Aliphatic C-H activation with aluminium trichloride-acetyl chloride: Expanding the scope of the Baddeley reaction for the functionalisation of saturated hydrocarbons

Article abstract of DOI:10.1039/c2ob26765a

The functionalisation of decalin by means of an "aliphatic Friedel-Crafts" reaction was reported over fifty years ago by Baddeley et al. This protocol is of current relevance in the context of C-H activation and here we demonstrate its applicability to a range of other saturated hydrocarbons. Structural elucidation of the products is described and a mechanistic rationale for their formation is presented. The "aliphatic Friedel-Crafts" procedure allows for production of novel oxygenated building blocks from abundant hydrocarbons and as such can be considered to add significant synthetic value in a single step.

Full text of DOI:10.1039/c2ob26765a

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Aliphatic C–H activation with aluminium trichloride–
acetyl chloride: expanding the scope of the Baddeley
reaction for the functionalisation of saturated
hydrocarbons†
Cite this: DOI: 10.1039/c2ob26765a
Catherine L. Lyall,a Mario Uosis-Martin,a John P. Lowe,a Mary F. Mahon,*b
G. Dan Pantoşa and Simon E. Lewis*a
The functionalisation of decalin by means of an “aliphatic Friedel–Crafts” reaction was reported over fifty
years ago by Baddeley et al. This protocol is of current relevance in the context of C–H activation and
here we demonstrate its applicability to a range of other saturated hydrocarbons. Structural elucidation
of the products is described and a mechanistic rationale for their formation is presented. The “aliphatic
Friedel–Crafts” procedure allows for production of novel oxygenated building blocks from abundant
hydrocarbons and as such can be considered to add significant synthetic value in a single step.
Received 7th September 2012,
Accepted 12th December 2012
DOI: 10.1039/c2ob26765a
www.rsc.org/obc
unwanted side reactions. However, since the C–H functionali-
sation of a saturated hydrocarbon will almost certainly be the
Introduction
C–H activation is currently of great interest to the synthetic com- first step of a synthetic sequence, it is harder to justify the use
munity.1 In contrast to conventional functional group intercon- of expensive transition metal catalysts. Rather, if the reaction
versions, C–H activation represents an alternative paradigm is to be carried out on a significant scale, the cost of the
whereby functionality may be introduced where none was reagents for C–H activation and also the cost of the substrate
present before. Such methodology enables the use of wholly itself are key considerations if the transformation is to be syn-
new retrosynthetic approaches to complex molecule synthesis.2
thetically useful.
Applications of C–H activation in synthesis may be broadly
In this latter context, reports from Baddeley on the reaction
subdivided into those reactions carried out on substrates with of decalin with aluminium trichloride and acetyl chloride are
extensive existing functionality and those carried out on sub- noteworthy. When an excess of aluminium trichloride is
strates that have minimal functionality or are entirely unfunc- employed, the reaction furnishes multiple products5a,c
tionalised. In the former category, desirable characteristics are (Scheme 1a). However, when an excess of acetyl chloride is
chemo- and regioselectivity as well as functional group com- employed at a lower temperature, tricyclic enol ether 6 is
patibility, which can restrict the reaction conditions that may formed cleanly5b–f (Scheme 1b).
be employed.3 These transformations often employ expensive
Such “aliphatic Friedel–Crafts” acetylations have been
transition metal catalysts4 for this “late stage” C–H activation, reported for other unfunctionalised alkanes6 and alkenes;7 the
which can be considered to be justified in terms of the products have been used in synthesis and the field has been
high value products that can be produced.2b In contrast, in the reviewed.8 However, the decalin case is uniquely attractive
latter category, the absence of functionality potentially allows a from the standpoint of C–H functionalisation, since not only
wider range of reaction conditions to be used without are the substrate and reagents inexpensive bulk commodity
chemicals, but also the product is formed in reasonable yield
(30–46%)5c,6l and has a boiling point which is distinct from
that of the starting material (which constitutes most of the
aDepartment of Chemistry, University of Bath, Bath, BA2 7AY, UK.
