Experimental and theoretical investigations for the tandem alkylation-isomerization reactions between unsaturated carboxylic acids and allyl halides

Article abstract of DOI:10.1016/S0040-4020(03)01028-7

Alkylation of dienediolates from unsaturated carboxylic acids with allylic halides when followed by solventless thermal treatment at 150 to 200°C afford rearranged products on a trend highly dependent on the α carbon substitution. Thus, 2,2-bisallylated acids with H atoms at C-2 lead to its 1,3-shift, whereas 2-methyl-2,2-bisallylated acids lead to the corresponding Cope rearrangement product. In the latter case, this tandem allylation-Cope reaction lead, in a highly regio and diastereoselective way, to products not accessible from direct alkylation. B3LYP/6-31G* energies for the compounds involved at these isomerizations are in reasonable agreement with the experiments, allowing to explain the formation of the more stable product under thermodynamic equilibrations.

Full text of DOI:10.1016/S0040-4020(03)01028-7

Tetrahedron 59 (2003) 6233–6239
Experimental and theoretical investigations for the tandem
alkylation–isomerization reactions between unsaturated
carboxylic acids and allyl halides
Luis R. Domingo,a,b Salvador Gil,a Margarita Parra,a Jose A. Saeza,b and Mercedes Torresa
,
*
´
´
a
´
´
`
Departament de Quımica Organica, Universitat de Valencia, C/Dr. Moliner 50, 46100 Burjassot, Spain
bInstituto de Ciencia Molecular, Universidad de Valencia, Spain
Received 8 May 2003; revised 2 June 2003; accepted 30 June 2003
Abstract—Alkylation of dienediolates from unsaturated carboxylic acids with allylic halides when followed by solventless thermal
treatment at 150 to 2008C afford rearranged products on a trend highly dependent on the a carbon substitution. Thus, 2,2-bisallylated acids
with H atoms at C-2 lead to its 1,3-shift, whereas 2-methyl-2,2-bisallylated acids lead to the corresponding Cope rearrangement product. In
the latter case, this tandem allylation-Cope reaction lead, in a highly regio and diastereoselective way, to products not accessible from direct
alkylation. B3LYP/6-31Gp energies for the compounds involved at these isomerizations are in reasonable agreement with the experiments,
allowing to explain the formation of the more stable product under thermodynamic equilibrations.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
satisfactorily achieved despite some limited success by
counter ion interchange,7,8 or addition of crown ethers.9 As
an alternative to diastereoselective g-alkylation, we have
described the esterification of 3-methyl-2-butenoic acid
with allylic alcohols and consecutive Ireland–Claisen and
Cope rearrangements.10
Regio and stereoselectivity studies on the reaction of
lithium dienediolates with several electrophiles have been
reported in the last years1–3 showing that, on reaction with
primary halides, the regioselectivity of the corresponding
alkylation products strongly depends on the reactivity of
the electrophile. Saturated alkyl halides show a high
a-selectivity regardless of steric effects, whereas highly
reactive allyl and benzyl halides lead to poor a-selectivities
when steric effects become significant.4 It is worth to note
that lithium halide and carboxylate, generated in the
ongoing reaction, have opposite effects on the regioselec-
tivity, a-selectivity is favoured by the first whereas the
second leads to lower a/g ratios. Combination of both
effects renders the alkylation process less selective along the
progress to its end.
The latter results showed the way to a simple approach to
g-regioselective alkylation by a tandem process of diene-
diolate alkylation-Cope rearrangement. The resulting pro-
ducts, equivalent to those g-products expected from a
0
conjugate substitution (SN ) of the corresponding allylic
halide and dienediolate, are not accessible by direct
alkylation because a complete regioselectivity towards the
direct substitution of the halide (SN2) have always been
observed.4 We want to report here the scope and limitations
of this method by using representatives unsaturated acids
and allyl halides.
Comparable small effects on the regioselectivity were
observed when reaction conditions are modified, such as
concentration of reagents, higher amounts of halide, deficit
of amine, temperature or inversion in the order of addition
of reagents. On the contrary, important changes were
observed when the nature of the leaving group was changed
and a-regioselectivity is obtained with sulfonyloxyalkene as
alkylating agent.5,6 However, regioselective g-alkylation of
dienediolates of unsaturated carboxylic acids has not yet
2. Results and discussion
We have prepared alkylation products of lithium p-exten-
ded enolates of unsaturated carboxylic acids (1–3) with
allylic primary halides (a–c) (Scheme 1). Alkylation have
been carried out under standard conditions11 (see Section 3).
Results, yield and a/g ratios, are summarized in Table 1.
Some structure-regioselectivity correlations can be found:
Allyl are less selective than saturated halides because
reaction time is very short and alkylation is practically
complete by the end of the addition of the electrophile at
Keywords: allyl halides; unsaturated carboxylic acids; Cope rearrangement;
H migration; regioselectivity; DFT calculation.
*
Corresponding author. Tel.: þ34-(9)63544339; fax: þ34-(9)63543152;
e-mail: margarita.parra@uv.es
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01028-7

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L. R. Domingo et al. / Tetrahedron 59 (2003) 6233–6239
Scheme 1.
2788C. a-Selectivity strongly depends on the steric
hindrance, but cinnamyl bromide (b) lead exclusively to
a-alkylation products regardless the substitution of the acid.
