Asymmetric Pauson-Khand reaction with chiral, electron-deficient mono- and bis-phosphine ligands

Article abstract of DOI:10.1016/j.tetlet.2004.07.091

The intermolecular Pauson-Khand reaction between norbornene and dicobalt carbonyl complexes of phenylacetylene substituted with chiral phosphorus ligands has been investigated. High yields (≥98%) and enantiomeric excesses of up to 56% have been observed.

Full text of DOI:10.1016/j.tetlet.2004.07.091

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6975–6978
Asymmetric Pauson–Khand reaction with chiral,
electron-deficient mono- and bis-phosphine ligands
*
´ ´
Denes Konya, Frederic Robert, Yves Gimbert and Andrew E. Greene
´
Universite Joseph Fourier, LEDSS (UMR 5616-CNRS), BP53X, 38041 Grenoble, France
Received 6 April 2004; accepted 19 May 2004
Abstract—The intermolecular Pauson–Khand reaction between norbornene and dicobalt carbonyl complexes of phenylacetylene
substituted with chiral phosphorus ligands has been investigated. High yields ( P 98%) and enantiomeric excesses of up to 56% have
been observed.
Ó 2004 Elsevier Ltd. All rights reserved.
The Pauson–Khand reaction, which unites an alkyne, an
alkene, and carbon monoxide through the agency of
dicobalt octacarbonyl, is an effective method for con-
structing cyclopentenones.1 Over the 30-year period
since its discovery in 1973, significant insight has been
gained into the mechanism of this intriguing reaction
and its usefulness has been broadened through the dis-
covery of promoters and catalytic techniques.2
phosphino)methane (dppm) had a markedly deleterious
effect on the cyclization of the phenylacetylene–dicobalt
complex with norbornene (24% yield vs 60% yield
without dppm);9 we felt, however, that diphosphine
complexes could be made more reactive through modifi-
cation of the electronic properties of the phosphine
substituents. In 1999, we were able to demonstrate7
that electron-deficient diphosphinoamine ligands did in-
deed lead to vastly improved yields in this reaction (up
to 98%). These novel ligands, relative to common phos-
phine ligands, facilitate the first step of the Pauson–
Khand reaction by rendering the carbon monoxides
more labile by virtue of the increase in the backbonding
from cobalt to phosphorus and, at the same time, pro-
tect the intermediate dicobalt–alkyne complex against
oxidation and clusterization pathways.
Effort has also been expended toward developing an
asymmetric variant of this reaction,3 principally through
the use of a chiral auxiliary attached to the alkyne or
alkene substrate,4 and by replacing a carbonyl ligand
in the complex with a chiral phosphine ligand.5 This lat-
ter approach has to date proven considerably more suc-
cessful in the intramolecular than intermolecular version
of this and similar reactions.6 The first intermolecular
enantioselective approach was disclosed in 1988 by
Pauson and co-workers, who used the chiral unidentate
phosphine GlyphosÒ.5a Improvements in this approach
were later reported,5b–e but still the two diastereomers
had to be separated prior to cyclization with the olefin.
The second phase of this program has focused on the use
of chiral electron-deficient ligands in the intermolecular
Pauson–Khand reaction.10 The simplest way to intro-
duce chirality in the diphosphinoamines, a priori, is by
placing a chiral substituent on nitrogen. In preliminary
work, it was found that the diphosphinoamine ligand
1a could be readily prepared from 1-phenylethylamine
and chlorodiphenylphosphine11 and then through reac-
tion with 2 transformed into the bridged complex 3a;12
in the presence of norbornene, 3a afforded cyclopente-
none 4 with a small, but encouraging, enantiomeric ex-
cess (16% ee, 57% yield) (Scheme 1).13
In an effort to overcome this major drawback, a few
years ago we undertook a study of bidentate bridging
ligands with the goal of ultimately being able to generate
unique chiral complexes that would be effective in the
asymmetric Pauson–Khand reaction.7 Pauson and co-
workers8 had reported in 1988 that achiral bis(diphenyl-
Since electron-withdrawing substituents on phosphorus
could be expected not only to improve the yield
as before, but in addition to increase the asymmetric
Keywords: Pauson–Khand chiral phosphines ligand.
