Reducing versus basic properties of 1,2-diaryl-1,2-disodioethanes

Article abstract of DOI:10.1016/j.tet.2011.03.037

The outcome of the reaction between halogenated arylacetic acids and 1,2-diaryl-1,2-disodioethanes strongly depends on the nature of both reaction partners, and it can be rationalized in terms of a competition between reducing and basic properties of the vic-diorganometals, as well as of the ease of the reductive cleavage of the different carbon-halide bonds. As an application of these findings, we developed a particularly mild approach to the synthesis of halogenated and non halogenated α-substituted arylacetic acids.

Full text of DOI:10.1016/j.tet.2011.03.037

Tetrahedron 67 (2011) 3470e3475
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reducing versus basic properties of 1,2-diaryl-1,2-disodioethanes
*
Ugo Azzena , Giovanna Dettori, Luisa Pisano, Mario Pittalis
ꢀ
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100 Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The outcome of the reaction between halogenated arylacetic acids and 1,2-diaryl-1,2-disodioethanes
strongly depends on the nature of both reaction partners, and it can be rationalized in terms of a com-
petition between reducing and basic properties of the vic-diorganometals, as well as of the ease of the
reductive cleavage of the different carbonehalide bonds. As an application of these findings, we de-
Received 8 December 2010
Received in revised form 22 February 2011
Accepted 14 March 2011
Available online 23 March 2011
veloped a particularly mild approach to the synthesis of halogenated and non halogenated
arylacetic acids.
a-substituted
Dedicated to Professor Serafino Gladiali, on
the occasion of his 66th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Arylalkanoic acids
Electron transfer
Hydrodehalogenation
Metalation
Reduction
vic-Diorganometals
1. Introduction
reaction of these dianions with halogenated arylacetic acids high-
lights a competition between their reducing and basic properties,
thus disclosing a new and particularly mild approach to the gen-
eration of enediolates of arylacetic acids.
Despite its low cost, easy availability, and high reducing power,
sodium metal is seldom employed in the generation of organoalkali
reagents, mostly due to practical problems in the generation and
storage of these intermediates.1 Accordingly, we found particularly
interesting the easy availability of 1,2-diaryl-1,2-disodioethanes,
a class of particularly stable vic-diorganometals, readily prepared by
the reductive sodiation of the corresponding 1,2-diarylalkenes.2,3
Besides describing their employment as dinucleophiles in the dia-
stereoselective synthesis of trans-1,2-diarylcyclopentanes,2 we re-
cently reported on their employment as effective Single Electron
Transfer (SET) reducing agents in the dehalogenation of aliphatic
vic-dihalides4 and halogenated benzoic acids.5 We were also able to
demonstrate that their reducing power strongly depends on the
substitution pattern of the parent 1,2-diarylethene employed as
a starting material in their generation, showing that the less delo-
calized dianions are the more powerful reducing agents, and vice
versa.6
2. Results and discussion
2.1. Competitive deprotonation versus reductive cleavage
reactions
For convenience, the numbering of 1,2-diaryl-1,2-disodio-
ethanes, 1aed, follows their relative order of increasing reducing
power, i.e., 1a is the least powerful and 1d is the most powerful
reducing agent employed in the present study (Scheme 1).6
The reaction of a dicarbanion with a halogenated carboxylic acid
can be foreseen to give rise to a competition between deprotona-
tion and dehalogenation reaction pathways. By taking into account
Following our interest in the reductive dehalogenation of aro-
matic substrates, a reaction of potential interest in the degradation
of persistent organic pollutants,7 we wish now to report that the
* Corresponding author. Tel.: þ39 079229549; fax: þ39 079229559; e-mail
Scheme 1. Formulas of the various dianions employed as reducing agents.
address: ugo@uniss.it (U. Azzena).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.037

U. Azzena et al. / Tetrahedron 67 (2011) 3470e3475
3471
the stoichiometry of these reactions, i.e., that a deprotonation re-
action should require a dianion versus acid ratio of 0.5:1, whilst
a reductive cleavage reaction could require a dianion versus aro-
matic halide ratio reaching up to 1:1,5 we decided to investigate the
reactivity of halogenated arylacetic acids, 2aec, with an excess of
the different dianions. Accordingly, we ran most of the reactions
reported below with a dianion versus halogenated arylacetic acid
molar ratio of 2:1.
Deep red (0.20e0.25 M) solutions of 1,2-diaryl-1,2-disodio-
ethanes in THF, were prepared and filtered from unreacted sodium
metal as described elsewhere.2,4e6 0.12 M THF solutions of halo-
genated arylacetic acids 2aec were added dropwise to a solution of
the appropriate dianion chilled at 0 ꢀC, under dry Ar. No attempt
was made to determine the minimum reaction time required to
lead to complete reaction. Accordingly, reaction mixtures were
stirred for 12 h whilst allowed to warm to rt, quenched with H2O,
and the resulting carboxylic acids were recovered after acidifying
the aqueous phase with 1 N HCl (Scheme 2). The results are
reported in Table 1.
however worth noting that quenching these reaction mixtures with
D2O afforded a reaction product almost quantitatively deuterated at
the benzylic position (Table 1, entries 1e3).
This behavior can be rationalized by assuming that the vic-
diorganometals reacted with the fluoroacid as bases, and not as
reducing agents.
