Microwave promoted Pauson-Khand reactions

Article abstract of DOI:10.1016/S0040-4039(02)01912-3

The synthesis of various cyclopentenones via the Pauson-Khand reaction, employing for the first time microwave energy to initiate this cycloaddition process is reported.

Full text of DOI:10.1016/S0040-4039(02)01912-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7859–7862
Microwave promoted Pauson–Khand reactions
Mazhar Iqbal, Nicola Vyse, J e´ r oˆ me Dauvergne and Paul Evans*
Charterhouse Therapeutics, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Received 26 July 2002; accepted 6 September 2002
Abstract—The synthesis of various cyclopentenones via the Pauson–Khand reaction, employing for the first time microwave
energy to initiate this cycloaddition process is reported. © 2002 Elsevier Science Ltd. All rights reserved.
1
The Pauson–Khand reaction (PKR) is the now classic
method for the synthesis of cyclopentenones 4 from an
alkyne 1 and an alkene 3 under the influence of a
the prolonged reaction periods of standard PKR pro-
cesses. Therefore, we selected a series of Pauson–
Khand processes and performed the cyclisations under
microwave conditions.
8
transition metal carbonyl, usually dicobaltoctacarbonyl
Fig. 1). Traditional reaction conditions for the synthe-
sis of cyclopentenones in this manner include thermal
promotion (for example, toluene, 110°C) or the use of
the N-oxides at ambient temperature. Pauson–Khand
2
(
7
Gratifyingly, initial experiments confirmed that this
was indeed the case (see Table 1). The intermolecular
PKR, performed in a sealed vessel, between the pre-
3
cycloadditions are often hampered by sluggish reaction
periods; additionally low yields (dependent on the
choice of alkene and alkyne) and troublesome purifica-
tion protocols are frequently encountered. In recent
years various groups have reported the inclusion of
formed
trimethylsilylacetylene–dicobalthexacarbonyl
9
complex 2a and norbornadiene 3a (5 equiv.) proceeded
efficiently under a variety of experimental conditions.
Using toluene as the solvent gave excellent yields of the
corresponding cyclopentenone 4a after only 5 minutes
of microwave irradiation (entry 1). However, purifica-
tion proved difficult, presumably due to norbornadiene
derived by-products; additionally small amounts of the
4
additional additives and modifications of the standard
5
conditions that appear to accelerate or promote the
PKR.
10
corresponding endo-diastereoisomer were observed.
Use of 1,2-dichloroethane (DCE) required increased
reaction periods in order to obtain comparable yields at
identical temperatures (entry 2). Product purification
proved simpler by comparison and less of the corre-
sponding endo-diastereomer was detected. Toluene
(exhibiting no dipole moment) is almost transparent to
microwave energy, whereas it is absorbed more
efficiently by DCE. Consequently, the amount of
energy required to reach a given temperature is far
greater in toluene than in DCE and is almost quantita-
6
Microwave promoted reactions are gaining more wide-
spread use in organic chemistry particularly as efficient,
practical machines for the generation of microwaves in
a laboratory environment become available. These
published examples clearly demonstrate that microwave
energy may be harnessed, significantly reducing reac-
tion periods for a diverse selection of chemical pro-
cesses traditionally performed under conductive heating
via an external thermal source. We were intrigued to
ascertain whether the use of microwaves could reduce
7
Figure 1. The Pauson–Khand cycloaddition reaction.
*
0
Corresponding author. E-mail: pjevans@liv.ac.uk
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01912-3

