Sequential [3+2] cycloaddition/air oxidation reactions: Triazoloyl ion assisted oxidative cleavage of alkynes

Article abstract of DOI:10.1002/ejoc.201300441

Upon treatment with sodium azide in DMF, bisalkynes undergo chemoselective [3+2] cycloaddition followed by oxidative cleavage of the other alkyne unit by atmospheric oxygen. The neighboring triazoloyl ion is found to assist the cleavage process ultimately to deliver an acid and an aldehyde. Cycloaddition of azide with a bisalkyne chemoselectively forms a triazole, which subsequently undergoes oxidative cleavage by atmospheric oxygen to yield a carboxylic acid and an aldehyde. The mechanism for this reaction is investigated in depth. Copyright

Full text of DOI:10.1002/ejoc.201300441

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300441
Sequential [3+2] Cycloaddition/Air Oxidation Reactions: Triazoloyl Ion
Assisted Oxidative Cleavage of Alkynes
Thanasekaran Ponpandian,[a,b] Shanmugam Muthusubramanian,*[a] and
Sridharan Rajagopal[b]
Keywords: Nitrogen heterocycles / Oxidation / Cycloaddition / Carboxylic acids / Chemoselectivity
Upon treatment with sodium azide in DMF, bisalkynes un-
dergo chemoselective [3+2] cycloaddition followed by oxi-
dative cleavage of the other alkyne unit by atmospheric oxy-
gen. The neighboring triazoloyl ion is found to assist the
cleavage process ultimately to deliver an acid and an alde-
hyde.
best of our knowledge, no successful methodology is avail-
able for the isolation of carboxylic acids (RCOOH) and car-
boxaldehydes (RЈCHO) from alkynes of the type RCϵCRЈ
by oxidative cleavage. This article describes the formation
of carboxylic acid and carboxaldehyde derivatives by the
one-pot reaction of bisalkynes with sodium azide and
cheaper, abundant, and environmentally friendly molecular
oxygen through sequential [3+2] cycloaddition and oxi-
dation reactions.
Introduction
Oxidative cleavage of alkynes to carboxylic acids is one
of the most important organic reactions. α-Diketones have
been shown to be intermediates during the formation of the
carboxylic acids. Various oxidants have been reported to
effect this transformation, including KMnO4,[1] RuO4,[2]
molybdenum and tungsten polyoxometalates,[3] methylrhe-
nium trioxide,[4] an osmium(VI)–oxo complex in
tBuOOH,[5] InCl3/tBuOOH,[6] NaBO3/AcOH,[7] CrVI/
H2SO4,[8] and Pd(OAc)/ZnCl2/O2.[9] Recently, Hong
et al.[10] and Enthaler[11] independently reported the FeCl3-
catalyzed cleavage of alkynes to carboxylic acids with
tBuOOH and H2O2, respectively. In all of these methods,
two molecules of a carboxylic acid were obtained from one
molecule of an alkyne. Reports on the oxidative cleavage of
alkynes to carboxylic acids and carboxaldehydes, however,
are limited. Hatakeyama et al.[12] and Elrod et al.[13] re-
ported that the OH radical initiated oxidation of alkynes
with molecular oxygen could lead to the formation of carb-
oxylic acids and carboxaldehydes, and this was investi-
gated by FTIR and mass spectrometry, respectively. The
role of neighboring groups in altering the course of the re-
action and enhancing the reaction rate tremendously has
been well recognized. Recently, the amide-directed oxi-
dation of alkynes to α-diketones by using ceric ammonium
nitrate as the oxidant was reported by Wang et al.,[14] and
the formyl-assisted oxidation of alkynes to α-diketones by
using I2/H2O was reported by Srinivasan et al.[15] To the
Results and Discussion
The generation triazoles by the addition of azides to alk-
ynes is a popular protocol,[16] and recently, Gulevskaya
and co-workers reported the reaction of 2,3-dialkynylpyr-
azines with sodium azide to yield triazole derivatives
through [3+2] cycloaddition followed by nucleophilic ad-
dition.[17] Inspired by this work, it was proposed to prepare
novel triazole derivatives 2 from bisalkyne 1a. Aiming for
target molecule 2, the reaction of 1a with sodium azide
(1.2 equiv.) in DMF at room temperature for 24 h was per-
formed. However, this reaction afforded triazole
3
(Scheme 1) and not expected product 2. When the reaction
was carried out at 80 °C with cuprous iodide in DMSO as
the catalyst to activate the alkyne to facilitate the cyclo-
isomerization reaction, three different products (i.e., 4, 5a,
and benzaldehyde) were isolated. Here again, expected
product 2 was not detected (Scheme 1). The formation of
bistriazole derivative 4 can be explained by the double cy-
cloaddition of 1a with sodium azide at the triple bonds.
