Birch reaction followed by asymmetric iridium-catalysed hydrogenation

Article abstract of DOI:10.1055/s-0031-1289569

Birch reaction products are asymmetrically hydrogenated with high enantio- and diastereoselectivity via iridium catalysts. This new method of producing chiral compounds was explored for a variety of 1,3-di- and 1,2,4-tri-substituted cyclohexadienes. Georg

Full text of DOI:10.1055/s-0031-1289569

3796
PRACTICAL SYNTHETIC PROCEDURES
Birch Reaction Followed by Asymmetric Iridium-Catalysed Hydrogenation
S
uccessive Birch
R
l
eactio
b
a
ndAsymm
a
e
tric
H
ydr
n
ogenation Cadu,a Alexander Paptchikhine,a Pher G. Andersson*a,b
a
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, 75123 Uppsala, Sweden
Fax +46(18)4713818; E-mail: pher.andersson@biorg.uu.se
School of Chemistry, University of KwaZulu-Natal, Durban, South Africa
b
PSP
Received 5 September 2011; revised 20 September 2011
No210
Abstract: Birch reaction products are asymmetrically hydrogenated with high enantio- and diastereoselectivity via iridium catalysts. This
new method of producing chiral compounds was explored for a variety of 1,3-di- and 1,2,4-tri-substituted cyclohexadienes.
Key words: asymmetric catalysis, iridium, hydrogenation, reduction, radical reaction
OH
MeO
MeO
MeO
[A-Ir(cod)]BArF
∗
Na, liq NH3
EtOH
∗
Bu
Bu
Bu
H2 (20 bar), 18 h
CH2Cl2
PPh2
N
trans/cis: 83:17
trans: 98% ee
cis: 62% ee
Ph
S
A
Scheme 1 Birch reaction of substrate 1a followed by asymmetric hydrogenation
Introduction
cyclohexadienes using Li or Na in liquid ammonia using
large excess of EtOH for all compounds reported (though
a near stoichiometric amount of t-BuOH for less encum-
bered compounds such as R1 = OMe, R2 = Me, R3 = H,
and R1 = R2 = Me, R3 = H)4 (Scheme 2). More hindered
substrates needed larger excess of Na (8–30 equiv) and
EtOH (20–40 equiv) to go to completion. For compounds
where small amounts of alcohol were used, THF was used
as a co-solvent to facilitate stirring. The metal was added
to the mixture at ammonia’s reflux temperature under
powerful stirring to limit foaming or the reaction getting
too vigorous. Afterwards, the ammonia was evaporated
and any remaining metal was quenched with ethanol
(Table 1).
The Birch reaction is a well-known method of conversion
of aromatic compounds into nonconjugated dienes.1 It is a
highly regioselective reaction, when the substitution pat-
tern is chosen accordingly. The reaction is commonly
used to synthesise natural product intermediates,2 and the
large selection of existing substituted benzene compounds
offers a great variety of easily obtained target molecules.
Iridium catalysis is a highly efficient method of asymmet-
ric hydrogenation,3 gaining in popularity over the recent
years. However, asymmetric hydrogenation of Birch
products has only been reported once so far,4 despite the
Birch reaction’s regular use prior to introduction of chiral
centres.5
Once purified by distillation or column chromatography,
four representative substrates were screened against ten
different compounds from our library of N,P-chelated iri-
dium catalysts. The best catalysts were found to be [A-
Ir(cod)]BArF and [B-Ir(cod)]BArF [BArF = tetrakis(3,5-
bis(trifluoromethyl)-phenyl)borate]. No hydrolysis of the
methoxy ethers were noticed during the hydrogenation
process, though methoxy enolate dienes tend to dispropor-
tionate back to aromaticity over time at room temperature
(though they are stable for months when stored under ar-
gon at –20 °C, in polypropylene containers).
The iridium catalysts used in this study, were originally
developed on aryl alkene esters,6 and have also been test-
ed on vinyl fluorides and other olefins within this research
group,7 but lend themselves very well to being ported over
to tri-substituted compounds such as the Birch products
studied here (Scheme 1).
