Regioselective alkylation of lithium dienediolates of α,β- unsaturated carboxylic acids

Article abstract of DOI:10.1055/s-2000-6323

Lithium carboxylic acids dienediolates are regioselectively alkylated at the α-carbon by reaction with tosylates derived from both primary and secondary alcohols. Both regio- and diastereoselectivity are improved when compared with those obtained in the c

Full text of DOI:10.1055/s-2000-6323

1160
PAPER
Regioselective Alkylation of Lithium Dienediolates of a,b-Unsaturated
Carboxylic Acids
Eva M. Brun, Salvador Gil, Ramón Mestres, Margarita Parra*
Departament de Química Orgánica, Universitat de València, Burjassot, València, Spain
Received 5 January 2000; revised 14 March 2000
scribed in early studies5 but no systematic study of the in-
fluence of the leaving group has been reported. It is well
known that the nature of the leaving group plays an impor-
tant role in C- versus O-alkylation regioselectivity of
enolates6 but, as far as we know, little attention has been
paid to its effect on the alkylation of related C,C-ambident
nucleophiles. For example, introduction of regio-directive
groups in the g-position of carboxylic acids, namely silyl
or sulfonyl groups, does not improve g-regioselectivity
for alkylations.7
Abstract: Lithium carboxylic acids dienediolates are regioselec-
tively alkylated at the a-carbon by reaction with tosylates derived
from both primary and secondary alcohols. Both regio- and diaste-
reoselectivity are improved when compared with those obtained in
the corresponding alkylation with alkyl halides.
Key words: lithium enolates, alkylation, alkyl sulfonates, carboxy-
lic acids, diastereoselectivity
Regio- and stereoselectivity studies on the reaction of lith-
ium dienediolates of unsaturated carboxylic acids with
several electrophiles have been reported in the last years.1
Alkylation of these dienolates with primary halides is
known to proceed mainly through the a-carbon rather than
the g-carbon.2 For allylic halides, the a-selectivity trend
can be reversed by counterion interchange with copper (I)
salts.3 In order to attain high a-regioselectivities primary
alkyl chlorides are required. These lead to moderate yields
after long reaction times and are prone to give dialkylation
products.2 With secondary halides significant deviations
from a-selectivity were observed and chlorides gave no
reaction at all.4 The regioselectivity of these alkylations
strongly depends on the reactivity of the electrophile
prompting us to study the influence of the leaving group
upon regioselectivity. Scattered low a/g ratios are de-
We have studied here the alkylation of lithium diene-
diolates of unsaturated carboxylic acids with alkylsul-
fonates (Scheme). We have not found in the literature any
comprehensive study but just one example of this kind of
reaction, namely 4-phenyl-3-butenoic acid with 2-tosy-
loxybutane.8
Alkylations have been carried out under standard
conditions9 originally devised for preparative purposes,
usually 2.25 mmol of both the dienediolate and the tosyl-
ate,10,11 and a slight excess (4.8 mmol) of lithium diethyl-
amide (LDE) as a base. After slow addition (about during
5 min) of the tosylate, in THF, to the dienediolate in the
same solvent at -78 ºC, the solution was stirred at 0 °C or
at room temperature for a period of time (2 to 5 hours),
which was optimised for each tosylate and acid. In the
R2
O
R2 OLi
OLi
R1
2 LDE
THF
R3
R3
OH
R1
1: R1 = R2 = R3 = H
X
a : R4 = CH2CH3 ; R5 = CH3
b : R4 = (CH2)6CH3 ; R5= H
c : R4 = CH2(CH2)3CH2 = R5
2: R1 = CH3 ; R2 = R3 = H
3: R2 = CH3 ; R1 = R3 = H
4: R2 = H ; R1 = R3 = CH3
R4 R5
d : R4 = Ph ; R5 = CH3
H2O
5: R1 = R2 = R3 = H
R2
H
R5
R4
6: R1 = CH3 ; R2 = R3 = H
7: R2 = CH3 ; R1 = R3 = H
8: R2 = H ; R1 = R3 = CH3
R3
R1
HO2C
R5
H
2 LDE
Ph
R4
Ph
CO2H
X
HO2C
H
9
10
R4 R5
Scheme
Synthesis 2000, No. 8, 1160–1165 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Alkylation of Lithium Dienediolates of a,b-Unsaturated Carboxylic Acids
1161
work up, the acidic layer is obtained by acidification with A variety of conditions were tested and the best results are
phosphoric acid (pH ~2) leading to isolation of crude shown in the Table. Higher temperatures or longer reac-
products, usually pure according to their 1H and 13C NMR tion times did not increase the yields. In the reaction of
spectra. Lower pH values, as obtained with HCl, led to alkyl halides with dienediolates,4,9 better results were ob-
contamination of the product with p-toluenesulfonic acid, tained on addition of 1,3-dimethylimidazolin-2-one
whereas acidification to a higher pH (~6-7), leads to low- (DMI) than when other amines (or a catalytic amount of
er yield but, in some cases, allows isolation of pure anti amine) were used for the generation of the lithium amide.
