Synthesis of carbo- and heterocyclic aldehydes bearing an adjacent donor group - Ozonolysis versus OsO4/KIO4-oxidation

Article abstract of DOI:10.1007/s00706-004-0163-0

The synthesis of carbo- and heterocyclic aldehydes bearing an ipso-methoxy group is investigated. The synthetic sequence is based on an initial Grignard addition of an olefin to a cyclic ketone followed by methylation of the resulting tertiary alcohol. The terminal olefin serves as precursor for the aldehyde functionality. Oxidation by ozonolysis turned out to depend significantly on the distance of the donor methoxy group. The observed side reactions could be circumvented by applying a one-pot OsO₄ mediated diol formation followed by Malaprade oxidation using KIO₄. A series of carbo- and heterocyclic precursors were successfully converted to the title products. Springer-Verlag 2004.

Full text of DOI:10.1007/s00706-004-0163-0

Monatshefte f€ur Chemie 135, 899–909 (2004)
DOI 10.1007/s00706-004-0163-0
Synthesis of Carbo- and Heterocyclic
Aldehydes Bearing an Adjacent Donor
Group – Ozonolysis versus
OsO4=KIO4-Oxidation
ꢀ
Marko D. Mihovilovic , Markus Spina, Bernhard Mu¨ller,
and Peter Stanetty
Institute of Applied Synthetic Chemistry, Vienna University of Technology,
A-1060 Vienna, Austria (EU)
Received January 8, 2004; accepted January 13, 2004
Published online April 9, 2004 # Springer-Verlag 2004
Summary. The synthesis of carbo- and heterocyclic aldehydes bearing an ipso-methoxy group is
investigated. The synthetic sequence is based on an initial Grignard addition of an olefin to a cyclic
ketone followed by methylation of the resulting tertiary alcohol. The terminal olefin serves as precursor
for the aldehyde functionality. Oxidation by ozonolysis turned out to depend significantly on the
distance of the donor methoxy group. The observed side reactions could be circumvented by applying
a one-pot OsO4 mediated diol formation followed by Malaprade oxidation using KIO4. A series of
carbo- and heterocyclic precursors were successfully converted to the title products.
Keywords. Oxidation; Ozonolysis; Malaprade reaction; Osmium tetroxide; Potassium periodate.
Introduction
Recently we presented a facile and convenient one-pot procedure for the synthesis
of ꢀ-lactams from imines and various carboxylic acids in a Staudinger process
(Scheme 1) [1]. We utilized such structures in a bioreductive approach to paclitaxel
[2] and analogs [3] as efficient cytostatics. In an ongoing research program we
required access to such compounds with sterically demanding and structurally rigid
substituents bearing a donor group as versatile building blocks for the preparation
of bioactive compounds [4].
In this publication we disclose our synthetic efforts to the required aldehyde
precursors with a methoxy donor functionality (Scheme 2). Retrosynthetic analysis
suggested a straightforward entry starting from corresponding ketone precursors as
ꢀ
Corresponding author. E-mail: mmihovil@pop.tuwien.ac.at

900
M. D. Mihovilovic et al.
Scheme 1
commodity compounds. The aldehyde functionality was planned to be generated
from an olefin via oxidation at a later stage. Two major methods are available for
such a conversion: (i) transformation of an olefin into a 1,2-diol and subsequent
cleavage [5]; (ii) direct ozonolysis of an alkene [6]. Consequently, an olefin moiety
served as masked aldehyde group and the corresponding Grignard reagent was an
obvious first choice to generate the quaternary center. The route to aldehydes 5 is
outlined in Scheme 2.
Results and Discussion
Addition of vinyl Grignard compound 2a was based on a procedure by Marcou and
Normant [7] and a series of carbo- and heterocyclic ketones was converted to
alcohols 3a–3g (Table 1). The products were usually pure enough to be introduced
Scheme 2
Table 1. Compiled results of the synthetic sequence towards aldehydes 5
Ketone
X
n
Grignard addition
Methylation
Olefin oxidation
Alcohol
Yield=%
Ether
Yield=%
Aldehyde
Yield=%
1a
1b
1c
1d
1e
1f
ꢁ
0
0
0
0
0
0
0
1
1
1
3a
3b
3c
3d
3e
3f
69
66
86
69
98
86
98
98
83
96
4a
4b
4c
4d
4e
4f
71
81
87
76
89
97
87
87
83
87
5aa
5ba
5ca
5da
5ea
5fa
25
33
56
96
96
20
42
64
74
74
CH2
(CH2)2
O
N-Boc
N-COOMe
N-Tos
ꢁ
1g
1a
1b
1c
3g
3h
3i
4g
4h
4i
5ga
5hb
5ib
CH2
(CH2)2
3j
4j
5jb
a
b
OsO4=KIO4 oxidation; ozonolysis

Synthesis of Carbo- and Heterocyclic Aldehydes
901
directly into the next step or were purified by Kugelrohr distillation. Preparation of
the corresponding methyl ethers 4a–4g was carried out with NaH and one equiva-
lent of dimethyl sulfate in excellent yields [8]. The slightly decreased yield for 4a
can be explained by the volatility of the compound.
