Nucleophilic displacement of homoallylic tosylates: Influence of steric hindrance and conformational rigidity

Article abstract of DOI:10.1016/S0040-4020(01)00415-X

A comparative study on the nucleophilic displacement of homoallylic tosylates with different degrees of hindrance and rigidity is reported. π Bond participation is favoured by hindrance and rigidity, and also by weak nucleophiles such as water or dimethylformamide.

Full text of DOI:10.1016/S0040-4020(01)00415-X

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 4873±4879
Nucleophilic displacement of homoallylic tosylates:
in¯uence of steric hindrance and conformational rigidity
p
A. Fernandez-Mateos, M. Rentzsch, L. Rodrõguez Sanchez and R. Rubio Gonzalez
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Departamento de Quõmica Organica, Facultad de C. Quõmicas, Universidad de Salamanca, Plaza de los Caõdos 1-5,
37008 Salamanca, Spain
Received 1 August 2000; revised 24 January 2001; accepted 9 April 2001
AbstractÐA comparative study on the nucleophilic displacement of homoallylic tosylates with different degrees of hindrance and rigidity is
reported. p Bond participation is favoured by hindrance and rigidity, and also by weak nucleophiles such as water or dimethylformamide.
q 2001 Elsevier Science Ltd. All rights reserved.
The neighboring group participation by p bonds in aliphatic
nucleophilic substitution has been demonstrated for nor-
bornyl systems in kinetic and spectroscopic studies.1 We
have recently reported that tosylate 1 undergoes nucleo-
philic displacement with participation of the p bond when
it reacts with malonate and hydroxyl anions, while other
nucleophiles give a normal SN2 displacement.2
pivalate anion on the product distribution from the nucleo-
philic displacement of allylic substrates.6
The reactions were approached with two solvents and refer
to Eq. 41) and Table 1. Both solvents have a common
feature; the reaction rate increases as the size of the counter-
ion increased. The order of reactivity based on the size of
the cation is attributed to a decrease in ion pairing as the size
of the cation increases, taking into account that coulombic
attraction dominates over the counterion solvation.7
Among the plethora of factors that may affect the displace-
ment of homoallylic tosylates, here we have tested two that
to our knowledge have not been studied previously: the
in¯uence of steric hindrance in the homoallylic system
and the conformational rigidity of the system.
Signi®cant differences in the reaction products were
observed for each solvent. In DMPU, only the normal
displacement product 5 4XˆOPiv) was obtained. However,
in DMF, besides the SN2 product 5 4XˆOPiv) the bicyclic
formate 4 4XˆOCOH) was obtained, corresponding to the
homoallylic displacement of tosylate 1 by the solvent DMF.
The very low reactivity of lithium pivalate makes DMF a
good competitor 4Eq. 42)).
For the comparative displacement study we chose three
tosylates, a hindered and ¯exible one 1, an unhindered
and ¯exible one 2, and a hindered and rigid one 3 4Fig. 1).
The simplest compound 2, among the selected tosylates,
was obtained from Hagemann's ester by selective deoxy-
genation by the Srikrishna method,3 followed by reduction
and tosylation. The sterically hindered tosylate 1 was
obtained from a-cyclogeraniol4 and the rigid tosylate 3
from epi-drimenol.5
Tosylate 2 was selected for its functional and structural
characteristics, very similar to those of tosylate 1. The
main structural difference of tosylate 2 with respect to its
analogue 1 is the absence of the gem-dimethyl in the envir-
onment of the homoallylic system, which is expected to
facilitate normal SN2 nucleophilic displacement. The reac-
tion of 2 with a basic aqueous solution in DMF at 508C gave
exclusively the alcohol 6 4XˆOH). All the reactions
We began the study with the hindered and ¯exible tosylate 1
for which preliminary results obtained by reaction of 1 with
several nucleophiles have been reported elsewhere.2 Here,
the nucleophilic displacement study was extended to weak
nucleophiles such as pivalate salts. We were interested also
for the in¯uence of the size of the counterion in the nucleo-
philic displacement of tosylate 1 by the pivalate anion, in
relation with the reported effect of the cation associates to
Keywords: tosylate; nucleophile; hindrance.
Corresponding author. Fax: 1923-294574;
e-mail: afmateos@gugu.usal.es
p
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00 415-X

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A. Fernandez-Mateos et al. / Tetrahedron 57 -2001) 4873±4879
4874
The reaction of tosylate 2 with other nucleophiles, in a
parallel way to that described for tosylate 1 by us
previously,2 gave exclusively the products of normal
displacement 4Eq. 44)). Differences in the behaviour of
tosylates 1 and 2 were only found for the reaction with
sodium malonate. The hindered tosylate 1 gave homoallylic
ꢀ1†
Table 1.
