Chemo- and regioselective palladium-catalyzed oxycyclization reactions of allendiols: preparation of five-, six-, and eight-membered cycles

Article abstract of DOI:10.1002/chem.200802675

A study was conducted to demonstrate chemo- and regioselective palladium-catalyzed oxyclyclization reactions of β,γ and γ,δ-allendiols. The study also demonstrated the preparation of five-, six-, and eight-membered cycles for the investigations. β,γ allen

Full text of DOI:10.1002/chem.200802675

DOI: 10.1002/chem.200802675
Chemo- and Regioselective Palladium-Catalyzed Oxycyclization Reactions of
Allendiols: Preparation of Five-, Six-, and Eight-Membered Cycles
Benito Alcaide,*[a] Pedro Almendros,*[b] Rocꢀo Carrascosa,[a] and
Teresa Martꢀnez del Campo[a]
Oxacycles are the major component of many biologically
important natural products and functional molecules.[1] Thus,
the synthesis of these heterocycles is of current interest. Al-
lenes are a class of compounds with two cumulative carbon–
carbon double bonds, which have become more and more
interesting not only as targets in natural products synthesis,
but also as valuable synthetic precursors for complex mole-
cules.[2] In this context, carbon–heteroatom cyclization is of
major interest.[3] However, regioselectivity problems are sig-
nificant (endo-trig versus endo-dig versus exo-dig versus exo-
trig cyclization). A cyclization process that involves a selec-
tive carbon–heteroatom bond formation, even if the struc-
ture of the substrate suggests numerous possibilities for re-
activity, represents an attractive strategy. Although many ef-
forts have been made in these fields, metal-catalyzed hetero-
cyclizations of allenes bearing two contiguous nucleophilic
centers have rarely been mentioned; only Krause et al. have
recently reported the gold-catalyzed 5-endo cycloisomeriza-
tion of both an a,a’-allendiol as well as an a,b-allendiol to
give dihydrofurans.[4] The main cause of this relative lack of
success might be attributed to additional chemoselectivity
problems. Namely, the product distribution depends on the
chemo- and regioselectivity of the heterocyclization, but in
principle, eight different products are possible. Encouraged
by our recent results in heterocyclic and allene chemistry,[5]
we thought that chemo- and regioselective palladium-cata-
lyzed cycloetherification of allendiols, namely b,g- and g,d-
allendiols, may occur by judicious choice of catalyst owing
to their potential ability to discriminate both nucleophilic
sites, and the results of our investigations are discussed
herein.
b,g-Allendiol 1a was chosen as a model substrate for pal-
ladium-catalyzed oxycyclization reactions.[6] To screen the
reactivity of the b,g-allendiol moiety, heterocyclization was
studied by using 1a in the presence of a Pd0 catalyst. The
2H-pyran 2, which arises from a totally chemo- and regiose-
lective 6-exo oxycyclization of the primary hydroxy group to
the central allene carbon with concomitant dehydration, was
obtained in moderate yield, together with a complicated
mixture of side products (Scheme 1). Next, 1a was exposed
Scheme 1. Palladium-catalyzed preparation of dihydropyrans 2 and 3. Re-
agents and conditions: i) 5 mol% [PdACTHNUTRGNE(UNG PPh3)4], PhI, K2CO3, toluene,
808C, 24 h; ii) allyl bromide, 5 mol% PdCl2, DMF, RT, 3a: 3 h; 3b: 2 h.
PMP=4-MeOC6H4.
[a] Prof. Dr. B. Alcaide, Dipl.-Chem. R. Carrascosa,
Dipl.-Chem. T. Martꢀnez del Campo
Departamento de Quꢀmica Orgꢁnica I, Facultad de Quꢀmica
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax : (+34)91-3944103
to allyl bromide under PdII catalysis in DMF. Gratifyingly,
the functionalized dihydropyran 3a was isolated as the sole
isomer in 65% yield. Similar behavior was observed for the
phenyl derivative 1b (Scheme 1). This result could be ex-
plained through a 6-endo cyclization by chemo- and regio-
specific attack of the secondary hydroxy group at the termi-
nal allene carbon atom.
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
Instituto de Quꢀmica Orgꢁnica General
Consejo Superior de Investigaciones Cientꢀficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
To probe the feasibility of cycloetherification in b,g-allen-
diols by way of palladium-induced oxybromination, allen-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802675.
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Chem. Eur. J. 2009, 15, 2496 – 2499

