Purified mCPBA, a Useful Reagent for the Oxidation of Aldehydes

Article abstract of DOI:10.1002/ejoc.201701645

Purified mCPBA is a useful reagent for the oxidation of several classes of aldehyde. Although linear unbranched aliphatic aldehydes are oxidized to the corresponding carboxylic acids, α-branched ones undergo Baeyer–Villiger oxidation to formates. α-Branched α,β-unsaturated aldehydes provide enolformates and/or epoxides, which can be saponified to α-hydroxy ketones with shortening of the carbon chain by 1 carbon. Unbranched α,β-unsaturated aldehydes undergo an interesting Baeyer–Villiger oxidation/epoxidation/formate migration/BV oxidation cascade, which results in formyl-protected hydrates with an overall loss of two carbon atoms.

Full text of DOI:10.1002/ejoc.201701645

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Title: Purified mCPBA, a useful reagent for the oxidation of aldehydes
Authors: Alexander Horn and Uli Kazmaier
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10.1002/ejoc.201701645
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
Purified mCPBA, a useful reagent for the oxidation of aldehydes
Alexander Horn and Uli Kazmaier*[a]
Keywords: Bayer Villiger oxidation / Enolformates / Epoxides / -Hydroxyketones / Peracids
Purified mCPBA is an useful reagent for the oxidation of several
classes of aldehyde. While linear unbranched aliphatic aldehydes
are oxidized to the corresponding carboxylic acids, -branched ones
undergo BV oxidation to formates. -Branched -unsaturated
aldehydes provide enolformates and/or the epoxides thereof, which
can be saponified to -hydroxy ketones with an shortening of the
carbon chain by 1 carbon.
Unbranched -unsaturated aldehydes undergo an interesting
BV oxidation / epoxidation / formate migration / BV oxidation
cascade, resulting in formyl-protected hydrates with an overall
loss of two carbon atoms.
(© WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2015)
Therefore, one might expect that increasing the electron density
in the alkyl substituent might accelerate the alkyl group migration,
what is in agreement with an observation made by the Knochel
group, that -quaternary aldehydes undergo BV-oxidation towards
the tert.-alcohol derivatives.[8] Other, less -substituted aldehydes
have not been applied in this study. In 2012, Ochiai and Nakanishi
described for the first time a BV oxidation of unbranched aliphatic
aldehydes using hypervalent 3-bromanes.[9] These reagents have to
be prepared from explosive BrF3,[10] which is highly sensitive
towards water and most organic compounds, what is a severe
limitation of this protocol.
We became interested into BV oxidations of aldehydes during
our efforts in stereoselective syntheses of -hydroxyamino acids.
Such amino acids can be obtained e.g. via aldol reaction of chelated
enolates.[11] Although good diastereoselectivities can be obtained,
the control of the absolute configuration is not a trivial issue.
Therefore, we were interested to obtain the same type of amino acids
from -unsaturated amino acids, which can easily be obtained
either via Claisen rearrangement or via Pd-catalyzed allylic
alkylation in a highly enantio- and diastereoselective fashion.[12]
While the Claisen rearrangement gives rise to syn-products,[13] the
opposite anti-diastereomers can be obtained via allylic alkylation.[14]
The absolute configuration can be controlled either by using chiral
allyl alcohol derivatives[15] or chiral ligands.[16] Therefore, an
oxidative degradation of the unsaturated side chain might be an
attractive protocol (Scheme 2).