Scope and Limitations
A variety of 1,3, 1,4,4 and 1,2,4 di- and trisubstituted ben-
zenes were used; some commercially available and others
had to be synthesised. They were reduced to substituted
Hydrogenation was conducted on a 1.25 mmol scale, by
loading the substrate in anhydrous dichloromethane along
with the appropriate catalyst ([A-Ir(cod)]BArF or [B-
Ir(cod)]BArF, 0.5 mol%), flushing eight times with argon
SYNTHESIS 2011, No. 23, pp 3796–3800
Advanced online publication: 20.10.2011
DOI: 10.1055/s-0031-1289569; Art ID: Z86611SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

PRACTICAL SYNTHETIC PROCEDURES
Successive Birch Reaction and Asymmetric Hydrogenation
3797
[A-Ir(cod)]BArF
or
R1
R3
R1
R3
R1
R3
R2
R2
R2
∗
[B-Ir(cod)]BArF
∗
Na, Liq NH3
EtOH or t-BuOH
H2 (20 bar), 18 h
CH2Cl2
3
1
2
R1, R2 = H, Alk, OAlk, C(OH)Me, CMe2OH
3 = H, Alk, OMe
PPh2
PPh2
N
R
N
S
Ph
Ph
N
A
B
Scheme 2 General reaction scheme
Table 1 Reduction and Hydrogenation Steps on Substituted Aromatic Compounds (Scheme 2)
Entry
1
R1
R2
R3
2b
Yield (%)a
ee (%)
Ligandd
2
3
trans
cisc
trans
98
cis
62
66
60
–
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
OMe
OMe
OMe
OMe
OMe
i-Pr
CH(OH)Bu
i-Bu
H
2a, R2 = C5H11 70
81
68
84
56
60f
76
83
82
78
>99
–
17
18
22
<1
–
A
A
A
B
A
B
H
2b
2ce
2d
2e
2f
52
82
65
69
45
98
CH(OH)Ph
OMe
H
>99
>99
97g
>99
H
i-Pr
Me
H
–
i-Pr
75
25
–
a Isolated yields.
b Same substituents as compounds 1a–f, unless specified.
c Determined by NMR spectroscopy.
d Ligand used: [A-Ir(cod)]BArF or [B-Ir(cod)]BArF.
e The alcohol is reduced to CH2 and the Ph group is reduced to cyclohexa-1,4-diene.
f Isolated yield of the corresponding ketone.
g Poly(4-vinylpyridine) is used as an additive, the methoxy substituted double bond remains intact.
gas (6 bar), before applying H2 (10 bar) for 18–20 hours, ( 97%), whereas the cis-isomers gave middling ee values
depending on substituents. It should be noted that the cat- (60–66%), as per Table 1. This is especially marked for
alyst can be deactivated towards the methoxy-substituted substrate 1d, which displayed excellent stereo- (>99%)
p-bond using poly(4-vinylpyridine) as an additive.4
and regioselectivity (99:1). This was also true of the sub-
stituted naphthalene, which could in turn be oxidised by
RuCl3/NaIO4, (Scheme 4). We can presume that this trend
As depicted in Scheme 3, should the intermediate a be
produced they will be converted subsequently to cis-iso-
mer due to catalytic coordination preference, thus artifi-
cially enhancing the ee.
MeO
OMe
MeO
OMe
i
The hydrogenation gave, in most cases, a high preference
towards trans- over cis-isomers (>75:25). In turn, the
trans-isomers were hydrogenated with very high ee
2g
1
MeO
OMe
ii
trans/cis: >99:1
ee (trans): 99%
∗
∗
R1
R1
slow
R1
R2
R2
fast
R2
3g
OMe
α
β
O
iii
2
R1
R1
R1
R1
R2
R2
R2
R2
MeO
O
4
trans-3
minor
cis
cis
trans-3
major
Scheme 4 Conversion of the substituted naphthalene compound.
Reagents and conditions: (i) Li, NH3, EtOH, 93%; (ii) [A-
Ir(cod)]BArF, H2 (20 bar), CH2Cl2, 18 h, 72%; (iii) RuCl3·n-H2O,
NaIO4, 54% (absolute configuration unknown).
Scheme 3 Source of the ee enhancement. Large arrows indicate pre-
ferred catalyst coordination. Red indicates coordination from below
and blue from above.
Synthesis 2011, No. 23, 3796–3800 © Thieme Stuttgart · New York

3798
A. Cadu et al.
PRACTICAL SYNTHETIC PROCEDURES
general workup and chromatography, 0.77 g (52% with regard to re-
covered starting material) of 2b was obtained as a colourless oil.
