Ni-catalyzed activation of α-chloroesters: a simple method for the synthesis of α-arylesters and β-hydroxyesters

Article abstract of DOI:10.1016/j.tet.2006.11.055

Coupling reactions of α-chloroesters with aryl halides (α-arylation) or carbonyl compounds (Reformatsky) using nickel catalyst allow, under mild conditions, the preparation of various functionalized aryl propionic acid derivatives or β-hydroxyesters. In the synthesis of aryl propionic acid derivatives, the process is efficient with aryl halides bearing either electron-withdrawing or electron-donating groups.

Full text of DOI:10.1016/j.tet.2006.11.055

Tetrahedron 63 (2007) 1146–1153
Ni-catalyzed activation of a-chloroesters: a simple method for the
synthesis of a-arylesters and b-hydroxyesters
*
Muriel Durandetti, Corinne Gosmini and Jacques Perichon
ꢀ
´
Laboratoire d’Electrochimie, Catalyse et Syntheꢁse Organique, UMR 7582 CNRS-Universite Paris 12 Val de Marne,
2 Rue Henri-Dunant, 94320 Thiais, France
Received 23 October 2006; revised 15 November 2006; accepted 20 November 2006
Available online 13 December 2006
Abstract—Coupling reactions of a-chloroesters with aryl halides (a-arylation) or carbonyl compounds (Reformatsky) using nickel catalyst
allow, under mild conditions, the preparation of various functionalized aryl propionic acid derivatives or b-hydroxyesters. In the synthesis of
aryl propionic acid derivatives, the process is efficient with aryl halides bearing either electron-withdrawing or electron-donating groups.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
halides was. However electrochemical reactions are often
considered as being more difficult to handle than conven-
tional classical methods. Thus, electrochemical processes
are poorly applied in industrial scale and therefore we devel-
oped pure ‘chemical’ processes instead of electrochemical
processes.8d,e,13 We now report a chemical method for a
nickel-catalyzed activation of a-chloroesters, leading to
aryl propanoic esters (Eq. 2) and b-hydroxyesters (Eq. 1),
using NiBr2bipy as catalyst in the presence of an appropriate
reducing metal (Scheme 1). The usual chemical routes to the
arylnickel compounds however require the tedious prepara-
tion of Ni(0) complexes such as Ni(cod)2. But we developed
an interesting alternative, which is the in situ generation of
Ni(0) complexes in the presence of both the aromatic halide
and the electrophile. The main advantages of the method are
the use of an easily prepared Ni(II)bipy complex in catalytic
amounts and the easy control of the overall reactions.
The nucleophilic character coupled with low basicity of
Reformatsky reagents has resulted in their renewed interest
as enolates sources. For example, they have been found
to be effective in nucleophilic addition to carbonyl com-
pounds,1 and more recently as nucleophilic partners in cou-
pling reactions with aryl halides mediated by palladium.2
Since the Reformatsky reaction is initiated by the insertion
of zinc into halogen–carbon bond, most efforts have been
focused on the activation of zinc. In addition a number of
other metals and catalysts,3 such as nickel,4 manganese,5
chromium,6 indium,7 . were also found active. In our lab-
oratory, we have already described some electrochemical
processes for the Reformatsky reaction.8
Aryl propanoic acids, like ibuprofen, are known to be non-
steroidal anti-inflammatory drugs.9 A mild and an efficient
procedure to obtain functionalized aryl acetic or propanoic
acid is thus of great interest. Many routes to selected struc-
tures of therapeutic interest have been described, from either
a benzylic10 or an aromatic derivative,11 or by rearrangement
of propiophenone,9 but the obtention of this products by an
arylation-type reaction will be much interesting, taking
into consideration that variously substituted aryl halides
are commonly available. We have developed the electro-
chemical cross-coupling reaction between aryl halides and
methyl chloroacetate or methyl 2-chloropropanoate, using
NiBr2bipy as catalyst.12 In all cases, isolated yields were
good to excellent, whatever the functional group in aryl
R3
R1 R2 R3
R1 R2
O
NiBr2bipy 0,07 eq.
DMF, Mn
(1)
OR4
OR4
+
Cl
HO
50-99%
O
O
R3 = H, CH3
R3
R3
X
NiBr2bipy 0,07 eq.
OR4
OR4
+
Cl
FG
(2)
DMF, Mn
FG
O
O
R3 = H, CH3
X = Br, I
40-88%
FG = electrodonating or electrowithdrawing groups
Scheme 1. Nickel-catalyzed activation of a-chloroesters.