(means between acid group and R5 in Scheme) diastereoi- When these modified conditions were applied to the reac-
somer.
tion of these dienediolates with alkyl tosylates no im-
provement in yield or d.e. were observed. Just one
improvement may be noticed for entry 7 (Table), when
0.6 equivalents of diethylamine (instead of the stoichio-
metric, 2 equivalents) were used for the generation of the
lithium diethylamide, a 90% yield was attained, but 6%
starting acid was recovered and no improvement in dias-
teroselectivity was observed. From these observations, it
may be deduced that neither the amine, nor solvent nor ad-
ditives modify the transition states that govern the diaster-
oselectivity ratios.
Sulfonylation of alcohols is recognised as a fundamental
process in organic synthesis but some problems remain
unsolved. Thus, despite the large number of tosylation
methods known, new procedures are continuously being
developed.12,13 We have tested a representative sample of
each tosylate type obtained from different procedures in-
dicated in the experimental part, 1-phenyl-1-tosyloxy-
ethane is particularly tricky to synthesise and its storage
was avoided by using THF solutions of freshly prepared
tosylate.
In contrast, the leaving group effect was shown to be re-
markable. We have found better yields in these alkyla-
tions when compared with similar reactions with
secondary bromides,4 most probably because the reaction
is quicker and the elimination reaction is reduced. Regi-
oselectivity of the alkylation was tested with crotonic (1)
and (E)-2-methyl-2-butenoic acid (2). Exclusively a-alky-
lation product is obtained with sulfonyloxyalkane. Even
with a dienediolate particularly prone to g-alkylation,4
such as acid 2 with the highly reactive 1-phenyl-1-tosy-
loxyethane (d), only 5% g-alkylation product was ob-
tained. With iodoalkanes (entry 22) a mixture of a- and g-
alkylation is obtained. Benzenesulfonyloxy was also suit-
able as a leaving group but with the methanesulfonyloxy
group (entry 4) proton abstraction by the anion occurs
leading to recovery of the starting acid (26%).
The results obtained in the alkylation of phenylacetic acid
(9), as a reference for a-deprotonation acids, and several
a,b-unsaturated acids (1-4) with 2-tosyloxybutane (a),
1-tosyloxyoctane (b), 1-tosyloxycyclohexane (c) and
1-phenyl-1-tosyloxyethane (d) are summarised in the Ta-
ble.
Table Alkylation of Dienediolates of Carboxylic Acids
Entry Acid
X
R4 and Yield Starting
a
syn/anti
R5
(%)
Acid
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1
1
1
1
1
2
3
4
9
1
2
3
4
9
1
2
3
4
9
1
1
2
2
3
4
9
Cl
Br
I
a
a
a
a
a
a
a
a
a
b
b
b
b
b
c
c
c
c
c
d
d
d
d
d
d
d
54
52
81
67
84
83
72
76
87
82
88
88
64
88
83
61
88
85
94
67
70
52
90
71
66
81
94a
–
–
100
–
–
20/804
–
100b
26
–
The high regioselectivity of these alkylations along with
its insensitivity to the reaction conditions may be ascribed
to a strong coordination of the lithium ions to the oxygen
atoms of the sulfonyloxy moiety that excludes the amine
(Figure).
OMs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
Br
74
15/85
11/89
57/43
12/88
56/44
12/88
–
–
–
–
–
100
100
100
83
–
–
17
5
95
92
8b
–
100
100
86
C6H4CH3
–
O
O
14
15
–
–
–
–
14
–
–
–
Li
Li
S
85
O
O
100
100
100
100
86
–
–
–
–
O
R5
R1
H
R3
–
83c
100
56c
95c
93
35/65
28/72
24/76
37/63
26/74
24/76
23/77
OTs
I
OTs
OTs
OTs
OTs
R2
R4
–
Figure
7
17b
8
83
92
A model of this arrangement shows that the carbon bear-
ing the sulfonyloxy group can be attacked by the a-carbon
of the dienediolate in an anti mode to the breaking C-O
a 6% of a-hydroxyacid.4
b Deconjugated (g-,d-) starting acid.
c The rest of 100% is g-alkylation product.
Synthesis 2000, No. 8, 1160–1165 ISSN 0039-7881 © Thieme Stuttgart · New York

1162
E. M. Brun et al.
PAPER
Alkylation of Carboxylic Acids; General Procedure
bond, while preserving electrophilic catalysis from lithi-
um ions coordinated to the oxygen atoms. On the other
hand, a similar arrangement for the g-carbon attack would
require a high distortion from planarity for the dihedral
angle encompassing the double bonds, which should lead
to a disruption of the g-carbon nucleophility.