1H NMR (300 MHz, CDCl3): d = 0.86 (d, J = 6.5 Hz, 6 H, 2 × CH3),
1.77 (m, 1 H, CH), 1.86 (m, 1 H, CH2) 1.89 (m, 1 H, CH2), 2.56–
2.64 (m, 2 H, C=CCH2C=C), 2.75–2.85 (m, 2 H, C=CCH2C=C),
3.56 (s, 3 H, OCH3), 4.63 (m, 1 H, CH=CO), 5.39 (m, 1 H, CH=C).
13C NMR (125 MHz, CDCl3): d = 22.6, 25.8, 26.9, 31.6, 46.9, 54.0,
90.5, 119.8, 133.5, 153.2.
MS (EI): m/z (%) = 166 (M+, 53), 151 (25), 124 (17), 109 (100), 91
(23), 77 (21).
is not limited to monoaromatic, but in fact polyaromatic
compounds could be subjected to similar treatments with
similar results.
All reactions were conducted under dry N2 atmosphere using mag-
netic stirring. CH2Cl2 was freshly distilled from CaH2 under N2.
THF was distilled from Na with benzophenone under N2 prior to
use. All reagents were used as supplied commercially without fur-
ther purification. Li (99.9%) was purchased from Sigma-Aldrich as
a wire with 0.01% Na.
Chromatographic separations were performed on Kieselgel 60H sil-
ica gel (particle size: 0.063–0.100mm). TLC was performed on alu-
minum plates coated with Kieselgel 60 (0.20mm, UV 254) and
visualised under ultraviolet light (l = 254 nm), I2 vapours, by stain-
ing with basic aqueous KMnO4 solution, or ethanolic phosphomo-
lybdic acid and heating.
1H NMR spectra were recorded at 500, 400, or 300 MHz in CDCl3
at 25 °C and referenced internally with the residual CHCl3 peak
(7.26 ppm). Prior to use, CDCl3 was neutralised by passage through
a short plug of basic alumina. Chemical shifts are reported in ppm
(d scale). Mass spectra were measured at 70 eV (EI). IR spectra
were recorded on an FT-IR apparatus. Enantiomeric excesses were
determined using chiral GC with an MS detector. Racemic com-
pounds were used for comparison.
1-(Cyclohexa-1,4-dienylmethyl)-5-methoxycyclohexa-1,4-diene
(2c)
According to the general procedure, the following amounts were
used: 1c (5.00 g, 23.3 mmol, 1 equiv) and EtOH (41 mL, 702 mmol,
30 equiv). Ammonia was condensed to a total volume of 250 mL.
Na (4.29 g, 187 mmol, 8 equiv) was added over 20 min. After gen-
eral workup and chromatography, 3.89 g (82%) of 2c was obtained
as a colourless oil.
1H NMR (400 MHz, CDCl3): d = 2.49–2.61 (m, 4 H, 2 × CH2),
2.62–2.73 (m, 4 H, 2 × CH2), 2.78–2.85 (m, 2 H, CH2), 3.55 (s, 3 H,
OCH3), 4.62 (m, 1 H, CH=CO), 5.44–5.50 (m, 2 H, CH2), 5.66–5.70
(m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 27.0 (2 C), 28.6, 31.2, 45.8, 54.0,
90.4, 120.5, 120.7, 124.2, 124.6, 132.2, 132.6, 153.3.
MS (EI): m/z (%) = 202 (M+, 5), 130 (10), 109 (100), 94 (25), 77
Birch Reaction; General Procedure
The reactions were conducted in a 3-necked round-bottomed flask
with a dry ice condenser, an NH3 (g) inlet, and a stopper for Na ad-
dition. Ammonia was condensed from a commercial NH3 tube into
a mixture of aromatic substrate, alcohol, and a cosolvent while cool-
ing flask in a dry ice bath. Addition of the metal was done at reflux
temperature of NH3 with such a speed so as to prevent vigorous re-
action/foaming. On discolouration of reaction, dry ice was removed
from condenser and ammonia was evaporated. If unreacted Na was
present, it was quenched with 95% EtOH. Reaction was carefully
diluted with H2O (50 mL), extracted with Et2O (3 × 50 mL), the
combined Et2O extracts were washed with brine (30 mL), and dried
(Na2SO4). Solvent was removed and product was purified either by
distillation under reduced pressure or by chromatography on deac-
tivated (Et3N) silica gel with pentane as eluent.
(21).
