An efficient oxidation of element-containing propargyl alcohols and acetylenic γ-diols by 2-iodoxybenzoic acid (IBX)

Article abstract of DOI:10.1055/s-0028-1087225

An efficient and convenient procedure for the oxidation of acetylenic alcohols and diols by o-iodoxybenzoic acid (IBX) is reported. Simple heating of the corresponding alcohol with a suspension of IBX in acetone or tetrahydrofuran leads to the silicon(ger

Full text of DOI:10.1055/s-0028-1087225

PAPER
3797
An Efficient Oxidation of Element-Containing Propargyl Alcohols and
Acetylenic g-Diols by 2-Iodoxybenzoic Acid (IBX)
O
xidatio
r
n
by 2-Io
i
doxyb
nenzoic Acid
a
(IBX
)
A. Novokshonova, Vladimir V. Novokshonov, Alevtina S. Medvedeva*
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Street, 664033 Irkutsk,
Russia
Fax +7(3952)419346; E-mail: amedved@irioch.irk.ru
Received 14 July 2008; revised 6 August 2008
the presence of an oxovanadium complex.21 Activated
Abstract: An efficient and convenient procedure for the oxidation
manganese dioxide and pyridinium chlorochromate are
of acetylenic alcohols and diols by o-iodoxybenzoic acid (IBX) is
reported. Simple heating of the corresponding alcohol with a sus-
the most commonly used reagents for this purpose.18b
pension of IBX in acetone or tetrahydrofuran leads to the sili-
con(germanium)-containing propynals or g-hydroxypropynals in
high yields.
Oxidation of primary/tertiary g-diols 1a–e by neutral
manganese dioxide gives hydroxyaldehydes 2a–e in 50–
70% yields.22 The disadvantages of this method are long
Key words: propargyl alcohols, acetylenic diols, oxidation, IBX,
propynals
reaction times and the requirement to use excess oxidant
(from 522,23 to 26 equiv24) that can be accompanied by a
decrease in the yield of the aldehyde due to absorption
onto manganese dioxide. (Trialkylsilyl)- and (trialkylger-
Substituted a,b-acetylenic aldehydes are of great impor-
tance in modern organic chemistry. Propynals are applied
in the synthesis of optically active acetylenic alcohols,1
homoallylic amines and amino acids,2 b-lactams, structur-
al fragments of natural antibiotic malingolide,3 ethynyl
steroids, effective spasmolytics and antitumor drugs,4 ep-
oxydiynes, and key motifs of neocarzinostatin.5 Propynals
containing a hydroxy moiety in the g-position to the car-
bonyl group, represent polyfunctional substrates for the
design of diverse heterocyclic compounds.6 It is known
that the simplest g-hydroxypropynal, generated in vivo by
to enzymatic oxidation of but-2-yne-1,4-diol, participates
in the irreversible inhibition of enzymes via the interac-
tion of the aldehyde with the nucleophilic core of the en-
zymes.7 The a-silicon- or germanium-containing groups
stabilize acetylenic compounds and the products of their
transformations, while subsequent heterolysis of the M–
Csp bond will lead to analogues with a terminal triple
bond. Element-substituted propynals are used in the total