E-mail: S.E.Lewis@bath.ac.uk; Tel: +44 (0) 1225 386568
bDepartment of Chemical Crystallography, University of Bath, Bath, BA2 7AY, UK.
mass balance) and from the boiling points of any byproducts.
This permits large-scale purification without recourse to
chromatography; we have prepared pure 6 by distillation on a
70 g scale.† Functionalised decalins are key building blocks for
terpenoid9 and steroid10 natural products and are also impor-
tant in the fragrance industry;11 indeed, 6 has seen diverse
E-mail: M.F.Mahon@bath.ac.uk
†Electronic supplementary information (ESI) available: NMR spectroscopic data
for all novel compounds and for enol ether 6. Large scale procedure for prep-
aration of 6. Procedures for preparation of 28 and 30. CCDC 900347 (23), 900348
(24). For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob26765a
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Scheme 1 C–H activation of decalin with aluminium trichloride and acetyl
chloride.
synthetic applications.12 Other examples of the functionalisa-
tion of decalin with aluminium trichloride include the use of
benzenesulfonyl chloride to form several mono substituted
chlorodecalins.13 We identified several saturated hydrocarbon
substrates for which such aliphatic Friedel–Crafts reactions
have not been reported and from which synthetically valuable
products might be accessed. Products that were obtained from
these substrates are described in this paper.
Scheme 2 Baddeley’s and Santelli’s mechanistic proposals.
Results and discussion
Mechanistic rationalisation of Baddeley’s transformation is
important to aid in the structural elucidation of any products
that form from its application to other substrates. Baddeley’s
original proposal5b invoked an oxonium intermediate incor-
porated into a 4-membered ring (8, Scheme 2). Such an inter-
mediate would be exceedingly strained; subsequently, Santelli
et al. were the first to propose6m a variant on this mechanism
which did not include such a strained oxonium. Our mechan-
istic proposal (Scheme 3) has several features in common with
the previous proposals. In the absence of unsaturation for the
acylating agent to react with, it instead acts as a hydride sink
(such reactivity is precedented8), leading to the formation of a
tertiary cation at the decalin ring junction. Loss of a proton
affords Δ9,10-octalin 7. A second equivalent of acylating agent
reacts with the newly introduced unsaturation to give cation
13. Rather than formation of a 4-membered ring, we propose a
[1,2]-hydride shift and attack of the oxygen at the position α- to
the ring junction, as in Santelli’s proposal. Such a process may
be concerted or stepwise. Finally on work up, loss of a proton
affords enol ether 6. Overall, our proposal differs from Santel-
li’s in that 13 and 9 possess an sp2 carbon (Santelli proposes
this carbon to be sp3 with a bond to a chlorine, cf. 10 and 11).
In situ reaction monitoring by NMR spectroscopy shows for-
mation of 9 prior to work up. Key proton Ha is observed at
Scheme 3 Our mechanistic proposal.
6.08 ppm in the 1H-NMR spectrum, a comparable shift to
similar compounds in the literature.14
The proposal that the initial C–H activation step proceeds
by hydride abstraction guided our choice of other hydrocarbon
substrates for Baddeley’s protocol. Specifically, we selected
only those able to form tertiary carbocations by hydride
abstraction, i.e. those possessing (non-bridgehead) methines.
In the first instance, we sought commercially available and
inexpensive substrates. Bicyclohexyl meets these criteria,15
being produced by hydrogenation of the kerosene fraction of
coal distillate.16 Thus, in the first instance, bicyclohexyl was
subjected to the reaction conditions determined by Baddeley
to be optimal for production of 6 from decalin. Gratifyingly,
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Scheme 4 C–H activation of bicyclohexyl.
13C-NMR analysis of the crude reaction mixture after workup
indicated the presence of a single product in addition to
unreacted bicyclohexyl (Scheme 4).