The formation of 5a and benzaldehyde may be due to the
oxidative cleavage of the alkyne moiety of monotriazole 6,
which should be the intermediate for this reaction – the
ynone reacts faster than the alkyne in the cycloaddition
with sodium azide. The driving force for the observed oxi-
dation is uncertain.
[a] Department of Organic Chemistry, School of Chemistry,
Madurai Kamaraj University,
Madurai 625021, India
Fax: +91-452 2459845
E-mail: muthumanian2001@yahoo.com
[b] Department of Medicinal Chemistry, Orchid Chemicals and
Pharmaceuticals Ltd.,
Chennai 600119, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300441.
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Sequential [3+2] Cycloaddition/Air Oxidation Reactions
Scheme 1. Reaction between bisalkyne 1a and sodium azide.
To investigate this oxidative cleavage in detail, the oxi- Table 1. Reaction conditions for the oxidation of alkynes.
dation of monotriazole 3, prepared from 1a and sodium
azide (1 equiv.) at room temperature, was subjected to dif-
ferent reaction conditions (Table 1). When heated in the
presence of cuprous iodide as the catalyst under a nitrogen
atmosphere in DMSO, monotriazole 3 did not yield any
product and the starting material was recovered (Table 1,
entries 1 to 3). Interestingly, when the reaction was carried
Entry
Catalyst
Base (equiv.)
Time [h] Yield 5a [%][a]
out with sodium carbonate under a nitrogen atmosphere, a
small amount of 5a (5%; Table 1, entry 4) and benzalde-
hyde were isolated. As indicated in Scheme 1, the sodium
salt of triazole 3 (i.e., 6) may be involved in the oxidation,
and the trace amount of oxygen in the reaction medium
plays the role of the oxidant. Then, the reaction of monotri-
azole 3 with CuI/Na2CO3 in DMSO was carried out in an
open flask at 80 °C for 1 h, and this resulted in good yield
of the oxidative cleavage product (71%; Table 1, entry 5).
This proves that atmospheric oxygen is involved in the oxi-
dation. During the optimization process for the formation
of 5a from 3 under atmospheric oxygen, it was realized that
the copper catalyst does not have any effect on the reaction
1
2
3
4
5
6
7
8
9
10
CuI
CuI
CuI
CuI
CuI
–
–
–
–
–
–
–
3
0[b]
24
24
5
0[b]
Et3N (1.2)
Na2CO3 (1.2)
Na2CO3 (1.2)
Na2CO3 (1.2)
Li2CO3 (1.2)
K2CO3 (1.2)
Cs2CO3 (1.2)
–
0[b]
5[b]
1
1
1
2
71[c]
70[c]
15[c]
58[c]
32[c]
0[c]
1
24
[a] Isolated yield. [b] Reaction was carried out under a nitrogen at-
mosphere. [c] Reaction was carried out in an open flask.