A p-stacking effect, in the transition state, between both
p-systems could approach the C–Br bond to the dienedio-
late C-2 and thus, overcoming steric effects.
a-adducts to the tautomeric products 13HM is observed by
1,3-hydrogen migration. No CR products were observed in
any case, despite several modifications of reaction con-
ditions. 13HM products are synthetically interesting as they
are not accessible by direct alkylation and this curious result
deserved a theoretical study.
Cope rearrangement (CR) was optimized by previous
purification of each a-regioisomer. But we have checked
that a tandem procedure (alkylation and heating of the
evaporated crude acidic fraction) is feasible with a minor
decrease of yield. The best conditions were to heat at 2008C
the acid in a sealed pressure tube for 5 days without solvent.
In some cases, no more than 1508C can be used as higher
temperature leads to decomposition of product (see Table
1). Yields are quantitative in every case, with no loss of
starting mass. Isomerization is very successful for a-allyl
derivatives and only the addition product from acid 1 and
halide a gives a final isomerization product with 39% of
a-adduct unconverted (entry 1, Table 1). This ratio does not
change with time and the mixture lead to decomposition at
higher temperatures. Similar behavior is obtained for the
a-adducts of tiglic acid 2 with halides b and c where a final
mixture a:CR (ca. 30:70) is obtained despite time and
temperature modifications (entries 5 and 8; Table 1). As
mentioned above, this CR products would match with those
Density functional theory (DFT) calculations at the
B3LYP/6-31Gp level have been performed in order to
rationalize the experimental results. The mechanism of the
CR for the 1,5-hexadiene has been widely studied.12–22 The
barrier for the CR reaction computed at the B3LYP/6-31Gp
level, 34.2 kcal/mol, was estimated closer to the experi-
mental value, 33.5 kcal/mol.12 The reaction takes place
trough a chair transition state where the bonds are breaking
and forming in a concerted fashion. The barrier for the CR
for the acid derivative 1a presents a lower value, 28.4 kcal/
mol. The presence of the carboxyl substituent on the
1,5-hexadiene system decreases the barrier of the CR in ca.
5 kcal/mol. These large barriers justify the high temperature
required for these CRs. The geometry of the corresponding
chair transition structure, TS-CR, is given in Figure 1. The
lengths of the breaking and forming bonds along the
˚
concerted process are 2.083 and 2.133 A. These values are
slightly larger than those computed for the CR of the
12
˚
1,5-hexadiene 1.969 A. On the other hand, we have also
0
from an hypothetical g-addition-SN of acid 2 to halides b
and c.
calculated the barrier for the concerted 13HM process. For
but-3-enoic acid, as a reduced model of the b,g-unsaturated
acids 1a–3b, the barrier for the 13HM is 82.8 kcal/mol.
This very large value prevents the 13HM through a
Surprisingly, in some cases, a quantitative conversion of
Table 1. Alkylation of dienolate of tiglic acid (1). Introduction of additives
Entry
Acid
R–X
Addition yield (%)
Proportion a:g
Isomerization yield (%)
Proportion
a
cr
hm
1
2
3
4
5
6
7
8
9
1
2
3
1
2
3
1
2
3
a
a
a
b
b
b
c
c
c
77
90
68
58
84
58
63
72
70
68:32
71:29
82:18
100:0
100:0
100:0
64:36
36:64
89:11
100
100
100
100
100
100
100
100
100
39
0
0
0
23
0
0
34
0
61
100
100
0
77
0
0
66
0
0
0
0
100a
0
100a
100a
0b
100
a
At 1508C.
Starting form isolated a-adduct only.
b

L. R. Domingo et al. / Tetrahedron 59 (2003) 6233–6239
6235
Scheme 2.
Figure 1. B3LYP/6-31Gp geometry of the TS corresponding to Cope
rearrangement of 1a, TS-CR. The bond lengths directly involved in the
reaction are given in angstroms.
For the phenyl derivative series, 1b–3b the isomers
containing the framework IV, isomers of the 13HM, are
thermodynamically more favorable than the those contain-
ing the framework V, isomers of the CR, because of the lost
of conjugation at the latter. For 1b and 3b there are a
complete conversion on the 13HM products (100%) (entries
4 and 6, Table 1) in clear agreement with the energetic
results (1b–hm and 3b–hm in Table 2). The more stable
isomer under equilibrium conditions corresponds to the
structure III/IV where the two C–C double bonds remain
conjugated to both carboxyl and phenyl p systems. For
the CR of the derivatives 1b and 3b the processes are
endothermic in 0.8 and 1.2 kcal/mol, respectively. For the
2-methyl derivative 2b, for with the 13HM is not feasible,
the 23:77 composition of the mixture of reaction account for
a DG437¼21.13 kcal/mol. This value is in reasonable
agreement with that computed for DE for the CR,
21.7 kcal/mol. The low conversion for 2b can be
rationalized as a consequence of the lost of the phenyl
conjugation on the framework V along the CR.
concerted path. Therefore, 13HM must take place though a
stepwise mechanism involving radical or ionic species.
An analysis of the thermodynamic data for the CR and
13HM isomerizations of the acid derivative 1a shows that
these reactions present a very low value of DS503, 0.7 and
0.8 cal/mol K, respectively. In consequence, the TDS
contribution to DG is less than 0.5 kcal/mol. As a
consequence, the computed values of DE for both reactions,
27.2 kcal/mol for the CR and 26.0 kcal/mol for the 13HM,
are found to be closer to the computed values of DG503
,
27.0 and 25.0 kcal/mol, respectively. Therefore, the values
of DE for the CR and 13HM reactions of the acids 1a–3b
will be used for the energetic discussion. The calculated
B3LYP/6-31Gp total and relative energies of compounds
involved in CR and 13HM reactions of the tiglic acid
derivatives 1a–3c are given in Table 2. A first analysis of
the energetic results indicates that while the 13HM
processes are exothermic in the range of 22.8 to
26.8 kcal/mol, the DE for the CR processes are between
2.2 and 29.6 kcal/mol.
