A simple and efficient method for mild and selective oxidation of propargylic alcohols using TEMPO and calcium hypochlorite

Article abstract of DOI:10.1039/c3ra41721b

Oxidation of propargylic alcohols to the corresponding aldehydes and ketones was achieved at room temperature using 2,2,6,6-tetramethylpiperidine-1- oxyl (TEMPO) and calcium hypochlorite (Ca(OCl)₂). Propargylic diols yielded corresponding dialdehydes as the product. This system was found to be very efficient for both the electron donating and electron withdrawing groups such as methoxy and nitro substituted alcohols, respectively. This method does not require any additives and demonstrates the controlled, selective oxidation of propargylic alcohols affording up to 97% isolated yield. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra41721b

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A simple and efficient method for mild and selective
oxidation of propargylic alcohols using TEMPO and
calcium hypochlorite3
Cite this: DOI: 10.1039/c3ra41721b
Received 17th April 2013,
Accepted 9th July 2013
Sabbasani Rajasekhara Reddyab and Anju Chadha*bc
DOI: 10.1039/c3ra41721b
www.rsc.org/advances
Oxidation of propargylic alcohols to the corresponding aldehydes
and ketones was achieved at room temperature using 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) and calcium hypochlorite
(Ca(OCl)2). Propargylic diols yielded corresponding dialdehydes as
the product. This system was found to be very efficient for both
the electron donating and electron withdrawing groups such as
methoxy and nitro substituted alcohols, respectively. This method
does not require any additives and demonstrates the controlled,
selective oxidation of propargylic alcohols affording up to 97%
isolated yield.
Various methods for the oxidation of propargylic alcohols have
been developed using stoichiometric oxidants such as MnO2,
chromium salts with a combination of dimethyl sulfoxide and
oxalyl chloride (Swern oxidation), TiCl4/Et3N system and Dess–
Martin reagent.7 Furthermore, Ishii and coworkers have used
Cu(acac)2–NHPI(N-hydroxyphthalimide) and Katsuki and cow-
orkers have used (nitroso)(selene) ruthenium(II) chloride as
catalysts.8
Oxidation of propargylic alcohols under aerobic condition with
palladium(II) catalyst9 failed to produce the corresponding
carbonyl compounds due to the formation of inactive metallic
palladium forming unidentified tarry compounds. The instability
of the produced carbonyl compounds in the reaction system,
catalyst deactivation by the formation of metallic polymers and the
formation of stable complexes between metal salts and some
electron donors on the starting alcohols (hetero atoms and
unsaturated carbon-carbon bonds) are some of the limitations of
the oxidation of these alcohols. Further vanadium and Fe3+/
TEMPO based catalysts were developed for the aerobic oxidation
of propargylic alcohols.10 Hypochlorites are useful reagents for
many organic reactions,11a oxidation of propargylic alcohols to
alkyne carboxylic acids using nitroxyl radical with hypohalites has
a,b-Acetylenic carbonyl compounds and ynones are important
precursors in the preparation of a variety of heterocyclic
compounds,1a such as a,b-unsaturated ketones,1b cyclopentano-
nes,1c C-nucleosides1d,e and chiral pheromones,1f,g whisky lactones
(found in wine and other alcoholic beverages), which are used as
starting materials for various bioactive compounds.2a Such
compounds act as core elements of many potentially useful
natural products (Fig. 1(i)),2b,c such as b-lactams (structural
fragments of natural antibiotic malyngolide, Fig. 1(ii))3 and
epoxydiynes, which are motifs of neocarzinostatin (antibacterial
and antitumor, Fig. 1(iii)).4
a,b-Acetylenic dialdehydes and aldehydes are key intermediates
for making compounds with high birefringence. Examples are
acetylenes with long molecular size such as bis(phenyldiynyl)ben-
zenes and diphenylhexatriynes (Fig. 2).5 A crucial role is played by
these high birefringence liquid crystals in the field of display
technology and they have been used widely in spatial light
modulators and in compensation films for viewing angle,
reflectors and polarizers.6
aSchool of Advanced Sciences, Organic Chemistry Division, VIT University, VELLORE:
632014, Chennai 600036, India. E-mail: sekharareddyiitm@gmail.com
bLaboratory of Bioorganic Chemistry, Department of Biotechnology, Indian Institute
of Technology Madras, Chennai 600036, India. E-mail: anjuc@iitm.ac.in; Fax: +91
44 2257 4102; Tel: +91 44 2257 4106
cNational Center for Catalysis Research, Indian Institute of Technology Madras,
Chennai 600036, India
Electronic supplementary information (ESI) available: Full synthetic experimental
3
and spectroscopic details of characterization data and 1H and 13C NMR spectra. See
DOI: 10.1039/c3ra41721b
Fig. 1 Some biologically important compounds from a,b-acetylenic carbonyl
compounds.
