Regioselectivity in intermolecular pauson-khand reactions of dissymmetric fluorinated alkynes

Article abstract of DOI:10.1021/ol102283c

Stoichiometric and catalytic intermolecular Pauson - Khand reactions (PKRs) of dissymmetric fluorinated alkynes were performed, affording regioselectively -fluorinated cyclopentenones. Ethyl 4,4,4-trifluorobutynoate was an excellent substrate; its reactio

Full text of DOI:10.1021/ol102283c

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5620-5623
Regioselectivity in Intermolecular
Pauson-Khand Reactions of
Dissymmetric Fluorinated Alkynes
Jean-Claude Kizirian,*,†,‡,§ Nuria Aiguabella,† Albert Pesquer,† Santos Fustero,|,⊥
Paula Bello,|,⊥ Xavier Verdaguer,† and Antoni Riera*,†
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Institute for Research in
Biomedicine (IRB) and Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona,
c/Baldiri Reixac, 10, E-0 8028 Barcelona, Spain, Laboratoire de Physicochimie des
Mate´riaux et des Biomole´cules, EA4244, Faculte´ des Sciences de Tours, Parc de
Grandmont, 37200 Tours, France, Departamento de Qu´ımica Orga´nica, UniVersidad
de Valencia, E-46100 Burjassot, Spain, and Laboratorio de Mole´culas Orga´nicas,
Centro de InVestigacio´n Pr´ıncipe Felipe, E-46012 Valencia, Spain
antoni.riera@irbbarcelona.org; jean-claude.kizirian@uniV-tours.fr
Received September 23, 2010
ABSTRACT
Stoichiometric and catalytic intermolecular Pauson-Khand reactions (PKRs) of dissymmetric fluorinated alkynes were performed, affording
regioselectively r-fluorinated cyclopentenones. Ethyl 4,4,4-trifluorobutynoate was an excellent substrate; its reaction with norbornadiene gave
the corresponding PKR adduct in good yield and complete regioselectivity. Conjugate addition of nitroalkanes or cyanide to this adduct is
stereospecific and entails concomitant loss of a trifluoromethyl group. This reaction can be exploited to prepare cyclopentenones featuring
quaternary centers.
The Pauson-Khand reaction (PKR) has become one of the
preeminent transformations for synthesizing cyclic and
polycyclic targets with five-membered rings,1,2 as it enables
rapid access to valuable functionalized intermediates for
diverse chemistries. Furthermore, the recent development of
catalytic3 and enantioselective4 methodologies for intermo-
lecular PKRs has facilitated preparation of enantiomerically
enriched cyclopentenones.2,5 Whereas the intermolecular
reaction of terminal alkynes to give R-substituted cyclopen-
tenones6 is always regioselective, the less frequently used
internal alkynes can afford two regioisomers. Although the
PKR can sometimes be highly regioselective,5a the regio-
chemistry is influenced by steric and electronic effects and
† Universitat de Barcelona.
‡ Faculte´ des Sciences de Tours.
§ Visiting professor at the IRB Barcelona.
(3) (a) Cabot, R.; Lledo, A.; Reves, M.; Riera, A.; Verdaguer, X.
Organometallics 2007, 26, 1134. (b) Lledo, A.; Sola, J.; Verdaguer, X.;
Riera, A.; Maestro, M. A. AdV. Synth. Catal. 2007, 349, 2121.