COMMUNICATION
diols 1a and 1c were treated
with lithium bromide using a
Pd–Cu
system. Interestingly, the bro-
moetherification products
bimetallic
catalytic
4
were observed and, upon further
optimization, could be obtained
in reasonable yields. These con-
ditions were applied to b,g-al-
lendiols 1b and 1d. To our de-
light, in contrast to the oxybro-
mination reaction of methyl al-
lendiols 1a and 1c which led to
a bromodihydropyran, the reac-
Scheme 2. Palladium-catalyzed preparation of dihydropyrans 4 and tetrahydrofurans 5. Reagents and condi-
tions: i) 7 mol% Pd
diphenylsilyl.
ACHTUNTGNERN(UG OAc)2, LiBr, CuAHCUTTGNRENN(GUN OAc)2, K2CO3, MeCN, O2, RT, 2 h. PMP=4-MeOC6H4. TPS=tert-butyl-
tion of phenyl allendiols 1b and 1d under identical condi-
tions afforded 2-(1-bromovinyl)tetrahydrofurans
5
(Scheme 2).[7] Thus, by a subtle variation in the substitution
pattern of the b,g-allendiol (Ph versus Me) both the chemo-
and the regioselectivity can be completely reversed. The dif-
ference in reactivity between both types of allendiols could
be explained by considering the electron-withdrawing ca-
pacity of the phenyl substituent compared to the electron-
donating capacity of the methyl group. Probably, the pres-
ence of a Ph substituent in the allene moiety strengthened
the electrophilicity of the benzylic-like carbon, favoring the
5-exo cyclization of the primary hydroxy group over the 6-
endo cyclization of the secondary hydroxy group. The p-me-
thoxybenzoyloxy group comprises a large substituent; how-
ever, the cis attack, which would be disfavored with a larger
ZO group, increases with 1b (Z=COPMP) in comparison
with 1d (Z=Me). The reason for the total diastereoselectiv-
ity for the 5-exo cyclization toward the internal allene
carbon atom on phenyl allendiol 1d to give adduct 5b com-
pared to the moderate diastereoselectivity of phenyl allen-
diol 1b to give adduct 5a in the examples in Scheme 2, may
be related to unfavorable steric interactions between the
ZO group and Pd in the p-allylpalladium intermediate de-
rived from 1b, hampering the required conformation for the
trans attack.
Scheme 3. Preparation of oxocines 8 and oxocinone 9. Reagents and con-
ditions: i) 5 mol% [Pd(PPh3)4], PhI, K2CO3, toluene, 808C, 120 h; ii)
5 mol% PdCl2, DMF, RT, 8a: 14 h; 8b: 16 h; 8c: 16 h; 8d: 15 h; 8e:
15 h; iii) Dess–Martin periodinane, CH2Cl2, RT, 2 h. PMP=4-MeOC6H4.
AHCTUNGTRENNUNG
cyclization by attack of the primary hydroxy group at the
terminal allene carbon atom.[9] To the best of our knowl-
edge, no example of an 8-endo cyclization at the terminal
allene carbon atom of a d-allenol has been reported. Thus,
we present experimental evidence concerning the 8-endo-
trig cyclization pathways in allene oxycyclization reactions
that enriches Baldwinꢃs rules for ring closure. Besides, oxo-
To assess the scope of the reaction, the even more chal-
lenging 2-azetidinone-tethered g,d-allendiols 6 were tested
as cycloetherification substrates. Attempts to generate a bi-
cyclic structure from 6a by using Pd0 catalysts in the pres-
ence of iodobenzene failed, because b-hydride elimination
to afford diene
more effectively.[8] Accordingly,
solutions of g,d-allendiols
7 competes
6
were exposed to the above-
mentioned conditions for PdII-
catalyzed
heterocyclizations.
Much to our delight, adducts
8a–e were obtained in good
yields in a totally chemo- and
regioselective fashion using the
PdCl2-catalyzed cyclizative cou-
pling reaction with allyl halides
Scheme 4. Preparation of oxocines 10 and dibromide 11. Reagents and conditions: i) 7 mol% Pd
ACHTUNGRTENUN(NG OAc)2, LiBr,
(Scheme 3), through a 8-endo Cu
ACHTUNGTRENNUNG
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B. Alcaide, P. Almendros et al.
cines 8 are remarkable as they
