Efficient one-pot ring-opening/aldol reactions using (cyclopropyl) methylstannanes

Article abstract of DOI:10.1016/j.tetlet.2005.03.023

(Cyclopropyl)methylstannanes, substituted with an electron-withdrawing group, have been found to be effective homoallylating reagents of aldehydes and ketones. The reaction proceeds by Lewis-acid catalyzed ring opening, followed by an aldol condensation of the resulting enolate, providing homoallylation products in excellent yields. The diastereoselectivity of the process was found to be highly dependent upon the temperature and the solvent, the reaction giving mainly anti adducts at -78°C and syn compounds at 0°C.

Full text of DOI:10.1016/j.tetlet.2005.03.023

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3025–3028
Efficient one-pot ring-opening/aldol reactions
using (cyclopropyl)methylstannanes
Bernard Leroy*
´ ´ ´
Universite catholique de Louvain, Departement de Chimie, Unite de Chimie organique et medicinale, Pl. Pasteur 1,
1348 Louvain-la-Neuve, Belgium
´
Received 24 January 2005; revised 25 February 2005; accepted 3 March 2005
Available online 18 March 2005
Abstract—(Cyclopropyl)methylstannanes, substituted with an electron-withdrawing group, have been found to be effective homo-
allylating reagents of aldehydes and ketones. The reaction proceeds by Lewis-acid catalyzed ring opening, followed by an aldol
condensation of the resulting enolate, providing homoallylation products in excellent yields. The diastereoselectivity of the process
was found to be highly dependent upon the temperature and the solvent, the reaction giving mainly anti adducts at À78 ꢀC and syn
compounds at 0 ꢀC.
ꢁ 2005 Elsevier Ltd. All rights reserved.
Allylation reactions of electrophiles such as carbonyl
compounds with allylsilanes and allylstannanes have be-
come, over the years, one of the most reliable methods
for carbon–carbon bond formation.1 However, the anal-
ogous transformation using (cyclopropane)methylsil-
anes 1 or -stannanes 2 to achieve homoallylation has
been far less studied (Scheme 1). This relative disinterest
is due to the lack of reactivity of these derivatives com-
pared to their allyl counterparts, the limited number of
electrophiles suitable for this coupling, as well as the dif-
ficulty in controlling the regiochemistry of the process
with substituted cyclopropanes.2
The ring opening of (cyclopropyl)methylsilanes is
known to be easy and highly regioselective when the ring
is substituted with a group able to stabilize a negative
charge, such as an electron-withdrawing substituent.3
However, few attempts have been made to use com-
pounds such as 5 for one-pot ring-opening and subse-
quent condensation with electrophiles, which would
correspond to a formal homoallylation process.4 Re-
cently, trimethylsilylmethyl cyclopropyl ketones, such
as 7, have been found to undergo smooth ring opening
to afford the corresponding enolates, which reacts with
aldehydes and ketones to afford aldol products.5
We became interested in applying this methodology to
the corresponding cyclopropanes substituted with an
ester function instead of a ketone derivative. Much to
our surprise, we observed that, in contrast to ketone 7,
which underwent rapid and quantitative ring opening
in the presence of boron trifluoride, ester 9 was com-
pletely unreactive under similar conditions (Scheme 2).
The use of various other Lewis acids, Brønsted acids
or treatment of 9 with fluoride anion never afforded
any traces of the ring-opened product 10.
R
R
SiMe3
SnBu3
E+
R
R
1
or
+
E
E
4
3
2
L.A.
EWG
EWG
SiMe3
6
5
In order to circumvent the lack of reactivity of silane 9,
we turned our attention to the use of (cyclopropyl)-
methyl stannanes such as 12. This derivative, as well
as the other esters 13 and 14, are easily prepared by rho-
dium-catalysed cyclopropanation of allyltributyltin with
various diazo esters (Scheme 3).6 The cyclopropanated
Scheme 1.
Keywords: Cyclopropane; Homoallylation; Aldol reaction; Tin.
*
Tel.: +32 10 47 29 19; fax: +32 10 47 27 88; e-mail: leroy@chim.
ucl.ac.be
0040-4039/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.023