DMF
DMPU
Nucleophile
Counterion
Time 48 h
conversion 4%)
Product ratio
5 4XˆOPiv):
Time 48 h
conversion 4%)
Product ratio
5 4XˆOPiv):
4 4XˆOCOH)
4 4XˆOCOH)
PivO2
PivO2
PivO2
Li1
Na1
K1
56
86
93
50:50
60:40
80:20
10
60
80
100:0
100:0
100:0
described in Eq. 43) and Table 2 with DMF as solvent were
slower than the correspondent was for tosylate 1 4Eq. 41),
Table 1). Likewise, all the products obtained arise from
normal SN2 nucleophilic displacement. These results
contrast with those obtained for the hindered tosylate 1
4Table 1) for which homoallylic displacement in the reac-
tion with the very weak nucleophile DMF was found. This,
together with the faster displacement reaction of tosylate 1,
is evidence of the neighboring group participation or the
existence of a homoallylic carbocation. It is thought that
in the case of tosylate 1 the hindered environment 4i.e.
gem-dimethyl) is responsible for this behaviour.
displacement, whereas the unhindered tosylate 2 gave
normal SN2 displacement.
ꢀ4†
The third substrate selected for the displacement study was
the bicyclic tosylate 3, which has both the steric hindrance
factor, found in tosylate 1, and a new factor: the confor-
mational rigidity. The results found for the reactions of
tosylate 3 with several different nucleophiles are described
in Eq. 45) and Table 3.
ꢀ2†
Table 3 shows those weak nucleophiles such as water and
ethanol 4entries 1 and 2) gave homoallylic displacement
exclusively, while pivalate and acetate anions 4entries 3
and 4) gave products from normal and homoallylic dis-
placement in equal amounts. This result contrasts with
that found for tosylate 1, for which no homoallylic displace-
ment was observed in the reaction with the pivalate anion.
The hydroxide anion is a stronger nucleophile than carbox-
ylates, but at the same time is a stronger base; these proper-
ties are re¯ected in the reaction with tosylate 3, which
afforded equal amounts of normal 7 and homoallylic 8
displacement and the elimination product 9 4entry 5).
Nothing new was observed for the reaction of 3 with respect
to 1 with the malonate anion 4homoallylic displacement)
and the phenyl sul®de anion 4normal displacement), 4entries
6 and 12). The results were completely new for the reaction
with the bromide or iodide anions, which afforded the elimi-
nation product 9, and the tricyclic unsaturated hydrocarbon
10, presumably formed by homoallylic displacement
The in¯uence of counterion size in the displacement of
tosylate 2 by pivalate anion in two solvents, DMF and
DMPU 4Table 2) was similar to that of the hindered tosylate
1. A small but signi®cant difference was found in DMPU
when tosylates 1 and 2 were compared. The normal SN2
displacement was faster for the less hindered tosylate 2 as
would be expected 4Tables 1 and 2).
ꢀ3†
Table 2.
Nucleophile
Counterion
DMF
DMPU
Time 48 h conversion 4%)
Product
Time 48 h conversion 4%)
Product
PivO2
PivO2
PivO2
Li1
Na1
K1
30
50
70
6 4XˆOPiv)
6 4XˆOPiv)
6 4XˆOPiv)
50
100
100
6 4XˆOPiv)
6 4XˆOPiv)
6 4XˆOPiv)

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4875
ꢀ5†
Table 3.
Entry
Nucleophile
T48C)
t 4h)
% Yield
7
8
9
10
1
2
3
4
5
6
7
8
EtOHa
5016
5016
506
506
7016
100
50340X
5016
5016
606
25
25
4X
4X
ˆOEt) 100
ˆOH) 95
5N H2O/NaOHb
NaOPiv
KOAc
4X
4X
4X
6
ˆOPiv) 46
ˆOAc) 504X
ˆOH) 36
4XˆOPiv) 53
ˆOAc) 48
4XˆOH) 32
4XˆCH4CO2Me)2) 86
4XˆCN) 19
37
NaOHc
NaCH4CO2Me)2
NaCN
NaBr
27
ˆCN) 73
61
61
9
10NaNO
11
12
NaI
32
4X
12
24
ˆONO) 56
4XˆOH) 97
4XˆSPh) 93
4XˆONO) 40
2
Me2CuLi
NaSPh/Bu4NBr
a
No DMF.
Solvent DMF.
No H2O.
b
c
followed by dehydrohalogenation 4entries 8 and 9). The
cyanide anion 4entry 7) gave mainly the normal displace-
ment product 7 4XˆCN) and some homoallylic displace-
ment 8 4XˆCN)8 as occurred for the nitrite anion 4entry
10). In the reaction of 3 with nitrite anion the respective
alkyl nitrites 10 and 11 4XˆONO) was obtained, which
were hydrolysed in the isolation procedure to alcohols 10
and 11 4XˆOH), respectively. It is interesting to note that
the last two nucleophiles gave the normal displacement
product 4i.e. the cyano and nitro compounds) in the reaction
with tosylate 1. Moreover, the ambidentate anion nitrite
attacks the tosylate 3 with the oxygen atom and the tosylate
1 with the nitrogen atom.
that found for tosylate 1 which afforded the normal displace-
ment product 5 4XˆMe) 4Eq. 41)).
1. Stereochemical outcome of nucleophilic displacements
The sterochemistry of the tricyclic alcohol 8 4XˆOH) 4Fig.