Finally, an analysis of the experimental result given in Table
1 for the dimethyl substituted alkenes 1c–3c indicates a
similar behavior than that found for the phenyl substituted
1b–3b one. For the derivatives 1c and 3c the 13HM take
place in a 100%, in clear agreement with the DE given in
Table 2. The structures containing the framework IV
present a larger stabilization than those containing the
framework V, because the larger alkyl substitution on
the former. For the b,g-unsaturated acid 2c, for which the
13HM is not feasible, the 36:66 composition of the mixture
of the CR account for a DG443¼20.50 kcal/mol. This low
value indicates a closer stabilization for the conjugated
carboxyl system present at the framework III, and the
trialkyl substituted C–C double bond present at the
framework IV. Along the CR of 2c the energetic
In order to perform a systematic analysis of both
experimental and theoretical results the structures of the
compounds involved in the isomerizations of the acid
derivatives 1a–3c have been shared in the frameworks I–V
given in Scheme 2. In this Scheme the frameworks II/V
correspond with the CR products, while III/IV ones
correspond with the 13HM products. For 1a the IV and V
frameworks are structural equivalents with the same energy.
Therefore, the absence of the product of the 13HM together
with the closer energies computed for CR and 13HM
products for 1a indicate that the barrier for the 13HM of 1a
must be larger than that for the CR one.
Table 2. Total (in au) and relative energies (DE, in kcal/mol, in parenthesis) for reactants and CR and 13HM products for the thermal isomerization of the acid
derivatives 1a–3c
a-al
1a-cr
1a-hm
2423.175058
2423.187060 (27.5)
2423.184669 (26.0)
a-al
2a-cr
2462.487829
2462.503168 (29.6)
a-al
3a-cr
3a-hm
2462.492282
2462.503866 (27.3)
2462.499158 (24.3)
1b-al
1b-cr
1b-hm
2654.235589
2654.234389 (0.8)
2654.246417 (26.8)
2b-al
2b-cr
2693.547524
2693.550169 (21.7)
3b-al
3b-cr
3b-hm
2693.552768
2693.550793 (1.2)
2693.559906 (24.5)
1c-al
1c-cr
1c-hm
2501.812494
2501.812242 (0.2)
2501.820791 (25.2)
2c-al
2c-cr
2541.123653
2541.128177 (22.8)
3c-al
3c-cr
3c-hm
2541.130733
2541.127149 (2.2)
2541.135225 (22.8)
Relative to 1a-al–3c-al. The -al, -cr and -hm acronyms are related to the alkylation, the Cope rearrangement and the -hydrogen migration products,
respectively.

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L. R. Domingo et al. / Tetrahedron 59 (2003) 6233–6239
stabilization obtained with the carboxyl conjugation is lost
in part with the destabilization of the non-conjugated C–C
double bond, and a mixture of both isomers is obtained in
agreement with the reversible character of the CR process.
(3£15 mL). The aqueous layer was acidified under ice-
cooling bath by careful addition of conc. hydrochloric acid,
and then extracted with ethyl acetate (3£15 mL). The
organic layer was washed with brine and dried (MgSO4).
Evaporation of solvent gave the crude acid reaction mixture.
For analytical purposes individual components of mixtures
were isolated by column chromatography.
In conclusion, thermal treatment of the alkylation products
of dienediolates from unsaturated carboxylic acids with
allylic halides affords rearranged products depending on the
a carbon substitution. Thus, 2,2-bisallylated acids with H
atoms at C-2 lead to its 1,3-shift, whereas when 2-methyl
substituted, the corresponding Cope rearrangement products
are obtained. In the latter case, this tandem allylation-Cope
reaction lead, in a highly regio and diastereoselective way,
to products not accessible from direct alkylation.
3.1.1. Alkylation of (E)-2-butenoic acid with allyl
bromide. From (E)-2-butenoic acid
1
(194 mg,
2.25 mmol) and allyl bromide a (0.2 mL, 2.25 mmol).
Work-up gave white oil (219 mg, 77%) as a a:g mixture
(68:32), which on separation by column chromatography
gave 2-vinyl-pent-4-enoic acid 1a-a4,7 as a white oil:
HRMS found Mþ 126.0678, C7H10O2 requires 126.0680;
nmax 3100–2740 (OH), 1695 (CvO), 1415, 1275 and
910 cm21; dH 11.66 (1H, br s, COOH), 5.89–5.68 (2H, m,
2CHvCH2), 5.22–5.00 (4H, m, 2CHvCH2), 3.12 (1H, dd,
J¼14.7, 4.5 Hz, CH–CO2H), 2.39–2.30 (1H, m, CH2),
2.23–2.19 (1H, m, CH2) ppm; dC 179.9 (COOH),
135.1 (CH2vCHCH2), 134.8 (CH2vCH), 117.5
(CH2vCHCHCOOH), 115.9 (CH2vCHCH2), 50.1
(CHCOOH), 36.3 (CH2CHCOOH) ppm.