3026
B. Leroy / Tetrahedron Letters 46 (2005) 3025–3028
standard chromatographic techniques, and therefore
O
O
.
BF3 OEt2
were used as a mixture for subsequent reactions. We
were delighted to find that, upon treatment with boron
trifluoride, 12 underwent smooth and quantitative ring
opening to afford pentenoate 10, presumably via an
intermediate equivalent to the enolate 15.
CH2Cl2
SiMe3
8
7
9
quant.
.
BF3 OEt2
O
O
CH2Cl2
Having demonstrated that the ring opening of 12 was an
efficient process, we next turned our attention to the
trapping of the in situ generated enolate by a carbonyl
derivative. For preliminary studies, the ring-opening
reaction was performed in the presence of dihydrocin-
namaldehyde, to afford aldol product 16 as a mixture
of syn and anti isomers. The most significant results
are summarized in Table 1.
SiMe3
EtO
EtO
10
Scheme 2.
AllylSnBu3
[Rh(OAc)2]2
CH2Cl2
O
O
N2
SnBu3
Moderate yields were initially obtained with BF3ÆOEt2
(entries 1–5) and TiCl2(O-i-Pr)2 (entries 6–7), which gave
generally 16-syn as the major product. An interesting
change in the diastereoselectivity was observed with
SnCl4 and Et2AlCl (entries 9–12). Finally, TiCl4 was
found to be the most efficient Lewis acid for this trans-
formation. The diastereoselectivity is affected by the sol-
vent (entries 13–14), the amount of Lewis acid (entry 15)
and the temperature. In diethyl ether, 16-anti was the
major product when the reaction was carried on at
À78 ꢀC (entry 16). However, 16-syn became predomi-
nant when working at 0 ꢀC (entry 17).7
RO
RO
12 R= Et 69% cis/trans : 1/1
13 R= Me 64% cis/trans : 1/1.3
14 R= tBu 42% cis/trans : 1/1
11
quant.
(R=Et)
.
BF3 OEt2
CH2Cl2
O-
O
EtO
EtO
10
15
Scheme 3.
The influence of the geometry of the cyclopropane on
the diastereoselectivity of the final adduct was then
investigated. Pure cis or trans cyclopropanes 12 were en-
gaged in a tandem ring-opening/condensation reaction,
products are usually obtained as a 1/1 mixture of cis and
trans isomers, which are rather difficult to separate by
Table 1. Optimization of the one-pot ring-opening/aldol reaction
O
Ph
H
O
OH
O
OH
O
L.A.
EtO
Ph
EtO
Ph
SnBu3
+
EtO
16-syn
16-anti
12
Entry
Lewis acid
Solvent
Temperature (ꢀC)
Yielda (%)
16-syn:16-antib
1
BF3ÆOEt2 (1 equiv)
BF3ÆOEt2 (2 equiv)
BF3ÆOEt2 (2 equiv)
BF3ÆOEt2 (2 equiv)
BF3ÆOEt2 (2 equiv)
TiCl2(O-i-Pr)2 (2 equiv)
TiCl2(O-i-Pr)2 (2 equiv)
SnCl4 (2 equiv)
CH2Cl2
CH2Cl2
Et2O
À78
À78
À78
À78
0
Traces
43
56
—
1/1
2
3
1.5/1
—
4
THF
Traces
62
33
5
Benzene
CH2Cl2
Et2O
2.3/1
1.5/1
1.2/1
1.2/1
1/3.4
1/1.8
1/1.8
1/1.2
2.1/1
2.3/1
1.7/1
1/2.2
3.2/1
6
À78
À78
À78
À78
À78
À78
0
7
42
10
8
CH2Cl2
Et2O
9
SnCl4 (2 equiv)
27
75
10
11
12
13
14
15
16
17
Et2AlCl (2 equiv)
Et2AlCl (2 equiv)
Et2AlCl (2 equiv)
TiCl4 (2 equiv)
CH2Cl2
Et2O
68
57
Benzene
CH2Cl2
Benzene
Et2O
À78
0
47
68
TiCl4 (2 equiv)
TiCl4 (1 equiv)
À78
À78
0
54
90
TiCl4 (2 equiv)
TiCl4 (2 equiv)
Et2O
Et2O
73
a All yields refer to pure, isolated product. All the reactions were complete after 2 h at the given temperature.
b Determined by NMR analysis of the crude reaction mixture.

