Asymmetrie intermodular Pauson-Khand reaction of symmetrically substituted alkynes

Article abstract of DOI:10.1021/ol901728r

The asymmetric intermolecular Pauson-Khand reaction of symmetric alkynes has been accomplished for the first time. A/-Phosphino-ptolylsulfinamlde (PNSO) ligands have been indentified as efficient ligands in this process. The chirality of the cobalt S-bond

Full text of DOI:10.1021/ol901728r

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4346-4349
Asymmetric Intermolecular
Pauson-Khand Reaction of
Symmetrically Substituted Alkynes
Yining Ji, Antoni Riera,* and Xavier Verdaguer*
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-08028 Barcelona, Spain
antoni.riera@irbbarcelona.org; xaVier.Verdaguer@irbbarcelona.org
Received July 28, 2009
ABSTRACT
The asymmetric intermolecular Pauson-Khand reaction of symmetric alkynes has been accomplished for the first time. N-Phosphino-p-
tolylsulfinamide (PNSO) ligands have been indentified as efficient ligands in this process. The chirality of the cobalt S-bonded sulfinyl moiety
was found to direct olefin insertion into one of the two possible cobalt-carbon bonds in the alkyne complex. Reaction of symmetric alkynes
allows for a simplified experimental protocol since there is no need for separation of diastereomeric complexes.
Since its discovery, the Pauson-Khand reaction (PKR) has
attracted the interest of the community of chemists because
it provides the most simple and attractive access to cyclo-
pentenone compounds, which in turn are valuable synthetic
intermediates.1,2 The use of cobalt,3,4 rhodium,5 iridium,6
and titanium7 complexes has allowed the development of
efficient asymmetric intramolecular versions of this process.
Although great advances have been made in this field, one
major challenge remains,8 namely the use of symmetrically
substituted alkynes in an enantioselective intermolecular
process. From the synthetic point of view, an intermolecular
reaction offers a clear advantage over an intramolecular one:
from three simple components (alkene, alkyne, CO) it
provides high added-value molecules in a single step.
The standard methodology used in the asymmetric
cobalt-mediated intermolecular PKR relies on the use of
chiral phosphines and terminal alkynes.9 The reaction of
a chiral phosphine with a terminal dicobalt-alkyne
complex provides two diastereomers. Once these are
separated, olefin reaction with each diastereomer usually
leads to the corresponding PKR product in high optical
purity. The success of this approach depends on two
(8) For selected reviews on the PKR, see: (a) Shibata, T. AdV. Synth.
Catal. 2006, 348, 2328. (b) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int.
Ed. 2005, 44, 3022. (c) Laschat, S.; Becheanu, A.; Bell, T.; Baro, A. Synlett
2005, 2547. (d) Bonaga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60,
9795. (e) Blanco-Urgoiti, J.; Anorbe, L.; Pe´rez-Serrano, L.; Dominguez,
G.; Pe´rez-Castells, J. Chem. Soc. ReV. 2004, 33, 32. (f) Gibson, S. E.;
Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800. (g) Brummond,
K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (h) Perica`s, M. A.; Balsells,
J.; Castro, J.; Marchueta, I.; Moyano, A.; Riera, A.; Vazquez, J.; Verdaguer,
X. Pure Appl. Chem. 2002, 74, 167.
(1) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman,
M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977
(2) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.
Soc., Chem. Commun. 1971, 36
(3) Gibson, S. E.; Lewis, S. E.; Loch, J. A.; Steed, J. W.; Tozer, M. J.
Organometallics 2003, 22, 5382
(4) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron:
Asymmetry 2000, 11, 797
(5) Jeong, N.; Sung, B. K.; Choi, Y. K. J. Am. Chem. Soc. 2000, 122,
.
.
.
.
(9) (a) Bladon, P.; Pauson, P. L.; Brunner, H.; Eder, R. J. Organomet.
Chem. 1988, 355, 449. (b) Hay, A. M.; Kerr, W. J.; Kirk, G. G.; Middlemiss,
D. Organometallics 1995, 14, 4986. (c) Castro, J.; Moyano, A.; Perica`s,
M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J. F. J. Am. Chem. Soc.
2000, 122, 7944.
6771.
(6) Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852.
(7) Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 7026.
10.1021/ol901728r CCC: $40.75
Published on Web 09/09/2009
 2009 American Chemical Society

