Development of new iron catalysts for the tandem isomerization-aldol condensation of allylic alcohols

Article abstract of DOI:10.1016/S0040-4039(03)01556-9

(bda)Fe(CO)₃ and (COT)Fe(CO)₃ are shown to be excellent catalysts for the tandem isomerization-aldol reaction of allylic alcohols with aldehydes and to significantly increase the scope of this aldolization process, especially, in the

Full text of DOI:10.1016/S0040-4039(03)01556-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6187–6190
Development of new iron catalysts for the tandem
isomerization–aldol condensation of allylic alcohols
Ramalinga Uma, Nicolas Gouault, Christophe Cre´visy and Rene´ Gre´e*
ENSCR, Laboratoire de Synthe`ses et Activations de Biomole´cules, CNRS UMR 6052, Avenue du Ge´ne´ral Leclerc,
35700 Rennes, France
Received 15 March 2003; revised 21 June 2003; accepted 21 June 2003
Abstract—(bda)Fe(CO)3 and (COT)Fe(CO)3 are shown to be excellent catalysts for the tandem isomerization–aldol reaction of
allylic alcohols with aldehydes and to significantly increase the scope of this aldolization process, especially, in the case of sterically
hindered aldehydes.
© 2003 Elsevier Ltd. All rights reserved.
The aldol reaction is a fundamental process for the
creation of CꢀC bonds.1 We have discovered recently a
novel approach to this reaction via a tandem isomeriza-
tion–aldolization of allylic alcohols, mediated by transi-
tion metal catalysts.2 Following a known process,3 the
allylic alcohol is isomerized by the catalyst into a
complexed enol and/or transition metal enolate which
can be trapped in situ by an aldehyde to give the aldol
adduct (Scheme 1).2 This new aldol type reaction is a
complete atom economy process which furthermore
occurs under mild and neutral conditions.
aldols 3 with small amounts of the regioisomers 4 and
ketones 5 (Scheme 2). However, some limitations have
been recognized, especially with sterically hindered car-
bonyls affording low yields of aldol products. In order
to improve this new reaction, experiments in different
directions have been already reported. A first possibility
was the extension to other metals: rhodium as well as
ruthenium catalysts proved to be completely regioselec-
tive, however, with a more limited scope for the addi-
tion.4 The latter approach could also be combined with
the use of other solvents such as water or ionic liquids,
however with similar results.5
As a first example, Fe(CO)5 proved to be a versatile
catalyst for this reaction, allowing addition of various
types of allylic alcohols 1 with aldehydes 2: at only 2–5
mol% and under irradiation, it afforded mainly the
For the iron carbonyl mediated reaction a mechanism
has been proposed, where Fe(CO)3 was postulated to be
the active catalytic species.2 Therefore, in order to
improve this reaction another attractive possibility was
to screen various iron carbonyl complexes (Fig. 1). We
report here our results establishing that (bda)Fe(CO)3
and (COT)Fe(CO)3 are efficient catalysts that further
extend the scope of this tandem isomerization–aldoliza-
tion reaction.
Scheme 1.
Scheme 2.
* Corresponding author. Tel.: +33-(0)2-2323-8070; fax: +33-(0)2-2323-8108; e-mail: rene.gree@ensc-rennes.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01556-9