Introduction
The Baeyer-Villiger (BV) oxidation, already discovered in
1899,[1] became one of the fundamental oxidation processes in
organic synthesis. While in their original work Baeyer and Villiger
used Caro’s acid (H2SO5) to oxidize menthone towards the
corresponding lactone, a wide range of peracids are generally used
nowadays, while the oxidation power of the peracids correlates with
the acidity of the corresponding carboxylic acid.[2] Weaker oxidation
reagents such as H2O2 do not undergo BV oxidation but require
„activation“, either by transition metal complexes,[2] or nitriles,
which generate imido peracids in situ.[3] Especially the oxidation of
ketones became a standard protocol in organic synthesis and finds
also widespread application in industry.[4] In contrast, reports of
successful BV oxidations of aldehydes are extremely rare.[4] While
some electron rich aromatic aldehydes can be oxidized already with
H2O2 in the presence of SeO2,[6] a process which is known as Dakin
oxidation,[7] aliphatic aldehydes behave different. In general, not the
desired formates B are formed, but carboxylic acids C as oxidation
products. This might be caused by direct oxidation of aliphatic
aldehyde, and/or by a faster migration of the hydrogen atom (b)
[compared to the alkyl substituent (a)] in the primarily formed
Criegee intermediate A (Scheme 1).
Scheme 1. Baeyer-Villiger oxidation of aliphatic aldehydes
Scheme 2. Planned synthesis of -hydroxylated amino acid derivatives

[a] Institute for Organic Chemistry, Saarland University
P.O. Box 151150, 66041 Saarbrücken (Germany)
Fax: +49-681-302-2409
Results and Discussion
E-mail: u.kazmaier@mx.uni-saarland.de
Homepage: http://www.uni-saarland.de/lehrstuhl/kazmaier.html
We began our investigations with the oxidation of phenyl-
propionaldehydes.[17] With 3-phenylpropionaldehyde 1a first the
BV oxidation was investigated with the mild imidoperacids using a
variety of nitriles. Best results were obtained with trichloroaceto-
nitrile, which gave high conversion rates in a range of unpolar

Supporting information for this article is available on the WWW
under http://dx.doi.org/
1
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10.1002/ejoc.201701645
European Journal of Organic Chemistry
Table 2. BV-oxidation of -unsaturated aldehyde 7
solvents such as CH2Cl2, CHCl3, toluene, ether or ethyl acetate
(Table 1, entry 1), but did not provide the desired BV product 2a,
but the carboxylic acid 3a. Polar and protic solvents (THF, DMF,
alcohols, H2O and mixtures thereof) showed only moderate conver-
sion. Interestingly, fluorinated alcohols gave good conversion, and
for the first time some significant amounts of the desired BV product
2a (entries 2 and 3), but still not in a preparatively useful amount.
Therefore, we decided to investigate also the commonly used
peracids. With commercial m-chloroperbenzoic acid (mCPBA) a
clean reaction was observed providing the carboxylic acid 3a as the
sole product (entry 4). Oxidation of the secondary aldehyde 1b gave
a comparable result although the conversion was lower in this case
(entry 5).[18] Also here, the desired formate 2b was formed only in
tiny amounts. This situation did not change by using the imido
peracids. As a last attempt, we decided to purify the commercial
mCPBA according to a protocol described by Aggarwal et al.[19] The
mCPBA was washed with phosphate buffer and was dried over
MgSO4. With this purified peracid, the situation changed
dramatically. While the conversion was the same as in the previous
reaction, the product ratio changed completely (entry 6). Under these
conditions, the desired formate 2b was the sole product.
Interestingly, applying the purified peracid to the linear aldehyde 1a
showed no influence, neither on the conversion rate nor product ratio
(entries 4 and 7). Now the question arose, if the strong effect
observed for 1b results from the -branching, or if a (-substituted)
benzyl group migrates more easily. Therefore, we investigated also
the oxidation of -unbranched phenylacetaldehyde 1c (entry 8).
Already after 1 h, complete conversion was observed and the
formate could be isolated in 59% yield. In addition, phenylacetic
acid 3c was obtained in 25% as by-product. According to these
results, the migration tendency of the substituents can be arranged:
sec.-benzyl > benzyl > H > alkyl.
Entry Aldehyde
R
R1
R2
Formate Conv.
