Iron-catalysed Reformatsky-type reactions

Article abstract of DOI:10.1055/s-2006-926432

A Reformatsky-type reaction has been developed using iron catalysis in acetonitrile or DMF. Reduction of iron(II) bromide by manganese metal in acetonitrile provides a low-valent iron catalyst, which is the active species; under these conditions, α-chloro

Full text of DOI:10.1055/s-2006-926432

1542
PAPER
Iron-Catalysed Reformatsky-Type Reactions
Iron-Catalysed
R
efor
m
u
atsky-Type
R
r
eaction
i
s
el Durandetti,*1 Jacques Périchon
Laboratoire d’Electrochimie, Catalyse et Synthèse Organique, UMR 7582, CNRS-Université Paris, 12 Val de Marne, 2 rue Henri-Dunant,
94320 Thiais, France
Fax +33(2)35522971; E-mail: muriel.durandetti@univ-rouen.fr
Received 6 December 2005; revised 9 January 2006
to 70:30). With the purpose of devising a less toxic pro-
Abstract: A Reformatsky-type reaction has been developed using
cess, we then reported an original version of the Refor-
iron catalysis in acetonitrile or DMF. Reduction of iron(II) bromide
matsky reaction, by iron catalysis, associated with an
by manganese metal in acetonitrile provides a low-valent iron cata-
lyst, which is the active species; under these conditions, a-chlo-
electrochemical reaction.19 This electrochemical method
roesters or nitriles can both be converted into their corresponding is as efficient with ketones as with aldehydes. In addition,
derivatives. The method was applicable to both ketones and alde-
as the process employs a simple iron complex in an undi-
hydes, resulting in the formation of b-hydroxyesters under mild
conditions.
vided cell and sacrificial iron anode, the process is very
easy, cheap, non-toxic and original. However, electro-
Key words: iron, Reformatsky reaction, a-haloester, carbonyl
compounds, C–C coupling
chemical reactions are often considered as being more dif-
ficult to handle than conventional classical methods.
Electrochemical processes are not readily applicable on
an industrial scale, therefore we now report a chemical
method for an iron Reformatsky-type reaction, using
FeBr2 as a catalyst in the presence of an appropriate reduc-
ing metal (Equation 2),20 taking advantage of cheap, non-
toxic and environmentally benign iron salts. It was al-
ready reported that simple iron salts such as Fe(acac)3
could catalyse the cross-coupling of Grignard reagents.21
Herein we report the results of our investigations to realise
a non-electrochemical iron-catalysed Reformatsky-type
reaction, detailing the efficiency and scope of the proce-
dure.
In 1887, Reformatsky prepared b-hydroxyesters by the re-
action of a-iodo or a-bromoesters with zinc metal in ben-
zene and subsequent addition to carbonyl compounds.2
(Equation 1)
R1
CO2R2
R4
O
Zn
R3
R1
+
CO2R2
R3
R4
Br
OH
Equation 1 The Reformatsky reaction
To extend the scope of this reaction, various parameters
have been extensively investigated.3 Since the reaction is
initiated by the insertion of zinc into the halogen–carbon
bond, the main emphasis has focused on the activation of
zinc, such as, Rieke-Zn,4 Zn–Cu couple,5 Zn/Ag-graph-
ite,6 ultrasound7 or sonoelectroreduction.8 Recently, a Re-
formatsky-type reaction was developed, using
RhCl(PPh3)3 and diethylzinc.9 Another process has been
performed, in aqueous THF, using BF3·OEt2 and Zn dust
but is limited to aldehydes.10 In addition, a number of oth-
er metals and catalysts,11 such as nickel,12 manganese,13
chromium14 and indium15 were also found to be active. An
aqueous metal-free electrochemical Reformatsky reaction
has also been reported recently.16 We have already de-
scribed some electrochemical processes for the Refor-
matsky reaction,17 more recently, we reported an
electrochemical method employing catalytic amounts of
both chromium and nickel salts, using a sacrificial stain-
less-steel or an iron rod anode.18 Under these conditions,
b-hydroxyesters were obtained in good yields (60–80%)
and moderate diastereoselectivity (erythro/threo ca. 60:40
OH
O
FeBr2, L, M red.
solvent
O
O
Cl
+
O
O
a
1
1a
Equation 2 Iron Reformatsky-type reaction
We began by studying a range of parameters including the
solvent, the ligand, and particularly the reducing metal
(Table 1). The iron dibromide catalysed reaction of a-
chloroesters is performed in a Barbier-type fashion.22
We have found that manganese is the best metal for the re-
duction of FeBr2 (Table 1, entries 1–3, 6 and 7). With Zn
as the reducing metal, the process occurs very slowly even
when stoichiometric amounts of the iron salt are em-
ployed (Table 1, entries 4 and 8). Aluminium could not be
used as a reducing metal, no cross-coupling occurs even
after a reaction time of four days (Table 1, entries 5 and
9). Then depending on the solvent, two alternative sets of
conditions can be used. The first one is derived from the
electrochemical process, with DMF as the solvent,
FeBr2bipy as the catalyst (0.25 equiv) and the reaction is
conducted at room temperature (Table 1, entry 1 and
Equation 3). Under these conditions, b-hydroxyesters are
obtained in good yields (65–95%) in four to seven hours.
