A general approach to chemo- and regioselective cyclotrimerization reactions

Article abstract of DOI:10.1002/anie.200700802

(Figure Presented) Microwave-ready heterocycles: Cobalt-catalyzed [2+2+2] cyclotrimerization of nitrile derivatives with diynes anchored to a solid support under microwave irradiation provides a universal approach to pyridine, pyridone, and iminopyridine

Full text of DOI:10.1002/anie.200700802

Angewandte
Chemie
DOI: 10.1002/anie.200700802
Heterocycle Synthesis
AGeneral Approach to Chemo- and Regioselective Cyclotrimerization
Reactions**
Douglas D. Young and Alexander Deiters*
Traditional optimization of transition-metal-catalyzed reac-
tions involves the tailoring of substrates, metals, and ligands to
achieve the desired transformation with high efficiency. Here
we report a more generally applicable and more practical
approach to this problem through the combination of spatial
separation of the substrates and microwave irradiation. We
employed the [2+2+2] cyclotrimerization as an example, and
thereby solved persisting reactivity and selectivity issues of
this reaction. The [2+2+2] cyclotrimerization reaction is an
efficient tool for the construction of carbo- and heterocyclic
structures.[1,2] Traditionally, the most commonly used catalyst
systems are based on cobalt and rhodium. These catalysts, in
conjunction with a partially intramolecular reaction using
tethered alkynes, have led to several practical applications of
the [2+2+2] cyclotrimerization in the construction of fused
pyridine and benzene molecules, including several total
syntheses.[3] However, a variety of problems regarding
classical cobalt-catalyzed [2+2+2] cyclotrimerizations for
the synthesis of heterocycles still persist. These include long
reaction times, high-dilution conditions, high reaction temper-
atures, and the necessity to activate the catalyst through
irradiation with light or additives.[1] Moreover, low reactivity
cation of microwave[6–8] irradiation and a polymeric solid
support also makes the [2+2+2] cyclotrimerization highly
applicable to a variety of substrates.
An initial solution-phase investigation to give the fused
pyridine 3 (Scheme 1) was conducted using trityl-protected
Scheme 1. Microwave-mediated solid-supported formation of fused
pyridine rings. Trt=trityl, Cp=C5H5, Pip=piperidine, TFA=trifluoro-
acetic acid, gray sphere=solid support. [a] [CpCo(CO)2], toluene,
1108C, 24 h, microwave irradiation (MW, 300 W), no solid support.
[b] [CpCo(CO)2], toluene, 1158C, 24 h, no MW irradiation.
with certain substrates, as well as side reactions leading to
[1]
complexproduct mixtures have been observed.
The recent
development of Co, Ni, Rh, and Ru catalysts have led to
milder reaction conditions and shorter reaction times, but
often require specifically designed ligands.[4,5] Furthermore,
chemoselectivity (di- and trimerization of starting materials)
and regioselectivity issues are still persistent with many of the
catalysts, unless specifically designed substrates are used (for
example, triynes or internal diynes). As a result, no high-
yielding universal approach to the [2+2+2] cyclotrimeriza-
tion of a wide range of substrates has been developed to date.
Herein we report a different approach to the development of
highly efficient [2+2+2] cyclotrimerizations which has the
potential to provide unifying conditions for other transition-
metal-catalyzed cycloadditions as well. The synergistic appli-
dipropargylamine and benzonitrile as the starting materials.
The cyclotrimerization was performed in nonpolar toluene as
the solvent at 1108C with 10 mol% [CpCo(CO)2] under
microwave irradiation (300 W) for 10 min. After removal of
the protecting group with TFA, 3 was obtained in 46% yield
(similar results have recently been observed by others[9,10]).