[%]
Yield
[%]
1
2
3
4
1d
1e
1f
Me
Me
Et
Me
Me
Et
Me
H
H
2d
2e
2f
100
100
100
100
99
85
1g
Bu
Et
H
2g
To illustrate, that this approach is not limited to simple
aldehydes but can also be applied to complex structures, we
investigated the oxidation of steroidal aldehyde 4. Its BV oxidation
should result in the formation of a monoformylated hydrate 5, which
eliminates formic acid to give ketone 6. And indeed, under our
optimized conditions 6 could be isolated in good yield (Scheme 3).
Scheme 3. BV oxidation of steroidal aldehyde 4
Table 1. BV-oxidation of aliphatic aldehydes 1
Next, we focused on -unsaturated aldehydes such as 7 (Table
3).[20] The electron-poor double bond should not be effected by the
mCPBA, and with this -branched aldehyde, we expected 8 to be
the preferred product. Under our standard reaction conditions using
1.5-equiv. mCPBA 8 was indeed formed, but as a 1:1 mixture with
epoxide 9 (enrty 1). Since full conversion was observed, the excess
of mCPBA underwent a Prileschajew epoxidation of the now
electron-rich double bond. Reducing the excess of mCPBA resulted
in a lower conversion rate (enrty 2,3), because the epoxidation
competes with the BV oxidation, the first step of the sequence. With
an excess, the reaction could be shifted completely to the side of
epoxide 9, which could be isolated in excellent yield (entry 4).
Entry Aldehyde Ox.-agent
(equiv.)
Solvent
Et2O
Conversion
[%]
Ratio
2:3
H2O2·urea (1.5)
1
1a
Cl3CCN (2.5)
KHCO3 (0.5)
ibid.
88
1:99
2
3
1a
1a
TFE[a]
75
75
14:86
20:80
ibid.
HFIP[a]
Table 3. BV-oxidation of -unsaturated aldehyde 7
4
5
1a
1b
mCPBA (1.5)[b] CH2Cl2
100
65
65 (51)[d]
100
100 (59)[d]
1:99
5:95
ibid.
CH2Cl2
6
7
8
1b
1a
1c
mCPBA (1.5)[c] CH2Cl2
99:1
1:99
70:30
ibid.
ibid.
CH2Cl2
CH2Cl2
[e]
Conversion [%]
Ratio
[a] TFE: trifluoroethanol; HFIP: hexafluoroisopropanol. [b] commercial
mCPBA (<77%). [c] Purified mCPBA (>90%). [d] Isolated yield. [e] Reaction
time: 1 h
Entry
Equiv. mCPBA
8:9
1
2
3
4
1.5
1.0
1.2
2.5
100
51:49
84:16
74:26
2:98
85
96 (67)[a]
With our primary goal in mind, the stereoselective synthesis of
-hydroxy amino acids, the results of the linear aldehydes are
irrelevant and we therefore focused on -branched aldehydes (Table
2). In all cases, already after 1 h at room temperature, a complete
conversion was observed and the desired formates were formed
almost exclusively. Because of the volatility of the methylated
derivatives (bp: 68−83°C) the formates 2d and 2e could not be
isolated in significant amounts. But in the case of the larger
derivatives 2f and 2g the products could be obtained in high yields.
100 (85)[b]
[a] Yield determined by NMR [b] Isolated yield
Saponification of 9 provided -hydroxyketone 10 in almost
quantitative yield. Therefore, the sequence BV oxidation
/
epoxidation / saponification is a straightforward protocol for the
conversion of -substituted -unsaturated aldehydes into -
hydroxyketones (Scheme 4).