(Table 1, entry 6). Bases such as Li2CO3, K2CO3, and lowed by oxidation of the alkyne (Scheme 2). This clearly
Cs2CO3 did not improve the product yield (Table 1, en- shows that the carbonyl group is essential for the oxidation
tries 7 to 9). The reaction did not take place in the absence of the alkyne.
of sodium carbonate, even if the reaction was performed
at a higher temperature for 24 h in an open flask (Table 1,
entry 10).
When phenyl [2-(2-phenylethylnyl)phenyl]methanone (9)
was subjected to the same reaction condition, no reac-
tion took place, and this indicates that the conversion of 3
[18]
Different solvents were tested for their suitability to this into 5a requires the triazole group (Scheme 3). Thus, it is
reaction, and it was noticed that DMF was superior to the clear that the sodium salt of the triazole ring and the carb-
other solvents (Table 2, entry 4). Solvents such as dioxane, onyl group have their roles in the oxidation process.
THF, toluene, CH3CN, acetone, water, ethanol, and
CH3CN/H2O were completely ineffective for this class of course of the reaction was attempted in a sequential manner
oxidation (Table 2). staring from 1a and involving [3+2] cycloaddition and oxi-
After stabilizing the oxidative cleavage reaction of 3, the
In an attempt to understand the mechanism of the reac- dation. In an open flask, the initial cycloaddition of ynone
tion, the carbonyl group in 3 was reduced with sodium 1a with sodium azide (1 equiv.) was carried out at room
borohydride to obtain alcohol 7. Alcohol 7, when treated temperature for 0.5 h, and the resulting reaction mixture
with sodium carbonate in DMF at 100 °C for 24 h, did not was heated to 80 °C for 1 h. Product 5a was easily isolated
yield expected 8, but instead it yielded acid 5a and benzal- from the reaction mixture through acid–base workup in
dehyde, probably by oxidation of the hydroxy group fol- 68% yield (Scheme 4).
Eur. J. Org. Chem. 2013, 3974–3977
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Ponpandian, S. Muthusubramanian, S. Rajagopal
SHORT COMMUNICATION
Table 2. Effect of solvent for the oxidation of alkyne 3.
Entry
Solvent
Yield of 5a[a]
1
2
3
4
5
6
7
8
9
10
toluene
dioxane
DMSO
DMF
EtOH
H2O
acetone
CH3CN
THF
n.r.
n.r.
Scheme 5. Sequential [3+2] cycloaddition and oxidation of 1.
71[b]
75[b]
n.r.
Terminal alkyne 1h also participated efficiently in the re-
action sequence. Treatment of 1h with sodium azide under
the optimized reaction condition yielded carboxylic acid 5b
in 62% yield, and the other expected oxidation product was
formaldehyde (Scheme 6).
n.r.
n.r.[c]
n.r.
n.r.
n.r.
CH3CN/H2O
[a] Isolated product. n.r.: no reaction. [b] Reaction time was 1 h.
[c] Reaction was carried out at 60 °C.
Scheme 6. [3+2] Cycloaddition and air oxidation of 1h.
In these reactions, sodium azide undergoes [3+2] cyclo-
addition followed by the cleavage of the alkyne with one
molecule of oxygen and water stoichiometrically. The water
molecule involved does not come from the water employed
during workup, which was confirmed by the isolation of the
sodium salt of 5c (i.e., X) directly from the reaction mixture
without any water workup, that is, the reaction mixture was
cooled to 5 °C, and the solid obtained was filtered
(Scheme 7), and the filtrate contained benzaldehyde. Moist-
ure from the atmosphere or the solvent (DMF has a moist-
ure content of Ͻ0.2% ) may be the source of the water
molecule. When the reaction of bisalkyne 1f and sodium
azide was carried out under the above-optimized conditions
along with a small amount of added water, the yield of 5f
was not altered. Recently, Klapötke et al.[20] described the
reaction of 4,5-dicyano-2H-1,2,3-triazole and sodium car-
bonate in acetonitrile to give the sodium salt of 4,5-di-
cyano-1,2,3-triazole in a monohydrate form without em-
ploying water during the reaction or isolation, and this
shows that the sodium salt of 1,2,3-triazole is capable of
absorbing water from the air.
