Diastereoselective alkylation reactions of 1-methylcyclohexa-2,5-diene-1- carboxylic acid

Article abstract of DOI:10.1039/c2ob25211b

The deprotonation and alkylation of 1-methylcyclohexa-2,5-diene-1- carboxylic acid has been investigated under a range of conditions. In all cases, the formation of compounds 14 was found to be completely stereoselective, although compound 14c was formed as an impurity when alkyl iodides were used as electrophiles, and doubly-alkylated compounds 17 were formed in some cases when alkyl bromides were used.

Full text of DOI:10.1039/c2ob25211b

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PAPER
Diastereoselective alkylation reactions of 1-methylcyclohexa-2,5-diene-1-
carboxylic acid†
Nicholas J. Bennett,a Mark C. Elliott,*b Natalie L. Hewitt,b Benson M. Kariuki,b Clare A. Morton,b
Steven A. Rawc and Simone Tomasic
Received 27th January 2012, Accepted 22nd March 2012
DOI: 10.1039/c2ob25211b
The deprotonation and alkylation of 1-methylcyclohexa-2,5-diene-1-carboxylic acid has been investigated
under a range of conditions. In all cases, the formation of compounds 14 was found to be completely
stereoselective, although compound 14c was formed as an impurity when alkyl iodides were used as
electrophiles, and doubly-alkylated compounds 17 were formed in some cases when alkyl bromides were
used.
Introduction
Cyclohexa-1,4-dienes are versatile intermediates in synthetic
organic chemistry, most commonly prepared by various permu-
tations of the Birch reduction.1 In particular, with appropriate
substitution patterns the two double bonds are either enantiotopic
(achiral cyclohexadienes) or diastereotopic (chiral cyclohexa-
dienes) and therefore their elaboration can lead to the formation
of one or more new stereogenic centres2 using either inter-3 or
intramolecular4 transformations.
The desymmetrisation reactions of cyclohexa-1,4-dienes have
significant potential in target synthesis, particularly where a qua-
ternary stereogenic centre is introduced by way of a Birch
reduction/alkylation approach. For example, we have recently
demonstrated a synthetic approach to the cores of the complex
Fig. 1 Complex targets to which cyclohexadiene desymmetrisation
lycopodium alkaloids lycoposerramine A (1)5 and lycoposerra-
methodology has been applied.
mine S (2),6 and model studies towards the core of cladiellin
diterpenes such as 7-deacetoxyalcyonin acetate (3).7
There is still one major challenge to be addressed in the devel-
opment of this methodology. On each of the structures in Fig. 1,
a substituent is highlighted in red. This substituent is attached to
Birch reduction/alkylation proceeds with little or no stereocon-
trol6,8 (Scheme 1, route (a)) to form 5 (the only exception to this
is if both R1 and R2 are very bulky9). However, late introduction
the carbon that was the 4-position in the benzoic acid precursor.
of this substituent can require multiple steps and functional
If this substituent is present at the start (R1 in structure 4), the
group interconversions (Scheme 1, route (b)).
Early introduction of R1 is preferable, since the desymmetrisa-
tion process to form 6 can proceed with the selective formation
aChemistry Department, AstraZeneca R&D Charnwood, Bakewell Road,
of four stereogenic centres in a single step, controlled by a
Loughborough, LE11 5RH, UK
stereogenic substituent R3. In fact, by using a desymmetrisation
process which gives reaction at both cyclohexadiene double-
bonds, it is possible to form six contiguous stereogenic centres
with complete stereoselectivity in a single step, demonstrating
the power of this approach.10
bSchool of Chemistry, Cardiff University, Park Place, Cardiff, CF10
3AT, UK. E-mail: elliottmc@cardiff.ac.uk; Fax: +44(0)29 20874030;
Tel: +44(0)29 20874686
cAstraZeneca, Medicines Evaluation Chemistry, Pharmaceutical
Development, Silk Road Business Park, Charter Way, Macclesfield,
Cheshire, SK10 2NA, UK
†Electronic supplementary information (ESI) available: Experimental
The ideal method therefore features the stereoselective for-
mation of compounds such as 5. An alternative method for the
formation of such compounds would be the deprotonation and
alkylation of a compound of general structure 8. In 1976,
1
procedures; copies of H and 13C NMR spectra for all new compounds;
details of computational methods. CCDC 854352. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2ob25211b
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Scheme 1 Difficulties in introducing substituents at the 4-position of
1-alkylcyclohexa-2,5-diene-1-carboxylic acids, either early or late in a
synthetic sequence.
Scheme 2 Reported alkylation of 1-methylcyclohexa-2,5-diene-1-car-
boxylic acid.9
Scheme 3 Synthesis and stereochemical determination of compound
13a.
Zhurkovich and Ioffe reported11 that the deprotonation of com-
pound 10 with sodium amide followed by alkylation with a
range of alkyl halides gave good yields but only moderate and
variable stereoselectivity in the formation of the 1,4-dienes 11
(Scheme 2). The stereochemical outcome of these reactions was
not proven.12 Alkylation at the 2-position was also observed
resulting in formation of the conjugated diene 12. A number of
groups have reported the direct deprotonation/alkylation of
cyclohexa-1,4-diene itself,13 while various other substituted
cyclohexa-1,4-dienes have been directly alkylated14 although
these reactions do not have the opportunity for stereocontrol.