7
860
M. Iqbal et al. / Tetrahedron Letters 43 (2002) 7859–7862
tively absorbed by the reagents. This possibly explains
the experimental observation that the reaction process
is more rapid in toluene than DCE and somewhat less
selective and clean. Increased temperature (entry 3)
drastically reduced the reaction period; however, con-
comitant pressure increases proved problematic.
regiochemistry of the adduct 4e was confirmed by
1
HMBC H NMR experiments. The efficiency of the
microwave mediated process decreased with less reac-
tive alkenes (entries 5–7) in parallel with standard PK
2
processes. For example, reaction between the phenyl-
acetylene–dicobalthexacarbonyl complex 2c and dihy-
drofuran gave the corresponding cyclopentenone 4f in
Significantly this process could be effectively performed
5
5% yield comparing favourably with the literature
4c
using 0.5 equiv. of Co (CO) (entry 4). In this experi-
2
8
yield for the corresponding thermal process (35%).
ment the dicobaltoctacarbonyl, trimethylsilylacetylene
a (R=SiMe ) and norbornadiene 3a were combined in
Cyclohexene gave the corresponding adduct 4g in 20%
1
12
3
yield, compared to the previously reported 3% yield
DCE and heated in the microwave at 120°C for 100
seconds. The pressure of carbon monoxide was vented
and the reaction mixture heated for a further 100
seconds at 120°C. Purification by flash column chro-
matography afforded 4a in 93% yield. By way of com-
parison identical thermal (entry 5) and NMO (entry 6)
mediated cycloadditions were performed, demonstrat-
ing the difference in both time and efficiency under
these typical conditions for this particular reaction.
(
entry 6). The cis-stereochemistry was suggested from
an NOE between the 4- and 5-protons. This trend was
also seen with 4,4-dimethoxycarbonylcyclopentene, syn-
thesised via ring closing olefin metathesis (entry 7). In
this case cyclopentenone 4h was isolated in 11% yield.
Intramolecular Pauson–Khand reactions may also be
effectively performed under microwave conditions
(
entries 8 and 9). In the standard examples selected it
proved crucial to both perform the reaction at reduced
To investigate further the scope and limitations of these
initial experiments a series of additional microwave
promoted Pauson–Khand reactions were performed
−
3
concentration (0.05 mol dm ) and to reduce the reac-
tion periods in comparison to their intermolecular
counterparts. Thus, both the reactions were complete
after 100 seconds at 90°C; indeed prolonged microwave
irradiation led to reduced yields. Reactions that pro-
ceed efficiently only under ambient temperature, N-
1
1
(
see Table 2).
The acetylene–dicobalthexacarbonyl complex 2b
reacted smoothly with norbornadiene 3a under
microwave irradiation, either in toluene (90°C, 5 min)
or DCE (90°C, 20 min), generating the corresponding
enone 4b in good yield (entry 1). Interestingly, a signifi-
cant improvement in diastereoselectivity was observed
under the microwave mediated conditions by compari-
son to the corresponding thermal and NMO promoted
processes. Similarly, phenylacetylene complex 2c gave
the adduct 4c on reaction with norbornadiene 3a (entry
1
3a
oxide mediated conditions, for example allenes
a,b-unsaturated esters,
and
13b
were found not to generate
the corresponding cyclopentenones under the condi-
tions described in this communication.
In summary, we have demonstrated that microwave
technology may be efficiently applied for the extremely
rapid synthesis of various cyclopentenones. A demon-
stration of the robustness of this method was given
when the cycloadditions described in Table 1 were also
successfully performed using CEM ‘Discover,’
2
). 1,2-Disubstituted cyclopentenones were also
efficiently accessed from the corresponding internal
alkynes and norbornadiene 3a (entries 3 and 4). The
Table 1.
e
Entry
1a
Solvent
Temperature (°C)
Time
Yield (%)d
exo-4a:endo-4a
PhMe
DCE
DCE
DCE
90
90
180
120
5 min
20 min
100 s
97
98
91
93
95:5
\95:5
95:5
a
2
a
3
b
4
200 s
\95:5
a
5
PhMe
DCM
110
25
16 h
16 h
99
50
\95:5
90:10
c
6
a
−3
Method: 3a (5 equiv.) was added to a solution (0.25 mol dm ) of 2a.
b
c
Method: 1a (R=SiMe ; 1 equiv.), cobalt octacarbonyl (0.5 equiv.) and 3a (5 equiv.) were dissolved in DCE (0.25 mol dm−3).
Method: NMO (5 equiv.) was added to a solution of 2a (1 equiv.) and 3a (5 equiv.) in DCM (0.25 mol dm ) at room temperature.
3
−3
d
e
Yield after purification by flash column chromatography.
1
Ratio determined by H NMR spectroscopy.