DFT calculations for DE for the CR and 13HM of the
a-alkylated b,g unsaturated acids 1a–3c are in reasonable
agreement with the expected DG for the isomerization
processes. An analysis for the thermodynamic stabilization
of the alkenyl frameworks I–V present on the CR and
13HM products of isomerization reactions allows to explain
the behaviors of these acid derivatives. Under equilibrium
conditions these reactions appear to be controlled by the
maximum stabilization of the diene systems present on these
acid derivatives.
Further elution allowed isolation of (E)-hepta-2,6-dienoic
acid 1a-g4,7 as a white oil: HRMS found Mþ 126.0686,
C7H10O2 requires 126.0680; nmax 3100–2740 (OH), 1635
(CvO), 1220 and 975 cm21; dH 11.66 (1H, br s, COOH),
7.07 (1H, dt, J¼15.9, 6.9 Hz, CHvCHCO2H), 6.78 (2H,
m, CHvCH2 and CHvCHCO2H), 5.22–5.00 (2H, m,
CHvCH2); 2.58–2.48 and 2.39–2.30 (4H, m, 2CH2) ppm;
dC 172.3 (COOH), 151.6 (CHvCHCOOH), 137.1
(CH2vCH), 121.3 (CHCOOH), 118.2 (CH2v), 32.1
(CH2vCHCH2), 31.8 (HOOCCHvCHCH2) ppm.
3. Experimental
Mps were determined with a Reichert apparatus and are
uncorrected. IR spectral data were obtained for liquid film or
KBr discs, with a Perkin–Elmer 281 spectrophotometer.
NMR spectra were recorded for CDCl3 solutions, with a
Varian Unity 300 or Unity 400 spectrometers. High
resolution mass spectra were determined with a UG
Autoespec spectrometer. Silica gel Merck 60 (230–400
mesh) was used for flash column chromatography, with
hexane/diethylether mixtures for elution.
3.1.2. Alkylation of (E)-2-methyl-2-butenoic acid with
allyl bromide. From (E)-2-methyl-2-butenoic acid 2
(225 mg, 2.25 mmol) and allyl bromide a (0.2 mL,
2.25 mmol). Work-up gave a white oil (284 mg, 90%) as a
a:g mixture (71:29), which on separation by column
chromatography gave 2-methyl-2-vinyl-pent-4-enoic acid
2a-a4,7 as a white oil: HRMS found Mþ 140.0835, C8H12O2
requires 140.0837; nmax 3100–2800 (OH), 1690 (CvO),
1640 (CvC), 1415, 1280, 995 and 915 cm21; dH 6.02
(1H, dd, J¼17.1, 10.8 Hz, CHvCH2), 5.84–5.68 (1H, m,
CH2–CHvCH2), 5.18–4.98 (4H, m, 2CHvCH2), 2.50
(1H, dd, J¼13.8, 7.2 Hz, CH2), 2.34 (1H, dd, J¼13.8,
7.2 Hz, CH2), 1.27 (3H, s, CH3) ppm; dC 182.1 (COOH),
140.5 (CHv), 133.3 (CH2–CHv), 118.5 (CH2vCH–CH2),
114.5 (CH2v), 43.1 (C–CO2H), 28.2 (CH2), 20.1
(CH3) ppm.
All reactions were carried out under argon atmosphere,
using standard conditions for exclusion of moisture, in oven
dried glassware, in THF freshly distilled from blue
benzophenone ketyl and with diethyl amine and diisopro-
pylamine distilled from CaH2. The reaction temperature
(2788C) was achieved by cooling with a CO2/acetone bath.
Organic extracts were dried over anhydrous MgSO4, and
solutions were evaporated under reduced pressure with a
rotatory evaporator and a bath at 408C.
Melting point value and spectroscopic data are in agreement
with these already described. Other starting compounds
were purchased and used without purification.
Further elution allowed isolation of (E)-2-methyl-hepta-2,
6-dienoic acid 2a-g4,7 as a white oil: HRMS found Mþ
140.0839, C8H12O2 requires 140.0837; nmax 3100–2800
(OH), 1690 (CvO), 1640 (CvC), 1415, 1280, 995 and
915 cm21; dH 6.90 (1H, t, J¼7.2 Hz, CH2–CHvC), 5.84–
5.68 (1H, m, CHvCH2), 5.18–4.98 (2H, m, CHvCH2),
2.28 (2H, t, J¼6.9 Hz, CH2 –CHvC), 2.20 (2H, t,
J¼6.9 Hz, CH2–CHvCH2), 1.82 (3H, s, CH3) ppm.
3.1. General procedure for alkylation of carboxylic acids
Carboxylic acid (2.25 mmol) in THF (2 mL) was slowly
added to stirred lithium diethylamide (0.5 mL, 4.8 mmol) in
THF (2 mL) at 2788C, according to the method already
described.5 The solution was stirred for 30 min at 08C and
cooled again to 2788C. Halide (2.25 mmol) in THF (2 mL)
was added dropwise (5 min), and the solution stirred 1 h at
room temperature. The reaction was quenched with water
(20 mL) and the mixture extracted with diethyl ether
3.1.3. Alkylation of 3-methyl-2-butenoic acid with allyl
bromide. From 3-methyl-2-butenoic acid 3 (225 mg,

L. R. Domingo et al. / Tetrahedron 59 (2003) 6233–6239
6237
2.25 mmol) and allyl bromide a (0.2 mL, 2.25 mmol).