2), which arose from the homoallylic displacement of the
tosylate 3, was assigned according to its 1H NMR spectrum,
which among others shows a doublet signal centred at
4.18 ppm with a coupling constant of Jˆ5.5 Hz attributed
to the hydrogen geminal to the axial hydroxyl group 4Fig. 2).
The analogous signal of the corresponding acetate 8 4Xˆ
OAc) 4Fig. 2) appears as a double doublet at 5.18 ppm with
Jˆ6 Hz and J0ˆ2 Hz. The same tricyclic alcohol was
obtained by hydrolysis of the acetate 8 4XˆOAc), pivalate
8 4XˆOPiv) and nitrite 8 4XˆONO). From these data it is
clear that the entering nucleophile has the a orientation, which
is cis with respect to the cyclopropanic methylene. The situa-
tion must be similar for the cyano8 and malonate derivatives.
Finally, the reaction of 3 with the dimethyl lithium cuprate
reagent 4entry 11) afforded the alcohol 7 4XˆOH) which
must arise from the attack on the sulphur atom of the tosyl
group by the `methyl anion'. This result is also different to
The relative cis orientations of the hydroxyl group and the
cyclopropanic methylene in the bicyclic alcohols 4 4XˆOH)
are the same, as has been shown for the tricyclic alcohol 8.
1
These structures were elucidated through their H NMR
spectra, H±C correlations and NOE experiments. For the
trimethyl acetate 4, the signal triplet centred at 5.08 ppm
and JˆJ0ˆ6 Hz indicate an axial orientation for the acetate
group, which can be accommodated in two isomers; only
the isomer in which the cyclopropanic methylene and the
acetate group are cis can justify the NOE between the cyclo-
propanic hydrogen and the gem-dimethyl system.
Figure 2.

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A. Fernandez-Mateos et al. / Tetrahedron 57 -2001) 4873±4879
4876
Figure 3.
2. Discussion
GC/QP 5000 MS at 70 eV 4EI). Elemental analyses were
obtained on a LECO CHNS-932 instrument. All reactions
were carried out under an argon atmosphere in glassware
dried overnight and cooled under argon. Reactions were
monitored by TLC. Flash column chromatographies were
carried out using silica gel 60 40.040±0.063 mm Merck).
Organic extracts were dried with anhydrous Na2SO4 and
concentrated under reduced pressure with the aid of a rotary
evaporator.
From the data it is observed that while tosylate 2 only
afforded SN2 displacement products with all kind of nucleo-
philes assayed, the tosylate 3 gave mixtures of homoallylic
and normal displacements products, exception made of thio-
late and `methyl' nucleophiles. In the middle is the tosylate
1, which gave homoallylic displacement only with poor
nucleophiles 4H2O, DMF), and malonate anion. It seems
to be clear that nucleophile nature exclusively does not
control the regioselectivity observed. For example, pivalate
anion gave normal SN2 displacement with tosylates 1 and 2,
and homoallylic with 3; malonate anion gave normal displa-
cement with 2 and homoallylic with 1 and 3, We have not
found a general criterion to explain the reactivity pattern of
nucleophiles, for example, with tosylate 3, the anions iodide
and thiolate, which are both good nucleophiles and soft
bases shown different behaviour. Likewise, iodide 4good
nucleophile and soft base) and pivalate 4poor nucleophile
and hard base) anions show behaviour af®nities.
3.1.1. Reaction of tosylate 1 with pivalates saltsÐ
General procedure. To a stirred solution of tosylate 1
4308 mg, 1 mmol) in DMF or DMPU 44 ml) was added
pivalate salt 41.5 mmol). The reaction mixture was stirred
at 508C under argon atmosphere for 48 h. Diethyl ether was
added and the organic layer was washed with aqueous HCl
42N), NaHCO3 45%), brine, dried and evaporated. The resi-
due was chromatographed using hexane±diethyl ether.
3.1.2. 1,5,5-Trimethyl-bicyclo[4.1.0]heptan-2-yl formate
1
4 2XˆOCOH). Colourless oil: IR n 2955, 1724 cm21; H
The conformational rigidity and the good orientation of the
leaving group are the factors, which govern the p partici-
pation to give homoallylic displacement. In the bicyclic
tosylate 3 the double bond is in a geometric favourable
position for backward attack on the carbon bearing the
leaving group.
NMR d 0.25 41H, dd, Jˆ4 Hz, J0ˆ8 Hz), 0.60 42H, m), 0.92
43H, s), 1.06 43H, s), 1.12 43H, s), 5.21 41H, t, Jˆ6 Hz), 8.10
41H, s) ppm; MS m/z 4relative intensity) 182 41, M1), 154
45), 136 440), 121 479), 107 448), 93 4100), 81 455), 67 450),
55 462); HRMS 4EI) calcd for C11H18O2 182.1307, found
182.1336.