4-Isopropyl-2-methoxy-1-methylcyclohexa-1,4-diene (2e)
According to the general procedure, the following amounts were
used: 1e (4.31 g, 26.4 mmol, 1 equiv) and EtOH (48 mL, 822 mmol,
31 equiv). Ammonia was condensed to a total volume of 250 mL.
Na (7.24 g, 315 mmol, 12 equiv) was added over 40 min. After gen-
eral workup and distillation at 9 Torr, 3.01 g (69%) of 2e was ob-
tained as a colourless oil; 74–76 °C.
1H NMR (400 MHz, CDCl3): d = 1.04 (d, J = 9.2 Hz, 6 H, 2 × CH3),
1.64 (s, 3 H, CH3), 2.82 (m, 1 H, CH), 2.70 (m, 2 × CH2), 3.55 (s,
OCH3), 5.38 (m, 1 H, CH=C).
MS (EI): m/z (%) = 167 (MH+, 25), 166 (M+, 73), 151 (35), 123
(100), 108 (34), 91 (39).
1-Methoxy-5-pentylcyclohexa-1,4-diene (2a)
According to the general procedure, the following amounts were
used: 1a (5.00 g, 25.7 mmol, 1 equiv) and EtOH (45 mL, 771 mmol,
30 equiv). Ammonia was condensed to a total volume of 250 mL.
Na (3.60 g, 157 mmol, 6 equiv) was added over 20 min. After gen-
eral workup and chromatography, 3.68 g (79%) of 2a was obtained
as a colourless oil.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.2 Hz, 3 H, CH3),
1.20–1.36 (m, 4 H, 2 × CH2), 1.37–147 (m, 2 H, CH2), 1.96–2.02
(m, 2 H, CH2), 2.57–2.66 (m, 2 H, C=CCH2C=C), 2.75–2.83 (m, 2
H, C=CCH2C=C), 3.56 (s, 3 H, OCH3), 4.63 (m, 1 H, CH=CO), 5.41
(m, 1 H, CH=C).
13C NMR (100 MHz, CDCl3): d = 14.2, 22.7, 26.9, 27.1, 31.6, 31.7,
37.0, 54.0, 90.5, 118.3, 134.7, 153.2.
MS (EI): m/z (%) = 180 (M+, 70), 137 (100), 124 (35), 109 (83), 91
(22).
1,5-Diisopropylcyclohexa-1,4-diene (2f)
According to the general procedure, the following amounts were
used: 1f (4.66 g, 28.7 mmol, 1 equiv) and EtOH (50 mL, 856 mmol,
30 equiv). Ammonia was condensed to a total volume of 250 mL.
Na (6.60 g, 287 mmol, 10 equiv) was added over 25 min. After gen-
eral workup and chromatography, 2.11 g (45%) of 2f was obtained
as a colourless oil.
1H NMR (500 MHz, CDCl3): d = 1.04 (d, J = 6.8 Hz, 12 H, 4 ×
CH3), 2.21 (sept, J = 6.8 Hz, 2 H, 2 × CH), 2.53–2.58 (m, 2 H, CH2),
2.67–2.73 (m, 2 H, CH2), 5.43 (m, 2 H, 2 × CH=C).
13C NMR (125 MHz, CDCl3): d = 21.4, 27.8, 28.0, 34.9, 116.0,
148.9.
MS (EI): m/z (%) = 164 (M+, 15), 163 (18), 147 (15), 121 (64), 120
(100), 105 (70), 91 (43), 79 (93), 77 (52).
Compounds 2d8 and the naphthalene derivative 2g9 were prepared
using literature procedures.
1-Isobutyl-5-methoxycyclohexa-1,4-diene (2b)
According to the general procedure, the following amounts were
used: 1b (2.00 g, 12.2 mmol, 1 equiv) and EtOH (3.6 mL, 61.6
mmol, 5 equiv). Ammonia was condensed to a total volume of 80
mL. Na (0.84 g, 36.5 mmol, 5 equiv) was added over 10 min. After
Hydrogenation; General Procedure
Substrate 2 (1.25 mmol) was loaded into a vial with a magnetic stir-
rer and a lid with septa. A stock solution of the catalyst (5 mL, 6.25
mmol, 0.5 mol%) in anhyd CH2Cl2 was added under argon through
the septa and the vial was placed into high pressure hydrogenation
Synthesis 2011, No. 23, 3796–3800 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Successive Birch Reaction and Asymmetric Hydrogenation
1,3-Dimethoxycyclohexane (3d)
3799
equipment. Argon was applied 8 times at 6 bar, then H2 atmosphere
was applied, and left for the specified time (18–20 h). H2 was re-
leased, the solvent evaporated, and the residue was analysed by
With catalyst [B-Ir(cod)]BArF, using the general procedure; yield:
101 mg (56%); oil (volatile); trans/cis >99:1 (by 1H NMR and GC–
MS).