Decreasing the amount of FeBr2bipy to 0.15 equivalents
SYNTHESIS 2006, No. 9, pp 1542–1548
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.04.2006
DOI: 10.1055/s-2006-926432; Art ID: Z23705SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iron-Catalysed Reformatsky-Type Reactions
1543
Table 1 Factors Affecting the Coupling Reaction between Cyclo-
hexanone and Methyl 2-Chloro-propanoate Using FeBr2 as a Catalyst
O
O
S
O
Entry Catalyst (equiv)
Solvent
DMFa
Metal
Mn
Mn
Mn
Zn
Time (h) Yield (%)
O
1
2
3
4
1
2
3
4
5
6
7
8
9
FeBr2bpy (0.25)
FeBr2bpy (0.15)
FeBr2bpy (0.15)
FeBr2bpy (0.50)
FeBr2bpy (0.25)
FeBr2 (0.25)
7
30
95
64
71
55
0
O
O
DMFa
O
5
6
7
DMFb
28
CHO
O
H
DMFa
100
100
17
O
8
9
10
DMFa
Al
CHO
CHO
CHO
MeCNa
MeCNb
MeCNb
MeCNb
Mn
Mn
Zn
88
86
5
F3C
MeO
MeS
FeBr2 (0.15)
1.5
11
12
13
FeBr2 (0.15)
24
Figure 1 Carbonyl compounds used in the iron Reformatsky reac-
tion
FeBr2 (0.15)
Al
100
0
a Reaction conducted at r.t.
were detected; no conjugated addition was observed with
this enone, thus indicating that the reaction is regiospecif-
ic.
b Reaction conducted at 50 °C.
R1 R2 R3
R1
R2
Cl
O
O
In the case of dissymmetric carbonyl compounds, we ob-
tained the two diastereoisomers with moderate diastereo-
selectivity (Table 2, entries 2–4, 7–10), depending on the
nature of the carbonyl compounds.
FeBr2Bipy (0.25 equiv)
+
HO
65–95%
O
DMF, Mn (3 equiv), r.t.
4–7 h
R3
O
O
Equation 3 Iron Reformatsky-type reaction with DMF as solvent
Coupling methyl 2-chloroacetate with ketones 1–7 also
gave good yields of b-hydroxyesters (50–70% isolated
yield, Table 3). As already observed in the case of elec-
troreductive coupling carried out with a-chloroester,23 the
coupling with chloropropionate is more efficient than
with chloroacetate. The excess of a-chloroester, necessary
to consume the carbonyl compounds, is more important
with methyl 2-chloroacetate than with methyl 2-chloro-
propanoate (1.5 equivalents instead of 1.3 equivalents are
necessary).
resulted in a longer reaction time of 30 hours (Table 1, en-
try 2), even when the reduction was carried out at 50 °C
(Table 1, entry 3).
Although this process is efficient, we have developed a
second set of conditions, which was less expensive and
less toxic, since the reactions are performed with only
0.15 equivalents of FeBr2, without any ligand with aceto-
nitrile as the solvent, at 50 °C (Equation 4). The chemical
yields were similar (40–90%) but the reaction was com-
plete in two to four hours.
We then looked at a-bromoesters, thus methyl 2-bro-
mopropanoate was reacted with a range of ketones and al-
dehydes (Table 4). With ketones, chemical yields are
similar using either a-chloroesters or a-bromoesters
(compare Table 4, entry 1 with Table 2, entry 1). In the
case of aldehydes, chemical yields are similar or better for
a-bromoesters, the major benefit here was that it was not
necessary to add the aldehyde in four portions (compare
Table 4, entries 2 and 3 with Table 2, entries 9 and 10);
this is probably due to the higher reactivity of the a-bro-
moester. We also demonstrated that the cross-coupling is
efficient with aryl aldehydes bearing electron-donating
(Table 4, entries 5-6) as well as electron-withdrawing
groups (Table 4, entry 4).
R1 R2 R3
R1
R2
X
EWG
FeBr2 (0.15 equiv)
+
MeCN, Mn (2 equiv)
50 °C, 1.5–6 h
O
R3
EWG = CO2R4, CN
OH
EWG
40–90%
Equation 4 Iron Reformatsky reaction in acetonitrile as solvent
We then extended this protocol to a large variety of car-
bonyl compounds (1–10), which were coupled with meth-
yl 2-chloropropanoate (Table 2).