The only asymmetric variant that we are aware of is the silver
BINAP-mediated addition of cyclohexadienylstannanes to
aldehydes.15
Scheme 4 Methylation of 1-methylcyclohexa-2,5-diene-1-carboxylic
acid.
Results and discussion
In an effort to establish the levels of stereoselectivity that are
achievable, and determine the stereochemical outcome, we there-
fore reinvestigated the alkylation of 1-methylcyclohexa-2,5-
diene-1-carboxylic acid 10. Deprotonation of this compound
with n-BuLi/TMEDA followed by alkylation with 2-bromopro-
pane gave a high yield of a single diastereoisomer of product
13a (Scheme 3), which was characterised after conversion into
the corresponding methyl ester 14a (55% yield over 2 steps).
The stereochemistry of the compound was confirmed by
reduction of the ester to the alcohol and preparation of the 2,4-
dinitrobenzoate ester 16 (X-ray structure as shown in Scheme 3).
This stereochemical outcome is the same as suggested by
Zhurkovich and Ioffe, although the present conditions give much
higher levels of both stereocontrol and regiocontrol.
When iodomethane was used as electrophile, the reaction also
gave a single diastereoisomer of the desired product 14b. Unfor-
tunately this was contaminated with approximately equal
amounts of the corresponding butylated product 14c (Scheme 4).
This is presumably formed by exchange of excess n-butyllithium
with the iodomethane, even though only a slight excess (2.2
equivalents) of butyllithium was used, and could be attributed to
possible presence of the corresponding carboxylate salt in car-
boxylic acid 10. Any amount of this salt would mean that
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effectively a larger excess of butyllithium was being used.
However, attempts to reduce the number of equivalents of butyl-
lithium led to incomplete alkylation, while initial deprotonation
with NaH followed by the use of a single equivalent of n-BuLi
led to the formation of complex mixtures of products. Despite
extensive experimentation, we have been unable to establish
reaction conditions that lead to complete alkylation to give a
single product in this case. Other methyl electrophiles (methyl
triflate, dimethyl sulfate) gave very poor results (low yields or
complex mixtures of products). LDA and LIDAKOR (LDA and
potassium t-butoxide) were less effective as bases, giving 53%
and 37% yields respectively after esterification. In each case only
one diastereoisomer was formed, along with a small amount of
unreacted starting material (as the methyl ester). Careful examin-
ation of NMR spectra strongly suggest that the same stereo-
isomer is formed as when n-butyllithium is used as base. Using
the same alkyl residue in the electrophile and alkyllithium would
seem to be a logical approach for avoiding the formation of mix-
tures of products. Unfortunately methyllithium/TMEDA is in-
effective as a base, with starting material being recovered almost
quantitatively.
The scope of the reaction was next probed with a range of
electrophiles (Table 1). Similar complications were observed
with other primary alkyl iodides. With iodoethane (entry 6) an
approximately 1 : 1 mixture of products was obtained. With iodo-
heptane, significantly less of the butyl product 14c was obtained,
and the pure heptyl product 14e was obtained in 54% yield after
esterification (entry 8). Alkyl bromides do not give the same
problem, with none of the butyl product 14c being observed. For
example, with bromoethane, the desired product 14e was
obtained as a single stereoisomer in 51% yield after esterification
(entry 10). With alkyl bromides, it is also possible to obtain
doubly-alkylated products 17, and these were formed in very
small quantities in most reactions (entries 7, 9) although they
were readily removed during purification. These compounds
become the major products when an excess of the base/electro-
phile is used (entry 12).
The reaction is, as shown by the examples in Table 1, quite
general. In all cases, only a single stereoisomer can be observed/
isolated, and of the reactions we have tried, the only electrophile
that has failed is ethyl 2-bromoacetate, this giving a complex
mixture of products.
When stabilised organolithium reagents react with electro-
philes, the stereochemical outcome is strongly dependant on the
nature of the electrophile. For example, alkyl halides tend to give
inversion, while carbonyl electrophiles tend to give retention.
Therefore, the observed outcome is consistent with a directed
lithiation followed by alkylation with inversion.16 DFT calcu-
lations with Gaussian 0917 at the wB97XD/6-311++G(2df,2p)/
B3LYP/6-31+G* level comparing the relative stabilities of meta-
lated 1-methylcyclohexadienyl-1-carboxylates indicated that,
neither the ‘annelated’ intermediate 18 nor the ‘bridged’ isomer
19 are local minima. Both were minimised to an identical struc-
ture, corresponding to η5 coordination of the lithium to the
cyclohexadienyl ligand. Saturation of the Li coordination
spheres by THF or TMEDA molecules is favoured. Including
thermal contributions and standard state corrections, the free
energy of complexation of four THF molecules at −78 °C is
−46.9 kcal mol−1. Complexation of two molecules of TMEDA
(structure 20, Fig. 2) is even more favourable at −51.5 kcal
mol−1, therefore this should be considered to be the dominant
complex of the lithiated cyclohexadiene. The presence of
strongly interacting ligands that block the upper face provides a
clear explanation for the observed stereoselectivity.
