Rhodium-catalyzed cycloisomerization involving cyclopropenes: Efficient stereoselective synthesis of medium-sized heterocyclic scaffolds

Article abstract of DOI:10.1002/anie.201101220

A happy medium: The title reaction of cyclopropenyl carbinols and carbinylamines gives carbo- and heterocycles with a [6.1.0] bicyclic ring fused to an aromatic ring (see scheme, Alloc=allyloxycarbonyl, Boc=tert- butyloxycarbonyl). These reactions are the first examples of the formation of medium-sized rings by the intramolecular cyclopropanation of an alkene with a donor-substituted rhodium carbenoid, which is not generated from a diazo compound.

Full text of DOI:10.1002/anie.201101220

Communications
DOI: 10.1002/anie.201101220
Rhodium Catalysis
Rhodium-Catalyzed Cycloisomerization Involving Cyclopropenes:
Efficient Stereoselective Synthesis of Medium-Sized Heterocyclic
Scaffolds
Frꢀdꢀric Miege, Christophe Meyer,* and Janine Cossy*
The intramolecular cyclopropanation of an olefin using a
carbene that is generated by the decomposition of a diazo
compound in the presence of a catalytic amount of a
transition-metal complex, is a powerful strategy for the
synthesis of [n.1.0] bicyclic ring systems.[1] In recent years,
Scheme 2. Metal carbenes by ring opening of cyclopropenes.
the transition-metal-catalyzed cycloisomerization of enynes
has emerged as a useful complementary alternative method
that avoids the use of the potentially hazardous diazo
compounds.[2,3] In particular, the platinum- and gold-cata-
lyzed cycloisomerization of enynes has attracted considerable
interest. The selective activation of the alkyne by these Lewis
p acids triggers the nucleophilic attack of the alkene and
generates a metal carbene intermediate, the [n.1.0] bicyclic
core of which can be retained in the final product depending
on the substitution pattern.[2,4]
In particular, enynes A, which contain a propargylic ester,
constitute interesting synthetic equivalents of a-diazo ketones
since the initially generated cyclopropyl carbenes B can
evolve by a 1,2-acyl shift to give enol esters C that produce
bicyclo[n.1.0]alkanones D, which include those possessing
medium-sized rings, after cleavage of the acyl group
(Scheme 1, Eq. (1)).[5] The alternative mechanism, in which
the 1,2-acyl shift leading to a metal carbene intermediate
precedes the cyclopropanation of the olefin,[6,7] can also
operate for some substrates, such as the benzylic propargylic
esters E. The cycloisomerization of E proceeds via the gold
carbene intermediate F and leads to medium-sized rings G,
which can be enantioenriched if chiral diphosphanes are used
as ligands (Scheme 1, Eq. (2)).[8]
The development of an efficient route toward bicyclo-
[n.1.0]alkanes of various ring sizes and substitution patterns,
which relies on a transition-metal-catalyzed intramolecular
olefin cyclopropanation using carbenes that are not generated
from diazo compounds, is an interesting challenge. Because of
their ability to undergo ring opening in the presence of
transition-metal complexes, cyclopropenes are interesting
precursors of alkenyl carbenes,[9] which can be viewed not
only as synthetic equivalents of alkenyl diazoalkanes, but also
of a-diazo ketones if the generated olefin is later subjected to
an oxidative cleavage (Scheme 2).
The reactivity of alkenyl rhodium carbenoids, which are
generated by the rhodium-catalyzed reaction of a-diazo
ketones with alkynes, has been the subject of considerable
investigation.[10–12] Examples of intramolecular trapping with
an alkene of such vinylogous acceptor-substituted carbe-
noids,[13] which can in principle also be generated by the ring
opening of cyclopropenyl ketones, have been reported.[10–12]
However, the synthetic potential of a transition-metal-cata-
lyzed cycloisomerization of appropriately substituted cyclo-
propene-enes that proceeds through the intramolecular cyclo-
propanation of the remote olefin, remains largely unexplored.
The silver-catalyzed rearrangement of 3-allyl-1,2-diphenyl-
cyclopropene into the corresponding substituted bicyclo-
[3.1.0]hex-2-ene constitutes one of the first examples of such
a process.[14] Recently, we have reported the gold-catalyzed
cycloisomerization of cyclopropene-enes H, thus leading to
the 3-oxa- or 3-azabicyclo[4.1.0]heptanes I in high yields and
excellent diastereoselectivities.[15,16] Since the isopropylidene
group can undergo subsequent ozonolysis to afford the
corresponding [4.1.0]bicycloheptan-2-ones J,[15] this strategy
favorably compares with the copper-catalyzed intramolecular
cyclopropanation of the corresponding a-diazo d-alkenyl
ketones,[17] in terms of efficiency and diastereoselectivity
(Scheme 3).
