A one-pot access to cyclopropanes from allylic ethers via hydrozirconation-deoxygenative ring formation

Article abstract of DOI:10.1039/b203762a

A synthetic method for the direct transformation of allylic ethers into mono-, di- and trisubstituted cyclopropanes is presented.

Full text of DOI:10.1039/b203762a

A one-pot access to cyclopropanes from allylic ethers via
hydrozirconation–deoxygenative ring formation
Vincent Gandon and Jan Szymoniak*
Réactions Sélectives et Applications, CNRS (UMR 6519) and Université de Reims Champagne Ardenne,
51687 Reims cedex 2, France. E-mail: jan.szymoniak@univ-reims.fr; Fax: +33 3 26 91 31 66
Received (in Cambridge, UK) 19th April 2002, Accepted 8th May 2002
First published as an Advance Article on the web 20th May 2002
A synthetic method for the direct transformation of allylic
ethers into mono-, di- and trisubstituted cyclopropanes is
presented.
out in THF, CH
by heating the reaction mixture up to 60 °C (in C
Lewis acids, namely TiCl , BF ·OEt , ZrCl and Me
3
were tested to induce the cyclopropanation step. When using
allylic ethers with a terminal CNC double bond, mild reaction
conditions made it possible to avoid undesirable side-products.
2
Cl
2
or C
6
H
6
as solvents, at room temperature or
). Several
SiOTf
6 6
H
4
3
2
4
Among the known methods employed for constructing three-
membered rings, a large number are based upon the direct
cyclopropanation of alkenes.1 We recently reported a new
Thus, hydrozirconation cleanly occurred in CH
2
Cl
2
at room
approach to cyclopropanes from carbonyl compounds and
temperature. As expected, the deoxygenative cyclopropanation
Zr(II) chemistry.2 The de-
,3
8
to afford the
Grignard reagents through Cp
2
3 2
step next proceeded by adding BF ·OEt
scribed reaction involves a deoxygenative contraction of an
intermediate oxazirconacycle under Lewis acid activation
conditions [Scheme 1, eqn. (1)]. An analogous process was next
applied for developing a new synthesis of primary cyclopropyl-
amines from nitriles [(eqn. (2)].4
corresponding cyclopropanes in good to excellent yields (Table
1), systematically better than those obtained starting from
aldehydes.2
The reaction proceeded smoothly from the methyl or benzyl
allylic ethers bearing both alkyl and aryl substituents (entries 1
and 2). It also took place starting from the ether 5 with a
quaternary C3 atom (entry 3). Additional substituted CNC
double bonds can be present in the substrate and tolerated by an
equivalent of Schwartz reagent (entry 4). The reactions
employing the allylic acetals 9 and 11 could also be accom-
plished leading to the cyclopropyl ethers 10 and 12 (entries 5
and 6).
Table 1 Synthesis of cyclopropanes from allylic ethers with a terminal CNC
double bond.
Scheme 1 a Generated from Cp
Ti(OiPr) and EtMgBr. L.A. = TiCl
ZrCl
or BF
and EtMgBr. b Generated from
·OEt
2
2
4
4
3
2
.
Time Yield
We envisioned that a Lewis acid-mediated contraction of
heterozirconacycles might be a more general reaction leading to
carbocycles and especially cyclopropanes. For this purpose, the
zirconium intermediate could be formed indifferently, not only
Entry
1
Substrate
Product
(h)
(%)
a
1
80
2
by employing Cp Zr(II) chemistry. This idea led us to explore
the feasibility of converting allylic ethers in cyclopropanes
following Scheme 2.5
2
0.5
6
89
79
Hydrozirconation of the CNC double bond in allylic ethers
6
has been reported. In several cases, alkenes and alkanes were
formed as side-products in these reactions, due to a b-
elimination of the alkoxy group from the hydrozirconated
intermediate, and a possible second hydrozirconation. Fur-
thermore, complex reaction mixtures were often obtained
starting from the allylic trimethylsilyl ethers, because of the
reductive cleavage of the O–Si bond. In order to avoid such
secondary reactions and favour the cyclopropanation, we
examined various reaction conditions. The hydrozirconation
3b
4
5
0.6
78
was carried out with Schwartz reagent (Cp
2
Zr(H)Cl), but also
7
with Cp
2
Zr(H)OTf in some cases. The reactions were carried
0.5
65
6
0.25
92c
a
Yields of isolated products after hydrolytic workup (NaHCO
3
aq) and
b
flash chromatography. Requires 1.5 eq. of Cp
BF ·OEt . Estimated by H NMR.