The tosylates 1 and 2 can adopt two main conformations
4Fig. 3) which differ in 0.3 kcal/mol, approximately;9
while for the trimethyl tosylate 1 the axial conformation is
favourite, the equatorial one is the main for the monomethyl
tosylate 2. The little energy difference between axial and
equatorial conformation will not justify the reactivity differ-
ences between 1 and 2, but it do if is added the steric
hindrance factor. In conclusion, when the leaving group is
in a correct orientation hindrance, rigidity, and poor nucleo-
philicity favour the p bond participation.
3.1.3. a-Cyclogeranyl pivalate 5 2XˆOCOPiv). Colour-
1
less oil: IR n 2967, 1728 cm21; H NMR d 0.91 43H, s),
0.94 43H, s), 1.18 49H, s), 1.71 43H, s), 4.04 41H, dd, Jˆ
3 Hz, J0ˆ11 Hz), 4.14 41H, dd, Jˆ5.5 Hz, J0ˆ11 Hz), 5.45
41H, m) ppm; MS m/z 4relative intensity) 238 41, M1), 181
412), 154 420), 136 422), 121 473), 107 425), 93 478), 81 440),
57 4100), 41 425); HRMS 4EI) calcd for C15H26O2 238.1933,
found 238.2001.
3.1.4. Reaction of tosylate 2 with H2O/NaOH. To a stirred
solution of tosylate 2 4280mg, 1 mmol) in DMF 44 ml) was
added 5N aqueous solution of NaOH 41 ml). The reaction
mixture was stirred at 508C under argon atmosphere for
48 h, and diluted with diethyl ether. The organic layer was
washed with aqueous HCl 42N), NaHCO3 45%), brine, dried
and evaporated. The residue was chromatographed using
hexane±diethyl ether to yield 42-methyl-cyclohex-2-enyl)-
methanol 6 4XˆOH) as a colorless oil 438 mg, 30%):
3. Experimental
3.1. General methods
Commercial reagents were used as received. Diethyl ether
was distilled from sodium. Dimethylformamide was
distilled under nitrogen from BaO. Hexane and ethyl acetate
were distilled before use. Melting points were determined
on a hot-stage apparatus and are not corrected. IR spectra
were obtained on a Bomem FT MB-100 as thin ®lms. 1H and
13C NMR spectra were recorded in CDCl3 solution on a
Bruker WP 200 SY 4200 and 50 MHz, respectively) or on
a Bruker Advance DRX 400 4400 and 100 MHz, respec-
tively). Mass spectra were obtained on a Shimadzu 17A
1
IR n 3349, 1022 cm21; H NMR d 1.63 43H, s), 1.89 43H,
m), 3.6042H, m), 5.47 41H, m) ppm; MS m/z 4relative
intensity) 126 442, M1), 108 478), 93 4100), 79 468), 67
492), 41 470).
3.1.5. Reaction of tosylate 2 with pivalates saltsÐ
General procedure. To a stirred solution of tosylate 2
4280mg, 1 mmol) in DMF or DMPU 44 ml) was added

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A. Fernandez-Mateos et al. / Tetrahedron 57 -2001) 4873±4879
4877
pivalate salt 41.5 mmol). The reaction mixture was stirred at
508C under argon atmosphere for 48 h. Diethyl ether was
added and the organic layer was washed with aqueous HCl
42N), NaHCO3 45%), brine, dried and evaporated. The resi-
due was chromatographed using hexane±diethyl ether.
HCl 42N), NaHCO3 45%), brine, dried and evaporated.
Evaporation of the solvent left the unsaturated ester 6
4XˆCH4CO2CH3)2) as a colorless oil 4306 mg, 85%): IR
m), 3.69 43H, s), 3.71 43H, s), 5.4041H, s) ppm; 13C NMR
d 21.7 42), 25.2, 26.9, 31.7, 36.5, 49.9, 52.3 42), 123.2,
135.6, 169.7, 170.0 ppm; MS m/z 4relative intensity) 240
45, M1), 206 422), 149 4100), 132 413), 123 4160, 105
415), 91 4660, 71 414), 57 430), 40 496); HRMS 4EI) calcd
for C13H26O4 240.1362, found 240.1357.
1
n 2980, 1750 cm21; H NMR d 1.63 43H, s), 3.46 41H,
3.1.6. 2-Methyl-cyclohex-2-enyl-methyl pivalate 6 2Xˆ
1
OCOPiv). Colorless oil: IR n 2930, 1732 cm21; H NMR
d 1.2049H, s), 1.7043H, s), 1.97 43H, m), 4.01 41H, dd,
Jˆ7 Hz, J0ˆ11 Hz), 4.15 41H, dd, Jˆ5 Hz, J0ˆ11 Hz), 5.50
1
41H, m) ppm; MS m/z 4relative intensity) 21041, M ), 108
488), 93 4100), 79 445), 67 421), 57 495); HRMS 4EI) calcd
for C13H22O2 210.1620, found 210.1653.