1
NMR and GC–MS with a chiral column. H NMR spectrum was
taken in CDCl3 (passed through basic alumina before use). For GC
MS analysis, a small part of reaction mixture was applied on a short
plug of silica gel (deactivated by Et3N) and eluted with Et2O–pen-
tane (1:1). Flash chromatography (pentane–Et2O, 100:0 to 90:10)
was used for purification of the compounds.
1H NMR (400 MHz, CDCl3): d (trans-3d) = 1.38–1.55 (m, 4 H),
1.56–1.66 (m, 2 H), 1.68–1.73 (m, 2 H), 3.27 (s, 6 H, 2 × OCH3),
3.42–3.50 (m, 2 H, 2 × CHO).
13C NMR (100 MHz, CDCl3): d (trans-3d) = 19.0, 30.2, 35.9, 55.7,
75.8.
The cis-isomer was not seen by 13C NMR spectroscopy.
1-Methoxy-3-pentylcyclohexane (3a)
With catalyst [A-Ir(cod)]BArF, using the general procedure; yield:
187 mg (81%); oil; trans/cis = 83:17 (by NMR); trans/cis = 91:9
(by GC–MS).
1H NMR (400 MHz, CDCl3): d (trans-3a) = 0.83 (t, J = 7.0 Hz),
3.24 (s, OCH3), 3.42 (m, CHO).
13C NMR (100 MHz, CDCl3): d (trans-3a) = 14.1, 20.4, 22.8, 26.6,
29.8, 31.7, 32.3, 32.5, 36.7, 36.9, 55.6, 75.7.
1H NMR (400 MHz, CDCl3): d (cis-3a) = 0.88 (t, J = 7.1 Hz), 3.09
(tt, J = 11.0, 4.2 Hz, CHO), 3.35 (s, OCH3).
MS (EI): m/z (%) = 183 ([M – H]+, 3), 152 (36), 141 (35), 123 (17),
113 (49), 109 (38), 96 (45), 95 (39), 81 (82), 71 (100), 67 (47), 55
(23).
MS (EI): m/z (%) = 143 ([M – H]+, 1), 113 (7), 112 (100), 111 (71),
101 (18).
GC–MS (column: Hydrodex b-PM, temp: 60 °C isothermal, flow:
1.0 mL/min): trans: 39.3 (minor) and 40.2 min (major), >99% ee;
cis: 26.8 min.
4-Isopropyl-2-methoxy-1-methylcyclohex-1-ene (3e)
With catalyst [A-Ir(cod)]BArF, together with poly(4-vinylpyridine)
(30 mg) using the general procedure; the crude product (460 mg)
was used without purification.
MS (EI): m/z (%) = 168 (MH+, 52), 153 (27), 139 (15), 125 (35), 111
(28), 93 (30), 86 (100), 71 (33).
GC–MS (column: Chiraldex b-DM, temp: 30 min at 60 °C followed
by an increase of 3 °C/min, pressure: 14.5 psi): 44.2 (minor) and
44.7 min (major); 97% ee.
GC–MS (column: Hydrodex b-6 TBDM, temp: 100 °C isothermal,
flow: 1.0 mL/min): trans-3a: 23.7 (major) and 26.6 min (minor),
98% ee; cis-3a: 30.1 (minor) and 31.0 min (major), 62% ee.
5-Isopropyl-2-methylcyclohexanone (3e¢)
1-Isobutyl-3-methoxycyclohexane (3b)
Hydrolysis of Enolate 2e: After completion of asymmetric hydroge-
nation of 2e (416 mg, 2.5 mmol), the solvent was removed and the
crude enolate 3e was dissolved in MeOH–H2O (5 mL:1 mL).
(COOH)2·H2O (16 mg, 5 mol%) was added and the reaction mixture
was stirred at r.t. for 2 h until completion of reaction by TLC.