Scheme 2. Alkyne oxidation reaction of hydroxy derivative 7.
Scheme 3. Oxidation of [2(2-phenylethylnyl)phenyl]methanone (9).
Scheme 4. One-pot conversion of bisalkyne 1a into 5a and alde-
hyde.
To expand the substrate scope of this protocol, a range
of bisalkyne derivatives 1 were prepared from 2-ethynyl
benzaldehyde (see the Supporting Information).[19] The op-
timized, open-flask, domino, sequential [3+2] cycload-
dition/oxidation process was then effected on bisalkynes
1b–f to generate a library of triazolecarboxylic acids 5b–f
(Scheme 5) in 66–72% yield. In the case of 1g, in which the
R substituent is a phenoxymethyl group, a complex reaction
mixture was obtained.
Scheme 7. Preparation of X, the sodium salt of 5c.
All the above results help us to propose a plausible
mechanism for the conversion of 1 into 5 (Figure 1).
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Eur. J. Org. Chem. 2013, 3974–3977

Sequential [3+2] Cycloaddition/Air Oxidation Reactions
Figure 1. Proposed mechanism for the oxidation of alkynes mediated by the triazoloyl ion.
the NMR Facility at Madurai Kamaraj University and Orchid Re-
search Laboratory, Ltd., for providing facilities.
Conclusions
A simple, environmentally benign, metal-free method for
the oxidative cleavage of alkynes to the corresponding car-
boxylic acids and aldehydes was developed. This reaction
proceeds by neighboring group participation of the triaz-
oloyl ion to the alkyne.
[1] D. G. Lee, V. S. Chang, J. Org. Chem. 1979, 44, 2726–2730.
[2] a) C. Mukai, M. Miyakawa, M. Hanaoka, Synlett 1994, 165–
166; b) W. P. Griffith, A. G. Shoair, M. Suriaatmaja, Synth.
Commun. 2000, 30, 3091–3095; c) J. Cornely, L. M. S. Ham,
D. E. Meade, V. Dragojlovic, Green Chem. 2003, 5, 34–37; d)
D. Yang, F. Chen, Z. M. Dong, D. W. Zhang, J. Org. Chem.
2004, 69, 2221–2223.
[3] F. P. Ballistreri, S. Failla, E. Spina, G. A. Tomaselli, J. Org.
Chem. 1989, 54, 947–949.
[4] Z. L. Zhu, J. H. Espenson, J. Org. Chem. 1995, 60, 7728–7732.
[5] S. Samanta, L. Adak, R. Jana, G. Mostafa, H. M. Tuononen,
B. C. Ranu, S. Goswami, Inorg. Chem. 2008, 47, 11062–11070.
[6] B. C. Ranu, S. Bhadra, L. Adak, Tetrahedron Lett. 2008, 49,
2588–2591.
[7] A. Banerjee, B. Hazra, A. Bhattacharya, S. Banerjee, G. C.
Banerjee, S. Sengupta, Synthesis 1989, 765–766.
[8] W. B. Sheats, L. K. Olli, R. Stout, J. T. Lundeen, R. Justus,
W. G. Nigh, J. Org. Chem. 1979, 44, 4075–4078.
[9] A. Wang, H. Jiang, J. Am. Chem. Soc. 2008, 130, 5030–5031.
[10] T. M. Shaikh, F. E. Hong, Adv. Synth. Catal. 2011, 353, 1491–
1496.
[11] S. Enthaler, ChemCatChem 2011, 3, 1929–1934.
[12] S. Hatakeyama, N. Washida, H. Akimoto, J. Phys. Chem. 1986,
90, 173–178.
[13] L. Y. Yeung, M. J. Pennino, A. M. Miller, M. J. Elrod, J. Phys.