B. Leroy / Tetrahedron Letters 46 (2005) 3025–3028
3027
ester group was also examined. Methyl ester 13 gave re-
sults similar to the ethyl ester 12, but no selectivity was
observed with a more hindered ester such as 14 (Scheme
4).
O
O
OH
Ph
H
O
TiCl4
Et2O, -78 ˚C
RO
Ph
SnBu3
RO
With an efficient method for one-pot ring-opening/aldol
condensation of (cyclopropyl)methylstannane 12 in
hand, we applied this strategy to other carbonyl electro-
philes. As described in Table 2, the reaction proved to be
very efficient in most cases, giving aldol products in
excellent yields. Substrates such as primary, secondary
or tertiary aliphatic aldehydes (entries 1–3), aromatic
and unsaturated aldehydes (entries 4–5) and ketones
(entry 6) are tolerated for this transformation.8 As in
the case of dihydrocinnamaldehyde, an important effect
of the temperature on the diastereoselectivity was
12 R= Et
13 R= Me
14 R= tBu
R= Et 90% 16-syn / 16-anti 1 / 2.2
R= Me 59% 17-syn / 17-anti 1 / 2.1
R= tBu 67% 18-syn / 18-anti 1 / 1
Scheme 4.
using BF3ÆOEt2 or TiCl4 as Lewis acid. In both cases,
the aldol products were obtained in the same diastereo-
isomeric ratio as observed when a mixture of cyclo-
propanes was used. The influence of the nature of the
Table 2. Scope of the one-pot ring-opening/aldol reaction
O
R1
R2
O
OH
R1
R2
O
OH
R1
R2
TiCl4, Et2O
O
EtO
EtO
+
SnBu3
EtO
-78˚C or 0˚C
12
Entry
1
Electrophile
Product
Yielda (À78 ꢀC, %)
syn/anti (À78 ꢀC)
Yielda (0 ꢀC, %)
syn/antib (0 ꢀC)
O
OH
O
94
1/1.6
99
4/1
EtO
H
19
O
OH
OH
OH
O
O
2
3
4
5
6
81
95
95
71
1.9/1
1.5/1
1/1.5
1/1.9
96
89
96
48
99
2.9/1
1.1/1
1.7/1
>20/1
—
EtO
H
H
20
21
22
23
24
O
EtO
O
O
EtO
Ph
Ph
Ph
H
O
OH
OH
O
EtO
Ph
H
O
O
EtO
a All yields refer to pure, isolated product. All the reactions were complete after 2 h at the temperature given.
b Determined by NMR analysis of the crude reaction mixture.