*
Corresponding author. Tel.: +33-04-7651-4344; fax: +33-04-7663-
5754; e-mail: yves.gimbert@ujf-grenoble.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.091

6976
D. Konya et al. / Tetrahedron Letters 45 (2004) 6975–6978
CH3
C6H5
CO
CO
CO
.OC
OC
OC
Co
Co
N
O
X2P
PX2
CO
CO
H
CH3
X2P
C6H5
PX2
C6H5
C6H5
H
2
OC
OC
Co Co
N
toluene
toluene
80 ˚C
C6H5
70-80 ˚C
4
1a, X=C6H5
b, X=F
3a, X=C6H5
b, X=F
c, X=OCH(CF3)2
c, X=OCH(CF3)2
.
Scheme 1.
induction in the reaction by bringing the chiral ligand
nearer to the diastereotopic cobalts through a shorten-
ing of the Co–P bonds, the derivatives 1b,c were next
prepared.14 The corresponding chiral complexes 3b,c,
formed in 40–45% yield, on exposure to norbornene in
warm toluene produced the expected cyclopentenone 4
in 90% and 99% yield, respectively, but, surprisingly,
devoid of enantiomeric excess (Scheme 1).
Figure 1.
It has long been known that two ligands can be intro-
duced into acetylene–dicobalt hexacarbonyl complexes
and these ligands occupy the two axial positions21
(Fig. 1). In a recent example, Pericas and co-workers
prepared a phenylacetylene–dicobalt tetracarbonyl com-
plex in which achiral tripyrrolylphosphines were in the
axial positions.22 Significantly, they also reported an
85% yield in the reaction with norbornene, showing that
the beneficial effect of electron-deficient substituents in
diphosphinoamines, which we had previously observed,
is also found with the monophosphine ligands. The
chiral ligands we chose to investigate were the readily
Given that asymmetric induction depends on the
ligandÕs ability to provide a chiral environment close
to the reaction center and that the distance of the chiral
center on the amine is significant in the complexes 3,
induction in 3a must occur through transmission, that
is, through the spatial orientation imposed on the phen-
yl groups on phosphorus.15 Hence, the small fluoro and
the mobile hexafluoroisopropoxy16 substituents should
be, and are, ineffective. Merely increasing the size of
the amine cannot provide a workable solution to this
problem: bulky amines in reaction with PCl3 tend to give
cyclodiphosphazanes17 and with chlorodiphenylphos-
phine rearranged products18 and, in fact, all reactions
directed toward diphosphinoamine formation from
1-(2,6-dichlorophenyl)ethylamine and 2-amino-3,3-di-
methylbutane did indeed fail.
Table 1. BINOL phosphoramidite and phosphite derivatives
Placing the chiral groups on phosphorus, thereby bring-
ing the chiral and the reactive centers into closer proxi-
mity, was also investigated. The Pauson–Khand
reaction of complex 7, prepared as shown in Scheme
2,19 with norbornene gave cyclopentenone 4 in 83%
yield, but unfortunately with only 17% ee, again a high
yield but low enantiomeric excess.20
R
R0
Ref.
8a
8b
8c
8d
8e
8f
OC6H5
OCH(CF3)2
N(CH3)2
H
25
26
H
The difficulties encountered in this bridging-ligand
approach led us to consider an attractive alternative:
complexation of each of the cobalts with identical chiral
monophosphine ligands. This approach, as that above,
effectively obviates the necessity of a high degree of Co
discrimination in the complexation.
H
27
27
N(i-C3H7)2
N(C2H5)2
N(C2H5)2
N(C2H5)2
H
H
27
This work
This work
CH3
C6H5
8g
Scheme 2.

D. Konya et al. / Tetrahedron Letters 45 (2004) 6975–6978
6977
CO
CO
OC
OC
CO
CO
OC
OC
O
8
Co Co
C6H5
Co Co
OC
CO
L*
L*
toluene, 80 ˚C
30-40 %
toluene, 80 ˚C,
C6H5
H
C6H5
9a-g (L* = 8a-g)
H
4
2
yield (%) ee (%)
9a
9b
9c
9d
9e
9f
65
75
75
60
70
40
30
24
36
13
21
38
30
16
9g
Scheme 3.
prepared BINOL phosphoramidite and phosphite deriv-
atives 8a–g (Table 1).23,24
References and notes
1. For general reviews on the Pauson–Khand reaction, see:
(a) Schore, N. E. Org. React. 1991, 40, 1–88; (b) Geis, O.;
Schmaltz, H. G. Angew. Chem., Int. Ed. 1998, 37, 911–914;
(c) Jeong, N. Trans. Met. Org. Synth. 1998, 1, 560–577; (d)
Chung, Y. K. Coord. Chem. Rev. 1999, 188, 297–341; (e)
Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56,
3263–3283; (f) Fletcher, A. J.; Christie, S. D. R. J. Chem.