2
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10.1002/ejoc.201701645
European Journal of Organic Chemistry
Scheme 4. Hydrolysis of epoxyformate 9
That this protocol is not limited to cinnamaldehydes but can also
be applied to other systems is illustrated with the conversion of
myrtenal 11 (Scheme 5). With an excess of mCPBA the -
hydroxyketone 13 was formed directly as the major product,
accompanied by a small amount of formate 12. Its saponification
provided 13 almost quantitatively, so that the hydroxy ketone was
isolated in 77% overall yield. One might assume that the
epoxyformate intermediate 14 formed primarily undergoes ring
opening catalyzed by the acid, resulting in a formate shift onto the
secondary alcohol. The configuration of its stereogenic center was
confirmed by nmr showing a NOE between one of the geminal
methyl groups and the -proton of the alcohol.
Scheme 7. Oxidative degradation of ,-unsaturated amino acids
Conclusions
In conclusion, we could show that oxidation of aldehydes with
purified mCPBA is an interesting entry to several classes of
compounds depending on the aldehyde used. While linear
unbranched aliphatic aldehydes are oxidized to the corresponding
carboxylic acids, -branched ones undergo BV oxidation to forma-
tes. -Branched -unsaturated aldehydes provide enolformates
and/or the epoxides thereof, which can be saponified to -hydroxy
ketones with an shortening of the carbon chain by 1 carbon.
Unbranched -unsaturated aldehydes undergo an interesting BV
oxidation / epoxidation / formate migration / BV oxidation cascade,
resulting in formyl-protected hydrates with an overall loss of two
carbon atoms. -Formylated amino acid does not undergo BV-
oxidation but oxidation to the corresponding substituted aspartates.
Further attempts towards BV oxidations of amino acids are currently
under investigation.
Experimental Section
General remarks: All air- or moisture-sensitive reactions were
carried out in dried glassware (>100 °C) under an atmosphere of
nitrogen. Dried solvents were distilled before use: Dichloromethane
was purchased from Sigma-Aldrich. The products were purified by
flash chromatography on silica gel (0.063−0.2 mm). Mixtures of
EtOAc and petroleum ether were generally used as eluents.
Analytical TLC was performed on pre-coated silica gel plates
(Macherey-Nagel, Polygram® SIL G/UV254). Visualization was
accomplished with UV-light, Ceric Ammonium Sulfate solution,
KMnO4 solution or ninhydrin solution. Melting points were
determined with a MEL-TEMP II (Laboratory Devices) melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded with a Bruker AC-400 [400 MHz (1H) and 100 MHz (13C)].
Chemical shifts are reported in ppm relative to TMS or internal
solvent. Mass spectra were recorded with a Finnigan MAT 95
spectrometer (quadrupole) using the CI technique.
Scheme 5. Oxidation of myrtenal 11
To figure out, if an -substituent on the double bond is required
or not, we subjected also unsubstituted cinnamaldehyde to the
optimized conditions. In this case, diformate 15 was obtained in
good yield and as sole product, probably formed in the reaction
cascade shown in scheme 6. The reaction might start with a classical
BV oxidation to provide the corresponding vinylformate 16 which
undergoes epoxidation / formyl shift. In this case formylated -
hydroxyaldehyde 17 is formed which undergoes a second BV
oxidation, comparable to steroid 4, providing a yield of 74% for the
whole cascade.
Purification of mCPBA[19]
Preparation of the buffer solution (pH 7.5): In a 1 L volumetric flask
0.1 N NaOH (410 mL) and 0.2 M KH2PO4 (250 mL) were mixed.
The flask was filled up to 1 L with distilled water, the solution was
stirred vigorously for 2 minutes, while the pH was controlled via pH
meter.
Purification of mCPBA: Commercial mCPBA (30.0 g, 70−75 %)
was dissolved in Et2O (200 mL) and washed thrice with buffer
solution (pH 7.5) (150 mL). The organic layer was dried (MgSO4)
and carefully evaporated to afford mCPBA (18.3 g, 91−99 % purity)
as dry, white solid. The peracid was transferred to a plastic container
and stored at +4 °C for up to 6 months without decomposition. The
purity was determined by NMR spectroscopy.