(4) (a) Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Maestro,
M. A.; Mahia, J. J. Am. Chem. Soc. 2000, 122, 10242. (b) Verdaguer, X.;
Perica`s, M. A.; Riera, A.; Maestro, M. A.; Mahia, J. Organometallics 2003,
22, 1868. (c) Verdaguer, X.; Lledo´, A.; Lo´pez-Mosquera, C.; Maestro,
M. A.; Perica`s, M.; Riera, A. J. Org. Chem. 2004, 69, 8053. (d) Sola, J.;
Riera, A.; Verdaguer, X.; Maestro, M. A. J. Am. Chem. Soc. 2005, 127,
13629. (e) Sola`, J.; Reve´s, M.; Riera, A.; Verdaguer, X. Angew. Chem.,
Int. Ed. 2007, 46, 5020. (f) Reve´s, M.; Achard, T.; Sola`, J.; Riera, A.;
Verdaguer, X. J. Org. Chem. 2008, 73, 7080. (g) Ji, Y.; Riera, A.; Verdaguer,
X. Org. Lett. 2009, 11, 4346.
| Universidad de Valencia.
⊥ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.
Soc., Chem. Commun. 1971, 36. (b) Khand, I. U.; Knox, G. R.; Pauson,
P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973,
977
.
(2) For recent reviews on the Pauson-Khand reaction, see: (a) Lee,
H. W.; Kwong, F. Y. Eur. J. Org. Chem. 2010, 789. (b) Park, J. H.; Chang,
K. M.; Chung, Y. K. Coord. Chem. ReV. 2009, 253, 2461. (c) Gibson, S. E.;
Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022. (d) Park, K. H.; Chung,
Y. K. Synlett 2005, 545. (e) Bon˜aga, L V. R.; Krafft, M. E. Tetrahedron
2004, 60, 9795
.
10.1021/ol102283c  2010 American Chemical Society
Published on Web 11/17/2010

may be difficult to predict.7 In general, the bulkiest sub-
stituent on the alkyne tends to end up R to the carbonyl
group. Among sterically similar substituents on the alkyne,
the more strongly electron-withdrawing group tends to end
up at the ꢀ position6d (Scheme 1).
Scheme 2.
Preparation of the Fluorinated Alkynes 1-3a
Scheme 1.
Regioselectivity of the Pauson-Khand Reactiona
a Method A: NaH/R2NH2/THF/-50 °C/1-3 h. Method B: AlMe3/
R2NH2/CH2Cl2/0 °C/2-4 h (ref 11).
a EWG: electron-withdrawing group. EDG: electron-donating group.
able, was prepared from trifluoroacetic anhydride by the highly
convenient Hamper’s procedure.12
Stoichiometric PKRs of the terminal alkyne 1 and of the
internal alkynes 2 and 3 were first studied. The alkynes were
treated with dicobalt octacarbonyl in toluene at room temper-
ature to cleanly form the corresponding hexacarbonyl cobalt
complexes (monitored by TLC). Once the complexes had been
formed, norbornadiene (10 equiv) was added, and the solution
was heated at 70 °C until the starting cobalt complexes
disappeared by TLC. The adducts 7-9 (derived from 1-3,
respectively) were obtained in moderate yields with complete
regioselectivity (7 and 8, as racemates; and 9, as a 1:1 mixture
of diastereoisomers) (Table 1). Most surprisingly, in all cases,
the fluorinated moiety was located at the R-position of the
enone. Contrary to our expectations, the bulky phenyl group
was ꢀ to the carbonyl and the EWG R. The regiochemistry of
adducts 7-9 was unambiguously established by NMR on the
basis of the coupling between the carbon and fluorine atoms.
Furthermore, the calculated chemical shifts of the olefinic
carbons fit particularly well with the recorded values. Lastly,
these results were confirmed by X-ray crystallography of
compound 8 (Figure 2).
Fluorinated substrates are very rarely used in PKRs. Indeed,
only a few examples of intramolecular PKR of fluorinated
enynes have been described.8,9 Moreover, to the best of our
knowledge, there are no reports on intermolecular PKR of
fluorinated substrates. Considering the importance of fluori-
nated compounds,10 we sought to explore intermolecular
PKRs of fluorinated alkynes and investigate how these
strongly electron-withdrawing groups affect regioselectivity.
We chose several terminal or internal alkynes (1-4) contain-
ing fluorine atoms at the propargylic position (Figure 1).