Structural elucidation of 15 was by means of DEPT and 2D
NMR experiments in conjunction with crystallographic studies
on derivatives (vide infra). The observations that both sp2
carbons and one sp3 carbon in 15 were quaternary and that a
1
methyl group was present (3H singlet in the H spectrum) led
to the proposal of the structure shown, on the basis of the
mechanism given in Scheme 5. Abstraction of the tertiary
hydride gives cation 16, from which two isomeric alkenes are
accessible. In contrast to the decalin case (where the tetrasub-
stituted alkene is formed), we propose that loss of a proton
from 16 leads to trisubstituted alkene 18 as opposed to 17.
Regioselective reaction with a second acylium ion gives the
second tertiary cation intermediate 19. Attack of the oxygen
and [1,2]-hydride shift, analogous with the decalin case, forms
the spiro-centre and gives oxonium 20. Of the two isomeric
enol ethers available from deprotonation of 20, it is 15 that is
formed in preference to 21. That neither cyclohexyl ring under-
goes ring contraction is noteworthy, as AlCl3-mediated for-
mation of 2,2′-dimethylbicyclopentyl from bicyclohexyl (in the
absence of acetyl chloride) has been reported.17
Fig. 1 (a) Energy profile for formation of bicyclohexylidene 17 (left) and 1-
cyclohexylcyclohexene 18 (right) from cation 16. (b) Energy profile for formation
of Δ1,9-octalin (left) and Δ9,10-octalin 7 (right) from cation 12.
DFT modelling studies (M06/6-31G(d) basis set)18 support
the contention that in the bicyclohexyl case, formation of tri-
substituted alkene 18 is favoured over tetrasubstituted alkene 17. The transition state for formation of 18 via deprotonation of
cation 16 by a chloride anion was calculated to be lower in
energy by 10.8 kJ mol−1 than the corresponding transition
state for formation of 17 (Fig. 1a). Alkene 18 is also the ther-
modynamic product, lower in energy than 17 by 2.4 kJ mol−1
.
In contrast, the situation is reversed for decalin, wherein the
transition state for formation of Δ9,10-octalin 7 from cation 12
was found to be lower in energy by 31.6 kJ mol−1 than the cor-
responding transition state for formation of its trisubstituted
alkene isomer, Δ1,9-octalin (Fig. 1b); Δ9,10-octalin 7 was also
calculated to be lower in energy than Δ1,9-octalin by 6.7 kJ
mol−1. This quantitation of ΔΔG‡ for the divergent elimination
pathways from cations 12 and 16 supports the mechanistic
proposals in Schemes 3 and 5; only few experimental data on
directly comparable eliminations have been reported
previously.19,20
Complete separation of 15 from unreacted bicyclohexyl 14
proved problematic – complete removal of bicyclohexyl (b.pt.
227 °C/1 atm) under vacuum distillation required elevated
temperatures which induced rearrangement of 15. The
rearrangement product was identified as 22, with the relative
configuration being assigned on the basis of Karplus
Scheme 5 C–H activation of bicyclohexyl.
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Scheme 7 Hydration of 15 upon chromatography.
Scheme 6 Rearrangement of 15 to 22.
Fig. 3 Solid state structure of 24. Ellipsoids are represented at 50% probability.
H atoms are shown as spheres of arbitrary radius. Only one of two molecules in
the unit cell is shown for clarity.
3
analysis21 of the JHH coupling constants for the ketone
α-methine (Scheme 6). The identity of 22 was further con-
firmed by formation of a 2,4-dinitrophenylhydrazone derivative
23 and its X-ray crystallographic analysis (Fig. 2).
Separation of enol ether 15 from unreacted bicyclohexyl 14
was also attempted by chromatography. In the event, 15 proved
hygroscopic, undergoing quantitative incorporation of adventi-
tious moisture upon contact with silica to give hydrate 24
(Scheme 7). This hydrate was amenable to X-ray crystallo-
graphic analysis, which confirmed the relative stereochemistry
as shown in Fig. 3.