Scheme 6. Oxidation of cinnamaldehyde
Finally, coming back to our earlier intension, we tried to apply
the BV oxidation also to our -unsaturated amino acids. Several -
substituted and different N- and C-protected amino acids such as 18
have been subjected to ozonolysis and subsequent BV oxidation,
using several conditions. While ozonolysis was not a problem,
giving yields for the corresponding aldehydes in the range of
80−92%, the BV oxidation towards -formylated amino acids failed
in all cases. Only -substituted aspartates (19) could be observed.
The same products and yields were also obtained in oxidations using
Jones reagent.
Caution! It has been determined that 95−100% mCPBA can be
detonated by shock or sparks, while the commercial 70−85%
mCPBA is not shock-sensitive. It should be stored in a refrigerator
in tightly closed containers.
General procedure A: Baeyer-Villiger Oxidation of aliphatic
aldehydes: The corresponding aldehyde (1.0 equiv.) was dissolved
in CH2Cl2 (0.4 M according to the aldehyde), purified mCPBA
3
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10.1002/ejoc.201701645
European Journal of Organic Chemistry
(91−98%, 1.5 equiv.) was added and the reaction mixture was stirred
at room temperature until complete consumption of the starting
material was observed (TLC). After dilution with CH2Cl2 the
organic layer was washed with sat. Na2S2O3, sat. NaHCO3 (3x) and
sat. NaCl, dried (Na2SO4) and evaporated in vacuo.
sat. Na2S2O3 (5 mL), sat. NaHCO3 (3 x 10 mL) and sat. NaCl (5 mL),
dried (Na2SO4) and evaporated in vacuo. The crude product was
purified by flash chromatography (silica, pentane/diethyl ether 9:1)
to afford 9 (605 mg, 3.40 mmol, 85%) as a colourless liquid. Rf =
1
0.24 (pentane/diethyl ether 9:1). H NMR (400 MHz, CDCl3): δ =
1.53 (s, 3 H), 4.17 (s, 1 H), 7.33−7.42 (m, 5 H), 8.05 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 15.4, 63.1, 85.2, 126.1, 128.4,
128.4, 133.0, 159.1 ppm. HRMS (CI): m/z calcd. C10H11O3 [M+H]+
179.0703; found 179.0715.
1-Phenylethyl formate (2b):[21] According to general procedure A
1b (134 mg, 1.00 mmol) was reacted with purified mCPBA (91%,
284 mg, 1.50 mmol) for 16 hours at room temperature. Flash
chromatography (silica, petroleum ether/ethylacetate 9:1) provided
2b (76.7 mg, 511 µmol, 51%) as a colourless liquid. Rf = 0.48
(petroleum ether/ethyl acetate 3:1). 1H NMR (400 MHz, CDCl3): δ
= 1.59 (d, J = 6.7 Hz, 3 H), 6.01 (q, J = 6.6 Hz, 1 H), 7.28−7.38 (m,
5 H), 8.09 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.1, 72.2,
126.1, 128.1, 128.6, 140.9, 160.3 ppm. HRMS (CI): m/z calcd.
C9H11O2 [M+H]+ 151.0754; found 151.0759.
1-Phenyl-1-hydroxy-acetone (10):[20] To a solution of 9 (250 mg,
1.42 mmol) in H2O/THF (2:1, 3.6 mL) NaHCO3 (237 mg, 2.82
mmol) was added. After vigorous stirring for 2 days the mixture was
diluted with H2O (15 mL) and extracted with Et2O (3 x 10 mL). The
combined organic layer was dried (Na2SO4) and evaporated in vacuo
to afford 10 (213 mg, 1.42 mmol, quant.) as colourless liquid. Rf =
0.51 (petroleum ether/ethyl acetate 1:1). 1H NMR (400 MHz,
CDCl3): δ = 2.08 (s, 3 H), 4.30 (bs, 1 H), 5.10 (s, 1 H), 7.32−7.42
(m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.2, 80.1, 127.3,
128.7, 129.0, 137.9, 207.1 ppm. HRMS (CI): m/z calcd. C9H11O2
[M+H]+ 151.0754; found 151.0759.
