1,2-Bisanionic coupling approach to 2,3-disubstituted cyclopentenols and cyclopentenones

Article abstract of DOI:10.1021/ol060654y

We describe a new approach to 2,3-disubstituted cyclopentenols and cyclopentenones through two consecutive regioselective additions of equal or different electrophiles to a cyclopentene bisanionic synthon. Indeed, on exposure to BuLi, 3-bromo-2-iodocyclopent-2-enol O-TBS ether undergoes iodine-lithium permutation with complete regioselectivity. Successive reaction of the monolithium anion with different C(sp²)- and C(sp ³)-electrophiles affords the corresponding 2-substituted-3- bromocyclopentenol derivative. Subsequent bromo-lithium exchange with t-BuLi, followed by reaction with an equal or different electrophile, affords the desired 2,3-disubstituted cyclopentenol.

Full text of DOI:10.1021/ol060654y

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2147-2150
1,2-Bisanionic Coupling Approach to
2,3-Disubstituted Cyclopentenols and
Cyclopentenones
Marco Luparia, Alessandro Vadala`, Giuseppe Zanoni, and Giovanni Vidari*
Dipartimento di Chimica Organica, UniVersita` di PaVia,
Via Taramelli 10, 27100 PaVia, Italy
Vidari@unipV.it
Received March 16, 2006
ABSTRACT
We describe a new approach to 2,3-disubstituted cyclopentenols and cyclopentenones through two consecutive regioselective additions of
equal or different electrophiles to a cyclopentene bisanionic synthon. Indeed, on exposure to BuLi, 3-bromo-2-iodocyclopent-2-enol O-TBS
ether undergoes iodine
and C(sp3)-electrophiles affords the corresponding 2-substituted-3-bromocyclopentenol derivative. Subsequent bromo
t-BuLi, followed by reaction with an equal or different electrophile, affords the desired 2,3-disubstituted cyclopentenol.
−
lithium permutation with complete regioselectivity. Successive reaction of the monolithium anion with different C(sp2)-
−lithium exchange with
The 2,3-disubstituted cyclopentenol and cyclopentenone
structural units are present in a wide range of useful synthetic
intermediates and in a vast number of natural products
endowed with a broad spectrum of biological activity.1
Therefore, new methods of their construction are intensively
searched.2 With some notable exceptions,3 disubstituted
cyclopentenes are built up from acyclic precursors.2 In
contrast, as shown in Scheme 1, we foresaw the possible
In principle, this novel strategy could be realized through
two regioselective halogen-lithium permutations4 of a
protected 2,3-dihalocyclopentenol 2,5 each followed by
reaction with an electrophile. Thus, a straightforward route
to a great variety of disubstituted cyclopentenes appeared
easily at hand, thanks to the ready preparation of dihalo-
derivatives of type 2 (vide infra) and the well-known
chemistry of organolithium compounds.6
At the onset of our work, the prospect of achieving this
appealing dianionic synthon appeared, indeed, to be an
uneasy task. In fact, regioselective monolithiation of unsym-
metrically substituted halogenated compounds has been
observed so far only for a handful of aromatic derivatives,7
Scheme 1
(2) (a) Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet. Chem.
2004, 689, 3873-3890. (b) Trost, B. M.; Pinkerton, A. B. J. Org. Chem.
2001, 66, 7714-7722 and references therein. (c) Fru¨hauf, H.-W. Chem.
ReV. 1997, 97, 523-596.
(3) See, for example: (a) Mikolajczyk, M.; Mikina, M.; Zurawinski, R.
Pure Appl. Chem. 1999, 71, 473-480. (b) Pour, M.; Negishi, E.-i.
Tetrahedron Lett. 1997, 38, 525-528. (c) Ho, T.-L. Synth. Commun. 1974,
4, 265-287.
(4) Jones, R. G.; Gilman, H. In Organic Reactions; Adams, R., Ed.;
Wiley: New York, 1951; Vol VI, pp 339-366.
(5) Introduction of a protecting group was necessary in light of the
prospected reactions of 2 with aliphatic halides.
(6) (a) Chinchilla, R.; Na´jera, C.; Yus, M. Tetrahedron 2005, 61, 3139-
3176. (b) The Chemistry of Organolithium Compounds; Rappoport, Z.,
Marek, I., Eds.; Wiley: New York, 2004.
assembly of such units through two consecutive regioselec-
tive additions of equal or different electrophiles to a
cyclopentene bisanionic synthon 1.
(1) Representative examples: (a) for prostaglandins, see: Straus, D. S.;
Glass, C. K. Med. Res. ReV. 2001, 21, 185-210. (b) For jasmonates, see:
Beale, M. H.; Ward, J. L. Nat. Prod. Rep. 1998, 533-548. (c) For
phytoprostanes, see: Thoma, I.; Krischke, M.; Loeffler, C.; Mueller, M. J.
Chem. Phys. Lipids 2004, 128, 135-148. (d) For dicranenones, see: Sakai,
K.; Fujimoto, T.; Yamashita, M.; Kondo, K. Tetrahedron Lett. 1985, 26,
2089-2092.
10.1021/ol060654y CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/21/2006