crucial chemical events: (a) olefin coordination to the
phosphine-free cobalt atom and (b) olefin insertion on the
Co-C(terminal) bond, as illustrated in Figure 1.
alkynes.11-14 We have recently introduced N-phosphinosul-
finamides (PNSO) ligands as novel and efficient chiral
controllers for the intermolecular PKR (Figure 2).15,16 When
Figure 2. N-Phosphine-sulfinamide (PNSO) ligands and their
Co2-alkyne complexes.
Figure 1. Olefin insertion in phosphine-alkyne complexes.
coordinated to Co2-alkyne complexes (R′ ) H), ligands 2
and 3 function as bridged P,S ligands. The main feature of
the resulting complexes (A) is that the chiral sulfur atom is
directly bound to one of the cobalt atoms. We consider that
the chirality of the sulfinyl group is ideally suited to direct
the insertion of the olefin in type A complexes derived from
symmetric alkynes (R ) R′). Here we provide the first report
on a highly enantioselective intermolecular asymmetric PKR
with internal symmetric alkynes.
Several factors hamper the use of internal symmetric
alkynes in the asymmetric PKR. First, these compounds are
intrinsically less reactive than terminal ones. In addition, once
a phosphine is bound to the alkyne-Co2 complex, the struc-
tural element containing the chiral information is too far away
to direct olefin insertion. Consequently, olefin is inserted
indistinctively on either side of the alkyne, which leads to a
racemic product (Figure 1). To illustrate this behavior, we
synthesized the corresponding (R)-MonoPHOS-Co2(CO)5-
C2Ph2 complex 1 (Scheme 1). When 1 was reacted with
For exploratory purposes, we began using diphenylacety-
lene as a benchmark internal symmetric alkyne (Scheme 2).
Scheme 1
.
PKR of Diphenylacetylene Complex with
MonoPHOS
Scheme 2
.
Asymmetric Intermolecular Pauson-Khand
Reactions of Diphenylethyne
norbornadiene in the presence of N-methylmorpholine N-
oxide (NMO), the corresponding PKR cyclopentenone was
produced in only 10% yield and a 53:47 enantiomeric ratio.
This observation confirmed that when the chiral information
is placed away from the olefin insertion it does not induce
any relevant selectivity.10
Ligand-exchange reaction of the corresponding dicobalt
hexacarbonyl complex with PNSO ligand 2, bearing a tert-
butylsulfinyl group, provided the desired bridged single
enantiopure complex (2a) in 52% yield. Reaction of 2a with
Over the past decade, we have developed hemilabile chiral
bidentate P,S ligands for the intermolecular PKR of terminal
(10) An attractive alternative could be the use of chiral C2 diphosphines.
However, double phosphorus coordination turns the resulting complexes
completely unreactive; see: Derdau, V.; Laschat, S.; Dix, I.; Jones, P. G.
Organometallics 1999, 18, 3859.
(13) Verdaguer, X.; Lledo´, A.; Lo´pez-Mosquera, C.; Maestro, M. A.;
Perica`s, M. A.; Riera, A. J. Org. Chem. 2004, 69, 8053
(14) Sola`, J.; Riera, A.; Verdaguer, X.; Maestro, M. A. J. Am. Chem.
Soc. 2005, 127, 13629
(15) Sola`, J.; Reve´s, M.; Riera, A.; Verdaguer, X. Angew. Chem., Int.
Ed. 2007, 46, 5020
(16) Reve´s, M.; Achard, T.; Sola`, J.; Riera, A.; Verdaguer, X. J. Org.
Chem. 2008, 73, 7080
.
.
(11) Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Maestro,
M. A.; Mahia, J. J. Am. Chem. Soc. 2000, 122, 10242.
(12) Verdaguer, X.; Perica`s, M. A.; Riera, A.; Maestro, M. A.; Mah´ıa,
J. Organometallics 2003, 22, 1868.
.
.
Org. Lett., Vol. 11, No. 19, 2009
4347

