On the mechanism of the addition of organolithium reagents to cinnamic acids

Article abstract of DOI:10.1016/S0040-4020(00)01096-6

The regioselectivity of the addition of tert-butyllithium to cinnamic acid is subject to reaction conditions and to substituent electronic effects. Significant effects are observed in the presence of several additives including a radical trap such as α-methylstyrene. Competition experiments by addition of the organolithium reagent to mixtures of substituted cinnamic acids show that the relative rates of both conversion of the starting acids and formation of the 1,3-adducts are subject to electronic effects, whereas rates for 1,4-addition are independent of the substituents. These features are in agreement with a polar addition mechanism, but a fast SET equilibrium followed by slow radical combination would be possible as well.

Full text of DOI:10.1016/S0040-4020(00)01096-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1067±1074
On the mechanism of the addition of organolithium reagents to
cinnamic acids
a
Marõa Jose Aurell, Marõa Jose BanÄuls, Ramon Mestres and Elena MunÄoz
b
a,p
a
Â
Â
Â
Â
a
Á Á Á
Departament de Quimica Organica, Universitat de Valencia, Burjassot 46100, Valencia, Spain
Á Á Á
Escola Tecnica Universitaria de Ciencies Experimentals i Tecnologia, Universitat Internacional de Catalunya, Tortosa 43500, Spain
b
Received 26 June 2000; revised 10 November 2000; accepted 24 November 2000
AbstractÐThe regioselectivity of the addition of tert-butyllithium to cinnamic acid is subject to reaction conditions and to substituent
electronic effects. Signi®cant effects are observed in the presence of several additives including a radical trap such as a-methylstyrene.
Competition experiments by addition of the organolithium reagent to mixtures of substituted cinnamic acids show that the relative rates of
both conversion of the starting acids and formation of the 1,3-adducts are subject to electronic effects, whereas rates for 1,4-addition are
independent of the substituents. These features are in agreement with a polar addition mechanism, but a fast SET equilibrium followed by
slow radical combination would be possible as well. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
tion of the benzylic anion form of the 1,3-adduct and
recovery of one molecule of cinnamic acid lithium salt.
This stepwise radical mechanism was supported by lower
amounts of the 1,3-adduct reported by Crossland when the
reaction was carried out in the presence of a-methylstyrene,
as a radical trap.
Reports on the synthetic applications of addition of organo-
lithium reagents to activated double bonds of acrylic
acids,1±5 styrene,6 cinnamyl alcohols, ethers, amines and
dioxolanes,7 or cinnamic aldehydes,8 esters,9 or amides,10,11
have been recently published. Many of these additions
afford single regioisomers, but cinnamic acid 1a, its esters
or primary or secondary amides afford mixtures of 3- and
2-alkyl-substituted phenylpropanoic acids 2a and 3a
(Scheme 1), or their corresponding derivatives, on reaction
with alkyllithium or magnesium reagents. This behaviour
was ®rst observed by Crossland on reaction of tert-butyl-
magnesium chloride with ethyl cinnamoate and later by
Klumpp for tert-butyllithium and cinnamic acid 1a.12±15
Mixtures of Michael and contra-Michael adducts were
also reported independently by Mortier and by ourselves
on reaction of cinnamic acid with other alkyllithium
reagents.4,5,16 However, the mechanism of these additions
has not yet been clari®ed. According to Crossland and
Klumpp, a single electron transfer (SET) would ®rst afford
the tert-butyl radical and a cinnamic radical lithium enolate
A, as shown in Scheme 2 for cinnamic acid 1a (Scheme 2,
path a). Diffusionless radical combination would give the
1,4-adduct as an enolate (path b), whereas diffusion of the
tert-butyl radical would lead to the 1,3-addition of the radi-
cal to a second molecule of cinnamic acid lithium salt (path
c) giving the benzylic radical B and this would undergo a
second SET (path d) with the radical enolate A, with forma-
Keywords: lithium; organolithium Michael reaction; carboxylic acids;
linear free-energy relations.
p
Corresponding author. Tel./fax: 134-96-398-3152;
e-mail: ramon.mestres@uv.es
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01096-6

1068
M. J. Aurell et al. / Tetrahedron 57 (2001) 1067±1074
Scheme 2.