Soc., Perkin Trans. 1 2000, 1657–1668.
2. For reviews on catalytic processes see: (a) Hanson, B. E.
Comments Inorg. Chem. 2002, 23, 289–318; (b) Gibson, S.
E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42,
1800–1810.
3. For a review on the asymmetric Pauson–Khand reaction,
see: Ingate, S. T.; Marco-Contelles, J. Org. Prep. Proced.
Int. 1998, 30, 121–143.
4. See, for example: (a) Castro, J.; So¨rensen, H.; Riera, A.;
Morin, C.; Moyano, A.; Pericas, M. A.; Greene, A. E.
J. Am. Chem. Soc. 1990, 112, 9388–9389; (b) Bernardes,
These chiral, unidentate ligands could be introduced
into the axial positions of the phenylacetylene–dicobalt
hexacarbonyl complex in moderate (nonoptimized)
yields. On warming in toluene solution in the presence
of excess norbornene for 12h, these new complexes pro-
vided cycloadduct 4 in generally good yield and with the
indicated enantiomeric excess (Scheme 3).
While the yields are roughly comparable to those
obtained with the bis-phosphine ligands, in several cases
the induction is significantly better, particularly with the
phosphoramidite 8e. Disappointingly, ortho substitution
in this ligand (8f,g) did not yield an improved enantio-
meric excess, but this is in line with results obtained by
Feringa and co-workers in the conjugate addition of di-
ethylzinc in the presence of chiral copper complexes.27 A
significant improvement with ligand 8e was observed,
however, on lowering the reaction temperature to
60°C and replacing the toluene with DME: 56% ee,
60% yield.28,29 Although the reaction time is considera-
bly lengthened under these conditions (96h vs 12h), this
represents the best result reported to date (previ-
ously10<10% ee, 29% yield) for the intermolecular Pau-
son–Khand reaction using chiral ligands without
separation of diastereomers.
`
V.; Kann, N.; Riera, A.; Moyano, A.; Pericas, M. A.;
Greene, A. E. J. Org. Chem. 1995, 60, 6670–6671; (c) Park,
H.-J.; Lee, B. Y.; Kang, Y. K.; Chung, Y. K. Organo-
metallics 1995, 14, 3104–3107; (d) Rivero, M. R.; de la
Rosa, J. C.; Carretero, J. C. J. Am. Chem. Soc. 2003, 125,
14992–14993.
5. See, for example: (a) Bladon, P.; Pauson, P. L.; Brunner,
H.; Eder, R. J. Organomet. Chem. 1988, 355, 449–453; (b)
Brunner, H.; Niedernhuber, A. Tetrahedron: Asymmetry
1990, 1, 711–714; (c) Hay, A. M.; Kerr, W. J.; Kirk, G. G.;
Middlemiss, D. Organometallics 1995, 14, 4986–4988; (d)
`
Castro, J.; Moyano, A.; Pericas, M. A.; Riera, A.;
In conclusion, chiral monophosphine ligands at each of
the axial positions in the acetylene–dicobalt complex
appear to be generally more effective in the asymmetric
intermolecular Pauson–Khand reaction than chiral bis-
phosphine ligands that bridge the two cobalts in equato-
rial positions. The level of enantioselectivity reached
with the chiral phosphoramidites encourages further re-
search on this approach to asymmetric induction in this
important reaction.
Alvarez-Larena, A.; Piniella, J. F. J. Am. Chem. Soc.
2000, 122, 7944–7952; (e) Verdaguer, X.; Moyano, A.;
Pericas, M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.
F. J. Am. Chem. Soc. 2000, 122, 10242–10243. Chiral
amine N-oxides have also been investigated: (f) Derdau,
V.; Laschat, S.; Jones, P. G. Heterocycles 1998, 48,
1445–1453; Kerr, W. J.; Lindsay, D. M.; Rankin, E. M.;
Scott, J. S.; Watson, S. P. Tetrahedron Lett. 2000, 41,
3229–3233.
`
6. (a) Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 7026–7033; (b) Hicks, F. A.; Kabaloui, N. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 5881–5898;
(c) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I.