The stoichiometric PKR of ethyl 4,4,4-trifluorobutynoate (4)12
under the standard conditions afforded the cyclopentenone 10
in excellent yield (Table 1). Purification of the intermediate
cobalt hexacarbonyl complex (11) did not improve the yield.
The structure of the major isomer was carefully analyzed by
NMR: again, the trifluoromethyl group was found to be at the
R position of the enone. For the sake of comparison, ethyl
Figure 1. Four R-fluorinated alkynes studied.
The amides 1-3 were easily prepared from the readily
available bromodifluoroacetylenes 5.11 The Grignard derivative
of the corresponding acetylenes were treated in Barbier-type
conditions with ethyl chloroformate to give the esters 6.
Amination using sodium hydride in THF or AlMe3 in CH2Cl2
provided amides 1-3 in good yields (69-85%) (Scheme 2).11
Ethyl 4,4,4-trifluorobutynoate (4), although commercially avail-
(7) De Bruin, T. J. M.; Michel, C.; Vekey, K.; Greene, A. E.; Gimbert,
Y.; Milet, A. J. Organomet. Chem. 2006, 691, 4281.
(8) (a) Arimitsu, S.; Bottom, R. L.; Hammond, G. B. J. Fluorine Chem.
2008, 129, 1047. (b) Ferry, A.; Billard, T.; Langlois, B. R. Synlett 2005,
1027. (c) Harthong, S.; Billard, T.; Langlois, B. R. Synthesis 2005, 2253.
(d) Ishizaki, M.; Suzuki, D.; Hoshino, O. J. Fluorine Chem. 2001, 111, 81.
(9) (a) Nadano, R.; Ichikawa, J. Chem. Lett. 2007, 36, 22. (b) Nadano,
R.; Fuchibe, K.; Ikeda, M.; Takahashi, H.; Ichikawa, J. Chem. Asian J.
2010, 5, 1875.
(5) (a) Vazquez-Romero, A.; Cardenas, L.; Blasi, E.; Verdaguer, X.;
Riera, A. Org. Lett. 2009, 11, 3104. (b) Vazquez-Romero, A.; Rodriguez,
J.; Lledo, A.; Verdaguer, X.; Riera, A. Org. Lett. 2008, 10, 4509. (c) Iqbal,
M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.; Verdaguer,
X.; Riera, A. Org. Biomol. Chem 2008, 6, 4649. (d) Iqbal, M.; Evans, P.;
Lledo, A.; Verdaguer, X.; Pericas, M. A.; Riera, A.; Loeffler, C.; Sinha,
(10) Modern fluoroorganic chemistry: synthesis, reactiVity, applications;
Peer, K., Eds.; Wiley-VCH: Weinheim, 2004.
(11) (a) Fustero, S.; Ferna´ndez, B.; Bello, P.; del Pozo, C.; Arimitsu,
S.; Hammond, G. B. Org. Lett. 2007, 9, 4251. and literature cited therein.
(b) Arimitsu, S.; Ferna´ndez, B.; del Pozo, C.; Fustero, S.; Hammond, G. B.
J. Org. Chem. 2008, 73, 2656. See also: (c) Fustero, S.; Bello, P.; Ferna´ndez,
B.; del Pozo, C.; Hammond, G. B. J. Org. Chem. 2009, 74, 7690.
(12) (a) Hamper, B. C. J. Org. Chem. 1988, 53, 5558. (b) Hamper, B. C.
Org. Synth. 1992, 70, 246.
A. K.; Mueller, M. J. ChemBioChem 2005, 6, 276
.
(6) (a) Schore, N. E. Org. React. 1991, 40, 1. (b) Krafft, M. E.; Romero,
R. H.; Scott, I. L. J. Org. Chem. 1992, 57, 5277. (c) Arjona, O.; Csa´ky¨,
A. G.; Murcia, M. C.; Plumet, J. J. Org. Chem. 1999, 64, 7338. (d) Robert,
F.; Millet, A.; Gimbert, Y.; Konya, D.; Greene, A. E. J. Am. Chem. Soc.