Benzyl formate (2c):[22] According to general procedure A freshly
distilled 1c (120 mg, 1.00 mmol) was reacted with purified mCPBA
(91%, 284 mg, 1.50 mmol) over night. Aqueous work-up provided
2c (79.9 mg, 587 µmol, 59%) as a colourless liquid. Rf = 0.30
1
(pentane/diethyl ether 9:1). H NMR (400 MHz, CDCl3): δ = 5.22
(1R,3S,5R)-3-hydroxy-6,6-dimethylbicyclo[3.1.1]heptan-2-one
(13):[24] To a solution of (−)-myrtenal 11 (155 µL, 1.00 mmol) in
CH2Cl2 (2.5 mL) was added purified mCPBA (91%, 474 mg,
2.50 mmol) and the mixture was stirred at room temperature over
night. The reaction mixture was diluted with CH2Cl2 (15 mL) and
subsequently washed with sat. Na2S2O3, sat. NaHCO3 (3x) and sat.
NaCl before the organic layer was dried (Na2SO4) and evaporated in
vacuo. Purification by flash chromatography (silica, petroleum
ether/ethylacetate 9:1 to 4:1) afforded 12 (29.5 mg, 162 µmol, 16%)
and 13 (95.6 mg, 620 µmol, 62%) as colourless liquids. Formate 12
was dissolved in H2O/THF (2:1, 0.6 mL) and NaHCO3 (27.2 mg,
364 µmol) was added. After vigorous stirring over night the mixture
was diluted with H2O (10 mL) and extracted with Et2O (3 x 10 mL).
The organic layer was dried (Na2SO4) and evaporated in vacuo to
afford 13 (24.5 mg, 159 µmol, 16%) as colourless liquid. Rf = 0.22
(petroleum ether/ethyl acetate 4:1). 1H NMR (400 MHz, CDCl3): δ
= 0.90 (s, 3 H), 1.37 (s, 3 H), 1.61 (dd, J = 15.5, 5.6 Hz, 1 H), 1.90
(dt, J = 14.3 Hz, 3.1 Hz, 1 H), 2.26 (tt, J = 5.5 Hz, 2.9 Hz, 1 H), 2.55
(ddt, J = 14.3 Hz, 9.5 Hz, 2.3 Hz, 1 H), 2.70 (td, J = 6.1 Hz, 2.3 Hz,
1 H), 2.73 (q, J = 5.6 Hz, 1 H), 3.21 (bs, 1 H), 4.17 (dd, J = 9.5 Hz,
3.1 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.2, 26.0, 28.0,
32.4, 40.4, 40.7, 57.6, 69.3, 213.7 ppm. HRMS (CI): m/z calcd.
C9H15O2 [M+H]+ 155.1067; found 155.1075.
(d, J = 0.6 Hz, 2 H), 7.34−7.41 (m, 5 H), 8.16 (t, J = 0.9 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 65.7, 128.3, 128.5, 128.6,
135.1, 160.8 ppm. HRMS (CI): m/z calcd. C8H9O2 [M+H]+
137.0597; found 137.0601.
Pentan-3-yl formate (2f): According to general procedure A
2-Ethylbutanal 1f (267 µL, 2.00 mmol) was reacted with purified
mCPBA (96%, 539 mg, 3.00 mmol). After aqueous work-up the
organic layer was carefully evaporated in vacuo to afford 2f
(231 mg, 1.99 mmol, 99%) as a colourless liquid. Rf = 0.63
(petroleum ether/ethyl acetate 4:1). 1H NMR (400 MHz, CDCl3): δ
= 0.91 (t, J = 7.5 Hz, 6 H), 1.59−1.63 (m, 4 H), 4,88 (quint., J = 6.1
Hz, 1 H), 8.12 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 9.5,
26.4, 76.8, 161.1 ppm. GC-MS (CI, 1.5 keV) m/z [u] (%), 117.1 (3),
87.1 (6), 71.0 (100), 59.0 (65).