More complex results were obtained in the reaction of 2-
chlorophenylacetic acid, 2b, with dianions 1bed. Indeed, reactions
run in the presence of dianion 1b led to quantitative recovery of the
starting material, and D2O quenching suggested the intermediate
formation of the corresponding enediolate (Table 1, entry 4). In
contrast with this result, partial conversion to phenylacetic acid, 2d,
was observed in reactions ran in the presence of the dio-
rganometals endowed with more powerful reducing properties,
i.e., 1c and 1d. Once again, D2O quenching supported the in-
termediate formation of the enediolates of the recovered acids
(Table 1, entries 5 and 6).
Finally, it is worth noting that 2-bromophenylacetic acid, 2c, was
quantitatively dehalogenated in the presence of dianions 1b and 1c
Scheme 2. Reaction of 2-halogenated arylacetic acids 2aec with dianions 1aed. 2a, X¼F; 2b, X¼Cl; 2c, X¼Br.
Table 1
(Table 1, entries 8 and 9), whilst a minor amount of the starting
material was recovered in a reaction run in the presence of the least
powerful reducing agent, i.e., dianion 1a (Table 1, entry 7). Under
theseconditions, theintermediateformationof theenediolateofacid
2d was suggested upon D2O quenching. A last example, run with
a reduced amount of dianion 1c, afforded a significant amount of acid
2d, but D2O quenching did not result in the incorporation of deute-
Dehalogenation versus metalation of 2-halogenated arylacetic acids 2aeca
Entry
Substrate, X¼
Dianion
Product Distribution (%)b
2 (%D)c
2d (%D)c
1
2
3
4
5
6
7
8
9
2a, X¼F
2a, X¼F
2a, X¼F
2b, X¼Cl
2b, X¼Cl
2b, X¼Cl
2c, X¼Br
2c, X¼Br
2c, X¼Br
2c, X¼Br
1b
1c
1d
1b
1c
2a, >95 (>90)
2a, >95 (>90)
2a, >95 (>90)
2b, >95 (>90)
2b, 37 (>90)
2b, 35
2c, 10 (90)
2c, <5
2c, <5
<5
<5
<5
<5
63 (>90)
65
90 (89)
>95 (84)
>95 (78)
27 (<5)
rium at the a-position of recovered products (Table 1, entry 10).
To further highlight the effect of dianions possessing different
reducing power on the course of the above described reactions, we
reacted chloroacid 2b in a 1:1 M ratio with a dianion endowed with
a relatively low reducing power, i.e., 1b; the resulting mixture was
either quenched with D2O, or reacted with of an equimolar amount
of a relatively stronger reducing agent, i.e., dianion 1c. The out-
comes of these experiments are illustrated in Scheme 3, where the
most significant products of each reaction are reported.
1d
1a
1b
1c
10
1cd
2c, 73 (<5)
a
All reactions were run in dry THF, under Ar, for 12 h, with a dianion to substrate
molar ratio of 2:1, unless otherwise indicated.
b
As determined by 1H NMR analyses of crude reaction mixtures.
c
As determined by 1H NMR spectroscopy by monitoring the percentage of deu-
Clearly, the first one is an acidebase reaction, leading to the
formation of the enediolate of the carboxylic acid, as evidenced by
the recovery of regioselectively deuterated 2b as well as of non
deuterated 1,2,3,4-tetraphenylethane, 3. The second reaction,
leading to the recovery of significant amounts of phenylacetic acid,
2d, evidenced that the intermediate enediolate was reductively
dehalogenated in the presence of a stronger reducing agent.
terium incorporation at the benzylic position, after D2O quenching.
d
The dianion to substrate molar ratio was 1:1.
Despite the ability of these dianions to promote the reductive
cleavage of the aromatic carbonehalogen bond of isomeric fluo-
robenzoic acids,5 their reaction with 2-fluorophenylacetic acid, 2a,
led to the quantitative recovery of the starting material. It is
Scheme 3. Deprotonation and successive dehalogenation of 2-chlorophenylacetic acid, 2b.

3472
U. Azzena et al. / Tetrahedron 67 (2011) 3470e3475
2.2. Metalation of arylacetic acids and reactions with
electrophiles
Finally, it is worth noting that we never observed the formation
of products of a double metalation reaction. Accordingly, the re-
action of 3-methyl-2-phenylbutanoic acid, 2dc, with dianion 1c
under the conditions reported above, followed by quenching with
D2O and aqueous work up, did not lead to the incorporation of
The results reported in the above paragraph highlight the pos-
sibility to employ 1,2-diaryl-1,2-disodioethanes 1b or 1c as metal-
ating reagents in the generation of dianions of arylacetic acids 2a
and 2b, under particularly mild reaction conditions. To extend the
scope of this methodology, we investigated the reactivity of the
above mentioned vic-diorganometals with arylacetic acids 2deg,
and investigated the reactivity of the resulting enediolates with
different electrophiles (Scheme 4).
deuterium at the a-position of the starting material.
3. Conclusions
The above reported results highlight a competition between
basic and reducing properties of 1,2-diaryl-1,2-disodioethanes,
showing their use either as dehalogenation reagents or as organic
bases in the generation of enediolates of halogenated and non
halogenated arylacetic acids, with both reactions occurring under
mild reaction conditions.
Concerning the results obtained with the halogenated acids, the
outcome of the reaction between a given halogenated arylacetic
acids and a specified 1,2-diaryl-1,2-disodioethanes strongly de-
pends on the nature of both reaction partners, i.e., on the relative
strength of the aromatic carbonehalogen bond9 and on the basic/
reducing properties of the vic-diorganometal.