The carboxylic acid (2.25 mmol) in THF (2 mL) was slowly added
to stirred lithium diethylamide (4.8 mmol) in THF (2 mL) at -78 ºC,
by cooling with CO2/cetone bath (prepared according to the method
already described).9 The solution was stirred for 30 min at 0 ºC for
unsaturated acids (-78 ºC for phenylacetic acid and 1 h at 0 ºC for
2-trans-methyl-2-pentenoic acid), and cooled again at -78 ºC. To-
syloxyalkane (2.25 mmol) in THF (2 mL) was added dropwise, and
the solution stirred at a temperature and for a period which is given
in each case. H2O (20 mL) was added and the solution was extracted
with Et2O (3 ¥ 15 mL). The aqueous layer was acidified under ice-
cooling by careful addition of 85% H3PO4, and then extracted with
EtOAc (3 ¥ 15 mL). The organic layer was washed with aq NaCl
(2 ¥ 10 mL), and dried (MgSO4). Evaporation of the solvent gave
the crude acid, which was used for spectroscopic analysis. When the
starting acid was present, column chromatography led to the pure
product in the proportions indicated (Table). Only for combustion
analysis, was an aliquot of product purified.
Assuming a stereochemical outcome for the alkylation of
100% inversion (SN2) and arranging R groups in the Fig-
ure for least steric hindrance when R1 = H, lead to an anti
configuration for the major diastereoisomer. This is the
case for acids 1 and 3 and accordingly we have found
moderate anti:syn diastereoisomeric ratios. The major di-
astereoisomer configuration depends on the R4 and R5
groups, and has been determined by comparison with lit-
erature,14 comparative study of their NMR data and by
n.O.e. experiments, when feasible. These diastereoiso-
meric ratios are considerably higher than those obtained in
the alkylation with secondary halides. This is probably
due to a lesser lithium coordination with the halogen at-
om, leading to a looser transition state than that assumed
in the Figure for the reaction with tosylates. The arrange-
ment shown (Figure) also provides an explanation for the
diasteroselectivity loss when R1 = Me, as is the case for
acids 2 and 4, due to the similar steric hindrance of vinyl
and methyl groups.
2-(1-Methylpropyl)-3-butenoic Acid (5a)
From (E)-2-butenoic acid (1) (194 mg, 2.25 mmol) and 2-tosylox-
ybutane (a) (513 mg, 2.25 mmol); the reaction mixture was stirred
at 0ºC for 5 h. Work-up gave a diastereoisomeric mixture
(R*R*:R*S*, 89:11) of 2-(1-methylpropyl)-3-butenoic acid (5a)4 as
a yellow oil (268 mg, 84%, entry 5).
2-Methyl-2-(1-methylpropyl)-3-butenoic Acid (6a)
According to the general method using (E)-2-methyl-2-butenoic
acid (2) (225 mg, 2.25 mmol) and 2-tosyloxybutane (a) (513 mg,
2.25 mmol); the reaction mixture was stirred at 0 ºC for 5 h. Work-
up gave a diastereoisomeric mixture (R*S*:R*R*, 57:43) of 2-me-
thyl-2-(1-methylpropyl)-3-butenoic acid (6a)4 as a colourless oil
(293 mg, 83%, entry 6).
As a conclusion, we have found that regioselectivity for
the alkylation of 2-butenoic acids (1-4) strongly depends
on the nature and reactivity of the electrophile. Regiose-
lective a-alkylated products always result for sulphonates,
most probably due to a coordinative transition state,
which also leads to a moderate diastereoselectivity, in
those cases studied here.
3-Methyl-2-(1-methylpropyl)-3-butenoic Acid (7a)
From 3-methyl-2-butenoic acid (3) (225 mg, 2.25 mmol) and 2-to-
syloxybutane (a) (513 mg, 2.25 mmol); the reaction mixture was
stirred at 0ºC for 5 h. Work-up gave a diastereoisomeric mixture
(R*R*:R*S*, 88:12) of 3-methyl-2-(1-methylpropyl)-3-butenoic
acid (7a)4 as a white solid (252 mg, 72%, entry 7).
Mps were determined with a Reichert apparatus and are uncorrect-
ed. IR spectral data were obtained for liquid film or KBr discs, with
a Perkin-Elmer 281 spectrophotometer. NMR spectra were record-
ed for CDCl3 solutions, with a Varian Unity 300 (13C NMR) or Uni-
ty 400 (1H NMR) spectrometers. Elemental analyses were
determined by “Servicio de Semimicroanálisis del Centro de Inves-
tigación y Desarrollo (CSIC) de Barcelona”. Mass spectra were de-
termined with a UG Autoespec spectrometer. Silica gel Merck 60
(230-400 mesh) was used for flash column chromatography, with
hexane/Et2O mixtures as eluent.
