Synthesis of (E)-α,β-unsaturated ketones with total or high diastereoselectivity by using samarium diiodide or triiodide

Article abstract of DOI:10.1016/S0040-4039(03)00079-0

(E)-α,β-Unsaturated ketones are obtained by reaction of α-chloro-β-hydroxy ketones with samarium diiodide or with samarium triiodide with total or high diastereoselectivity and in good yield.

Full text of DOI:10.1016/S0040-4039(03)00079-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1931–1934
Synthesis of (E)-a,b-unsaturated ketones with total or high
diastereoselectivity by using samarium diiodide or triiodide
Jose´ M. Concello´n* and Mo´nica Huerta
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo, Julia´n Claver´ıa, 8, 33071 Oviedo,
Spain
Received 5 November 2002; accepted 5 January 2003
Abstract—(E)-a,b-Unsaturated ketones are obtained by reaction of a-chloro-b-hydroxy ketones with samarium diiodide or with
samarium triiodide with total or high diastereoselectivity and in good yield. © 2003 Elsevier Science Ltd. All rights reserved.
The diastereoselective synthesis of a,b-unsaturated
ketones has been extensively developed due to their
synthetic applications.1
samarium diiodide, and in just a few cases roughly 1:1
mixtures of 2 and 3 were obtained.
Surprisingly, a,b-unsaturated ketones 3 were obtained
by using 1 equiv. of SmI2 (Scheme 1). Thus, when a
solution of 1 equiv. of SmI2 in THF was added to
several a-chloro-b-hydroxy ketones 1 at −25°C and
then heated at reflux, the corresponding a,b-unsatu-
rated ketones 3 were isolated, after hydrolysis, with
total or high diastereoselectivity and in high yield.
Transformation was complete after 1 h at reflux.14
Several procedures have been described for the general
synthesis of these compounds2 such as condensation,3
oxidation,4 elimination5 and acylation6 reactions, and
by insertion of carbon monoxide,7 among others. How-
ever an alternative synthesis of a,b-unsaturated ketones
simple, general and highly diastereoselective would still
be desirable.
Recently, we have described a new diastereoselective
b-elimination reaction promoted by samarium diiodide.
In this sense we have reported several obtentions of
functionalized alkenes, such as (Z)-vinyl halides,8 a,b-
unsaturated esters,9 a,b-unsaturated amides,10 (Z)-
The starting ketones 1a–d were easily obtained by
reaction of the corresponding potassium enolate of 4
[generated by treatment of the starting ketone 4 (a-
vinylsilanes,11
and
a,d-dideuterio-b,g-unsaturated
esters.12 Here, we wish to report a new preparation of
a,b-unsaturated ketones with total diastereoselectivity
by treatment of the easily available a-chloro-b-hydroxy
ketones with solutions of samarium diodide or triiodide
in THF.
Scheme 1.
Our first attempts were carried out to establish the
reaction conditions of the b-elimination process. Thus,
several a-chloro-b-hydroxy ketones 1, were treated with
a solution of 2.5 equiv. of SmI2 in THF at room
temperature.13 However, 3-hydroxy ketones 2 were iso-
lated instead of a,b-unsaturated ketones 3. The same
products 2 were obtained performing the reaction at
several temperatures and with different amount of
* Corresponding author. Tel.: +34-985-103457; fax: +34-98-510-3446;
e-mail: jmcg@sauron.quimica.uniovi.es
Scheme 2.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00079-0