Scheme 4. Reactions of arylacetic acids 2aeg with 1,2-diaryl-1,2-disodioethanes 1b or
1c, and reaction with electrophiles. 1b and 1c, see Scheme 1; Ar, EX, see Table 2.
Table 2
Metalations of arylacetic acids 2, and reactions with electrophilesa
Indeed, in the presence of a strong carbonehalide bond, as in
the case of the fluoroacid 2a, the generation of the enediolate is the
only detectable reaction. The effective and regioselective metal-
ation of the ortho-chloroarylacetic acid 2b was realized employing
as a base the highly delocalized dianion 1b, whilst, in the presence
of a dianion endowed with a stronger reducing power, i.e., 1c, it was
possible to observe the cleavage of the carbonechlorine bond of the
corresponding intermediate enediolate. Finally, cleavage of the
relatively weak carbonebromine bond was the main reaction path
in the case of the arylacetic acid 2c.
Leaving aside the redox reaction, our results display a new and
particularly mild approach to the generation of enediolates of ha-
logenated and non halogenated arylacetic acids. Usually, the gen-
eration of enediolate of arylacetic heavily relies on the
deprotonation of the appropriate acid with an organolithium
base,10 and relatively few examples concerns the preparation of the
corresponding sodium diorganometals. With few exceptions,11
sodium dianions of arylacetic acids are generated by the reaction
of a carboxylic acids with NaNH2 in THF/HMPA12 or liquid NH3.13
From this point of view, it is worth noting that our procedure
compares well both with organolithium10 and organosodium11e13
based literature procedures, in terms of ease of handling and sta-
bility of the organometallics employed as bases, the mildness of
reaction conditions, and the yields of recovered reaction products.
As a final remark, we wish to emphasize that substituents lo-
cated on the aromatic or benzylic positions of 1,2-diaryl-1,2-dis-
odioethanes, besides affecting their reducing power, should affect
their basicity as well. Most probably, our results do not highlight
such an effect due to the relatively high acidity of the compounds
submitted to the deprotonation procedure.
Entry Substrate, Ar¼
Dianion EX
Product, E¼
2aa, D
2ab, (CH3)2CH
2ac, (CH2)3Cl
2ba, D
2bb, CH3
2bc, (CH3)2CH
2da, D
2db, CH3
2dc, (CH3)2CH
2dd, (CH2)3Cl
Yieldb (%)
>90c
80
1
2
3
4
5
6
7
2a, 2-FC6H4
2a, 2-FC6H4
2a, 2-FC6H4
2b, 2-ClC6H4
2b, 2-ClC6H4
2b, 2-ClC6H4
2d, C6H5
1c
1c
1c
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
D2O
(CH3)2CHI
Cl(CH2)3Br
D2O
CH3I
(CH3)2CHI
D2O
74
>90c
60
55
>90c
>90
>90
83
8
2d, C6H5
CH3I
9
2d, C6H5
(CH3)2CHI
Cl(CH2)3Br
10
11
12
13
14
15
16
17
18
19
20
2d, C6H5
2d, C6H5
2d, C6H5
2e, 4-FC6H4
2e, 4-FC6H4
2f, 2-Naphthyl
2f, 2-Naphthyl
2f, 2-Naphthyl
2g, 2-CH3C6H4
(CH2CH2)Od 2de, CH2CH2Oe
58
(C6H5)2CO
D2O
Cl(CH2)3Br
D2O
2df, (C6H5)2COHf
2ea, D
2eb, (CH2)3Cl
2fa, D
60
>90c
85
>90c
86
CH3I
2fb, CH3
(CH3)2CHI
(CH3)2CHI
CH3I
2fc, (CH3)2CH
2ga, (CH3)2CH
2ha, CH3
80
70
71
68
2h, 2-CH3OC6H4 1c
2h, 2-CH3OC6H4 1c
(CH3)2CHI
2hb, (CH3)2CH
a
All reactions were run in the presence of 1.1 equiv of either 1b or 1c, for 2 h at
0
ꢀC.
b
c
Determined on isolated products, unless otherwise indicated.
As determined by 1H NMR analysis of the crude reaction mixture.
(CH2CH2)O was bubbled into the reaction mixture chilled at ꢁ30 ꢀC during
d
30 min.
e
Lactonization occurred spontaneously during the acidic work up.
See Experimental section for the work-up procedure.
f
The metalation reaction were performed in THF with a slight
excess (1.1 equiv) of the appropriate dianion, at 0 ꢀC for 2 h, under
dry Ar. The resulting mixture was quenched with different elec-
trophiles, including D2O, several functionalized and non-function-
alized alkyl halides, benzophenone, and ethylene oxide. The results
are reported in Table 2.
4. Experimental
4.1. General
Under these reaction conditions, dianion 1c is an effective
metalating reagent toward 2- and 4-fluorophenylacetic acid, 2a and
2e (Table 2, entries 1e3, 13 and 14), as well as towards non halo-
genated carboxylic acids 2deh (Table 2, entries 7e12 and 15e20).
At variance with these results,
acetic acid, 2b, was successfully realized employing dianion 1b as
a base (Table 2, entries 4e6).