Heptan-3-yl formate (2g): According to general procedure A 1g
(311 µL, 2.00 mmol) was reacted with purified mCPBA (96%,
539 mg, 3.00 mmol). After aqueous work up the organic layer was
carefully evaporated in vacuo to afford 2f (243 mg, 1.69 mmol, 85%)
as a colourless liquid. Rf = 0.53 (petroleum ether/ethyl acetate 4:1).
1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 6.7 Hz, 3 H), 0.91 (t, J
= 7.5 Hz, 3 H), 1.24−1.36 (m, 4 H), 1.54−1.65 (m, 4 H), 4,93 (quint.,
J = 6.2 Hz, 1 H), 8.11 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 9.5, 13.9, 22.5, 26.9, 27.4, 33.2, 75.7, 161.1 ppm. GC-MS (CI, 1.5
keV) m/z [u] (%), 145.3 (1), 115.1 (8), 99.1 (29), 87.1 (26), 69.0
(60), 57.1 (100).
Phenylmethylene diformate (15):[20] To a solution of trans-
cinnamaldehyde (189 µL, 1.50 mmol) in CH2Cl2 (3.75 mL) mCPBA
(91%, 1.14 g, 6.00 mmol) was added. After stirring over night the
mixture was diluted with CH2Cl2 (10 mL) and washed with sat.
Na2S2O3 (10 mL), sat. NaHCO3 (3 x 10 mL) and sat. NaCl (10 mL).
The organic layer was dried (Na2SO4) and evaporated in vacuo to
afford 15 (199 mg, 1.10 mmol, 74%) as a colourless liquid. Rf = 0.26
(pentane/diethyl ether 9:1). 1H NMR (400 MHz, CDCl3): δ =
7.43−7.47 (m, 3 H), 7.55−7.57 (m, 2 H), 7.88 (s, 1 H), 8.15 (d, J =
1.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 88.5, 126.7,
128.8, 130.3, 134.1, 158.4 ppm. HRMS (CI): m/z calcd. C9H9O4
[M+H]+ 181.0495; found 181.0486.
17-Hydroxy-androstan-3-one (6):[23] According to general
procedure A 4 (79.0 mg, 248 µmol) in CH2Cl2 (620 µL) was treated
with mCPBA (91%, 70.5 mg, 372 µmol). Aqueous work up and
flash chromatography (silica, petroleum ether/ethylacetate 2:1 to
1:1) provided 6 (51.4 mg, 177 µmol, 71%) as a white solid. m.p.
173−176 °C. Rf = 0.32 (petroleum ether/ethyl acetate 1:1). 1H NMR
(400 MHz, CDCl3): δ = 0.70−0.74 (m, 1 H), 0.76 (s, 3 H), 0.84−0.99
(m, 2 H), 1.02 (s, 3 H), 1.08 (td, J = 12.9, 4.3 Hz, 1 H), 1.21−1.74
(m, 11 H), 1.82 (dt, J = 12.4, 3.3 Hz, 1 H), 2.00−2.11 (m, 3 H),
2.24−2.31 (m, 2 H), 2.33−2.44 (m, 1 H), 3.64 (t, J = 8.6 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 11.1, 11.5, 21.0, 23.4, 28.8,
30.5, 31.2, 35.4, 35.7, 36.6, 38.1, 38.5, 43.0, 44.7, 46.7, 50.8, 53.9,
81.8, 212.1 ppm. HRMS (CI): m/z calcd. C19H31O2 [M+H]+
291.2319; found 291.2318.