The process is efficient with ketones, whatever their struc-
ture (aromatic, aliphatic or cyclic), giving the desired
cross-coupled products in good to excellent yields (55–
93%) (Table 2, entries 1–8). With aldehydes the reaction
is less efficient, as pinacolisation is the favoured reaction.
However, if the aldehyde is added portionwise, the yields
are increased (Table 2, entries 9 and 10). Lower yields
were obtained with cyclohexenone 2 even though the ke-
tone was completely consumed and no other products
We then tried to realise the reaction between cyclohex-
anone 1 and the a-chloro- or bromoester without FeBr2 as
catalyst. In the case of a-chloroester, no coupling product
was obtained even after a reaction time of five days, there-
fore iron catalysis is necessary to obtain the coupling
product. However, with a-bromoester, we obtained 2% of
b-hydroxyester after two hours, compared to 91% in the
presence of FeBr2 after the same reaction time (Table 4,
Synthesis 2006, No. 9, 1542–1548 © Thieme Stuttgart · New York

1544
M. Durandetti, J. Périchon
PAPER
Table 2 Iron-Catalysed Cross-Coupling between Methyl 2-Chloro-
Table 3 Iron-Catalysed Cross-Coupling between Methyl 2-Chloro-
propanoate and Carbonyl Compoundsa
acetate and Carbonyl Compoundsa
Entry Carbonyl Product
compound
Yield anti/syn
Entry Carbonyl compound Product
Yield (%)b
51
(%)b
1
2
1
3
OH
1
2
3
1
2
3
86
_
OH
OH
O
O
O
O
1b
1a
2a
69
55c 46:54
O
O
O
HO
O
O
3b
4b
3
4
4
5
45c
50d
O
OH
93
70:30
O
S
HO
O
3a
4a
4
5
4
5
82
80
52:48
_
O
OH
O
HO
S
O
O
5b
5
6
6
7
52
50
OH
O
O
O
HO
O
6b
7b
5a
HO
O
6
6
88
_
OH
O
O
O
a Typical procedure: see experimental section.
6a
7a
8a
b Isolated yields, based on initial carbonyl compounds. All products
gave satisfactory analytical data.
7
8
9
7
65
61
64
60:40
60:40
65:35
HO
O
c GC yield: 74%. Some spontaneous dehydration occurs during col-
umn chromatography on silica gel, thus, olefin 4d was obtained in
29% yield.
O
d Yield of recovered ketone: 50%.
8
HO
O
O
entry 1). When the reaction time was extended to three
days a yield of 74% was achieved without iron catalysis,
implying that insertion of manganese metal into the car-
bon–bromine bond was possible without iron catalysis.
9d
O
We then extended the process to coupling ketones with
a-chloronitrile under the same procedure described for
a-chloroesters (Table 5).
OH
O
9a
10
10d
35
61:39
O
The method can also be applied to a,a¢,a¢¢-trichloroester.
Thus, as a preliminary study, the coupling of 3-pentanone
(6) with a,a¢,a¢¢-trichloroester proceeded in good yield
(Equation 5), if the trichloroester is added slowly to min-
imise its direct reduction. Under these conditions two
equivalents of trichloroester are necessary to obtain a
good yield of coupling product.
The mechanism of the reaction is under investigation,24
but it appears that manganese metal has two roles. It is be-
lieved that reduction of Fe(II) to Fe(0) is effected by man-
OH
O
10a
a Typical procedure: see experimental section.
b Isolated yields, based on initial carbonyl compounds. All products
gave satisfactory analytical data.
c No 1,4-addition product was detected.
d RCHO was introduced in four portions to minimise direct reduction.
Synthesis 2006, No. 9, 1542–1548 © Thieme Stuttgart · New York

PAPER
Iron-Catalysed Reformatsky-Type Reactions
1545
Table 4 Iron-Catalysed Cross-Coupling between Methyl 2-Bromo-
propanoate and Carbonyl Compoundsa
FeBr2 (15%)
Cl
CO2Et
CO2Et
Cl C-CO Et
+
3
2
+
MeCN, Mn
60 °C, 4 h
O
72%
O
6%
O
Entry Carbonyl Product
compound
Yield anti/syn
(%)b
Equation 5 The addition of a,a¢a¢¢-trichloroester to 3-pentanone
1
2
1
9
91
_
OH
via iron catalysis
O
O
Table 5 Iron-Catalysed Cross-Coupling between a-Chloropropio-
1a
9a
nitrile and Carbonyl Compoundsa
78
67:33
Entry Carbonyl
compound
Product
Yield
(%)b
anti/syn
O
OH
O
1
2
3
1
3
6
46
57
66
_
OH
3
4
10
11
36
67
62:38
78:22
N
O
1c
OH
O
66:34
10a
F3C
HO
N
O
3c
_
OH
OH
O
11a
MeO
N
5
6
12
13
60
68
75:25
68:32
6c
O
O
a Typical procedure: see experimental section.