The mildness of our procedure is illustrated, e.g., by the synthesis
of 2-aryl-5-chloropentanoic acids 2ac, 2dd, and 2eb; indeed, these
and similar compounds, which are useful intermediates in the syn-
Starting materials were of the highest commercial quality and
were purified by distillation or recrystallization immediately prior
to use. THF was distilled from Na/K alloy under N2 immediately
prior to use. 1H NMR spectra were recorded at 300 MHz and 13C
NMR spectra were recorded at 75 MHz in CDCl3 (unless otherwise
indicated) with SiMe4 as internal standard on a Varian VXR 300
spectrometer. Deuterium incorporation was calculated by moni-
toring the 1H NMR spectra of crude reaction mixtures, and com-
paring the integration of the signal corresponding to protons in the
arylmethyl position with that of known signals. Resonances of the
a-metalation of 2-chlorophenyl-
thesis of 3-aryl-d-lactones, were recently prepared (in comparable
yields) via a similar procedure, involving a-metalation of the corre-
sponding arylacetic acids with n-hexyllithium in THF at ꢁ60 ꢀC.8

U. Azzena et al. / Tetrahedron 67 (2011) 3470e3475
3473
CHD protons are usually shifted 0.02e0.04 ppm (
to the resonances of the corresponding CH2 protons; the reso-
nances of the arylmethyl CHD carbons appear as triplets
d
) upfield relative
C
11H13FO2: C, 67.33; H, 6.68%. Found: C, 67.12; H, 6.89. IR (Nujol)
1710 cmꢁ1; 1H NMR:
d
0.75 (3H, d, J¼6.6 Hz, CH3),1.09 (3H, d, J¼6.6 Hz,
CH3), 2.26e2.38 (1H, m, CH), 3.67 (1H, d, J¼10.2 Hz, CHAr), 7.00e7.07
(1H, m, ArH), 7.11 (1H, td, J¼7.5, 1.5 Hz, ArH), 7.19e7.28 (1H, m, ArH),
(J¼18e20 Hz) shifted 0.3e0.5 ppm (
d) upfield relatively to the
corresponding arylmethyl CH2 carbons. IR spectra were recorded
on an FT-IR Jacso 680 P. Flash chromatography was performed on
7.66 (1H, td, J¼7.5, 1.8 Hz, ArH); 13C NMR:
d 19.7, 21.3, 31.3, 50.5 (d,
J¼2 Hz), 115.3 (d, J¼23 Hz), 124.3 (d, J¼4 Hz), 126.7 (d, J¼15 Hz), 128.9
Merck silica gel 60 (40e63 mm), and TLC analyses on Macher-
(d, J¼8 Hz), 129.3 (d, J¼3 Hz), 160.8 (d, J¼244 Hz), 179.8.
eyeNagel silica gel pre-coated plastic sheets (0.20 mm). Melting
and boiling points are uncorrected. Elemental analyses were per-
formed by the microanalytical laboratory of the Dipartimento di
4.4.2. 2-(2-Fluorophenyl)-5-chloropentanoic acid, 2ac. Purified by
flash chromatography (petroleum ether/AcOEt¼7:3), colorless
thick oil; Rf¼0.45 (petroleum ether/AcOEt¼7:3); Anal. Calcd for
C11H12ClFO2: C, 57.28; H, 5.24%. Found: C, 57.06; H, 5.38. IR (neat)
ꢀ
Chimica, Universita di Sassari.
4.2. Starting materials
2960, 1709 cmꢁ1; 1H NMR:
d 1.63e1.85 (2H, m, CH2), 1.85e2.02 (1H,
m, CHaHb), 2.16e2.30 (1H, m, CHaHb), 3.52 (2H, t, J¼6.6 Hz, CH2Cl),
3.95 (1H, t, J¼7.8 Hz, CHAr), 7.02e7.09 (1H, m, ArH), 7.13 (1H, td,
J¼7.5, 1.2 Hz, ArH), 7.22e7.29 (1H, m, ArH), 7.33 (1H, td, J¼7.5,
Arylacetic acids 2aeh are commercially available. 0.2e0.25 M
solutions of dianions 1aed in dry THF were prepared as already
described.2,4e6
1.5 Hz, ArH); 13C NMR:
d
29.2, 30.2, 43.0 (d, J¼3 Hz), 44.3, 115.6 (d,
J¼22 Hz), 124.5 (d, J¼4 Hz), 125.0 (d, J¼15 Hz), 129.0 (d, J¼3 Hz),
4.3. Reductive dehalogenation of halogenated carboxylic
acids 2aec. General procedure
129.2 (d, J¼8 Hz), 160.5 (d, J¼245 Hz), 179.3.
4.4.3. 2-(2-Chlorophenyl)propionic acid, 2bb. Purified by flash
chromatography (petroleum ether/AcOEt¼7:3), white powder, mp
76e78 ꢀC (lit.15a 77e78 ꢀC); Rf¼0.45 (petroleum ether/AcOEt¼7:3);
To 10 mL of a 0.24 M solution of a diorganometal 1 (2.4 mmol),
chilled at 0 ꢀC, was added a solution of the appropriate carboxylic
acid 2 (1.2 mmol) dissolved in 5 mL of dry THF. The mixture was
vigorously stirred and allowed to reach rt over 12 h, after which
time it was quenched by slow dropwise addition of H2O (15 mL).
