Alkynylcyclopropanes from terminal alkynes through consecutive coupling to Fischer carbene complexes and selective propargylene transfer

Article abstract of DOI:10.1002/chem.201003334

The transition-metal-catalyzed carbene transfer to alkenes ([2+1]-carbocyclization) to produce the relevant cyclopropane structure can be regarded as one of the most useful carboncarbon bond-forming reactions. In contrast, α,βunsaturated carbenes behave i

Full text of DOI:10.1002/chem.201003334

COMMUNICATION
DOI: 10.1002/chem.201003334
Alkynylcyclopropanes from Terminal Alkynes through Consecutive Coupling
to Fischer Carbene Complexes and Selective Propargylene Transfer
Josꢀ Barluenga,* Eva Tudela, Rubꢀn Vicente, Alfredo Ballesteros, and Miguel Tomꢁs[a]
The transition-metal-catalyzed carbene transfer to alkenes
([2+1]-carbocyclization) to produce the relevant cyclopro-
pane structure[1] can be regarded as one of the most useful
carbon–carbon bond-forming reactions.[2] In contrast, a,b-
unsaturated carbenes behave in general as a C3 synthon
either in metal-catalyzed[3] or -mediated reactions.[4] In this
context it should be particularly noted that examples dealing
with the alkynyl cyclopropanation reaction of alkenes are
very rare, in spite of the great interest of the resulting alky-
nylcyclopropane framework.[5] In fact, such a system is gen-
erally made by alkynylation of appropriate cyclopropane
precursors.[6]
We envisioned Group 6 non-heteroatom-stabilized metal
carbenes as candidates to accomplish this transformation on
the basis that 1) although they are still in their infancy, they
have proved to be extremely more reactive than the corre-
sponding metal alkoxycarbenes and 2) our preliminary re-
sults[9] suggest that metal alkynylcarbene complexes of this
type might be effective electrophilic b-centered propargyl
carbene equivalents.[10]
Based on this idea, herein we report that chromium and
tungsten alkynylcarbenes, readily available from terminal al-
kynes and classical methoxycarbenes, behave as equivalent
species of single propargyl carbenes, providing a selective
access to a variety of alkynylcyclopropanes upon reaction
with non-activated alkenes and dienes (Scheme 1).
The first step consists of the sequential addition of acety-
lide 2 to methoxycarbene 1 followed by TMSOTf-induced
methoxy elimination.[9] An alkene (5.0 equiv) was added to
the resulting solution of alkynylcarbene 3 in THF and the
mixture was warmed to À408C (ca. 2 h). Removal of the
solvent followed by chromatographic purification afforded
alkynylcyclopropanes 4 with variable efficiency (Scheme 2).
The yield varies from acceptable to good for arylethylenes,
methylenecyclopentane, and methylenecyclohexane (cyclo-
adducts 4a–h). The yield decreases to some extent for meth-
ylenecyclobutane and diethylethylene (cycloadducts 4h and
i). Interestingly, a sole regioisomer was formed in all cases;
It would be of interest to design synthetic equivalents of
propargyl carbenes for regioselective cyclopropanation
(Scheme 1). In this context, the intramolecular cyclopropa-
Scheme 1. Propargyl carbene synthetic equivalents.
nation of w-alkenylpropargyl alcohols in the presence of Bi-
ACHTUNGTRENNUNG(OTf)3 (OTf=triflate) has been successfully addressed by
Komeyama et al.[7] In relation to the intermolecular process,
a sole particular case has been described with 2-(alk-1-yn-1-
yl)-2-(trialkylsilyl)-1,3-dithianes and [Cp2Ti{PACTHNUTRGNE(UNG OEt)3}2], in
which the cyclopropanation is directed by the trialkylsilyl
group.[8]
[a] Prof. Dr. J. Barluenga, E. Tudela, Dr. R. Vicente, Dr. A. Ballesteros,
Prof. Dr. M. Tomꢀs
Instituto Universitario de Quꢁmica Organometꢀlica “Enrique Moles”
Unidad Asociada al CSIC, Universidad de Oviedo
33006 Oviedo (Spain)
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003334.
Scheme 2. Synthesis of alkynylcyclopropanes 4a–i (PMP=4-MeO-C6H4).
Chem. Eur. J. 2011, 17, 2349 – 2352
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moreover, cycloadducts 4a–c were isolated as single diaste-
reoisomers.[11]
Despite the great tendency to undergo [4+2]-cycloaddi-
tion to electrophilic alkynes,[12,13] cyclopentadiene was select-
ed as the model system to test the reaction of 3 toward
dienes. Thus, metal carbenes 3 smoothly react with cyclo-
pentadiene (5.0 equiv, THF, À80 to À408C) to produce cy-
clopropane derivatives 5 in very high yields with complete
endo stereoselectivity (Scheme 3).[11] A broad range of car-
Scheme 4. Proposed reaction pathway.
tion state with favorable interactions between the aryl or al-
kenyl groups and the incipient alkynyl function.
The process is also suitable for diynyl- and triynylcyclo-
propanes (Scheme 5). Firstly, bisACTHUNTGRNEUNG(alkynyl)carbenes 3 react
Scheme 5. Regioselective synthesis of polyalkynyl cyclopropanes (PCP=
4-Cl-C6H4-, TIPS=triisopropylsilyl).
with methylenecyclopentane or cyclopentadiene providing
butadiynylcyclopropanes in a regioselective manner. The
Bu/Ph-substituted carbene 3 reacted with methylenecyclo-
À
pentene at the Cb Bu carbon atom to yield a single regioiso-
mer (6), whereas the reaction between cyclopentadiene and
the PCP/TIPS-substituted carbene 3 provided 7 through the
Scheme 3. Synthesis of alkynylcyclopropanes 5a–p.
À
reaction at the Cb PCP carbon atom. Compound 7 was
slightly contaminated (<5%) with the isomer resulting from
À
the reaction of the Cb TIPS carbon atom and cyclopenta-
bene substitutions (electron-rich and -poor aryl, prim-, sec-,
and tert-alkyl, trimethylsilyl, and alkenyl functionalization)
was tolerated. Note that the reaction that gives structure 5m
is perfectly compatible with an alkene function in a position
favorable for cyclopropanation (for the intramolecular cy-
clopropanation of this substrate see Scheme 6, later). The
selectivity and flexibility of the reaction makes it feasible to
readily access complementary regioisomers (see, for in-
stance, 5d and 5e).
Although a definite reaction pathway cannot be estab-
lished yet, a tentative working proposal is displayed in
Scheme 4. The cyclopropanation would involve the conju-
gated Markovnikov-type addition of alkene to the electro-
philic alkynylcarbene 3 to generate a zwitterion intermedi-
ate, which would collapse into the final cyclopropane 4 or 5
by metal elimination. The cis stereoselectivity observed in
the case of styrenes and cycloalkadienes points to a transi-
diene. These results suggest that the regioselectivity of the
reaction (nucleophilic attack of the alkene/diene) is a bal-
ance of the different electrophilicities and steric congestions
of the C-3 and the C-3’ carbon atoms of 3. Secondly, the re-
action of alkynylACTHNUTRGNEUNG(diynyl)carbene 8, which features three
electrophilic carbon centers (C-3, C-5, and C-3’), yielded ex-
clusively the hexatriynylcyclopropane 9 upon cyclopropana-
tion with cyclopentadiene (at the Cb Bu carbon atom).
We were fortunate to find the intramolecular process to
also be operative toward aryl- and heteroatom-containing
1,6-enyne structures. According to the general protocol, the
process was executed by simply adding the lithium acetylide
of enynes 10 to methoxycarbene 1 (À808C, THF) followed
by treatment with TMSOTf and stirring until reaching 08C
(15 h). Chromatographic purification provided cycloadducts
11a–c in good yields. Overall, a new transformation of 1,6-
enynes has been accomplished that comprises consecutive
À
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Chem. Eur. J. 2011, 17, 2349 – 2352