2. Results and discussion
* Corresponding author at present address: Laboratoire des Fonctions
ꢀ
ꢀ ꢀ
Azotees & Oxygenees Complexes de L’IRCOF, UMR 6014 CNRS, Uni-
versite de Rouen, 76821 Mont Saint-Aignan Cedex, France. Tel.: +33 2 35
At first we studied different parameters such as the solvent,
the ligands, and particularly the reducing metal. Results are
ꢀ
52 24 37; fax: +33 2 35 52 29 71; e-mail: muriel.durandetti@univ-rouen.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.055

M. Durandetti et al. / Tetrahedron 63 (2007) 1146–1153
1147
Table 1. Optimization of the cross-coupling reaction between cyclohexa-
none and methyl 2-chloropropanoate using NiBr2 salt as catalyst
Concerning the Reformatsky reaction, this process was
applied to a large variety of carbonyl compounds (1–10)
(Fig. 1). Results for the coupling with methyl 2-chloropropa-
noate are given in Table 3.
Entry
Catalyst
Solvent
M
Time
Yields (%)
1
2
3
4
5
NiBr2 10%
MeCN
DMF
DMF
DMF
DMF
Mn
Mn
Mg
Zn
24 h
1 h
30 min
100 h
100 h
76
88
11a
50b
0
NiBr2bipy 10%
NiBr2bipy 10%
NiBr2bipy 10%
NiBr2bipy 10%
O
O
Al
S
O
4
a
O
1
2
Claisen product is obtained as the major product.
Ketone (48%) is recovered.
3
b
O
O
O
5
6
7
reported in Table 1, concerning the Reformatsky reaction
and in Table 2 for the syntheses of aryl propanoic esters.
CHO
O
H
We have found that manganese is the best metal for the re-
duction of NiBr2bipy (Table 1, entries 1 and 2 and Table 2,
entries 1 and 2) in both reactions. The use of manganese
as a benign reducing agent in combination with an effective
metal salt has already been originally described.8e,13a,14 The
decrease in the chemical yield with magnesium metal can be
explained by the occurrence of Claisen condensation as side
reaction (Table 1, entry 3 and Table 2, entry 4). This reaction
could be minimized by adding a large excess of a-chloro-
ester using the portionwise addition (Table 2, entry 5).
With Zn as the reducing metal, the Reformatsky reaction
occurs very slowly (Table 1, entry 4), but Zn cannot be
employed for the cross-coupling with aryl halides (Table 2,
entry 3). Aluminum could not be used as a reducing metal,
no cross-coupling occurred in both reactions even after
four days (Table 1, entry 5 and Table 2, entry 6). With man-
ganese metal, we observed at first that the Reformatsky reac-
tion is best performed at room temperature using NiBr2bipy
in DMF, than NiBr2 in acetonitrile (Table 1, entries 1 and 2).
However, the cross-coupling with aryl halide occurs faster at
50 ꢀC than at room temperature (Table 2, entries 1 and 2).
The amount of nickel salt could be decreased to 3%, but in
these conditions reaction times are sometimes longer.
O
8
9
10
Figure 1. Carbonyl compounds used in the nickel Reformatsky reaction.
Table 3. Nickel-catalyzed cross-coupling between methyl 2-chloropropa-
noate and carbonyl compoundsa
Entry Carbonyl
compounds
Isolated yields (%) of coupling
productb
anti/syn
OH
O
1
1
88
—
O
OH
O
2
3
4
2
3
4
61c 63/37
69 72/28
92 54/46
O
O
HO
O
O
OH
OH
S
O
O
5
5d
33e
90
—
—
After optimization the best conditions are found to be
0.07 equiv of NiBr2bipy versus carbonyl compounds or
aryl halides in the presence of manganese metal in DMF
as solvent at room temperature for the Reformatsky reaction
and 50 ꢀC for the synthesis of arylesters, and yields 40–99%
of coupling product in 15 min to 2 h depending on the sub-
strate (Scheme 1).
HO
HO
O
O
O
6
7
6
7
O
99 60/40
O
Table 2. Optimization of the cross-coupling reaction between m-trifluoro-
methyl bromobenzene and methyl 2-chloropropanoate using NiBr2bipy
(10%) as catalyst
HO
O
8
9
8
92 60/40
46 59/41
19 58/42
O
O
Entry
Solvent
M
Time
Yields (%)
9d
1
2
3
4
5
6
DMFa
DMFb
DMFb
DMFb
DMFb
DMFb
Mn
Mn
Zn
Mg
Mgd
Al
5 h
1 h
24 h
30 min
1 h
82
78
4
OH
O
O
10
10d
11c
39c
0
OH
O
100 h
a
Typical procedure: see Section 3.
Isolated yields, based on initial carbonyl compounds. All products gave
satisfactory analytical data.
No 1,4-addition product was detected.
Reaction is carried out at 50 ꢀC.
Ketone (60%) is recovered.
a
b
Reaction is carried out at room temperature.
Reaction is carried out at 50 ꢀC.
Claisen product and m-CF3PhCHO were obtained as major products.
a-Chloroesters (5 equiv) were introduced in five portions to minimize the
Claisen condensation.
b
c
d
c
d
e

1148
M. Durandetti et al. / Tetrahedron 63 (2007) 1146–1153
OH
Results in Table 3 show that the cross-coupling is efficient
with ketones, whatever their structures are (aromatic,
aliphatic or cyclic) (Table 3, entries 1–8). Chemical yields
are good to excellent (61–99%), except for benzophenone
5, which needs a higher temperature. With aldehydes the
efficiency is less due to a major pinacolization reaction.
