Synthesis of 3-oxa- and 3-azabicyclo[4.1.0]heptanes by gold-catalyzed cycloisomerization of cyclopropenes

Article abstract of DOI:10.1021/ol101741f

Equation Presented Allyl 3,3-dimethylcyclopropenylcarbinyl ethers or sulfonamides undergo gold-catalyzed cycloisomerization leading to 5-isopropylidene-3-oxa- and 3-azabicyclo[4.1.0]heptanes in excellent yields and with high diastereoselectivities. These reactions constitute the first examples of intramolecular cyclopropanation of an alkene by a gold carbene generated by electrophilic ring opening of a cyclopropene in the presence of gold(I) chloride.

Full text of DOI:10.1021/ol101741f

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4144-4147
Synthesis of 3-Oxa- and
3-Azabicyclo[4.1.0]heptanes by
Gold-Catalyzed Cycloisomerization of
Cyclopropenes
Fre´de´ric Miege, Christophe Meyer,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received July 26, 2010
ABSTRACT
Allyl 3,3-dimethylcyclopropenylcarbinyl ethers or sulfonamides undergo gold-catalyzed cycloisomerization leading to 5-isopropylidene-3-oxa-
and 3-azabicyclo[4.1.0]heptanes in excellent yields and with high diastereoselectivities. These reactions constitute the first examples of
intramolecular cyclopropanation of an alkene by a gold carbene generated by electrophilic ring opening of a cyclopropene in the presence of
gold(I) chloride.
Homogeneous gold catalysis has become a particularly active
research area due to the exceptional ability of gold complexes
to act as carbophilic Lewis acids and hence activate unsaturated
compounds, notably alkynes, alkenes, and allenes, toward
nucleophilic attack.1 The formation of compounds containing
three-membered rings by gold-catalyzed reactions has elicited
considerable interest. Efficient intermolecular cyclopropanation
of olefins has been reported with gold carbenes generated from
diazoesters,2 from enynes by cycloisomerization,3-5 or from
propargylic esters by 1,2-acyl migration.6 Gold-catalyzed
reactions of enynes that proceed with intramolecular cyclo-
propanation of the olefin are also well-documented.1,3 In
particular, propargylic esters have been widely used as
valuable synthetic equivalents of R-diazoketones.7-9 How-
ever, for this latter class of substrates, a gold carbene is not
responsible for the cyclopropanation of the olefin which more
likely proceeds through nucleophilic attack of the alkene onto
(4) Lo´pez, S.; Herrero-Go´mez, E.; Pe´rez-Gala´n, P.; Nieto-Oberhuber,
C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 6029–6032. See
also ref 11.
(5) For one example of intermolecular cyclopropanation of styrene with
a gold carbene generated by cycloisomerization of a 2-alkynylaryl oxirane,
see: Lin, G.-Y.; Li, C.-W.; Hung, S.-H.; Liu, R.-S. Org. Lett. 2008, 10,
5059–5062.
(1) For selected reviews, see: (a) Fu¨rstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410–3449. (b) Hashmi, A. S. K. Chem. ReV.
2007, 107, 3180–3211. (c) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem.
ReV. 2008, 108, 3326–3350. (d) Li, Z.; Brouwer, C.; He, C. Chem. ReV.
2008, 108, 3239–3265. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
ReV. 2008, 108, 3351–3378. (f) Hashmi, A. S. K.; Rudolph, M. Chem. Soc.
ReV. 2008, 37, 1766–1775. (g) Shen, H. C. Tetrahedron 2008, 64, 3885–
3903. (h) Shen, H. C. Tetrahedron 2008, 64, 7847–7870. (i) Muzart, J.
Tetrahedron 2008, 64, 5815–5849. (j) Fu¨rstner, A. Chem. Soc. ReV. 2009,
38, 3208–3221.
(6) (a) Miki, K.; Ohe, K.; Uemura, S. Tetrahedron Lett. 2003, 44, 2019–
2022. (b) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 18002–18003. (c) Gorin, D. J.; Dube´, P.; Toste,
F. D. J. Am. Chem. Soc. 2006, 128, 14480–14481.
(7) (a) Fu¨rstner, A.; Hannen, P. Chem. Commun. 2004, 2546–2547.
