Preparation and applications of a novel bis(tributylstannyl)cyclopropane: A synthetic equivalent of a cyclopropane-1,2-dianion

Article abstract of DOI:10.1016/j.tetlet.2004.11.036

The preparation of the novel trans-1,2-bis-stannylcyclopropane 4 is described. Its applications in Kosugi-Migita-Stille cross-coupling and in tin-lithium exchange reactions are presented and discussed.

Full text of DOI:10.1016/j.tetlet.2004.11.036

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 79–83
Preparation and applications of a novel
bis(tributylstannyl)cyclopropane: a synthetic equivalent of a
cyclopropane-1,2-dianion
´
Nicolas Heureux, Melanie Marchant, Nuno Maulide, Guillaume Berthon-Gelloz,
´
´ ´
Pierre Wasnaire and Istvan E. Marko
´
Christophe Hermans, Sebastien Hermant, Eleonora Kiss, Bernard Leroy,
*
´ ´ ˆ
Universite catholique de Louvain, Departement de Chimie, Batiment Lavoisier Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Received 2 September 2004; revised 25 October 2004; accepted 5 November 2004
Abstract—The preparation of the novel trans-1,2-bis-stannylcyclopropane 4 is described. Its applications in Kosugi–Migita–Stille
cross-coupling and in tin–lithium exchange reactions are presented and discussed.
Ó 2004 Elsevier Ltd. All rights reserved.
Cyclopropane motifs are ubiquitous in a wide diversity
of naturally occurring substances.1 trans-Disubstituted
cyclopropane cores constitute an interesting backbone
that can be found, for example, in grenadadiene 1 and
constanolactone A 2 (Fig. 1).2
rely on the generation of the unusual and stereodefined
cyclopropyl dianion retron 3 (Scheme 1). We thus be-
came interested in the possibility of generating the bis-
stannylcyclopropane 4 and employing it as a synthetic
equivalent of dianion 3. Surprisingly, whilst consider-
able attention has been devoted to the synthesis and
reactivity of mono-stannylated cyclopropanes,4 there
have been few reports on the preparation of three-mem-
bered rings analogous to 4.5 To the best of our knowl-
edge and despite its synthetic potential, 4 itself is
hitherto an unknown compound.
The strategic importance of the cyclopropyl moiety is
clearly revealed by the wealth of contributions devoted
to its preparation and subsequent functionalisation.3
Whilst examining the structures of natural products
embodying a trans-disubstituted cyclopropane subunit,
we became interested in delineating an efficient and con-
nective methodology for their rapid assembly. From a
retrosynthetic viewpoint, the simplest approach would
In this communication, we wish to report the straight-
forward assembly of 4 as well as some of our preliminary
O
O
H
OH
H
AcO
O
H
OH
Br
O
2
1
Figure 1.
Keywords: Small ring systems; Tributyltin; Cyclopropanation; Cross-coupling; Lithiation.
*
Corresponding author. Tel.: +32 010 47 87 73; fax: +32 010 47 27 88; e-mail: marko@chim.ucl.ac.be
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.036

80
N. Heureux et al. / Tetrahedron Letters 46 (2005) 79–83
H
H
H
"
H
H
i
+
Ph
Bu3Sn
Ph
Bu3Sn
1 or 2
Ph
SnBu3
SnBu3
SnBu3
(60%)
H
H
H
H
H
"
4
3
9
4
8
ii
Bu3Sn
SnBu3
SnBu3
(55%)
5
7
Scheme 3. Reagents and conditions: (i) 5mol% Pd(OAc)2, 5mol%
CuI, 15% AsPPh3, 3equiv LiCl, 1 or 2equiv PhI, DMF, 80°C; (ii)
10mol% Pd(OAc)2, 10mol% CuI, 30% AsPPh3, 6equiv LiCl, 4equiv
PhI, DMF, 80°C.
Scheme 1.
results in its subsequent functionalisation and use as a
dianion building block equivalent.