When the same cyclotrimerization was conducted without
microwave irradiation, only 9% product formation was
observed, even after a prolonged reaction time of 24 h at
1108C. Previously this has been compensated by irradiation
with light, increased reaction temperatures (for example,
1448C), addition of catalyst activating agents, and extended
reaction times (up to 5 days).[11,12] The modest yield of 3
(46%) in the solution-phase cyclotrimerization is a result of
the formation of benzene by-products through di- and
trimerization of the diyne starting material, a problem
commonly seen in cyclotrimerization reactions of reactive
diynes (especially of terminal diynes).[5,13] This problem was
solved through spatial separation of the diyne substrates by
immobilization on a polystyrene resin.[14] We employed this
strategy previously in chemoselective solid-supported cyclo-
trimerizations under classical conditions.[15] By using micro-
wave heating, the immobilized diyne 1 delivered the fused
pyridines 3–6 in excellent yields (92–95%) and high purities
(> 90%) after cleavage from the resin (Scheme 1). The
implementation of microwave irradiation together with the
[*] D. D. Young, Prof. Dr. A. Deiters
North Carolina State University
Department of Chemistry
Raleigh, NC 27695-8204 (USA)
Fax: (+1)919-515-5079
E-mail: alex_deiters@ncsu.edu
[**] We gratefully acknowledge support from the Department of
Education (GAANN Fellowship to D.D.Y), the NCSU Faculty
Research and Development Fund, and the Donors of the American
Chemical Society Petroleum Research Fund. We thank Ramesh S.
Senaiar for conductingexploratory solution-phase reactions.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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solid support affords a significant increase in the yield,
extremely shortened reaction times, and the elimination of
catalyst activating additives, excessive heating, or irradiation
with light. Interestingly, the solid-supported reaction 1!3
could not be performed under thermal conditions (24 h,
1108C) and failed to yield significant amounts of product (<
5% yield). The dramatic improvement through microwave
irradiation cannot be attributed just to efficient heating (in
fact the reaction temperature is lower than under traditional
conditions[12]), but represents one of the most pronounced
examples of nonthermal microwave effects, a topic that is still
controversial.[8,16] To our surprise, electron-poor nitriles could
not be used in the reaction to give 2.[17]
We initially employed the symmetrical diyne 1 to inves-
tigate the effect of the combination of microwave irradiation
and a solid support, while alleviating the potential formation
of regioisomers. However, to explore the ability to impose
regioselectivity upon these cyclotrimerization reactions and
to investigate potential effects of microwave irradiation on
the regioselectivity, we selected 7 (and the structurally related
14) as cyclotrimerization precursors for several reasons:
1) the generated products are chemically stable, 2) the
possibility of using less-reactive internal double bonds will
be demonstrated, and 3) the regio-inducing effect of a
methylene group can be probed. Employing the previously
discovered reaction conditions in the cyclotrimerization of 7
to 8 using five different nitriles afforded the fused pyridines 9–
13 in excellent yields (87–94%) and high purities (> 90%)
after cleavage from the resin (Scheme 2). Most importantly,
Scheme 3. Formation of fused pyridine rings from a,w-alkynenitriles
under microwave irradiation.
reactions are completely suppressed through the spatial
separation on the solid support.
The cyclotrimerization of alkynes and isocyanates is an
effective means of generating pyridones, and catalyst systems
based on Ni, Co, Rh, and Ru have been employed.[1,17,20,21]
However, these reactions either require specifically tailored
substrates (for example, internal diynes or isocyanate-teth-
ered alkynes and alkenes) or specifically tailored ligands.
Reported reactions using a,w-diynes in conjunction with
[CpCo(CO)2] and [CpCo(cod)] (cod = cycloocta-1,5-diene)
catalysts produce pyridones only with low efficiency.[1,20]
When these cyclotrimerizations were performed under our
reaction conditions, that is, a solid support in conjunction with
microwave irradiation, highly efficient conversion of 1 into
25–27 (87–96% yield) was observed after cleavage from the
resin (Scheme 4). Under classical thermal conditions (1108C,
24 h) virtually no formation of 25 was detected (< 1% yield),
thus providing additional evidence for nonthermal microwave
effects.
Using carbodiimides in cyclotrimerization reactions under
Co and Ni catalysis provides a synthetic entry to 2-iminopyr-
idines.[1,22] Traditionally, these reactions only show moderate
chemoselectivity with respect to the formation of benzene
rings and generally low yields, even when conducted with
Scheme 2. Solid-supported regioselective formation of fused pyridine
rings under microwave irradiation. Anth=anthracene.
complete regioselectivity was obtained under microwave
irradiation conditions and the obtained regioisomer is in
agreement with the generally accepted cyclotrimerization
mechanism for the [CpCo(CO)2] catalyst.[1]
The synthesis of positional pyridine isomers was achieved
through the application of a nitrile group tethered to an
alkyne.[18] Two alkynyl nitrile substrates were employed for
the formation of both 5- and 6-membered fused rings.