The organic solvent was evaporated in vacuo and the resulting
mixture was extracted with CH2Cl2 (3ꢂ10 mL). The aqueous phase
was acidified with 1 N HCl, extracted with CH2Cl2 (3ꢂ10 mL), and
the organic phases were collected, washed with H2O (1ꢂ10 mL),
brine (10 mL), and dried (Na2SO4). After evaporation of the solvent,
the resulting mixture was analyzed by 1H NMR.
Quenching with D2O was performed by adding 0.75 mL of D2O
to the reaction mixture, followed by aqueous work up as described
above.
Reaction products were characterized by comparison with
commercially available samples.
IR (Nujol) 1706 cmꢁ1
;
1H NMR:
d
1.52 (3H, d, J¼7.2 Hz, CH3), 4.28
(1H, q, J¼7.2 Hz, CHAr), 7.18e7.27 (2H, m, 2ꢂ ArH), 7.33e7.41 (2H,
m, 2ꢂ ArH); 13C NMR:
d 17.2, 42.0, 127.1, 128.4, 128.5, 129.6, 133.8,
137.6, 180.5; NMR spectra in agreement with the literature.15b
4.4.4. 2-(2-Chlorophenyl)-3-methylbutanoic acid, 2bc. Purified by
flash chromatography (petroleum ether/AcOEt¼7:3), thick oil,
which solidifies upon standing, mp 94e96 ꢀC; Rf¼0.50 (petroleum
ether/AcOEt¼7:3); Anal. Calcd for C11H13ClO2: C, 62.12; H, 6.16%.
Found: C, 61.83; H, 6.37. IR (Nujol) 1709 cmꢁ1; 1H NMR:
d 0.74 (3H, d,
J¼6.6 Hz, CH3), 1.12 (3H, d, J¼6.6 Hz, CH3), 2.27e2.37 (1H, m, CH),
3.97 (1H, d, J¼10.5 Hz, CHAr), 7.15e7.29 (2H, m, 2ꢂ ArH), 7.38 (1H,
dd, J¼7.8, 1.5 Hz, ArH), 7.52 (1H, td, J¼7.5, 1.8 Hz, ArH); 13C NMR:
d
19.6, 21.3, 32.1, 54.1, 127.1, 128.4, 129.0, 129.6, 134.8, 135.5, 179.6.
4.4. Metalation of arylacetic acids 2, and reaction with
electrophiles. General procedure
4.4.5. 2-Phenylpropionic acid, 2db. Purified by flash chromatogra-
phy (petroleumether/AcOEt¼8:2), white powder, mp 63 ꢀC (lit.16a mp
62 ꢀC); Rf¼0.53 (petroleum ether/AcOEt¼8:2); IR (Nujol) 1705 cmꢁ1
;
To 5 mLofa 0.24 M solutionofdiorganometal1b or1c(1.2 mmol),
chilled at 0 ꢀC, was added a solution of the appropriate arylacetic acid
2 (1.1 mmol) dissolved in 5 mL of dry THF, and the resulting mixture
was vigorously stirred for 2 h at 0 ꢀC. To the resulting dark brown
mixture, chilled at the same temperature, were added 1.7 mmol of
the appropriate electrophile. The resulting mixture was vigorously
stirred and allowed to reach rt overnight, after which time it was
quenched by slow dropwise addition of H2O (15 mL). The organic
solvent was evaporated in vacuo and the resulting mixture was
extracted with CH2Cl2 (3ꢂ10 mL). The aqueous phase was acidified
with 1 N HCl, extracted with CH2Cl2 (3ꢂ10 mL), and the organic
phases were collected, washed with H2O (1ꢂ10 mL), brine (10 mL),
dried (Na2SO4), and the solvent was evaporated. Crude reaction
products were purified and characterized as reported below.
1H NMR:
d
1.51 (3H, d, J¼7.2 Hz, CH3), 3.73 (1H, q, J¼7.2 Hz, CH),
7.25e7.33 (5H, m, 5ꢂ ArH); 13C NMR:
d 18.1, 45.4, 127.4, 127.6, 128.7,
139.8, 180.5; NMR spectra in agreement with the literature.16
4.4.6. 2-Phenyl-3-methylbutanoic acid, 2dc. Purified by flash chro-
matography (petroleum ether/AcOEt¼8:2), white powder, mp
56e58 ꢀC (lit.17a 58e60 ꢀC, CH3OH); Rf¼0.61 (petroleum ether/
AcOEt¼8:2); IR (Nujol) 1707 cmꢁ1; 1H NMR:
0.71 (3H, d, J¼6.6 Hz,
d
CH3), 1.08 (3H, d, J¼6.6 Hz, CH3), 2.26e2.42 (1H, m, CH), 3.15 (1H, d,
J¼10.5 Hz, CHAr), 7.28e7.35 (5H, m, 5ꢂ ArH); 13C NMR:
d 20.1, 21.4,
31.5, 60.0,127.6,128.5, 128.6, 137.7, 180.1; NMR spectra in agreement
with the literature.17
4.4.7. 2-Phenyl-5-chloropentanoic acid, 2dd. Purified by flash
chromatography (petroleum ether/AcOEt¼7:3), colorless thick oil;
The reaction mixture containing crude b-hydroxyacid 2df was
quenched by adding it to 15 mL of 10% HCl containing about 15 g of
crushed ice,14 and worked up as described above. After evaporation
of the solvent, the resulting crude material was purified and char-
acterized as reported below.
Quenching with D2O was realized as described in the above
paragraph.