In previous work, attention was paid to the scope of this
unusual addition and to the experimental conditions which
modi®ed the regioselectivity. Several organolithium
reagents were then allowed to react with cinnamic acid,
whereas tert-butyllithium was added to a variety of
b-aryl-acrylic acids.16 Klumpp had found that addition of
n-butyllithum to cinnamic acid led to the 1,4-adduct along
with a small amount (6%) of the 1,3-adduct.15 With the
same acid as acceptor we con®rmed the latter result and
found that sec-butyllithium afforded a 60:40 ratio for
Michael and contra-Michael adducts and that phenyllithium
gave exclusively the Michael adduct.4,5,16 Some of the
regioselectivity trends then observed for alkyllithium
reagents on addition to cinnamic acid and to other b-aryl-
acrylic acids could be simply explained through steric
hindrance, but signi®cant electronic effects were found
when additions of tert-butyllithium to para- and meta-
substituted cinnamic acids were carried out. Inverted regio-
selectivity trends for 1,4/1,3 ratios were obtained for
p-dimethylamino- and m-chloro-cinnamic acids (84:16 to
21:79, respectively) and linear correlations were obtained
for the logarithms of the 1,4/1,3 regioselectivity ratios
versus the substituent s constants(r ˆ 2 1:02). We felt
thus that a simple polar addition mechanism (Scheme 3,
paths a, b) could give account of the observed regio-
selectivity. However, the evidence for the polar nature of
the addition then became blurred by the fact that a linear
correlation was obtained as well for a radical sz constant17
and, more importantly, because the decrease of 1,3-addition
product in the presence of a-methylstyrene reported by
Crossland was con®rmed. p-Dinitrobenzene was assayed
as well as a radical trap, but the reaction became very
complex and conclusions could not be drawn.
In the present study we want to provide new experimental
support for the polar mechanism of the addition of tert-
butyllithium to cinnamic acids 1. A wider variety of the
reaction conditions for cinnamic acid 1a has shown now
that signi®cant effects on the regioselectivity of the addition
may be caused by a variety of additives other than
a-methylstyrene. On the other hand, competition experi-
ments by addition of limited amounts of the organolithium
reagent to mixtures of substituted cinnamic acids 1b to 1f
and cinnamic acid 1a have shown that the relative rates of
conversion of the starting acids and formation of the 1,3-
adducts are both subject to electronic effects, whereas 1,4-
addition is independent of the substituents. The study of the
acidic reaction mixtures by GLC-MS has not afforded any
clear evidence for side-products expected from radical
intermediates.
Scheme 3.

M. J. Aurell et al. / Tetrahedron 57 (2001) 1067±1074
1069
Table 1. Addition of tert-butyllithium to cinnamic acid 1a. In¯uence of reaction conditions on regioselectivity
Entry
Methoda
Starting 1a
tert-BuLi
Additive
Crude yield (%)
Recovered 1a (%)
Regioselectivity ratios 2a/3a
mmol
mL
mmol
mL
mmol
1
2
3
4
5
6
7
8
Ab
Ab
Ab
Bb
A
2.25
2.25
2.25
2.25
0.5
20
5
4.5
4.5
4.5
4.5
1.2
1.2
5.0
5.0
5.0
5.0
4.5
5.0
4.3
5.0
10
8
100
2.8
10
0.8
2.9
2.9
2.9
2.9
10
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
LiBr
Benzene
MSd
MS
MS
Hexane
82
70
70
96
Ð
64
80
62
81
88
84
82
78
95
Ð
Ð
20
Ð
Ð
6
3.5
trace
trace
trace
13
trace
trace
trace
37:63
49:51
39:61
47:53
53:47
38:62
45:55
62:38
58:42
68:32
50:50
48:52
48:52
50:50
20
10
20
30
30
30
30
30
20
30
30
15
B
0.5
B
2.25
2.25
2.25
2.25
2.25
2.25
2.25
1.0
Bc
B
9
5
30
5
2.2
37.7
15
10
11
12
13
14
B
Ab
B
5
2.9
2.5
B
B
a Method A: Slow addition of acid 1a in THF to the stirred organolithium reagent at 2708C in pentane/THF; Method B: Slow addition of the organolithium
reagent in pentane to the stirred acid 1a in THF at 2708C
b Regioselectivity ratios established by 1H NMR.16
c Addition carried out at 08C.