MeOH was evaporated, the mixture diluted with H2O (10 mL), and
extracted with Et2O (2 × 30 mL). The organic phase was dried
(Na2SO4) and evaporated. Chromatography on silica gel (pentane–
Et2O, 100:0 to 90:10) afforded 232 mg of a clear oil (60% over two
steps, asymmetric hydrogenation and hydrolysis) with 48:52 cis/
trans ratio as determined by 1H NMR spectroscopy.
1H NMR (500 MHz, CDCl3): d = 0.86–0.90 (m, 6 H, 2 × CH3), 0.99
(d, J = 6.4 Hz, CH3 major trans-isomer), 1.07 (d, J = 7.1 Hz, CH3
minor cis-isomer), 1.28 (qd, J = 12.9, 3.5 Hz, 1 H), 1.42 (m, 1 H),
1.49–1.72 (m, 2 H), 1.83 (m, 1 H), 2.00–2.11 (m, 2 H), 2.26–2.45
(m, 2 H).
With catalyst [B-Ir(cod)]BArF using the general procedure; yield:
144 mg (68%); oil; trans/cis = 82:18 (by NMR); trans/cis = 96:4
(by GC–MS).
1H NMR (500 MHz, CDCl3): d (trans-3b) = 3.28 (s, OCH3), 3.45
(m, CHO).
13C NMR (125 MHz, CDCl3): d (trans-3b) = 20.5, 22.9, 24.9, 29.2,
30.0, 32.7, 36.8, 46.5, 55.8, 75.8.
1H NMR (500 MHz, CDCl3): d (cis-3b) = 3.08 (tt, J = 11.0, 4.1 Hz,
CHO), 3.33 (s, OCH3).
13C NMR (125 MHz, CDCl3): d (cis-3b)= 23.0, 23.2, 24.2, 32.2,
32.8, 34.1, 39.3, 46.8, 55.6, 79.7.
MS (EI): m/z (%) = 169 ([M – H]+, 5), 138 (100), 127 (35), 123 (71),
113 (47), 109 (42).
GC–MS (column: Hydrodex b-6 TBDM, temp: 90 °C isothermal,
flow: 1.0 mL/min): trans: 13.5 (minor) and 16.6 min (major), 98%
ee; cis: 17.7 (minor) and 19.0 min (major), 66% ee.
MS (EI): m/z (%) = 154 (M+, 49), 125 (6), 111 (100), 95 (25), 83
(24), 69 (20), 55 (85).
GC–MS (column: Chiraldex b-DM, temp: 30 min at 60 °C followed
by an increase of 3 °C/min, pressure: 14.5 psi): cis: 44.1 min, trans:
45.9 min, absolute configuration is not defined.
1-(Cyclohexylmethyl)-3-methoxycyclohexane (3c)
With catalyst [A-Ir(cod)]BArF, using the general procedure; yield:
222 mg (84%); 3c; oil; trans/cis = 78:22 (by NMR); trans/
cis = 97:3 (by GC–MS).
1H NMR (400 MHz, CDCl3): d (trans-3c) = 3.28 (s, OCH3), 3.45
(m, CHO).
13C NMR (100 MHz, CDCl3): d (trans-3c) = 20.4, 26.6, 26.6, 26.9,
28.5, 29.9, 32.8, 33.7, 34.0, 34.5, 37.0, 45.0, 55.7, 75.8.
1H NMR (400 MHz, CDCl3): d (cis-3c) = 3.07 (tt, J = 10.9, 4.1 Hz,
CHO), 3.33 (s, OCH3).
Equilibration: The above ketone (117 mg, 0.759 mmol, 1 equiv)
was dissolved in anhyd EtOH (2 mL) and NaOMe (21 mg, 0.389
mmol, 0.5 equiv) was added. After stirring for 2 h, the mixture was
diluted with Et2O (30 mL) and washed with sat. aq NH4Cl (10 mL).
The aqueous phase was extracted with Et2O (2 × 30 mL) and the
combined organic phases were dried (MgSO4). Removal of solvent
afforded 93 mg (79%) of pure product with 11:89 cis/trans ratio as
determined by 1H NMR spectroscopy.
MS (EI): m/z (%) = 209 ([M – H ]+, 2), 178 (70), 167 (3), 149 (25),
135 (100), 121 (18), 113 (25), 107 (17).
1,3-Diisopropylcyclohexane (3f)
With catalyst [B-Ir(cod)]BArF, using the general procedure; yield:
GC–MS (column: Hydrodex b-6 TBDM, temp: 110 °C isothermal,
flow: 1.0 mL/min): trans: 66.3 (minor) and 73.7 min (major), 99%
ee; cis: 85.9 (minor) and 89.7 min (major), 66% ee.