Rf¼0.47 (petroleum ether/AcOEt¼7:3); IR (Nujol) 1696 cmꢁ1
;
1H
NMR:
d 1.61e1.86 (2H, m, CH2), 1.89e2.02 (1H, m, CHaHb),
2.13e2.26 (1H, m, CHaHb), 3.51 (2H, t, J¼6.3 Hz, CH2Cl), 3.54 (1H, t,
J¼7.5 Hz, CH), 7.23e7.38 (5H, m, 5ꢂ ArH); 13C NMR:
d 30.1, 30.2,
44.3, 50.8, 127.6, 128.0, 128.7, 137.7, 180.1; NMR spectra in agree-
ment with the literature.18
4.4.1. 2-(2-Fluorophenyl)-3-methylbutanoic acid, 2ab. Purified by
flash chromatography (petroleum ether/AcOEt¼7:3), white powder,
mp 70e72 ꢀC; Rf¼0.62 (petroleum ether/AcOEt¼7:3); Anal. Calcd for
4.4.8. 3-Phenyl-dihydrofuran-2(3H)-one, 2de. Purified by flash
chromatography (petroleum ether/AcOEt¼9:1), colorless oil; Rf¼0.52
(petroleum ether/AcOEt¼9:1); IR (neat): 1771 cmꢁ1
;
1H NMR

3474
U. Azzena et al. / Tetrahedron 67 (2011) 3470e3475
2.35e2.53 (m, 1H), 2.66e2.78 (m, 1H), 3.82 (t, J¼9.6 Hz, 1H), 4.36 (td,
J¼8.7, 6.6 Hz, 1H), 4.49 (td, J¼8.7, 3.0 Hz, 1H), 7.27e7.41 (m, 5H); 13C
NMR 31.6, 45.5, 66.5, 127.6, 127.9, 128.9, 136.6, 177.4; NMR spectra in
agreement with the literature.19
d
0.71(3H, d,J¼6.6 Hz,CH3),1.08 (3H, d, J¼6.6 Hz, CH3), 2.26e2.38(1H,
m, CH), 2.39 (3H, s, CH3Ar), 3.82 (3H, s, CH3O), 3.89 (1H, d, J¼10.5 Hz,
CHAr), 6.84e6.90 (1H, m, ArH), 6.94 (1H, td, J¼7.5, 1.2 Hz, ArH),
7.19e7.26 (1H, m, ArH), 7.38 (1H, dd, J¼7.5, 1.8 Hz, ArH); 13C NMR:
d
19.7, 21.5, 31.1, 50.3, 55.7,110.8,120.8,126.4,128.2,128.6,157.3,180.1.
4.4.9. 3-Hydroxy-2,3,3-triphenylpropionic acid, 2df. Purified by
flash chromatography (petroleum ether/AcOEt/AcOH¼6:4:0.5),
white solid, mp 200e203 ꢀC (Et2O) (lit.13 205e206 ꢀC, dioxane);
Rf¼0.54 (petroleum ether/AcOEt/AcOH¼6:4:0.5); IR (Nujol) 3502,
1678 cmꢁ1; 1H NMR (DMSO) 3.27 (br s, 2H, 2ꢂ OH), 5.03 (1H, s, CH),
6.90e7.15 (m, 6H, 6ꢂ ArH), 7.18e7.38 (m, 7H, 7ꢂ ArH), 7.52e7.71
(m, 2H, 2ꢂ ArH); 13C NMR (DMSO) 56.9, 78.5, 125.5, 125.5, 126.6,
126.8, 127.3, 127.4, 128.1, 130.1, 135.2, 144.1, 148.5, 176.0.
Acknowledgements
Financial support from the Fondazione Banco di Sardegna
(Sassari, Italy), through the project ‘Dealogenazione di inquinanti
organici persistenti’, and from the Universita di Sassari (Fondo di
Ateneo per la Ricerca) is gratefully acknowledged. M.P. acknowl-
edges financial support from the Regione Autonoma della Sardegna
(Italy), through the project ‘Promozione della Ricerca Scientifica e
dell’Innovazione Tecnologica in Sardegna’.
ꢀ
4.4.10. 2-(4-Fluorophenyl)-5-chloropentanoic acid, 2eb. Purified by
flash chromatography (petroleum ether/AcOEt¼6:4), colourless oil;
Rf¼0.57 (petroleum ether/AcOEt¼6:4); IR (neat): 1707 cmꢁ1
;
1H
NMR: 1.65e1.98 (m, 4H, 2ꢂ CH2), 3.52 (t, J¼6.4 Hz, 2H, CH2Cl), 3.56
(t, J¼7.6 Hz, 1H, CHAr), 6.97e7.07 (m, 2H, 2ꢂ ArH), 7.07e7.01 (m,
2H, 2ꢂ ArH); 13C NMR: 30.1, 30.2, 44.3, 50.0, 115.6 (d, J¼22 Hz),
129.5 (d, J¼8 Hz), 133.4 (d, J¼3 Hz), 162.2 (d, J¼245 Hz),179.9; NMR
spectra in agreement with the literature.8
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.03.037.
References and notes
4.4.11. 2-(2-Naphthyl)propionic acid, 2fb. Purified by flash chro-
matography (petroleum ether/AcOEt/AcOH¼8:2:0.2), thick oil,
which solidifies upon standing, mp 118e120 ꢀC (lit.15a 119e120 ꢀC,
ꢁ ꢀ
1. Gissot, A.; Becht, J.-M.; Desmurs, J. R.; Pevere, V.; Wagner, A.; Mioskowski, C.
Angew. Chem., Int. Ed. 2002, 41, 340e343.