3 2
2
Zr(H)Cl and 1.6 eq. of
c
1
Scheme 2
CHEM. COMMUN., 2002, 1308–1309
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308
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We next employed 2-substituted allylic ethers as substrates.
When using CH Cl as solvent, the reaction times were long at
0 to 40 °C, undesirable side-products were formed and the
reagent,12 the described procedure should be synthetically
useful. Studies are underway to further explore the reaction.
2
2
2
yields of cyclopropanes were moderate or low. However,
synthetically useful yields were achieved after modifying the
reaction conditions. The hydrozirconation step was typically
Notes and references
1
L. A. Paquette, Comprehensive Organic Synthesis, ed. B. M. Trost and
I. Fleming, Pergamon, Oxford, 1991, vol. 5, p. 899; P. J. Murphy,
Comprehensive Organic Functional Group Transformations, ed. A. R.
Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon, Oxford, 1995, vol.
1, p. 801; J. Salaün, in The Chemistry of the Cyclopropyl Group, ed. Z.
Rappoport, Wiley, New-York, 1987, p. 809; T. Tsuji and S. Nishida, in
The Chemistry of the Cyclopropyl Group, ed. Z. Rappoport, Wiley,
New-York, 1987, p. 3; Houben-Weyl, Methods of Organic Chemistry,
ed. A. de Meijere, Thieme, Stuttgart, 1997, vol. E17a-f.
carried out at 60 °C in C
cyclopropanation step was promoted as before with BF
6
H
6
instead of CH
2
Cl
2
. The
·OEt
3
2
.
Table 2 summarizes the results of reactions employing
various allylic ethers.9,10 Both 1,2-disubstituted and 1,1,2-tri-
substituted cyclopropanes having alkyl and aryl groups could be
obtained. The trans configuration was assigned to the major or
unique diastereomers of compounds 14, 16, 18, 20 and 22 from
the vicinal coupling constants and on the basis of NOE
measurements. We noticed that not only yields but also
2
(a) P. Bertus, V. Gandon and J. Szymoniak, Chem. Commun., 2000,
1
71; (b) V. Gandon, P. Bertus and J. Szymoniak, Eur. J. Org. Chem.,
stereoselectivity increased when using C
6
H
6
as solvent in place
2
000, 3713.
11
of CH
2
Cl
2
.
The degree of trans stereoselectivity in entry 1
3 For reviews of ACp ZrA Chemistry, see E. Negishi and T. Takahashi,
2
appears to be dependent on the nature of the –OR group, and
increases with decreasing of steric demand from R = Bn
Bull. Chem. Soc. Jpn., 1998, 71, 755; E. Negishi and D. Y. Kondakov,
Chem. Soc. Rev., 1996, 26, 417; E. Negishi and T. Takahashi, Acc.
Chem. Res., 1994, 27, 124; E. Negishi, Chem. Scr., 1989, 29, 457.
(
trans+cis = 71+29) to R = Me (trans+cis = 97+3). A similar
4
5
(a) P. Bertus and J. Szymoniak, Chem. Commun., 2001, 1792; (b) P.
Bertus and J. Szymoniak, J. Org. Chem., 2002, 67, 3965.
stereochemical trend is observed in entry 2. The influence of the
–
OR group on stereoselectivity possibly indicates a concerted
Allylic ethers or acetals have only rarely been used as 3 C-components
for the construction of the cyclopropane ring. For some particular
transformations, see: monosubstituted cyclopropanes via hydroalumi-
nation and thermolysis, L. I. Zakharkin and L. A. Savina, Izv. Akad.
Nauk SSSR, Ser. Khim., 1963, 9, 1693; cyclopropylmethanols via
hydrozirconation of 1-butenyl- and vinyloxiranes; S. Harada, N.
Kowase, N. Tabuchi, T. Taguchi, Y. Dobashi, A. Dobashi and Y.