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subtituted fluorene and fluorene (Table 1, Entries 6–11) gave
corresponding aldehydes in good to excellent yields (62 to .99%).
Similarly, secondary alcohols having the phenyl and acetylene
moiety gave the corresponding ketone in 90% yield (Table 1, Entry
2). Next the secondary alcohols attached to the groups such as
methyl and phenyl acetylene, phenyl and phenyl acetylene, hexyl
and acetylene (Table 1, Entries 3 to 5) provided the corresponding
ketones in good to high yields (63 to 86%). In addition the
secondary alcohol is attached to the phenyl acetylene group and
the ester moiety (Table 1, Entry 12) is efficiently converted to the
corresponding ketones in 85% yield. In the case of diols (Table 1,
Entries 7 and 8), the reaction gave the corresponding dialdehydes
in excellent yields (97 and .99%). The developed catalytic system
was found to be a very efficient method for both electron donating
and withdrawing groups such as methoxy and nitro substituted
alcohols (Table 1, Entries 9 and 10). It is also important to note
that this is the first ever report on oxidation of aryl heterocyclic
propargylic diols (Table 1, Entries 6 and 7), fluorene and fluorene
substituted propargylic alcohols (Table 1, Entries 10 and 11) to the
corresponding aldehydes to the best of our knowledge. Here, the
starting materials (Table 1, Entries 3 and 6–11) were prepared
using the reported Sonogashira coupling reaction,16a and further
the propargylic a-hydroxy ester (Table 1, Entry 12, 1l) was prepared
via cross-coupling reaction of terminal alkyne and monooxalyl
chloride in the presence of copper catalyst.16b
In the oxidation of propargylic alcohols, nitrosonium ion
(TEMPO+ I), is the actual oxidant, while in the absence of TEMPO,
no oxidation takes place. All the added substrate (.99%
conversion, Table 1, Entry 7) is directly converted to dialdehyde
upon addition of 1 mol% TEMPO. The mechanism can be
formulated on the basis of similar cases as shown in Scheme 2.17
Generated OCl2 from Ca(OCl)2 should react with TEMPO to form
intermediate I, which oxidizes the alcohol to the corresponding
carbonyl compound giving the TEMPOH II, which shows the
signal at m/z 158.2 (Fig. 3). Further intermediate II gets oxidized to
the oxoammonium derivative I from OCl2 (Scheme 2) and the pH
of the reaction remains almost neutral. The generated acid (H+)
[Ca(OCl)2reacts with water to produce HOCl and (Ca(OH)2) and the
available chlorine (65%) in Ca(OCl)2 reacts with water to produce
HOCl and HCl] is neutralized by base Ca(OH)2 (pKb = 2.43).18 In
the case of NaOCl (the available chlorine is 10–15%) the pH of the
reaction medium is 13, because of the caustic by-product NaOH
(pKb = 0.2) produced in the reaction. In order to control the pH of
the reaction medium and improving the selectivity of the reaction,
the addition of additives and buffers inside the reaction medium
is necessary. Hence, when Ca(OCl)2 is used as an oxidant the
reaction does not required additives and buffers due to the neutral
reaction conditions.
Fig. 2 High birefringent bisdiynes and hexatriynes from a,b-acetylenic dialdehydes
and aldehydes.