2001, 123, 5396
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Org. Lett., Vol. 12, No. 24, 2010
5621

Table 1. Intermolecular Pauson-Khand Reaction of the
Fluorinated Alkynes 1-4
Table 2. Conjugate Additions to the PKR Adduct 10
base (equiv),
reagent
temp (°C), time (h)
R
yield (%)
a
MeNO2
MeNO2
MeNO2
MeNO2
TBAFb (0.4), 80, 15 CH2NO2
12a
12a
12a
12a
65
99
36
56
57
50
a
a
a
TBAFb (1), 90, 3
DBU (0.2), 80, 18
DBU (1)c, 90, 1.5
CH2NO2
CH2NO2
CH2NO2
a
EtNO2
TBAFd (0.4), 65, 1.5 CH(CH3)NO2 12b
KCNe
90, 1.5
CN
12c
a Used as a solvent. b Trihydrated salt. c Water (16 equiv) was added.
d 1 M solution in THF. e In actonitrile as solvent.
The unexpected main product, 12a, resulted from 1,4-
addition of nitromethane with concomitant loss of the
trifluoromethyl group. The structure of 12a was confirmed
by X-ray diffraction, enabling unambiguous assignment of
the regiochemistry of the PKR adduct 10 (see Figure 3). The
Figure 2. X-ray structure of compound 8.
2-butynoate, the nonfluorinated analogue of 4, was also tested.
As described,13 it gave regioisomer with the methyl group in
the R position (analogous to 10) in 91% yield.6a,13 The fact
that the same regioselectivity was observed for two electroni-
cally divergent compounds suggests that the strongly electron-
withdrawing trifluoromethyl group slightly influences the
regiochemistry of the reaction.
To confirm the surprising regiochemistry of adduct 10, and
to explore its synthetic potential, we attempted several conju-
gated additions of diverse nucleophiles to this compound
beginning with lithium dialkylcuprates. Somewhat surprisingly,
all attempts led to rapid decomposition of the products. A
literature survey revealed that R-trifluoromethyl lithium enolates
decompose easily by lithium fluoride elimination.14 Seeking to
avoid using lithium, we then tried conjugate addition of 10 to
Grignard reagents, catalyzed by different sources of copper (CuI,
CuCN, and CuBr), and to diethylzinc catalyzed by nickel(II).
Unfortunately, these efforts also failed. Copper-catalyzed ad-
dition of trimethylaluminum gave the expected product as a
mixture of diastereomers; however, the product was unstable
and could not be fully characterized. However, heating enone
10 in nitromethane solution with a base (DBU or TBAF) gave
a clean reaction (Table 2).
Figure 3. X-ray structure of compound 12a.
same reaction (conjugate addition and loss of the trifluoro-
methyl group) also occurred when nitroethane or cyanide
was used as nucleophile (see table 2). The yields improved
when 1 equiv of base was used and, in the case of DBU, by
addition of a small amount of water. The reaction was
monitored by 19F NMR, and a signal corresponding to HF-
DBU was observed. A conceivable mechanism for the loss
of the CF3 group consistent with all these facts is shown in
Scheme 3; after the conjugate addition, elimination of
fluoride similar to the one proposed by Mikami14 would give
a difluoro enone. Conjugate addition of water (or ni-
tromethane) to this enone followed by retro-aldol reaction
(or retro-Michael) would afford the cyclopentanone 12a.
To explore the synthetic potential of this unexpected
reaction in the preparation of cyclopentenones with a
quaternary center in C4, compound 12a was subjected to
(13) Fonquerna, S.; Moyano, A.; Pericas, M. A.; Riera, A. J. Am. Chem.
Soc. 1997, 119, 10225.