OH
OH
O
b Isolated yields, based on initial carbonyl compounds. All products
gave satisfactory analytical data.
12a
MeS
ganese metal; Fe(0) is stabilised by acetonitrile itself and
can react with an a-chloroester. Then, the addition of the
organoiron species to the carbonyl compound leads to an
iron alkoxide. The process will be catalytic in iron only if
the Mn(II) obtained during the redox reaction between
Mn(0) and Fe(II), reacts with the alkoxide to lead a man-
ganese alkoxide (Scheme 1).
O
13a
a Typical procedure: see experimental section.
b Isolated yields, based on initial carbonyl compounds. All products
gave satisfactory analytical data.
FeIIX
X
FeII
O
O
O
O
O
O
Fe0
iron enolate
MnIIBr2
R
R'
O
FeIIBr2
Mn0
R
R'
R
O
R'
OH
R
O
R'
O
MnIIBr2
H2O, H+
O
FeII
+
FeII
MnII
O
O
O
O
manganese alkoxide
Scheme 1 Proposed mechanism of the iron-catalysed Reformatsky-type reaction
Synthesis 2006, No. 9, 1542–1548 © Thieme Stuttgart · New York

1546
M. Durandetti, J. Périchon
PAPER
Methyl 3-Hydroxy-2,3-dimethyl-3-thienylpropanoate (4a)
In conclusion, we have reported an efficient cross-cou-
pling of carbonyl compounds and activated alkyl halides,
enabling the preparation of valuable target molecules such
as b-hydroxyesters. A broad range of organic compounds
can be applied, such as, a-chloro- or a-bromoesters and a-
chloronitrile. The method is applicable to both ketones
and aldehydes (portionwise addition with chloroesters).
The efficiency of iron salts in this process has been clearly
demonstrated. The method is also very easy, cheap, non-
toxic and totally original.
1H NMR (anti): d = 7.17–7.14 (m, 1 H), 6.92–6.85 (m, 2 H), 4.40
(s, 1 H), 3.57 (s, 3 H), 2.99 (q, J = 7.13 Hz, 1 H), 1.54 (s, 3 H), 1.28
(d, J = 7.13 Hz, 3 H).
1H NMR (syn): d = 7.70–7.60 (m, 1 H), 7.20–7.10 (m, 2 H), 4.09 (s,
1 H), 3.70 (s, 3 H), 2.87 (q, J = 6.7 Hz, 1 H), 1.62 (s, 3 H), 1.11 (d,
J = 6.7 Hz, 3 H).
MS: m/z (%) = 214 (M+), 197 (M+ – OH), 127 (M+ – C2H7O2, 100),
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.
To the best of our knowledge this is the first chemical
iron-catalysed Reformatsky-type reaction reported so far.
Further investigations are necessary to determine the or-
ganoiron species involved in this mechanism.
Methyl 3,3-Diphenyl-3-hydroxy-2-methylpropanoate (5a)
1H NMR: d = 7.50 (m, 4 H), 7.20 (m, 6 H), 4.68 (s, 1 H), 3.66 (q,
J = 7.1 Hz, 1 H), 3.00 (s, 3 H), 1.16 (d, J = 7.1 Hz, 3 H).
MS: m/z (%) = 270 (M+), 253 (M+ – OH), 183 (100), 105, 77.
GC analysis was carried out using a 4-m capillary column. MS were
recorded with a spectrometer coupled to a GC. Column chromatog-
raphy was performed on silica gel 60, 70–200 mm. 1H and 13C NMR
spectra were recorded in CDCl3 at 200 and 50 MHz, respectively,
with TMS as internal standard.
Methyl 3-Ethyl-3-hydroxy-2-methylpentanoate (6a)
1H NMR: d = 3.71 (s, 3 H), 3.20 (s, 1 H), 2.61 (q, J = 7.2 Hz, 1 H),
1.50 (m, 4 H), 1.17 (d, J = 7.2 Hz, 3 H), 0.88 (t, J = 7.4 Hz, 3 H),
0.82 (t, J = 7.6 Hz, 3 H).
MS: m/z (%) = 175 (M+ + 1), 157 (M+ – OH), 145 (M+ – Et), 113,
97, 88, 57 (100).
All solvents and reagents were purchased and used without further
purification. DMF and MeCN were stored under argon. 2,2¢-Bipy-
ridine was used as obtained.
Methyl 3-Hydroxy-2,3-dimethylhexanoate (7a)
1H NMR (anti): d = 3.71 (s, 3 H), 3.12 (s, 1 H), 2.57 (q, J = 7.15 Hz,
1 H), 1.42–1.25 (m, 4 H), 1.19 (d, J = 7.15 Hz, 3 H), 1.18 (s, 3 H),
0.91–0.79 (m, 3 H).