norbornadiene for 2 days at 65 °C provided the corresponding
levorotatory product 4a in good yield but low enantioselec-
tivity (40:60 er). When the same reaction was performed
under N-oxide-promoted conditions (NMO, CH2Cl2, rt), the
reaction time increased to 17 days and the yield was only
23%; however, the product showed excellent optical purity
(2:98 er). We subsequently explored the p-tolylsulfinyl PNSO
ligand 3 in the same process (Figure 2, Scheme 2). For
reasons of stability, ligand 3 is better stored as its borane
complex.16 This is not an inconvenience since borane
removal and ligand exchange reaction can be performed in
a one-pot procedure. Complex 3a was obtained from
diphenylacetylene in an improved 83% yield. Gratifyingly,
N-oxide-promoted reaction led to 4a in good yield (71%)
and excellent enantiomeric excess (96:4 er). Again, thermal
conditions provided the PKR product in lower enantiomeric
purity (78:22 er) than the N-oxide-mediated reaction.
Most interestingly, the stereochemistry of the sulfinyl
moiety in ligands 2 and 3 determined the absolute config-
uration of the PKR adducts. Thus, RS ligand 2 provided
levorotatory cyclopentenones, while SS ligand 3 afforded
dextrorotatory ones. The absolute configuration of the
disubstituted adducts was determined by means of X-ray
crystallography of a dichloro analogue (Figure 3).17
Figure 4. Novel PNSO ligands with a range of diarylphosphine
groups. Yield in parentheses corresponds to the one-pot phosphinyla-
tion-borane protection of the corresponding N-isobutyl-p-tolyl-
sulfinamide (n-BuLi, THF, -78 °C, Ar2PCl, then BH3-SMe2 at
-30 °C).
With the novel ligands in hand, we proceeded to check
their efficiency toward the PKR of diphenylacetylene (Table
1, entries 2-5). While ligands 3, 6, and 8 afforded the
corresponding bridged complexes in excellent yield, the
PNSO ligand 7 failed to produce the desired complex 7a.
Again, it is highly probable that the steric encumbrance
caused by the ortho substituents on the phosphine moiety
obstructed the ligand-exchange reaction. The novel PNSO
ligands exhibited small differences in selectivity, all of them
giving higher than 95:5 er. Among these, compound 6,
holding a bis(p-methoxyphenyl)phosphine group, afforded
the final PKR adduct in an enhanced 97:3 enantiomeric ratio
(Table 1, entry 3). We then proceeded to explore the scope
of the reaction with respect to the nature of the alkyne
component. We found that neither electron-releasing nor
electron-withdrawing groups on the aromatic rings attached
to the alkyne have any effect on the outcome of the reaction
(Table 1, entries 6-10). Again, for both methoxy- and
fluorine-substituted substrates, ligand 6 provided a better
enantiomeric ratio than ligand 3. Alkynes with nonaromatic
substituents were also studied. Triisopropylsilyl (TIPS)-
protected 2-butyne-1,4-diol provided a good yield of the
bridged complex and an enantiomeric ratio of 93:7 (Table
1, entry 12). Finally, complex 6f derived from 4-octyne
provided the cyclization product in low yield (27%) but
excellent enantioselectivity (94:6 er).
Figure 3. Dihydro derivative of (+)-4d and its X-ray structure.
Despite a slightly lower selectivity, overall, the p-tolyl
ligand 3 was more effective than the tert-butyl analogue since
it afforded higher yields in the ligand exchange and cycload-
dition steps. At this point, in an attempt to improve
selectivity, we undertook the optimization of the phosphine
moiety in ligand 3. For this purpose, ligands 5-8 were
synthesized from the corresponding N-isobutyl-p-tolylsulfi-
namide. Reaction of lithium sulfinamide with the corre-
sponding Ar2PCl reagent followed by treatment with
BH3-SMe2 in a one-pot procedure afforded the desired
borane-protected ligands in good to excellent yield (Figure
4). In the case of ligand 7, increased steric hindrance around
the phosphorus atom prevented borane protection allowing
the isolation of 7 as a free phosphine.
Previous research on intermolecular PKR of terminal
alkynes has shown that directing olefin insertion to a specific
Co-C bond is essential to accomplish stereoselective cy-
clization.9 With this in mind, a feasible mechanistic scenario
that would account for the observed results is that in the
presence of N-oxide the PNSO ligand works mainly as a
(18) For a review on sulfoxide-metal bonding, see: Calligaris, M.
Coord. Chem. ReV. 2004, 248, 351.
(19) (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron
Lett. 1990, 31, 5289. (b) Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera,
A.; Bernardes, V.; Greene, A. E.; Alvarez-Larena, A.; Piniella, J. F. J. Am.
Chem. Soc. 1994, 116, 2153. (c) Montenegro, E.; Poch, M.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1998, 39, 335. (d) Verdaguer,
X.; Vazquez, J.; Fuster, G.; Bernardes-Genisson, V.; Greene, A. E.; Moyano,
A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 1998, 63, 7037.
(17) Compound (+)-4d was partially hydrogenated (H2, Pd/C, MeOH).
The dihydro derivative provided single crystals suitable for X-ray analysis.
The absolute configuration was determined by the anomalous dispersion
method.
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Org. Lett., Vol. 11, No. 19, 2009