d MS stands for a-methylstyrene.
2. Results
(entry 14). The effect of diverse ligands on the addition of
n-butyllithium to secondary cinnamamides reported by
Normant are in keeping with the present observations.10,11
Regioselectivity ratios had formerly been obtained through
1H NMR spectra of crude reaction acid fractions. Relative
amounts of all components of these mixtures have been
established now by GLC after esteri®cation with diazo-
methane. Chromatographic peaks for the adducts have
been unambiguously identi®ed thanks to the exclusive
esteri®cation of the 1,4-adducts by the Fischer method,
and the esteri®cation of both regioisomers with diazo-
methane, as previously done for the study of composition
In connection with the above results, some experiments of
addition of limited amounts of the organolithium reagent to
cinnamic acid 1a and to p-chlorocinnamic acid 1e have
shown that regioselectivity ratios depend to a small extent,
but reproducibly, on the relative amounts of starting acid
and organolithium reagent. Thus for 0.5 mmol of cinnamic
acid 1,4/1,3 ratios 32/68, 47/53 and 36/64 have been
obtained for addition of 0.3, 0.75 and 0.9 mmol of tert-
butyllithium. Similarly, for the same amount of p-chloro-
cinnamic acid 1e additions of 0.45, 0.81 and 1.17 mmol led
to 25/75, 40/60 and 45/55 1,4/1,3 ratios, respectively.
of mixtures through H NMR spectra.16 Ethyl 3-phenyl-
propanoate has been used as reference and calibration
curves have been established against this reference for the
methyl esters of all the starting acids and their adducts.
1
The fact that regioselectivity could be a function of reaction
conditions was cause for concern. Indeed, in the competition
experiments the mixture of cinnamic acids is subjected to
limited amounts of reagent (see below) and this limitation
may differ from one competing acceptor to another on
account of their relative reactivity; the competition results
could then be unreliable. In order to ®nd the extent of the
error owing to this origin, regioselectivities have been
established for additions of slight excess of tert-butyllithium
to cinnamic acids under the same conditions as for
the competition experiments and compared to the regio-
selectivities obtained in these experiments. 1,4/1,3 Ratios
(2:3) for cinnamic acid 1a and substituted cinnamic acids
Modi®cation of the regioselectivity of the addition of tert-
butyllithium to cinnamic acid 1a as a function of reaction
conditions is shown in Table 1. Inversion in the order of
addition of the reagents, their relative amounts (entries 1 to
7) and changes of concentrations are accompanied by modi-
®cation of the 1,4/1,3 ratios, although the regioselectivity
trend is either preserved or only slightly inverted (entry 5).
More signi®cant changes, with clear inversion of regio-
chemical trend, are observed when the reaction is carried
out at 08C (entry 8), or in the presence of lithium bromide, or
benzene (entries 9 and 10). What is more important, the
effect of a-methylstyrene (MS) as additive (entries
11±13) is completely comparable to that caused by hexane
Table 2. Addition of tert-butyllithium to cinnamic acidsa
Starting acid 1
Crude yield (%)
Recovered acid 1 (%)
2 (%)
3 (%)
Regioselectivity ratios 2:3
1a
1b
1c
1d
1e
1f
75
74
85
90
82
89
9
10
7
7
trace
trace
34.5
73.0
62.0
30.2
48.0
26.2
56.4
16.6
30.5
62.4
52.0
73.7
38:62
81:19
67:33
33:67
48:52
26:74
a tert-Butyllithium (1.2 mmol) in pentane (0.8 mL) added to cinnamic acid 1x (0.5 mmol) in THF (30 mL) at 2708C.