1932
J. M. Concello´n, M. Huerta / Tetrahedron Letters 44 (2003) 1931–1934
chloroacetophenone or 1-bromopinacolone) with potas-
sium hexamethyldisilazide (KHMDS) at −78°C] with
different aldehydes, at temperatures ranging from −78
to 25°C; further treatment of the obtained epoxyke-
aliphatic (linear or cyclic) or aromatic, or it can contain
other double bonds CꢀC (entry 7).
The observed results and the stereochemistry of prod-
ucts 3 may be explained (Scheme 4) by assuming two
mechanisms for each starting diastereoisomer. In both
cases the reaction is initiated by traces of SmI3, present
in the solution of SmI2 in THF. For the anti
diastereoisomer, dissociation of SmI3 produces iodide
and cationic species of samarium diiodide(III). Forma-
tion of a chelated species between the hydroxyl, SmIII,
and oxygen atom of the carbonyl group produces a
six-membered ring and increases the ability of the
hydroxyl group as a leaving group.18 Tentatively we
propose a chair transition state model I with an equato-
rial R2 group (to avoid 1,3-diaxial interactions). Elimi-
nation from I affords (E)-a,b-unsaturated ketones 3.
tones
5 with chlorotrimethylsilane (TMSCl) and
dimethylsulphoxide (DMSO),15 afforded compounds
1a–d (Scheme 2). Compounds 1a–c and 1e can be also
obtained by reaction of the potassium or lithium eno-
late of a-chloroacetophenone 4 (generated from a-
chloroacetophenone 4 and KHMDS or LDA at −85°C)
with different aldehydes and further hydrolysis at
−85°C16 (Scheme 2). Compounds 1f and 1g were pre-
pared by reaction of the ester 6 with bromochloro-
methyllithium obtaining the 1-bromo-1-chlorohexan-2-
one 7, which was treated with the corresponding alde-
hyde in the presence of Zn/CuBr/Et2AlCl (Scheme 3)17
yielding the halohydrin as a 1:1 two diastereoisomer
mixture.
For the syn diastereoisomer, iodide (from the SmI3
dissociation) could substitute the chloro atom, previ-
ously to the elimination, to obtain the anti diastereoiso-
mer with the appropriate conformation for
coordination of the samarium center with the two
oxygen atoms. Supporting this substitution reaction, in
some cases, iodoacetophenone and aldehyde (retroal-
dolic reaction) have been characterized in the crude
reaction.
The diastereoisomeric excess was determined on the
crude reaction products by H NMR spectroscopy (300
1
MHz) and GC–MS, showing the presence of a single
diastereoisomer (except compound 3g). The E stereo-
chemistry in the double bond CꢀC of a,b-unsaturated
ketones 3 was assigned on the basis of the value of their
1H NMR coupling constant between the olefinic pro-
tons (J$15 Hz).
It is noteworthy that although 1:1 mixtures of
diastereoisomers 1 were used in some cases, the corre-
sponding a,b-unsaturated ketones 3 were obtained with
total diastereoselectivity.
The remaining SmI2 reacts with the obtained ClI or I2
generating halides of Sm(III), which continue the indi-
cated b-elimination reaction. Indirect support for the
proposed mechanism is provided by the observed
appearance of I2 and/or ICl in the crude reaction.
This proposed methodology to obtain a,b-unsaturated
ketones is quite general (Table 1): R1 can be aromatic
or aliphatic (linear or branched) and R2 can be
To prove that the b-elimination is promoted by species
of Sm(III), the same reaction was carried out by using
Scheme 3.
Table 1. Synthesis of (E)-a,b-unsaturated ketones 2
SmI2
deb
SmI3
Entry
Product
R1
R2
Yielda
Yielda
deb
1
2
3
4
5
6
7
3a
3b
3c
Ph
Ph
Ph
t-C4H9
Ph
n-C4H9
n-C7H15
Cyclohexyl
n-C4H9
Ph
96
98
67
65
73
82
76
\98
\98
\98
\98
\98
\98
84
72
91
72
58
80
70
\98
\98
\98
\98
\98
\98
–
3d
3ec
3f
n-C4H9
n-C4H9
Ph
3gd
(E)-CHꢀCHPh
–
e
a Isolated yield after column chromatography based on the starting carbonyl compound 1.
b de determined by 300 MHz 1H NMR spectroscopy and GC–MS analysis on the crude product.
c The starting compound 1e was prepared by reaction of the lithium enolate (from 2-chloroacetophenone and lithium diisopropylamide at −85°C)
and benzaldehyde.
d This elimination reaction was performed at −25°C overnight.
e No reaction by using SmI3 was carried out.