been patented11b and reported using sodium hypochlorite (yield ,
5%) and sodium chlorite11c with improved yields (90%) of the
product acid. TEMPO (2,2,6,6-tetramethyl piperidine-1-oxyl) with
various oxidants used stoichiometrically or catalytically is well
known for the oxidation of alcohols to carbonyl compounds.12,11b
Oxidant sodium hypochlorite (NaOCl) with TEMPO along with
additives like phase transfer catalysts and base is well-liked for the
oxidation of primary and secondary alcohols.13 In contrast to
sodium hypochlorite, calcium hypochlorite Ca(OCl)2 is a readily
available, stable, solid, inexpensive and an easy-to-use oxidizing
agent in numerous organic tranformations.14 Recently, we have
noticed that TEMPO with oxidant Ca(OCl)2 catalyzes the oxidation
of benzylic alcohols to aldehydes and ketones without addition of
acid or base and other additives like phase transfer catalysts under
very mild reaction conditions.15 Further, we have gone through the
literature on oxidation of proparglic alcohol to aldehydes and
ketone, and we found that still there are limitations, like the use of
high temperature, prolonged reaction time, inconvenient reaction
conditions (additional usage of acids or bases, additives and usage
of buffers to maintain the pH conditions) and toxic reagents for
the same.11
In the present study, the oxidation of propargylic alcohols
containing other functional groups, which are sensitive to
oxidation and high temperatures, without addition of acid or
base using catalytic amount of TEMPO in the presence of calcium
hypochlorite in acetonitrile at room temperature (Scheme 1) has
been pursued.{ Initial experiments tried with primary propargylic
alcohols attached to the phenyl moiety gave the corresponding
aldehyde in 85% yield (Table 1, Entry 1). Next the primary
propargylic alcohols connected to the groups such as bromo
substituted pyridine, pyridine, methoxy substitued phenyl, nitro
In conclusion, calcium hypochlorite with catalytic amount of
TEMPO was found to be a versatile terminal oxidant to provide
high yields of aldehydes, dialdehydes and ketones from a variety of
propargylic alcohols at room temperature. The oxidation was
carried out under atmospheric oxygen. The above catalytic system
can be readily adjusted to suit various substrates under very mild
conditions. Significantly, this protocol does not require any acid or
base and does not give any side products and dialcohols selectively
Scheme 1 Oxidation of propargylic alcohols to a,b-acetylenic carbonyl com-
pounds.
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Table 1 Oxidation of propargylic alcohols to a,b-acetylenic carbonyl compounds
Entry
1
Substrate
Product
Reported Yield %g (Time [h])
% Yield [this study] (Time [h])c
85b(3)
.9819a(2)
2
3
9419b(30)
3310a(3)
90b(1)
63b(2)
4
8110a(3)
86b(1.5)
5
6
6510a(36)
N.R.a
66b(4)
85b(3.5)
7
8
N.R.a
N.D.a
.99de(1)
97d(3)
9
8519c(48)
62b(4)
10
11
N.R.a
N.R.a
.99bef(4)
95b(3.5)
12
5019d
85b(1.5)
a
b
N. R.: not reported; N.D.: yields not determined. Conditions: 1 mmol substrate, 1.56 mg TEMPO (1 mol%). 142 mg, Ca(OCl)2, acetonitrile
(4 mL). Isolated Yields. Two equivalents of calcium hypochlorite was used along with TEMPO (1 mol%). Conversion was measured by 1H
NMR. Tetrahydrofuran was used as solvent. Reference number.
c
d
e
f
g
gave corresponding dialdehydes in excellent yields, and sensitive
groups like ester, alkynes and hetero atom were also stable under
these conditions.
Acknowledgements
Funding from DST-SERB (FAST-TRACK-SCHEME), Govt. of
India is gratefully acknowledged. We thank the SAIF-IIT
Madras, SIF-VIT-DST-FIST and Department of Chemistry (VIT
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solvent to give 3-(9H-fluoren-2-yl)prop-2-yn-1-al (2k) as a white colour solid,
mp: 110–112 uC 1H NMR (400 MHz, CDCl3,TMS) d = 3.92 (s, 2H), 7.38–7.82
(m, 7H), 9.45 (s, 1H) 13C NMR(400 MHz, CDCl3,TMS): d = 37.0, 89.2, 97.0,
117.3, 120.4, 121.0, 126.0, 127.5, 128.4, 130.2, 133.0, 141.0, 144.0, 144.3,
145.3, 177.0; I.R (KBr) n = cm21: 700, 888, 1644, 1604, 2179, 2925, 3060
HRMS: Calc for C16H11O; 219.0810; Obs. 219.0811. Data for unreported
compounds is given in the supplementary information.
3
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Scheme 2 Proposed mechanism for oxidation of propargylic alcohos with
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Notes and references
{ Experimental. All commercially available alcohols and solvents were used
as received without any further purification, non commercial alcohols were
freshly prepared and characterised fully before use. Typical procedure for
oxidation of propargylic alcohols. A mixture of TEMPO (1.56 mg, 1 mol%)
and 3-(9H-fluoren-2-yl)prop-2-yn-1-ol (1k) (1 mmol) in acetonitrile (4 mL)
was taken in 25 mL round bottom flask. Calcium hypochlorite (142 mg, 1
mmol) was added in portions over 10 min at 0 uC and the reaction mixture
was allowed to room temperature until completion. The suspension was
filtered, the organic phase was washed with saturated aq. NaHCO3 (8 mL)
followed by brine (8 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel, using hexane:ethylacetate (99 : 1) as the
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