The elegant contribution of de Meijere and co-workers
in the Kosugi–Migita–Stille reaction of cycloprop-
yl(stannyl)amines attracted our attention, and we
decided to apply their optimised conditions to the cou-
pling of cyclopropane 4 with iodobenzene.11
As shown in Scheme 1, our antithetic analysis of 4 re-
vealed that the symmetric trans-1,2-bis(tributylstann-
yl)ethylene 5 would be the substrate of choice. Alkene
5 would itself derive from the readily available alkyne
7.6 Accordingly, we prepared trans-1,2-bis(tributylstann-
yl)ethylene 5, following a two-step procedure reported in
the literature (Scheme 2).7 Addition of the lithium anion
of acetylene (ethylene diamine complex) to tributyltin
chloride furnished tri-n-butylethynylstannane 7 in mod-
erate yields. Subsequent treatment of 7 with tributyltin
hydride and AIBN, in a solvent-free procedure, afforded
the desired alkene 5 in excellent yield.
The use of such a procedure in the case of 4, obviously
raises the important question of selectivity in the
replacement of one of the two tributylstannyl
substituents.
In the event, treatment of cyclopropyl bis-stannane 4
under the de Meijere conditions (Pd(OAc)2, CuI, Ph3As,
LiCl), in the presence of 2equiv of iodobenzene, led to
an inseparable mixture of mono- and bis-substituted
cyclopropanes 8 and 9 in 60% yield (Scheme 3). Employ-
ing an equimolar amount of iodobenzene did not
obviate this problem. However, using 4equiv of
iodobenzene and doubling the catalyst loading afforded
exclusively trans-1,2-diphenylcyclopropane 9 in 55% iso-
lated yield.
The stage was now set for the crucial cyclopropanation
step. In connection with our previous studies on the
cyclopropanation of vinyl- and dienyl-boronates,8 we
treated trans-1,2-bis(tributylstannyl)ethylene 5 with an
excess of freshly prepared diazomethane, in the presence
of a catalytic amount of palladium(II) acetate.9 To our
delight, trans-cyclopropyl stannane 4 was obtained in
82% yield (Scheme 2). It is interesting to note that
increasing the scale of this cyclopropanation reaction
leads to improved yields.10
The obvious limitations of this procedure in terms of
chemoselectivity prompted us to examine tin–lithium
exchange reactions. Such exchange reactions are well-
known in the cyclopropane context and overwhelming
precedents4 in the literature point towards retention of
stereochemistry in the subsequent capture of the lithium
species.12 Nevertheless, to the best of our knowledge, no
report has been published on exchange reactions using
di-stannylated substrates such as 4.
With a ready access to large quantities of trans-cyclo-
propyl stannane 4, we next turned our attention to its
subsequent, stereocontrolled functionalisation.
i
Li. H2NCH2CH2NH2
SnBu3
In the event, treatment of 4 with 1.3equiv of n-butyl-
lithium, in anhydrous THF, at À78°C, gave rise to a
deep orange solution of mono-lithiated species 10.
Gratifyingly, anion 10 reacted smoothly with a range
of electrophiles (Scheme 4). Some selected examples
are displayed in Table 1.
(42%)
6
7
H
iii
ii
Bu3Sn
It can be seen from Table 1 that a wide variety of func-
tionalised tributylstannyl cyclopropanes can be pre-
pared by this method in good to excellent yields. In all
cases except 11a (entry 1), the trans-disubstituted cyclo-
propane is obtained exclusively.13
SnBu3
Bu3Sn
SnBu3
(98%)
H
(82-90%)
5
4
Scheme 2. Reagents and conditions: (i) 0.8equiv Bu3SnCl, THF, 0°C
to rt; (ii) 1.5equiv Bu3SnH, 5mol% AIBN, 90°C; (iii) ca. 5equiv
CH2N2, 5mol% Pd(OAc)2, Et2O, 0°C to rt.