Table 1 Summary of results
Entry
Basea
Electrophile
Yields (products)
1
2
3
4
5
6
7
8
n-BuLi/TMEDA
n-BuLi/TMEDA
LDA
2-Bromopropane
Iodomethane
Iodomethane
Iodomethane
1-Bromobutane
Iodoethane
Bromoethane
1-Iodoheptane
1-Bromooctane
Benzyl bromide
Allyl bromide
Bromoethane
55% (14a)
58% (1 : 1 14b : 14c)
53% (14b)b
LIDAKOR
37% (14b)b
n-BuLi/TMEDA
n-BuLi/TMEDA
n-BuLi/TMEDA
n-BuLi/TMEDA
n-BuLi/TMEDA
n-BuLi/TMEDA
n-BuLi/TMEDA
n-BuLi/TMEDAe
64% (14c) + 4% (17c)
43% (1 : 1 14d : 14c)
51% (14d)c
53% (14e)
9
43% (14f)d
10
11
12
77% (14g)
54% (14h)
48% (17d)
a 2.2 equivalents of n-BuLi and TMEDA were used unless otherwise stated. b The products from these reactions were contaminated by approximately
20% of the methyl ester of compound 10. c Small but variable amounts of the double alkylation product 17d were observed in NMR spectra of the
crude reaction mixtures. These were readily removed during purification. d A small amount of the double-alkylation product 17f was observed, but this
was not obtained pure. e n-BuLi (5.0 equiv.), TMEDA (2.5 equiv.), bromoethane (3.0 equiv.).
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was extracted into CH2Cl2 (3 × 20 mL), which was then dried
over MgSO4, and concentrated in vacuo. The crude products
were purified as described below.
(1r,4r)-Methyl 4-isopropyl-1-methylcyclohexa-2,5-
dienecarboxylate (14a)
Prepared according to the general procedure, using 14.5 mmol of
1-methylcyclohexa-2,5-diene-1-carboxylic acid (10), and using
2-bromopropane (1.5 mL, 15.9 mmol, 1.1 equiv.) as electrophile.
Purification by flash column chromatography (9 : 1 hexane–
diethyl ether) gave the title compound (1.55 g, 55%) as a colour-
less oil (Found: MH+, 195.1377. C12H19O2 requires M,
195.1385); νmax. (neat) 2961, 2875, 1734, 1250 and 1114 cm−1
;
δH (400 MHz; CDCl3) 5.83 (2H, dd, J 10.4, 2.0, 2 × alkene
CH), 5.70 (2H, dd, J 10.4, 3.1, alkene CH), 3.69 (3H, s, OCH3),
2.67 (1H, app. dtt, J 4.0, 3.1, 2.0, CHvCH–CH), 1.77 (1H,
septet of doublets, J 6.9, 4.0, CH–CH(CH3)2), 1.32 (3H, s, CH3)
and 0.89 (6H, d J 6.9, 2 × CH3); δC (500 MHz; CDCl3) 175.8
(CvO), 129.4 (CH), 127.7 (CH), 52.3 (CH3), 44.7 (C), 41.6
(CH), 32.0 (CH), 27.6 (CH3) and 19.3 (CH3); m/z (APCI) 195
(MH+, 100) and 115 (34).
Fig. 2 Structure of the double-lithiated dianion (TMEDA complex)
derived from compound 10.
(1r,4r)-Methyl 1,4-dimethylcyclohexa-2,5-dienecarboxylate (14b)
Prepared according to the general procedure, using 3.6 mmol of
1-methylcyclohexa-2,5-diene-1-carboxylic acid (10), and using
iodomethane (0.46 mL, 7.7 mmol, 2.1 equiv.) as electrophile.
Purification by flash column chromatography (9 : 1 hexane–
diethyl ether) gave the title compound (0.39 g, 58%) as a pale
yellow oil, approximately 1 : 1 ratio of 14b : 14c with spectro-
scopic data in line with those from the individual compounds as
given below.
Conclusions
In conclusion, deprotonation of 1-methylcyclohexa-2,5-diene-1-
carboxylic acid 10 with n-BuLi in the presence of TMEDA, fol-
lowed by alkylation, offers a direct and highly diastereoselective
route to the corresponding 4-substituted products in which the
alkyl group introduced is trans to the carboxylic acid. This is
complementary to the results of van Bekkum in which a 4-sub-
stituted benzoic acid is reductively alkylated. In that case, where
any selectivity is observed, the alkyl group and the carboxylic
acid are preferentially cis.