2. Azzena, U.; Dettori, G.; Lubinu, C.; Mannu, A.; Pisano, L. Tetrahedron 2005, 61,
8663e8669.
3. For the preparation of 1,2-dimetallo-1,2-diphenylethane by the metalation of
1,2-diphenylethane with n-BuLieKOCMe2Et in hexane, see: Wilhelm, D.; Clark,
T.; Courtneidge, J. L.; Davies, A. G. J. Chem. Soc., Chem. Commun. 1983, 213e214.
4. Azzena, U.; Dettori, G.; Pisano, L.; Pittalis, M.; Azara, E. J. Organomet. Chem. 2007,
692, 3892e3900.
CHCl3/petroleum
ether);
Rf¼0.28
(petroleum
ether/
AcOEt¼8:2:0.2); IR (Nujol) 1696 cmꢁ1
;
1H NMR:
d
1.49 (3H, d,
J¼7.2 Hz, CH3), 3.77 (1H, q, J¼7.2 Hz, CH), 7.32e7.45 (3H, m, 3ꢂ
ArH), 7.65e7.76 (4H, m, 4ꢂ ArH); 13C NMR:
d 18.1, 45.5, 125.7, 125.9,
126.2, 126.3, 127.6, 127.8, 128.4, 132.6, 133.4, 137.2, 180.8; NMR
spectra in agreement with the literature.16b
5. Azzena, U.; Dettori, G.; Mocci, S.; Pisano, L.; Cerioni, G.; Mocci, F. Tetrahedron
2010, 9171e9174.
4.4.12. 2-(2-Naphthyl)-3-methylbutanoic acid, 2fc. Purified by flash
chromatography (petroleum ether/AcOEt/AcOH¼7:3:0.2), white
powder, mp 133e135 ꢀC (lit.20 132e134 ꢀC); Rf¼0.55 (petroleum
6. Azzena, U.; Pisano, L.; Antonello, S.; Maran, F. J. Org. Chem. 2009, 74, 8064e8070.
7. (a) For a review see: Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102,
4009e4091 for a selection of relevant literature, see: (b) Calo, V.; Nacci, A.;
ꢀ
Monopoli, A.; Damascelli, A.; Ieva, E.; Cioffi, N. J. Organomet. Chem. 2007, 692,
4397e4401; (c) Huang, H.; Kobayashi, N.; Hasatani, M.; Matsuyama, K.; Sasaki,
T. Chem. Eng. Sci. 2007, 62, 5144e5149; (d) Moglie, Y.; Alonso, F.; Vitale, C.; Yus,
M.; Radivoy, G. Appl. Catal., A 2006, 313, 94e100; (e) Matsunaga, A.; Yasuhara, A.
Chemosphere 2005, 58, 897e904; (f) Alonso, F.; Moglie, Y.; Radivoy, G.; Vitale,
C.; Yus, M. Appl. Catal., A 2006, 271, 171e176; (g) Miyoshi, K.; Nishio, T.; Yasu-
hara, A.; Morita, M.; Shibamoto, T. Chemosphere 2004, 55, 1439e1446; (h)
Miyoshi, K.; Kamegaya, Y.; Matsumura, M. Chemosphere 2004, 56, 187e193; (i)
Sajiki, H.; Kume, A.; Hattori, K.; Hirota, K. Tetrahedron Lett. 2002, 43,
7247e7250; (j) Jackman, S. A.; Knowles, C. J.; Robinson, G. K. Chemosphere 1999,
38, 1889e1900.
ether/AcOEt/AcOH¼7:3:0.2); IR (Nujol) 1693 cmꢁ1; 1H NMR:
d 0.68
(3H, d, J¼6.6 Hz, CH3), 1.05 (3H, d, J¼6.6 Hz, CH3), 2.33e2.46 (1H, m,
CH), 3.25 (1H, d, J¼10.5 Hz, CHAr), 7.40e7.48 (3H, m, 3ꢂ ArH),
7.70e7.82 (4H, m, 4ꢂ ArH); 13C NMR:
d 20.2, 21.5, 31.4, 60.3, 125.8,
126.1, 126.2, 127.6, 127.7, 127.8, 128.2, 132.7, 133.3, 135.4, 180.0.
4.4.13. 2-(2-Methylphenyl)-3-methylbutanoic acid, 2ga. Purified by
flash chromatography (petroleum ether/AcOEt/AcOH¼8:2:0.2),
white powder, mp¼92e93 ꢀC (MeOH/H2O) (lit.21 mp 91e92 ꢀC);
Rf¼0.50 (petroleum ether/AcOEt/AcOH¼8:2:0.2); IR (Nujol)
8. Rosen, J. D.; Nelson, T. D.; Huffman, M. A.; McNamara, J. M. Tetrahedron Lett.
2003, 44, 365e368.
9. The ease of reductive dehalogenation of organic halides follows the order
I>Br>Cl>>F; see, for example, Refs. 5 and 7a.