(14) Itoh, Y.; Mikami, K. Org. Lett. 2005, 7, 4883.
5622
Org. Lett., Vol. 12, No. 24, 2010

cobalt complex 11 with cyclopentene at 70 °C for 24 h gave
the expected cyclopentenone 15 in 36% yield (Scheme 6).
Scheme 3. Proposed Mechanism for the Loss of CF3 Group
Scheme 6. Stoichiometric PKR of 4 with Cyclopentene
Given the (well-known) poor reactivity of cyclopentene in
PKRs,6a this yield is actually rather good.
Grieco’s retro-Diels-Alder conditions,15 affording cyclo-
pentenone 13a in 60% yield (Scheme 4).
In summary, PKRs of fluorinated alkynes under standard
thermal conditions provided moderate to good yields of the
desired cyclopentenones. Our most striking result was that
the intermolecular version of the PKR is highly regioselec-
tive: in all the desired cyclopentenones formed, the fluori-
nated group was R to the enone. This is somewhat surprising,
since for alkynes with sterically similar functional groups,
the major regioisomer of the product usually has the EWG
at the ꢀ position. Since the regioselectivity of the intermo-
lecular PKR stems from a delicate balance between steric
and electronic factors, our results indicate that the fluorine
substituent’s electronic effect is either much weaker than
expected or is overridden by its steric hindrance. Therefore,
a detailed theoretical study is clearly warranted to explain
the regioselectivity of the PKR of fluorinated internal
alkynes. We are planning to undertake such a study and will
report on it in due course.
We also found that the PK adduct of ethyl 4,4,4-
trifluorobutynoate and norbornadiene 10 can be prepared in
good yield and with complete regioselectivity by either the
stoichiometric or the catalytic version of this chemistry.
Conjugate addition of nitroalkanes or cyanide to this adduct
entails concomitant loss of the trifluoromethyl group. This
reaction can be harnessed to prepare cyclopentenones having
quaternary centers.
Scheme 4. Retro-Diels-Alder Reaction of Compound 12a
Having explored the reactivity and the regioselectivity of
the stoichiometric reaction, we turned our attention to the
catalytic PKR of the alkyne 4 and norbornadiene. The
reaction was done using 10 mol % of the cobalt-alkyne
complex 11 formed in situ,and the reaction was run under
CO (2 bar). In this case, cyclopentenone 10 was obtained in
a moderate yield of 57%: the product was accompanied with
substantial amounts of endo isomer, which had to be
separated out by chromatography. To minimize the amount
of the undesired endo isomer, another reaction was run using
the less reactive triphenylphosphine dicobaltpentacarbonyl
complex 14 as catalyst. This gave diastereomerically pure
10 in a noteworthy 73% yield (Scheme 5).
We are continuing to explore the vast synthetic potential
of fluorinated alkynes as regioselective directors in inter-
molecular PKR in our laboratory.
Acknowledgment. We thank MICINN (CTQ2008-00763/
BQU and CTQ2010-19774-C02-01) of Spain, the IRB
Barcelona, and the Generalitat de Catalunya (2009SGR
00901) for financial support. P.B. and N.A. express their
gratitude to MICINN and IRB Barcelona for predoctoral
fellowships.
Scheme 5. Catalytic PKR of 4 with Norbornadiene
Supporting Information Available: Experimental pro-
1
cedures and characterization of compounds 7-15; H /13C
NMR spectra of compounds 7-10, 12a-c, 13a, and 15;
X-ray crystallographic data of 8 and 12a (CIF). This material
is available free of charge via the Internet http://pubs.acs.org.
OL102283C
The reactivity of alkyne 4 was also tested with a less
reactive olefin: cyclopentene. Reaction of the intermediate
(15) Grieco, P. A.; Abood, N. J. Org. Chem. 1989, 54, 6008.
Org. Lett., Vol. 12, No. 24, 2010
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