1H NMR (syn): d = 3.70 (s, 3 H), 3.10 (s, 1 H), 2.54 (q, J = 7.1 Hz,
1 H), 1.40–1.20 (m, 4 H), 1.20 (d, J = 7.1 Hz, 3 H), 1.10 (s, 3 H),
0.90–0.80 (m, 3 H).
FeBr2-Catalysed Synthesis; General Procedure
Carbonyl compound (10 mmol) and a-haloester or nitrile (13 mmol)
in MeCN (15 mL) were stirred in a flask under argon at 50 °C. Then
Mn (1.10 g, 20 mmol) was introduced, followed by FeBr2 (0.32 g,
1.5 mmol) and then CF3CO2H (20 mL) to activate Mn metal. The re-
action is conducted at 50 °C and monitored by GC (reaction time,
ca. 2 h). The mixture was then hydrolysed with 1 N HCl (30 mL)
and diluted with Et2O (30 mL). The aqueous layer was extracted
with Et2O (2 × 30 mL), the combined organic layers were washed
with H2O (30 mL) and a sat. solution of NaCl, dried over MgSO4
and the solvent was evaporated. The oil thus obtained was purified
by column chromatography to give the desired compounds.
MS: m/z (%) = 175 (M+ + 1), 157 (M+ – OH, 100), 131 (M+ – C3H7),
99, 71, 57.
Methyl 3-Hydroxy-2,3,7-trimethyl-6-octenoate (8a)
1H NMR (anti): d = 5.13–5.05 (m, 1 H), 3.70 (s, 3 H), 3.24 (s, 1 H),
2.59 (q, J = 7.1 Hz, 1 H), 2.08–2.01 (m, 2 H), 1.67 (s, 3 H), 1.61 (s,
3 H), 1.53–1.43 (m, 2 H), 1.21 (s, 3 H), 1.20 (d, J = 7.1 Hz, 3 H).
Methyl (1-Hydroxy-a-methylcyclohexane)acetate (1a)
1H NMR: d = 3.70 (s, 3 H), 3.04 (s, 1 H), 2.52 (q, J = 7.1 Hz, 1 H),
1.48 (m, 10 H), 1.19 (d, J = 7.1 Hz, 3 H).
MS: m/z (%) = 187 (M+ + 1), 169 (M+ – OH), 155 (M+ – OMe), 143,
1H NMR (syn): d = 5.13–5.05 (m, 1 H), 3.70 (s, 3 H), 3.24 (s, 1 H),
2.57 (q, J = 7.09 Hz, 1 H), 2.08–2.01 (m, 2 H), 1.67 (s, 3 H), 1.61
(s, 3 H), 1.53–1.43 (m, 2 H), 1.15 (s, 3 H), 1.20 (d, J = 7.09 Hz, 3 H).
MS: m/z (%) = 215 (M+ + 1), 196 (M+ – OH), 136, 121, 109 (100),
99, 93, 81, 67, 57.
130, 113, 99, 81 (100), 55.
Methyl (1-Hydroxy-a-methyl-2-cyclohexene)acetate (2a)
1H NMR (anti): d = 5.50–5.92 (m, 2 H), 3.70 (s, 3 H), 2.98 (s, 1 H),
2.63 (q, J = 7.2 Hz, 1 H), 2.10–1.50 (m, 6 H), 1.22 (d, J = 7.2 Hz, 3
H).
1H NMR (syn): d = 5.90–5.50 (m, 2 H), 3.70 (s, 3 H), 3.00 (s, 1 H),
2.60 (q, J = 7.4 Hz, 1 H), 2.10–1.50 (m, 6 H), 1.18 (d, J = 7.4 Hz, 3
Methyl 3-Hydroxy-2-methyl-3-phenylpropanoate (9a)
1H NMR (anti): d = 7.23 (m, 5 H), 4.97 (d, J = 5.1 Hz, 1 H), 3.76 (s,
1 H), 3.53 (s, 3 H), 2.73 (qd, J = 7.0, 5.1 Hz, 1 H), 1.10 (d, J = 7.0
Hz, 3 H).
1H NMR (syn): d = 7.28 (m, 5 H), 4.68 (d, J = 8.7 Hz, 1 H), 3.65 (s,
3 H), 3.51 (s, 1 H), 2.76 (dq, J = 8.7, 7.2 Hz, 1 H), 0.91 (d, J = 7.2
Hz, 3 H).
H).
MS: m/z (%) = 184 (M+), 156 (M+ – CO), 124 (M+ – CO2Me), 97
(100), 79, 55.
MS: m/z (%) = 195, 177 (100), 121, 107, 88, 79, 57.
Methyl 3-Hydroxy-2-methylundecanoate (10a)
1H NMR (anti): d = 3.88 (m, 1 H), 3.69 (s, 3 H), 2.54 (dq,
J = 7.1, 4.5 Hz, 1 H), 1.45–1.28 (m, 15 H), 1.18 (d, J = 7.1 Hz, 3 H),
0.88 (t, J = 6.4 Hz, 3 H).