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R. Uma et al. / Tetrahedron Letters 44 (2003) 6187–6190
Scheme 3.
a well known Fe(CO)3 donor under thermal conditions,
Figure 1.
an attractive hypothesis to explain this result would be
the presence of a higher energy step requiring photo-
chemical activation in the reaction pathway.10 Although
this mechanistic point needs further studies, it is possi-
ble to conclude that (bda)Fe(CO)3 appears as a useful
alternative catalyst for this reaction.
As (bda)Fe(CO)3 is a well known Fe(CO)3 donor,6 we
first tried it as a catalyst. The results are given in Tables
1 and 2. The irradiation7 of a THF solution of the
allylic alcohol and the aldehyde in the presence of the
catalyst at 5 mol% gives good isolated yields of the
mixture of the aldols with a good regioselectivity but a
low diastereoselectivity.8 Ketone 5 is also isolated,
albeit in low yield. The reaction is compatible with the
presence of alkyl substituents on both positions of the
double bond as well as with different side chains in the
allylic alcohol moiety. It is particularly interesting to
note that the reaction is compatible with different alde-
hydes, including one with an amide nitrogen atom
(entry e, Table 1). It can also be observed that the
reaction of allylic alcohol 6a (Scheme 3, Table 2) gives
the two aldols with a good diastereomeric ratio (ꢀ6/1)
and good yields, even with the sterically hindered
isobutyraldehyde (entry b).
Next, we investigated the reactivity of (COT)Fe(CO)3.
This complex has been the subject of in-depth physico-
chemical studies (structure and fluxional behavior for
instance), as well as reactivity studies.11 However, to the
best of our knowledge, it has never been reported as a
Fe(CO)3 transfer agent. Therefore, we first screened
different aldehydes, octen-3-ol being taken as the model
allylic alcohol (Table 3). A remarkable increase of the
reactivity, as compared to Fe(CO)5, was observed: with
only 2–4 mol% of the catalyst, the reaction is complete
within 20–60 minutes and the aldols are obtained in
good yields, even in the case of very bulky aldehydes. It
is important to note that under Fe(CO)5 catalysis only
low yields (<20%) of aldols were obtained with cyclo-
hexane carboxaldehyde or isobutyraldehyde for
instance.2 When (COT)Fe(CO)3 is used, the corre-
sponding aldols are isolated in ca. 63% yield (entries d
and e, Table 3). However, the diastereoselectivity
remains similar to that obtained with Fe(CO)5 as the
catalyst. Furthermore, it is particularly interesting to
note that the reaction of aldehydes bearing an isolated
double bond occurs with no bond shift, as shown by
It can be noted that, in most cases, the isolated yields
are higher than those obtained when Fe(CO)5 is used as
a catalyst. Finally, it is important to underline that this
tandem isomerization–aldolization is not observed
when (bda)Fe(CO)3 is used under thermal reaction
conditions;9 therefore, irradiation is necessary for the
reaction to occur, as it was previously established for
the reaction catalyzed by Fe(CO)5. As (bda)Fe(CO)3 is
Table 1. Tandem isomerization–aldolization condensation of alcohol 1 using bdaFe(CO)3 as the catalyst
Entry
R
R1
R2
Time (min)
3+4 (yield %)
3+4 Fe(CO)5 as cat.2
3syn/3anti/4/4%
5 (yield %)
a
b
c
d
e
Ph
Ph
Ph
H
Me
H
H
H
H
H
40
75
91
70
85
62
58
74
46
73
49/46/3/2
57/32/7/4
90/–/6/4
5
15
5
Me 120
H
H
(Me)2CH
p-AcNHPh
120
90
<20
61/32/4/3
17
37/60/3<1b
a
a Unknown.
b Ratio calculated on the mixture after chromatography.
Table 2. Tandem isomerization–aldolization condensation of alcohols 6a and 6b using bdaFe(CO)3 as the catalyst
Entry
R
R1
Time (min)
7 (yield %)
7 Fe(CO)3 as cat.2
7syn/anti
8 (yield %)
a
a
b
c
Ph
(Me)2CH
Ph
C(Me)2COOEt
C(Me)2COOEt
Ph
60
240
90
83
70
74
73
86/14
86/14
39/61
a
12
12
73
a Unknown.

