Ring-rearrangement metathesis of cyclopropenes: Synthesis of heterocycles

Article abstract of DOI:10.1021/ol9025606

(Figure presented) Cyclopropenes substituted by an unsaturated side chain have been successfully involved in ring-rearrangement metatheses leading to heterocyclic compounds, thereby expanding the synthetic potential of metathesis reactions with this class

Full text of DOI:10.1021/ol9025606

ORGANIC
LETTERS
2010
Vol. 12, No. 2
248-251
Ring-Rearrangement Metathesis of
Cyclopropenes: Synthesis of
Heterocycles
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 November 4, 2009
ABSTRACT
Cyclopropenes substituted by an unsaturated side chain have been successfully involved in ring-rearrangement metatheses leading to heterocyclic
compounds, thereby expanding the synthetic potential of metathesis reactions with this class of highly strained cycloalkenes.
Ring-rearrangement metathesis (RRM) involves the sequen-
tial combination of ring-opening metathesis (ROM) and ring-
Scheme 1. Ring-Rearrangement Metathesis
closing metathesis (RCM). According to this process, an
equilibrium can be established between cycloalkene deriva-
tives A, bearing an unsaturated side chain, and unsaturated
carbo- or heterocycles B in the presence of a metathesis
initiator (Scheme 1).1-7
The position of this equilibrium is affected by thermody-
namic parameters and notably by the difference of ring strain
between the two unsaturated rings in compounds A and B,
as well as their substitution pattern. Kinetic effects can also
affect the rates of formation of the possible metallacyclobu-
tane intermediates depending on the steric and electronic
environment of the reacting metal carbene and its olefinic
(1) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 6634–6640
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(2) For examples of RRM involving ROM of cyclobutenes, see:
(a) White, B. H.; Snapper, M. L. J. Am. Chem. Soc. 2003, 125, 14901–
14904. (b) Nicolaou, K. C.; Vega, J. A.; Vassilikogiannakis, G. Angew.
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Chem. Soc. 2006, 128, 6306–6307. (d) Mori, M.; Wakamatsu, H.; Tonogaki,
(5) For the synthesis of nitrogen heterocycles by RRM with ROM of
medium-size cycloalkenes, see: (a) Stragies, R.; Blechert, S. Tetrahedron
1999, 55, 8179–8188. (b) Voigtmann, U.; Blechert, S. Synthesis 2000, 893–
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(3) For RRM with ROM of bicyclic alkenes, see: (a) Stragies, R.;
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.
10.1021/ol9025606  2010 American Chemical Society
Published on Web 12/08/2009

