Propargyltrimethylsilanes as allene equivalents in transition metal-catalyzed [5 + 2] cycloadditions

Article abstract of DOI:10.1021/ol501114q

Conventional allenes have not been effective π-reactive 2-carbon components in many intermolecular cycloadditions including metal-catalyzed [5 + 2] cycloadditions. We report herein that rhodium-catalyzed [5 + 2] cycloadditions of propargyltrimethylsilanes and vinylcyclopropanes provide, after in situ protodesilylation, a highly efficient route to formal allene cycloadducts. Propargyltrimethylsilanes function as safe, easily handled synthetic equivalents of gaseous allenes and hard-to-access monosubstituted allenes. In this one-flask procedure, they provide cycloadducts of what is formally addition to the more sterically encumbered allene double bond.

Full text of DOI:10.1021/ol501114q

Letter
pubs.acs.org/OrgLett
Propargyltrimethylsilanes as Allene Equivalents in Transition Metal-
Catalyzed [5 + 2] Cycloadditions
Paul A. Wender,* Fuyuhiko Inagaki, Magnus Pfaffenbach, and Matthew C. Stevens
Department of Chemistry, Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305-5080,
United States
S
* Supporting Information
ABSTRACT: Conventional allenes have not been effective π-
reactive 2-carbon components in many intermolecular cyclo-
additions including metal-catalyzed [5 + 2] cycloadditions. We
report herein that rhodium-catalyzed [5 + 2] cycloadditions of
propargyltrimethylsilanes and vinylcyclopropanes provide, after in situ protodesilylation, a highly efficient route to formal allene
cycloadducts. Propargyltrimethylsilanes function as safe, easily handled synthetic equivalents of gaseous allenes and hard-to-
access monosubstituted allenes. In this one-flask procedure, they provide cycloadducts of what is formally addition to the more
sterically encumbered allene double bond.
ince its introduction in 1995, the metal-catalyzed [5 + 2]
difficult to measure amounts into a sealable pressure tube and a
Scycloaddition of vinylcyclopropanes (VCPs) and π-systems, similarly complicated work-up procedure. In contrast, com-
mercially available propargyltrimethylsilane, a candidate equiv-
alent of allene itself, has a boiling point of 91 °C, allowing for
its easy handling, and upon cycloaddition and acidic
protodesilylation7 would in principle give the same product
as that derived from a [5 + 2] cycloaddition to allene itself. This
equivalency represents a significant contribution to the rather
limited body of known functional allene equivalents8 and a
highly effective solution to the thus far unsolved problem of
accessing allene [5 + 2] cycloadducts.
the homologous Diels−Alder reaction, has been shown to work
intramolecularly with alkynes, alkenes, and allenes and
successfully applied to step-economical syntheses of various
seven-membered ring-containing natural products.1,2 In con-
trast, the intermolecular reaction has proven to be less general,
working only with rhodium catalysts and being limited thus far
to alkynes and some “activated” allenes incorporating a second
coordinating group (e.g., alkyne or nitrile).3 Activated
monosubstituted or 1,1-disubstituted allenes do not react
while activated 1,3-disubstituted allenes react but with marginal
regioselectivity (1:1−7:2). Some substituted allenes are also
catalyst poisons. Importantly, the direct cycloaddition of VCPs
with the larger family of unactivated allenes has not been
reported. We realized, however, that for many allenes, including
those highly useful for total syntheses4 and other synthetic
applications,5 the use of an allene equivalent would be highly
preferred, providing a potentially superior, more controllable,
safer, and more chemoselective reaction (Scheme 1). For
example, with respect to safety and handling,6 allene itself is a
gas at room temperature. Its use thus requires a rather
challenging and hazardous low temperature distillation of
In principle, the propargyl silane cycloaddition and
protodesilylation could be effected in one operation. Other
propargyl silanes would similarly serve as allene equivalents
providing access to [5 + 2] cycloadducts that thus far are not
accessible directly from allenes. Moreover because the addition
to an alkyne has unambiguous chemoselectivity, this strategy
could be used to access cycloadducts that would not be
selectively accessed, if at all (addition to more substituted π-
bond), from allenes themselves. Herein, we report the first
experimental study of the stepwise or one-flask [5 + 2]
cycloaddition/protodesilylation of propargyltrimethylsilanes
and VCPs providing a new, facile, and practical method for
accessing what are formally allene [5 + 2] cycloadducts.
A catalyst screen was first conducted. Recently, we reported
that cationic Rh(I) complexes featuring a cyclooctadiene
(COD) or a dinaphtho[a,e]cyclooctatetraene (dnCOT) ligand,
Scheme 1. A General Route to Allene Cycloadducts
9
such as [Rh(C10H8)(COD)]SbF6 and [Rh(dnCOT)-
(MeCN)2]SbF6,10 are highly efficient catalysts for both inter-
and intramolecular [5 + 2] cycloaddition reactions between
VCPs and alkynes. To investigate the proposed cycloaddition
between VCP 1 and propargyltrimethylsilane (2a), multiple
catalysts were examined (see Supporting Information). When
Received: April 17, 2014
Published: May 12, 2014
© 2014 American Chemical Society