No conjugated addition was observed with enone 2, thus
indicating that the reaction is regioselective.
Cl
NiBr2bipy 0,07 eq.
DMF, Mn
+
N
O
N
62%
Scheme 2. The addition of a-chloropropionitrile to 3-pentanone via nickel
catalyst.
To extend the scope of this process, we intend to show that
this method can be suitable for the activation of allyl ace-
tates. The first results show that the method can also be ap-
plied to the preparation of homoallylic alcohols (Scheme 3,
and Table 5).
In the case of dissymmetric carbonyl compounds, we ob-
tained the two diastereoisomers with moderate diastereo-
selectivities (Table 3, entries 2–4, 7–10), depending on the
nature of the carbonyl compound.
R2
R3
R1
In all of cases, 1.3 equiv of a-chloroester is necessary.
R1
R2
B
HO
O
+
Coupling methyl 2-chloroacetate with the same ketones
1–8 also gave moderate to good yields of b-hydroxyesters
(50–90% isolated yield, Table 4).
NiBr2bipy 0,07 eq
DMF, Mn, 80°C
+
R2
R1
HO
R3
R3
L
AcO
R3 = H, Me
As already observed in the case of electroreductive cou-
pling between aryl halide and a-chloroester with a nickel
catalyst,12 the coupling with chloroacetate (Table 4) is less
efficient than with chloropropionate (Table 3). Furthermore
the excess of a-chloroester, necessary to consume totally
the carbonyl compounds, is more important with methyl 2-
chloroacetate than with methyl 2-chloropropanoate (1.7–2
instead of 1.3 equiv are necessary).
Scheme 3. The Addition of allyl acetates to ketones via nickel catalyst.
Thus, as a preliminary study, the coupling between ketones
and allylic acetates proceeds in good yields, if the reaction is
carried out at 80 ꢀC (Table 5, entries 1 and 2). Then we
wanted to test the regioselectivity of this coupling reaction.
So we have run experiment using crotyl acetate. Reactions
involving allylic derivatives generally give two isomeric
products due to allylic transposition (Scheme 3). The ratio
of branched to linear alcohol (B/L) is known to depend
mainly on the nature of the metal in the organometallic re-
agent.15 However, in this method, the major product formed
seems to be the branched product B, with a ratio B/L of 95/5
(Table 5, entry 3).
We have then extended the process to a-chloronitrile.
Thus, as a preliminary study, the coupling between 3-penta-
none 6 and a-chloropropionitrile proceeds in good yield
(Scheme 2).
We have then focused on the second reaction, leading di-
rectly the ester of the desired aryl acetic and a-aryl-propa-
noic acid, in a simple and an efficient process compared to
Table 4. Nickel-catalyzed cross-coupling between methyl 2-chloroacetate
and carbonyl compoundsa
Entry
1
Ketones
Isolated yields (%) of coupling productb
Table 5. Allylation of ketones using NiBr2bipy as catalysta
OH
O
1
64
Entry
Ketone
Reaction
time (h)
Isolated yields
(%) of coupling
productb
Ratio B/L
O
O
2
3
3
5
62
HO
HO
O
1
2
3
1
1
1
4
9
2
3
5
59c
74d
69d
54d,e
—
OH
OH
46c
O
O
—
OH
O
O
4
6
8
52d
92
95/5
—
OH
OH
HO
O
4
5
S
O
a
a
Typical procedure: see Section 3.
Typical procedure: see Section 3.
Isolated yields, based on initial ketones. All products gave satisfactory
analytical data.
Reaction is carried out at room temperature.
Reaction is carried out at 80 ꢀC.
Ketone (20%) is recovered.
b
b
Isolated yields, based on initial carbonyl compounds. All products gave
satisfactory analytical data.
Ketone (50%) is recovered.
Ketone (20%) is recovered and 6% of methyl 3,3-diethyl-2-oxiranecar-
boxylate is obtained.
c
c
d
e
d

M. Durandetti et al. / Tetrahedron 63 (2007) 1146–1153
1149
other describes routes (Scheme 1, Eq. 2). Results for the
cross-coupling reaction between aryl halides and methyl
2-chloropropanoate, using NiBr2bipy as catalyst, are given
in Table 6.
yields were obtained with aryl bromides). With electron-
withdrawing groups aryl bromides or iodides could be
used. However, aryl chlorides are not enough reactive to al-
low good yields of coupling product (Table 6, entries 3 and
7). With an ortho-substituent, a lower yield is obtained due to
steric effects (Table 6, entry 8). The reaction is highly
chemoselective, as no addition products with ketones groups
are detected (Table 6, entry 9), even if acetophenone 3 allows
good yields with methyl 2-chloropropanoate in the Refor-
matsky reaction (Table 3, entry 3).
In all cases, the reactions are conducted in the presence of
1.3 equiv or less of the chloroester relative to the aryl halide.
