From allylic alcohols to aldols via a novel, tandem isomerization-condensation catalyzed by Fe(CO)5

Article abstract of DOI:10.1016/S0040-4039(00)02000-1

Allylic alcohols react with aldehydes, in the presence of catalytic amounts of Fe(CO)₅ and under irradiation, to give mainly aldol products. A small amount of ketone resulting from the classical isomerization process is also isolated. This new aldol-type reaction is a complete atom economy process occurring under neutral conditions.

Full text of DOI:10.1016/S0040-4039(00)02000-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 395–398
From allylic alcohols to aldols via a novel, tandem
isomerization–condensation catalyzed by Fe(CO)5
Christophe Cre´visy, Marina Wietrich, Virginie Le Boulaire, Ramalinga Uma and Rene´ Gre´e*
Laboratoire de Synthe`ses et Activations de Biomole´cules, associe´ au CNRS, ENSCR, Avenue du Ge´neral Leclerc,
35700 Rennes Beaulieu, France
Received 6 October 2000; accepted 30 October 2000
Abstract—Allylic alcohols react with aldehydes, in the presence of catalytic amounts of Fe(CO)5 and under irradiation, to give
mainly aldol products. A small amount of ketone resulting from the classical isomerization process is also isolated. This new
aldol-type reaction is a complete atom economy process occurring under neutral conditions. © 2001 Elsevier Science Ltd. All
rights reserved.
The aldol condensation is a fundamental process for
the CꢀC bond formation. Extensive studies on the
reaction conditions,1 the nature of metal and ligands
have led in many cases to excellent regio- and stereo-
control in this reaction.2 However, it is important to
note that most of these procedures use, at some stage,
strongly basic or acidic conditions. The extension to
middle- and late transition metal enolates appeared
more recently. Noteworthy are the seminal studies by
Bergman and Heathcock3 and the recent developments
in asymmetric synthesis.4 Such derivatives are usually5
prepared by reaction of standard metal enolates with
transition metal halides. More recently,
a
new
approach6 based upon the known transition metal me-
diated isomerization of allylic alcohols to saturated
carbonyl derivatives7 was developed. Using appropriate
Rh and Ni based catalysts, allylic alcoholates have been
isomerized to corresponding enolates, followed by aldol
reactions.6 However, this attractive procedure still oc-
curs under strongly basic conditions.
Scheme 1.
Table 1.
Entry
RCHO
2+3 (yield %)
4 (yield %)
2 syn/2 anti/3/3%
1
2
3
4
5
6
PhCHO
HCHO (anh.)
CH3CHO
PhCH2CHO
(iPr)2CHCHO
5-Acetoxymethyl-2-furaldehyde
74
65
73
73
54
79
6
60/29/6.5/4.5
95/ /5
66/23/7/3.5
64/24/8/4
62/28/7/3
59/31/7/3
18
14
7
28
12
Keywords: aldols; catalysts; transition metals.
* Corresponding author. Tel: +33 (0)2 99 87 13 83; fax: +33 (0)2 99 87 13 84; e-mail: rene.gree@ensc-rennes.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02000-1

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C. Cre´6isy et al. / Tetrahedron Letters 42 (2001) 395–398
Scheme 2.
Scheme 3.
Table 2.
Entry
Alcohol
Aldehyde
8+9 (yield)
10 (yield)
8 syn/8 anti/9/9%
1
2
3
4
7a
7a
7b
7b
R=Ph
R=CH3
R=Ph
46
53
73
55
18
24
5
50/38/6/4
62/28/6/4
86//7/7
R=CH3
7
83//14/3
For iron carbonyl mediated isomerization of allylic
alcohols, labeling studies have established a mechanism
via p-allyl and enol intermediates.8 Trapping of such
intermediates (or compounds derived from them) could
lead to derivatives equivalent to aldol adducts.9 In this
communication, we report our preliminary results
demonstrating the feasibility of this conceptually ap-
pealing strategy. A range of allylic alcohols readily
reacted with a variety of aldehydes, in the presence of
catalytic amounts (2–5%) of Fe(CO)5 and under irradi-
ation, to afford the corresponding aldol products in
good yield. Additionally, small amounts of ketone re-
sulting from the competitive isomerization reaction
were also isolated.
Diastereoselective anti reduction of 2a and 2b,14 fol-
lowed by acetonide formation gave 5 and 6 (35% yield,
Scheme 2). Comparison of their NMR data with re-
lated compounds15 indicated that 2a is the syn aldol
while 2b is the anti.
It is worth noting that 2a and 2b are stable under the
reaction conditions (neither reversibility nor epimeriza-
tion were observed). Furthermore, 4 does not react with
benzaldehyde under these conditions.
This reaction could be extended to various aliphatic
and heterocyclic aldehydes. In each case, small amounts
of regioisomeric aldols and ketones were also obtained
(Table 1). This reaction does not require moisture free
conditions as exemplified by the result (47% yield)
obtained using formaldehyde solution (37% in H2O).
However, lower yields (10–20%) were obtained for
sterically hindered aldehydes such as cyclohexane carb-
oxaldehyde and isovaleraldehyde with significant
amount of ketone 4.
Allylic alcohol 1, efficiently isomerized under iron catal-
ysis,10 was chosen for the preliminary studies. Irradiat-
ing a pentane solution of 1 and benzaldehyde in the
presence of 2 mol% of Fe(CO)5 readily furnished the
expected aldols 2 along with a small amount of their
regioisomers 3 in 74% yield (2+3). The ketone 4 (6%)
resulting from the isomerization of 1 was also isolated
(Scheme 1 and Table 1, entry 1).11
The regio- and stereoisomeric ratios were established by
13C NMR on the crude reaction mixture.12 A ratio of
60/29/6.5/4.5 was obtained for 2a, 2b, 3a, 3b. Authentic
samples of 2 and 3 were obtained by a classical aldol
condensation between 3-octanone and benzaldehyde,13
however, in very different ratios (29/28/15/28).
Scheme 4.