synthesis of natural cytostatics, phorboxazoles8 (inhibi-
tors of thrombocytes aggregation), xemilofiban,9 as well
as for the preparation of 1H-1,2,3-triazolecarbaldehydes,10
3,4-dihydropyrimidin-2-ones,11 [(trimethylsilyl)ethynyl]-
4H-pyran-3,5-dicarbaldehyde,12 imidazo[1,2-a]pyridine-
3-carbaldehydes,13 silicon(germanium)-containing yn-
imines and enynes,14 substituted porphyrins,15 and poly-
functional Baylis–Hillman adducts.16
myl)acetylenic alcohols 1f,g are effectively oxidized by
pyridinium chlorochromate to afford the corresponding
propynals 2f,g.25 However, 3-(trimethylsilyl)prop-2-ynal
(2g) prepared by this method polymerizes during storage.
We have shown that pyridinium chlorochromate is unsuit-
able for the preparation of g-hydroxypropynals 2a–e be-
cause of their strong resinification. Efforts to isolate
aldehyde 2g during the oxidation of 3-(trimethylsi-
lyl)prop-2-yn-1-ol by potassium chromate/sulfuric acid
under phase-transfer catalysis failed due to strong resini-
fication.26 This fact is indicative of the sensitivity of the
acetylenic aldehydes 2a–g to the reaction conditions.
Therefore, a search for mild and effective oxidants seems
to be an urgent synthetic challenge.
Over the last few decades, hypervalent iodine compounds
such as Dess–Martin periodinane (DMP) and o-iodoxy-
benzoic acid (IBX) have been shown to have mild and se-
lective properties and, thus, they have been used
extensively for the oxidation of alcohols to carbonyl com-
pounds.27,28 For example, primary alcohols are trans-
formed to aldehydes using IBX without overoxidation to
acids,29 amino alcohols are oxidized to the corresponding
carbonyl derivatives without protection of the amino
group, and sensitive heterocycles are not affected.30,31
Compared to Dess–Martin periodinane, IBX is more
readily available, it has moisture- and air-resistant proper-
ties, it can be generated in situ,32 it does not cleave the C–
C bond during the oxidation of 1,2-diols,29 and it is easily
recovered.33 Moreover, although IBX only dissolves in
dimethyl sulfoxide, it is possible to perform the oxidation
of alcohols with IBX suspended in other solvents (THF,30
MeCN, acetone, EtOAc,34 aq acetone in presence of b-
cyclodextrin35) thus avoiding tedious workup problems
typical of dimethyl sulfoxide.
One of the most widespread methods for the synthesis of
propynals is by the oxidation of the corresponding acety-
lenic alcohols using different oxidants such as activated
manganese dioxide,17 chromium(VI) compounds,18 di-
methyl sulfoxide (Swern oxidation),19 titanium(IV) chlo-
ride–triethylamine complex,20 and molecular oxygen in
SYNTHESIS 2008, No. 23, pp 3797–3800
x
x.
x
x
.
2
0
0
8
Various examples have been reported of the use of hyper-
valent iodine compounds for the oxidation of acetylenic
Advanced online publication: 06.11.2008
DOI: 10.1055/s-0028-1087225; Art ID: Z16408SS
© Georg Thieme Verlag Stuttgart · New York