(b) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc.
2004, 126, 8654–8655. (c) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed.
2006, 45, 2901–2904. (d) Fu¨rstner, A.; Hannen, P. Chem.sEur. J. 2006,
12, 3006–3019. (e) Boyer, F.-D.; Le Goff, X.; Hanna, I. J. Org. Chem.
2008, 73, 5163–5166. (f) Fu¨rstner, A.; Schlecker, A. Chem.sEur. J. 2008,
14, 9181–9191. (g) Moreau, X.; Goddard, J.-P.; Bernard, M.; Lemie`re,
G.; Lo´pez-Romero, J. M.; Mainetti, E.; Marion, N.; Mourie`s, V.; Thorim-
bert, S.; Fensterbank, L.; Malacria, M. AdV. Synth. Catal. 2008, 350, 43–
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Gala´n, P.; Delpont, N.; Echavarren, A. M. Tetrahedron 2009, 65, 1790–
1793, and references therein.
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10.1021/ol101741f  2010 American Chemical Society
Published on Web 08/20/2010

the activated alkyne, followed by stepwise 1,2-acyl migra-
tion.7-9 Intramolecular cyclopropanation of olefins has been
successfully achieved with cyclopropyl gold carbenes gener-
ated from enynes by cycloisomerization10,11 or with cyclo-
pentenylidene gold complexes produced by Nazarov-type
cyclization from vinyl allenes.12 However, due to their mode
of formation, such gold carbenes are unavoidably either
attached to or embedded in cyclic structures.
The rearrangement of cyclopropenes in the presence of
transition metal complexes is a well-known method for
generating metal vinylcarbene complexes.13 The implication
of cyclopropenes in gold-catalyzed reactions is relatively
recent, and not surprisingly, the observed reactivity stems
from the formation of gold-stabilized allylic carbocations or
gold carbenes.14-16 The actual nature of such species has
been a matter of discussion,16,17 but recent studies reveal
that the degree of bonding and the reactivity of such
organogold species depend on the substituents and the
ancillary ligand (Scheme 1).15-18
illustrated by the addition of alcohols to 3,3-dialkylcyclopro-
penes leading to allylic ethers,14c the isomerization of 1-aryl-
2-vinyl- or 3-aryl-cyclopropenes to indenes,14a,b and the
formation of regioisomeric mixtures of indenes and furanones
from 3-aryl-3-cyclopropene carboxylates.14c Additionally,
their carbenoid character was highlighted by examples of
intermolecular cyclopropanation of styrene or (Z)-stilbene
using 3,3-disubstituted cyclopropenes as substrates.14c,d,15
However, no examples of intramolecular cyclopropanation
of an alkene by an organogold, generated from cycloprope-
nes, have yet been disclosed.19
Herein, we report the first examples of gold-catalyzed
cycloisomerizations of cyclopropene derivatives that proceed
with intramolecular cyclopropanation of an olefin and lead
to 3-oxa- and 3-azabicyclo[4.1.0]heptanes in excellent yields
and with high diastereoselectivities.
Allyl cyclopropenylcarbinyl ethers or sulfonamides A were
considered as substrates to examine whether the allyl gold
cations resulting from their ring opening would achieve the
cyclopropanation of the remote olefin. Regioselectivity was
a first critical issue to consider. We surmised that for
cyclopropenes A attack of a gold(I) electrophilic species
would preferentially generate a secondary cyclopropyl cation
B. Subsequent ring opening would then produce the gold-
stabilized carbocation C regioselectively, a precursor of
3-oxa- and 3-azabicyclo[4.1.0]heptanes D if the planned
transformation could be successfully achieved. However,
substitution at C3 became mandatory to handle stable
cyclopropene derivatives, and allyl 3,3-dimethylcyclopro-
penylcarbinyl ethers or sulfonamides A (R′ ) Me) were thus
selected as substrates. Additionally, their synthesis was
readily achieved in two steps by addition of 3,3-dimethyl-
cyclopropenyllithium, generated in situ from 1,1,2-tribromo-
3,3-dimethylcyclopropane, to various aldehydes or N-tosyl-
aldimines, followed by alkylation with allylic bromides
(Scheme 2).20
Scheme 1. Reactivity of Cyclopropenes with Gold Catalysts
To date, allyl gold carbocations arising from the ring opening
of cyclopropenes have been intercepted by nucleophiles as
(8) For theoretical studies, see: (a) Nieto Faza, O.; Silva Lo´pez,
´
C.; Alvarez, R.; de Lera, A. R. J. Am. Chem. Soc. 2006, 128,
2434–2437. (b) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.;
Nolan, S. P.; Cavallo, L. Angew. Chem., Int. Ed. 2008, 47, 718–721.