(1r,4r)-Methyl 1,4-dimethylcyclohexa-2,5-dienecarboxylate (14b)
using LDA as base
A solution of n-butyllithium (2.0 M in cyclohexane, 2.80 mL,
5.60 mmol) was added to a solution of diisopropylamine
(0.81 mL, 5.60 mmol) in THF (10 mL) at −78 °C. After stirring
for 30 minutes, 1-methylcyclohexa-2,5-diene-1-carboxylic acid
(10) (0.25 g, 1.81 mmol) in THF (2 mL) was added and the
resulting solution stirred for a further 30 minutes before addition
of iodomethane (0.56 mL, 9.05 mmol). The solution was then
stirred for 10 minutes at −78 °C, allowed to warm to room temp-
erature and stirred for a further 1 h. The reaction was quenched
with 2 M hydrochloric acid (5 mL), and the product extracted
into CH2Cl2 (3 × 20 mL). The combined organic extracts were
dried over Na2SO4, concentrated in vacuo and the residue re-
dissolved in methanol (10 mL). Concentrated sulfuric acid
(0.05 mL) added and the resulting solution stirred at 25 °C for
17 h. The methanol was removed in vacuo and the reaction
quenched with saturated aqueous NaHCO3 solution (5 mL). The
organic material was extracted into CH2Cl2 (3 × 20 mL), which
was then dried over MgSO4, and concentrated in vacuo. Purifi-
cation by flash column chromatography (9 : 1 hexane–diethyl
ether) gave the title compound (0.16 g, 53%) as a colourless oil
as an inseparable 4 : 1 mixture of 14b and the methyl ester of
Experimental section
General procedure for the alkylation of 1-methylcyclohexa-2,5-
diene-1-carboxylic acid (10)
A solution of n-butyllithium (2.0 M in cyclohexane, 1.99 mL,
3.98 mmol) was added to 1-methylcyclohexa-2,5-diene-1-car-
boxylic acid (6) (0.25 g, 1.81 mmol) in THF (10 mL) at −78 °C.
TMEDA (0.59 mL, 3.98 mmol) was then added and the solution
stirred for 30 minutes. The electrophile (for number of equiva-
lents see individual compounds below) was added and the reac-
tion stirred for 10 minutes at −78 °C, then allowed to warm to
room temperature and stirred for a further 1 h. The reaction was
quenched with 2 M hydrochloric acid (5 mL) and the product
extracted into CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried over Na2SO4, concentrated in vacuo and the
residue re-dissolved in methanol (10 mL). Concentrated sulfuric
acid (0.05 mL) added and the resulting solution stirred at 25 °C
for 17 h. The methanol was removed in vacuo and saturated
aqueous NaHCO3 solution (5 mL) added. The organic material
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unreacted acid 10 (Found: MH+, 167.1075. C10H15O2 requires
M, 167.1072); νmax. (neat) 2956, 1733, 1248, 1116 and
733 cm−1; δH (400 MHz; CDCl3) 5.67–5.65 (4H, m, alkene
CH), 3.68 (3H, s, CH3O), 2.78–2.70 (1H, m, CH), 1.33 (3H, s,
CH3) and 1.08 (3H, d, J 7.3, CH3); δC (500 MHz; CDCl3) 175.7
(CvO), 131.0 (CH), 127.8 (CH), 52.3 (CH3), 44.3 (C), 30.4
(CH), 27.9 (CH3) and 21.8 (CH3); m/z (APCI) 167 (MH+,
100%).
5.81–5.69 (4H, m, alkene CH), 3.68 (3H, s, CH3O), 2.76–2.67
(1H, m, CH), 1.45–1.38 (2H, m, CH2), 1.33 (3H, s, CH3),
1.32–1.19 (4H, m, 2 × CH2) and 0.89 (3H, t, J 6.9, CH3); δC
(500 MHz; CDCl3) 175.8 (CvO), 129.6 (CH), 128.4 (CH), 52.3
(CH3), 44.5 (C), 35.4 (CH), 35.4 (CH2), 28.6 (CH2), 27.8 (CH3),
23.0 (CH2) and 14.2 (CH3); m/z (ES) 208 (M+, 20%), 164 (18),
149 (100), 121 (25), 105 (68) and 93 (78).
(1r,4r)-Methyl 4-ethyl-1-methylcyclohexa-2,5-dienecarboxylate
(14d)
(1r,4r)-Methyl 1,4-dimethylcyclohexa-2,5-dienecarboxylate (14b)
using LIDAKOR as base
Prepared according to the general procedure using bromoethane
(0.15 mL, 1.99 mmol, 1.1 equiv.) as electrophile. Purification by
flash column chromatography (50 : 1 hexane–diethyl ether) gave
the title compound (165 mg, 51%) as a pale yellow oil (Found:
MH+, 181.1230. C11H17O2 requires M, 181.1229); νmax. (neat)
3023, 2965, 2931, 2875 and 1736 cm−1; δH (400 MHz; CDCl3)
5.79 (2H, dd, J 10.3, 1.9, alkene CH), 5.71 (2H, dd, J 10.3, 3.1,
alkene CH), 3.68 (3H, s, CH3O), 2.73–2.67 (1H, m, CH), 1.47
(2H, qd, J 7.4, 6.0, CH2), 1.33 (3H, s, CH3) and 0.87 (3H, t, J
7.4, CH3); δC (500 MHz; CDCl3) 175.8 (CvO), 129.2 (CH),
128.7 (CH), 52.4 (CH3), 44.4 (C), 36.4 (CH), 28.1 (CH2), 27.8
(CH3) and 10.5 (CH3); m/z (APCI) 181 (MH+, 100%) and 115
(62).