(E)-2-(1-Methylpropyl)-2-methyl-3-pentenoic Acid (8a)
From (E)-2-methyl-2-pentenoic acid (4) (257 mg, 2.25 mmol) and
2-tosyloxybutane (a) (513 mg, 2.25 mmol); the reaction mixture
was stirred at 0 ºC for 5 h. Work-up gave a yellow solid (291 mg,
76%, entry 8). Column chromatography led to isolation of a diaste-
reoisomeric mixture (R*S*:R*R*, 56:44) of (E)-2-(1-methylpro-
pyl)-2-methyl-3-pentenoic acid (8a) as a colourless oil.4
3-Methyl-2-phenylpentenoic Acid (10a)
Generation and reactions of the dienediolates were carried out under
Ar atm in a 25 mL two necked round bottomed flasks provided with
rubber septa, using standard conditions for exclusion of moisture.
All additions were carried out with a syringe. THF was distilled
from blue sodium diphenylketyl immediately before use. Diethy-
lamine was dried (CaH2) and distilled before use. The reaction tem-
perature (-78 ºC) was achieved by cooling with a CO2/acetone bath.
Evaporation of solvents on work-up was carried out with a vacuum
rotatory evaporator and a bath at 40 ºC. BuLi (1.6 M in hexane) was
purchased from Aldrich. Carboxylic acids were purchased from Al-
drich and crystallised before use.
From phenylacetic acid (9) (306 mg, 2.25 mmol) and 2-tosyloxyb-
utane (a) (513 mg, 2.25 mmol); the reaction mixture was stirred at
0 ºC for 3 h, and then allowed to reach r.t. for 2h. Work-up gave a
diastereoisomeric mixture (R*R*:R*S*, 88:12) of 3-methyl-2-phe-
nylpentenoic acid (10a) as a yellow solid (376 mg, 87%, entry 9).
Column chromatography led to isolation of pure material as white
needles.4,14
2-Octyl-3-butenoic Acid (5b)
From (E)-2-butenoic acid (1) (194 mg, 2.25 mmol) and 2-tosyloxy-
octane (b) (639 mg, 2.25 mmol); the reaction mixture was stirred at
0 ºC for 2 h. Work-up gave 2-octyl-3-butenoic acid (5b) as a colour-
less oil (364 mg, 82%, entry 10). Column chromatography led to
isolation of pure material as a colourless oil.
Alkyl tosylates were obtained by the Kabalka method10 leading to
2-tosyloxybutane (a),8 1-tosyloxyoctane (b),12 and 1-tosyloxycy-
clohexane (c).15 1-Phenyl-1-tosyloxyethane (d) was generated in
situ by Hoffmann procedure.11
IR (NaCl): nmax = 3084, 2928, 2857, 1709, 1640, 1467, 1413, 1285,
1221, 992, 921 cm-1.
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PAPER
Regioselective Alkylation of Lithium Dienediolates of a,b-Unsaturated Carboxylic Acids
1163
1H NMR (CDCl3, 400 MHz): d = 5.81 (ddd, 1H, J = 16.5, 10.5, 9
Hz, CH=CH2), 5.16 (d, 1H, J = 16.5 Hz, CH=CH2), 5.17 (d, 1H, J =
10.5 Hz, CH=CH2), 3.01 (dt, 1H, J = 5.9, 5.7 Hz, CH-CO2H), 1.79-
1.75 (m, 1H, CH2-CH), 1.67-1.54 (m, 1H, CH2-CH), 1.25 (m, 12H,
6CH2), 0.87 (t, 3H, J = 7.2 Hz, CH3).
13C NMR (CDCl3, 400 MHz): d = 180.9 (CO2H), 135.6 (CH=CH2),
117.8 (CH=CH2), 50.4 (CH-CO2H), 32.2 (CH2), 32.1 (CH2), 29.6
(CH2), 29.5 (CH2), 29.5 (CH2), 27.2 (CH2), 22.9 (CH2), 14.3 (CH3).
13C NMR (CDCl3): d = 182.4 (CO2H), 134.2 (CH=CH-CH3), 124.5
(CH=CH-CH3), 47.6 (C-CO2H), 39.4 (CH-C-CO2H), 31.8 (CH2),
30.0 (CH2), 29.4 (CH2), 29.3 (CH2), 24.5 (CH2), 22.6 (CH2), 20.7
(CH3), 18.1 (CH3), 14.1 (CH3).
EIMS: m/z (%) = 226 (M+, 22), 211 (M-CH3, 10), 181 (M-CO2H,
90), 114 (M-C8H16, 100), 113 (M-C8H17, 100).
HRMS: m/z calcd for C14H26O2 (M+) 226.1933. Found: 226.1931.
EIMS: m/z (%) = 198 (M+, 21), 183 (M-CH3, 13), 170 (M-CO, 5),
2-Phenyldecanoic Acid (10b)
99 (M-C7H15, 70), 86 (M-C8H16, 100).