Encouraged by the ease and selectivity with which 15 may
be transformed into functionalised products, we sought to
examine the analogous reaction of other bicycloalkyls. Bicyclo-
pentyl 2522 was subjected to Baddeley’s conditions with the
expectation of obtaining a product analogous to 15. In fact, 25
Scheme 8 C–H activation of 25 and its transformation into 6 by skeletal
rearrangement.
instead furnished the same product 6 originally observed by
Baddeley (Scheme 8). In addition, both cis- and trans-decalin
were recovered. We rationalise the formation of 6 by a skeletal
rearrangement of bicyclopentyl cation 26 occurring to give
decalin cation 12 prior to any loss of a proton (formation of 6
then proceeds as per the decalin case). The observed for-
mation of decalin itself in the reaction of 25 is also suggestive
of this sequence of events. It should also be noted that AlCl3-
mediated isomerisation of bicyclopentyl to decalin (in the
absence of acetyl chloride) is in fact a known process.23
We next examined substrates that shared the bicyclo[m.n.0]-
alkane skeleton of decalin. Hydrindane, the ring contracted
bicyclo[4.3.0]nonane analogue of decalin, has been reported6n
to undergo the Baddeley reaction, albeit less cleanly, furnish-
ing ring contracted analogues of 6. Thus, we instead examined
the reactivity of bicyclo[5.4.0]undecane 28.24 Upon exposure to
Baddeley’s conditions, 28 gave a mixture of an acylated species
Fig. 2 Solid state structure of 23. Ellipsoids are represented at 50% probability.
H atoms are shown as spheres of arbitrary radius. Only one of two molecules in
the unit cell is shown for clarity.
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Scheme 10 C–H activation of 30 and its transformation into 6 by skeletal
rearrangement.
Scheme 9 Baddeley reaction of bicyclo[5.4.0]undecane 28.
29 and various enol ether products, of which only 29 proved to
be isolable in pure form. Unambiguous assignment of 29
required extensive characterisation by NMR spectroscopic
means at high frequency, to minimise overlap of resonances.
The structure was assigned as follows. The presence of a
ketone as the sole sp2 carbon in the 13C spectrum and a clear
3H singlet (δ 2.02 ppm) in the 1H spectrum implied a structure
analogous with 2 (i.e. a monoacylated species having only 3
double bond equivalents in total, confirmed by mass spec-
trometry). Secondly, the existence of a quaternary sp3 carbon
environment (present in the 13C spectrum but absent in the
HSQC spectrum) implies the acyl group is located on a ring
junction. Thirdly, a characteristic 3H doublet (δ 0.82 ppm,
Scheme 11 C–H activation of isopropylhexane 31.
undertook to explore its C–H activation chemistry as it is
commercially available and inexpensive.27 Application of the
standard conditions gave a reaction mixture in which a single
product predominated. NMR spectroscopic data indicated
both sp2 carbons to be quaternary and as such 32 was assigned
the structure shown, analogous with the product derived from
reaction of bicyclohexyl28 (Scheme 11). This functionalisation
of 31 in the cyclohexane 2-position is regiocomplimentary to
the functionalisation of 31 with GaCl3 which reportedly exhi-
bits a preference for the 3- and 4-positions.29 Unreacted 31
could be removed by cold trap vacuum distillation at room
temperature, but attempted distillation of 32 itself resulted in
decomposition to an intractable mixture.