Hanzawa, Tetrahedron, 1998, 54, 753; chiral phenyl- and vinylcyclo-
propanes via carbolithiation of the mixed acetals of acetone with
cinnamyl or dienyl alcohols, I. Marek, J. Chem. Soc., Perkin Trans. 1,
process for the ring formation.
Table 2 Synthesis of cyclopropanes from 2-substituted allylic ethers
Time Yield (%)a
1
999, 535; S. Majumdar, A. de Meijere and I. Marek, Synlett, 2002, 423;
Entry Substrate
1
Product
(h)
(trans+cis)b
vinylcyclopropylcarbinols via carbozincation of g-lithiated allylic
ethers, F. Ferreira, C. Herse, E. Riguet and J. F. Normant, Tetrahedron
lett., 2000, 41, 1733.
1
1
1
76 (71+29)
80 (85+15)
86 (97+3)
6
7
(a) E. Uhlig, B. Bürglen, C. Krüger and P. Betz, J. Organomet. Chem.,
1
990, 382, 77; (b) S. Karlsson, A. Hallberg and S. Gronowitz, J.
Organomet. Chem., 1991, 403, 133.
For the preparation of Cp Zr(H)Cl and Cp
a) S. L. Buchwald, S. J. LaMaire, R. B. Nielsen, B. T. Watson and S.
2
2
Zr(H)OTf, see respectively:
2
2
75 (83+17)
72 (90+10)
2
3
4
(
M. King, Org. Synth., Coll. Vol. IX, 1998, 162; (b) P. Wipf, H.
Takahashi and N. Zhuang, Pure Appl. Chem., 1998, 70, 1077.
No cyclopropanes were obtained when using THF as solvent. Among
the Lewis acid tested the distinctly best yields were observed with
8
9
1.5
2
60 (100+0)
75 (90+10)
BF
Selected data for 16: R
CDCl ) cis isomer: d 20.27 (q, J = 5.2 Hz, 1 H), 0.64 (td, J = 8.2, J
5.2 Hz, 1 H), 0.69–0.83 (m, 2 H), 1.05 (d, J = 6.1 Hz, 3 H), 1.58–1.70
3 2
·OEt .
1
f
(Petroleum ether) 0.80; H-NMR (250 MHz;
3
=
(
(
m, 2 H), 2.65–2.76 (m, 2 H), 7.15–7.30 (m, 5 H), trans isomer: d 0.17
dt, J = 7.9, J = 4.3 Hz, 1 H), 0.22 (dt, J = 7.8, J = 4.3 Hz, 1 H),
0
2
.37–0.48 (m, 2 H), 1.02 (d, J = 5.5 Hz, 3 H), 1.50–1.60 (m, 2 H),
.65–2.76 (m, 2 H), 7.15–7.30 (m, 5 H); 13C-NMR (63 MHz; CDCl
3
) cis
5
2
42 (100+0)
isomer: d 9.5, 12.0, 13.2, 15.4, 30.7, 36.5, 125.6, 128.2, 128.4, 142.8,
trans isomer: d 12.8, 12.9, 19.0, 19.6, 36.0, 36.3, 125.5, 128.2, 128.5,
142.7; IR (neat) n (cm ) 2925, 1453; MS (70eV) m/z 160 (M ·, 20),
21
+
a
3
Yields of isolated products after hydrolytic workup (NaHCO aq) and
b 1
117 (36), 104 (40), 91 (100); Analysis calculated for C12H16: C, 89,94;
flash chromatography. H-NMR ratios.
H, 10,06; found C, 89,63; H, 10,36%.
1
1
0 Allylic ethers having exocyclic or internal disubstituted CNC double
2
bond did not give cyclopropanes, even when using Cp Zr(H)OTf for
In summary, cyclopropanes can be prepared directly from
allylic ethers by combining hydrozirconation and the Lewis
acid-promoted deoxygenative ring formation. Since several
functional groups can be tolerated by an equivalent of Schwartz
hydrozirconation.
1 Comparatively, 14 was obtained from 13c in 50% yield (trans:cis =
75+25) with CH Cl .
2
2
12 P. Wipf and H. Jahn, Tetrahedron, 1996, 52, 12853.
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