First aldehyde formation via ozonolysis was performed in analogy to a report
by Clark et al. [9], where a similar vinyl group adjacent to a quaternary carbon
center bearing a protected peroxo group was converted to the corresponding
carbonyl functionality. The reaction with 4b was carried out in dry MeOH at
ꢁ65 ꢂ 5ꢃC using Me2S to quench the secondary ozonide and the starting material
was completely consumed. Although a tenfold excess of Me2S was used, over-
oxidation to the corresponding carboxylic acid [10] was observed, however. Only
traces of the desired aldehyde 5b were detected. Changing from methylene chlo-
ride to methanol as solvent did not improve the yield of 5b.
Consequently, we carried out the reaction in the presence of tetracyanoethene
as reducing agent to avoid over-oxidation [11]. While this modification decreased
the amount of carboxylic acid produced to some extent, a new side reaction was
observed: significant amounts of cyclohexanone (1b) were detected in the crude
reaction mixture after work-up. We attribute the formation of this unexpected
compound to a so called ‘‘abnormal’’ ozonolysis process [12]. This reaction path-
way can be observed when substituents with strong þI- or þM-effects are present
adjacent to the C–C double bond, as demonstrated for groups OH, OR, and OCOR.
In the case of 1b both the þM-effect of the methoxy group and the þI-effect of an
adjacent quaternary carbon seem to promote this alternative pathway for ozono-
lysis, as outlined in Scheme 3.
After the formation of the primary ozonide A the rearrangement process
towards the secondary ozonide proceeds via the zwitterionic form B and its meso-
meric structure C. In the case of strong donating effects at the quaternary center a
migration reaction can take place to form the ester D. This of course represents a
very susceptible structure to hydrolysis upon aqueous work-up to finally generate
Scheme 3

902
M. D. Mihovilovic et al.
the ketone 1b. Although this undesired pathway could be suppressed to some
extent by the utilization of protic solvents and addition of reducing agents
(Me2S), the amount of aldehyde 5b could not be increased to more than 10%
according to NMR based on the crude material after work-up.
These findings prompted us to extend our study to the corresponding homologs
4h–4j with an additional methylene moiety between the quaternary center an the
terminal olefin. Synthesis of these compounds was carried out according to the
above methodology (Table 1). As expected, the ozonolysis in methanol followed by
quenching with Me2S proceeded smoothly to the corresponding aldehydes 5h–5j in
this series. This further supports our hypothesis of the significant influence of the
adjacent quaternary center bearing a donor functionality.
In order to complete our synthetic route to aldehydes 5a–5g we utilized a two-
step sequence based on 1,2-diol oxidation followed by Malaprade type cleavage.
Such transformations have been developed into one-pot protocols based on catalytic
amounts of RuCl3 [13] or OsO4 [14] in the presence on an additional oxidant. We
chose KIO4 as suitable oxidant for both regeneration of the OsO4 and diol cleavage
and the reaction was carried out in a mixture of THF and water. Isolated yields of
aldehydes 5a–5g were moderate to good. All aldehydes 5a–5j required storage at
ꢁ20ꢃC in inert atmosphere after purification to avoid oxidation to the corresponding
acids upon exposure to air. Especially in the case of volatile products 5a and 5b
removal of solvent by distillation led to decreased yields. However, considering
the range of functionally different precursors, the methodology allows access to a
large variety of sterically demanding aldehydes bearing a donor group.
Conclusion
We have developed a general synthetic route to sterically demanding olefin pre-
cursors bearing a donor functionality for the subsequent oxidative formation of
aldehydes. While ozonolysis failed to give the desired products 5 in those cases,
when the alkene was directly attached to a quaternary carbon center, the homologs
with an additional methylene linker gave smooth oxidation to the aldehydes. A
mechanistic rationale was developed for the observed side products based on the
‘‘abnormal’’ ozonolysis concept.
Alternatively, the oxidation of the olefin substrates by OsO4 in presence of
KIO4 as both regenerating oxidant for osmium and reagent for the 1,2-diol cleav-
age was demonstrated to circumvent the obstacles of the ozonolysis. Using a one-
pot protocol, aldehydes 5a–5g were prepared in moderate to excellent yields from
a broad range of carbo- and heterocyclic precursors.