1
J 6.3 Hz) in the H spectrum was indicative of the presence of
a methyl group adjacent to a methine, which we ascribe to a
(precedented) ring contraction of the seven-membered ring.6l
Establishing which ring position bears the methyl group was
more complex. An H2BC spectrum was acquired,25 in which
both tertiary carbon environments (the carbons bearing Ha
and Hb, see Scheme 9) showed clear coupling to Hc. As the
H2BC experiment only shows 2-bond H–C correlations, this
served to establish unambiguously which ring carbon bears
the methyl group. The gross structure of 29 having been
assigned, the final elucidation of relative stereochemistry was
by means of a NOESY spectrum. Specifically, a clear through-
space coupling between Ha and Hb was observed, indicating
that they are 1,3-diaxially disposed and finally confirming the
structure of 29.
Conclusions
We have demonstrated the applicability of Baddeley’s “ali-
phatic Friedel–Crafts” procedure to a range of saturated hydro-
carbon substrates. A variety of novel oxygenated structures
have been produced, identified and, in the case of bicyclo-
hexyl, have been further elaborated. A mechanistic explanation
has been proposed that rationalises Baddeley’s original results
and also the formation of the products described here. We
anticipate that the products described here will serve as useful
building blocks in a variety of synthetic contexts.
We also examined the reactivity of bicyclo[5.3.0]decane
30,26 isomeric with decalin. As per our other C10 substrate, 25,
the sole product was once again Baddeley’s original enol ether
6 (Scheme 10).
For each of the substrates described above, all the methines
are equivalent. In contrast, isopropylcyclohexane 31 (available
from reduction of cumene or α-methylstyrene) has two
Experimental
General
inequivalent sites of possible hydride abstraction. Whilst Reactions which required the use of anhydrous, inert atmos-
this increases the number of possible products that may be phere techniques were carried out under an atmosphere of
formed from 31 under Baddeley conditions, we nevertheless nitrogen. Solvents were dried and degassed by passing
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through anhydrous alumina columns using an Innovative δC (75 MHz) 212.4 (CvO), 139.9, 121.8, 55.1, 48.1, 31.5, 29.2,
Technology Inc. PS-400-7 solvent purification system. Petrol 28.5, 26.0, 25.8, 25.4, 25.0, 22.9, 22.4 ppm; vmax 2923, 2854,
refers to petroleum ether, bp 40–60 °C. TLCs were performed 1705, 1447, 1355, 1244, 1220, 1161, 920, 882 cm−1; HRMS
using aluminium-backed plates precoated with Alugram®SIL (ESI+) m/z calcd for (C14H22O + H)+ 207.1743; found 207.1765.
G/UV and visualized by UV light (254 nm) and/or KMnO4 fol-
trans-Methyl 2-(cyclohex-1-enyl)cyclohexyl 2-(2,4-dinitrophe-
lowed by gentle warming. Flash column chromatography was nyl)hydrazone 23. Ketone 22 (1.70 g, 8.24 mmol, 1.0 eq.) was
carried out using Davisil LC 60 Å silica gel (35–70 micron) pur- dissolved in ethanol (20 mL) and the solution stirred.
chased from Fisher Scientific. IR spectra were recorded on a (2,4-Dinitrophenyl)hydrazine (2.50 g, 12.4 mmol, 1.5 eq.) was
Perkin-Elmer 1600 FT IR spectrometer with absorbances added, resulting in a red/orange mixture. H2SO4 (conc, 0.40 g,
quoted as ν in cm−1. NMR spectra were run in CDCl3 (unless 4.12 mmol, 0.5 eq.) was added over 10 min, then the solution
otherwise specified) on Bruker Avance 250, 300, 400 or was heated to reflux for 2.5 h. Additional (2,4-dinitrophenyl)-
500 MHz instruments at 298 K. Mass spectra were recorded hydrazine (0.80 g, 4.12 mmol, 0.5 eq.) was added and reflux
with a micrOTOF electrospray time-of-flight (ESI-TOF) mass continued until reaction complete; orange precipitate observed
spectrometer (Bruker Daltonik). Aluminium trichloride (98%, in red solution. The precipitate was filtered and air-dried over-
#206911), acetyl chloride (98%, #11,418-9) and 1,2-dichloro- night. Pure product was obtained by dissolving the precipitate
ethane (99.8%, anhydrous, #284505) were purchased from in 95 : 5 petrol : EtOAc and removing 2,4-DNP (red crystals) by
Sigma-Aldrich. Caution was taken when using large quanti- vacuum filtration. The filtrate was then concentrated under
ties of possibly carcinogenic chlorinated solvents; reaction reduced pressure to give the product 23 as yellow crystals
workup, product isolation and purification was performed in a (2.56 g, 81%); a portion was re-crystallised from hot ethanol to
fume hood with appropriate personal protective equipment form crystals for X-ray analysis. m.p. 121–122 °C; δH (250 MHz)
employed.