Scheme 1. Cycloisomerization of enynes bearing a propargyl ester.
[*] F. Miege, Dr. C. Meyer, Prof. Dr. J. Cossy
Laboratoire de Chimie Organique
ESPCI ParisTech, CNRS (UMR 7084)
10 rue Vauquelin 75231 Paris Cedex 05—France
Fax : (+33)1-40-79-46-60
E-mail: christophe.meyer@espci.fr
janine.cossy@espci.fr
Herein, we report a new highly efficient and diastereose-
lective rhodium-catalyzed cycloisomerization of cyclopro-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101220.
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anticipated, the monosubstituted cyclopropene olefin in 1,
the stability of which is ensured by the vicinal gem-dimethyl
group, underwent regioselective electrophilic activation by
[Rh2(OAc)4] to generate the secondary cyclopropyl cation 3,
which has the rhodium atom at the less-hindered site. Ring
opening of cation 3 would then generate the rhodium
carbenoid 4 that promotes the intramolecular cyclopropana-
tion of the alkene (Scheme 4). Rationalization of the
observed high diastereoselectivity deserves further investiga-
tion but the gem-dimethyl substitution of the olefin in the
rhodium carbenoid 4 is presumably a key control element,
owing to minimization of the A1,3 strain in the cyclic transition
state, as previously observed in the gold-catalyzed cyclo-
isomerization of cyclopropenes H.[15]
Scheme 3. Gold-catalyzed cycloisomerization of cyclopropene-ene com-
pounds. Ts=p-toluenesulfonyl.
pene-enes that does not involve diazo compounds. This
reaction proceeds by an intramolecular olefin cyclopropana-
tion to afford functionalized unusual heterocyclic scaffolds,
which possess a [6.1.0] bicyclic ring system fused to an
aromatic ring.
The conversion of cyclopropene 1 into benzoxocane 2 is
clearly distinct from the previously reported rhodium-cata-
lyzed cycloisomerizations that involve cyclopropenes and
proceed by a ring-opening reaction.[24] Notably the donor-
substituted rhodium(II) carbenoid 4 displays an unprece-
dented high reactivity toward the olefin cyclopropanation,
despite its lower electrophilicity compared with rhodium
carbenoids that are generated from a-diazo carbonyl com-
pounds that bear at least one electron-withdrawing group.[1,13]
The scope of this new rhodium-catalyzed cycloisomeriza-
tion involving cyclopropenes was first evaluated with (2-
allyloxyphenyl)cyclopropenyl carbinols 5–11, which bear a
variety of substituents on the aromatic ring, and were
synthesized in two steps from the corresponding substituted
salicylaldehydes.[25] Unsurprisingly, when a methyl or a
methoxy group was present on the aromatic ring the
corresponding cycloisomerization products 12 and 13 were
isolated in 99% and 97% yield (Table 1, entries 1 and 2). The
5-fluoro-, 5-bromo-, or 3-bromo-substituted analogues 7–9,
also underwent a clean rhodium-catalyzed cycloisomerization
to provide the corresponding eight-membered oxygen hetero-
cycles 14–16, in high yields (Table 1, entries 3–5). The
presence of a bromide substituent, which could be potentially
useful for further functionalization, was tolerated, and a nitro
group was also compatible, as exemplified by the cyclo-
isomerization of cyclopropenyl carbinol 10 leading to com-
pound 17 (Table 1, entry 6). The alkynyl substituent in the
cyclopropenyl carbinol 11 did not interfere with the reaction
and the corresponding cycloisomerization product 18 was
isolated in almost quantitative yield (Table 1, entry 7). In all
To cycloisomerize cyclopropene-enes into medium-sized
heterocycles, the reactivity of cyclopropenyl carbinol 1
(Scheme 4), which is readily available by condensation of
3,3-dimethylcyclopropenyl lithium to O-allyl salicylalde-
hyde,[18] was investigated in the presence of gold catalysts.