Interestingly, only mono-substitution of one of the two
tributyltin substituents is observed. The stereocontrolled

N. Heureux et al. / Tetrahedron Letters 46 (2005) 79–83
81
Whilst coupling of anion 10 with benzaldehyde provides
the desired adduct 11e in excellent yield, only a complex
mixture of products is obtained when acetaldehyde is
employed, probably owing to the basicity of 10 (com-
pare entries 5 and 6).
H
H
i
Bu3Sn
Bu3Sn
Li
SnBu3
H
10
H
H
4
The stereoselective replacement of one of the two tin res-
idues by a silicon group proceeds quantitatively, afford-
ing the interesting cyclopropane 11d (entry 4).
ii
Bu3Sn
R
H
Table 1
In contrast, only moderate yields of adduct 11c, bearing
a sulfur substituent, have been obtained for the moment
(entry 3). No reaction is observed with a phosphorus-
containing electrophile (entry 8).
11a-i
Scheme 4. Reagents and conditions: (i) 1.3equiv n-BuLi, THF,
À78°C; (ii) 3–20equiv electrophile, THF, À78°C to rt.
It is interesting to note that the preparation of most of
the compounds listed in Table 1 would either be difficult
or impossible by direct cyclopropanation of the corre-
sponding alkene or would require a lengthy sequence
formation of new C–C bonds proceeds smoothly and
generally in high yields, as exemplified by entries 2, 5,
7 and 9.
Table 1.
Entry
Electrophile
NH4Cl aq
–R
–H
Compound
Yielda (%)
>99
H
1
Bu3Sn
H
11a
H
H
2
3
4
5
6
7
DMF
–CHO
82
37
Bu3Sn
H
11b
CHO
H
PhSSO2Ph
Me3SiCl
PhCHO
CH3CHO
ClCO2Me
–SPh
Bu3Sn
H
11c
SPh
H
–SiMe3
>99
81
Bu3Sn
H
11d
SiMe3
H
Bu3Sn
H
–CH(OH)Ph
–CH(OH)CH3
–CO2Me
OH
Ph
11e
H
––b
Bu3Sn
Bu3Sn
Bu3Sn
OH
H
11f
H
64
CO2Me
H
11g
H
8
9
ClP(O)(OEt)2
–P(O)(OEt)2
––c
P OEt
O OEt
H
11h
H
CH3I
–CH3
95
Bu3Sn
Me
H
11i
a All yields are for pure, isolated products.
b A complex mixture of products was obtained.
c Compound 11a was obtained in 75% yield.

82
N. Heureux et al. / Tetrahedron Letters 46 (2005) 79–83
Wiley and Sons: New York; (b) Donaldson, W. A.
H
H
H
i
ii
Tetrahedron 2001, 57, 8589–8627; (c) Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977–1050; (d) Pietruszka, J. Chem. Rev. 2003, 103, 1051–
1070.
Bu3Sn
E2
Bu3Sn
E1
E1
SnBu3
H
H
H
4
12
13
2. (a) Grenadadiene: Sitachitta, N.; Gerwick, W. H. J. Nat.
Prod. 1998, 61, 681–684; (b) Constanolactone A: Nagle,
D. G.; Gerwick, W. H. Tetrahedron Lett. 1990, 31, 2995–
2998.
Scheme 5. Reagents: (i) (a) n-BuLi, THF; (b) E1–X; (ii) (a) n-BuLi,
THF; (b) E2–X.
3. For leading references in cyclopropanation of functional-
ised olefins, see: (a) Molander, G. A.; Harring, L. S. J.
Org. Chem. 1989, 54, 3525–3532; (b) Imai, T.; Mineta, H.;
Nishida, S. J. Org. Chem. 1990, 55, 4986–4988; (c)
Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem.
1995, 60, 1081–1083; (d) Charette, A. B.; Marcoux, J.-F.
Synlett 1995, 1197–1207; (e) Hildebrand, J. P.; Marsden,
S. P. Synlett 1996, 893–894; (f) Charette, A. B.; Juteau, H.;
Lebel, H.; Molinaro, H. J. Am. Chem. Soc. 1998, 120,
11943–11952; (g) Hohn, E.; Pietruszka, J. Adv. Synth.