10.96 (1H, s, –NH), 9.12 (1H, d, J 2.5 Hz, aryl CH), 8.29 (1H,
3′-Methyl-5′,6′,7′,7a′-tetrahydro-4′H-spiro(cyclohexane-1,1′- dd, J 9.5, 2.5 Hz, aryl CH), 7.93 (1H, d, J 9.5 Hz, aryl CH), 5.36
isobenzofuran) 15. AcCl (28.3 g, 0.361 mol, 2.4 eq.) was added (1H, s,vCHR), 2.54, (1H, td, J 11.0, 2.8 Hz), 2.21–1.22 (20H, m
over 15 min to a suspension of AlCl3 (30.0 g, 0.223 mol, [including 1.93 (3H, s, –CH3)]) ppm; δC (75 MHz) 161.6, 145.2,
1.5 eq.) in CH2ClCH2Cl (70 mL) and stirred for 20 min. The 140.2, 137.5, 129.9, 128.9, 123.6, 122.3, 116.3, 50.2, 49.7, 31.6,
resulting yellow solution was then cooled to 0 °C. Over 20 min, 30.5, 26.2, 25.6, 25.5, 24.6, 22.9, 22.6, 13.1 ppm; vmax 3636,
bicyclohexyl (25.0 g, 0.150 mol, 1.0 eq.) was added, and the 2981, 1619, 1518, 1139, 1074, 955 cm−1; TOF-MS (ESI+) m/z
reaction mixture stirred for a further 3 h. The resulting orange calcd for (C20H26N4O4 + Na)+ 409.1852; found 409.1868.
solution was gradually added to a vigorously stirred slurry of
(3′S*,3a′R*,7a′R*)-3′-Methylhexahydro-3′H-spiro(cyclohexane-
ice-water (500 mL); a cherry-red colour was observed. The reac- 1,1′-isobenzofuran)-3′-ol 24. A mixture of 3′-methyl-5′,6′,7′,7a′-
tion mixture was transferred to a separating funnel and tetrahydro-4′H-spiro(cyclohexane-1,1′-isobenzofuran) 15 and
extracted with CH2Cl2. Organic extracts were combined and bicyclohexyl 14 was subjected to column chromatography
washed with ice-water (2 × 250 mL), dried over MgSO4 and fil- (2.5 : 97.5 EtOAc : pet). (3′S*,3a′R*,7a′R*)-3′-Methylhexahydro-
tered. The filtrate was concentrated under reduced pressure 3′H-spiro(cyclohexane-1,1′-isobenzofuran)-3′-ol 24 was identi-
on a rotary evaporator to give crude product. Bicyclohexyl fied as a white crystalline solid. m.p. 46–47 °C; Rf 0.35
(19.9 g, 80%) was recovered by fractional distillation (64–66 °C, (2.5 : 97.5 EtOAc : petrol); δH (500 MHz, C6D6) 2.10 (1H, s,
1.6–1.7 torr), and the orange residue identified as 3′-methyl- –OH), 1.98–1.88 (1H, m), 1.88–1.80 (1H, m), 1.80–1.66 (5H, m),
5′,6′,7′,7a′-tetrahydro-4′H-spiro(cyclohexane-1,1′-isobenzofuran) 1.63–1.57 (1H, m), 1.57–1.38 (8H, m) 1.35 (3H, s, CH3),
15 (2.19 g, 33% based on recovered starting material) and bi- 1.31–1.19 (2H, m), 1.14–1.03 (1H, m) ppm; δC (500 MHz, C6D6)
cyclohexyl mixture as an oil. δH (250 MHz) 2.33–0.80 (19H, m 105.9, 83.7, 45.8, 44.2, 38.8, 34.3, 29.1, 26.3, 25.2, 24.1, 24.0,