Reactions involving aryl iodides were run at room tempera-
ture approximately for 1 h to give good yields (Table 6, en-
tries 1, 10, and 11). With aryl bromides, even if the reaction
is efficient at room temperature, a faster reaction is obtained
at 50 ꢀC (vide supra) (Table 2, entries 1 and 2). The yields are
good to excellent and do not seem to greatly depend on the
nature of the ring substituents. Reaction is as efficient with
electron-donating (Table 6, entry 10) than with electron-
withdrawing group (Table 6, entries 2–9). With electron-
donating substituents, aryl iodides are best performed (lower
Coupling methyl chloroacetate with aryl halides also gave
good yields of aryl acetic esters (55–88% isolated yield,
Table 7), using the same procedure.
During these studies, a minor biaryl by-product (less than
10%) was observed arising from homocoupling of the aryl
halide. This homocoupled by-product has been observed pre-
viously in other aryl halide cross-coupling reaction.8b,12,16
Optimization of the coupling reaction allowed the major for-
mation of the desired heterocoupled product. However, we
thought that it would also be possible to refine conditions
that would facilitate the formation of the homocoupling prod-
uct. The chemical process was first optimized with 1-bromo-
naphthalene because its homocouplingwas generallylimited,
and 1,10-binaphthyl, when substituted in the 2,20-positions, is
a good candidate for the formation of atropisomers.17 Using
the same process, 92% of binaphthyl is obtained in 2 h at
50 ꢀC using 7 mol % of NiBr2bipy (Scheme 4).
Table 6. Nickel-catalyzed cross-coupling between methyl 2-chloropropa-
noate and aryl halidesa
Entry
Aryl halides
Isolated yields (%) of coupling
productb
OMe
1
2
3
87
I
O
F3C
Br
Cl
F3C
F3C
OMe
OMe
78
20
O
O
F3C
Table 7. Nickel-catalyzed cross-coupling between methyl 2-chloroacetates
and aryl halidesa
Entry
1
Aryl halides
Isolated yields (%) of coupling
productb
F3C
NC
4
5
70
75
F3C
NC
Br
OMe
OMe
F3C
F3C
Br
OMe
O
62
O
Br
F3C
NC
O
2
3
4
88
55
72
F3C
NC
Br
OMe
OMe
O
MeO2C
MeO2C
6
7
65
20
MeO2C
MeO2C
Br
OMe
O
O
Br
O
Cl
OMe
MeO2C
MeO2C
Br
OMe
CO2Me
O
O
CO2Me
Br
8
40
OMe
Br
5
77
O
OMe
O
O
a
Typical procedure: see Section 3.
Isolated yields, based on initial aryl halides. All products gave satisfactory
analytical data.
Br
9
70
69
82
b
O
OMe
O
O
MeO
10
MeO
I
OMe
O
O
I
Br
NiBr2bipy 0,07 eq.
11
OMe
DMF, Mn, 50°C
a
Typical procedure: see Section 3.
Isolated yields, based on initial aryl halides. All products gave satisfactory
analytical data.
92%
b
Scheme 4. Homocoupling reaction of 1-bromonaphthalene.

1150
M. Durandetti et al. / Tetrahedron 63 (2007) 1146–1153
In conclusion, we have reported in this paper an efficient
cross-coupling of aryl halides and a-chloroesters, as well
as the Refortmatsky reaction, enabling the preparation of
valuable target molecules such as aryl propanoic acid deriv-
atives or b-hydroxyesters. The scope of the method is wide
concerning the type of organic compounds involved as a-
chloroesters can be used. For the Reformatsky reaction,
the method is efficient with ketones. Aryl propanoic acid de-
rivatives could be obtained with a large variety of functional
groups (electron-donating as well as electron-withdrawing
groups), using aryl bromides or iodides. The method is
also very easy, cheap, and totally original.
3.1.2.1. Methyl (1-hydroxy-a-methylcyclohexane)ace-
tate. 1H NMR: 3.70 (s, 3H); 3.04 (s, 1H); 2.52 (q, J¼7.1 Hz,
1H); 1.48 (m, 10H); 1.19 (d, J¼7.1 Hz, 3H).
MS: 187 (M+1), 169 (M–OH), 155 (M–OMe), 143, 130, 113,
99, 81 (base), 55.
3.1.2.2. Methyl (1-hydroxy-a-methyl-2-cyclohexene)-
acetate. 1H NMR: anti: 5.50–5.92 (m, 2H); 3.70 (s, 3H);
2.98 (s, 1H); 2.63 (q, J¼7.2 Hz, 1H), 2.10–1.50 (m, 6H);
1.22 (d, J¼7.2 Hz, 3H).
syn: 5.9–5.5 (m, 2H); 3.7 (s, 3H); 3 (s, 1H); 2.60 (q,
J¼7.4 Hz, 1H), 2.10–1.50 (m, 6H); 1.18 (d, J¼7.4 Hz, 3H).
Furtherinvestigationstoexploitthemechanismareinprogress.