From phenylacetic acid (9) (306 mg, 2.25 mmol) and 2-tosyloxyoc-
tane (b) (639 mg, 2.25 mmol); the reaction mixture was stirred at
0 ºC for 2 h. Work-up gave a white solid (492 mg, 88%, entry 14).
Column chromatography led to isolation of 2-phenyldecanoic acid
(10b) as a white solid.
IR (KBr): nmax = 3300-2500, 1695, 1410, 1275, 925, 690 cm-1.
1H NMR (CDCl3): d = 7.32-7.25 (m, 5H, Ph), 3.53 (t, 1H, J = 7.6
Hz, CH-Ph), 2.08-2.03 (m, 1H, CH2-CH), 1.79-1.75 (m, 1H, CH2-
CH), 1.27-1.23 (m, 12H, 6CH2), 0.86 (t, 3H, J = 6.8 Hz, CH3-CH2).
13C NMR (CDCl3): d = 182.5 (CO2H), 136.6, 128.6, 128.1, 127.4
(Ar), 51.7 (CH-CO2H), 33.1, 33.0, 31.8, 29.4, 29.2, 29.1, 27.5 (7
CH2), 14.1 (CH3).
EIMS: m/z (%) = 248 (M+, 12), 203 (M-CO2H, 6), 136 (M-C8H16,
100), 91 (C7H7, 56).
HRMS: m/z calcd for C12H22O2 (M+) 198.1620. Found: 198.1616.
2-Methyl-2-octyl-3-butenoic Acid (6b)
From (E)-2-methyl-2-butenoic acid (2) (225 mg, 2.25 mmol) and
2-tosyloxyoctane (b) (639 mg, 2.25 mmol); the reaction mixture
was stirred at 0 ºC for 2 h. Work-up gave 2-methyl-2-octyl-3-
butenoic acid (6b) as yellow oil (420 mg, 88%, entry 11).
IR (NaCl): nmax = 3400-2500, 1695, 1450, 1410, 1375, 1270, 990,
920 cm-1.
1H NMR (CDCl3) d = 6.03 (dd, 1H, J = 17.7, 11.4 Hz, CH=CH2),
5.14 (d, 1H, J = 11.4 Hz, CH=CH2), 5.13 (d, 1H, J = 17.7 Hz,
CH=CH2), 1.75-1.54 (m, 2H, CH2-C-CO2H), 1.28 (s, 3H, CH3),
1.26 (m, 12H, 6CH2), 0.87 (t, 3H, J = 6.6 Hz, CH3-CH2).
13C NMR (CDCl3) d = 182.8 (CO2H), 141.2 (CH=CH2), 113.7
(CH=CH2), 48.4 (C-CO2H), 39.1 (CH2-C-CO2H), 31.8 (CH2), 30.0
(CH2), 29.3 (CH2), 29.2 (CH2), 24.4 (CH2), 22.6 (CH2), 20.2 (CH3-
C-CO2H), 13.9 (CH3-CH2).
HRMS: m/z calcd. for C16H24O2 (M+) 248.1776. Found: 248.1770.
2-Cyclohexyl-3-butenoic Acid (5c)
From (E)-2-butenoic acid (1) (194 mg, 2.25 mmol) and 2-tosyloxy-
cyclohexane (c) (571.5 mg, 2.25 mmol); the reaction mixture was
stirred at r.t. for 4 h. Work-up gave 2-cyclohexyl-3-butenoic acid
(5c) as a yellow solid (312 mg, 83%, entry 15). Column chromatog-
raphy led to isolation of analytically pure material as a white solid,
mp: 55-57 ºC.
Anal. calcd for C13H24O2 (212.2): C, 73.52; H, 11.40. Found: C,
73.55; H, 11.57.
3-Methyl-2-octyl-3-butenoic Acid (7b)
From 3-methyl-2-butenoic acid (3) (225 mg, 2.25 mmol) and 2-to-
syloxyoctane (b) (639 mg, 2.25 mmol); the reaction mixture was
stirred at 0 ºC for 2 h. Work-up gave 3-methyl-2-octyl-3-butenoic
acid (7b) as a colourless oil (419 mg, 88%, entry 12). Column chro-
matography led to isolation of pure material.
IR (KBr): nmax = 3200-2600, 1695, 1420, 1300, 1225, 1200, 1000,
950 and 920 cm-1.
1H NMR (CDCl3): d = 5.79 (ddd, 1H, J = 17.0, 10.1, 9.9 Hz,
CH=CH2), 5.17 (dd, 1H, J = 10.1, 1.8 Hz, CH=CH2), 5.13 (dd, 1H,
J = 17.1, 1.2 Hz, CH=CH2), 2.76 (dd, 1H, J = 8.9, 9.3 Hz, CH-
CO2H), 1.78-1.63 (m, 6H, CH-CH-CO2H and 5CHeq), 1.34-1.00
(m, 4H, 4CHax), 0.95-0.82 (m, 1H, 1CHax).