Chem. A 2005, 109, 1879–1889.
[14] C. F. Su, W. P. Hu, J. K. Vandavasi, C. C. Liao, C. Y. Hung,
J. J. Wang, Synlett 2012, 2132–2136.
Experimental Section
General Procedure for the Synthesis of Triazolecarboxylic Acids 5
from 1: In an open flask, a mixture of bisalkyne 1 (150 mg, 1 equiv.)
and sodium azide (1 equiv.) in DMF (15 mL) was stirred at room
temperature for 0.5 h and then at 80 °C for 1 h. The reaction mix-
ture was poured into cold water and extracted with ethyl acetate.
The mass obtained after evaporation of ethyl acetate was purified
by column chromatography (hexane/ethyl acetate) to obtain benzal-
dehyde. The aqueous layer was acidified with dilute hydrochloric
acid (pH 2 to 3) and then extracted with methylene dichloride. The
organic layer was washed with brine solution, dried with anhydrous
sodium sulfate, and concentrated to afford 5 in pure form.
2-(5-Phenethyl-2H-1,2,3-triazole-4-carbonyl)benzoic Acid (5a): Pale
yellow solid, m.p. 170–171 °C. IR (KBr): ν = 3435, 3172, 3060,
˜
3022, 1681, 1666, 1598, 1567, 1489, 1453 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 2.98 (t, J = 8.2 Hz, 2 H, -CH2), 3.24
(t, J = 8.2 Hz, 2 H, -CH2), 7.20–7.32 (m, 5 H, Ar-H), 7.44–7.50
(m, 1 H, Ar-H), 7.55–7.71 (m, 2 H, Ar-H), 7.93 (t, J = 7.4 Hz, 1
H, Ar-H), 13.06 (br. s, 1 H, -COOH), 15.2 (br. s, 1 H, -NH) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 24.5, 33.7, 125.9, 126.1,
127.6, 128.3, 128.4, 129.3, 129.8, 130.5, 130.7, 132.0, 140.7, 141.7,
167.3, 190.8 ppm. C18H15N3O3 (321.33): calcd. C 67.28, H 4.71, N
13.08; found C 67.35, H 4.73, N 13.12. MS (ESI–): m/z = 322.1
[C18H15N3O3 + H]+.
[15] K. Sakthivel, K. Srinivasan, Eur. J. Org. Chem. 2011, 2781–2484.
[16] a) J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless, V. V.
Fokin, Angew. Chem. 2009, 121, 8162–8165; Angew. Chem. Int.
Ed. 2009, 48, 8018–8021; b) W. Qian, D. Winternheimer, J.
Allen, Org. Lett. 2011, 13, 1682–1685; c) T. Ramana, T. Punni-
yamurthy, Chem. Eur. J. 2012, 18, 13279–13283.
[17] A. V. Gulevskaya, S. V. Dang, A. S. Tyaglivy, A. F. Pozharskii,
O. N. Kazheva, A. N. Chekhlov, O. A. Dyachenko, Tetrahedron
2010, 66, 146–151.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of the key starting materials 1, 3, and 7 and copies
1
of the H NMR and 13C NMR spectra and other data for 1, 3, 5,
[18] J. D. Tovar, T. M. Swager, J. Org. Chem. 1999, 64, 6499–6504.
[19] N. T. Patil, N. K. Pahadi, Y. Yamamoto, J. Org. Chem. 2005,
70, 10096–10098.
7, and X.
[20] M. J. Crawford, K. Karaghiosoff, T. M. Klapötke, F. A. Mar-
tin, Inorg. Chem. 2009, 48, 1731–1743.
Acknowledgments
Received: March 25, 2013
The authors thank the Department of Science and Technology
(DST), New Delhi, for assistance under the IRHPA program, and
Published Online: May 16, 2013
Eur. J. Org. Chem. 2013, 3974–3977
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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