We consider the two complementary strategies as versatile and convenient
methods to access the desired aldehydes as valuable intermediates for subsequent
bioactive compound synthesis.
Experimental
Unless otherwise noted, chemicals were purchased from commercial suppliers and used without
further purification. All solvents were distilled prior to use. Flash column chromatography was per-
€
formed on silica gel 60 from Merck (40–63 ꢁm). Kugelrohr distillation was carried out using a Buchi

Synthesis of Carbo- and Heterocyclic Aldehydes
903
GKR-51 apparatus. Melting points were determined using a Kofler-type Leica Galen III micro hot
stage microscope and are uncorrected. NMR spectra were recorded from CDCl3 solutions on a Bruker
AC 200 (200MHz) or Bruker Avance UltraShield 400 (400 MHz) spectrometer and chemical shifts are
reported in ppm using TMS as internal standard.
General Procedure for Grignard Addition
The Grignard reagent (1.3 equiv of commercial vinyl magnesium bromide, 1 M in THF; 1.5 equiv of
freshlypreparedallyl magnesiumbromide [15], 10%solutionindry diethyl ether)was added toa solution
of1 (1equiv, 10% in dry diethyl ether) at ꢁ5 ꢂ 5ꢃC. The reactionmixturewas kept at this temperature for
2 h and thenwarmedtoroom temperature. Stirring was continued until TLC showed complete conversion
(2–12 h). The mixture was hydrolyzed with NH4Cl solution (10%) and extracted with diethyl ether. The
combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated.
1-Ethenylcyclopentanol (3a)
Cyclopentanone (1a, 5.00 g, 59mmol) was converted with vinyl magnesium bromide according to the
above procedure to give 4.54g of 3a [7] (69%) as colorless liquid after Kugelrohr distillation; bp 80–
90ꢃC=16 mbar (KRD); 1H NMR (200MHz): ꢂ ¼ 1.53–2.00 (m, 8H), 5.05 (dd, J ¼ 9, ꢄ1 Hz, 1H), 5.27
(dd, J ¼ 16, ꢄ1 Hz, 1H), 6.03 (dd, J ¼ 16, 9 Hz, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 23.7 (t), 40.2 (t),
82.1 (s), 111.0 (t), 144.4 (d) ppm.
1-Ethenylcyclohexanol (3b)
Cyclohexanone (1b, 7.00 g, 71 mmol) was converted with vinyl magnesium bromide according to the
above procedure to give 5.92g of 3b [7] (66%) as colorless liquid after distillation; bp 71ꢃC=16mbar;
1H NMR (200 MHz): ꢂ ¼ 1.35–1.75 (m, 10H), 4.97 (dd, J ¼ 13, ꢄ1 Hz, 1H), 5.16 (dd, J ¼ 16, ꢄ1 Hz,
1H), 5.92 (dd, J ¼ 16, 12.7Hz, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 21.9 (t), 25.5 (t), 37.5 (t), 71.7 (s),
111.4 (t), 146.0 (d) ppm.
1-Ethenylcycloheptanol (3c)
Cycloheptanone (1c, 5.00 g, 45 mmol) was converted with vinyl magnesium bromide according to the
above procedure to give 5.30 g of 3c [7] (86%) as colorless liquid after Kugelrohr distillation; bp 125–
1
130ꢃC=20 mbar (KRD); H NMR (200 MHz): ꢂ ¼ 1.32–2.10 (m, 12H), 5.00 (dd, J ¼ 9, ꢄ1 Hz, 1H),
5.20 (dd, J ¼ 16, ꢄ1 Hz, 1H), 6.02 (dd, J ¼ 16, 9 Hz, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 22.1 (t), 29.5
(t), 41.1 (t), 75.6 (s), 110.1 (t), 146.6 (d) ppm.
1-Ethenyltetrahydropyran-4-ol (3d)
Tetrahydropyran-4-one (1d, 5.00 g, 50 mmol)was converted withvinylmagnesium bromideaccording to
the above procedure to give 4.42 g of 3d [16] (69%) as colorless liquid after Kugelrohr distillation; bp
145–150ꢃC=11 mbar (KRD); 1H NMR (200MHz): ꢂ ¼ 1.40–1.58 (m, 2H), 1.70–1.90 (m, 2H), 2.19 (bs,
1H), 3.58–3.90 (m, 4H), 5.10 (dd, J ¼ 12.7, ꢄ1 Hz, 1H), 5.26 (dd, J ¼ 16, ꢄ1 Hz, 1H), 5.99 (dd, J ¼ 16,
12.7Hz, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 37.3 (t), 63.5 (t), 68.9 (s), 112.2 (t), 145.0 (d) ppm.