157 mg (76%); oil; trans/cis = 75:25 (by NMR).
13C NMR (100 MHz; CDCl3): d (trans-3f) = 20.5, 20.8, 21.6, 29.6,
29.7, 32.1, 39.6.
Synthesis 2011, No. 23, 3796–3800 © Thieme Stuttgart · New York

3800
A. Cadu et al.
PRACTICAL SYNTHETIC PROCEDURES
References
13C NMR (100 MHz; CDCl3): d (cis-3f) =19.8, 20.1, 26.9, 29.9,
33.4, 33.6, 44.4.
MS (EI): m/z (%) = 167 ([M – H]+, 1), 125 (26), 124 (66), 109 (14),
95 (7), 83 (54), 69 (100), 67 (31), 57 (27), 55 (37).
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GC–MS (column: Hydrodex b-6 TBDM, temp: 50 °C isothermal,
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>99%; cis: 95.9 min.
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2,7-Dimethoxy-1,2,3,4,5,6,7,8-octahydronaphthalene (trans-3g)
Catalyst used: [A-Ir(cod)]BArF. Flash chromatography (pentane–
Et2O, 90:10 to 80:20) afforded 177 mg (72%) of trans-3g as an oil;
trans/cis >99:1 (by 1H NMR and GC–MS).
1H NMR (400 MHz, CDCl3): d (trans-3g) = 1.45–1.61 (m, 2 H),
1.77–2.03 (m, 8 H), 2.15–2.26 (m, 2 H), 3.35 (s, 6 H, 2 × OCH3),
3.39–3.47 (m, 2 H, 2 × CHO).
13C NMR (75 MHz, CDCl3): d (trans-3g) = 27.7, 28.3, 36.3, 55.9,
76.2, 122.9, 127.7.
The cis-isomer was not seen by 13C NMR spectroscopy.
MS (EI): m/z (%) = 196 (MH+, 2), 164 (20), 132 (100), 117 (37), 104
(55).
GC–MS (column: Hydrodex b-6 TBDM, temperature: 120 °C iso-
thermal, flow: 1.0 mL/min): trans: 49.0 (minor) and 51.4 min (ma-
jor), >99.9% ee; cis: 47.4 min.
3,9-Dimethoxycyclodecane-1,6-dione (4)
Alkene trans-3g (162 mg, 0.825 mmol, 1 equiv) was added to THF–
H2O (5 mL, 2:1), followed by NaIO4 (747 mg, 3.49 mmol, 4.2
equiv) and RuCl3·nH2O (1 mg). The reaction was stirred vigorously
for 23 h, filtered, and inorganic salts were washed with THF (10
mL). After removal of THF, brine (20 mL) was added, followed by
extraction with CH2Cl2 (3 × 30 mL). The combined organic phases
were dried (Na2SO4), evaporated, and the residue was purified on
silica gel (pentane–Et2O, 20:80 to 0:100) to afford 102 mg (54%) of
colourless crystals; mp 116.6–119.7 °C.
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IR (neat): 2931, 2823, 1696 (C=O), 1418, 1377, 1085, 975, 939, 634
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.78–1.86 (m, 2 H), 2.23–2.32 (m,
4 H), 2.48–2.61 (m, 4 H), 2.63–2.69 (m, 2 H), 3.34 (s, 6 H, 2 × CH3),
3.82 (m, 2 H, 2 × CH).
13C NMR (100 MHz, CDCl3): d = 28.2 (2 × CH2CH2CO), 37.3 (2 ×
CH2CO), 47.3 (2 × CH2CO), 56.6 (CHO), 75.8 (2 × CH3), 208.6
(C=O), 212.7 (C=O).
MS (EI): m/z (%) = 229 (MH+, 100), 211 (42), 197 (56), 179 (67),
164 (68), 136 (49), 123 (47), 99 (62), 95 (95), 85 (59), 81 (97), 67
(64).
Acknowledgment
Our thanks go to the Swedish research council (VR), the Knut and
Alice Wallenberg Foundation, AstraZeneca, VR/SIDA, NordForsk
and Nordic Energy Research, Swedish energy agency, and SYN-
FLOW (FP7) for supporting this work.
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Synthesis 2011, No. 23, 3796–3800 © Thieme Stuttgart · New York