3.1.11. Reaction of tosylate 3 with CH3CH2OH. To a
solution of tosylate 3 4150mg, 0.4 mmol) in ethanol
42 ml) was heated at 508C under argon for 16 h. The solvent
was evaporated under reduced pressure to afford a residue,
which was dissolved in water and extracted with diethyl
ether. The extracts were washed with brine, dried and
evaporated to afford a colorless oil 4100 mg, 100%) identi-
®ed as 2-ethoxy-1a,4,4,7a-tetramethyl-decahydro-cyclo-
propa[a]naphthalene 8 4XˆOCH2CH3): IR n 2940, 1125
41H, dd, Jˆ6 Hz, J0ˆ9 Hz), 0.80 43H, s), 0.82 43H, s),
1.04 43H, s), 1.14 43H, s), 1.18 43H, t, Jˆ7 Hz), 3.51 43H,
m) ppm; 13C NMR d 11.7, 15.6, 19.0, 20.0, 21.5, 23.1, 25.6,
28.0, 32.4, 33.0, 33.4, 38.1, 40.0 42), 42.3, 63.2, 77.7 ppm;
HRMS 4EI) calcd for C17H30O 250.2297, found 250.2288.
3.1.7. 6-Bromomethyl-1-methyl-cyclohexene 6 2XˆBr).
A solution of tosylate 2 4200 mg, 0.7 mmol) in DMF
46 ml) was added NaBr 4216 mg, 2.1 mmol), and the reac-
tion mixture was stirred under argon at 808C for 48 h. Water
was added and the mixture was extracted with diethyl ether.
The organic layer was washed with aqueous NaHSO3 45%),
brine, dried and evaporated to yield a yellow oil 4119 mg,
88%) identi®ed as the bromo derivative 6 4XˆBr): IR n
1
cm21; H NMR d 0.13 41H, dd, Jˆ5 Hz, J0ˆ9 Hz), 0.45
1
2930, 1449, 648 cm21, H NMR d 1.7043H, s), 1.95 43H,
m), 3.4041H, dd, Jˆ9 Hz, J0ˆ10Hz), 3.60 41H, dd, Jˆ
4 Hz, J0ˆ10Hz), 5.55 41H, m) ppm; HRMS 4EI) calcd for
C8H13Br 188.0201, found 188.0197.
3.1.8. 2-Methyl-cyclohex-2-enylmethyl-azide 6 2XˆN3).
A solution of tosylate 2 4200 mg, 0.7 mmol) in DMF
43 ml) was added NaN3 4247 mg, 3.4 mmol), and the reac-
tion mixture was stirred under argon at 808C for 4 h. Diethyl
ether was added and the organic layer was washed with
water, brine, dried and evaporated to yield a colorless oil
4105 mg, 97%) identi®ed as the methyl azide 6 4XˆN3): IR
n 2930, 2097 cm21, 1H NMR d 1.69 43H, s), 1.98 43H, m),
3.25 41H, dd, Jˆ7, 12 Hz), 3.45 41H, dd, Jˆ4.5 Hz, J0ˆ
12 Hz), 5.55 41H, m) ppm, HRMS 4EI) calcd for C8H13N3
151.1109, found 151.1162.
3.1.12. Displacement of tosylate 3 with H2O/NaOH. To a
stirred solution of tosylate 3 4200 mg, 0.53 mmol) in DMF
42 ml) was added 5N aqueous solution of NaOH 40.5 ml).
The reaction mixture was stirred at 508C under argon atmos-
phere for 16 h and then diluted with diethyl ether. The
organic layer was washed with aqueous HCl 42N),
NaHCO3 45%), brine, dried and evaporated. The residue
was chromatographed using hexane±diethyl ether 480:20)
to yield 1a,4,4,7a-tetramethyl-decahydro-cyclopropa[a]-
naftalen-2-ol 8 4XˆOH) as a colorless solid 4112 mg,
41H, dd, Jˆ4 Hz, J0ˆ8 Hz), 0.6 42H, m), 0.82 43H, s), 0.84
43H, s), 1.05 43H, s), 1.18 43H, s), 4.13 41H, d, Jˆ
5.5 Hz) ppm; 13C NMR d 10.7, 18.8, 21.3, 22.8, 22.9,
26.7, 28.4, 32.3, 32.4, 33.4, 38.7, 39.6, 39.8, 42.1,
70.7 ppm; MS m/z 4relative intensity) 204 498, M1
2H2O), 189 451), 161 487), 148 438), 133 480), 119 4100),
105 492), 91 479), 77 460), 55 471), 41 481); Anal. calcd for
C15H260: C, 81.02, H, 11.79, found: C, 81.13, H, 11.91.
1
95%): mp 708C, IR n 3374, 2924 cm21; H NMR d 0.08
3.1.9. 1-Methyl-6-nitromethyl-cyclohexene 6 2XˆNO2).
A solution of tosylate 2 4200 mg, 0.7 mmol) in DMF
43 ml) was added NaNO2 4192 mg, 2.8 mmol), and the reac-
tion mixture was stirred under argon at 808C for 12 h.