4-Ethenyl-4-hydroxypiperidin-1-carboxylic acid 1,1-dimethylethyl ester (3e)
4-Oxopiperidin-1-carboxylic acid 1,1-dimethylethyl ester (1e, 5.00g, 25mmol) was converted with
vinyl magnesium bromide according to the above procedure to give 5.56g of 3e [16] (98%) as beige oil

904
M. D. Mihovilovic et al.
1
after Kugelrohr distillation; bp 205–210ꢃC=11mbar (KRD); H NMR (200 MHz): ꢂ ¼ 1.45 (s, 9H),
1.50–1.90 (m, 4H), 3.11–3.30 (m, 2H), 3.70–3.89 (m, 2H), 5.10 (dd, J ¼ 9, ꢄ1 Hz, 1H), 5.27 (dd,
J ¼ 16, ꢄ1 Hz, 1H), 5.94 (dd, J ¼ 16, 9 Hz, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 28.3 (q), 28.4 (q), 36.6
(t), 41.1 (t), 39.6 (bt), 42.9 (bt), 70.0 (s), 79.4 (s), 80.4 (s), 112.3 (t), 144.9 (d), 154.8 (s) ppm (carbon
NMR showed presence of E=Z isomers).
4-Ethenyl-4-hydroxypiperidin-1-carboxylic acid methyl ester (3f, C9H15NO3)
4-Oxopiperidin-1-carboxylic acid methyl ester (1f, 3.05 g, 19mmol) was converted with vinyl magne-
1
sium bromide according to the above procedure to give 3.10 g of 3f (86%) as beige oil; H NMR
(200 MHz): ꢂ ¼ 1.45–1.84 (m, 4H), 3.10–3.39 (m, 2H), 3.70 (s, 3H), 3.71–3.99 (m, 2H), 5.10 (dd,
J ¼ 9, ꢄ1 Hz, 1H), 5.28 (dd, J ¼ 16, ꢄ1 Hz, 1H), 5.94 (dd, J ¼ 16, 9 Hz, 1H) ppm; 13C NMR
(50 MHz): ꢂ ¼ 36.5 (t), 39.7 (t), 52.5 (q), 69.8 (s), 112.4 (t), 144.8 (d), 155.9 (s) ppm.
1-[(4-Methylphenyl)sulfonyl]-4-ethenylpiperidin-4-ol (3g, C14H19NO3S)
1-[(4-Methylphenyl)sulfonyl]piperidin-4-one (1g, 5.00 g, 26mmol) was converted with vinyl magne-
sium bromide according to the above procedure to give 5.45 g of 3g (98%) as beige crystals; mp 95–
1
98ꢃC; H NMR (200MHz): ꢂ ¼ 1.30–1.97 (m, 4H), 2.45 (s, 3H), 2.60–2.80 (m, 2H), 3.45–3.80 (m,
2H), 5.08 (dd, J ¼ 9, ꢄ1 Hz, 1H), 5.22 (dd, J ¼ 16, ꢄ1 Hz, 1H), 5.90 (dd, J ¼ 16, 9 Hz, 1H), 7.32 (d,
J ¼ 6 Hz, 2H), 7.64 (d, J ¼ 6 Hz, 2H) ppm; 13C NMR (50 MHz): ꢂ ¼ 21.5 (q), 36.2 (t), 42.0 (t), 69.0
(s), 112.7 (t), 127.6 (d), 129.6 (d), 133.4 (s), 143.4 (s), 144.5 (d) ppm.
1-(2-Propenyl)cyclopentanol (3h)
Cyclopentanone (1a, 10 cm3, 113 mmol, 9.52g) was converted with freshly prepared allyl magnesium
1
bromide according to the above procedure to give 13.52 g of 3h [17] (98%) as colorless liquid; H
NMR (200 MHz): ꢂ ¼ 1.55–1.82 (m, 9H), 2.34 (d, J ¼ 7 Hz, 2H), 5.02–5.12 (m, 1H), 5.17 (bs, 1H),
5.80–6.01 (m, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 23.8 (t), 39.3 (t), 45.8 (t), 81.3 (s), 118.3 (t), 134.6
(d) ppm.