A solution of n-butyllithium (2.0 M in cyclohexane, 1.53 mL,
3.05 mmol) was added to a solution of potassium tert-butoxide
(0.36 g, 3.19 mmol) in THF (7 mL) at −78 °C, followed by di-
isopropylamine (0.45 mL, 3.19 mmol) and left to stir for
30 minutes. 1-Methylcyclohexa-2,5-diene-1-carboxylic acid (10)
(0.20 g, 1.45 mmol) in THF (1 mL) was added and stirred for a
further 30 minutes before iodomethane (0.45 mL, 7.25 mmol)
was added, stirred for 10 minutes at −78 °C and then 1 h at
25 °C. The reaction was quenched with 2 M hydrochloric acid
(5 mL), and the product extracted into CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried over Na2SO4, concentrated
in vacuo and the residue re-dissolved in methanol (10 mL). Con-
centrated sulfuric acid (0.04 mL) added and the resulting sol-
ution stirred at 25 °C for 17 h. The methanol was removed in
vacuo and the reaction quenched with saturated aqueous
NaHCO3 solution (5 mL). The organic material was extracted
into CH2Cl2 (3 × 20 mL), which was then dried over MgSO4,
and concentrated in vacuo. Purification by flash column chrom-
atography (9 : 1 hexane–diethyl ether) gave the title compound
(90 mg, 37%) as a colourless oil as an inseparable 4 : 1 mixture
of 14b and the methyl ester of unreacted acid 10. Spectroscopic
data are as above.
(1r,4r)-Methyl 4-heptyl-1-methylcyclohexa-2,5-dienecarboxylate
(14e)
Prepared according to the general procedure using 1-iodoheptane
(0.59 mL, 3.62 mmol, 2.0 equiv.) as electrophile. Purification by
flash column chromatography (9 : 1 hexane–diethyl ether) gave
the title compound (240 mg, 53%) as a clear oil (Found: M+,
250.1936. C16H26O2 requires M, 250.1933); νmax. (neat) 3026,
2955, 2927, 2856, 1735, 1240, 1114, 795 and 733 cm−1; δH
(400 MHz; CDCl3) 5.79–5.70 (4H, m, 4 × alkene CH), 3.68
(3H, s, CH3O), 2.74–2.67 (1H, m, CH), 1.45–1.36 (2H, m,
CH2), 1.33 (3H, s, CH3), 1.33–1.20 (10H, m, 5 × CH2), and
0.88 (3H, t, J 7.0, CH3); δC (500 MHz; CDCl3) 175.6 (Cv0),
129.5 (CH), 128.2 (CH), 52.2 (CH3), 44.3 (C), 35.6 (CH2), 35.2
(CH), 31.9 (CH2), 29.8 (CH2), 29.2 (CH2), 27.6 (CH3), 26.2
(CH2), 22.6 (CH2) and 14.1 (CH3); m/z (EI) 250 (M+, 20%), 191
(100), 105 (80) and 91 (97).
(1r,4r)-Methyl 4-butyl-1-methylcyclohexa-2,5-dienecarboxylate
(14c) and methyl 4,4-dibutyl-1-methylcyclohexa-2,5-
dienecarboxylate (17c)
Prepared according to the general procedure using bromobutane
(0.21 mL, 1.99 mmol, 1.1 equiv.) as electrophile. Purification by
flash column chromatography (20 : 1 hexane–diethyl ether) gave
the di-butyl compound 17c (20 mg, 4%) as a pale yellow oil,
and mono-butyl compound 14c (240 mg, 64%) as a colourless
oil.
(1r,4r)-Methyl 1-methyl-4-octylcyclohexa-2,5-dienecarboxylate
(14f)
Data for compound 17c: Found: MH+, 265.2178. C17H29O2
requires M, 265.2168; νmax. (neat) 2956, 2929, 1735, 1238,
1112 and 800 cm−1; δH (400 MHz; CDCl3) 5.77 (2H, d, J 10.2,
2 × alkene CH), 5.39 (2H, d, J 10.2, alkene CH), 3.67 (3H, s,
CH3O), 1.31 (3H, s, CH3), 1.31–1.00 (12H, m, 6 × CH2) and
0.85 (3H, t, J 7.0, CH3) and 0.83 (3H, t, J 7.0, CH3); δC
(500 MHz; CDCl3) 175.8 (CvO), 133.4 (CH), 128.5 (CH), 52.2
(CH3), 44.6 (C), 41.6 (CH2), 41.2 (C), 41.2 (CH2), 27.4 (CH2),
27.4 (CH3), 27.1 (CH2), 23.4 (CH2), 23.4 (CH2), 14.2 (CH3) and
14.2 (CH3); m/z (ES) 265 (MH+, 100%), 205 (14) and 146 (14).