3. Experimental
MS: 184 (M), 156 (MꢁCO), 124 (MꢁCO2Me), 97 (base),
79, 55.
3.1. Analytical methods
3.1.2.3. Methyl 3-hydroxy-2-methyl-3-phenylbuta-
noate. 1H NMR: anti: 7.41 (m, 2H); 7.20 (m, 3H); 4.15
(s, 1H); 3.33 (s, 3H); 2.98 (q, J¼7.07 Hz, 1H); 1.42 (s,
3H); 1.23 (d, J¼7.07 Hz, 3H).
GC analysis was carried out using a 4-m capillary column.
Mass spectra were recorded with a spectrometer coupled
to a gas chromatograph. Column chromatography was per-
1
formed on silica gel 60, 70–230 mesh. H, 13C, and 19F
NMR spectra were recorded in CDCl3 at 200, 50, and
188 MHz, respectively, with TMS as an internal standard.
All solvents and reagents were purchased and used without
further purification. DMF is stored under argon. The catalyst
precursor NiBr2bipy was either prepared separately accord-
ing to the literature.18
syn: 7.40 (m, 2H); 7.25 (m, 3H); 3.91 (s, 1H); 3.70 (s, 3H);
2.86 (q, J¼7.12 Hz, 1H); 1.55 (s, 3H); 0.95 (d, J¼7.12 Hz,
3H).
MS: 209 (M+1), 191 (MꢁOH), 121 (base), 105, 77.
3.1.2.4. Methyl 3-hydroxy-2,3-dimethyl-3-thienylpro-
panoate. 1H NMR: anti: 7.17–7.14 (m, 1H); 6.92–6.85
(m, 2H); 4.4 (s, 1H); 3.57 (s, 3H); 2.99 (q, J¼7.13 Hz,
1H); 1.54 (s, 3H); 1.28 (d, J¼7.13 Hz, 3H).
3.1.1. General procedure for the Reformatsky reaction
(Scheme 1, Eq. 1). Carbonyl compounds (10 mmol) and
13 mmol of a-chloroester were added in a stirred flask under
argon at room temperature with 15 mL of DMF. Then 1.1 g
of Mn (20 mmol) is introduced, followed up by 0.26 g of
NiBr2bipy (0.7 mmol) and finally 20 mL of CF3CO2H to
activate manganese metal. The reaction is conducted at
room temperature. The reaction was monitored by GC and
stopped after carbonyl compound was consumed (ca. 1 h).
The mixture was then hydrolyzed with 1 N hydrochloric
acid and diluted with diethyl ether. The aqueous layer was
extracted with diethyl ether, the combined organic layers
were washed with water and saturated NaCl solution, dried
over MgSO4 and the solvent was evaporated. The oil thus
obtained was purified by column chromatography to give
desired compounds.
syn: 7.7–7.6 (m, 1H); 7.2–7.1 (m, 2H); 4.09 (s, 1H); 3.7 (s,
3H); 2.87 (q, J¼6.7 Hz, 1H); 1.62 (s, 3H); 1.11 (d,
J¼6.7 Hz, 3H).
MS: 214 (M), 197 (MꢁOH), 127 (MꢁC2H7O2, base), 111,
97, 85, 57.
Anal. Calcd for C10H14O3S: C, 56.05; H, 6.58; S 14.96.
Found: C, 56.17; H, 6.53; S, 15.04.
3.1.2.5. Methyl 3,3-diphenyl-3-hydroxy-2-methylpro-
panoate. 1H NMR: 7.50 (m, 4H); 7.20 (m, 6H); 4.68 (s,
1H); 3.66 (q, J¼7.1 Hz, 1H); 3.00 (s, 3H); 1.16 (d,
J¼7.1 Hz, 3H).
3.1.2. General procedure for the synthesis of aryl propa-
noic esters (Scheme 1, Eq. 2). Aryl halides (10 mmol) and
13 mmol of a-chloroester were added in a stirred flask under
argon at room temperature with 15 mL of DMF. Then 1.1 g
of Mn (20 mmol) is introduced, followed up by 0.26 g of
NiBr2bipy (0.7 mmol) and finally 20 mL of CF3CO2H to ac-
tivate manganese metal. The reaction is conducted at room
temperature for aryl iodide or 50 ꢀC for aryl bromide. The
reaction was monitored by GC and stopped after aryl halide
was consumed (ca. 1 h). The mixture was then hydrolyzed
with 1 N hydrochloric acid and diluted with diethyl ether.
The aqueous layer was extracted with diethyl ether, the
combined organic layers were washed with water and satu-
rated NaCl solution, dried over MgSO4, and the solvent was
evaporated. The oil thus obtained was purified by column
chromatography to give desired compounds.
MS: 270 (M); 253 (MꢁOH), 183 (base), 105, 77.
3.1.2.6. Methyl 3-ethyl-3-hydroxy-2-methylpenta-
noate. 1H NMR: 3.71 (s, 3H); 3.20 (s, 1H); 2.61 (q,
J¼7.2 Hz, 1H); 1.50 (m, 4H); 1.17 (d, J¼7.2 Hz, 3H);
0.88 (t, J¼7.4 Hz, 3H); 0.82 (t, J¼7.6 Hz, 3H).