Work-up gave white oil (215 mg, 68%) as a a:g mixture
(82:18), which on separation by column chromatography
gave 2-isopropenyl-pent-4-enoic acid 3a-a as a white oil:
HRMS found Mþ 140.0834, C8H12O2 requires 140.0837;
nmax 3100–2853 (OH), 1701 (CvO), 1638 (CvC), 1458
and 912 cm21; dH 5.80 (1H, m, CHvCH2), 5.05 (2H, m,
CH2vC), 4.95 (2H, d, J¼6.4 Hz, CH2vCH), 3.12 (1H,
t, J¼8 Hz, HOOC–CH), 2.58 (1H, dt, J¼14.8, 6.8 Hz,
CH2–CH–COOH), 1.79 (3H, s, CH3) ppm; dC 179.0
(COOH), 141.4 (CCH3), 135.1 (CH2vCH), 116.8
(CH2vCH), 114.6 (CH2vC), 52.6 (HOOC–CH), 34.1
(HOOC–CH–CH2), 20.3 (CH3) ppm.
3.1.6. Alkylation of 3-methyl-2-butenoic acid with 1-[(E)-
3-bromo-1-propenyl]benzene. From 3-methyl-2-butenoic
acid 3 (225 mg, 2.25 mmol) and 1-[(E)-3-bromo-1-propenyl]-
benzene b (443 mg, 2.25 mmol). Work-up gave white oil
(282 mg, 58%) as a a$99%, which on separation by
column chromatography gave (E)-2-isopropenyl-5-phenyl-
pent-4-enoic acid 3b-a as a white oil: HRMS found Mþ
216.1142, C14H16O2 requires 216.1150; nmax 3606–3303,
3136–2878 (OH), 1767 (CvO), 1650 (CvC), 1166, 1023
and 702 cm21; dH 7.31 (5H, m, Ar–H), 6.46 (1H, d, J¼
16.0 Hz, Ph–CH), 6.17 (1H, dt, J¼14.4, 7.2 Hz,
PhCHvCH), 5.03 (2H, s, CH2vC), 3.26 (1H, t, J¼
7.6 Hz, HOOC–CH), 2.56 (1H, dt, J¼14.4, 7.2 Hz,
vCH–CH2) and 1.87 (3H, s, CH3) ppm; dC 179.0
(COOH), 141.8 (CH2vC), 137.6 (CAr), 132.3, 128.8 and
126.5 (5CHAr), 127.5 (PhCHv), 127.2 (Ph–CHvCH),
115.0 (CH2v), 53.3 (HOOC–CH), 33.8 (HOOCCH2) and
20.7 (CH3) ppm.
Further elution allowed isolation of (E)-3-methyl-hepta-2,
6-dienoic acid 3a-g as a white oil: HRMS found Mþ
140.0837, C8H12O2 requires 140.0837; nmax 3100–2848
(OH), 1727 (CvO), 1636 (CvC), 1454, 1151, 909
and 727 cm21; dH 5.80 (1H, m, CHvCH2), 5.71 (1H, s,
CH–COOH), 5.02 (2H, m, CH2vC), 2.74 (2H, t, J¼7.6 Hz,
CH2–CCH3), 2.27 (3H, s, CH3), 2.25 (3H, s, CH3) ppm; dC
172.0 (COOH), 162.5 (CCH3), 137.7 (CHvCH2), 115.5
(CH–COOH), 115.0 (CH2vC), 41.0 (CH2CH3), 32.8
(CH2CHvCH2), 19.5 (CH3) ppm.
3.1.7. Alkylation of (E)-2-butenoic acid with 1-bromo-3-
methyl-2-butene. From (E)-2-butenoic acid 1 (194 mg,
2.25 mmol) and 1-bromo-3-methyl-2-butene c (0.26 mL,
2.25 mmol). Work-up gave white oil (219 mg, 63%) as a
a:g mixture (64:36), which on separation by column
chromatography gave 5-methyl-2-vinyl-hex-4-enoic acid
1c-a as a white oil: HRMS found Mþ 154.0997, C9H14O2
requires 154.0993; nmax 3100–2647 (OH), 1707 (CvO),
1638 (CvC), 1438, 1283 and 922 cm21; dH 5.84 (1H, ddd,
J¼17.4, 10.2, 8.4 Hz, CH2vCH), 5.18 (1H, d, J¼18 Hz,
CH2v), 5.17 (1H, d, J¼10 Hz, CH2vCH), 5.08 (1H, t,
J¼9 Hz, CvCH), 3.03 (1H, q, J¼7.5 Hz, HOOCCH), 2.48
(1H, dt, J¼14.4, 7.2 Hz, vCHCH2), 2.28 (1H, dt, J¼14.4,
7.2 Hz, vCH–CH2), 1.69 (3H, s, CH3) and 1.61 (3H, t,
CH3) ppm; dC 180.6 (COOH), 135.6 (Cv), 134.7
(CH2vC), 120.5 (CH2v), 118.1 (CvCH), 50.6 (HOOC–
CH), 31.1 (CH3), 26.2 (CH3) and 18.3 (CH2) ppm.