comprise a C3–C4 trans-fused
b-lactam.[10] HMBC experi-
ments on derivatives 8 estab-
lished the presence of a new
eight-membered oxacycle fused
to the b-lactam ring. Chemical
evidence was obtained by oxi-
dation of the adduct 8a with
Dess–Martin
which gave
periodinane,
ketone
9
(Scheme 3). Similarly, only the
hydroxy group in the d-position
participates in the PdACTHNUTRGENUN(G OAc)2-
catalyzed regiocontrolled oxy-
bromination reaction of methyl-
and ethyl-g,d-allendiols 6a, 6d,
and 6e, giving exclusively the
eight-membered fused deriva-
tives 10 (Scheme 4). The use of
the above oxybromination reac-
tion conditions on phenyl g,d-
allendiol 6b changes the reac-
tivity pattern, suppressing the
Scheme 5. Mechanistic explanation for the PdII-catalyzed bromoheterocyclization reaction of b,g-allendiols 1.
oxycyclization while retaining the same regioselectivity of
the bromination step. Thus, in the case of phenyl allendiol
6b we observed exclusive formation of the monocyclic di-
bromide 11. The divergence between alkyl- and arylallen-
diols 6 may arise from the different stereolectronic effect
imparted by the phenyl group in the oxycyclization step,
which directs the reaction toward a new bromide attack at
the terminal allene carbon atom rather than toward a cyclo-
etherification.
A likely mechanism for the generation of bromodihydro-
pyrans 4 and tetrahydrofurans 5 should involve the initial
formation of a (p-allyl)palladium species.[11] The allenepalla-
dium complex 12 is formed initially and suffers a nucleophil-
ic attack by the bromide to produce s-allylpalladium species,
which rapidly equilibrate to the corresponding (p-allyl)palla-
dium intermediate 13. Then, a chemo- and regiospecific in-
tramolecular cycloetherification reaction by attack of either
the secondary hydroxy group at the terminal allene carbon
atom or the primary hydroxy group at the internal allene
carbon atom onto the (p-allyl)palladium complex must ac-
count for the formation of dihydropyrans 4 or tetrahydrofur-
ans 5 (Scheme 5). Finally, in situ oxidation of Pd0 to PdII by
CuACHTUNGTRENNUNG(OAc)2 completes the catalytic cycle.
The pathway proposed in Scheme 6 appears valid for the
formation of products 8. The oxybromination reaction in-
volves the addition of the halide ion to the allenic moiety to
give a (p-allyl)palladium intermediate, whereas the hetero-
cyclizative coupling with allyl halides involves the chemo-
and regiocontrolled oxypalladation of the allenic moiety, fol-
lowed by a Heck-type reaction, and regeneration of the PdII
catalyst through b-halide elimination (Scheme 6).
Scheme 6. Mechanistic explanation for the PdII-catalyzed heterocycliza-
tive coupling reaction of g,d-allendiols 6.
um-catalyzed O–C cyclization of allendiols can be achieved.
Thus, starting from b,g- and g,d-allendiols this metal-cata-
lyzed methodology provides access to a variety of different-
sized (five-, six-, and eight-membered) enantiopure oxacy-
cles.
In conclusion, we have demonstrated for the first time
that both chemo- and regioselectivity control in the palladi-
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Pd-Catalyzed Oxycyclization Reactions of Allendiols
COMMUNICATION
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Acknowledgements
This work was supported by the DGI-MEC (Project CTQ2006-10292),
Comunidad Autꢄnoma de Madrid (CCG-07-UCM/PPQ-2308), and the
Universidad Complutense de Madrid (Grant GR74/07). T. M. C. and R.
C. thank MEC for predoctoral grants.
À
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Keywords: allenes
·
chemoselectivity
·
heterocycles
·
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Received: December 18, 2008
Published online: February 2, 2009
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