MS: 175 (M+1), 157 (MꢁOH), 145 (MꢁEt), 113, 97, 88, 57
(base).
3.1.2.7. Methyl 3-hydroxy-2,3-dimethyl hexanoate. 1H
NMR: anti: 3.71 (s, 3H); 3.12 (s, 1H); 2.57 (q, J¼7 Hz, 1H);
1.42 (m, 4H); 1.19 (d, J¼7 Hz, 3H); 1.18 (s, 3H); 0.91
(m, 3H).

M. Durandetti et al. / Tetrahedron 63 (2007) 1146–1153
1151
syn: 3.7 (s, 3H); 3.1 (s, 1H); 2.54 (q, J¼7 Hz, 1H); 1.4 (m,
4H); 1.2 (d, J¼7 Hz, 3H); 1.1 (s, 3H); 0.9 (m, 3H).
3.1.2.14. Methyl 3-ethyl-3-hydroxypentanoate. 1H
NMR: 3.69 (s, 3H); 3.46 (s, 1H); 2.46 (s, 2H); 1.54 (q,
J¼7.2 Hz, 4H); 0.88 (t, J¼7.2 Hz, 6H).
MS: 175 (M+1), 157 (MꢁOH, base), 131 (MꢁC3H7), 99,
71, 57.
MS: 161 (M+1, base), 143 (MꢁOH), 131 (MꢁC2H5), 111,
99, 83, 69, 57.
3.1.2.8. Methyl 3-hydroxy-2,3,7-trimethyl-6-octe-
noate. 1H NMR: anti: 5.13–5.05 (m, 1H); 3.70 (s, 3H);
3.24 (s, 1H); 2.59 (q, J¼7.1 Hz, 1H); 2.08–2.01 (m, 2H);
1.67 (s, 3H); 1.61 (s, 3H); 1.53–1.43 (m, 2H); 1.21 (s, 3H);
1.20 (d, J¼7.1 Hz, 3H).
3.1.2.15.
Methyl
3-hydroxy-3,7-dimethyloct-6-
enoate. 1H NMR: 5.13–5.05 (m, 1H); 3.69 (s, 3H); 3.50
(s, 1H); 2.57 (d, J¼15.8 Hz, 1H); 2.38 (d, J¼15.8 Hz, 1H);
2.08–2.01 (m, 2H); 1.67 (s, 6H); 1.53–1.43 (m, 2H); 1.31
(s, 3H).
syn: 5.13–5.05 (m, 1H); 3.70 (s, 3H); 3.24 (s, 1H); 2.57 (q,
J¼7.09 Hz, 1H); 2.08–2.01 (m, 2H); 1.67 (s, 3H); 1.61 (s,
3H); 1.53–1.43 (m, 2H); 1.15 (s, 3H); 1.20 (d, J¼7.09 Hz,
3H).
MS: 201 (M+1), 182 (MꢁH2O), 123, 109 (base), 57.
3.1.2.16. 3-Ethyl-3-hydroxy-2-methylpentanenitrile. 1H
NMR: 2.9 (s, 1H); 2.79 (q, J¼7.2 Hz, 1H); 1.66 (q, J¼7.1 Hz,
2H); 1.61 (q, J¼7.7 Hz, 2H); 1.29 (d, J¼7.2 Hz, 3H); 0.92 (t,
J¼7.1 Hz, 3H); 0.89 (t, J¼7.7 Hz, 3H).
MS: 215 (M+1), 196 (MꢁOH), 136, 121, 109 (base), 99, 93,
81, 67, 57.
3.1.2.9. Methyl 3-hydroxy-2-methyl-3-phenylpropa-
noate. 1H NMR: anti: 7.23 (m, 5H); 4.97 (d, J¼5.1 Hz,
1H); 3.76 (s, 1H); 3.53 (s, 3H); 2.73 (qd, J1¼7.0 Hz,
J2¼5.1 Hz, 1H); 1.10 (d, J¼7.0 Hz, 3H).
MS: 142 (M+1), 124 (MꢁOH), 112, 87, 69, 56 (base).
3.1.2.17. (Propenyl-2)-1-cyclohexanol. 1H NMR: 5.9
(ddt, J¼16.8 Hz, J¼10.8 Hz, J¼7.5 Hz, 1H); 5.11 (d,
J¼16.8 Hz, 1H); 5.09 (d, J¼10.8 Hz, 1H); 2.34 (s, 1H);
2.2 (d, J¼7.5 Hz, 2H); 2.04–0.84 (m, 10H).
syn: 7.28 (m, 5H); 4.68 (d, J¼8.7 Hz, 1H); 3.65 (s, 3H); 3.51
(s, 1H); 2.76 (qd, J1¼8.7 Hz, J2¼7.2 Hz, 1H); 0.91 (d,
J¼7.2 Hz, 3H).