1-(2-Propenyl)cyclohexanol (3i)
Cyclohexanone (1b, 9.02 g, 92 mmol) was converted with freshly prepared allyl magnesium bromide
1
according to the above procedure to give 10.69 g of 3i [17] (83%) as colorless liquid; H NMR
(200 MHz): ꢂ ¼ 1.12–1.75 (m, 11H), 2.21 (d, J ¼ 7 Hz, 2H), 5.05–5.17 (m, 2H), 5.82–6.03 (m, 1H)
ppm; 13C NMR (50 MHz): ꢂ ¼ 22.1 (t), 25.7 (t), 37.3 (t), 46.7 (t), 70.9 (s), 118.5 (t), 133.7 (d) ppm.
1-(2-Propenyl)cycloheptanol (3j)
Cycloheptanone (1c, 9.50 g, 85mmol) was converted with freshly prepared allyl magnesium bromide
according to the above procedure to give 12.60 g of 3j [17] (97%) as colorless oil; 1H NMR
(200 MHz): ꢂ ¼ 1.22–1.70 (m, 13H), 2.20 (d, J ¼ 10Hz, 2H), 5.00–5.22 (m, 2H), 5.75–6.05 (m,
1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 22.3 (t), 29.7 (t), 41.0 (t), 47.8 (t), 74.8 (s) 118.5 (t), 134.1 (d) ppm.
General Procedure for O-Methylation
Alcohol 1 (1 equiv) was added to a suspension (5%) of NaH (3 equiv) in dry THF. After refluxing for
2 h the mixture was cooled to room temperature and dimethyl sulfate (1.2 equiv) was added slowly.

Synthesis of Carbo- and Heterocyclic Aldehydes
905
The resulting mixture was refluxed overnight, cooled to room temperature, and hydrolyzed with ice
cooled NH4Cl solution. After extraction with diethyl ether, the combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated.
1-Ethenyl-1-methoxycyclopentane (4a)
Alcohol 3a (4.50 g, 40 mmol) was converted according to the above procedure to give 3.58g of 4a [18]
(71%) as colorless liquid after Kugelrohr distillation; bp 50–60ꢃC=24 mbar (KRD); 1H NMR
(200 MHz): ꢂ ¼ 1.50–1.91 (m, 8H), 3.13 (s, 3H), 5.10–5.22 (m, 2H), 5.88 (dd, J ¼ 16, 9 Hz, 1H)
ppm; 13C NMR (50 MHz): ꢂ ¼ 23.0 (t), 35.4 (t), 50.7 (q), 87.0 (s), 114.1 (t), 140.9 (d) ppm.
1-Ethenyl-1-methoxycyclohexane (4b)
Compound 3b (4.89 g, 38 mmol) was converted according to the above procedure to give 4.36 g of
1
4b [19] (81%) as colorless liquid after Kugelrohr distillation; bp 75–80ꢃC=22–40mbar (KRD); H
NMR (200MHz): ꢂ ¼ 1.10–1.82 (m, 10H), 3.11 (s, 3H), 5.01–5.23 (m, 2H), 5.71 (dd, J ¼ 16,
12.7Hz, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 21.7 (t), 25.7 (t), 33.8 (t), 49.2 (q), 75.6 (s), 114.7
(t), 142.8 (d) ppm.
1-Ethenyl-1-methoxycycloheptane (4c, C10H18O)
Product 3c (5.38 g, 38 mmol) was converted according to the above procedure to give 5.13 g of 4c
(87%) as colorless liquid after Kugelrohr distillation; bp 115–120ꢃC=30mbar (KRD); 1H NMR
(200 MHz): ꢂ ¼ 1.30–1.90 (m, 12H), 3.12 (s, 3H), 5.05–5.20 (m, 2H), 5.72 (dd, J ¼ 16, 9 Hz, 1H)
ppm; 13C NMR (50 MHz): ꢂ ¼ 21.6 (t), 29.5 (t), 36.8 (t), 49.8 (q), 80.0 (s), 113.8 (t), 143.6 (d) ppm.
4-Ethenyl-4-methoxytetrahydropyrane (4d, C8H14O2)
Alcohol 3d (4.00 g, 31 mmol) was converted according to the above procedure to give 3.32 g of 4d
(76%) as colorless liquid; 1H NMR (200MHz): ꢂ ¼ 1.70 (t, J ¼ 6 Hz, 4H), 3.11 (s, 3H), 3.58–3.81 (m,
4H), 5.16 (dd, J ¼ 9, ꢄ1 Hz, 1H), 5.22 (dd, J ¼ 16, ꢄ1 Hz, 1H), 5.69 (dd, J ¼ 16, 9 Hz, 1H) ppm; 13C
NMR (50 MHz): ꢂ ¼ 33.9 (t), 49.4 (q), 63.5 (t), 73.3 (s), 115.7 (t), 141.4 (d) ppm.