1H NMR (syn): d = 3.7 (m, 1 H), 3.69 (s, 3 H), 2.3 (m, 1 H), 1.45–
1.28 (m, 15 H), 1.18 (d, J = 7.1 Hz, 3 H), 0.88 (t, J = 6.4 Hz, 3 H).
Methyl 3-Hydroxy-2-methyl-3-phenylbutanoate (3a)
1H NMR (anti): d = 7.41 (m, 2 H), 7.20 (m, 3 H), 4.15 (s, 1 H), 3.33
(s, 3 H), 2.98 (q, J = 7.07 Hz, 1 H), 1.42 (s, 3 H), 1.23 (d, J = 7.07
Hz, 3 H).
1H NMR (syn): d = 7.40 (m, 2 H), 7.25 (m, 3 H), 3.91 (s, 1 H), 3.70
(s, 3 H), 2.86 (q, J = 7.12 Hz, 1 H), 1.55 (s, 3 H), 0.95 (d, J = 7.12
Hz, 3 H).
MS: m/z (%) = 231 (M+ + 1), 215 (M+ – CH3), 197, 181, 163, 117,
88 (100), 57.
MS: m/z (%) = 209 (M+ + 1), 191 (M+ – OH), 121 (100), 105, 77.
Synthesis 2006, No. 9, 1542–1548 © Thieme Stuttgart · New York

PAPER
Iron-Catalysed Reformatsky-Type Reactions
1547
Methyl 3-Hydroxy-2-methyl-3-(4-trifluoromethylphenyl)pro-
panoate (11a)
MS: m/z (%) = 256 (M+), 239 (M+ – OH), 183 (M+ – CH2CO2CH3),
105 (100), 77, 51.
1H NMR (anti): d = 7.62 (d, J = 8.2 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 2
H), 5.19 (d, J = 3.9 Hz, 1 H), 3.89 (s, 1 H), 3.71 (s, 3 H), 2.79 (qd,
J = 7.1, 3.9 Hz, 1 H), 1.11 (d, J = 7.1 Hz, 3 H).
Methyl 3-Ethyl-3-hydroxypentanoate (6b)
1H NMR: d = 3.69 (s, 3 H), 3.46 (s, 1 H), 2.46 (s, 2 H), 1.54 (q,
J = 7.2 Hz, 4 H), 0.88 (t, J = 7.2 Hz, 6 H).
1H NMR (syn): d = 7.62 (d, J = 8.2 Hz, 2 H), 7.46 (d, J = 8.2 Hz, 2
H), 4.81 (d, J = 8.1 Hz, 1 H), 3.72 (s, 1 H), 3.13 (s, 3 H), 2.79 (dq,
J = 8.1, 7.2 Hz, 1 H), 1.05 (d, J = 7.2 Hz, 3 H).
MS: m/z (%) = 161 (M+ + 1, 100), 143 (M+ – OH), 131 (M+ – C2H5),
111, 99, 83, 69, 57.
MS: m/z (%) = 260 (M+), 242 (M+ – H2O), 228, 213, 173 (100), 145,
125, 95.
Methyl 3-Hydroxy-3-methylhexanoate (7b)
1H NMR: d = 4.63 (s, 1 H), 3.72 (s, 3 H), 2.54 (d, J = 15.3 Hz, 1 H),
2.44 (d, J = 15.3 Hz, 1 H), 1.53–1.32 (m, 4 H), 1.23 (s, 3 H), 0.92
(t, J = 6 Hz, 3 H).
MS: m/z = 161 (M+ + 1), 145 (M+ – OH), 117 (M+ – C3H7), 85 (100),
71, 55.
Methyl 3-Hydroxy-2-methyl-3-(4-methoxyphenyl)propanoate
(12a)
1H NMR (anti): d = 7.23 (d, J = 8.3 Hz, 2 H), 6.85 (d, J = 8.3 Hz, 2
H), 4.97 (s, 1 H), 3.77 (s, 3 H), 3.61 (s, 3 H), 2.84–2.74 (m, 2 H),
1.19 (d, J = 6.7 Hz, 3 H).
2-(1-Hydroxycyclohexyl)propionitrile (1c)
1H NMR: d = 2.67 (q, J = 7.2 Hz, 1 H), 2.50 (s, 1 H), 1.79–1.34 (m,
10 H), 1.33 (d, J = 7.2 Hz, 3 H).
1H NMR (syn): d = 7.21 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2
H), 3.76 (s, 3 H), 3.68 (s, 3 H), 3.50 (s, 1 H), 2.79–2.71 (m, 2 H),
0.91 (d, J = 7.1 Hz, 3 H).
MS: m/z (%) = 154 (M+ + 1), 136 (M+ – OH), 99 (M+ – C3H4N), 81
MS: m/z (%) = 224 (M+), 206 (M – H2O), 193 (M+ – OMe), 151, 137
(100), 71 (M+ – C6H10), 55.