13C NMR (CDCl3): d = 180.3 (CO2H), 134.5 (CH=CH2), 118.5
(CH=CH2), 57.2 (CH-CO2H), 39.7 (CH-CH-CO2H), 31.1, 29.9,
26.1, 26.0, 26.0 (5CH2).
IR (NaCl): nmax = 3300-2600, 1695, 1400, 1375, 1310, 890 cm-1.
1H NMR (CDCl3): d = 4.93 (m, 2H, C=CH2), 3.04 (t, 1H, J = 7.8 Hz,
CH-CO2H), 1.84-1.77 (m, 1H, CH2-CH-CO2H), 1.77 (s, 3H, CH3-
C=CH2), 1.61-1.54 (m, 1H, CH2-CH-CO2H), 1.26 (m, 12H, 6CH2),
0.88 (t, 3H, J = 6.9 Hz, CH3-CH2).
13C NMR (CDCl3): d = 191.2 (CO2H), 142.1 (C=CH2), 114.3
(C=CH2), 52.8 (CH-CO2H), 31.8 (CH2), 29.8 (CH2), 29.4 (CH2),
29.2 (CH2), 27.3 (CH2), 22.6 (CH2), 20.1 (CH2), 20.1 (CH2), 14.1
(CH3-CH2).
Anal. Calcd for C10H16O2 (168.2): C, 71.38; H, 9.59%. Found: C,
71.37; H, 9.67.
EIMS: m/z (%) = 212 (M+, 50), 197 (M-CH3, 50), 169 (M-C3H7,
54), 112 (C8H16, 61), 100 (M-C8H16, 44).
HRMS: m/z calcd for C13H24O2 (M+) 212.1776. Found: 212.1778.
2-Cyclohexyl-2-methyl-3-butenoic Acid (6c)
From (E)-2-methyl-2-butenoic acid (2) (225 mg, 2.25 mmol) and
2-tosyloxycyclohexane (c) (571.5 mg, 2.25 mmol); the reaction
mixture was stirred at r.t. for 4 h. Work-up gave a white solid (124
mg, 61%, entry 16), which was characterised as pure 2-cyclohexyl-
2-methyl-3-butenoic acid (6c), mp: 80-82 ºC.
2-Methyl-2-octyl-3-pentenoic Acid (8b)
From (E)-2-methyl-2-pentenoic acid (4) (257 mg, 2.25 mmol) and
2-tosyloxyoctane (b) (639 mg, 2.25 mmol); the reaction mixture
was stirred at 0 ºC for 2 h. Work-up gave a yellow solid (325 mg,
64%, entry 13). Column chromatography led to isolation of 2-meth-
yl-2-octyl-3-pentenoic acid (8b) as a colourless oil.
IR (KBr): nmax = 3200-2600, 1685, 1285, 1240, 1170, 920, 900,
760, 680 cm-1.
1H NMR (CDCl3): d = 6.01 (dd, 1H, J = 17.4, 10.8 Hz, CH=CH2),
5.14 (d, 1H, J = 10.8 Hz, CH=CH2), 5.07 (d, 1H, J = 17.7 Hz,
CH=CH2), 1.80-1.50 (m, 6H, CH-C-CO2H and 5CHeq), 1.30-0.85
(m, 5H, 5CHax), 1.17 (s, 3H, CH3).
13C NMR (CDCl3): d = 182.0 (CO2H), 140.9 (CH=CH2), 114.5
(CH=CH2), 52.5 (C-CO2H), 45.0 (CH-C-CO2H), 28.0, 27.4, 26.8,
26.7, 26.5 (5CH2), 14.9 (CH3).
IR (KBr): nmax = 3200-2500, 1690, 1450, 1265, 965 cm-1.
1H NMR (CDCl3): d = 5.64-5.50 (m, 2H, CH=CH), 1.71-1.66 (t,
1H, CH2-C-CO2H), 1.70 (d, 3H, J = 4.5 Hz, CH3-C= ), 1.54 (t, 1H,
J = 12.2 Hz, CH2-C-CO2H), 1.31-1.19 (m, 12H, 6CH2), 1.25 (s, 3H,
CH3-C), 0.87 (t, 3H, J = 7.2 Hz, CH3-CH2).
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EIMS: m/z (%) = 183 (M++1, 4), 182 (M+, 1), 137 (M-CO2H, 8),
13C NMR (CDCl3): d = 179.5 (CO2H), 137.3 (C-CH-CO2H), 128.7
(2ArC2), 128.5 (2ArC3), 127.4 (ArC6), 58.7 (CH-CO2H), 40.7 (CH-
CH-CO2H), 31.9, 30.3, 26.2, 25.9, 25.9 (5CH2).