Whereas AuCl3 (5 mol%) led to the complete conversion of 1
within 1 hour (CH2Cl2, RT), the reaction did not go to
completion with AuCl (2/1 = 60:40 after 12 h); in both cases,
the expected cycloisomerized product 2 was accompanied by
several unidentified by-products that could not be easily
removed by flash chromatography on silica gel. The catalysts
[(Ph3P)AuSbF6] and [(Ph3P)AuNTf2] (Tf = trifluoromethane-
sulfonyl)[19] were even less satisfactory and led to complex
mixtures that contained either none ([(Ph3P)AuSbF6]) or
trace amounts of compound 2 ([(Ph3P)AuNTf2]). The use of
rhodium catalysts was then considered, and [Rh2(OAc)4]
(0.5 mol%) was found to smoothly catalyze the cycloisom-
erization of cyclopropenyl carbinol 1 into the desired eight-
membered oxygen heterocycle 2, which possesses a [6.1.0]
bicyclic ring system, in almost quantitative yield (99%) and
with excellent diastereoselectivity (d.r. ꢀ 97:3).[20] The relative
configuration of 2 was unambiguously determined by single-
crystal X-ray diffraction of the corresponding p-nitroben-
zoate derivative.[21]
Other rhodium(I) and rhodium(II) catalysts were also
screened but provided inferior results.[22] Notably the cyclo-
isomerization of the optically enriched (S)-1 (94% ee) led to 2
with the same optical purity, thereby indicating that the
hydroxy-substituted stereocenter was not affected.[23] As
1
cases, only a single diastereomer was detected by H NMR
spectroscopy (d.r. ꢀ 96:4).
The scope of the cycloisomerization was then evaluated
with (2-allyloxyphenyl)cyclopropenyl carbinols 19–23, which
bear substituted allylic ethers (Table 2).[25] Methallyl ether 19
gave the eight-membered oxygen heterocycle 24 (95%),
which possesses a trisubstituted cyclopropane, as a single
detectable diastereomer (Table 2, entry 1). An iodide sub-
stituent was tolerated, as shown for cyclopropene 20, which
led to the benzoxocane 25 in 96% yield (Table 2, entry 2). The
cinnamyl ether 21 was converted into the oxygen heterocycle
26 (99%), which bears an additional stereocenter on the
cyclopropane ring, as a single diasteromer (Table 2, entry 3).
As anticipated, the cycloisomerization proceeds with the
stereospecific cyclopropanation of the alkene; this stereo-
Scheme 4. Rhodium-catalyzed cycloisomerization of cyclopropenyl car-
binol 1.
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Communications
Table 1: Scope of the rhodium-catalyzed cycloisomerization of substi-
tuted (2-allyloxyphenyl)cyclopropenyl carbinols.
Table 2: Scope of the rhodium-catalyzed cycloisomerization.
Entry
Substrate
Product[a]
Yield
[%][b]
Entry
Substrate
Product[a]
Yield
[%][b]
1
2
19 R=Me
20 R=I
24 R=Me
25 R=I
95
96
1
2
5
6
12
13
99
97
3
4
21
22
26
27
90
95
3
4
7 X=F
8 X=Br
14 X=F
15 X=Br
91
95
5
23
28
98
[a] Reaction conditions: [Rh2(OAc)4] (0.5 mol%), CH2Cl2 (0.1m), RT,
0.5 h. [b] Yield of the isolated, analytically pure product (d.r. ꢀ96:4).
PMB=p-methoxybenzyl.
5
6
9
16
17
99
99
the eight-membered oxygen heterocycle 35 (Table 3, entry 2).
Interestingly, the hydroxy group could be replaced by an
amino substituent, as illustrated with the N-(tert-butoxycar-
bonyl)cyclopropenylcarbinyl amines 31 and 32, which were
easily prepared by the addition of 3,3-dimethylcyclopropenyl
lithium to the corresponding substituted N-Boc aldimines.[26]
The latter substrates underwent a slow cycloisomerization
(20 h, RT), the diastereoselectivity of which was difficult to
evaluate accurately by 1H NMR spectroscopy because of the
presence of rotamers. Thus, the crude cycloisomerization
products were directly treated with TFA to afford the amino-
substituted oxygen heterocycles 36 and 37 as single diaste-
reomers (d.r. ꢀ 96:4), isolated in 60% and 63% overall yield,
respectively (Table 3, entries 3 and 4). Preliminary results also
indicate that the rhodium-catalyzed cycloisomerization could
be applied to the synthesis of eight-membered nitrogen
heterocycles from N-allyl carbamates such as 33. After
palladium-catalyzed cleavage of the allyloxycarbamoyl pro-
tecting group, the desired benzazocane 38 was obtained as a
single diastereomer and isolated in 50% yield (unoptimized;
Table 3, entry 5).[27]
10
7
11
18
99
[a] Reaction conditions: [Rh2(OAc)4] (0.5 mol%), CH2Cl2 (0.1m), RT,
0.5 h. [b] Yield of isolated, analytically pure product (d.r. ꢀ96:4).
specificity is illustrated by the reaction of the geometric
isomers 22 and 23, which ultimately led to epimeric com-
pounds 27 (95%) and 28 (98%), respectively (Table 2,
entries 4 and 5).