Data for compound 14c: Found: M+, 208.1464. C13H20O2
requires M, 208.1458; νmax. (neat) 2956, 2931, 2873, 1733,
1248, 1117, 796 and 734 cm−1; δH (400 MHz; CDCl3)
Prepared according to the general procedure using 1-bromo-
octane (0.35 mL, 1.99 mmol, 1.1 equiv.) as electrophile. Purifi-
cation by flash column chromatography (9 : 1 hexane–diethyl
ether) gave the title compound (226 mg, 43%) as a colourless oil
(Found: MH+, 265.2164. C17H29O2 requires M, 265.2168); νmax
.
(neat) 2954, 2926, 2855, 1734, 1240, 1114, 734 cm−1; δH
(400 MHz; CDCl3) 5.76 (2H, dd, J 10.4, 1.5, alkene CH), 5.73
(2H, dd, J 10.4, 2.5, alkene CH), 3.68 (3H, s, CH3), 2.74–2.68
(1H, m, CH), 1.44–1.36 (2H, m, CH2), 1.32 (3H, s, CH3),
1.32–1.20 (12H, m, 7 × CH2) and 0.87 (3H, t, J 6.8, CH3); δC
(500 MHz; CDCl3) 175.8 (CvO), 129.6 (CH), 128.4 (CH), 52.3
(CH3), 44.5 (C), 35.8 (CH2), 35.4 (CH), 32.0 (CH2), 30.0 (CH2),
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29.7 (CH2), 29.5 (CH2), 27.8 (CH3), 26.4 (CH2), 22.8 (CH2) and
14.2 (CH3); m/z (APCl) 265 (MH+, 100%). Earlier fractions con-
tained approximately 20% of the double-octyl compound 17f,
but this was not sufficiently pure for characterisation purposes.
δC (500 MHz; CDCl3) 131.9 (CH), 129.5 (CH), 71.0 (CH2),
42.1 (CH), 39.9 (C), 32.1 (CH), 24.8 (CH3) and 19.3 (CH3); m/z
(ES) 167 (MH+, 21%), 149 (100) and 115 (56).
((1r,4r)-4-Isopropyl-1-methylcyclohexa-2,5-dienyl)methyl 2,4-
dinitrobenzoate (16)
(1r,4r)-Methyl 4-benzyl-1-methylcyclohexa-2,5-dienecarboxylate
(14g)
A solution of 2,4-dinitrobenzoyl chloride (0.14 g, 0.60 mmol) in
CH2Cl2 (1 mL) was added to ((1r,4r)-4-isopropyl-1-methyl-
cyclohexa-2,5-dienyl)methanol (15) (0.10 g, 0.60 mmol) in
CH2Cl2 (10 mL). Triethylamine (0.08 mL, 0.60 mmol) and 4-
DMAP (10 mg) were then added and the solution stirred for
24 h. The reaction was quenched with water (5 mL), extracted
with CH2Cl2 (3 × 15 mL) and dried over Na2SO4. Recrystallisa-
tion from 1 : 1 hexane–ethyl acetate gave the title compound
(0.12 g, 56%) as beige crystals (Found: MH+, 361.1392.
C18H21N2O6 requires M, 361.1394); νmax. (neat) 2959, 1738,
1538, 1349 and 1284 cm−1; δH (400 MHz; CDCl3) 8.74 (1H, d,
J 2.2, aromatic CH), 8.51 (1H, dd, J 8.4, 2.2, aromatic CH), 7.92
(1H, d, J 8.4, aromatic CH), 5.69 (2H, dd, J 10.4, 3.2, alkene
CH), 5.55 (2H, dd, J 10.4, 2.0, alkene CH), 4.15 (2H, s, CH2O),
2.62–2.58 (1H, m, CH), 1.75 (1H, septet of doublets, J 6.9, 3.9,
CH(CH3)2), 1.09 (3H, s, CH3) and 0.88 (6H, d, J 6.9, 2 × CH3);
δC (500 MHz: CDCl3) 131.6 (CH), 130.8 (2 × CH), 128.7 (2 ×
CH), 127.4 (CH), 119.7 (CH), 74.2 (CH2), 42.0 (CH), 37.6 (C),
32.1 (CH), 25.3 (CH3) and 19.3 (CH3) (The ester and aromatic
quaternary carbon atoms are not evident, presumably due to
slow relaxation. The reasons for this are not entirely clear); m/z
(ES) 361 (MH+, 50%), 163 (18) and 115 (100).
Prepared according to the general procedure using benzyl
bromide (0.43 mL, 3.62 mmol, 2.0 equiv.) as electrophile. Purifi-
cation by flash column chromatography (50 : 1 hexane–diethyl
ether) gave the title compound (340 mg, 77%) as a colourless oil
(Found: MH+, 243.1393. C16H19O2 requires M, 243.1385); νmax
.