(M+ – C4H7O2, 100), 109, 94, 77.
3-Hydroxy-2-methyl-3-phenylbutyronitrile (3c)
Methyl 3-Hydroxy-2-methyl-3-(4-sulfanylphenyl)propanoate
(13a)
1H NMR (anti): d = 7.41–7.20 (m, 5 H), 2.96 (q, J = 7.2 Hz, 1 H),
2.88 (s, 1 H), 1.73 (s, 3 H), 1.16 (d, J = 7.2 Hz, 3 H).
1H NMR (anti): d = 7.15 (m, 4 H), 4.96 (d, J = 4.3 Hz, 1 H), 3.59 (s,
3 H), 2.92 (s, 1 H), 2.68 (qd, J = 7.3, 4.3 Hz, 1 H), 2.39 (s, 3 H), 1.04
(d, J = 7.3 Hz, 3 H).
1H NMR (syn): d = 7.50–7.30 (m, 5 H), 2.96 (q, J = 7.2 Hz, 1 H),
2.81 (s, 1 H), 1.70 (s, 1 H), 1.14 (d, J = 7.2 Hz, 3 H).
1H NMR (syn): d = 7.16 (m, 4 H), 4.62 (d, J = 7.9 Hz, 1 H), 3.64 (s,
3 H), 2.89 (s, 1 H), 2.72 (dq, J = 7.9, 6.8 Hz, 1 H), 2.40 (s, 3 H), 0.91
(d, J = 6.8 Hz, 3 H).
MS: m/z (%) = 175 (M+), 158 (M+ – OH), 121 (M – C3H4N, base),
115, 105, 91, 77, 51.
3-Ethyl-3-hydroxy-2-methylpentanenitrile (6c)
MS: m/z (%) = 240 (M+), 209 (M+ – SMe), 166, 153 (M+ – C4H7O2,
100), 109, 125, 77.
1H NMR: d = 2.90 (s, 1 H), 2.79 (q, J = 7.2 Hz, 1 H), 1.66 (q, J = 7.1
Hz, 2 H), 1.61 (q, J = 7.7 Hz, 2 H), 1.29 (d, J = 7.2 Hz, 3 H), 0.92
(t, J = 7.1 Hz, 3 H), 0.89 (t, J = 7.7 Hz, 3 H).
Methyl (1-Hydroxycyclohexyl)acetate (1b)
1H NMR: d = 3.70 (s, 3 H), 3.38 (s, 1 H), 2.48 (s, 2 H), 1.68–1.36
(m, 10 H).
MS: m/z (%) = 142 (M+ + 1), 124 (M+ – OH), 112, 87, 69, 56 (100).
Methyl 3,3-Diethyl-2-oxiranecarboxylate
1H NMR: d = 3.78 (s, 3 H), 3.37 (s, 1 H), 1.71 (q, J = 7.5 Hz, 2 H),
1.67 (q, J = 7.7 Hz, 2 H), 0.94 (t, J = 7.7 Hz, 3 H), 0.95 (t, J = 7.5
Hz, 3 H).
MS: m/z (%) = 173 (M+ + 1), 155 (M+ – OH), 130, 123, 116, 97, 79
(100), 69, 55.
Methyl 3-Hydroxy-3-phenylbutanoate (3b)
1H NMR: d = 7.45–7.40 (m, 2 H), 7.39–7.15 (m, 3 H), 4.35 (s, 1 H),
3.53 (s, 3 H), 2.96 (d, J = 15.9 Hz, 1 H), 2.77 (d, J = 15.9 Hz, 1 H),
1.52 (s, 3 H).
MS: m/z (%) = 159, 141 (M+ – OH), 129, 101 (100), 67, 59.
References
MS: m/z (%) = 195 (M+ + 1), 179 (M+ – Me, 100), 177 (M+ – OH),
121 (M+ – CH2CO2CH3), 105, 91, 77, 51.
(1) New address: Dr. M. Durandetti, Laboratoire des Fonctions
Azotées & Oxygénées Complexes de L’IRCOF, UMR 6014
CNRS, Université de Rouen, 76821 Mont Saint-Aignan
Cedex, France.
(2) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210.
(3) For recent reviews on the Reformatsky reaction, see:
(a) Ocampo, R.; Dolbier, W. R. Jr. Tetrahedron 2004, 60,
9325. (b) Fürstner, A. Synthesis 1989, 571. (c) Rathke, M.
W.; Weipert, P. In Comprehensive Organic Synthesis, Vol.
2; Trost, B. M.; Fleming, I., Eds.; Elsevier: New York, 1991,
277–299. (d) Fürstner, A. In Organozinc Reagents;
Knochel, P.; Jones, P., Eds.; Oxford University Press: New
York, 1999, 287–305.
(4) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 452.