4-Ethenyl-4-methoxypiperidin-1-carboxylic acid 1,1-dimethylethyl ester (4e, C13H21NO3)
Compound 3e (5.56 g, 25mmol) was converted according to the above procedure to give 5.25g of
4e (89%) as colorless oil after flash column chromatography (SiO2, LP:EtOAc¼ 5:1); 1H NMR
(200 MHz): ꢂ ¼ 1.45 (s, 9H), 1.50–1.90 (m, 4H), 3.05–3.30 (m, 2H), 3.14 (s, 3H), 3.47–3.98 (m,
2H), 5.17 (dd, J ¼ 9, ꢄ1 Hz, 1H), 5.25 (dd, J ¼ 16, ꢄ1 Hz, 1H), 5.72 (dd, J ¼ 16, 9 Hz, 1H) ppm; 13C
NMR (50 MHz): ꢂ ¼ 28.4 (q), 33.0 (bt), 39.5 (bt), 49.6 (q), 74.0 (s), 79.3 (s), 115.8 (t), 141.5 (d), 154.9
(s) ppm.
4-Ethenyl-4-methoxypiperidin-1-carboxylic acid methyl ester (4f, C10H17NO3)
Product 3f (3.10 g, 17mmol) was converted according to the above procedure to give 3.22 g of 4f
(97%) as colorless oil; 1H NMR (200 MHz): ꢂ ¼ 1.48–1.89 (m, 4H), 3.14 (s, 3H), 3.08–3.30 (m, 2H),
3.70 (s, 3H), 3.71–3.93 (m, 2H), 5.17 (dd, J ¼ 19, ꢄ1 Hz, 1H), 5.24 (dd, J ¼ 9, ꢄ1 Hz, 1H), 5.27 (dd,
J ¼ 19, 9 Hz, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 32.9 (t), 39.5 (t), 49.5 (q), 52.4 (q), 73.8 (s), 115.8 (t),
141.3 (d), 155.9 (s) ppm.

906
M. D. Mihovilovic et al.
4-Ethenyl-4-methoxy-1-[(4-methylphenyl)sulfonyl]piperidine (4g, C15H21NO3S)
Alcohol 3g (9.84 g, 35mmol) was converted according to the above procedure to give 8.94 g of 4g
(87%) as beige oil; 1H NMR (200MHz): ꢂ ¼ 1.60–1.96 (m, 4H), 2.45 (s, 3H), 2.57–2.74 (m, 2H), 3.01
(s, 3H), 3.45–3.60 (m, 2H), 5.14 (dd, J ¼ 9, ꢄ1 Hz, 1H), 5.22 (dd, J ¼ 16, ꢄ1 Hz, 1H), 5.68 (dd,
J ¼ 16, 9 Hz, 1H), 7.32 (d, J ¼ 6 Hz, 2H), 7.68 (d, J ¼ 6 Hz, 2H) ppm; 13C NMR (50 MHz): ꢂ ¼ 21.4
(q), 32.5 (t), 41.7 (t), 49.4 (q), 72.9 (s), 116.0 (t), 127.5 (d), 129.6 (d), 133.4 (s), 140.9 (d), 143.4 (s)
ppm.
1-Methoxy-1-(2-propenyl)cyclopentane (4h, C9H16O)
Compound 3h (13.52g, 107 mmol) was converted according to the above procedure to give 13.04 g of
4h (87%) as beige liquid after distillation; bp 83–84ꢃC=81mbar; 1H NMR (200 MHz): ꢂ ¼ 1.38–1.89
(m, 8H), 2.35 (d, J ¼ 7 Hz, 2H), 3.18 (s, 3H), 5.00–5.15 (m, 2H), 5.78–5.85 (m, 1H) ppm; 13C NMR
(50 MHz): ꢂ ¼ 23.8 (t), 35.4 (t), 40.1(t), 49.5 (q), 86.3 (s), 116.8 (t), 134.8 (d) ppm.
1-Methoxy-1-(2-propenyl)cyclohexane (4i)
Product 3i (10.69 g, 76 mmol) was converted according to the above procedure to give 9.70 g of 4i [20]
(83%) as beige liquid after distillation; bp 113–115ꢃC=100 mbar; 1H NMR (200MHz): ꢂ ¼ 1.06–1.75
(m, 10H), 2.12 (d, J ¼ 9 Hz, 2H), 3.12 (s, 3H), 4.85–5.10 (m, 2H), 5.60–5.85 (m, 1H) ppm; 13C NMR
(50 MHz): ꢂ ¼ 19.7 (t), 23.8 (t), 31.8 (t), 39.9 (t), 47.0 (q), 74.4 (s), 116.1 (t), 133.0 (d) ppm.