3798
I. A. Novokshonova et al.
PAPER
alcohols: but-2-yne-1,4-diol and propargyl alcohol by The conversion of the alcohols is 90–99% (1H NMR),
Dess–Martin periodinane with the thus generated alde- while the isolated yields of aldehydes 2a–g after distilla-
hyde reacted with the Wittig reagent;36 and secondary tion in vacuo are 65–85% (Table 1).
acetylenic alcohols24 or chiral rhenium complexes of pri-
It has been pointed out that an increase of the reaction time
mary and secondary propynols37 by the action of IBX so-
(THF) up to 24 hours does not result in a rise in conver-
lution in dimethyl sulfoxide at ambient temperature.
sion. We have shown that the usage of almost equimolar
However, the oxidation of acetylenic g-diols and element-
amount of IBX (1.2 equiv) in the form of a suspension in
containing propargyl alcohols by IBX has not been stud-
tetrahydrofuran allows the oxidation of acetylenic alco-
ied yet.
hols and diols containing a primary hydroxy moiety in the
Despite the high efficiency of IBX solution in dimethyl a-position of the triple bond to be performed. Under the
sulfoxide, its application for the oxidation of glycols 1a–e conditions studied, competitive oxidation of the solvent is
is undesirable, since the relatively high hydrophilicity of not observed. The replacement of tetrahydrofuran by the
aldehydes 2a–e results in a considerable decrease in the less expensive solvent acetone enables the target alde-
yield when the reaction mixture is treated with water.
hydes to be prepared with equal efficiency.
Therefore, we have investigated the efficiency of the oxi- The decrease in yield of 4-hydroxy-4-phenylpent-2-ynal
dation of acetylenic g-diols and element-containing pro- (2e) to 65% is caused by its high boiling point that causes
pynols by IBX suspension in acetone or tetrahydrofuran. resinification under distillation in vacuo. The lower yield
The IBX suspension in tetrahydrofuran has been success- of 3-(trimethylsilyl)prop-2-ynal (2g) as compared to ger-
fully used for the first time for the oxidation of 2-hydroxy- manium analogue 2f is explained by product loss during
2-phenylacetophenone [IBX (1.44 equiv), reflux],30 while removal of solvent from the reaction mixture owing to the
during the oxidation of piperonyl alcohol with IBX (3 high volatility of this aldehyde.
equiv, reflux) with tetrahydrofuran as the solvent, oxida-
2-Iodosobenzoic acid filtered off from the reaction mix-
tion of the tetrahydrofuran does not allow the target alde-
ture has been reoxidized to IBX in 76% yield according to
hyde to be isolated.34
the literature procedure.33 The regenerated IBX has been
The application of IBX (1.2 equiv) in tetrahydrofuran or used repeatedly without decreasing the yield of the alde-
acetone made possible the successfully oxidation of pri- hydes.
mary/tertiary g-diols 1a–e and trialkylsilyl(germyl)acety-
lenic alcohols 2f,g under reflux for four hours (Scheme 1).
It should be noted that propynals 2a–f prepared by the
method discussed, as well as by oxidation with activated
manganese dioxide, are stable in long-term storage in a re-
frigerator.
O
OH
I
In summary, we have shown the high efficiency of the ap-
plication of IBX suspension in acetone or tetrahydrofuran
for the oxidation of primary a-acetylenic alcohols and pri-
mary/tertiary g-glycols to the corresponding propynals
under mild conditions.
O
OH
O
O
R
R
H
1a–g
2a–g: 65–85%
Scheme 1
IR spectra were taken on a Bruker IFS-25 spectrometer (400–4000
1
cm–1, thin film). H (400.13 MHz) and 13C NMR (101.62 MHz)
spectra were recorded on a Bruker DPX-400 instrument with CDCl3
as solvent and HMDS as internal standard. IBX was synthesized by
Table 1 Oxidation of Alcohols 1a–g to Propynals 2a–g
Alcohol
R
Conversiona (%)
Acetone
Propynal
Isolated yield (%)
Acetone
THF
95
THF
84
1a
C(OH)Me2
C(OH)MeEt
C(OH)MePr
1-hydroxycyclohexyl
C(OH)MePh
GeEt3
97
95
98
98
97
99
98
2a
2b
2c
2d
2e
2f
85
81
82
80
66
85
70
1b
92
79
1c
98
83
1d
90
76
1e
96
65
1f
99
82
1g
SiMe3
97
2g
71
a 1H NMR.
Synthesis 2008, No. 23, 3797–3800 © Thieme Stuttgart · New York