Diethyl ether was added and the organic layer was washed
with aqueous HCl 42N), NaHCO3 45%), brine, dried and
evaporated to yield a colorless oil 4102 mg, 92%) identi®ed
as the nitro compound 6 4XˆNO2): IR n 2928, 1553, 1451,
1020 cm21, 1H NMR d 1.7043H, s), 1.95 43H, m), 3.69 42H,
m), 5.6041H, m) ppm; MS m/z 4relative intensity) 155 44,
M1), 140 428), 125 44), 111 413), 95 4100), 79 446), 67 470),
3.1.13. Reaction of tosylate 3 with sodium pivalate. To a
stirred solution of tosylate 3 4151 mg, 0.40 mmol) in DMF
41.6 ml) was added sodium pivalate 474 mg, 0.6 mmol). The
reaction mixture was stirred at 508C under argon atmos-
phere for 6 h. Diethyl ether was added and the organic
layer was washed with aqueous HCl 42N), NaHCO3 45%),
brine, dried and evaporated. The residue 4120mg) was
heated at 508C for 1 h in a mixture of ethanol 41 ml) and
water 40.2 ml) containing potassium hydroxide 44.6 mg,
0.83 mmol). After cooling and solvent removal, the residue
solid was dissolved in water and the solution was extracted
with diethyl ether. The extract was washed with brine, dried,
®ltered and evaporated. Chromatography of the residue
4hexane±diethyl ether, 70:30) gave 42,5,5,8a-tetramethyl-
1,4,4a,5,6,7,8,8a-octahydro-naftalen-1-yl)-methanol 7 4Xˆ
OH) as an oily compound 441 mg, 46%): IR n 3675,
40458); HRMS 4EI) calcd for C H13NO2 155.0946, found
8
155.0976.
3.1.10. Dimethyl 2-22-methyl-cyclohex-2-enylmethyl)
malonate 6 2XˆCH2CO2CH3)2). To a mixture of dimethyl
malonate 4309 mg, 2.3 mmol) and NaH 475 mg, 1.6 mmol)
in DMF 42 ml) was stirred at room temperature under argon
for 1 h. To this clear solution was added tosylate 2 4420mg,
1.5 mmol) in DMF 40.5 ml), and the mixture was heated at
re¯ux for 23 h. Then, was cooled, diluted with diethyl ether
and water was added dropwise. The organic layer was
separated, and the aqueous phase was extracted with
ether. The combined extract were washed with aqueous

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A. Fernandez-Mateos et al. / Tetrahedron 57 -2001) 4873±4879
4878
1045 cm21; 1H NMR d 0.84 43H, s), 0.88 43H, s), 0.90 43H,
s), 1.72 43H, s), 3.71 42H, m), 5.55 41H, br s) ppm; 13C NMR
d 18.8, 21.7, 22.1, 23.0, 24.0, 33.0, 33.2, 36.1, 36.8, 42.7,
43.4, 57.8, 61.3, 124.4, 131.5 ppm; HRMS 4EI) calcd for
C15H26O 222.1984, found 222.1979.
The organic layer was separated, and the aqueous phase was
extracted with ether. The combined extract were washed
with aqueous HCl 42N), NaHCO3 45%), brine, dried and
evaporated. Evaporation of the solvent left dimethyl 2-
41a,4,4,7a-tetramethyl-decahydro-cyclopropa[a]naphthalen-
2-yl)-malonate 8 4XˆCH4CO2CH3)2) as a colorless oil
41H, dd, Jˆ5 Hz, J0ˆ8 Hz), 0.41 42H, m), 0.73 43H, s),
0.75 43H, s), 1.01 43H, s), 1.09 43H, s), 3.39 41H, d, Jˆ
10Hz), 3.71 43H, s), 3.73 43H, s) ppm; 13C NMR d 12.93,
17.42, 18.75, 21.27, 22.28, 23.16, 28.78, 32.42, 32.83,
33.36, 38.02, 38.44, 39.90, 41.16, 42.27, 52.14 42), 55.78,
169.29, 169.51 ppm; MS m/z 4relative intensity) 336 43,
M1), 204 495), 189 459), 175 414), 161 439), 138 434), 133
479), 119 4100), 105 467), 95 464), 69 467), 55 473), 41 473);
HRMS 4EI) calcd for C20H32O4 336.2301, found 336.2291.
1
The second fraction 447 mg, 53%) as identi®ed with alcohol
8 4XˆOH).
443 mg, 86%): IR n 2985, 1738 cm21; H NMR d 0.05
3.1.14. Reaction of tosylate 3 with potassium acetate. To
a stirred solution of tosylate 3 456 mg, 0.15 mmol) in DMF
41 ml) was added potassium acetate 444 mg, 0.45 mmol).