1-Methoxy-1-(2-propenyl)cycloheptane (4j, C12H20O)
Alcohol 3j (12.57 g, 81 mmol) was converted according to the above procedure to give 12.00 g of 4j
1
(87%) as beige liquid after distillation; bp 112–115ꢃC=40mbar; H NMR (200MHz): ꢂ ¼ 1.06–1.90
(m, 12H), 2.20 (d, J ¼ 10 Hz, 2H), 3.20 (s, 3H), 4.90–5.20 (m, 2H), 5.70–6.00 (m, 1H) ppm; 13C NMR
(50 MHz): ꢂ ¼ 22.0 (t), 29.7 (t), 37.2 (t), 42.3 (t), 48.5 (q), 79.0 (s), 117.0 (t), 134.4 (d) ppm.
General Procedure for OsO4=KIO4 Oxidation
A solution (5%) of ether 4 (1 equiv) in THF=H2O (3=1) was treated with OsO4 (0.05 equiv). Subse-
quently, KIO4 (2 equiv) was added in portions over a period of 4 h and the reaction was stirred
overnight at room temperature. Water was added to the mixture followed by repeated extraction with
diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated.
1-Methoxycyclopentanecarboxaldehyde (5a)
Ether 4a (3.55 g, 28 mmol) was converted according to the above procedure to give 0.87 g of 5a [18]
(25%) as colorless liquid after Kugelrohr distillation; bp 60–65ꢃC=100 mbar (KRD); 1H NMR
(200 MHz): ꢂ ¼ 1.60–1.90 (m, 8H), 3.31 (s, 3H), 9.70 (s, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 24.3
(t), 32.2 (t), 67.9 (q), 92.2 (s), 204.2 (d) ppm.
1-Methoxycyclohexanecarboxaldehyde (5b, C8H14O2)
Compound 4b (3.00 g, 21 mmol) was converted according to the above procedure to give 1.00 g of
1
5b (33%) as colorless liquid after Kugelrohr distillation; bp 70–75ꢃC=35mbar (KRD); H NMR
(200 MHz): ꢂ ¼ 1.18–1.80 (m, 10H), 3.28 (s, 3H), 9.51 (s, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 20.9
(t), 25.1 (t), 28.5 (t), 51.7 (q), 81.0 (s), 204.9 (d) ppm.

Synthesis of Carbo- and Heterocyclic Aldehydes
907
1-Methoxycycloheptanecarboxaldehyde (5c, C9H16O2)
Product 4c (5.10 g, 33 mmol) was converted according to the above procedure to give 2.86 g of 5c
(56%) as colorless liquid after Kugelrohr distillation; bp 130–135ꢃC=15mbar (KRD); 1H NMR
(200 MHz): ꢂ ¼ 1.40–1.85 (m, 12H), 3.25 (s, 3H), 9.50 (s, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 21.5
(t), 29.6 (t), 31.3 (t), 52.0 (q), 84.9 (s), 204.5 (d) ppm.
4-Methoxytetrahydropyran-4-carboxaldehyde (5d)
Olefin 4d (4.30 g, 30 mmol) was converted according to the above procedure to give 4.25g of 5d [21]
1
(95%) as colorless liquid; H NMR (200 MHz): ꢂ ¼ 1.63–1.95 (m, 4H), 3.31 (s, 3H), 3.66–3.81 (m,
4H), 9.53 (s, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 28.8 (t), 51.9 (q), 62.9 (t), 78.7 (s), 203.2 (d) ppm.
4-Formyl-4-methoxypiperidin-1-carboxylic acid 1,1-dimethylethyl ester (5e)
Alkene 4e (5.25 g, 27 mmol) was converted according to the above procedure to give 5.07g of 5e [22]
(96%) as colorless liquid after Kugelrohr distillation; bp 145–150ꢃC=0.2 mbar (KRD); 1H NMR
(200 MHz): ꢂ ¼ 1.28–1.50 (m, 9H), 1.50–1.79 (m, 4H), 3.00–3.28 (m, 2H), 3.25 (s, 3H), 9.50 (s,
1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 28.1 (t), 28.3 (q), 38.7 (t), 52.1 (q), 79.6 (s), 154.5 (s), 203.6 (d)
ppm.
4-Formyl-4-methoxypiperidin-1-carboxylic acid methyl ester (5f, C9H15NO4)
Ether 4f (3.22 g, 16 mmol) was converted according to the above procedure to give 0.65g of 5f (20%)
1
as colorless liquid after flash column chromatography (SiO2, LP:EtOAc¼ 4:1); H NMR (200MHz):
ꢂ ¼ 1.64–1.88 (m, 4H), 3.16–3.32 (m, 2H), 3.31 (s, 3H), 3.70 (s, 3H), 3.71–3.92 (m, 2H), 9.58 (s, 1H)
ppm; 13C NMR (50 MHz): ꢂ ¼ 28.0 (t), 38.8 (t), 52.0 (q), 52.4 (q), 79.4 (s), 155.6 (s), 203.3 (d) ppm.