(c) Soriano, E.; Marco-Contelles, J. Chem.sEur. J. 2008, 14, 6771–6779
.
(9) Formation of cyclopropanes from enynes connected through an
aromatic ring and bearing a propargylic acetate appeared to be promoted
by a cinnamyl gold carbene. See ref 7h.
(10) (a) Nieto-Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.;
Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402–
2406. (b) Nieto-Oberhuber, C.; Lo´pez, S.; Mun˜oz, M. P.; Jime´nez-Nu´n˜ez,
E.; Bun˜uel, E.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.sEur. J. 2006,
12, 1694–1702. (c) Kim, S. M.; Park, J. H.; Choi, S. Y.; Chung, Y. K.
Scheme 2
.
Gold-Catalyzed Cycloisomerization of
Cyclopropenes A
Angew. Chem., Int. Ed. 2007, 46, 6172–6175
.
(11) For examples of olefin cyclopropanation with allyl gold cations
generated from enynes bearing a propargyl ether, see: Jime´nez-Nu´n˜ez, E.;
Raducan, M.; Lauterbach, T.; Molawi, K.; Solorio, C. R.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2009, 48, 6152–6155
.
(12) Lemie`re, G.; Gandon, V.; Cariou, K.; Hours, A.; Fukuyama, T.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2009,
131, 2993–3006.
(13) For a review on transition metal chemistry of cyclopropenes, see:
Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117–3179.
(14) (a) Zhu, Z.-B.; Shi, M. Chem.sEur. J. 2008, 14, 10219–10222.
(b) Li, C.; Zeng, Y.; Wang, J. Tetrahedron Lett. 2009, 50, 2956–2959.
(c) Bauer, J. T.; Hadfield, M. S.; Lee, A.-L. Chem. Commun. 2008, 6405–
6407. (d) Zhou, Y.; Trewyn, B. G.; Angelici, R. J.; Woo, L. K. J. Am.
Chem. Soc. 2009, 131, 11734–11743. (e) After this manuscript was
submitted, gold-catalyzed cycloisomerization of enynes with cyclopropenes
have been also reported, see: (e) Li, C.; Zeng, Y.; Feng, J.; Zhang, Y.;
Initial studies were carried out with cyclopropene 1, and
the catalytic activity of various gold complexes was evaluated
(Table 1). Not surprisingly, no reaction took place with
(Ph3P)AuCl (Table 1, entry 1), but we were pleased to see
Wang, J. Angew. Chem., Int. Ed. 2010, 49, DOI: 10.1002/anie201002673
(15) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.; Goddard,
W. A., III; Toste, F. D. Nat. Chem. 2009, 1, 482–486
(16) Seidel, G.; Mynott, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2009,
48, 2510–2513
.
.
(19) Allylic argento-carbonium ions generated from aryl cyclopropenes
can achieve the cyclopropanation of the olefin of an allyl group at C3, see:
Padwa, A.; Blacklock, T. J.; Loza, R. J. Org. Chem. 1982, 47, 3712–3721.
(20) For the preparation of cyclopropenes A, see: (a) Simaan, S.;
Masarwa, A.; Zohar, E.; Stanger, A.; Bertus, P.; Marek, I. Chem.sEur. J.