in particular when an ortho-orienting metalation group is
present. In contrast, it has not yet been addressed to
unsymmetrical alicyclic 1,2-dihaloolefins, even though ex-
amples of generation of 1-lithio-2-bromocyclopentenes from
symmetrical dibromocyclopentenes, followed by alkylation,
are in the literature.7a,8
We focused our attention on the monolithiation of O-TBS-
protected 2-iodo-3-bromocyclopentenol 3,9 with the prospect
of achieving a faster halogen/metal exchange at C-2 than at
C-3 (Scheme 3). Our rationale was based on the higher
exchanged with complete regioselectivity. To complete our
test reactions, the bromocyclopentene 4a (Scheme 3, R )
H in formula 4) was subsequently exposed to t-BuLi (2.5
equiv) at -78 °C, followed by protonation (NH4Cl) of the
resulting anion, affording, uneventfully, the volatile debro-
minated cyclopentene 5a (Scheme 3, R ) R′ ) H in formula
5) in 72% yield.
Subsequently, with the aim to extend this new methodol-
ogy to the construction of mono- and disubstituted cyclo-
pentenes, we tested different C(sp2)- and C(sp3)-electrophiles
for quenching the vinyl anions produced from compound 3
(Scheme 3). Our results are summarized in Tables 1 and 2.
Scheme 2
Table 1. Electrophilic Additions to 2-Monolithium Species
Generated Regioselectively from Cyclopentene 3*
strength of the C-Br bond than the C-I bond10 and the
higher reactivity of iodides than bromides in the exchange
reaction.11 Moreover, the combined electron-withdrawing
effects of the oxygen and the bromine atoms on vicinal
carbons were expected to stabilize a negative charge at C-2
better than at C-3.
To test our assumption, compound 3 was exposed to BuLi
(1.1 equiv) at -78 °C in THF, and after 10 min, the resulting
yellowish anion was quenched by the addition of saturated
aqueous NH4Cl at the same temperature. GC-MS analysis
of the reaction mixture revealed a complete conversion of 3
into one monobromo derivative, which was isolated in 88%
yield and assigned as structure 4a (Scheme 3, R ) H in
Scheme 3
* General procedure: (i) 1.6 M BuLi (1.1 equiv), THF, -78 °C, 12 min;
(ii) electrophile (1.2 equiv), from -78 °C to -30 °C over 4 h. a General
procedure, except that the reaction was quenched after 1 h at -78 °C
(warming to -30 °C was not necessary). b General procedure, except that
HMPA (6 equiv, CAUTION: toxic!) was added before adding the
electrophile. c General procedure, except that 0.25 M lithium 2-thienylcy-
anocuprate (1.1 equiv) in THF, -78 °C, 20 min, was added before adding
the electrophile. d Mixture of diastereomers.
formula 4) by NMR COSY and NOESY experiments.
This result demonstrated that, on exposure to BuLi,
dihalocyclopentenol 3 underwent a single and efficient
halogen-lithium permutation, the iodine atom at C-2 being
The expected mono- (4b-k) and dialkylated (5b-n)
products were obtained from compound 3 with complete
regioselectivity and in satisfactory overall yields. To recon-
firm the site selectivity of the first halogen-lithium ex-
change, compounds 5b-n were produced in two separate
steps, with isolation and structure determination of the
corresponding intermediates of general formula 4.
In principle, sequential replacement of halogens by elec-
trophiles could be achieved in a one-pot operation; however,
the overall efficiency was lower. Thus, treatment of 3 with
BuLi (1.1 equiv), followed by propanal, afforded 4c as a
lithium alkoxide, which, without isolation, was exposed to
t-BuLi (3.3 equiv), followed by acetaldehyde, to afford 5e
in 50% yield, as compared to 70% for the two-step procedure.
(7) (a) Schlosser, M. In Organometallics in Synthesis: A Manual;
Schlosser, M., Ed.; Wiley: New York, 2002; pp 101-137. (b) Liu, Y.;
Gribble, G. W. Tetrahedron Lett. 2002, 43, 7135-7137.
(8) (a) Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9, 459-490. (b)
Dastan, A.; Uzundumlu, E.; Balci, M.; Fabris, F.; De Lucchi, O. Eur. J.
Org. Chem. 2004, 183-192. (c) Tranmer, G. K.; Yip, C.; Handerson, S.;
Jordan, R. W.; Tam, W. Can. J. Chem. 2000, 78, 527-535. (d) Paquette,
L. A.; Doyon, J. J. Am. Chem. Soc. 1995, 117, 6799-6800. (e) Gassman,
P. G.; Gennick, I. J. Am. Chem. Soc. 1980, 102, 6863-6864.
(9) Easily available in four steps from commercial 1,3-cyclopentanedione,
as depicted in Scheme 2.
(10) Vedeneyev, V. I.; Gurvich, L. V.; Kondrat’yev, V. N.; Medvedev,
V. A.; Fraukevich, Y. L. Bond Energies, Ionization Potentials and Electron
Affinities; E. Arnold: London, 1966.
(11) Gilman, H.; Langham, W.; Moore, F. W. J. Am. Chem. Soc. 1940,
62, 2327-2335.
2148
Org. Lett., Vol. 8, No. 10, 2006