EIMS: m/z (%) = 218 (M+, 52), 173 (M-CO2H, 21), 136 (M-
C6H10, 100), 118 (M-C6H10-H2O, 83), 91 (C7H7, 83).
100 (C5H8O2, 100), 83 (C6H11, 49).
HRMS: m/z calcd for C11H19O2 (M++1) 183.1385. Found:
183.1385.
HRMS: m/z calcd for C14H18O2 (M+) 218.1307. Found: 218.1302.
2-Cyclohexyl-3-methyl-3-butenoic Acid (7c)
From 3-methyl-2-butenoic acid (3) (225 mg, 2.25 mmol) and 2-to-
syloxycyclohexane (c) (571.5 mg, 2.25 mmol); the reaction mixture
was stirred at r.t. for 4 h. Work-up gave 2-cyclohexyl-3-methyl-3-
butenoic acid (7c) as a white solid (360 mg, 88%, entry 17), mp:
71-73 ºC.
Anal. Calcd for C14H18O2 (218.1): C, 77.02; H, 8.32. Found: C,
76.96; H, 8.37.
2-(1-Phenylethyl)-3-butenoic Acid (5d)
From (E)-2-butenoic acid (1) (194 mg, 2.25 mmol) and 1-phenyl-1-
tosyloxyethane (d) (directly transferred to the reaction vessel
through a cannula); the reaction mixture was stirred from -78 ºC to
0 ºC for 5 h. Work-up gave 2-(1-phenylethyl)-3-butenoic acid (5d)
as a diastereoisomeric mixture (R*S*:R*R*, 72:28)4; a yellow oil
(300 mg, 70%, entry 21).
IR (KBr): nmax = 3200-2500, 1690, 1420, 1300, 1250, 1225, 1190,
940, 890 cm-1.
1H NMR (CDCl3): d = 6.94 (s, 2H, C=CH2), 2.76 (d, 1H, J = 10.8
Hz, CH-CO2H), 1.80-1.63 (m, 6H, CH-CH-CO2H and 5CHeq), 1.77
(s, 3H, CH3), 1.31-1.16 (m, 3H, 3CHax), 1.05-0.90 (m, 1H, 1CHax),
0.85-0.75 (m, 1H, 1CHax).
13C NMR (CDCl3): d = 180.0 (CO2H), 141.0 (C=CH2), 115.7
(C=CH2), 60.3 (CH-CO2H), 37.2 (CH-CH-CO2H), 31.6, 30.1, 26.3,
26.0, 25.9 (5CH2), 19.8 (CH3).
EIMS: m/z (%) = 183 (M++1, 30), 182 (M+, 9), 137 (M-CO2H, 30),
100 (C5H8O2, 100), 83 (C6H11, 71).
2-Methyl-2-(1-phenylethyl)-3-butenoic Acid (6d)
From (E)-2-methyl-2-butenoic acid (2) (225 mg, 2.25 mmol) and
1-phenyl-1-tosyloxyethane (d) (directly transferred to the reaction
vessel through a cannula); the reaction mixture was stirred from
-78 ºC to 0 ºC for 4 h. Work-up gave a mixture of 2-methyl-2-(1-
phenylethyl)-3-butenoic acid (6d, 412 mg, 90%, entry 23) as a dias-
tereoisomeric mixture (R*R*:R*S*, 63:37) and (E)-2-methyl-5-
phenyl-2-hexenoic acid in a 95:5 ratio4; a yellow oil.
HRMS: m/z calcd for C11H18O2 (M+) 182.1307. Found: 182.1293.
2-Cyclohexyl-2-methyl-3-pentenoic Acid (8c)
3-Methyl-2-(1-phenylethyl)-3-butenoic Acid (7d)
From (E)-2-methyl-2-pentenoic acid (4) (257 mg, 2.25 mmol) and
2-tosyloxycyclohexane (c) (571.5 mg, 2.25 mmol); the reaction
mixture was stirred at r.t. for 4 h. Work-up gave 2-cyclohexyl-2-me-
thyl-3-pentenoic acid (8c) as a white solid (376 mg, 85%, entry 18).
Column chromatography led to isolation of analytically pure mate-
rial, mp: 68-69 ºC.
From 3-methyl-2-butenoic acid (3) (225 mg, 2.25 mmol) and 1-phe-
nyl-1-tosyloxyethane (d) (directly transferred to the reaction vessel
through a cannula); the reaction mixture was stirred from -78 ºC to
0 ºC for 4 h. Work-up gave 3-methyl-2-(1-phenylethyl)-3-butenoic
acid (7d) as a diastereoisomeric mixture (R*S*:R*R*, 74:26); a
yellow oil (325 mg, 71%, entry 24). Column Chromatography led
to isolation of the major diastereoisomer as a white solid, mp: 64-
66 ºC.4
IR (KBr): nmax = 3300-2500, 1680, 1440, 1270, 1240, 1170, 970
cm-1.