Catal. 2004, 346, 863–866.
of synthetic operations.3,14 The readily available com-
pounds 11a–e,g and 11i clearly constitute highly valuable
building blocks in the context of the total synthesis of
cyclopropane-containing natural products. For example,
the cyclopropyl aldehyde 11b, which can be Ôconvention-
allyÕ elaborated by directed-cyclopropanation of a
suitably functionalised allylic alcohol, followed by oxida-
tion, has been employed by Itoh et al. as an advanced
intermediate towards the synthesis of dictyopterene A,
an odoriferous marine natural product.15
4. For a recent review, see: Rubina, M.; Gevorgyan, V.
Tetrahedron 2004, 60, 3129–3159.
In summary, we have prepared a novel cyclopropyl bis-
stannane 4 through palladium-catalysed cyclopropana-
tion of the readily available alkene 5.16 The synthetic po-
tential of 4 was evaluated, initially by submitting it to a
Kosugi–Migita–Stille coupling and subsequently by per-
forming a selective tin–lithium exchange, followed by an
electrophilic quench. Whilst the former approach met
with limited success, the latter proved to be a fairly gen-
eral procedure for the preparation of functionalised,
trans-disubstituted tributylstannyl cyclopropanes. The
subsequent replacement of the tributyltin substituent,
present in adducts 11, by various electrophiles has been
well described in the literature.12 The ready availability
of cyclopropane 4 provides us, for the first time, with
the exciting possibility of generating a range of function-
alised trans-disubstituted cyclopropanes 13 by the
sequential, stereocontrolled substitution of both tin resi-
dues (Scheme 5). Further applications of compounds 4
and 11, including their use as building blocks in the total
synthesis of relevant natural products, are currently
being pursued in this laboratory. The results of these
investigations will be reported in due course.
5. (a) Mitchell, T. N.; Kowall, B. J. Organomet. Chem. 1995,
490(1–2), 239–242; (b) Rubina, M.; Rubin, M.; Gevorg-
yan, V. J. Am. Chem. Soc. 2002, 124, 11566–11567.
6. Ethynyl(tributyltin) 7 is commercially available from
Acros Organics. In order to access large amounts of 7,
we have prepared it following a literature procedure
reported in Ref. 7.
7. (a) Bottaro, J. C.; Hanson, R. N.; Seitz, D. E. J. Org.
Chem. 1981, 46, 5221–5222; (b) Suffert, J.; Salem, B.;
Klotz, P. J. Am. Chem. Soc. 2001, 123, 12107–12108; (c)
´
Queron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4553–
4557; (d) Mee, S.; Lee, V.; Baldwin, J. Angew. Chem., Int.
Ed. 2004, 43, 1132–1136, and references cited therein.
´
8. (a) Marko, I. E.; Giard, T.; Sumida, S.; Gies, A.-E.
Tetrahedron Lett. 2002, 43, 2317–2320; (b) Marko, I. E.;
´
Kumamoto, T.; Giard, T. Adv. Synth. Catal. 2002, 344,
1063–1067, and references cited therein.
9. Paulissen, R.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett.
1972, 15, 1465–1466.
10. Performing the cyclopropanation of 5 on a 3g scale
provides pure 4 in yields of up to 90%.
11. Wiedmann, S.; Rauch, K.; Savchenko, A.; Marek, I.; de
Meijere, A. Eur. J. Org. Chem. 2003, 3, 631–635.
12. For selected examples, see: (a) Corey, E. J.; Eckrich, T. M.
Tetrahedron Lett. 1984, 25, 2415–2418; (b) Tanaka, K.;
Minami, K.; Funaki, I.; Suzuki, H. Tetrahedron Lett.
1990, 31, 2727–2730; (c) Lautens, M.; Delanghe, P. H. M.;
Goh, J. B.; Zhang, C. H. J. Org. Chem. 1995, 60, 4213–
4227, See also Ref. 3.
13. The trans-stereochemistry of adducts 11 has been estab-
lished by NMR analysis and correlation with known
compounds.