Compounds 5b-n can be considered direct precursors of
2,3-disubstituted cyclopentenones, according to a well-
established chemistry. As a representative example, cyclo-
pentene 5m (Table 2, entry 13) was readily converted12 into
the well-known cis-jasmone 6.1b In this context, to have more
direct access to disubstituted cyclopentenones, we tried to
extend our methodology to acetal 7; however, the preparation
of 7 from the corresponding ketone, under different acetal-
ization conditions,13 was not a clean reaction and resulted
in some substrate decomposition. Indeed, unsuccessful ket-
alization of 3-bromocyclopentenones has been observed also
by other authors.14 Therefore, we abandoned this approach,
even if acetal 7 on exposure to BuLi at -78 °C in THF,
followed by protonation, gave the bromo derivative 8 in 75%
yield with complete regioselectivity.
Table 2. Electrophilic Additions to Lithium Species Generated
from Bromides 4*
An interesting observation was made about the structural
integrity of the 3-bromo-2-lithio anion 9, obtained from 3
by iodine exchange with BuLi (1.1 equiv) in THF at -78
°C. In an attempt to accelerate the alkylation step by
1-iodohexane (1.1 equiv), a solution of 9, to which the alkyl
iodide and DMPU (5 equiv) had been added, was brought
to 0 °C and left at this temperature for 5 h.
Chromatographic separation of the products afforded, in
an almost 1:1 ratio and 68% combined yields, the two
regioisomeric 2- and 3-hexyl derivatives, 11 and 12, respec-
tively, containing a bromine atom (MS) on carbons 3 and 2,
respectively. The formation of these compounds can likely
be explained by a bromine positional scramble, whose
mechanism has not yet been established, with isomerization
of 9 to 2-bromo-3-lithiocyclopentene 10, followed by alky-
lation of the two lithium regioisomers (Scheme 4). 1,2-
Scheme 4
* General procedure: (i) 2.7 M t-BuLi (2.5 equiv), THF, -78 °C, 30
min, followed by an increase of the temperature to -50 °C in 30 min; (ii)
electrophile (1.2 equiv), -78 °C f -20 °C over 5 h. a General procedure,
except that NaH (1.1 equiv), 0 °C, 10 min, was added before the addition
of t-BuLi (3.3 equiv) at -78 °C. b General procedure, except that HMPA
(6 equiv, CAUTION: toxic!) was added immediatly before the addition of
the electrophile. c Mixture of diastereomers.
Positional permutations of the lithium and bromine atoms
have been well studied for carbo- and heterocyclic aromatic
compounds,7a,15 but it appears to be an unprecedented process
for aliphatic compounds.
In general, reactions with C(sp3)-electrophiles (Table 1,
entries 6-11; Table 2, entries 10, 11, 13, 14) gave lower
yields than those with carbonyl compounds (Table 1, entries
2-5; Table 2, entries 2-9, 12) and certain electrophiles
required the general experimental procedure to be slightly
modified (see footnotes to Tables 1 and 2). Thus, either the
addition of HMPA as a cosolvent (Table 1, entry 7; Table
2, entries 11, 14) or the preparation of a mixed organocuprate
species (Table 1, entries 10, 11) was required before
electrophile addition.
(12) (i) 1 M TBAF (2 equiv), THF, room temperature; (ii) MnO2 (30
equiv), pentane, 5 h, room temperature; 85% overall yield.
(13) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; Wiley: New York, 1999.
(14) Shih, C.; Swenton, J. S. J. Org. Chem. 1982, 47, 2825-2832.
(15) Mongin, F.; Desponds, O.; Schlosser, M. Tetrahedron Lett. 1996,
37, 2767-2770 and references therein.
Org. Lett., Vol. 8, No. 10, 2006
2149