Table 3. Competition experimentsa
Starting acids
Crude yields (%)b
Recovered starting acids (%)c
Obtained 1,4-adducts (%)c
Obtained 1,3-adducts (%)c
Competition ratios (CR)d,e
Regioselectivity ratios
1a
1x
2a
2x
3a
3x
1x/1a
2x/2a
3x/3a
2a/3a
2x/3x
1b/1a
1c/1af
1d/1a
1e/1a
1f/1a
69
7
24
19.1
19.4
19.0
4.8
0.69
0.67
0.98
1.09
1.45
1c/1b
0.97
1.01
0.98
0.99
0.98
0.95
2c/2b
0.97
0.25
0.64
1.48
1.71
2.57
3c/3b
2.59
50:50
80:20
71
75
70
17
60
29
1b
40
18
57
8
1c
41
14.1
8.3
11.8
2b
14.0
8.1
11.2
2c
16.9
11.0
14.8
3b
25.0
18.8
38.0
3c
45:55
43:57
44:56
2b/3b
79:21
36:64
31:69
22:78
2c/3c
58:42
1c/1b
73
14.7
14.3
3.9
10.1
a tert-Butyllithium (1.2 mmol) in pentane (0.8 mL) added to a mixture of cinnamic acid 1a (0.5 mmol) and a substituted cinnamic acid 1x (0.5 mmol) in THF (30 mL) at 2708C.
b Crude yields are estimated for a complete conversion of starting acids to adducts.
c Amounts estimated from integration GLC peaks, calibration curves with ethyl 3-phenylpropanoate as reference and measured amounts of aliquots.
d Given for conversion of starting acids 1 and formation of adducts 2 and 3.
e For estimation of conversion yields of starting acids, the yields for recovered acids 1 are corrected by a recovery coef®cient, obtained from the crude yields of the mixture and summation of the estimated yields of all
components in the mixture.
f Ratios estimated by combining results of competition reactions 1b/1a and 1c/1b.

M. J. Aurell et al. / Tetrahedron 57 (2001) 1067±1074
1071
1b±1f both as single acceptor and under competition condi-
tions are shown in Tables 2 and 3, respectively. Regio-
selectivity ratios for p- and m-methoxy- and for m-chloro-
cinnamic acids 1b, 1d, and 1f, vary very little, but more
important changes are observed for cinnamic and p-chloro-
cinnamic acids 1a and 1e. An equivalent comparison for
p-methylcinnamic acid could not be done. These changes
are indicative of the limitation of the present method.
However, and most signi®cant, the regioselectivity ratios
2a/3a for cinnamic acid in the competition experiments do
not vary to any great extent; the values of the competition
ratios now obtained are thus reliable within experimental
error, although signi®cant value should not be granted to
small differences.
Competition experiments have been carried out by addition
of 1.2 mmol of tert-butyllithium in pentane (1.5 M) to
0.5 mmol each of both cinnamic acids in 30 mL of THF at
2708C. These standard conditions justify the assumption
that, within experimental error, the amounts of reactive or
product compounds now obtained keep a proportion with
their respective relative rates of conversion or formation.
Reactivity, solubility, or isolation dif®culties associated
with the nature of some substituents, as well as overlap of
some of the GLC peaks, have severely constrained the
number of substituted cinnamic acids now employed,
especially when compared to our previous work.16 For
p-methylcinnamic acid 1c, overlapping dif®culties were
overcome by combining results of the competition reactions
of this acid with p-methoxycinnamic acid 1b and of the
latter with cinnamic acid 1a.
Figure 1.
tioned adducts were the sole signi®cant products when the
esteri®ed crude reaction mixtures were studied by GLC.
Peaks for the esters of recovered cinnamic acids and 1,4-
and 1,3-adducts accounted for over 98% of the integration.