Table 1. Pauson-Khand Reaction of the PNSO-dicobalt
Complexes with Norbornadiene
complex time
Figure 5
complexes.
. Olefin insertion hypotheses for Co2-alkyne-PNSO
entry
R
ligand (yield %)a (days) yield (%)b er (%)c enone
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
3
5
6
7
8
3
6
3
6
6
3
6
3
6
3a (83)
5a (88)
6a (90)
7a
8a (80)
3b (86)
6b (78)
3c (82)
6c (85)
6d (88)
3e (78)
6e (74)
3f (43)
6f (66)
20
25
17
71
73
77
96:4
95:5
97:3
4a
4a
4a
This observation indicates that olefin insertion takes place
close to the chiral sulfur center. Second, better selectivities
were accomplished under N-oxide conditions, thereby indi-
cating that the PNSO ligand works as a solid bridging ligand
rather than a hemilabile one. N-Oxides favor depletion of
carbon monoxide in the reaction media, thus favoring closed
bridged species rather than open ones like II.19
In summary, we have developed for the first time an
asymmetric intermolecular PKR for internal symmetric
alkynes. N-phosphino-p-tolylsulfinamide ligands that function
as bridged P,S ligands were the most effective in this process.
Extended reactions times, mostly due to the intrinsic low
reactivity of internal alkynes, are not overly problematic since
reactions were performed at room temperature. From a
practical point of view, the use of symmetric alkynes prevents
the formation of diastereomeric complexes and their separa-
tion. We propose a novel mechanism in which the sulfinyl
group remains attached to cobalt and directs olefin insertion.
19
22
26
17
26
26
19
24
25
26
64
73
73
82
85
85
80
57
6
94:6
95:5
96:4
95:5
97:3
97:3
90:10
93:7
94:6
94:6
4a
4b
4b
4c
4c
4d
4e
4e
4f
4-MeO-Ph
4-MeO-Ph
4-F-Ph
4-F-Ph
10 4-Cl-Ph
11 TIPSOCH2
12 TIPSOCH2
13 n-Pr
14 n-Pr
27
4f
a Yields of isolated complexes after flash chromatography. Reaction
conditions: 1,4-diazabicyclo[2.2.2]octane (DABCO), toluene, 65 °C. b Yields
of isolated products after flash chromatography. Reaction conditions:
N-methylmorpholine N-oxide (NMO), CH2Cl2, rt. c Enantiomeric ratio
determined by chiral HPLC.
solid bridging ligand and that olefin insertion occurs on the
cobalt center where the sulfinyl group is bound, as depicted
in I (Figure 5). Steric factors and the higher π-acidity of the
sulfinyl ligand would favor olefin coordination at this cobalt
center rather than to the one where the phosphine is bonded.18
Once the olefin is bonded to cobalt, sulfur chirality would
direct olefin insertion toward one of the two Co-C bonds.
In contrast to terminal alkynes, a hemilabile ligand cannot
explain the selectivity observed in an internal symmetric
substrate since sulfur chirality would be too far away to direct
olefin insertion, as depicted in II (Figure 5). Several
experimental findings support the above mechanistic hy-
pothesis. First, the stereochemistry of the sulfinyl moiety
efficiently determines the configuration of the final product.
Acknowledgment. This work was supported by MICINN
(CTQ2008-00763/BQU). Y.J. thanks the MEC for a fellow-
ship.
Supporting Information Available: Experimetnal pro-
cedures; spectral and analytical data for all new compounds.
Crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL901728R
Org. Lett., Vol. 11, No. 19, 2009
4349