(5) Santaniello, E.; Manzocchi, A. Synthesis 1977, 698.
(6) Csuk, R.; Fürster, A.; Weidmann, H. J. Chem. Soc., Chem.
Commun. 1986, 775.
(7) (a) Han, B.; Boudjouk, P. J. Org. Chem. 1982, 47, 5030.
(b) Nishiyama, T.; Woodhall, J. F.; Lawson, E. N.; Kitching,
W. J. Org. Chem. 1989, 54, 2184.
Methyl 3-Hydroxy-3-(2-thienyl)butanoate (4b)
1H NMR: d = 7.26–7.19 (m, 1 H), 7.13–6.80 (m, 2 H), 5.07 (s, 1 H),
3.59 (s, 3 H), 2.94 (d, J = 16.0 Hz, 1 H), 2.76 (d, J = 16.0 Hz, 1 H),
1.57 (s, 3 H).
MS: m/z (%) = 200 (M+), 185 (M+ – CH3), 127 (M+ – C3H5O2, 100),
112, 97.
Methyl 3-(2-Thienyl)but-2-enoate (4d)
1H NMR: d = 7.26–7.19 (m, 1 H), 7.13–6.80 (m, 2 H), 6.19 (d,
J = 1.1 Hz, 1 H), 3.67 (s, 3 H), 2.54 (d, J = 1.1 Hz, 3 H).
MS: m/z (%) = 182 (M+), 150 (M+ – OCH3, 100), 123 (M+
–
CO2Me), 79.
Methyl 3-Hydroxy-3,3-diphenylpropanoate (5b)
1H NMR: d = 7.40–7.20 (m, 10 H), 5.04 (s, 1 H), 3.63 (s, 3 H), 3.28
(s, 2 H).
Synthesis 2006, No. 9, 1542–1548 © Thieme Stuttgart · New York

1548
M. Durandetti, J. Périchon
PAPER
(8) Durant, A.; Delplanche, J.; Libert, V.; Reisse, J. Eur. J. Org.
Chem. 1999, 2845.
(9) Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2,
2549.
(18) Durandetti, M.; Nédelec, J.-Y.; Périchon, J. Org. Lett. 2001,
3, 2073.
(19) Durandetti, M.; Meignein, C.; Périchon, J. Org. Lett. 2003,
5, 317.
(10) Chattopadhyay, A.; Salaskar, A. Synthesis 2000, 561.
(11) Orsini, F.; Sello, G. Curr. Org. Synth. 2004, 1, 111.
(12) Inab, S.-I.; Rieke, R. D. Tetrahedron Lett. 1985, 26, 155.
(13) (a) Kahiga, H.; Nishimae, S.; Shinokubo, H.; Oshima, K.
Tetrahedron 2001, 57, 8807. (b) Cahiez, G.; Chavant, P.-Y.
Tetrahedron Lett. 1989, 30, 7373.
(14) Wessjohann, L.; Gabriel, T. J. Org. Chem. 1997, 62, 3772.
(15) (a) Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.;
Araki, S. J. Chem. Soc., Perkin Trans. 1 2000, 5, 825.
(b) Lee, P. H.; Bang, K.; Sung, S.; Chang, S. Synth.
Commun. 2001, 31, 3781.
(20) Durandetti, M.; Périchon, J. Patent application FR 2004-
7230, 2004.
(21) (a) Fürstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856. (b) Quintin, J.; Franck, X.;
Hocquemiller, R.; Figadère, B. Tetrahedron Lett. 2002, 43,
3547. (c) Fakhfakh, M. A.; Franck, X.; Hocquemiller, R.;
Figadère, B. J. Organomet. Chem. 2001, 624, 131.
(d) Bogdanovic, B.; Schwickardi, M. Angew. Chem. Int. Ed.
2000, 39, 4610.
(22) Blomberg, C. The Barbier Reaction and Related One-Step
Processes; Springer: Berlin, 1993.
(16) Areias, M. C. C.; Bieber, L. W.; Navarro, M.; Diniz, F. B. J.
(23) (a) Durandetti, M.; Périchon, J. Synthesis 2004, 3079.
(b) Durandetti, M.; Nédelec, J.-Y.; Périchon, J. J. Org.
Chem. 1996, 61, 1748.
(24) The insertion of a low valent iron salt into an a-haloester is
already reported: Buriez, O.; Durandetti, M.; Périchon, J. J.
Electroanal. Chem. 2005, 578, 63.
Electroanal. Chem. 2003, 558, 125.
(17) (a) Rollin, Y.; Gebehenne, C.; Derien, S.; Dunach, E.;
Périchon, J. J. Orgonomet. Chem. 1993, 461, 9.
(b) Connan, A.; Sibille, S.; Périchon, J. J. Org. Chem. 1991,
56, 2018.
Synthesis 2006, No. 9, 1542–1548 © Thieme Stuttgart · New York