A useful synthetic equivalent of an acetone enolate

Article abstract of DOI:10.1016/j.tetlet.2009.09.113

2-Methoxymethoxy-3-chloropropene derived organometallics act as synthetic equivalents of an acetone enolate. Indium-promoted reaction of this reagent with aldehydes affords aldol adducts in moderate to excellent yields. When the reaction was performed wit

Full text of DOI:10.1016/j.tetlet.2009.09.113

Tetrahedron Letters 50 (2009) 6709–6711
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Tetrahedron Letters
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A useful synthetic equivalent of an acetone enolate
Veselin Maslak a, Zorana Tokic-Vujosevic b, Zorana Ferjancic a, Radomir N. Saicic a,
*
a Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia
b Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2009
Revised 8 September 2009
Accepted 18 September 2009
Available online 24 September 2009
2-Methoxymethoxy-3-chloropropene derived organometallics act as synthetic equivalents of an acetone
enolate. Indium-promoted reaction of this reagent with aldehydes affords aldol adducts in moderate to
excellent yields. When the reaction was performed with zinc, aldol products were isolated in protected
form as the corresponding MOM-enol ethers.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Allylation
Aldehydes
Indium
Zinc
Aldol reaction
Water
The aldol reaction is an important tool for carbon–carbon bond
formation in synthetic organic chemistry. This reaction allows for
high levels of chemo-, regio-, diastereo- and enantioselectivity in
the coupling of structurally complex reaction partners.1 Ironically,
the use of small, structurally simple proenolates can cause prob-
lems. Thus, acetone enolate is very difficult to be preformed, due
to its high basicity and reactivity; therefore, aldol reactions of ace-
tone are almost always performed under thermodynamic condi-
tions. In most cases, the products of aldol condensation, that is,
enones, are obtained, although a few examples are known where
aldol adducts were isolated.2 Under conventional experimental
conditions, reactions with aromatic or conjugated aldehydes al-
ways produce Claisen–Schmidt-type products.3 A major break-
through was the introduction of organocatalysis, which enabled
the enantioselective aldol additions of acetone (and the related
proenolates) to both aliphatic and aromatic aldehydes.4 Recently,
aldolase antibodies have been shown to efficiently catalyze aldol
additions of acetone.5 However, mechanistically different comple-
mentary methods for effecting this transformation are still re-
quired.6 It would also be desirable to obtain the aldol adduct in
either free or latent (protected) form, by slight modification of
the reaction conditions.
OPG
M
OH O
R-CHO
R
OPG
O
M
Scheme 1. Allylmetal as a synthetic equivalent of the acetone enolate.
is a well-known reaction, and the use of oxygenated allyl frag-
ments is not without precedent.7,8 However, the oxygen-contain-
ing substituents have always been bound to the terminal
positions of the allylic fragment.9 The use of 2-oxy-substituted
allylmetallics, which would give rise to aldol-type products, has
been far less investigated, maybe due to the anticipation of elimi-
nation of the oxy-substituent at the b-position with respect to the
metal. To the best of our knowledge, only two such reactions have
been reported: the first is the reaction of an 2-acetoxy-3-chloro-
propene-derived organostannane with aldehydes, which produces
a mixture of the expected aldol and the corresponding enol ace-
tate.10 The second example involves the reaction of a methoxy-
substituted allylindium reagent with aldehydes, a procedure which
was used as a synthetic equivalent of the Knoevenagel condensa-
tion.11 We set out to explore the possibility of using 2-methoxyme-
thoxy-3-chloropropene-derived organometallics as acetone
enolate synthons. Interestingly, the parent compound has already
been used as an electrophilic synthetic equivalent of acetone,
With this in mind we considered the allylation of aldehydes as
an alternative approach for effecting the aldol reaction of acetone
(Scheme 1). Indium- or zinc-mediated allylation of carbonyl groups
* Corresponding author. Tel./fax: +381 11 32 82 537.
E-mail address: rsaicic@chem.bg.ac.rs (R.N. Saicic).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.113