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Letter
VCP 1 and 2a were treated with 1 mol % of [Rh(C10H8)-
(COD)]SbF6 in DCE or a mixture of DCE/TFE (0.15 M) at
room temperature for 3 h, followed by a brief hydrolytic
workup (1% HCl in EtOH), the desired cycloheptenone 3a was
isolated in 93% yield. Changing the solvent from DCE to a 9:1
mixture of DCE/TFE shortened the reaction time to 1 h and
improved the yield to 98%. This represents the highest yield
and shortest time of all screened Rh(I) catalysts. [Rh(dnCOT)-
(MeCN)2]SbF6 and its analogues containing substituted
dnCOT ligands also gave 3a, albeit in lower yields and with
longer reaction times (12 h).
phenyl derivative (3e) did not undergo protodesilylation at all
over the course of 2 days, likely a result of its conjugated
(styrenyl) system.12 To address this problem, we screened
several acids and found that treating our 4-silylmethylcyclohept-
4-enones with 5 M HCl/EtOAc13 in DCM was highly effective
for the protodesilylation of all substrates (Table 2). These
Table 2. Protodesilylation of 4-Silylmethylcyclohept-4-
enones (3a−h) Using Brønsted Acid
Having determined the optimum catalyst and conditions, we
next studied the Rh(I)-catalyzed [5 + 2] cycloaddition of
various propargyltrimethylsilane derivatives (Table 1). VCP 1
Table 1. Rhodium-Catalyzed [5 + 2] Cycloaddition of VCP 1
and Propargyltrimethylsilanes 2a−h
conditions enabled us not only to shorten the reaction time (15
min or less for entries 1−3) but also to furnish 5-aryl-4-
methylenecycloheptanones 4e−g from the conjugated cyclo-
heptenones 3e−g in high yields at room temperature.
With the success of this two-step process, we next set out to
determine whether a serial, one-flask [5 + 2] cycloaddition/
protodesilylation could be developed that would produce 4-
methylenecycloheptanone derivatives in a single operation from
VCP 1 and select propargyltrimethylsilanes (Table 3). After the
cycloaddition was complete, the reaction was quenched with 1
M HCl/EtOAc to produce the (5-substituted-)4-methylene-
cycloheptanone derivatives 4a,c,e−h in yields comparable or
even superior to the overall yield of the two-flask procedure.
The 1 M HCl/EtOAc solution chosen to execute the single-
flask protodesilylation was superior to 5 M HCl/EtOAc, p-
TsOH·H2O, and concentrated aq. HCl in terms of yield and
minimization of side product formation.
In conclusion, we have developed efficient stepwise as well as
serial intermolecular [5 + 2] cycloaddition/protodesilylation
reactions of propargyltrimethylsilanes and VCPs for the
formation of 4-methylenecycloheptanones and a wide range
of 5-substituted-4-methylenecycloheptanone derivatives, allene
cycloadducts, in high yields. Significantly, the propargyl-
trimethylsilanes not only work as synthetic equivalents of
gaseous or otherwise difficult to handle allenes but also enable
access to a product that is derived from chemoselective
cycloaddition to the more hindered allene double bond. This
strategy provides simple, safe, and efficient access to previously
a
b
DCE/TFE (9:1, 0.15 M). DCE/TFE (3:1, 0.15 M) was used as a
c
d
solvent. TFE (0.15 M) was used as a solvent. Heated at 40 °C.
was reacted with 1.1 equiv of each substrate (2a−h) in the
presence of catalytic [Rh(C10H8)(COD)]SbF6 in DCE (0.15
M) at room temperature to provide, after brief hydrolytic
workup with 1% HCl in EtOH, a range of 5-substituted-4-
silylmethylcyclopt-4-enones (3a−h) in good to excellent yields.
The results indicate that the cycloaddition reaction is widely
tolerant of a variety of propargyltrimethylsilane substitutions
including hydrogen, n- and i-alkyl, aryl, and heteroatom groups.
We next examined the protodesilylation of 4-silylmethyl-
cyclohept-4-enones 3a−h with Brønsted acids to investigate
whether the [5 + 2] cycloaddition and protodesilylation could
be conducted in a stepwise manner. Treatment of 3a with 5
equiv of p-TsOH·H2O in Et2O at room temperature gave the
desired exo-methylene product 4a11 in excellent yield. While
cycloheptenones featuring methyl and hexyl groups (3b,c) were
converted to the desired product in high yields, long reaction
times (>24 h) and heating (in the case of 3c) were needed. The
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Table 3. One-Flask [5 + 2] Cycloaddition/Protodesilylation
Processes
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cycloadditions.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(10) Wender, P. A.; Lesser, A. B.; Sirois, L. E. Angew. Chem., Int. Ed.
2012, 51, 2736−2740.
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Chem. Soc. Jpn. 1972, 45, 1777−1781. (b) Barbero, A.; Blanco, Y.;
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AUTHOR INFORMATION
■
(12) Using TFE as solvent, <57% yield of 4e was obtained after 17 h.
(13) 5 M HCl in EtOAc was made by reacting 5 mol AcCl with 5
mol EtOH in a total volume of 1 L EtOAc.
Corresponding Author
*E-mail: wenderp@stanford.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Science
Foundation (NSF, CHE1265956) and the National Institutes
of Health (CA031841). Additional funding was provided by the
NSF Graduate Research Fellowship (M.C.S.), Kanazawa
University (F.I.), and the German Academic Exchange Service
(M.P.).
REFERENCES
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