The reaction mixture was stirred at 508C under argon atmos-
phere for 6 h. Diethyl ether was added and the organic layer
was washed with aqueous HCl 42N), NaHCO3 45%), brine,
dried and evaporated. Chromatography of the residue
4hexane±diethyl ether, 90:10) gave 1a,4,4,7a-tetramethyl-
decahydro-cyclopropa[a]naphthalen-2-yl acetate 8 4Xˆ
OCOCH3) as a colorless oil 419 mg, 48%): IR n 2940,
3.1.17. Displacement of tosylate 3 with NaCN. To a solu-
tion of tosylate 3 4100 mg, 0.26 mmol) in DMF 42 ml) was
added NaCN 473 mg, 1.5 mmol), and the reaction mixture
was stirred under argon at 508C for 30h. Diethyl ether was
added and the organic layer was washed with water, brine,
dried and evaporated. The residue was chromatographed
using hexane±diethyl ether 495:5). The ®rst fraction
412 mg, 19%) was identi®ed as 2-cyanato-1a,4,4,7-tetra-
methyl-decahydro-ciclopropa[a]naphthalene 8 4XˆCN):
1
1748 cm21; H NMR d 0.13 41H, dd, Jˆ5 Hz, J0ˆ4 Hz),
0.54 41H, dd, Jˆ6 Hz, J0ˆ8 Hz), 0.77 43H, s), 0.78 43H, s),
0.79 41H, m), 1.04 43H, s), 1.12 43H, s), 2.04 43H, s), 5.18
41H, dd, Jˆ2 Hz, J0ˆ6 Hz) ppm, MS m/z 4relative intensity)
264 410, M1), 222 413), 204 437), 189 455), 161 430), 149
432), 133 456), 119 4100), 105 470), 93 459), 69 459), 55 471),
43 487); HRMS 4EI) calcd for C17H28O2 264.2089, found
264.2091.
1
IR n 2965, 2250cm 21; H NMR d 0.36 41H, m), 0.68
42H, m), 0.83 43H, s), 0.86 43H, s),1.09 43H, s), 1.16 43H,
s), 3.00 41H, m) ppm; MS m/z 4relative intensity) 231 412,
M1), 216 478), 199 412), 191 412), 175 415), 160410), 146
416), 124 488), 119 441), 109 4100), 95 455), 81 465), 55 460),
41 470); HRMS 4EI) calcd for C16H25N 231.1987, found
231.1976.
The second fraction 421 mg, 53%) was identi®ed as
2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydro-naphthalen-
1-ylmethyl acetate 7 4XˆOCOCH3) as a colorless oil
1
420mg, 50%): IR n 2985, 1750cm 21; H NMR d 0.78
43H, s), 0.79 43H, s), 0.85 43H, s), 1.58 43H, s), 2.04 43H,
s), 4.1042H, m), 5.49 41H, br s) ppm; HRMS 4EI) calcd for
C17H28O2 264.2089, found 264.2075.
The second fraction 445 mg, 73%) was an oily compound
identi®ed as 42,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octa-
hydro-naphthalenyl)-acetonitrile 7 4XˆCN): IR n 2935,
3.1.15. Reaction of tosylate 3 with NaOH. To a stirred
solution of tosylate 3 447 mg, 0.12 mmol) in DMF 43 ml)
was added sodium hydroxide 415 mg, 0.37 mmol). The
reaction mixture was stirred at 708C under argon atmos-
phere for 16 h, and then diluted with diethyl ether. The
organic layer was washed with aqueous HCl 42N),
NaHCO3 45%), brine, dried and evaporated. The residue
was chromatographed using hexane±diethyl ether 495:5).
The ®rst fraction 47 mg, 27%) was an oily compound
identi®ed as 1,1,4a,6-tetramethyl-5-methylene-1,2,3,4,4a,
1
2239 cm21; H NMR d 0.87 43H, s), 0.89 43H, s), 1.16
43H, s), 1.76 43H, s), 2.34 42H, m), 5.47 41H, br s) ppm,
MS m/z 4relative intensity) 231 412, M1), 216 470), 188 414),
174 410), 160 412), 147 420), 135 426), 123 437), 107 428), 95
4100), 69 492), 55 470), 41 492); HRMS 4EI) calcd for
C16H25N 231.1987, found 231.1972.
3.1.18. Displacement of tosylate 3 with NaBr. A solution
of tosylate 3 454 mg, 0.14 mmol) in DMF 42 ml) was added
NaBr 444 mg, 0.4 mmol), and the reaction mixture was
stirred under argon at 508C for 16 h. Water was added and
the mixture was extracted with diethyl ether. The organic
layer was washed with aqueous NaHSO3 45%), brine, dried
and evaporated. The residue was chromatographed using
hexane±diethyl ether 499:1). The ®rst fraction 418 mg,
61%) was identi®ed as 1a,4,4,7a-tetramethyl-1a,3a,4,5,6,7,
7a,7b-octahydro-1H-cyclopropa[a]naphthalene 10: IR n
5,8,8a-octahydro-naphthalene 9: IR n 3078, 1650 cm21
;
1H NMR d 0.86 43H, s), 0.92 43H, s), 0.96 43H, s), 1.80
43H, s), 4.79 41H, s), 4.83 41H, s), 5.66 41H, br s) ppm, MS
m/z 4relative intensity) 204 416, M1), 189 411), 161 415),
133 446), 119 4100), 105 452), 91 437), 69 425), 55 441), 41
463); HRMS 4EI) calcd for C15H24 204.1878, found
204.1890. The second fraction 49 mg, 32%) was identi®ed
as the alcohol 8 4XˆOH). The third compound 410mg,
36%) was identi®ed as the alcohol 7 4XˆOH).