3.1.4. Alkylation of (E)-2-butenoic acid with 1-[(E)-3-
bromo-1-propenyl]benzene. From (E)-2-butenoic acid 1
(194 mg, 2.25 mmol) and 1-[(E)-3-bromo-1-propenyl]ben-
zene b (443 mg, 2.25 mmol). Work-up gave white oil
(263 mg, 58%) as a a$99%, which on separation by
column chromatography gave (E)-5-phenyl-2-vinyl-pent-4-
enoic acid 1b-a as a white oil: HRMS found Mþ 202.0993,
C13H14O2 requires 202.0993; nmax 3100–2890 (OH), 1705
(CvO), 1640 (CvC), 1413, 1283, 965 and 925 cm21; dH
7.32 (5H, m, Ar–H), 6.47 (1H, d, J¼15.6 Hz, Ph–CH), 6.15
(1H, dt, J¼15.6, 7.2 Hz, PhCHvCH), 5.88 (1H, ddd,
J¼17.1, 10.2, 8.4 Hz, CH2vCH), 5.25 (1H, d, J¼8.1 Hz,
CH2vCH), 5.21 (1H, s, CH2vCH), 3.22 (1H, q, J¼
7.5 Hz, HOOCCH), 2.70 (1H, dtd, J¼15, 7.8, 0.9 Hz,
HOOCCHCH2), 2.53 (1H, dtd, J¼14.1, 6.9, 1.2 Hz,
HOOCCHCH2) ppm; dC 179.7 (COOH), 137.5 (C Ar),
134.9 (CH2vCH), 132.8 (Ph–CH), 128.8, 127.5 and 126.4
(5CHAr), 126.4 (CHvCHCH2), 118.5 (CH2vCH), 50.2
(HOOC–CH) and 35.6 (CH2) ppm.
Further elution allowed isolation of (E)-7-methyl-octo-2,6-
dienoic acid 1c-g as a white oil: HRMS found Mþ 154.0998,
C9H14O2 requires 154.0993; nmax 3100–2673 (OH), 1651
(CvO), 1438, 1284 and 923 cm21; dH 7.06 (1H, dt, J¼13.6,
6.8 Hz, HOOCCHvCH), 5.84 (1H, m, HOOCCH), 5.10
(1H, m, CHvCH), 2.25 (2H, q, J¼6.8 Hz, CH2), 2.16
(2H, q, J¼6.8 Hz, CH2), 1.61 (3H, s, CH3) and 1.60 (3H, s,
CH3) ppm; dC 172.6 (COOH), 152.4 (HOOCCHvCH),
135.4 (CHvC), 122.9 (CHvC), 121.0 (HOOCCHv), 30.9
(HOOC–CHvCHCH2), 26.6 (CH3), 25.9 (CvCHCH2)
and 18.1 (CH3) ppm.
3.1.5. Alkylation of (E)-2-methyl-2-butenoic acid with 1-
[(E)-3-bromo-1-propenyl]benzene. From (E)-2-methyl-2-
butenoic acid 2 (225 mg, 2.25 mmol) and 1-[(E)-3-bromo-
1-propenyl]benzene b (443 mg, 2.25 mmol). Work-up gave
white oil (408 mg, 84%) as a a$99%, which on separation
by column chromatography gave (E)-5-phenyl-2-methyl-2-
vinyl-pent-4-enoic acid 2b-a as a white oil: HRMS found
Mþ 216.1150, C14H16O2 requires 216.1143; nmax 3090–
2500 (OH), 1690 (CvO), 1630 (CvC) cm21; dH 7.37–
7.22 (5H, m, Ar–H), 6.46 (1H, d, J¼15.9 Hz, Ph–CHvC),
6.15 (1H, dt, J¼15.6, 7.5 Hz, CHvCH2), 6.09 (1H, dd,
J¼17.1, 11.1 Hz, CHvCH2), 5.25 (1H, d, J¼11.0 Hz,
CHvCH2), 5.21 (1H, d, J¼17.1 Hz, CHvCH2), 2.68 (1H,
dd, J¼13.5, 7.5 Hz, CH2), 2.54 (1H, dd, J¼14.0, 7.3 Hz,
CH2) and 1.35 (3H, s, CH3) ppm; dC 182.0 (COOH), 140.5
(CH2vCH), 137.3 (CAr), 133.7, 127.3 and 126.2 (5CHAr),
128.5 (PhCHv), 125.1 (CH2CHv), 114.8 (CH2v), 48.8
(HOOC–CH), 42.3 (CH2C) and 20.3 (CH3) ppm.
3.1.8. Alkylation of (E)-2-methyl-2-butenoic acid with
1-bromo-3-methyl-2-butene.
From
(E)-2-methyl-2-
butenoic acid 2 (225 mg, 2.25 mmol) and 1-bromo-3-
methyl-2-butene c (0.26 mL, 2.25 mmol). Work-up gave
white oil (272 mg, 72%) as a a:g mixture (36:64), which on
separation by column chromatography gave 2,5-dimethyl-2-
vinyl-hex-4-enoic acid 2c-a as a white oil: HRMS found
Mþ 168.1155, C10H16O2 requires 168.1150; nmax 3087–
2650 (OH), 1696 (CvO), 1642 (CvC) and 923 cm21; dH
6.04 (1H, dd, J¼17.2, 10.2 Hz. CHvCH2), 5.12 (1H, m,
CvCH), 5.10 (2H, m, CHvCH2), 2.46 (1H, dd, J¼14.0,
7.6 Hz, CH–C–COOH), 2.30 (1H, dd, J¼14.0, 7.6 Hz,
CH–C–COOH), 1.70 (3H, s, CH3–Cv), 1.69 (3H, s,
CH3–Cv) and 1.27 (3H, s, CH3–C–COOH) ppm; dC

6238
L. R. Domingo et al. / Tetrahedron 59 (2003) 6233–6239
182.5 (COOH), 145.3 (CH2vCH), 141.2 ((CH3)2Cv),
119.2 (CHvC(CH3)2), 114.4 (CH2vCH), 49.1 (C–
COOH), 29.4 (CH2), 26.2 (CH3–C–COOH), 25.9 (CH3–
Cv) and 18.2 (CH3–Cv) ppm.