Small GLC peaks at higher retention times were occasion-
ally observed and GLC-MS analysis showed molecular
peaks M1 corresponding to pyrazolines 4 and pyrazoles 5
derived from 1,3-dipolar cycloaddition of excess diazo-
methane to unreacted cinnamic acids. Spectra of other
chromatographic peaks were in agreement with compounds
containing a tert-butyl group and two cinnamic acid
structural unities, such as, for instance 6 or 7, which could
result from a Michael addition of the carbanionic form of
the 1,3-adduct of cinnamic acid. Another group of small
Crude yields, estimated yields of conversion of the starting
acids and yields of adducts obtained in the competition
experiments, along with competition ratios are given in
Table 3. Observation of competition ratios (CR) reveal
that conversion of the starting acids is speeded up by
electron-withdrawing groups and slowed down by electron-
donating substituents. The same trend is observed for 1,3-
addition, with a competition ratio ranging from 2.57 for
m-chlorocinnamic acid 1f to 0.25 for p-methoxycinnamic
acid 1b. However and most signi®cantly, no electronic
effects are observed for 1,4-addition, all ratios ranging
between 0.95 and 1.01. When the logarithms of the com-
petition ratios (CR) are plotted against the Hammett
susbtituent s constants, good linear correlations are
obtained (Fig. 1), with positive reaction constants for the
converted starting acids (rˆ0.52, R2ˆ0.932) and for forma-
tion of 1,3-adducts (rˆ1.44, R2ˆ0.880), and a practically
zero reaction constant (rˆ20.035, R2ˆ0.728) for 1,4-addi-
tion. It was most interesting to observe now that correlations
against radical sz constants for the rather limited number of
para-substituted cinnamic acids now available deviate
strongly from linearity.
Signi®cant information for clari®cation of reaction mechan-
isms may be obtained from observation of side-products. In
the former study we stated that the organolithium additions
gave no other acidic compounds other than the 1,3- and 1,4-
adducts, as this could be concluded from observation of the
NMR spectra of crude mixtures. We were interested now to
®nd whether side-products could be found by the more
sensitive chromatographic technique. Again the aforemen-

1072
M. J. Aurell et al. / Tetrahedron 57 (2001) 1067±1074
peaks might derive from the former ones, as their MS spec-
tra were in agreement with the cyclopentanones 8 or 9,
which could result from a domino-1,3 addition±Michael
addition±Dieckmann cyclization, with decarboxylation of
the resulting keto acid after isolation of the acidic fraction
of the reaction mixture.18
The reaction constant rˆ1.44 here obtained for the 1,3-
addition is lower than the value expected for generation of
an anionic charge at the benzylic carbon. Reaction constants
with absolute values well above 2 are usually reported for
modi®cation of charge at a carbon atom directly bound to a
benzene ring.20,21 However, the charged benzylic carbon
resulting now from the polar 1,3-addition should be
expected to be tightly coordinated to a lithium atom, a
feature which should signi®cantly reduce the substituent
electronic effects and thus, the present result is not in contra-
diction with a polar mechanism. This lithium coordination
has been put forward for the known selective ionization of
the benzylic protons, instead of the protons a to carbonyl
protons, on treatment of hydrocinnamic secondary amides
with sec-butyllithium as base.22
3. Discussion
The regioselectivities obtained under diverse reaction
conditions show that the decrease of 1,3-addition observed
by Crossland and by ourselves on addition of a-methyl-
styrene does not prove the intermediacy of a radical species.
These effects may rather be explained by the diverse
solvated ion pair aggregation forms in which carboxylic
acids, their lithium salts and lithium enolates may be present
in solution. It is well established that the equilibria between
aggregates may be modi®ed by changes in solvent polarity
or by lithium halides or other additives present in the solu-
tion. This may be the case for the actual acceptors in the
reacting mixture, which are constituted initially by the free
acid and afterwards by mixtures of their lithium salts and of
the ®nal carbanionic adducts. [Luche has shown that for
organolithium reagents, addition to carboxylic acids and
deprotonation may be competitive processes. The same
might apply for additions to unsaturated carboxylic
acids.19] The above additives may thus contribute to modify
the relative accessibility of the C-2 and C-3 carbon atoms of
the acceptor to the attacking organolithium or radical
species. Regioselectivity changes found on addition of
limited amounts of reagents most probably re¯ect the
mobility of the ion pair aggregation equilibria during the
progress of the reaction.