partner. RRM has been applied to the preparation of highly
substituted carbocycles and heterocycles and has been used
as a key step in several total syntheses of natural products.1-7
In RRM, the endocyclic olefin involved in the ROM can be
a medium sized cycloalkene;1,5,6 however, bicyclic alk-
enes1,3,4 and cyclobutenes1,2,5 exhibit a higher reactivity
owing to their ring strain. Surprisingly, to our knowledge,
the highly strained cyclopropenes8 have not been involved
in RRM. It is known that Mo- or Ru-alkylidenes can initiate
the ROM polymerization of a few 3,3-disubstituted cyclo-
propenes.9 Though the hindered 3,3-diphenyl-cyclopro-
pene was found to be unreactive in ROM-cross-metathesis
(CM),10 cyclopropenone ketals have been identified as useful
partners in such processes.11,12 The terminal olefin generated
by ROM-CM of cyclopropenone ketals did not react further,
but after hydrolysis of the ketal, the resulting divinyl ketone
could be involved in a subsequent CM. This methodology
has been applied to the synthesis of natural products.12
Recently, enantio- and diastereoselective ROM-CM of 3,3-
disubstituted cyclopropenes were also reported as a useful
tool for the stereocontrolled formation of quaternary cen-
ters.13 Despite these reports, the behavior of a wider variety
of cyclopropenes, bearing tri- or tetrasubstituted endocyclic
olefins, in metathesis reactions is a rather unexplored field.
Recent progress in the synthesis of cyclopropene deriva-
tives14 encouraged us to examine RRM involving such
compounds as a route to heterocycles, and we would like to
report herein our results.
strates. Owing to the release of ring strain, it was anticipated
that their RRM would be favorable and should allow access to
heterocycles E and F, respectively (Scheme 2).
Scheme 2. RRM of Substituted Cyclopropenes
Several cyclopropenes C were synthesized from the
cyclopropenecarboxylic ester 2, easily prepared by rhodium-
catalyzed cyclopropenation of the terminal alkyne 1 with
ethyl diazoacetate (57%).15Saponification of ester 2 led to
acid 3 (66%) which was alkylated with allyl bromide to
afford allyl ester 4 (90%). Alternatively, reduction of ester
2 generated the primary alcohol 5 (87%) which was
converted to allyl ether 6 (73%) or condensed with acryloyl
chloride to deliver acrylate 7 (84%). Alcohol 5 was also
engaged in a Mitsunobu reaction with N-allyl-2-nitroben-
zenesulfonamide leading to sulfonamide 8 (60%) (Scheme 3).
For this study, substituted cyclopropenes C, possessing a
trisubstituted cyclic olefin, as well as derivatives of cyclopro-
penylcarbinyl alcohols or amines D were considered as sub-
Scheme 3. Preparation of Cyclopropenes C
(6) For the synthesis of oxygen heterocycles by RRM with ROM of
medium-size cycloalkenes, see: (a) Harrity, J. P. A.; Visser, M. S.; Gleason,
J. D.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 1488-1489.
(b) Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.; Hoveyda, A. H.
J. Am. Chem. Soc. 1998, 120, 8340–8347. (c) Adams, J. A.; Ford, J. G.;
Stamatos, P. J.; Hoveyda, A. H. J. Org. Chem. 1999, 64, 9690-9696.
(d) Burke, S. D.; Quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63, 8626–
8627.
(7) RRM can be combined with other metathesis processes in a domino
fashion (RCM or CM), see: (a) Hart, A. C.; Phillips, A. J. J. Am. Chem.
Soc. 2006, 128, 1094–1095. (b) Arjona, O.; Csa´ky¨, A. G.; Murcia, M. C.;
Plumet, J. Tetrahedron Lett. 2000, 41, 9777–9779. (c) Arjona, O.; Csa´ky¨,
A. G.; Medel, R.; Plumet, J. J. Org. Chem. 2002, 67, 1380–1383. (d) Funel,
J.-A.; Prunet, J. Synlett 2005, 235–238.
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9, 719–732. (d) Baird, M. S. Top. Curr. Chem. 1988, 144, 137–209.
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(b) Biewalski, C. W.; Grubbs, R. H. Prog. Polym. Sci. 2007, 32, 1–29.
(c) Singh, R.; Czekelius, C.; Schrock, R. R. Macromolecules 2006, 39, 1316–
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Wang, D.; Ku¨hnel, C.; Buchmeiser, M. R. Macromolecules 2008, 41, 8405–
8412.
Cyclopropenes D (with R′′ ) H) were prepared from the
trihalocyclopropanes 9a and 9b.16,17 Treatment with n-BuLi
(2 equiv) generated the corresponding lithiated cyclopropenes
10a and 10b, and subsequent addition of benzyloxyacetaldehyde
or 3-tert-butyldimethylsilyloxy-butanal afforded cyclopropenyl-
carbinols 11a (85%), 11b (62%) and 12a (84%), 12b (73%),
respectively. Several derivatives were then synthesized by
alkylation with allyl bromide [13a (92%), 13b (77%), 14a
(86%), and 14b (74%)], acylation with acryloyl chloride [15a
(89%), 15b (74%)], or silylation with allyldimethylsilyl chloride
[16a and 16b (unpurified)]. Alternatively, 10a and 10b were
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53, 16511–16520.
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Org. Lett., Vol. 12, No. 2, 2010
249