MS: 139 (MꢁH), 123 (MꢁOH), 99, 81 (base), 55.
MS: 195, 177 (base), 121, 107, 88, 79, 57.
3.1.2.18. 1-(1-Methyl-2-propenyl)-cyclohexanol. 1H
NMR: 5.92–5.74 (m, 1H); 5.09–5.01 (m, 2H); 2.17 (dq,
J¼7.7 Hz, J¼7 Hz, 1H); 1.62 (s, 1H); 1.56–1.3 (m, 10H);
1.0 (d, J¼7 Hz, 3H).
3.1.2.10. Methyl 3-hydroxy-2-methylundecanoate. 1H
NMR: anti: 3.88 (m, 1H); 3.69 (s, 3H); 2.54 (dq, J1¼7.1 Hz,
J2¼4.5 Hz, 1H); 1.45–1.28 (m, 15H); 1.18 (d, J¼7.1 Hz,
3H); 0.88 (t, J¼6.4 Hz, 3H).
MS: 154, 137 (MꢁOH), 99 (MꢁC4H7), 81 (base), 55.
syn: 3.7 (m, 1H); 3.69 (s, 3H); 2.3 (m, 1H); 1.45–1.28 (m,
15H); 1.18 (d, J¼7.1 Hz, 3H); 0.88 (t, J¼6.4 Hz, 3H).
3.1.2.19. 2-Thienyl-pent-4-en-2-ol. 1H NMR: 7.27–
7.17 (m, 1H); 6.97–6.89 (m, 2H); 5.80–5.63 (m, 1H);
5.19–5.11 (m, 2H); 2.75–2.54 (m, 2H); 2.32 (s, 1H); 1.62
(s, 3H).
MS: 231 (M+1), 215 (MꢁCH3), 197, 181, 163, 117, 88
(base), 57.
MS: 168 (M), 151 (MꢁOH), 127 (MꢁC3H5, base), 111, 97,
85 (MꢁC4H3S), 71, 57.
3.1.2.20. Methyl 2-phenylpropanoate. 1H NMR: 7.26
(s, 5H); 3.69 (q, J¼7.3 Hz, 1H); 3.58 (s, 3H); 1.46 (d,
J¼7.3 Hz, 3H).
3.1.2.11. Methyl (1-hydroxycyclohexyl)acetate. 1H
NMR: 3.7 (s, 3H); 3.38 (s, 1H); 2.48 (s, 2H); 1.68–1.36
(m, 10H).
MS: 173 (M+1), 155 (MꢁOH), 130, 123, 116, 97, 79 (base),
69, 55.
MS: 164 (M), 105 (MꢁCO2Me, base).
3.1.2.12. Methyl 3-hydroxy-3-phenylbutanoate. 1H
NMR: 7.45–7.40 (m, 2H); 7.39–7.15 (m, 3H); 4.35 (s, 1H),
3.53 (s, 3H); 2.96 (d, J¼15.9 Hz, 1H); 2.77 (d, J¼15.9 Hz,
1H); 1.52 (s, 3H).
3.1.2.21.
Methyl
2-(3-(trifluoromethyl)phenyl)-
propanoate. 1H NMR: 7.61 (s, 1H); 7.53–7.36 (m, 3H);
3.79 (q, J¼7.16 Hz, 1H); 3.63 (s, 3H); 1.51 (d, J¼7.16 Hz,
3H).
MS: 195 (M+1), 179 (MꢁCH3, base), 177 (MꢁOH), 121
(MꢁCH2CO2CH3), 105, 91, 77, 51.
19F NMR: ꢁ62.59 (s, 3F)/CFCl3.
3.1.2.13.
Methyl
3-hydroxy-3,3-diphenylpropa-
13C NMR: 174.0–141.6–130.83 (q, JCCF¼32 Hz)–130.82–
129.0 (q, JCCCF¼3.9 Hz)–124.4 (q, JCCCF¼3.9 Hz)–
124.13–124.09 (q, JCF¼272 Hz, CF3)–51.7–45.1–18.1.
noate. 1H NMR: 7.4–7.2 (m, 10H); 5.04 (s, 1H); 3.63 (s,
3H); 3.28 (s, 2H).
MS: 256 (M), 239 (MꢁOH), 183 (MꢁCH2CO2CH3), 105
MS: 232 (M), 213 (MꢁF), 182, 173 (MꢁCO2Me, base),
(base), 77, 51.
154.

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M. Durandetti et al. / Tetrahedron 63 (2007) 1146–1153
3.1.2.22. Methyl 2-(4-(trifluoromethyl)phenyl)propa-
3.1.2.30. Methyl 2-(3-(trifluoromethyl)phenyl)ace-
tate. 1H NMR: 7.57 (s, 1H); 7.49–7.32 (m, 3H); 3.67 (s,
3H); 3.66 (s, 2H).
1
noate. H NMR: 7.59 and 7.42 (2H each, AA0-BB0 system
J¼8.2 Hz); 3.80 (q, J¼7.1 Hz, 1H); 3.67 (s, 3H); 1.52 (d,
J¼7.1 Hz, 3H).