3028
B. Leroy / Tetrahedron Letters 46 (2005) 3025–3028
Synthesis 1992, 69; (d) Mohr, P. Tetrahedron Lett. 1995, 36,
7221; (e) Landais, Y.; Parra-Rapado, L. Eur. J. Org. Chem.
2000, 401; (f) Lucke, A. J.; Young, D. J. Tetrahedron Lett.
1994, 35, 1609.
observed for primary aliphatic, aromatic and unsatu-
rated aldehydes, which gave mostly anti products when
the reaction was performed at low temperature and
syn products at 0 ꢀC. In the case of cinnamaldehyde,
the syn product 23 was effectively the only isomer ob-
served, even if the yield was lower than usual, probably
due to partial degradation of the product. In contrast,
secondary and tertiary aliphatic aldehydes gave, under
all conditions, the syn compounds as the major adducts.
3. (a) Reichelt, I.; Reissig, H.-U. Liebigs Ann. Chem. 1984,
823; (b) Ochiai, M.; Sumi, K.; Fujita, E. Chem. Lett. 1982,
79; (c) Ochiai, M.; Sumi, K.; Fujita, E. Chem. Pharm. Bull.
1983, 31, 3931.
4. Hirao, T.; Misu, D.; Agawa, T. J. Chem. Soc., Chem.
Commun. 1986, 26.
5. Yadav, V. K.; Balamurugan, R. Org. Lett. 2003, 5,
4281.
In summary, we have developed an efficient and versatile
method for formal homallylation of aldehydes and
ketones. By controlling simple parameters such as the
temperature and the solvent, an easy access to both
diastereomers of the substituted aldol adducts has been
delineated. We are currently working on the application
of this methodology to the synthesis of related natural
products, as well as on the improvement of the stereo-
selectivity of the reaction. These results will be reported
in due course.
6. Lin, Y.-L.; Turos, E. J. Org. Chem. 2001, 66, 8751.
7. (a) The diastereoisomeric relationship for all aldol products
was assigned by comparison with literature NMR data
when available. The frequency of the resonance for the
hydrogen vicinal to the hydroxyl group is consistently
higher for the syn isomer than for the anti one. Marcantoni,
E.; Alessandrini, S.; Malavolta, M.; Bartoli, G.; Bellucci,
M. C.; Sambri, L.; Dalpozzo, R. J. Org. Chem. 1999, 64,
1986; (b) Curran, D. P.; Ramamoorthy, P. S. Tetrahedron
´
1993, 49, 4841; (c) Frater, G.; Muller, U.; Gunther, W.
Tetrahedron 1984, 40, 1269.
¨
¨
8. Typical experimental procedure: Preparation of 16: to a
solution of (cyclopropyl)methylstannane 12 (100 mg,
0.239 mmol) and dihydrocinnamaldehyde (38.5 mg,
0.287 mmol) in dry diethyl ether (5 mL) at À78 ꢀC was
added TiCl4 (479 lL, 0.479 mmol, 1 M solution in dichlo-
romethane). The reaction mixture was stirred at À78 ꢀC for
2 h, then allowed to warm to rt. The solution was diluted
with dichloromethane (20 mL) and quenched with satu-
rated NaHCO3 (20 mL). The aqueous layer was separated
and extracted with dichloromethane (2 · 20 mL). The
combined organic layers were dried (MgSO4) and evapo-
rated in vacuo. The residue was purified by column
chromatography (silica gel, petroleum ether–diethyl ether,
2:1) to give 16 (mixture, syn/anti 1/2.2) as a colourless oil
(57 mg, 90%). 1H NMR (300 MHz, CDCl3): d 7.15–7.31
(5H, m), 5.66–5.84 (1H, m), 4.98–5.11 (2H, m), 4.09–4.21
(2H, m), 3.85 (1Hsyn, dq, J = 9.1, 4.8 Hz), 3.71 (1Hanti,
hept, J = 4.3 Hz), 2.33–2.92 (6H, m), 1.69–1.84 (2H, m),
1.25 (3H, t, J = 7.2 Hz). IR (film) 3470, 3026, 2932, 1729,
1642, 1181, 1030. MS (CI) m/z : 263.1 (M+H+, 65), 244.9
(85), 217.0 (30), 198.9 (55), 171.0 (100).
Acknowledgements
´
The author is grateful to Professor I. E. Marko for
support and helpful suggestions. Financial support of
this work by the Fonds National de la Recherche Scien-
´
tifique (B.L., charge de recherche FNRS) is gratefully
acknowledged.
References and notes
1. (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207; (b)
Fleming, I. Allylsilanes, Allylstannanes and Related Sys-
tems. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds., 1991; Vol. 2, p 563.
2. (a) Grignon-Dubois, M.; Dunogues, J.; Calas, R. J.
Organomet. Chem. 1986, 309, 35; (b) Ryu, I.; Hirai, A.;
Suzuki, H.; Sonoda, N.; Murai, S. J. Org. Chem. 1990, 55,
1409; (c) Fleming, I.; Sanderson, P. E. J.; Terrett, N. K.