Whether the 2-allyloxy ether linkage and the presence of
the hydroxy group at the benzylic position were crucial for the
success of the rhodium-catalyzed cycloisomerization was next
investigated (Table 3). The allyloxy substituent could be
replaced by a but-3-enyl group, as shown for compound 29,
which was efficiently converted into benzocyclooctane 34 in
high yield (99%), albeit with slightly inferior diastereoselec-
tivity (Table 3, entry 1). Removal of the benzylic hydroxy
group also had no adverse effect on the reactivity since the (2-
allyloxybenzyl)cyclopropene 30 was smoothly converted into
To illustrate that 3,3-dimethylcyclopropenes could be
considered as a-diazo ketone surrogates, compounds 12, 14,
and 24 were subjected to ozonolysis after protection of the
alcohol as an acetate. The a-acetoxy cyclopropyl ketones 39
(94%), 40 (90%), and 41 (97%) were synthesized in excellent
yields over the two-step sequence (Scheme 5). Ozonolysis
could also be carried out without protection of the hydroxy
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Angew. Chem. Int. Ed. 2011, 50, 5932 –5937

Table 3: Scope of the rhodium-catalyzed cycloisomerization.
In conclusion, we have reported a new rhodium(II)-
catalyzed cycloisomerization of cyclopropenes that does not
rely on diazo compounds as substrates or precursors, and in
which the donor-substituted rhodium carbenoid generated by
ring opening achieves the highly diastereoselective intra-
molecular cyclopropanation of an alkene. The starting cyclo-
propene-ene substrates are readily prepared from salicyl-
aldehydes, and their rhodium-catalyzed cycloisomerization
efficiently provides access to new functionalized carbocycles
or heterocyclic scaffolds that contain a [6.1.0] bicyclic system
fused to an aromatic ring.[31] We are currently exploring the
reactivity of these donor-substituted rhodium(II) carbenoids
generated from cyclopropenes in other synthetically useful
transformations.
Entry
Substrate
Product[a]
t
Yield
[%][b]
[h]
1
2
29
30
34 (d.r.=93:7)
0.5
99
93
35
0.75
Received: February 17, 2011
Published online: May 12, 2011
Keywords: carbenoids · cyclopropanation · diastereoselectivity ·
homogeneous catalysis · rhodium
.
3
4
31 R=H
32 R=Br
36 R=H
37 R=Br
20
20
60[c]
63[c]
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33
38
1
50[d]
[a] Reaction conditions: [Rh2(OAc)4] (0.5 mol%), CH2Cl2 (0.1m), RT.
[b] Yield of the isolated, analytically pure product (d.r. ꢀ96:4, unless
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Scheme 5. Transformation of the cycloisomerization products into
cyclopropyl ketones and cyclopropyl carbinols. DMAP=4-dimethylami-
nopyridine.
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www.angewandte.org
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copy and supercritical fluid chromatography. For an accurate
unambiguous determination, a mixture of 2 and its epimer 2’ (2/
2’ = 60:40) was prepared by oxidation (MnO2, CH2Cl2, reflux)
followed by reduction with DIBAL-H (CH2Cl2, À788C).
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ccdc.cam.ac.uk/data_request/cif.
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appeared satisfactory, at least under the same mild reaction
conditions. [(Ph3P)3RhCl] showed no catalytic activity, in situ
generated [(Ph3P)3RhOTf] led to a complex mixture of products,
and [{(cod)RhCl}2] (cod = 1,5-cyclooctadiene) provided only
traces of 2 after 24 h at RT, along with unreacted 1 and other
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see: Ref. [24i] and k) A. Padwa, J. M. Kassir, S. L. Xu, J. Org.
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[25] The requisite substrates 5–11 and 19–23 were prepared in two
steps from the corresponding salicylaldehydes, see the Support-
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[27] A seven-membered ring by-product arising from the rhodium
[31] Preliminary results suggest that the method should be extended
to the formation of similar heterocyclic scaffolds possessing a
[7.1.0] bicyclic structure. In the absence of an aromatic linker,
products arising from C–H insertion are predominantly
obtained.
À
carbenoid insertion into the C H bond a to the nitrogen atom,
was also detected (see the Supporting Information).
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