R. Uma et al. / Tetrahedron Letters 44 (2003) 6187–6190
6189
Table 3. Tandem isomerization–aldolization condensation of alcohol 1 using (COT)Fe(CO)3 as the catalyst
Entry
R
R1
R2
Cat. (%)
Time (min)
3+4 (yield %)
3+4 Fe(CO)5
3syn/3anti/4/4%
5 (yield %)
as cat.2
a
b
c
d
e
f
g
h
i
Ph
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
2
4
3
3
3
3
4
5
5
5
20
45–60
35
35
35
84
84
72
63
64
36
78
54
74
64
54
<20
<20
64/28/5/3
94/–/6
12
9
Me2CHCH2
Me2CH
Cy
63/27/5/5
53/34/7/6
59/35/4/2
65/33/2/–
55/36/5/4
57/36/4/3
19
27
27
42
6
a
Et2CH
35
a
a
EtCHꢁCH(CH2)2
p-AcNHPh
Ph
180
180
4 h
4 h
4
<20% conv.
<20% conv.
46
73
j
Ph
a Unknown.
the reaction with 5-hepten-1-al (entry g, Table 3). Next
we studied the reactions starting from various allylic
alcohols. We observed that they did not go to comple-
tion (<20% conversion) when an alkyl substituent is
present on the double bond (entries i and j, Table 3).
The same fall in reactivity was observed starting from
alcohol 6a: an NMR control after 4 h of reaction
establishes the ketone as the major product whereas a
ꢀ7/3 ratio of allylic alcohol/aldols is obtained. We can
conclude that (COT)Fe(CO)3 gives better results than
Fe(CO)5 in the case of bulky aldehydes but is inefficient
in the case of bulky allylic alcohols.
References
1. Comprehensive Organic Synthesis, Additions to CꢀX y
bonds; Heathcock C. H., Ed.; Pergamon Press: Oxford,
1991; Vol. 2, Part 2, pp. 99–319.
2. Cre´visy, C.; Wietrich, M.; Le Boulaire, V.; Uma, R.;
Gre´e, R. Tetrahedron Lett. 2001, 42, 395.
3. (a) van der Drift, R. C.; Bowman, E.; Drent, E. J.
Organomet. Chem. 2002, 650; (b) Uma, R.; Cre´visy, C.;
Gre´e, R. Chem. Rev. 2003, 103, 27.
4. Uma, R.; Davies, M.; Cre´visy, C.; Gre´e, R. Tetrahedron
Lett. 2001, 42, 3069.
5. (a) Wang, M.; Li, C.-J. Tetrahedron Lett. 2002, 43, 3589;
(b) Yang, X.-F.; Wang, M.; Varma, R. S.; Li, C.-J. Org.
Lett. 2003, 5, 657.
Next, we investigated the structurally close
(CHD)Fe(CO)3: the reaction could be completed only
when unsubstituted allylic alcohols (such as 1a) and
reactive aldehydes (e.g. PhCHO) were used. Therefore,
this iron complex can not be used for this transforma-
tion. Although the results obtained with (COT)Fe(CO)3
and (CHD)Fe(CO)3 indicate that these catalysts are
probably not acting as simple Fe(CO)3 donors under
the reaction conditions, the origin of the change in
reactivity remains to be elucidated.
6. Howell, J. A. S.; Johnson, P. L.; Lewis, J. J. Organomet.
Chem. 1972, 39, 329.
7. Representative experimental procedure: In a two-necked
pyrex flask was placed (COT)Fe(CO)3 (2–4 mol%) under
nitrogen. Dry THF (8 mL), allylic alcohol (1 mmol) and
freshly distillated aldehyde (1.2 mmol) were added
sequentially. The reaction mixture was irradiated with a
Philips HPK 125 W lamp until disappearance of the
allylic alcohol. The reaction mixture was filtered through
silica gel (7 g) and purified by chromatography to afford
ketone and subsequently the aldol products. Most of the
diastereomers were separated and fully characterized. All
diastereomeric mixtures of aldol products gave spectra
In conclusion, we have investigated three new iron
catalysts in the tandem isomerization–aldol condensa-
tion of allylic alcohols. Two of them, (bda)Fe(CO)3 and
(COT)Fe(CO)3, show higher reactivity compared to the
previously used Fe(CO)5. In particular, (COT)Fe(CO)3
appears especially useful in the challenging case of
bulky aldehydes. Furthermore, we have also demon-
strated that both catalysts can perform the reaction
with aldehydes bearing either a protected nitrogen atom
or an isolated double bond. The third one,
(CHD)Fe(CO)3 is less reactive. So we have developed
two alternate catalysts that significantly extend the
scope of this tandem isomerization–aldol condensation.
We are currently studying the mechanism of these
reactions, as well as some applications to the synthesis
of natural products and structural analogues.
(IR, H, 13C NMR) consistent with their assigned struc-
ture and satisfactory high resolution mass measurement
and/or combustion analysis.
1
1
8. The regio- and stereomeric ratios were established by H
or/and 13C NMR on the crude mixture.2 The relative
configurations were established according to Ref. 2 and
to the following empirical rule: the C of the CHOH
group is deshielded in the anti adduct compared to the
syn adduct and the H of the CHOH group is shielded in
the anti adduct compared to the syn adduct.
9. At 80°C in toluene, neither aldol condensation nor iso-
merization was observed starting from 1a (R1=R2=H)

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R. Uma et al. / Tetrahedron Letters 44 (2003) 6187–6190
Ph) for 1.5 h at 110°C. However, in the presence of
and PhCHO. After 3 h at higher temperature (110°C),
catalytic bdaFe(CO)3,
observed.
11. The Organic Chemistry of Iron; Koerner Von Gustorf, E.
A.; Grevels, F.-W.; Fischler, I., Eds.; Academic Press:
New York, 1978; Vol. 1 and references cited therein.
a fast retroaldolization was
only a partial conversion (ꢀ50%) to the ketone was
observed, without any evidence (TLC, NMR) for the
aldol products.
10. It is worth noting that no (or very little, <10%) retroaldol
reaction was observed on heating 3a (R1=R2=H, R=