6710
V. Maslak et al. / Tetrahedron Letters 50 (2009) 6709–6711
Table 1
Table 2
Indium-mediated reactions of 2-methoxymethoxy-3-chloropropene with aromatic
aldehydes
Indium-promoted reactions with aliphatic aldehydes
Entry Carbonyl compound
Product
Yielda
(%)
OMOM
OH O
Cl
In,
OH O
CHO
1
50
(60)
ArCHO
n-C11H23
Ar
n-C11H23
THF, H2O
Entry
1
Aldehyde
Product
Yield (%)
70
2
59
85
OH O
CHO
CHO
OH O
OH O
CHO
3
n-C6H13
-C H
6 13
n
OH O
CHO
OH
CHO
OH O
2
3
4
5
66
93
69
73
4
40
57
OH
OH O
CHO
OMe
OH O
5
BnO CHO
BnO
O
NHBoc
OMe
NHBoc
6
35b
(45)
CO2Et
OAc
OH O
OHC
OHC
CO2Et
OAc
CHO
OH
Cl
O
OH
Cl
O
OH O
7
8
9
96
CHO
O
O
OAc
O
O
OAc
OAc
O
OAc
O
S
37b
(59)
6
7
99
97
CHO
CHO
S
O
O
OH O
OMs
HO
O
OMs
CHO
O
DMSO
O
DMSO
O
O
O
OH O
O
O
OH
CO2Et
87
CO2Et
which effects acetonylation of both carbon- and heteroatom-cen-
tered anionic species.12
a
Yield of isolated, pure compounds; yields in parentheses are calculated on the
basis of recovered starting compounds.
b
Our first experiment comprised indium-mediated reaction of 2-
methoxymethoxy-3-chloropropene with benzaldehyde, under Bar-
bier conditions.13 Pleasingly, the aldol product was obtained in a
good yield (Table 1, entry 1). It is of note that the product was ob-
tained as the free aldol: this indicates that the deprotection step is
assisted by the newly formed hydroxy group, as the organometallic
reagent is not hydrolyzed under the reaction conditions. Other
aromatic aldehydes behaved similarly, providing the expected
products in good to excellent yields. In the case of thiophenecarb-
aldehyde, or furfural, simple filtration of the crude product through
a short pad of silica afforded analytically pure products in essen-
tially quantitative yields.
Aliphatic aldehydes behaved similarly, although the reactions
were slower and the yields were somewhat lower (Table 2). With
both aromatic and aliphatic aldehydes, the reaction was some-
times preceded by quite a long induction period (from several
hours to even a day); activation of indium, by the addition of a cat-
alytic amount of 1,2-dibromoethane, resolved this problem and the
reactions started without a delay. The reaction works best with pri-
mary aldehydes, while with secondary aldehydes the conversions
were slower and incomplete (e.g., entries 4 and 6). The reactions
with aldehydes containing stereogenic centers were not stereose-
lective, as the products were obtained as equimolar mixtures of
diastereoisomers (entries 6 and 8). A highly enolizable b-ketoester
behaved as a nucleophile: apparently, an InCl3-catalyzed reaction
Obtained as an equimolar mixture of diastereoisomers. DMS = dimethylsilyl;
Ms = mesyl.
with the formaldehyde synthon (MOM-ether) is much faster than
the allylation (entry 9).
An attractive and synthetically useful variant of the reaction
would be the preparation of the aldol adducts in protected form.
When the reaction of 2-MOMO-allyl chloride with aldehydes was
performed with zinc, under anhydrous conditions, the correspond-
ing enol ethers were obtained (Table 3). The reaction works with
both aromatic and aliphatic aldehydes, although the yields are
somewhat lower, compared to the indium-promoted reactions. In
order to suppress the relatively long induction periods, the zinc
should be activated in situ by addition of a small amount of HgCl2
and iodine to the reaction mixture.14 In the case of crotonaldehyde,
pinacol coupling was a serious problem which reduced the yield
(entry 5); cinnamaldehyde also furnished the corresponding pina-
col as the dominant product, indicating that conjugated aldehydes,
which are capable of strong stabilization of the radical anion gen-
erated by a single electron reduction, are not suitable substrates for
this type of transformation.
In conclusion, we believe that the chemistry described offers a
potentially useful complement to the existing methods of aldoliza-
tion with acetone. Research directed towards the introduction of