4-Methoxy-1-[(4-methylphenyl)sulfonyl]piperidin-4-carboxaldehyde (5g, C14H19NO4S)
Compound 4g (6.80 g, 23 mmol) was converted according to the above procedure to give 2.88 g of 5g
(42%) as colorless crystals after flash column chromatography (SiO2, LP:EtOAc¼ 4:1); mp 98–102ꢃC;
1H NMR (200 MHz): ꢂ ¼ 1.75–1.97 (m, 4H), 2.45 (s, 3H), 2.62–2.82 (m, 2H), 3.20 (s, 3H), 3.37–3.58
(m, 2H), 7.32 (d, J ¼ 6 Hz, 2H), 7.65 (d, J ¼ 6 Hz, 2H), 9.51 (s, 1H) ppm; 13C NMR (50 MHz): ꢂ ¼ 21.5
(q), 27.9 (t), 41.3 (t), 52.0 (q), 78.6 (s), 127.6 (d), 129.8 (d), 133.4 (s), 143.6 (s), 203.0 (d) ppm.
General Procedure for Ozonolysis
The alkene 4 was dissolved in dry MeOH (5% solution) and cooled to ꢁ80ꢃC. Ozone generated by a
Sander laboratory ozonizer (1 bar pre-pressure, 0.4 A, 4 cm3) was passed through the reaction mixture
until the solution got dark blue. This process was repeated until the blue color remained for more than
10min. Dry N2 was passed through the reaction mixture to remove excess of ozone. The reaction was
quenched by addition of dimethylsulfide (10 equiv) and slowly warmed to room temperature upon
stirring overnight. Subsequent removal of solvents gave the crude aldehydes, which were purified by
flash column chromatography.
1-Methoxycyclopentane-1-acetaldehyde (5h, C8H14O2)
Ether 4h (1.00 g, 7.1mmol) was converted according to the above procedure to give 0.65g of 5h (64%)
1
as colorless liquid after flash column chromatography (SiO2, LP:EtOAc¼ 5:1); H NMR (200MHz):

908
M. D. Mihovilovic et al.
ꢂ ¼ 1.48–1.85 (m, 6H), 1.92–2.09 (m, 2H), 2.63 (d, J ¼ 3 Hz, 2H), 3.21 (s, 3H), 9.81 (t, J ¼ 2 Hz, 1H)
ppm; 13C NMR (50 MHz): ꢂ ¼ 23.4 (t), 36.0 (t), 40.9 (t), 49.3 (t), 49.8 (q), 67.9 (t), 84.8 (s), 202.1 (d)
ppm.
1-Methoxycyclohexane-1-acetaldehyde (5i, C9H16O2)
Ether 4i (4.27 g, 28mmol) was converted according to the above procedure to give 3.19 g of 5i (74%)
1
as beige liquid after flash column chromatography (SiO2, LP:EtOAc¼ 8:1); H NMR (200MHz):
ꢂ ¼ 1.10–1.93 (m, 10H), 2.48 (d, J ¼ 3 Hz, 2H), 3.23 (s, 3H), 9.80 (t, J ¼ 2 Hz, 1H) ppm; 13C
NMR (50 MHz): ꢂ ¼ 21.6 (t), 25.4 (t), 34.7 (t), 48.5 (d), 49.7 (t), 75.1 (q), 202.4 (d) ppm.
1-Methoxycycloheptane-1-acetaldehyde (5j, C10H18O2)
Ether 4j (1.00 g, 5.9mmol) was converted according to the above procedure to give 0.76 g of 5j
(74%) as colorless liquid after flash column chromatography (SiO2, LP:EtOAc¼ 5:1); bp 114–
115ꢃC=40 mbar; 1H NMR (200MHz): ꢂ ¼ 1.30–1.67 (m, 11H), 1.89–1.95 (m, 2H), 2.51 (d, J ¼ 5 Hz,
Hz, 2H), 3.25 (s, 3H), 9.81 (t, J ¼ 5 Hz, 1H) ppm.
Acknowledgement
Financial support for this project by the Austrian Science Fund (FWF – project no.: P15781) is
gratefully acknowledged. Additional support by Syngenta Crop Protection AG, Basel, Switzerland,
is highly appreciated.
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Synthesis of Carbo- and Heterocyclic Aldehydes
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