1707 cmꢁ1
;
1H NMR:
d
0.70 (3H, d, J¼6.6 Hz, CH3), 1.11 (3H, d,
10. For a selection of relevant literature on this topic, see: (a) n-BuLi in THF: Padwa,
A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N.;
Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993, 115, 8669e8680; (b)
n-HexylLi in THF: see Ref. 8; (c) LDA in THF: De Almeida, M. I.; do Amaral, A. T.;
do Amaral, L. J. Org. Chem. 1982, 47, 1567e1571; (d) LDA in THF/HMPA: Mai, A.;
Sbardella, G.; Artico, M.; Ragno, R.; Massa, S.; Novellino, E.; Greco, G.; Lavecchia,
A.; Musiu, C.; La Colla, M.; Murgioni, C.; La Colla, P.; Loddo, R. J. Med. Chem.
2001, 44, 2544e2554; (e) LDE in THF: Brun, E. M.; Gil, S.; Mestres, R.; Parra, M.
Synthesis 2000, 1160e1165; (f) LHMDS in THF/DMPU: Chen, C.-y.; Dagneau, P.;
Grabowski, E. J. J.; Oballa, R.; O’Shea, P.; Prasit, P.; Robichaud, J.; Tillyer, R.;
Wang, X. J. Org. Chem. 2003, 68, 2633e2638.
11. (a) Na naphthalenide in THF: Aaron, C.; Dull, D.; Schmiegel, J. L.; Jaeger, D.;
Ohashi, Y.; Mosher, H. S. J. Org. Chem. 1967, 32, 2797e2803; (b) NaHDMS in THF:
Yang, W.; Rozamus, L. W.; Narula, S.; Rollins, C. T.; Yuan, R.; Andrade, L. J.; Ram, M.
K.; Phillips, T. B.; van Schravendijk, M. R.; Dalgarno, D.; Clackson, T.; Holt, D. A.
J. Med. Chem. 2000, 43, 1135e1142.
J¼6.6 Hz, CH3), 2.25e2.50 (1H, m, CH), 2.39 (3H, s, CH3Ar), 3.50 (1H,
d, J¼10.8 Hz, CHAr), 7.07e7.23 (3H, m, 3ꢂ ArH), 7.42 (1H, d,
J¼6.9 Hz, ArH); 13C NMR:
d 19.6, 20.0, 21.4, 31.4, 54.4, 126.4, 127.0,
127.0, 130.3, 136.3, 136.7, 180.6.
4.4.14. 2-(2-Methoxyphenyl)propanoic acid, 2ha. Purified by flash
chromatography (petroleum ether/AcOEt¼1:1), white powder, mp
99e101 ꢀC (lit.22 101e102 ꢀC acetone/petroleum ether); Rf¼0.68
(petroleum ether/AcOEt¼1:1); IR (Nujol) 1702 cmꢁ1
;
1H NMR:
d
1.48 (3H, d, J¼7.2 Hz, CH3), 3.84 (3H, s, CH3O), 4.09 (1H, q,
J¼7.2 Hz, CH), 6.86e6.91 (1H, m, ArH), 6.96 (1H, td, J¼7.5, 1.2 Hz,
ArH), 7.23e7.29 (2H, m, 2ꢂ ArH); 13C NMR:
d 16.9, 39.1, 55.5, 110.7,
120.8, 128.0, 128.3, 128.8, 156.7, 180.8; NMR spectra in agreement
12. Normant, H.; Cuvigny, T. Bull. Soc. Chim. Fr. 1965, 1881e1888.
13. Hamrick, P. J.; Hauser, C. R. J. Am. Chem. Soc. 1960, 82, 1957e1959 and references
therein.
with the literature.22
14. In agreement with Ref. 13, this quenching procedure avoids a retro-aldol like
reaction, giving back the starting materials, which occurs when similar com-
pounds are submitted to basic work-up procedures.
15. (a) Shiima, I.; Nakata, K.; Ono, K.; Onda, Y.; Itagaki, M. J. Am. Chem. Soc. 2010,
132, 11629e11641; (b) Williams, C. M.; Johnson, J. B.; Rovis, T. J. Am. Chem. Soc.
2008, 130, 14936e14937.
4.4.15. 2-(2-Methoxyphenyl)-3-methylbutanoic acid, 2hb. Purified
by flash chromatography (petroleum ether/AcOEt¼7:3), thick oil;
Rf¼0.44 (petroleum ether/AcOEt¼7:3); Anal. Calcd for C12H16O3: C,
69.21; H, 7.74%. Found: C, 68.93; H, 7.96. IR (neat) 1697 cmꢁ1; 1H NMR:

U. Azzena et al. / Tetrahedron 67 (2011) 3470e3475
3475
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20. Piccolo, O.; Menicagli, R.; Lardicci, L. Tetrahedron 1979, 35, 1751e1758.
21. Herz, W. J. Am. Chem. Soc. 1958, 80, 3139e3141.
Yan, M.-C.; Liu, J.-Y.; Chuang, M.-C.; Shiue, J.-L. Tetrahedron 1998, 54, 791e822;
(b) Clericurzio, M.; Degani, I.; Dughera, S.; Fochi, R. Synthesis 2002, 921e927.
17. (a) Knorr, R.; Lattke, E. Chem. Ber. 1981, 114, 2116e2131; (b) Mermerian, A. H.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 5604e5607.
22. (a) Matsumoto, T.; Imai, S.; Miuchi, S.; Sugibayashi, H. Bull. Chem. Soc. Jpn. 1985,
€
€
58, 340e345; (b) Wurtz, S.; Lohre, C.; Frolich, R.; Bergander, K.; Glorius, F. J. Am.
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