Synthesis of Alkynylcyclopropanes
COMMUNICATION
À
À
C C coupling and cycloisomerization without the assistance
Keywords: alkynes · carbenes · C C coupling · cyclization ·
regioselectivity
of any electrophilic initiator (iodine[14] or Group 10 and 11
metals,[15] Scheme 6).
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Scheme 6. Intramolecular propargylene transfer (Ts=tosyl).
In conclusion, we have accomplished a very efficient pro-
tocol for accessing alkynylcyclopropanes that combines the
coupling of a terminal alkyne with a simple Fischer carbene
complex followed by the regio- and stereoselective cyclopro-
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dienes. The protocol also works efficiently (regarding yield
and selectivity) for cyclopropanes with conjugated polyalky-
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(312 mg, 1.00 mmol) was added and the resulting mixture was stirred at
À788C until disappearance of the carbene complex (the solution turned
from red to light yellow). Then, TMSOTf (0.30 mL, 1.66 mmol) was
added in one portion and the mixture was stirred at À788C for 5 min. Fi-
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successively added and the mixture was allowed to warm slowly. After
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Acknowledgements
We are grateful to the Ministerio de Ciencia e Innovaciꢃn of Spain (proj-
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AHCTUNGTRENNUNG
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Received: November 19, 2010
Published online: January 10, 2011
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Chem. Eur. J. 2011, 17, 2349 – 2352