(neat) 3028, 2928, 1732, 1242, 1114, 726 and 701 cm−1; δH
(400 MHz; CDCl3) 7.28 (2H, app. tt, J 7.0, 1.4, aromatic CH),
7.19 (1H, app. tt, J 7.3, 1.4, aromatic CH), 7.17–7.13 (2H, m,
aromatic CH), 5.78–5.70 (4H, m, alkene CH), 3.66 (3H, s,
OCH3), 3.05–2.99 (1H, m, CHPh), 2.71 (2H, d, J 7.0, CH2) and
1.14 (3H, s, CH3); δC (500 MHz; CDCl3) 175.6 (CvO), 139.3
(C), 129.5 (2 × CH), 128.9 (2 × CH), 128.7 (2 × CH), 128.2
(2 × CH), 126.3 (CH), 52.4 (CH3), 44.5 (C), 42.4 (CH2), 37.3
(CH) and 27.5 (CH3); m/z (TOF AP+) 284 (MH+ + CH3CN,
38%), 243 (MH+, 100) and 115 (40).
(1r,4r)-Methyl 4-allyl-1-methylcyclohexa-2,5-dienecarboxylate
(14h)
Prepared according to the general procedure using allyl bromide
(0.31 mL, 3.62 mmol, 2.0 equiv.) as electrophile. Purification by
flash column chromatography (20 : 1 hexane–diethyl ether) gave
the title compound (0.19 g, 54%) as a colourless oil (Found:
M − H, 191.1075. C12H15O2 requires M, 191.1072); νmax. (neat)
2953, 1732, 1244, 1115 and 734; δH (400 MHz; CDCl3)
5.82–5.70 (5H, m, alkene CH), 5.08–5.01 (2H, m, alkene CH2),
3.69 (3H, s, OCH3), 2.83–2.76 (1H, m, CH), 2.18 (2H, app. t, J
6.8, CH2) and 1.33 (3H, s, CH3); δC (500 MHz; CDCl3) 175.6
(CvO), 135.9 (CH), 128.9 (CH), 128.7 (CH), 116.8 (CH2), 52.4
(CH3), 44.4 (C), 40.1 (CH2), 35.2 (CH) and 27.7 (CH3); m/z
(TOF MS EI+) 191 (M+ − H, 32%), 151 (93), 107 (78), 91 (98)
and 84 (100).
Selected crystallographic data: C18H20N2O6, FW = 360.36,
ˉ
T = 150 K, λ = 0.71073 Å, triclinic, P1, a = 7.6377(3) Å, b =
7.8225(3) Å, c = 32.1299(10) Å, α = 93.748(2)°, β = 91.221
(2)°, γ = 109.094(2)°, V = 1808.28(11) Å3, Z = 4, ρ(calc) =
1.324 Mg m−3 , crystal size = 0.30 × 0.20 × 0.12 mm3, reflec-
tions collected = 8271, independent reflections = 6414, R(int) =
0.0393, parameters = 476, R1[I > 2σ(I)] = 0.0706, wR2[I > 2σ(I)]
= 0.1381, R1 (all data) = 0.1050, wR2 (all data) = 0.1588. Full
crystallographic data for this compound have been deposited
with the CCDC, reference number 854352.
Methyl 4,4-diethyl-1-methylcyclohexa-2,5-dienecarboxylate
(17d)
((1r,4r)-4-Isopropyl-1-methylcyclohexa-2,5-dienyl)methanol (15)
A solution of (1r,4r)-methyl 4-isopropyl-1-methylcyclohexa-2,5-
dienecarboxylate (14a) (1.00 g, 5.15 mmol) in THF (2 mL) was
added to a suspension of LiAlH4 (0.27 g, 7.22 mmol) in THF
(50 mL). The reaction was stirred at 25 °C for 1 h, then
quenched with 15% aqueous NaOH solution (0.19 mL) and
water (0.6 mL), stirred for 30 minutes, then dried over Na2SO4
and filtered before removing the solvent under reduced pressure
to give the title compound (0.66 g, 77%) as an essentially-pure
colourless oil (Found: MH+, 167.1433. C11H19O requires M,
167.1430); νmax. (neat) 3366, 3011, 2957, 2928, 2871, 1464,
1384 and 1366 cm−1; δH (400 MHz; CDCl3) 5.78 (2H, dd, J
10.4, 3.2, alkene CH), 5.51 (2H, dd, J 10.4, 2.0, alkene CH),
3.33 (2H, d, J 6.1, CH2OH), 2.69–2.65 (1H, m, CHvCH–CH),
1.76 (1H, septet of doublets, J 6.9, 4.1, CH(CH3)2), 1.36 (1H, t,
J 6.1, OH), 0.99 (3H, s, CH3) and 0.89 (6H, d, J 6.9, 2 × CH3);
A solution of n-butyllithium (2.0 M in cyclohexane, 4.52 mL,
9.05 mmol) was added to 1-methylcyclohexa-2,5-dienecar-
boxylic acid (10) (0.25 g, 1.81 mmol) in THF (10 mL) at
−78 °C. TMEDA (0.68 mL, 4.53 mmol) was then added and the
solution stirred for a further 30 minutes. Bromoethane (0.41 mL,
5.43 mmol) was added, the solution was stirred for 10 minutes at
−78 °C, allowed to warm to room temperature and stirred for a
further 1 h. The reaction was quenched with 2 M hydrochloric
acid (5 mL) and the organic material extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried over Na2SO4,
filtered and concentrated in vacuo to give the crude alkylated car-
boxylic acid. This was then dissolved in methanol (10 mL), con-
centrated sulfuric acid (0.05 mL) added and the resulting
solution stirred at 25 °C for 17 h. The solvent was removed in
vacuo, saturated NaHCO3 solution (5 mL) added and the product
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2006, 832–834; R. Lebeuf, F. Robert, K. Schenk and Y. Landais, Org.
