Cyclization of carbonyl groups onto alkynes upon reaction with IPy2BF4 and their trapping with nucleophiles: A versatile trigger for assembling oxygen heterocycles

Article abstract of DOI:10.1021/ja0355372

Iodonium ions liberated from bis(pyridine)iodonium(I) tetrafluoroborate react with ortho-alkynyl-substituted carbonyl compounds and different nucleophiles to give valuable iodinated heterocycles at room temperature, through a new and metal-free reaction sequence. Interestingly, the nature of the nucleophile can be widely modified, and not only alcohols but also several carbon-based nucleophiles can be nicely used. Copyright

Full text of DOI:10.1021/ja0355372

Published on Web 07/04/2003
Cyclization of Carbonyl Groups onto Alkynes upon Reaction with IPy2BF4 and
Their Trapping with Nucleophiles: A Versatile Trigger for Assembling Oxygen
Heterocycles
Jose´ Barluenga,* Henar Va´zquez-Villa, Alfredo Ballesteros, and Jose´ M. Gonza´lez
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”-Unidad Asociada al C.S.I.C., UniVersidad de
OViedo, Julia´n ClaVeria, 8, 33006 OViedo, Spain
Received April 9, 2003; E-mail: barluenga@sauron.quimica.uniovi.es
Scheme 1 a
Electrophilic addition reactions of polarized reagents across
unsaturated functionalities are of relevance to prepare difunctional
compounds.1 To this regard, different sources of halonium ions are
useful reagents.2 However, these intermediates have been scantly
reported for carbon-carbon bond-forming reactions,3 a bonus
routinely credited to metal-mediated transformations.4 Recently, an
interesting Pd(II)-catalyzed cyclization has been described for the
conversion of acetylenic aldehydes to alkenyl ethers.5 Herein, a
new, metal-free entry into related heterocycles is presented. Overall,
smooth access to a wide set of iodinated adducts is achieved upon
reaction of bis(pyridine) iodonium tetrafluoroborate (IPy2BF4)6 with
those unsaturated carbonyl precursors and, remarkably, with an
unprecedented set of nucleophiles. Alcohols, as well as different
C-nucleophiles, behave as efficient partners in this new reaction
of alkynes triggered by iodonium ions (eq 1).
a (a) Isolated yield for compound 2, referred to 1 (1 mmol scale). (b) 5
mmol of the corresponding starting material 1 was used. (c) Reaction time
4 h, after R2OH addition. (d) Using 0.5 mmol (OMe)3, 85% yield in 2 h.
(e) Reaction time 3 h.
5 in the reaction sequence. Interesting results were obtained using
silyl-masked C-nucleophiles,12 providing a straight and useful access
to more elaborated heterocycles 6 (Table 1).13 Overall, these
The cyclization of acetylenic aldehydes 1 by reaction with IPy2-
reactions offer nice examples of unprecedented Mukaiyama-like
BF4 and different alcohols was initially investigated. The reaction
cross-coupling14 and Hosomi-Sakurai allylation15 reactions trig-
uses the standard activation of the iodinating agent by addition of
gered by an unconventional Lewis acid, such as the result of the
HBF4, that liberates a more reactive form of the iodonium reagent.7
addition of an iodonium ion to an alkyne. Moreover, electron-rich
Sequential treatment of the iodinating mixture with several ortho-
arenes can be used as the nucleophile, resulting in a novel arylation
(alkynyl)benzaldehydes 1, and then with alcohols, nicely afforded
reaction of an aldehyde in acid media.
compounds 2. These results are summarized in Scheme 1 (method
A). Thus, not only linear and branched R2 side chains have been
used, but also the labile propargyl alcohol has been an effective
nucleophile. The R1 moiety can also be modified, the reaction being
found to work well for R1 ) aryl, alkyl, and alkenyl. The yields of
compounds 2 were much dependent on the reaction scale (see
entries 1,2 and 5,6); nevertheless, the values for conversion based
on the NMR analysis of crude reaction mixtures were essentially
comparable.8 Alternatively, this iodine-addition, ring-closing, nu-
cleophilic trapping sequence can also be carried out by reacting a
mixture of the iodinating agent and B(OMe)3 with 1 (Scheme 1,
method B). Thus, a single reagent such as B(OMe)3 acts both as
Lewis acid and as the source of the methoxy group to furnish
compounds 2. Furthermore, in this event, compounds 2 were
prepared in good yield in a 1 mmol scale process.
Besides its novelty, another intrinsic feature of this reaction deals
with the incorporation of iodine. This element could modulate the
biological profile of a bioactive compound,16 and its chemistry adds
synthetic interest.
We have found that compound 2d can be nicely cross-coupled
with phenylacetylene (eq 3).17
Using this approach, the enolizable ketone 3 gave 4 in moderate
yield, most probably because of partial decomposition under acid
media (eq 2).9 In this case, the cyclization follows the more common
5-exo-dig cyclization mode,10 furnishing a five-member ring, rather
than the 6-endo cyclization noticed for aldehydes 1.11
A mechanistic proposal accounting for the observed products is
outlined in eq 4. One can assume the initial attack of the iodonium
ion to the alkyne moiety18 assisted by the neighboring carbonyl
A distinctive feature of this novel approach to cyclize ω-alkynyl-
carbonyl derivatives is the introduction of carbon-based nucleophiles
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J. AM. CHEM. SOC. 2003, 125, 9028-9029
10.1021/ja0355372 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Cyclization with IPy2BF4 and Trapping with
C-Nucleophiles
Supporting Information Available: Experimental procedures and
characterization data for compounds 2, 4, 6, and 7 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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a Isolated yield for compounds 6, referred to 1 (reactions using 1 mmol
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1
of 1). b 1:1 mixture of diastereoisomers by H NMR of the crude reaction
mixture.
functionality to furnish the reactive species A.19 This intermediate
could equilibrate with B by incorporation of nucleophilic species
already present in the reaction media.20 Subsequent addition of the
external nucleophile would give rise to the observed compounds.21
(12) For an account on the π-nucleophilicity of these reagents, see: Mayr, H.;
Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
(13) The structures depicted for compounds 2 and 6 were based on their
spectroscopic and analytical data and were further supported by 2D-NMR
studies on 2e, 6a, and 6i and X-ray analysis of 6e (to be published
elsewhere).
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67, 3437 and references therein.
(20) We reported the fluorinating nature of this condition: (a) Barluenga, J.;
Campos, P. J.; Gonza´lez, J. M.; Sua´rez; J. L.; Asensio, G. J. Org. Chem.
1991, 56, 2234. Besides a metal-free activation of the substrate by the
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Overall, new metal-free protocols for consecutive C-O and C-C
bond making have been executed; as a consequence, new three-
component sequences have been established.22 The iodonium
approach offers some advantages, such as conceptually a broad
compatibility with the nucleophile, and also those related to the
incorporation of iodine. Its rich chemistry adds interest to this clean
process and highlights its role as an electrophilic promoter beyond
that of a proton. Further studies in this area are in progress in our
laboratory.
(21) At present, other alternative pathways cannot be ruled out (we thank one
of the referees for valuable comments).
Acknowledgment. This research was supported by DGI (Grant
BQU-2001-3853) and FYCYT (Grant PR-01-GE-09). A predoctoral
fellowship (MCYT) to H.V.-V. is gratefully acknowledged.
(22) For a recent review on multicomponent reactions, see, for instance:
Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
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