Tetrahedron Lett. 2000, 41, 891–895; (d) Hiroi, K.;
Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron:
Asymmetry 2000, 11, 797–808; (e) Shibata, T.; Takagi,
K. J. Am. Chem. Soc. 2000, 122, 9852–9853; (f) Jeong, N.;
Sung, B. L.; Kim, J. S.; Park, S. B.; Seo, S. D.; Shin, J. Y.;
In, K. Y.; Choi, Y. K. Pure Appl. Chem. 2002, 74, 85–91;
Acknowledgements
We are thankful to Dr. A. Durif and Dr. M.-T.
Averbuch for the X-ray structure determination. A
fellowship from MRES to F.R. and financial support
from the CNRS (UMR 5616, FR 2607) and the Univer-
´
site Joseph Fourier are gratefully acknowledged.

6978
D. Konya et al. / Tetrahedron Letters 45 (2004) 6975–6978
(g) Sturla, S. J.; Buchwald, S. L. J. Org. Chem. 2002, 67,
3398–3403.
7. Gimbert, Y.; Robert, F.; Durif, A.; Averbuch, M.-T.;
Kann, N.; Greene, A. E. J. Org. Chem. 1999, 64,
3492–3497.
8. Billington, D. C.; Helps, I. M.; Pauson, P. L.; Thomson,
W.; Willison, D. J. Organomet. Chem. 1988, 354, 233–242.
See, however, Ref. 7.
hydro-1,3,2-benzodiazaphosphol-2-yl)methylamine was
prepared (Konya, D.; Philouze, C.; Gimbert, Y.; Greene,
A. E. Acta Crystallogr., Sect. C 2002, C58, 108–111).
Unfortunately, this exceptionally stable, but large, novel
ligand could not be introduced into the complex (phenyl-
acetylene–dicobalt hexacarbonyl).
21. Bonnet, J.-J.; Mathieu, R. Inorg. Chem. 1978, 17,
1973–1976.
9. This may explain the general lack of interest over the
intervening years in the use of this type of ligand in the
Pauson–Khand reaction. More recently, it has been
reported that bridging BINAP completely shuts down
the Pauson–Khand reaction between the t-butylacetylene
complex and norbornene (Derdau, V.; Laschat, S.; Dix, I.;
Jones, P. G. Oganometallics 1999, 18, 3859–3864. See,
however, Refs. 6e,10). It should be noted that Gibson
et al. (Gibson, S. E.; Lewis, S. E.; Loch, J. A.; Steed, J. W.;
Tozer, M. J. Organometallics 2003, 22, 5382–5384) have
recently described an effective precatalyst for the intra-
molecular reaction in which BINAP chelates one of the
cobalts. (The actual reactive Pauson–Khand complex,
however, might not be the chelate, since chelated com-
plexes can undergo transformation to bridged complexes
at 80°C. Konya, D., unpublished results.).
10. The best result using a dicobalt complex and a (presumed)
bridging bisphosphine ligand has been reported by Hiroi
et al. 6d These authors obtained a 29% yield and less than a
10% ee in the intermolecular reaction between phenyl-
acetylene and norbornene in presence of BINAP.
11. Kamalesh Babu, R. P.; Krishnamurthy, S. S.; Nethaji, M.
Tetrahedron: Asymmetry 1995, 6, 427–438.
22. Castro, J.; Moyano, A.; Pericas, M. A.; Riera, A.;
Maestro, M. A.; Mahia, J. Organometallics 2000, 19,
1704–1712.
23. These ligands are known (8f,g, however, with N(CH3)2 in
place of N(C2H5)2).25–27 Their synthesis involves the
treatment of BINOL-PCl (from BINOL, PCl3, and
N(CH3)3) with the appropriate alcohol or amine.
24. Jeong, N. Mentions in a review1c unpublished work
involving a single example of a chiral phosphite with a
dicobalt complex in an intermolecular reaction. For the
use of chiral phosphites in an intramolecular version, see
Ref. 6g.
25. Dussault, P. H.; Woller, K. R. J. Org. Chem. 1997, 62,
1556–1559.
26. Reetz, M. T.; Mehler, G.; Meiswinkel, A. PCT Int. Appl.
(Studiengesellschaft Kohle m.b.H., Germany) 2001 WO
2001094278.
27. Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H.
M.; Naaz, R.; Feringa, B. L. Tetrahedron 2000, 56,
2865–2878.
28. At still lower temperatures, the reaction failed to proceed.
In the presence of NMO, the reaction could be run at
20°C, but the ee was lower (44%).