2009, 15, 8449–8464. (b) Miege, F.; Meyer, C.; Cossy, J. Org. Lett. 2010,
12, 248–251.
.
(17) Fu¨rstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030–
5033
.
(18) Salvi, N.; Belpassi, L.; Tarantelli, F. Chem.sEur. J. 2010, 16, 7231–
7240
.
Org. Lett., Vol. 12, No. 18, 2010
4145

The scope of the cycloisomerization was then evaluated
with various cyclopropenylcarbinyl ethers 5-10 bearing
substituents on the allylic ether moiety (Table 2).
Table 1. Gold-Catalyzed Cycloisomerization of Cyclopropene 1
Table 2. Scope with Substituted Allylic Ethers
entry
catalyst
yielda
1
2
3
4
5
6
7
(Ph3P)AuCl
(Ph3P)AuOTf
(Ph3P)AuSbF6
(Ph3P)AuNTf2
AuCl3
0%b
79%
83%
93%
99%
98%
98%
AuBr3
AuCl
a Isolated yield of 2. b No reaction took place after 12 h at rt.
that cationic complexes generated in situ from (Ph3P)AuCl
and AgOTf or AgSbF6 smoothly catalyzed the desired
transformation (CH2Cl2, 0 °C, 15 min) to afford the oxa-
bicyclic compound 2 in good yields (Table 1, entries 2 and
3).21 The air-stable catalyst (Ph3P)AuNTf2 could be conve-
niently used (Table 1, entry 4),22 but it was discovered that
simple gold salts such as AuCl3, AuBr3, and AuCl provided
the highest yields in compound 2 (Table 1, entries 5-7).
The latter were equally effective, but AuCl was preferred
since it is less hygroscopic and easier to handle. In all these
reactions, the oxabicyclic compound 2 was obtained as a
single detectable diastereomer (dr > 96:4).23
Attempts to determine the relative configuration of 2 by NMR
(nOe experiments) were unsuccessful. Therefore, 2 was con-
verted to the crystalline p-nitrobenzoate 3 by a two-step
sequence involving cleavage of the benzyl ether under reductive
conditions followed by esterification of the resulting alcohol
with p-nitrobenzoic acid (94%, two steps from 2). The structure
of 3 was unambiguously established by single-crystal X-ray
diffraction indicating an anti relative orientation between the
cyclopropane and the benzyloxymethyl group.24 It was also
shown that the use of gem-dimethyl-cyclopropenes A as
substrates did not represent a limitation as the isopropylidene
substituent in the cycloisomerization product 2 could be readily
cleaved by ozonolysis to provide the 3-oxabicyclo[4.1.0]heptan-
5-one (4) (86%) without epimerization (Scheme 3).25
a Reaction conditions: AuCl (5 mol %), CH2Cl2 (0.05 M), 0 °C. b Isolated
yield of the major diastereomer.
Intramolecular cyclopropanation of R,R-disubstituted (Table
2, entry 1) or R,ꢀ-disubstituted (Table 2, entries 2 and 3) and
R,ꢀ,ꢀ-trisubstituted olefins (Table 2, entries 4-6) induced by
intermediate allyl gold carbenes proceeded equally well, and
the corresponding 3-oxabicyclo[4.1.0]heptanes 11-16 were
isolated in good to excellent yields (72-99%). Except the
cycloisomerization of methallyl ether 5 which led to 11 (72%)
accompanied by a minor diastereomer (dr ) 87:13), all the other
oxabicyclic compounds 12-16 were generated as single detect-
able diastereomers.23 The cycloisomerization of the (E)-allylic
ethers 6 and 7 took place with retention of the olefin configu-
ration in the final cyclopropanes 12 and 13.25 The stereospeci-
ficity of the cyclopropanation process was confirmed by the
behavior of geranyl ether 9 and neryl ether 10 which led to the
Scheme 3. Determination of the Relative Configuration of 2 and
Access to 3-Oxabicyclo[4.1.0]heptan-5-one (4)
(21) AgSbF6 itself also catalyzed the formation of 2; however, the
reaction was not as clean as with gold salts, and traces of generated
byproducts were difficult to separate. Decomposition of 1 was observed in
the presence of TfOH. No reaction took place with p-TsOH in C6H6. See:
Al-Dulayymi, J. R.; Baird, M. S. Tetrahedron 1990, 46, 5703–5714.