1H NMR (CDCl3): d = 5.63-5.47 (m, 2H, CH=CH), 1.77-1.53 (m,
6H, CH-CH-CO2H and 5CHeq), 1.71 (d, 3H, J = 5.1 Hz, CH3CH= ),
1.29-0.85 (m, 5H, 5CHax), 1.16 (s, 3H, CH3).
13C NMR (CDCl3): d = 182.9 (CO2H), 133.5 (CH3CH=CH), 125.3
(CH3CH=CH), 51.6 (C-CO2H), 45.0 (CH-C-CO2H), 28.1, 27.3,
26.8, 26.7, 26.5 (5CH2), 18.2 (CH3CH= ), 15.2 (CH3).
(E)-2-Methyl-2-(1-phenylethyl)-3-pentenoic Acid (8d)
From (E)-2-methyl-2-pentenoic acid (4) (257 mg, 2.25 mmol) and
1-phenyl-1-tosyloxyethane (d) (directly transferred to the reaction
vessel through a cannula); the reaction mixture was stirred from -
78 ºC to 0 ºC for 4 h. Work-up gave (E)-2-methyl-2-(1-phenyleth-
yl)-3-pentenoic acid (8d) as
a diastereoisomeric mixture
EIMS: m/z (%) = 196 (M+, 16), 181 (M-CH3, 4), 151 (M-CO2H,
15), 115 (C6H11O2, 100), 114 (C6H10O2, 61), 83 (C6H11, 77).
(R*R*:R*S*, 76:24)4; a yellow oil (325 mg, 66%, entry 25).
HRMS: m/z calcd for C12H20O2 (M+) 196.1463. Found: 196.1465.
2,3-Diphenylbutanoic Acid (10d)
From phenylacetic acid (9) (306.3 mg, 2.25 mmol) and 1-phenyl-1-
tosyloxyethane (d) (directly transferred to the reaction vessel
through a cannula); the reaction mixture was stirred from -78 ºC to
0 ºC for 4 h. Work-up gave 2,3-diphenylbutanoic acid (10d) as a di-
astereoisomeric mixture (R*S*:R*R*, 77:23)4,14 as a yellow oil
(437 mg, 81%, entry 26). In an alternative work-up, controlled acid-
ification until pH = 6 led to the precipitation of pure (R*S*) 2,3-
diphenylbutanoic acid (10d) (281 mg, 52%). When the mother li-
quors were further acidified until pH = 2 a new precipitate could be
isolated (diastereoisomeric mixture, R*S*:R*R* = 20:80) (108 mg,
20%). Extraction of the remaining aqueous solution led to isolation
of an organic layer (48 mg, 9%) as mixture of starting acid (69%)
and 2,3-diphenylbutanoic acid (39%) (diastereoisomeric mixture,
R*S*:R*R* = 50:50).
Anal. Calcd for C12H20O2 (196.2): C, 73.41; H, 10.28. Found: C,
73.42; H, 10.45.
2-Cyclohexyl-2-phenylethanoic Acid (10c)
From phenylacetic acid (9) (306.3 mg, 2.25 mmol) and 2-tosyloxy-
cyclohexane (c) (571.5 mg, 2.25 mmol); the reaction mixture was
stirred at r.t. for 4 h. Work-up gave 2-cyclohexyl-2-phenylethanoic
acid (10c) as a white solid (460 mg, 94%, entry 19). Crystallisation
from MeOH/hexane led to isolation of white prisms, mp: 151-
153ºC.
IR (KBr): nmax = 3100-2600, 1690, 1445, 1410, 1290, 1230, 1200,
950, 700 cm-1.
1H NMR (CDCl3): d = 7.34-7.25 (m, 5H, Ph), 3.22 (d, 1H, J = 10.8
Hz, CH-Ph), 2.02-1.98 (m, 1H, H1¢), 1.92-1.88 (m, 1H, H2¢eq), 1.73
(m, 1H, H3¢eq), 1.63 (m, 2H, H3¢eq and H4’eq), 1.34-1.30 (m, 2H, H3¢ax
+H5¢ax), 1.17-1.06 (m, 3H, H6¢eq, H2¢ax and H4¢ax), 0.90-0.80 (m, 1H,
Acknowledgement
H6¢ax).
The present research was financed by DCICYT (PB-95-1121-C02-
01). One of us (E. M. B.) acknowledges a grant by DGICYT.
Synthesis 2000, No. 8, 1160–1165 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Regioselective Alkylation of Lithium Dienediolates of a,b-Unsaturated Carboxylic Acids
1165
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Article Identifier:
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Synthesis 2000, No. 8, 1160–1165 ISSN 0039-7881 © Thieme Stuttgart · New York