Nath and
Subhas Chandra Pan *
O
NH2
R1
O
NH2
O
R2
O
O
R1
Diphenyl phosphate
(10 mol%)
Page No. – Page No.
N
N
DIPEA (10 mol%)
OH
O
Ar
toluene, 80 o
30-42 h
C
toluene, 80 o
24 h
C
Direct Aerial Oxidative Reactions of
2-Hydroxyacetophenones
Ar
O
Pyrrolidine,
toluene,
80 o
12 examples
24 examples
40-70% yield
32-82% yield
Ar
C
O
5 examples
N
41-65% yield
Ar
O
Metal and external oxidant free aerial oxidative reactions of 2-
hydroxyacetopheonones has been developed. The reaction was based on the aerial
formation of small equilibrium queantity of 2-ketoaldehydes. This demonstration of
the reaction allows the formation of phthalides, quinoxalines, α-ketoamides and
olefins in moderate to good yields directly from alcohols.
This article is protected by copyright. All rights reserved.