When the SET±radical combination mechanisms are
considered (Scheme 3, pathways c, d and e), the substituent
effects cannot be taken separately, especially for the con-
version of the starting acids and for the formation of the 1,4-
adducts. If a SET±radical combination mechanism with a
slow electron transfer occurs, the substituent effects found
for the relative conversion rates of the cinnamic acids
should be re¯ected on the rates of product formation and
thus, the reaction constant for formation of 1,4-adducts
should not be zero, unless substituent effects would be
perfectly counterbalancedÐa most unlikely circumstance.
In contrast, a SET as a previous equilibrium cannot entirely
be ruled out, as assumption of substituent effects in one step
being counterbalanced in the other seem more feasible now.
Indeed, the equilibrium constants of previous fast equilibria
contribute to the observed rate constants and thus, the
substituent effects found for the following rate-determining
step cannot afford a reaction constant rˆ0 unless either the
equilibrium constants are not in¯uenced by substituent
effects, or these are exactly counterbalanced in the second
step. This might happen in the present case, where the elec-
tron transfer leads to an anion radical and thus a positive
reaction constant should be expected. The following radical
combination for the 1,4-addition does not neutralize the
anionic charge, but disrupts the conjugation of the aromatic
ring with the anionic chain and thus, a substituent effect of
opposite sign could be expected. The value for the reaction
constant found now for the 1,3-addition might be thought to
Once it was found that the experimental data that supported
the stepwise radical mechanism (Scheme 2) advanced by
Crossland and Holm14 could be understood through aggre-
gation effects, explanation of the results of the addition
should be attempted in simple terms by assumption of a
competition in the attack at one or other of the ethylenic
carbon atoms of the acceptor, by distinction between a polar
or a SET±radical combination mechanism (Scheme 3). For
the latter mechanism the rate-determining step should then
be established.
The observed trends for the free-energy linear correlation
reaction constants are qualitatively in agreement with a
polar mechanism, especially if rates are acknowledged to
be determined by product development. Indeed, an anionic
charge is being developed at the benzylic carbon when
attack occurs at C-2, whereas an enolate forms on attack
at C-3. The energy of the benzylic anion should then depend
on the nature of the phenyl ring substituents, whereas the
electron-withdrawing or releasing character of these would
be immaterial for the development of the enolate anion. The
value of the r reaction constant for the conversion of the
acids is intermediate between the values of the constants of
the 1,3- and 1,4-additions, a feature which ®ts with conver-
sions occurring through competition between two different
rate-determining steps, each of them leading to a different
compound and each being subject to different substituent
effects, as should happen in this polar mechanism.

M. J. Aurell et al. / Tetrahedron 57 (2001) 1067±1074
1073
®t with a SET leading to a delocalized radical anion
(Scheme 3, path c), but it is certainly much higher than
that reported for the reversible one-electron electrochemical
reduction of methylthioesters of cinnamic acids against
Hammett s2 constants (r<0.2).23
conditions are not entirely comparable with the present
additions, they suggest that only 1,4-adducts would again
be obtained, should the easily reduced tert-butyllithium
reagent add to cinnamic acid through a SET-radical
coupling mechanism. The answer to this riddle is beyond
the reach of the present study.
As for the side-products, adipic and cyclopentanones related
to structures 10 or 11 would be expected from SET
processes, but the observed structures 6±9 can be con-
veniently explained instead by polar additions.
4. Conclusion
Study of the effect of reaction conditions on the regio-
selectivity of the addition of tert-butyllithium on the CyC
double bond of cinnamic acid and competition experiments
of addition to substituted cinnamic acids show that the addi-
tion of tert-butyllithium to cinnamic acids can be explained
in a simple way by a polar addition mechanism, with
competition between attack at C-3 and C-2 carbon atoms
of the cinnamic lithium salts. However, a fast electron trans-
fer followed by a rate-determining radical coupling may be
possible as well.