PAPER
Oxidation by 2-Iodoxybenzoic Acid (IBX)
3799
a literature method.33 Compound 2e is a new compound; aldehydes
2a–d were previously characterized only by IR and 1H NMR spec-
tra.22
4-Hydroxy-4-phenylpent-2-ynal (2e)
Yield 65% (A), 66% (B); bp 138–142 °C/2.66 mbar; nD20 1.6070.
IR (film): 3400 (OH), 2215 (C≡C), 1675 cm–1 (C=O).
1H NMR (400.13 MHz, CDCl3): d = 1.77 (s, 3 H, CH3COH), 3.96
Propynals 2; General Procedure
(br s, 1 H, OH), 7.11–7.54 (m, 5 H, Ph), 9.15 (s, 1 H, CHO).
Method A: A mixture of alcohol (35.1 mmol) and IBX (42.1 mmol)
in THF (40 mL) was refluxed for 4 h with stirring. The mixture was
filtered and the precipitate was washed with Et2O
(4 × 25 mL).The combined filtrates were evaporated and distilled in
vacuo.
13C NMR (101.62 MHz, CDCl3): d = 32.42 (CH3COH), 69.93
(CH3COH), 83.60 (≡CCHO), 98.98 (CC≡), 124.85–128.57 (Ph),
176.89 (C=O).
Anal. Calcd for C11H10O2: C, 75.84; H, 5.78. Found: C, 75.67; H,
5.69.
Method B: A mixture of alcohol (35.1 mmol) and IBX (42.1 mmol)
in acetone (40 mL) was refluxed for 4 h with stirring. The mixture
was filtered and the precipitate was washed with acetone (4 × 25
mL). The combined filtrates were evaporated and distilled in vacuo.
3-(Triethylgermyl)prop-2-ynal (2f)
Yield: 82% (A), 85% (B); bp 81–82 °C/8 mbar; nD20 1.4861.
IR (film): 2145 (C≡C), 1670 cm–1 (C=O).
1H NMR (400.13 MHz, CDCl3): d = 0.94 (q, 6 H, CH2CH3), 1.13 (t,
9 H, CH2CH3), 9.11 (s, 1 H, CHO).
13C NMR (101.62 MHz, CDCl3): d = 5.66 (CH2CH3), 9.00
(CH2CH3), 103.40 (GeC≡), 104.50 (≡CC), 176.10 (C=O).
4-Hydroxy-4-methylpent-2-ynal (2a)
Yield: 84% (A), 85% (B); bp 56–58 °C/3.33 mbar; nD20 1.4708.
IR (film): 3400 (OH), 2205 (C≡C), 1670 cm–1 (C=O).
1H NMR (400.13 MHz, CDCl3): d = 1.57 [s, 6 H, (CH3)2COH], 9.22
(s, 1 H, CHO).
Anal. Calcd for C9H16GeO: C, 50.79; H, 7.57; Ge, 34.12. Found: C,
50.57; H, 7.39; Ge, 33.88.
13C NMR (101.62 MHz, CDCl3): d = 30.41 [(CH3)2COH], 65.10
[(CH3)2COH], 81.34 (≡CCHO), 100.16 (CC≡), 176.74 (C=O).
Anal. Calcd for C6H8O2: C, 64.27; H, 7.19. Found: C, 64.08; H,
7.13.
3-(Trimethylsilyl)prop-2-ynal (2g)
Yield: 71% (A), 70% (B); bp 53–55 °C/40 mbar; nD20 1.4448.
IR (film): 850, 2165 (C≡C), 1680 (C=O), 1260 cm–1 (Si–C).
1H NMR (400.13 MHz, CDCl3): d = 0.18 (s, 9 H, CH3), 9.10 (s, 1
H, CHO).
13C NMR (101.62 MHz, CDCl3): d = –1.80 (CH3), 102.11 (SiC≡),
102.69 (≡CC), 176.47 (C=O).
4-Hydroxy-4-methylhex-2-ynal (2b)
Yield: 79% (A), 81% (B); bp 67–68 °C/4 mbar; nD20 1.4726.
IR (film): 3380 (OH), 2215 (C≡C), 1675 cm–1 (C=O).
1H NMR (400.13 MHz, CDCl3): d = 1.05 (t, 3 H, CH2CH3), 1.53 (s,
3 H, CH3COH), 1.76 (q, 2 H, CH2CH3), 2.59 (br s, 1 H, OH), 9.23
(s, 1 H, CHO).
13C NMR (101.62 MHz, CDCl3): d = 8.89 (CH3CH2), 28.86
(CH3COH), 35.99 (CH3CH2), 68.71 (CH3COH), 82.77 (≡CCHO),
99.75 (CC≡), 176.59 (C=O).
Anal. Calcd for C6H10OSi: C, 57.09; H, 7.98; Si, 22.25. Found: C,
56.94; H, 7.79; Si, 22.01.
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Synthesis 2008, No. 23, 3797–3800 © Thieme Stuttgart · New York

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Synthesis 2008, No. 23, 3797–3800 © Thieme Stuttgart · New York