J. M. Concello´n, M. Huerta / Tetrahedron Letters 44 (2003) 1931–1934
1933
Scheme 4.
SmI3 (obtained from metallic samarium and iodine19).
Thus, treatment of ketones 1a–f with a solution of 1
equiv. of SmI3 in THF at −25°C for 2 h and later at
reflux for 1 h, afforded (E)-a,b-unsaturated ketones 3
with total diastereoselectivity20 (Table 1).
5. (a) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem.
Soc. 1975, 97, 5434–5447; (b) Resek, J. E.; Meyers, A. I.
Tetrahedron Lett. 1995, 36, 7051–7054; (c) Schwarz, I.;
Braun, M. Chem. Eur. J. 1999, 5, 2300–2305.
6. (a) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem.
1983, 48, 4634–4642; (b) Mitchell, T. N. Synthesis 1992,
9, 803–815.
7. Negishi, E.; Swanson, D. R.; Cederbaum, F. E.; Taka-
hashi, T. Tetrahedron Lett. 1987, 28, 917–920.
8. Concello´n, J. M.; Bernad, P. L.; Pe´rez-Andre´s, J. A.
Angew. Chem. 1999, 111, 2528–2530; Angew. Chem., Int.
Ed. 1999, 38, 2384–2386.
9. (a) Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodr´ıguez-
Solla, H. Angew. Chem. 2000, 112, 2866–2868; Angew.
Chem., Int. Ed. 2000, 39, 2773–2775; (b) Concello´n, J.
M.; Bardales, E. Org. Lett. 2002, 4, 189–191.
10. Concello´n, J. M.; Pe´rez-Andre´s, J. A.; Rodr´ıguez-Solla,
H. Chem. Eur. J. 2001, 7, 3062–3068.
When the reaction was carried out by using two equiv.
of SmI2, the metallation of the chloro atom can take
place, giving an enolate II, which is hydrolyzed by the
proton of the alcohol group (III), yielding, after hydrol-
ysis, the b-hydroxyketone 2.21
In conclusion, an easy, simple and general methodology
has been developed to synthesize a,b-unsaturated
ketones with total E-diastereoselectivity from the easily
available 2-halo-3-hydroxy ketones, the reaction being
promoted by samarium triiodide.
11. Concello´n, J. M.; Bernad, P. L.; Bardales, E. Org. Lett.
2001, 3, 937–939.
Acknowledgements
12. Concello´n, J. M.; Bernad, P.; Rodr´ıguez-Solla, H. Angew.
Chem. 2001, 113, 4015–4017; Angew. Chem., Int. Ed.
2001, 40, 3897–3899.
13. a,b-Unsaturated esters or amides were obtained from
2-chloro-3-hydroxyesters or amides and samarium diio-
dide by using these reaction conditions.
14. Over a solution of the starting a-chloro-b-hydroxyketone
1 (0.4 mmol) in dry THF (2 ml) a solution of samarium
diiodide [prepared from 0.069 g of Sm (0.4 mmol), 5 ml
of dry THF and 0.032 ml of CH2I2] was added dropwise
at −25°C. The reaction mixture was stirred at the same
temperature over 2 h and then heated at reflux for 1
additional hour (the color changed from yellow to
orange). The reaction mixture was quenched with 5 ml of
0.1 M HCl and the usual workup gave the crude a,b-
unsaturated ketone. Purification by flash column chro-
matography over silica or by distillation afforded the
pure compound 3.
We thank III Plan Regional de Investigacio´n del Princi-
pado de Asturias (PB-EX01-11) and Ministerio de Edu-
cacio´n y Cultura (BQU2001-3807) for financial support.
J.M.C. thanks Carmen Ferna´ndez-Flo´rez for her time.
M.H. thanks to Ministerio de Educacio´n, Cultura y
Deporte for a predoctoral fellowship. Our thanks to
Robin Walker for his revision of the English.
References
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1934
J. M. Concello´n, M. Huerta / Tetrahedron Letters 44 (2003) 1931–1934
16. When 1a–c were prepared from epoxyketones 4 only
the anti diastereoisomer was obtained, while both
19. Imamoto, T.; Kutsumoto, T.; Yokoyama, M. J. Chem.
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two diastereoisomers, as
were isolated when 1a–d were obtained by aldol conden-
sation.
a
mixture roughly 1:1,
20. 0.4 mmol of the starting ketone were treated with a
solution of 0.4 mmol of samarium triiodide (0.069 g of
Sm, 5 ml of dry THF and 0.150 g of I2) at −25°C during
2 h and later heated at reflux by 1 additional hour. The
reaction was quenched with 5 ml of 0.1 M HCl, extracted
with dichloromethane and concentrated. Purification by
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the pure enone 3.
21. This intramolecular hydrolysis was previously observed
in the transformation of 2-chloro-3-hydroxyesters into
a,b-unsaturated esters, in which the double bond CꢀC is
tetrasubstituted: see Ref. 9a.
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