(CAr), 128.7, 127.3 and 126.3 (5CHAr), 130.5 (CHPh),
126.6 (CHvCHPh), 29.6 (CH2) and 14.9 (CH3) ppm.
(E)-2-Methyl-5-phenyl-hepta-2,6-dienoic acid 2b–cr as a
colourless oil: HRMS found Mþ 216.1140, C14H16O2 requires
216.1143; nmax 3098–2882 (OH), 1788 (CvO), 1693 (CvC),
1494, 1277 and 919 cm21; dH 7.4–7.1 (5H, m, Ar–H), 6.91
(1H, t, J¼7.3 Hz, CHvCCOOH), 6.04 (1H, ddd, J¼17.0,
10.0, 7.3 Hz, CH2vCH–CPh), 5.11 (1H, d, J¼17.0 Hz,
HtransCHvCH), 5.14 (1H, d, J¼10.0 Hz, HcisCHvCH),
3.48 (1H, q, J¼7.3 Hz, CHPh), 2.66 (2H, q, J¼7.3 Hz,
CHPh) and 1.81 (3H, s, CH3) ppm; dC 173.7 (COOH), 143.5
(CAr), 143.2 (CHvCCOOH), 141.1 (CH2vCH), 133.8
(C–COOH), 129.0 (2CHAr), 126.9 (CHAr), 115.5 (CH2v),
49.1 (CH–Ph), 35.2 (CH2) and 12.6 (CH3) ppm.
Further elution allowed isolation of (E)-2,7-dimethyl-octo-
2,6-dienoic acid 2c-g as a white oil: HRMS found Mþ
168.1152, C10H16O2 requires 168.1150; nmax 3090–2700
(OH), 1700 (CvO), 1650 (CvC) and 965 cm21; dH 6.91
(1H, dt, J¼7.6, 1.6 Hz, CHvC–COOH), 5.06 (1H, t, J¼
8.8 Hz, CHvC(CH3)2), 2.23 (2H, dd, J¼14.4, 7.2 Hz,
CH2), 2.13 (2H, dd, J¼14.4, 7.2 Hz, CH2), 1.83 (3H, s,
CH3–C–COOH), 1.70 (3H, s, CH3Cv) and 1.69 (3H, s,
CH3Cv) ppm; dC 174.0 (COOH), 140.3 (C–COOH),
135.1 (CHvC–COOH), 133.0 (vC(CH3)2), 123.3
(CHvC(CH3)2), 37.4 (CH2–Cv), 25.9 (CH3–Cv), 20.2
(CH2–Cv) and 17.9 (2CH3) ppm.
(E)-2-(1-Isopropilidene)-5-phenyl-pent-4-enoic acid 3b–
hm as a colourless oil: HRMS found Mþ 216.1147,
C14H16O2 requires 216.1143; nmax 3575–3257, 3106–
2758 (OH), 1724 (CvO), 1664 (OH), 1451, 1194, 752
and 700 cm21; dH 7.2–7.5 (5H, m, Ar–H), 6.39 (1H, d,
J¼16.0 Hz, Ph–CH), 6.19 (1H, dt, J¼16.0, 7.0 Hz,
PhCHvCH), 2.91 (2H, t, J¼7.0 Hz, CH2), 1.76 (3H, s,
CH3) and 1.68 (3H, s, CH3) ppm; dC 171.5 (COOH), 138.8
(CAr), 129.9 (CHAr), 128.9 (CHAr), 127.7 (CHAr), 133.5
(PhCHv), 128.4 (Ph–CHvCH), 142.0 (C(CH3)2(, 122.0
(CCOOH), 33.9 (CH2), 26.3 and 20.8 (2CH3) ppm.
3.1.9. Alkylation of 3-methyl-2-butenoic acid with
1-bromo-3-methyl-2-butene. From 3-methyl-2-butenoic
acid 3 (225 mg, 2.25 mmol) and 1-bromo-3-methyl-2-
butene c (0.26 mL, 2.25 mmol). Work-up gave white oil
(265 mg, 70%) as a a:g mixture (89:11), which on
separation by column chromatography gave 2-isopro-
penyl-5-methyl-hex-4-enoic acid 3c-a as a white oil:
HRMS found Mþ 168.1149, C10H16O2 requires 168.1150;
nmax 3080–2731 (OH), 1708 (CvO), 1648 (CvC),1411
and 899 cm21; dH 5.05 (1H, t, J¼10.0 Hz, CvCH), 4.94
(2H, s, CH2v), 3.05 (1H, t, J¼7.6 Hz, HOOC–CH), 2.52
(1H, dt, J¼14.8, 7.6 Hz.vCH–CH2), 2.28 (1H, dt, J¼14.4,
6.8 Hz, vCH–CH2), 1.79 (3H, s, CH3),1.68 (3H, s, CH3)
and 1.61 (3H, s, CH3) ppm; dC 179.8 (COOH), 142.2
(CH2vC), 134.0 ((CH3)2Cv), 123.0 ((CH3)2CvCH2),
114.4 (CH2v), 53.4 (HOOC–CH), 29.0 ((CH3)2CvCH–
CH2), 26.0 ((CH3)2Cv), 20.7 ((CH3)2Cv) and 17.9
(CH3) ppm.