Lett., 2006, 8, 4755–4758; R. Beniazza, J. Dunet, F. Robert, K. Schenk
and Y. Landais, Org. Lett., 2007, 9, 3913–3916.
5 M. C. Elliott and J. S. Paine, Org. Biomol. Chem., 2009, 7, 3455–3462.
6 M. C. Elliott, N. N. E. El Sayed and J. S. Paine, Org. Biomol. Chem.,
2008, 6, 2611–2618.
7 M. Butters, M. C. Elliott, J. Hill-Cousins, J. S. Paine and
A. W. J. Westwood, Tetrahedron Lett., 2008, 49, 4446–4448.
8 It is also possible to carry out a direct Birch reduction/dialkylation
of benzoic acid derivatives, although the stereochemistry of the reaction
is not discussed. R. Castadeno, A. Covarrubias-Zúñiga and L.
A. Maldonado, Tetrahedron Lett., 2006, 47, 973–976.
9 H. van Bekkum, C. B. van den Bosch, G. van Minnen-Pathuis, J. C. de
Mos and A. M. van Wijk, Recl. Trav. Chim. Pays-Bas, 1971, 90, 137–
149.
extracted into CH2Cl2 (3 × 20 mL). The combined organic
layers were dried over MgSO4 and the solvent removed under
reduced pressure. Purification by flash column chromatography
(20 : 1 hexane–diethyl ether) gave the title compound (181 mg,
48%) as a pale yellow oil (Found: M+, 208.1469. C13H20O2
requires M, 208.1463); νmax. (neat) 2964, 2928, 1734 and
1241 cm−1; δH (400 MHz; CDCl3) 5.83 (2H, d, J 10.3, 2 ×
alkene CH), 5.32 (2H, d, J 10.3, 2 × alkene CH), 3.67 (3H, s,
CH3O), 1.34 (2H, q, J 7.5, CH2), 1.33 (2H, q, J 7.5, CH2), 1.32
(3H, s, CH3), 0.73 (3H, t, J 7.5, CH3) and 0.72 (3H, t, J 7.5,
CH3); δC (500 MHz; CDCl3) 175.8 (CvO), 132.5 (CH), 129.3
(CH), 52.2 (CH3), 44.6 (C), 42.1 (C), 34.0 (CH2), 33.5 (CH2),
27.5 (CH3), 9.5 (CH3) and 9.2 (CH3); m/z (EI) 208 (M+, 15%),
207 (17), 179 (100), 149 (90) and 107 (100).
10 M. Butters, D. J. Beetstra, M. C. Elliott, J. Hill-Cousins and B.
M. Kariuki, Org. Biomol. Chem., 2008, 6, 4426–4434.
11 I. K. Zhurkovich and D. V. Ioffe, Zh. Org. Khim., 1976, 12, 367–372.
12 Determining the stereochemical outcome of these reactions is not trivial,
particularly so with the instrumentation which would have been available
to these researchers in 1976. Zhurkovic and Ioffe11 did report that the
reaction placed the new alkyl group trans to the carboxylic acid. The
assignments of the cis/trans isomer mixtures of 11 and 12 were made by
comparing the relative GC retention times of the corresponding esters
with data in an earlier report from van Bekkum et al.9 However, they
only reported GC retention times for compounds lacking the quaternary
centres, and so the relevance of the comparison is not clear. Furthermore,
the basis of van Bekkum et al.’s assignment was not explained, being
based on results that were described as “to be published”. To the best of
our knowledge, the basis of these assignments was never actually pub-
lished, so that in extending this work it was clear that unambiguous
stereochemical assignments would be required.
Acknowledgements
The authors would like to thank Dr Robert Jenkins, Mr Robin
Hicks and Mr David Walker for technical assistance, and Astra-
Zeneca and EPSRC for financial support. We are grateful to
Dr Yulia Rabenkova for the translation of reference 11.
Notes and references
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Trans. 1, 2002, 304–309.
2 A. Studer and F. Schleth, Synlett, 2005, 3033–3041.
3 Y. Landais and E. Zekri, Eur. J. Org. Chem., 2002, 4037–4053; M.
S. Maji, R. Fröhlich and A. Studer, Org. Lett., 2008, 10, 1847–1850;
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4 H. Fujioka, N. Kotoku, Y. Sawama, H. Kitagawa, Y. Ohba, T.-L. Wang,
Y. Nagatomi and Y. Kita, Chem. Pharm. Bull., 2005, 53, 952–957;
H. Fujioka, K. Murai, Y. Ohba, H. Hirose and Y. Kita, Chem. Commun.,
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16 R. E. Gawley and Q. Zhang, J. Org. Chem., 1995, 60, 5763–5769.
17 M. J. Frisch et al., GAUSSIAN 09 (Revision A.2), Gaussian, Inc., Walling-
ford CT, 2009. For full reference, see ESI†.
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