12. The complexes in this paper do not undergo change in
toluene solution at 80°C in the absence of olefin (31P
NMR).
13. HPLC: Chiracel OD-H, 5lm, hexane : isopropanol=9:1,
0.5cm3/min, Tr 11.17 and 13.33min. Compounds have
been identified by IR, MS, and high-field NMR (1H, 13C,
31P, 19F).
29. l,l-Di-(S)-(O,2(O,2-O0,20)-binaphthyl-(N,N0)-diethylphos-
phoramidito-tetracarbonyl-l-(g:g2-phenyl-acetyl-ene)-di-
cobalt (9e). A solution of 194mg (0.50mmol) of the
dicobalt hexacarbonyl–acetylene complex 2 and 579mg
(1.50mmol) of ligand 8e in 10mL of toluene was heated at
80°C with stirring. After the disappearance of the initial
complex (TLC), the solution was stirred for an additional
10min and then filtered through a plug of silica gel. The
filtrate was concentrated under reduced pressure and the
resulting residue chromatographed (silica gel, pentane/
ethyl acetate 90/10) to provide 199mg (36%) of complex
14. Ligands 1b and 1c were prepared from N,N-bis(di-
chlorophosphino)-1-phenylethylamine
(1-phenylethyl-
amine, PCl3, C2H5N, ether) by using SbF3 in refluxing
methylcyclohexane (35%, two steps) and (CF3)2CHOH and
C2H5N in refluxing ether (40%, two steps), respectively.
15. The influence of the chiral center on the disposition of the
phenyls can be discerned in the X-ray structure of complex
3a. Crystallographic data for 3a have been deposited as
supplementary material at the Cambridge Crystallogra-
phic Data Centre.
1
9e: H NMR d 0.69 (t, J=6.9Hz, 6H), 0.86 (t, J=6.9Hz,
6H), 2.15–2.35 (m, 2H), 2.45–2.65 (m, 2H), 2.70–2.90
(m, 2H), 3.00–3.20 (m, 2H), 4.85 (t, J=5.1Hz, 1H),
6.55 (d, J=8.9Hz, 1H), 6.95–7.40(m, 2H0 ), 7.54 (d,
J=8.9Hz, 1H), 7.70–7.85 (m, 5H), 7.89 (d, J=8.9Hz, 1H),
7.97 (d, J=8.9Hz, 1H); 31P NMR d 183.5 (dd, J=28.6Hz,
J=17.9Hz, 2P); IR 2026, 1977cmꢀ1; MS (ES+) m/z
1105.9 (M+, 40%), 1128.9 (M+ + Na, 100%). Anal.
Calcd for C60H50Co2N2O8P2: C, 65.11; H, 4.55; N, 2.53.
Found: C, 65.34; H, 4.12; N, 2.41%. 3a,4,5,6,7,7a-Hexa-
´
16. Kundig, E. P.; Dupre, C.; Bourdin, B.; Cunningham, A.,
¨
Jr.; Pons, D. Helv. Chim. Acta 1994, 77, 421–428.
17. (a) Davies, A. R.; Dronsfield, A. T.; Haszeldine, R. N.;
Taylor, D. R. J. Chem. Soc., Dalton Trans. 1973, 379–385;
(b) Jefferson, R.; Nixon, J. F.; Painter, T. M.; Keat, R.;
Stobbs, L. J. Chem. Soc., Dalton Trans. 1973, 1414–1419.
18. Keat, R.; Manojlovic-Muir, L.; Muir, K. W.; Rycroft, D.
S. J. Chem. Soc., Dalton Trans. 1981, 2192–2198.
19. For the preparation of bis-dichlorophosphino-methyl-
amine, see: King, R. B.; Gimeno, J. Inorg. Chem. 1978,
17, 2390–2395.
hydro-4,7-methano-2-phenyl-1H-indene-1-one
(4).
A
solution of 221mg (0.20mmol) of complex 9e and
282mg (3.00mmol) of norbornene in 8.0mL of DME
was placed in a sealable glass reactor and heated at 60°C
for 96h. The reaction mixture was then filtered through
a plug of silica gel and the filtrate concentrated. Chroma-
tography of the residue on silica gel (pentane/ethyl acetate
as eluent) provided 27mg (60%) of known5a cyclopent-
enone 4.
20. In an attempt to bring asymmetry elements closer yet to
the cobalts ((4R,5R)-1,3-bis(trifluoromethanesulfonyl)per-