In conclusion, we have demonstrated that, under optimal
experimental conditions, the dihalocyclopentenol 3 can be
considered as a synthetic equivalent of the 2,3-bisanionic
synthon 1. We stress the simplicity with which the two
consecutive regioselective halogen/metal permutations can
be executed and the variety of electrophiles which can be
added to the corresponding vinyl anions. Thus, this approach
to different 2,3-disubstituted cyclopentenols compares quite
favorably to the existing methods. Moreover, in addition to
their oxidation to cyclopentenones, cyclopentenols are useful
intermediates for a number of other synthetic transformations
such as Claisen rearrangements, allylic couplings, allylic
transposition of the OH group, as well as simple hydrogena-
tion to cyclopentanols. Thus, we believe that this new
1,2-bisanionic coupling methodology can afford a general
and straightforward approach to a diverse range of five-
membered ring targets.16,17
Acknowledgment. This research was supported by Italian
MIUR (funds COFIN and FIRB). We thank Prof. Mariella
Mella and Prof. Giorgio Mellerio for recording NMR and
MS spectra, respectively.
(16) In contrast to 1-lithio-2-bromocyclopentene which is relatively stable
up to 25 °C, 1-lithio-2-bromocyclohexene is reported to lose LiBr even at
e120 °C, hampering the extension of this methodology to 1,2-dihalocy-
clohexenes.
(17) For studies on the stability of different 1-lithio-2-halocycloalkenes,
see: (a) Wittig, G.; Mayer, U. Chem. Ber. 1963, 96, 329-341. (b) Wittig,
G.; Mayer, U. Chem. Ber. 1963, 96, 342-348. (c) Wittig, G.; Weinlich, J.;
Wilson, E. R. Chem. Ber. 1965, 98, 458-470.
Supporting Information Available: General experimen-
tal procedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL060654Y
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