1
3049, 1653 cm21; H NMR d 0.41 41H, dd, Jˆ4 Hz, J0ˆ
7 Hz), 0.57 41H, dd, Jˆ5 Hz, J0ˆ8 Hz), 0.86 43H, s), 0.87
43H, s), 0.88 43H, s), 1.16 43H, s), 5.33 41H, dd, Jˆ3 Hz,
J0ˆ10Hz), 5.8041H, dd, Jˆ3 Hz, J0ˆ10Hz) ppm; MS m/z
4relative intensity) 204 465, M1), 189 432), 161 462), 147
424), 133 465), 119 490), 105 485), 91 467), 77 445), 55 468),
41 4100); HRMS 4EI) calcd for C15H24 204.1878, found
204.1854. The second fraction 411 mg, 37%) was identi®ed
as the alkene 9.
3.1.16. Reaction of tosylate 3 with NaCH2CO2CH3)2. A
mixture of dimethyl malonate 431 mg, 0.23 mmol) and 50%
NaH 48 mg, 0.18 mmol) in DMF 42 ml) was stirred at room
temperature under argon for 1 h. To this clear solution was
added tosylate 3 456 mg, 0.15 mmol) in DMF 40.5 ml), and
the mixture was heated at 1008C for 6 h. Then, was cooled,
diluted with diethyl ether and water was added dropwise.

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A. Fernandez-Mateos et al. / Tetrahedron 57 -2001) 4873±4879
4879
3.1.19. Displacement of tosylate 3 with NaI. A solution of
tosylate 3 463 mg, 0.16 mmol) in DMF 42 ml) was added
NaI 475 mg, 0.5 mmol), and the reaction mixture was stirred
under argon at 508C for 16 h. Water was added and the
mixture was extracted with diethyl ether. The organic
layer was washed with aqueous NaHSO3 45%), brine,
dried and evaporated The residue was chromatographed
using hexane±diethyl ether 499:1). The ®rst fraction
421 mg, 61%) was identi®ed as alkene 10. The second frac-
tion 411 mg, 32%) was identi®ed as the alkene 9.
combined extract were washed with brine and dried.
Evaporation of the solvent left 1a,4,4,7a-tetramethyl-2-
phenylsulfanyl-decahydro-cycloprop[a]naphthalene 7 4Xˆ
SPh) as a yellow oil 435 mg, 93%): IR n 3060, 2950,
1
1600, 1470 cm21; H NMR d 0.88 43H, s), 0.90 43H, s),
0.93 43H, s), 1.65 43H, d, Jˆ2 Hz), 2.8041H, dd, Jˆ
12 Hz, J0ˆ2 Hz), 3.08 41H, dd, Jˆ6 Hz, J0ˆ12 Hz), 5.38
41H, br s), 7.2±7.5 45H, m) ppm; 13C NMR d 18.61,
21.64, 21.92, 22.96, 24.06, 32.81, 33.01, 35.25, 36.58,
36.76, 42.44, 42.60, 54.36, 121.80, 127.06, 127.60,
128.64, 128.91, 129.18, 134.46, 138.21 ppm; MS m/z 4rela-
tive intensity) 314 43, M1), 264 45), 218 498), 185 410), 154
415), 109 4100), 95 420), 65 440); HRMS 4EI) calcd for
C21H30S 314.2068, found 314.2094.
3.1.20. Reaction of tosylate 3 with NaNO2. A solution of
tosylate 3 460mg, 0.16 mmol) in DMF 43 ml) was added
NaNO2 445 mg, 0.6 mmol), and the reaction mixture was
stirred under argon at 608C for 6 h. Diethyl ether was
added and the organic layer was washed with water, brine,
dried and evaporated. The residue was chromatographed
using hexane±diethyl ether 470:30). The ®rst fraction
420mg, 56%) was identi®ed as the alcohol 7; the second
fraction 414 mg, 40%) was identi®ed as the alcohol 8
4XˆOH).
Acknowledgements
Financial support for this work from Ministerio de Edu-
Â
Â
y Leon SA 24/00B is gratefully acknowledged.
cacion y Ciencia of Spain PB 98-0251 and Junta de Castilla
3.1.21. Reaction of tosylate 3 with CH3CuLi. To a suspen-
sion of CuI 493 mg, 0.65 mmol) in diethyl ether 42.5 ml) was
added 1 M CH3Li 41.3 mmol, 1.3 ml) at 08C and the reaction
mixture was stirred for 30min. To this clear solution was
added dropwise tosylate 3 4113 mg, 0.3 mmol) in diethyl
ether 41 ml) and the mixture was stirred at room temperature
for 12 h. Then, was added dropwise a saturated NH4Cl solu-
tion and the mixture was extracted with diethyl ether. The
organic layer was washed with brine, dried and evaporated.
Evaporation of the solvent afforded the unsaturated alcohol
7 4XˆOH) 465 mg, 97%).
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4
1023 mmol) in a mixture of benzene/H2O 40.5 ml, ben-
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aqueous phase was extracted with diethyl ether. The
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