(E)-2-Ethylidene-5-methyl-hex-4-enoic acid 1c–hm as a
colourless oil: HRMS found Mþ 154.0993 C9H14O2
requires 154.0998; nmax 3045–2758 (OH), 1706 (CvO),
1638 (CvC), 1281 and 1218 cm21; dH 6.98 (1H, q, J¼
7.2 Hz, CH3–CHv), 5.20 (1H, m, CvCH), 3.00 (2H, d,
J¼7.2 Hz, CH2), 1.84 (3H, d, J¼7.2 Hz, CH3CHv), 1.70
(3H, s, CH3Cv) and 1.68 (3H, t, CH3) ppm; dC 173.2
(COOH), 140.4 (CH3CHv), 132.6 (CvCH), 132.2
(CCOOH), 121.5 (CvCH), 25.4 (CH2), 27.8 (CH3Cv),
18.1 (CH3Cv) and 14.7 (CH3CHv) ppm.
Further elution allowed isolation of (E)-3,7-dimethyl-octo-
2,6-dienoic acid 2c-g as a white oil: HRMS found Mþ
168.1147, C10H16O2 requires 168.1150; nmax 3091–2727
(OH), 1702 (CvO), 1644 (CvC),1440 and 898 cm21; dH
5.68 (1H, m, CH–COOH), 4.94 (1H, m, CHvC(CH3)2),
2.63 (2H, t, J¼8.0 Hz, CH2), 2.52 (2H, m, CH2), 2.16 (3H, s,
CH3–Cv) and 1.60 (6H, s, 2CH3) ppm; dC 172.4 (COOH),
163.4 (HOOC–CvC), 132.9 ((CH3)2Cv), 123.7
(CHvC(CH3)2), 115.5 (HOOC–C), 41.4 (CH2–C–CH3),
27.0 (CH2–Cv), 25.8 (CH3) and 17.7 (CH3) ppm.
(E)-2,2,5-Trimethyl-hept-2,6-dienoic acid 2c–cr as a colour-
less oil: HRMS found Mþ 168.1145, C10H16O2 requires
168.1150; nmax 3030–2864 (OH), 1783 (CvO), 1698
(CvC), 1456 and 1120 cm21; dH 6.91 (1H, t, J¼7.6 Hz,
HOOCCvCH), 5.83 (1H, dd, J¼17.6, 10.4 Hz, CH2vCH),
5.16 (1H, d, J¼10.4 Hz, HCHcisvCH), 5.10 (1H, d,
J¼17.6 Hz, HCHtransvCH), 1.87 (2H, d, J¼7.6 Hz,
CH2–CHv), 1.39 (6H, s, 2CH3) and 1.36 (3H, s, CH3–
CCOOH) ppm.
3.1.10. General procedure for thermal treatment of
alkylation products. Pure a-alkylation product (or crude
allyl a:g mixtures) were introduced in a pressure tube. The
sealed tube was heated in a oven at 2008C for 5 h. The tube
was opened at room temperature and the product directly
identified.
2-Isopropilydene-5-methyl-5-phenyl-pent-4-enoic acid
3c–hm as a colourless oil: HRMS found Mþ 168.1154,
C10H16O2 requires 168.1150; nmax 3030–2879 (OH), 1702
(CvO), 1667 (CvC), 1454, 1290, 1111 and 956 cm21; dH
5.29 (1H, m, CHv), 2.50 (2H, s, CH2), 2.23 (3H, s,
CH3cisvCH), 1.85 (3H, s, CH3transvCH) and 1.35 (6H, s,
2CH3Cv) ppm; dC 171.2 (COOH), 152.0 (CvCCOOH),
123.7 (CHvC(CH3)2), 123.0 (CHv),122.3 (HOOC–Cv),
33.6 (CH2), 27.5 (2CH3Cv), 23.5 (CH3transvCCOOH),
23.4 (CH3cisvCCOOH) ppm.
(E)-2-((E)Ethylidene)-5-phenyl-pent-4-enoic acid 1b–hm
as a colourless oil: HRMS found Mþ 202.090, C13H14O2
requires 202.0994; nmax 3090–2848 (OH), 1697 (CvO),
1600 (CvC), 1418, 1285 and 966 cm21; dH 7.29 (5H, m,
Ar–H), 7.14 (1H, q, J¼7.2 Hz, CHvCH3), 6.39 (1H, d, J¼
16.0 Hz, CHPh), 6.20 (1H, dt, J¼16.0, 6.4 Hz, CHvCHPh),
3.23 (2H, d, J¼6.4 Hz, CH2) and 1.90 (3H, d, J¼7.2 Hz,
CH3) ppm; dC 173.0 (COOH), 141.9 (CHCH3), 137.6
3.2. Computational methods
DFT calculations have been carried out using the B3LYP23,24

L. R. Domingo et al. / Tetrahedron 59 (2003) 6233–6239
6239
13. Jiao, H. J.; Schleyer, P. V. Angew. Chem. Int. Ed. 1995, 34,
334–337.
exchange-correlation functionals, together with the standard
6-31Gp basis set.25 The optimizations were carried out using
the Berny analytical gradient optimization method.26,27 The
stationary points were characterized by frequency calcu-
lations in order to verify that the transition structures (TSs)
have one and only one imaginary frequency. The values of
the relative energies, DE, have been calculated based on the
total electronic energies of stationary points. Relative
enthalpies, DH, entropies, DS and free energies, DG, for
the 1a and the CR and 13HM products were calculated with
the standard statistical thermodynamics at 500.15 K and
1 atm.25 The thermal contributions to the vibrational energy
and entropy have been scaled by 0.96.28 All calculations
were carried out with the Gaussian 98 suite of programs.29
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The present research has been financed by DGCYT
(PPQ2002-00986 and BQU2002-01032 to L. R. D.).
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