[including 1.67 (3H, s, –CH3)]) ppm; δC (75 MHz) 141.7 (vC- 23.9, 23.9, 23.0 ppm; vmax 3389, 2928, 2850, 1444, 1404, 1374,
(CH3)–O, 4°), 108.4 (CvC–C, 4°), 84.4 (–C–O, 4°), 53.6, 38.3, 1197, 1171, 1160, 1151, 1092, 1074, 946, 890, 875 cm−1
;
31.8, 27.8, 26.8, 26.7, 25.5, 24.2, 22.6, 22.5, 11.0 (–CH3) ppm; HRMS (ESI+) m/z calcd for (C14H24O2 + Na)+ 247.1669; found
vmax (film) 2924, 2852, 1447, 1353, 1265, 1221, 1180, 1143, 247.1691.
1088, 1034, 953, 928, 890, 839, 815, 737 cm−1; HRMS (ESI+)
1-((2R*,4aS*,8aR*)-2-Methyldecahydronaphthalen-4a-yl)-
ethanone 29. AcCl (11.6 g, 0.236 mol, 2.4 eq.) was added over
m/z calcd for (C14H22O + H)+ 207.1743; found 207.1710.
trans-Methyl 2-(cyclohex-1-enyl)cyclohexyl ketone 22. The 5 min to a suspension of AlCl3 (19.7 g, 0.148 mol, 1.5 eq.) in
above procedure for formation of 15 was carried out using CH2ClCH2Cl (60 mL), with stirring. The resulting pale yellow
AcCl (226 g), AlCl3 (240 g) and bicyclohexyl (200 g). Purification solution was cooled to 0 °C and bicyclo[5.4.0]undecane, 28,
of the crude by vacuum distillation (64–66 °C, 1.6–1.7 torr) led (15.0 g, 0.099 mol, 1.0 eq.) was added over 20 min. The reac-
to recovery of bicyclohexyl (101 g, 50%); an increase in temp- tion mixture was left to stir at 0 °C for 5 h. The deeper yellow
erature (104–108 °C, 1.5 torr) led to the isolation of trans- solution was slowly poured into a stirred ice-water slurry,
methyl 2-(cyclohex-1-enyl)cyclohexyl ketone 22 (9.38 g, 7.6% turning orange and back to yellow. The organic layer was
based on recovered starting material). δH (300 MHz) 5.34–5.31 extracted with CH2Cl2 (3 × 100 mL), washed with brine and
(1H, m,vCHR), 2.46 (1H, app td, J 11.1, 2.7 Hz, C(O)–CH<), dried over MgSO4, then filtered. The filtrate was concentrated
2.18–0.72 (20H, m [including 1.99 (3H, s, –CH3)]) ppm; under reduced pressure. Crude product purified by vacuum
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distillation (2.1–2.3 Torr, 76–90 °C) gave a mixture of enol
ethers and 1-((2R*,4aS*,8aR*)-2-methyldecahydronaphthalen-
4a-yl)ethanone 29 (9.55 g) as the major product. This was puri-
fied further by column chromatography (100% pentane to
1 : 99 EtOAc : pentane) to give 29 as a single isomer (Rf 0.22
in 1 : 99 EtOAc : pentane) as a colourless oil (4.46 g, 23%).