MS: 218 (M), 199 (MꢁF), 159 (MꢁCO2Me, base), 140, 109.
19F NMR: ꢁ62.33 (s, 3F)/CFCl3.
3.1.2.31. Methyl 2-(4-(trifluoromethyl)phenyl)ace-
1
MS: 232 (M), 213 (MꢁF), 173 (MꢁCO2Me, base), 154.
tate. H NMR: 7.55 and 7.38 (2H each, AA0-BB0 system,
J¼8.16 Hz); 3.69 (s, 2H); 3.67 (s, 3H).
3.1.2.23. Methyl 2-(4-cyanophenyl)propanoate. 1H
NMR: 7.63 and 7.44 (2H each, AA0-BB0 system,
J¼8.2 Hz); 3.81 (q, J¼7.2 Hz, 1H); 3.68 (s, 3H); 1.53 (d,
J¼7.2 Hz, 3H).
13C NMR: 171.0–138.0–129.7 (2C)–129.2 (q, JCCF
32.2 Hz)–125.1 (q, JCCCF¼3.9 Hz, 2C)–124.1 (q, JCF
271.8 Hz, CF3)–51.8–40.5.
¼
¼
MS: 189 (M), 174 (MꢁMe), 158 (MꢁOMe), 130
(MꢁCO2Me, base), 115.
MS: 218 (M), 199 (MꢁF), 168, 159 (MꢁCO2Me, base), 140.
3.1.2.32. Methyl 2-(4-cyanophenyl)acetate. 1H NMR:
7.80 and 7.40 (2H each, AA0-BB0 system, J¼8.3 Hz); 3.70
(s, 3H); 3.65 (s, 2H).
3.1.2.24. Methyl 4-(1-methoxy-1-oxopropan-2-yl)ben-
1
zoate. H NMR: 8.00 and 7.37 (2H each, AA0-BB0 system,
J¼8.36 Hz); 3.91 (s, 3H); 3.79 (q, J¼7.19 Hz, 1H); 3.67 (s,
3H); 1.52 (d, J¼7.19 Hz, 3H).
MS: 175 (M), 160 (MꢁMe), 144 (M–OMe), 116 (M–
CO2Me, base), 89.
MS: 222 (M), 207 (MꢁMe), 191 (MꢁOMe), 163
(MꢁCO2Me, base), 131, 117, 103, 92.
3.1.2.33. Methyl 4-(2-methoxy-2-oxoethyl)benzoate. 1H
NMR: 7.99 and 7.35 (2H each, AA0-BB0 system, J¼8.14 Hz);
3.89 (s, 3H); 3.69 (s, 3H); 3.68 (s, 2H).
3.1.2.25. Methyl 2-(1-methoxy-1-oxopropan-2-yl)ben-
zoate. 1H NMR: 7.90 (dd, J¼7.79 Hz, J¼1.32 Hz, 1H);
7.51–7.24 (m, 3H); 4.65 (q, J¼7.16 Hz, 1H); 3.86 (s, 3H);
3.62 (s, 3H); 1.52 (d, J¼7.16 Hz, 3H).
13C NMR: 171.1–166.6–139.0–129.7 (2C)–129.3 (2C)–
129.0–52.0–51.8–40.9.
13C NMR: 174.5–167.4–141.8–132.0–130.5–129.0–128.2–
126.5–51.6–51.5–41.8–17.9.
MS: 208 (M), 177 (MꢁOMe, base), 149 (MꢁCO2Me),
121, 89.
MS: 222 (M), 190 (MꢁOMe), 162 (MꢁCO2Me, base), 147,
3.1.2.34. Methyl 2-(4-acetylphenyl)acetate. 1H NMR:
7.90 and 7.36 (2H each, AA0-BB0 system, J¼8.22 Hz);
3.68 (s, 5H); 2.56 (s, 3H).
131, 103, 77.
3.1.2.26. Methyl 2-(4-acetylphenyl)propanoate. 1H
NMR: 7.91 and 7.39 (2H each, AA0-BB0 system,
J¼8.36 Hz); 3.80 (q, J¼7.17 Hz, 1H); 3.64 (s, 3H); 2.56
(s, 3H); 1.51 (d, J¼7.17 Hz, 3H).
13C NMR: 197.2–170.9–139.1–135.7–129.3 (2C)–128.3
(2C)–51.8–40.6–26.4.
MS: 192 (M), 177 (MꢁMe, base), 133 (MꢁCO2Me), 89.
MS: 206 (M), 191 (MꢁMe, base), 147 (MꢁCO2Me),
References and notes
103.
3.1.2.27. Methyl 2-(4-methoxyphenyl)propanoate. 1H
NMR: 7.19 and 6.82 (2H each, AA0-BB0 system,
J¼8.68 Hz); 3.70 (s, 3H); 3.64 (q, J¼7.1 Hz, 1H); 3.59 (s,
3H); 1.44 (d, J¼7.1 Hz, 3H).
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