C. Cre´6isy et al. / Tetrahedron Letters 42 (2001) 395–398
397
Scheme 5.
complexed aldol 21 which could afford aldol 22 and
regenerate the catalyst. While an open transition state
can be speculated for this aldol reaction, a Zimmer-
mann–Traxler cyclic transition state appears more
likely since the 16 electron species 20 has a vacant
orbital ready for coordination to the carbonyl oxygen
atom. The minor amount of regioisomeric products (3,
9), observed when R=CH2R%, could be accounted by a
further 1,3-shift of 17 to 23 which would lead to a
regioisomeric iron enolate.
We then investigated the extension to allylic alcohols
substituted on the double bond (Scheme 3, Table 2).
While we were gratified to note that both 1,2 and 1,1
disubstituted alcohols 7a and 7b underwent facile con-
densation, the former gave slightly lower aldol/ketone
ratios (Table 2). The reaction of compound 7b is partic-
ularly interesting as the new CꢀC bond is formed on the
more hindered side, leading to quaternary centers. Such
regiocontrol is usually not observed under the classical
aldolization reaction conditions.1
In conclusion, we have demonstrated that iron enolates
generated catalyticaly from allylic alcohols can be
trapped efficiently in an aldol type process. Though the
regio- and stereoselectivity can be further improved,
this novel catalytic process appears very attractive since
it occurs under neutral conditions and complies with
total atom economy. We have also studied the exten-
sion to other transition metal complexes and this will be
reported in due course. Theoretical studies concerning
the mechanism is also being actively pursued.
Finally, replacement of pentyl chain by another group
was also studied (Scheme 4). The reaction of phenyl
substituted derivative 11a gave a mixture of aldols 12a
(73% yield, syn/anti: 58/42) with a small amount (10%)
of ketone 13a.16 The sterically hindered alcohol 11b is
especially interesting since it gave aldols 12b not only in
good yield (73%) but also with an excellent
diastereoselectivity16 (syn/anti: 87/13). Ketone 13b was
also isolated (20%).
A tentative mechanistic proposal can be made for this
reaction (Scheme 5). Initial complexation of iron car-
bonyl to allylic alcohol 14 results in an h2 complex 15
which undergoes a well-documented8 1,3-hydride mi-
gration to afford the enol 18 through the intermediacy
of 16 and 17. Then, the key step for this new reaction
would be the transformation of the p complex 17 to the
s complexed enol 20, possibly under irradiation.17
There is ample literature precedence for s–p equilibria
in various transition metal enolates.18 Furthermore, a
catalytic process starting from silyl enol ethers under
UV light irradiation has been demonstrated for the
preparation and reaction of rhodium enolates.3 This
key intermediate 20 can react with aldehydes to give the
Acknowledgements
We thank P. Guenot (CRMPO Rennes) for performing
the mass-spectra experiments and CNRS for a research
associate position to R.U.
References
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C. Cre´6isy et al. / Tetrahedron Letters 42 (2001) 395–398
2. For recent reviews on enantioselective aldol additions,
11. Representative experimental procedure: To a pentane
solution (10 ml) of octen-3-ol 1 (500 mg, 3.9 mmol) in 25
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(800 ml, 7.8 mmol). Argon was bubbled (10 min) through
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mmol). The reaction mixture was irradiated with a
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1
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.