(2S,3S)-3-((N-Boc)amino)-4-methoxy-2-methyl-4-oxobutanoic
acid (19):[25] 18 (300 mg, 1.17 mmol) was dissolved in acetone (24
mL), cooled to −78 °C and ozone was passed through the solution
until a blue color occured (2 min). The excess of ozone was removed
by a flow of nitrogen before the mixture was warmed to 0 °C and
Jones reagent (2.7 M CrO3 in 4.3 M H2SO4) was added dropwise
until an orange color persisted. After stirring at 0 °C for 20 minutes
iPrOH was added until the solution turned green and the mixture was
stirred for 15 minutes at 0 °C and 1 hour at room temperature. The
mixture was filtrated through a pad of celite, the precipitate was
rinsed with Et2O and the organic layer was extracted with sat.
2-Methyl-3-phenyloxiran-2-yl formate (9):[20] To a solution of
-methyl cinnamaldehyde 7 (98%, 568 µL, 4.00 mmol) in CH2Cl2
(10 mL) mCPBA (91%, 2.28 g, 12.0 mmol) was added. The reaction
mixture was stirred at room temperature for 4 hours before it was
diluted with CH2Cl2 (10 mL). The organic layer was washed with
4
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10.1002/ejoc.201701645
European Journal of Organic Chemistry
NaHCO3 (3 x 10 mL). The combined aqueous layer was acidified
with 6 N HCl (pH 2), extracted with Et2O (3 x 15 mL) and the
combined organic layer was dried (Na2SO4) and evaoporated in
vacuo. After lyophylisation 19 (305 mg, 1.17 mmol, 94%, 96:4 dr,
99% ee) was obtained as a white solid. m.p. 86−89 °C. Rf = 0.48
(petroleum ether/ethyl acetate 1:1 + 1% HOAc). Major rotamer and
Frontiers in Asymmetric Synthesis and Application of alpha-
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1
diastereomer H NMR (400 MHz, DMSO-d6): δ = 1.02 (d, J = 7.2
Hz, 3 H), 1.38 (s, 9 H), 2.78 (qd, J = 7.6, 7.2 Hz, 1 H), 3.61 (s, 3 H),
4.29 (t, J = 8.7, 1 H), 7.29 (d, J = 9.2 Hz, 1 H), 12.41 (bs, 1 H) ppm.
13C NMR (100 MHz, DMSO-d6): δ = 13.3, 28.2, 40.4, 52.0, 55.1,
78.5, 155.6, 171.7, 174.9 ppm. Minor Rotamer (selected signals): 1H
NMR (400 MHz, DMSO-d6): δ = 1.05 (m, 3 H), 1.34 (s, 9 H), 4.12
(t, J = 7.8 Hz, 1 H), 6.98 (m, 1 H), ppm. 13C NMR (100 MHz,
DMSO-d6): δ = 27.9, 52.0, 56.3, 78.6, 171.4, 174.5 ppm. Minor
diastereomer (selected signal) 1H NMR (400 MHz, DMSO-d6): δ =
4.37 (dd, J = 8.8 Hz, 5.7 Hz, 1 H) ppm. HRMS (CI): m/z calcd.
C11H20NO6 [M+H]+ 262.1285; found 262.1283.
Supporting Information (see footnote on the first page of this
article): Copies of NMR spectra and HPLC data of all new
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Acknowledgement
Financial support from the DFG was gratefully acknowledged.
___________
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5
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10.1002/ejoc.201701645
European Journal of Organic Chemistry
Entry for the Table of Contents
Baeyer Villiger oxidation
Alexander Horn and Uli Kazmaier
Page No. – Page No.
Purified mCPBA, a useful reagent for the
oxidation of aldehydes
Keywords: Bayer Villiger oxidation /
Enolformates / Epoxides / -Hydroxy-
ketones / Peracids
Purified mCPBA is an useful reagent for
the oxidation of several classes of alde-
hydes. -Branched aliphatic aldehydes
undergo BV oxidation to give formates.
-Branched -unsaturated aldehydes
provide enolformates and/or the epoxides
thereof, while -hydroxylated aldehydes
give rise to ketones.
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