V. Maslak et al. / Tetrahedron Letters 50 (2009) 6709–6711
6711
Table 3
Zinc-promoted reactions
Heathcock, C. H. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 133; (d) Heathcock, C. H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 2, p 181; (e) Kim, B. M.; Williams, S. F. Masamune. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 2, p 239; (f) Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004 (2 Volumes).
OMOM
Cl
OH OMOM
Zn,
R-CHO
R
DMF
Yielda (%)
72
2. (a) Dubois, J.-E. Bull. Soc. Chim. Fr. 1949, 16, 66; (b) Pastureau, J.; Zamenhof, M.
Compt. Rend. 1926, 182, 323.
Entry
1
Aldehyde
Product
3. With conjugated aldehydes: (a) Heilbron, I. M.; Jones, E. R. H.; Toogood, J. B.;
Weedon, B. C. L. J. Chem. Soc. 1949, 1827; (b) Ruttimann, A.; Mayer, H. Helv.
Chim. Acta 1980, 63, 1456; (c) Karrer, P.; Cochand, C.; Neuss, N. Helv. Chim. Acta
1946, 29, 1836; With aromatic aldehydes: (d) Marvel, C. S.; Quinn, J. M.;
Showell, J. S. J. Org. Chem. 1953, 18, 1730; (e) Buck, J. S.; Heilbron, I. M. J. Chem.
Soc. 1922, 121, 1095.
4. For review articles, see: (a) Mukherjee, S.; Yang, J. W.; Hoffman, S.; List, B. Chem.
Rev. 2007, 107, 5471; (b) List, B. In Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004; Vol. 1, p 161; (c) Notz, W.; Tanaka, F.; Barbas, C.
F., III Acc. Chem. Rev. 2004, 37, 580; (d) List, B. Acc. Chem. Rev. 2004, 37, 548.
5. For a review article, see: Tanaka, F.; Barbas, C. F., III. In Modern Aldol Reactions;
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1, p 273.
6. For a recent example of a Ti-catalyzed Reformatsky type reaction, see: Estevez,
R. E.; Paradas, M.; Millan, A.; Jimenez, T.; Robles, R.; Cuerva, J. M.; Oltra, J. E. J.
Org. Chem. 2008, 73, 1616.
7. For review articles, see: (a) Kargbo, R. B.; Cook, G. R. Curr. Org. Chem. 2007, 11,
1287; (b) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S. Tetrahedron 2004, 60, 1959;
(c) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763; (d) Pae, A. N.; Cho, Y. S.
Curr. Org. Chem. 2002, 6, 715; (e) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55,
11149; For a recent application in the total synthesis of antillatoxin, see: (f) Lee,
K.-C.; Loh, T.-P. Chem. Commun. 2006, 4209.
OH OMOM
CHO
OH OMOM
OMe
CHO
OMe
2
67
OH OMOM
CHO
3
4
40
Cl
Cl
OH OMOM
OMOM
CHO
49 (63)
n-C11H23
n
-C11H23
8. For a review article on allylations with other allylmetals, see: Roush, W. R. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 2, p 1.
5
6
35
54
CHO
CHO
OH
9. (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Cabrero, G.; Callejo, R.; Ruiz, M. P.
Eur. J. Org. Chem. 2008, 4434; (b) Bottoni, A.; Lombardo, M.; Miscione, G. P.;
Pujol Algue, J. B.; Trombini, C. J. Org. Chem. 2008, 73, 418; (c) Keinicke, L.;
Madsen, R. Org. Biomol. Chem. 2005, 3, 4124; (d) Keinicke, L.; Fristrup, P.;
Norrby, P.-O.; Madsen, R. J. Am. Chem. Soc. 2005, 127, 15756; (e) Palmelund, A.;
Madsen, R. J. Org. Chem. 2005, 70, 8248; (f) Lombardo, M.; Morganti, S.;
Trombini, C. J. Org. Chem. 2003, 68, 997; (g) Lombardo, M.; Morganti, S.;
d’Ambrosio, F.; Trombini, C. Tetrahedron Lett. 2003, 44, 2823.
OH OMOM
a
Yield of isolated, pure compounds; yield in parentheses is calculated on the
basis of recovered starting compound.
10. Mandai, T.; Nokami, J.; Yano, T.; Yoshinaga, Y.; Otera, J. J. Org. Chem. 1984, 49,
172.
11. Paquette, L. A.; Kern, B. A.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4129.
12. (a) Gu, X.-P.; Nishida, N.; Ikeda, I.; Okahara, M. J. Org. Chem. 1987, 52, 3192; (b)
Janicki, S. Z.; Fairgrieve, J. M.; Petillo, P. A. J. Org. Chem. 1998, 63, 3694.
other protecting groups, as well as the application of this method
to different enolate synthons is underway.
13. Typical experimental procedure:
A mixture of aldehyde (0.11 mmol), 2-
Acknowledgement
methoxymethoxy-3-chloropropene (0.33 mmol), In powder (0.33 mmol), THF
(0.3 mL), H2O (0.9 mL) and one drop of 1,2-dibromoethane was stirred at rt,
while the progress of the reaction was monitored by TLC. Upon completion, the
reaction mixture was diluted with H2O, extracted with CH2Cl2, dried over
anhyd MgSO4 and concentrated under reduced pressure. Purification of the
residue by dry-flash chromatography on SiO2 afforded the analytically pure
product. Complete characterization data for all products can be found in the
Supplementary data.
This research was supported by the Serbian Ministry of Science
(Project No. 142021).
Supplementary data
14. Typical experimental procedure: To
a mixture of aldehyde (0.33 mmol), 2-
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tetlet.2009.09.113.
methoxymethoxy-3-chloropropene (1 mmol) and Zn powder (1 mmol) in DMF
(1 mL) were added catalytic amounts of HgCl2 and I2, and the reaction mixture
was stirred at rt, while the progress of the reaction was monitored by TLC.
Upon completion, the reaction mixture was partitioned between Et2O and
NaHCO3, the organic extract was washed with H2O, dried over anhyd MgSO4,
concentrated under reduced pressure and purified by dry-flash
chromatography on SiO2, to afford the analytically pure product. Complete
characterization data for all products can be found in the Supplementary data.
References and notes
1. For books on this topic and review articles, see: (a) Nielsen, A. T.; Houlihan, W.
J. Org. React. 1968, 16, 1; (b) Mukaiyama, T. Org. React. 1982, 28, 203; (c)