(22) Me´zailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–
4136.
(23) The diastereoselectivity was determined by analysis of the 1H NMR
spectrum of the crude material.
(24) CCDC 773862 (3) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
4146
Org. Lett., Vol. 12, No. 18, 2010

epimeric cycloisomerization products 15 (97%) and 16 (99%),
respectively (Table 2, entries 5 and 6).25
36 both in 99% yield (Table 3, entries 9 and 10). As observed
previously in the allylic ether series (Table 2, entry 1), the
diastereoselectivity was lower for the methallyl-substituted
sulfonamide 26 which provided the azabicyclic compound
36 as a 92:8 mixture of diastereomers (Table 3, entry 10).
The gem-dimethyl group, which was crucial for substrate
stability, presumably has a marked influence not only on the
regioselectivity but also on the diastereoselectivity of the
cycloisomerization of cyclopropenes A.26 Since intramolecular
cyclopropanation of the alkene induced by the gold-stabilized
carbocation/gold carbene should proceed through a six-
membered cyclic reactive conformer, the isopropylidene group
should force the adjacent R substituent to occupy a pseudoaxial
position to minimize allylic 1,3-strain. A chairlike transition
state, which would predict the opposite sense of stereoinduction,
may be disfavored as the R group, and the gold center would
be both in an axial position. However, a twist-boat transition
state would nicely account for the observed stereochemical
outcome and explain the lower diastereoselectivity observed for
methallyl ethers or sulfonamides (R3 ) Me) due to steric
interactions between the methyl and both the gold center and
the R substituent (Scheme 4).
The reactivity of a variety of cyclopropenylcarbinyl ethers
or sulfonamides A was next investigated (Table 3). As for
substrates 1 and 5-10 substituted by a benzyloxymethyl
group, the diastereoselectivity and the yields of the cyclo-
isomerization were excellent for cyclopropenes 17-24
having a benzylic ether at the remote position of an n-propyl
chain (Table 3, entry 1) or if the chain was branched (Table
Table 3. Cycloisomerization of Cyclopropenes A
Scheme 4. Rationalization of the Stereochemical Outcome
In conclusion, we have reported the first examples of gold-
catalyzed cycloisomerization of cyclopropenes in which the
intermediate gold carbenes promote the intramolecular cyclopro-
panation of an alkene leading to 3-oxa- and 3-azabicyclo[4.1.0]-
heptanes with high diastereoselectivity. These reactions further
expand the interest of gold carbenes in cyclopropanation and appear
complementary to other gold-catalyzed reactions as a route to
bicyclo[n.1.0]alkanes.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR data for all compounds and
crystallographic data (CIF fomat) for compound 3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101741F
(25) The relative configuration of 4 was determined by NMR (nOe).
The relative orientation of the cyclopropane substituent (Ph and
CH2OTBDPS) with the ring junction hydrogens in compounds 12 and 13
was determined by 1H NMR (see Supporting Information). The relative
configuration of the other bicyclo[4.1.0]heptanes was assigned by analogy
with the results for compounds 2, 12, and 13.
(26) For a cyclopropenylcarbinyl ether bearing a methyl at C2 and
lacking the gem-dimethyl group, the cycloisomerization seems to occur with
a lower level of regio- and diastereoselectivity. The behavior of cyclopro-
penes bearing various substitution patterns is currently under investiga-
tion.
a Reaction conditions: AuCl (5 mol %), CH2Cl2 (0.05 M), 0 °C.
3, entries 2-8), whatever the relative configuration of the
two stereogenic centers or the substituents on the allylic ether
moiety.23 Preliminary results also indicate that 3-azabicyclo-
[4.1.0]heptanes are accessible by the cycloisomerization of
sulfonamides 25 and 26 which afforded compounds 35 and
Org. Lett., Vol. 12, No. 18, 2010
4147