Some further comments about the distinction between polar
and SET mechanisms may be convenient here. Recent
publications by Gajewski and by Holm discuss the vast
amount of work done on the additions of magnesium and
lithium organometallic reagents to aldehydes and ketones
and stress the dif®culties for the experimental distinction
between polar and SET±radical combination mechan-
isms.24,25 Thus, the conversion pathway is determined not
only by the redox potentials of the organometallic reagent
and the electrophilic acceptor, the ergonicity of the polar
addition and steric effects, which may retard CZC bond
formation, but also by reaction conditions, such as tempera-
ture. According to these publications butyllithium reagents
are fairly readily oxidized to their corresponding radicals by
transfer of one electron to carbonyl groups, but the exo-
thermicity of the polar addition may render the latter path-
way more favourable than the SET±radical combination
process. Unfortunately, as far as we know, there are no
equivalent studies on the 1,4-additions of organolithium
reagents to unsaturated carboxylic acids or their derivatives.
It is not feasible now to ascertain, for instance, to what
extent the present acceptors may be reduced by butyllithium
in a SET process and what is the exothermicity of the polar
addition to the C-2 or C-3 atoms of the carboxyl- and
phenyl-activated double bond of cinnamic acid.
5. Experimental
Gas chromatographic determinations were carried out with
a ThermoQuest Trace 2130 gas chromatograph, with a FID
detector, a 0.25 mm ®lm DB-5 30 m capillary column and
nitrogen as carrier gas. Introduction of sample at 2308C by
splitless mode, detector at 3108C and a gradient program
(5 min at 1208C, one 58C/min ramp up to 2008C and 3 min
hold time) were employed. Mass spectra were determined
with VG Autospec or Trio 1000 spectrometers by electronic
impact or chemical ionization. Tetrahydrofuran (THF) was
distilled from blue sodium diphenylketyl immediately
before use. All reactions were carried out under nitrogen
atmosphere, using standard conditions for exclusion of
moisture. The reaction temperature (2708C) was achieved
by cooling with a CO2/acetone bath. Evaporation of solvents
was carried out with a vacuum rotatory evaporator at 408C.
Cinnamic acids and 1.6 M tert-butyllithium in pentane were
purchased from Aldrich. The concentration of the latter was
established volumetrically with salicylaldehyde phenyl-
hydrazone as 1.5 M.30
Comparison of the present regioselectivity results with
related processes and consideration of their mechanisms is
rather puzzling, as exclusive 1,4-addition of the tert-butyl-
lithium reagent to cinnamic acid would be advanced regard-
less of the polar or SET nature of its mechanism. On the one
hand, phenyllithium is known to add to carbonyl groups
through a two-electron CZC bonding process owing to its
reluctance to be oxidized by one-electron transfer.24 The
same polar mechanism is most likely to be operative for
the reaction of phenyllithium with cinnamic acids and
esters, an addition which leads exclusively to 1,4-
adducts.4,5,9,16 On assumption then of a similar two-electron
process for the addition of the tert-butyllithium reagent to
cinnamic acid, only the 1,4-adduct would be expected,
instead of the observed 1,4 and 1,3 mixture. On the other
hand, there is ample experience indicating that radical
anions generated by reduction of cinnamic systems tend to
afford radical combination products through their C-3
carbons. Thus, cathodic and samarium(II) reductive reac-
tions of cinnamic derivatives lead to 1,4-homo-coupling
products, namely 3,4-diphenyladipic derivatives 10, or
their corresponding Dieckmann condensation cyclopenta-
nones 11.23,26±28 Further, a 1,4-hetero-coupling of cinnamic
amides and acetic anhydride, to give amides 12 under reduc-
tive electrochemically induced conditions, has also been
reported.29 Although these reductive and electrochemical
The methyl esters of the cinnamic acids 1 are well-known
compounds and have been obtained now by esteri®cation
with diazomethane. The methyl esters of the 1,3- and 1,4-
adducts have been previously described,16 and prepared
either with diazomethane or by selective esteri®cation of
the reaction mixtures with methanol, as already described.16
Ethyl 3-phenylpropanoate has been prepared by esteri®ca-
1
tion of hydrocinnamic acid with ethanol. H and 13C NMR
spectra of common esters prepared now were in agreement
with expectancy.