Cyclotrimerization of 14 to 15, followed by acid-mediated
cleavage from the resin, afforded pyridines 16–23 in high
yields (73–91%), excellent purities (> 90%), and as single
regioisomers (Scheme 3). These yields are significantly higher
than in previous solution-phase reactions (especially in the
case of reactive terminal alkynes)[9,19] as competing side-
Scheme 4. Microwave-mediated cyclotrimerization of the diyne 1 with
isocyanates, and carbodiimides. [a] [CpCo(CO)2], toluene, 1108C, 24 h,
no MW irradiation. Cy=cyclohexyl.
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Angewandte
Chemie
specifically tailored internal akynes.[22] As a result, iminopyr-
idines have not been extensively synthesized by
biologically and pharmacologically important heterocyclic
molecules (for example, those based on the 4-azaisoindoline
core structure), and we believe that the described approach
can be applied to the optimization of other cycloaddition
reactions. We observed similar enhancing effects in
[2+2+2] cyclotrimerization reactions to give benzene deriv-
atives which we will report in due course.
[2+2+2] cyclotrimerizations.
Moreover,
the
classical
[CpCo(CO)2] catalyst has not been successfully employed in
these reactions. We solved this problem, as demonstrated by
the microwave-mediated solid-supported cyclotrimerization
of 1 with carbodiimides (Scheme 4). Compound 24 (Y= N) is
formed rapidly and the fused iminopyridines 28 and 29 were
obtained in excellent yields (91 and 93%, respectively) and
high purity (> 90%). These examples demonstrate that Experimental Section
General cyclotrimerization protocol: Derivatized resin (40 mg, 0.5–
microwave irradiation can activate otherwise inactive Co
catalysts for new cyclotrimerization reactions. Again, no
iminopyridine 28 could be detected under simple thermal
heating (1108C, 24 h).
To validate the enhancing effects of spatial separation on
the solid support, a set of microwave-mediated control
reactions to give 30–32 (10 mol% [CpCo(CO)2], toluene,
1108C, MW 300 W, 10 min) were conducted in the solution
phase (a substrate concentration of 70 mm was employed,
resembling solid-phase conditions). These reactions led to the
1.2 mmolgꢀ1 substrate loading) was placed in a microwave reaction
vessel and swelled in anhydrous toluene (500 mL) for 10 min. The
soluble reaction partner (10 equiv) was added followed by
[CpCo(CO)2] (0.1 equiv), and the reaction was irradiated in a CEM
Discover microwave synthesizer for 10 min at 300 W. The vessel was
removed and the resin was washed in a syringe filter with four
alternating cycles of CH2Cl2 and MeOH (2 mL each) The resin was
dried in vacuo, transferred into a vial, and cleaved for one hour with
500 mL of a solution of either 1% TFA in CH2Cl2 (for 2 and 24) or 1%
anhydrous HCl in CH2Cl2/MeOH (3:2; for 8 and 15). The solution was
filtered through a celite plug, concentrated, and then analyzed by
1H NMR spectroscopy and LC/MS.
Received: February 22, 2007
Published online: May 25, 2007
Keywords: cycloaddition · heterocycles · microwave synthesis ·
.
solid-phase synthesis · transition metals
formation of complexproduct mixtures, which necessitated
chromatographic separation, and greatly diminished the
yields (16–44%) as a result of undesired side-reactions.
In conclusion we have reported the development of
microwave-mediated [2+2+2] cyclotrimerization reactions
that lead to the formation of pyridines, pyridones, and
iminopyridines. The mild and unifying reaction conditions
enable the utilization of a wide range of substrates that deliver
products in high yields, excellent purities, and with complete
chemo- and regioselectivity. The universal nature of these
mild reaction conditions provides a significant advantage over
existing technologies, since the commercially available
[CpCo(CO)2] catalyst is used for all transformations, and
the rapid reaction rates do not require an inert atmosphere.
The observed activating effects of microwave irradiation can
not be explained as simply a consequence of more effective
heating, but represent pronounced examples of nonthermal
microwave effects. Mechanistic explanations of nonthermal
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currently investigating the details of the observed rate
enhancements. A possible explanation could be the lowering
of activation barriers in the multistep cyclotrimerization
mechanism[1,2] through specific dipole–dipole interactions of
the electric field induced by microwave irradiation of polar
intermediates (for example, metallacyclopentadienes) or
polar transition states. Through this methodology, we have
demonstrated the potential to employ microwave irradiation
in the activation of a catalyst system for new synthetic
transformations.
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