condensed with N-tosylbenzaldimine, and subsequent allylation
of the intermediate secondary sulfonamides provided 17a (67%)
and 17b (46%) (Scheme 4).
Table 1. RRM of Cyclopropenes C
Scheme 4. Preparation of Cyclopropenes D
also investigated. Thus, allyldimethylsilyl ethers 16a and 16b
underwent efficient RRM, and the corresponding sensitive
cyclic siloxanes were immediately treated with MeLi to
provide the allylic silanes 26a (73%) and 26b (62%). Finally,
RRM of sulfonamides 17a and 17b proceeded smoothly and
afforded pyrrolines 27a (99%) and 27b (70%) (Table 2).
The RRM of the substituted cyclopropenes C was then
investigated. When allyl ester 4 was treated with Grubbs second-
generation catalyst [Grubbs II (2.5 mol %), CH2Cl2, reflux]
under an atmosphere of ethylene, no conversion occurred. Under
more forcing conditions (toluene, reflux), only 1,4-diene 18
resulting from ROM-CM of the cyclopropene with ethylene
was isolated (43%). RCM of the latter compound could be
achieved subsequently, provided that Ti(Oi-Pr)4 was used as
an additive, and led to the desired ꢀ,γ-unsaturated δ-lactone
19 (64%).18 The RRM of the allylic ether 6 occurred under
milder conditions (CH2Cl2, reflux), but the yield of dihydropyran
20 could be significantly improved under an ethylene atmo-
sphere (57% vs 40%). Acrylate 7 exhibited a lower reactivity
since no conversion was observed in refluxing CH2Cl2, even
in the presence of ethylene. More forcing conditions were
required to achieve the RRM of this substrate (ethylene, C6H6,
reflux) leading to the R,ꢀ-unsaturated lactone 21 (64%). Under
similar conditions, the RRM of sulfonamide 8 delivered tetrahy-
dropyridine 22 along with a minor regioisomer 22′ which was
detected by NMR in this case (22:22′ ) 87:13, 68%) (Table 1).
The RRM of cyclopropenes D (with R′′ ) H) was then
investigated. Treatment of allyl ethers 13a, 13b, 14a, and
14b with Grubbs II [(2.5 mol %), CH2Cl2, reflux] led in high
yields to the corresponding dihydrofurans 23a (87%), 23b
(83%), 24a (82%), and 24b (92%), respectively, and it is
noteworthy that the presence of ethylene was not required.
RRM of acrylates 15a and 15b turned out to be more difficult
as Grubbs II failed to initiate the reaction in refluxing CH2Cl2.
Fortunately, the use of toluene led to lactones 25a (41%)
and 25b (50%), albeit in modest yields, but switching to
Grela’s catalyst19 significantly improved the yield in 25a
(66%). The preparation of other classes of heterocycles was
Table 2. RRM of Cyclopropenes D
250
Org. Lett., Vol. 12, No. 2, 2010

These results indicate that cyclopropenes are valuable
partners in usual RRM and that their reactivity can be
controlled in spite of their high strain.
Scheme 6. RRM of Cyclopropenes D
As there are two olefins in cyclopropenes C and D, different
mechanistic pathways may intervene. For cyclopropenes C,
initiation at the less congested exocyclic terminal alkene leading
to alkylidene ruthenium complex [Ru]-I may be kinetically
favored, but subsequent RCM-ROM would imply the forma-
tion of the highly strained tricyclic metallacyclobutanes [Ru]-II
and/or [Ru]-III, to reach intermediates [Ru]-IV or [Ru]-V,
which is rather unlikely. Thus, ROM should preferentially occur
first and generate ruthenium carbenes [Ru]-VI and/or
[Ru]-VII, the latter species being presumably favored for steric
reasons. This would explain why heterocycles E (and not G)
are preferentially formed. Also noteworthy is that the presence
of ethylene is beneficial, if not necessary, for RRM of
cyclopropenes C, presumably because equilibria are shifted
toward trienes H. Thus, the success of the RRM process would
depend on the ability of trienes H to undergo efficient RCM to
heterocycles E (Scheme 5).
formation of larger ring-size heterocycles I from substrates
D bearing a trisubstituted exocyclic alkene (R′′ * H). Thus,
prenyl ether 28 was synthesized by alkylation of 11a with
prenyl bromide (85%). As anticipated, the RRM produced a
mixture of the five-membered ring 29 and the seven-
membered ring 30 in a 40/60 ratio (97%) confirming the
influence of an initial ROM event of the cyclopropene on
the regioselectivity of the RRM of substrates D (Scheme 7).
Scheme 5. RRM of Cyclopropenes C
Scheme 7. RRM of a Cyclopropenylcarbinyl Prenyl Ether
In conclusion, we have significantly expanded the synthetic
potential of metathesis reactions with cyclopropenes by
demonstrating that such substrates can be successfully
involved in RRM to provide a variety of heterocyclic
compounds.
The RRM of cyclopropenes D (Scheme 6), which is easier
than for cyclopropenes C and does not necessitate ethylene,
is likely to be initiated at the kinetically favored less hindered
exocyclic alkene (R′′ ) H) leading to carbene [Ru]-VIII.
After RCM-ROM, the resulting [Ru]-IX would propagate
the catalytic cycle by reaction with the substrate to afford
heterocycles F. The possibility that ROM occurred simul-
taneously cannot be ruled out especially for acrylates 15a,b
since initiation at an electron-deficient exocyclic alkene may
be less favorable. ROM would then generate carbenes
[Ru]-X and/or [Ru]-XI, and their subsequent RCM would
lead to regioisomeric mixtures of heterocycles F and I;
however, the latter compounds were not detected with
substrates 13-17 (R′′ ) H). Thus, RCM of [Ru]-XI, if
formed, may be slower than its conversion into triene J (by
reaction with the terminal olefin in D when R′′ ) H), and
the smaller ring-size heterocycles F would be produced even
if both pathways operate (Scheme 6).
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9025606
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