14. Imai, N.; Sakamoto, K.; Takahashi, H.; Kobayashi, S.
Tetrahedron Lett. 1994, 35, 7045–7048.
Acknowledgements
We are grateful to Dr. Philippe Klotz and Dr. Jean Suff-
´
ert (Faculte de Pharmacie, Strasbourg, France) and to
Dr. Joe¨lle Prunet (Ecole Polytechnique, Palaiseau,
France) for experimental details in the preparation of
´
5 and 7. Financial support of this work by the Universite
catholique de Louvain (studentship to S.H.), the Fonds
pour la Recherche dans lÕIndustrie et lÕAgriculture
(F.R.I.A., studentships to N.M. and P.W.), the Fond
National de la Recherche Scientifique (N.H., Aspirant
´
FNRS and B.L., Charge de Recherches FNRS), Rhodia
(studentships to G.B. and E.K.) and the Actions de
15. Itoh, T.; Inoue, H.; Emoto, S. Bull. Chem. Soc. Jpn. 2000,
73, 409–416, and references cited therein.
16. Typical experimental procedure: Preparation of cyclopro-
pane 4. To a suspension of N-methyl-N-nitrosourea (6.3g,
61.2mmol, 12equiv) in dry ether (45mL), was added
12.3mL (21.6equiv) of 50% aq KOH dropwise at 0°C.
After 15min stirring at this temperature, the yellow
organic phase was transferred to a solution of trans-1,2-
bis(tributylstannyl)ethylene 5 (3.0g, 5.1mmol, 1equiv)
and Pd(OAc)2 (57mg, 0.25mmol, 5mol%) in 22.5mL of
dry ether. The resulting dark suspension was stirred at 0°C
for 30min before being filtered through a pad of Celite.
The solvents were evaporated under reduced pressure to
´
Recherche Concertees (convention 96/01-197) is grate-
fully acknowledged.
References and notes
1. For general reviews on cyclopropanes, see: (a) Patai, S.;
Rappoport, Z. The Chemistry of the Cyclopropyl Group;

N. Heureux et al. / Tetrahedron Letters 46 (2005) 79–83
83
afford the crude product, which was further purified by
chromatography (silica gel, petroleum ether) to afford 2.8g
(90%) of cyclopropyl bis-stannane 4. 1H NMR (300MHz,
CDCl3): d = À0.32 (t, J = 7.5Hz, 1H), 0.56 (t, J = 7.5Hz,
1H), 0.68–0.85 (m, 32H), 1.18–1.30 (m, 14H), 1.37–1.47
(m, 10H). 13C NMR (75MHz, CDCl3): d = À3.65, 5.38,
8.68, 13.80, 27.50, 29.32.
Preparation of aldehyde 11b. In a 25mL flame-dried
round-bottomed flask were introduced 421mg of cyclo-
propyl bis-stannane 4 (0.7mmol, 1equiv) and 4mL of dry
THF. After cooling to À78°C, 0.56mL (0.9mmol,
1.3equiv) of n-BuLi (1.6M in hexanes) was added drop-
wise. The resulting orange suspension was stirred at
À78°C for an additional hour, then 0.5mL (7.0mmol,
10equiv) of DMF was added at once. The resulting clear-
yellow solution was stirred for a further 2h at À78°C. The
reaction was quenched by the addition of 3mL of H2O.
The organic layer was repeatedly extracted with ether,
dried over MgSO4 and the solvents were removed under
reduced pressure. The crude aldehyde was purified by
chromatography (silica gel, petroleum ether) to afford
1
205mg (82%) of pure aldehyde 11b. H NMR (300MHz,
CDCl3): d = 0.54–0.65 (m, 1H), 0.78–0.92 (m, 16H), 0.98–
1.1 (m, 1H), 1.22–1.60 (m, 12H), 1.68–1.76 (m, 1H), 8.53
(d, 1H, J = 6.9Hz); 13C NMR (75MHz, CDCl3): d = 1.87,
8.86, 11.21, 13.72, 26.92, 27.33, 29.13, 201.24.