δH (400 MHz) 2.02 (3H, s, COCH3), 2.01–1.96 (2H, m),
1.91–1.80 (1H, m), 1.75–1.68 (1H, m), 1.59–1.49 (3H, m [includ-
ing 1.54, 1H, app q, J 11.9 Hz, Hc]), 1.48–1.36 (1H, m, Hb),
1.32–1.04 (7H, m [including 1.25–1.22, 1H, m, Ha]), 0.84 (3H,
d, J 6.3 Hz, CHCH3), 0.81–0.70 (1H, m) ppm; δC (100 MHz)
213.3 (CvO), 53.0 (4° C–CvO), 46.0 (3° HC–C–CvO), 37.9,
37.9, 37.8, 33.6 (CH–CH3), 32.0, 29.0, 26.9, 26.0 (COCH3), 23.5,
22.4 (CH–CH3) ppm; vmax 2922, 2856, 1700, 1453, 1352, 1299,
1209, 1184, 1164, 1135, 1113, 940, 914 cm−1; HRMS (ESI+) m/z
calcd for (C13H22O + Na)+ 217.1563; found 217.1564.
2 (a) W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011,
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J. W. Rasburn, Proc. Chem. Soc., 1959, 395; (c) G. Baddeley,
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1,1,3-Trimethyl-1,4,5,6,7,7a-hexahydroisobenzofuran 32. AcCl
(300 g, 3.82 mol, 2.4 eq.) was added over 20 min to a suspen-
sion of AlCl3 (319 g, 2.39 mol, 1.5 eq.) in CH2ClCH2Cl
(500 mL) and stirred for 20 min. The resulting yellow solution
was cooled to 0 °C. Over 90 min isopropylcyclohexane 31
(200 g, 1.59 mol, 1.0 eq.) was added, and the reaction mixture
stirred for a further 3.5 h. The resulting orange solution was
gradually added to a vigorously stirred slurry of ice-water
(500 mL); a cherry-red colour was observed, then orange. The
reaction mixture was divided into 5 portions; each one in turn
was transferred to a separating funnel and extracted with 1,2-
dichloroethane (2 × 100 mL). Organic extracts were combined
and washed with ice-water (2 × 100 mL), dried over MgSO4 and
filtered. The filtrate was concentrated under reduced pressure
to give the crude product. Distillation was performed at room
temperature under reduced pressure – unreacted isopropylcy-
clohexane was collected in a cold trap, as a mixture with a
byproduct identified as 1-chloroethylacetate. The residue was
shown by NMR to contain 1,1,3-trimethyl-1,4,5,6,7,7a-hexahy-
droisobenzofuran 32 as the major product. δH (250 MHz)
2.33–0.69 (18H, m) ppm; δC (75 MHz) 141.6 (vC(Me)–O, 4°),
108.2 (–C–O, 4°), 83.3 (CvC–C, 4°), 53.6, 29.6, 28.5, 26.6, 25.7,
24.2, 22.9, 11.2 ppm; TOF-MS (ESI+) m/z calcd for (C11H18O + H)+
167.1436; found 167.1440.
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Acknowledgements
We thank the University of Bath (studentship to C.L.L.) and
EPSRC (DTA studentship to M.U.-M.) for funding. We also
thank Dr Matthew Jones for use of a Parr hydrogenator,
Maksims Jevglevskis for translation and Dr Andrew L. Johnson
and the late Prof. J. Grant Buchanan for helpful discussions.
7 (a) Ethylene: H. T. Taylor, J. Chem. Soc., 1958, 3922–3924;
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H. T. Taylor and E. Rudd, J. Chem. Soc., 1961, 1342–1345;
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Soc., 1961, 1345–1347; (e) Cyclopentene, cyclohexene,
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This journal is © The Royal Society of Chemistry 2012
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Organic & Biomolecular Chemistry
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16 N. White, Patent #WO85/00619, 1985.
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32 has been reported previously, but complete
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20 Further experimental evidence for the mechanism 29 F. Yonehara, Y. Kido, H. Sugimoto, S. Morita and
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Org. Biomol. Chem.
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