5.1. General procedure for addition of tert-butyllithium
to cinnamic acids
tert-Butyllithium (1.5 M) in pentane (0.8 ml) was added
dropwise over 3 min with the aid of a syringe to the stirred
cinnamic acid (0.5 mmol) in THF (30 ml) at 2708C. The
solution was stirred for 1 h at the same temperature, water
(30 ml) was added, and the mixture extracted with hexane

1074
M. J. Aurell et al. / Tetrahedron 57 (2001) 1067±1074
9. Frey, L. F.; Tillyer, R. D.; Caille, A. S.; Tschaen, D. M.;
Dolling, U. H.; Grabowski, J. J.; Reider, P. J. J. Org. Chem.
1998, 63, 3120.
(3£15 ml). The aqueous layer was acidi®ed, under stirring
and ice-water cooling, by slow addition of conc. hydro-
chloric acid and then extracted with ethyl acetate
(4£15 ml). The joint organic layers were dried. Evaporation
of the solvent gave a mixture of recovered starting acids and
adduct carboxylic acids, whose weight was determined. An
aliquot of the mixture was esteri®ed with an ether solution
of diazomethane; a known amount of ethyl 3-phenyl-
propanoate was added; the solution was diluted to a
convenient volume and analysed by GLC.
10. Bremand, N.; Marek, H.; Normant, J. F. Tetrahedron Lett.
1999, 40, 3379.
11. Bremand, N.; Marek, H.; Normant, J. F. Tetrahedron Lett.
1999, 40, 3383.
12. Crossland, I. Acta Chem. Scand. B 1975, 29, 468.
13. Holm, T.; Crossland, I. Acta Chem. Scand. B 1971, 25, 59.
14. Holm, T.; Crossland, I.; Madsen, J. O. Acta Chem. Scand. B
1978, 32, 754.
5.2. General procedure for competition experiments of
addition of tert-butyllithium to cinnamic acid (or p-
methoxycinnamic acid) and a substituted cinnamic acid
15. Kruithof, K. J. H.; Mateboer, A.; Schakel, M.; Klumpp, G. W.
Recl. Trav. Chim. Pays-Bas 1986, 105, 62.
16. Aurell, M. J.; BanÄuls, M. J.; Mestres, R.; MunÄoz, E. Tetrahedron
1999, 55, 831.
The same procedure of addition was followed as above,
except for the use of 0.5 mmol of both cinnamic acid 1a
and the substituted acid 1b±1d.
17. Isaacs, N. Y. In Physical Organic Chemistry, 2nd Edition,
Longman: Harlow, 1995; pp 805.
18. Aurell, M. J.; GavinÄa, P.; Mestres, R. Tetrahedron 1994, 50,
2571.
19. Einhorn, C.; Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1991,
32, 2771.
Acknowledgements
20. Isaacs, N. Y. In Physical Organic Chemistry, 2nd Edition,
Longman: Harlow, 1995; pp 146.
The present work has been ®nanced by DGICYT. One of us
(E. M.) acknowledges a research grant by Conselleria de
Cultura de la Generalitat Valenciana.
21. Lowry, T. H.; Richardson, K. S. In Mechanism and Theory in
Organic Chemistry, 3rd Edition, Harper Collins: New York,
1987; pp 143.
22. (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (b)
Lutz, G. P.; Du, H.; Gallagher, G. J.; Beak, P. J. Org. Chem.
1996, 61, 4542. (c) Pippel, D. J.; Du, H.; Curtis, M. D.; Beak,
P. J. Org. Chem. 1998, 63, 2.
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