M. Iqbal et al. / Tetrahedron Letters 43 (2002) 7859–7862
7861
monomode cavity system (both in open and closed
the microwave energy, or from ‘super-heating’ of the
6c,15
1
4
reaction vessels ) and the Milestone multimode cavity
apparatus. At this stage it seems to be a matter of
conjecture as to whether the rate enhancements
described in this study stem directly from an effect of
media as recently highlighted.
Future work will
include studies aimed towards determining a specific
microwave effect in addition to broadening the sub-
strate scope of the process.
Table 2.

7
862
M. Iqbal et al. / Tetrahedron Letters 43 (2002) 7859–7862
Acknowledgements
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
7, 9225 (10229).
5
This research was funded by Charterhouse Therapeu-
tics, Oxford. We would like to thank the Ministry of
Science and Technology and NIBGE, Pakistan for the
Ph.D. scholarship awarded to M.I. and also Drs. Pelle
Lidstr o¨ m and Hadi Ghane, Personal Chemistry and
Professor Stan Roberts, University of Liverpool for
helpful advice and discussions.
7. Focused microwave irradiations used in this study were
generated by a Coherent Synthesis-Smith Workstation
package (Personal Chemistry AB, Sweden).
8. For a theoretical study concerning the energetics of the
various reaction intermediates along the Magnus path-
way see: Yamanaka, M.; Nakamura, E. J. Am. Chem.
Soc. 2001, 123, 1703.
9
. Representative
trimethylsilyl-3a,4,7,7a-tetrahydro-4,7-methanoinde-1-one
a: At room temperature Co (CO) (352 mg, 1.03 mmol,
experimental
procedure:
exo-2-
4
2
8
References
1 equiv.) was added to a solution of trimethylsilyl-
3
acetylene 1a (0.15 cm , 1.06 mmol, 1 equiv.) in DCE (4
3
1
2
. Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977.
. (a) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56,
cm ). Stirring was continued for 1 h. Norbornadiene 3a
3
(0.55 cm , 5.0 mmol, 5 equiv.) was added and the mixture
6
was heated in the microwave at 90°C for 20 min. Silica
3
263; (b) Schore, N. E. Org. React. 1991, 40, 1; (c)
(ca. 2 g) was added to the crude reaction mixture and the
solvent was removed under reduced pressure. Purification
by flash column chromatography (Hex“Hex/EtOAc; 9:1)
afforded the title compound 4a (218 mg, 94%) as a
Schore, N. E. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, Ch. 9.1; (d) Pauson, P. L. Tetrahedron 1985, 41,
5
855; (e) Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc.,
colourless solid. R
EtOAc; 9:1); wmax (CDCl
1247; l (400 MHz, CDCl
(1H, d, J=11.25 Hz, CH ), 1.22 (1H, d, J=11.25 Hz,
CH ), 2.01 (1H, d, J=6.25 Hz, CH), 2.52 (1H, s, CH),
2.72–2.74 (1H, m, CH), 2.80 (1H, s, CH), 6.21–6.30 (2H,
m, 2×CH), 7.65 (1H, d, J=2.5 Hz, CH); l (100 MHz,
CDCl ) −2.1, 41.1, 42.8, 43.7, 51.9, 53.2, 137.2, 138.1,
152.0, 172.7, 213.0; m/z (CI) 219 (MH , 100%); Found:
f
exo-4a=0.25 [endo-4a=0.2] (Hex/
−
1
Perkin Trans. 1 2000, 1657; (f) Chung, Y. K. Coord.
Chem. Rev. 1999, 188, 297; (g) Geis, O.; Schmalz, H.-G.
Angew. Chem., Int. Ed. Engl. 1998, 37, 911.
. (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetra-
hedron Lett. 1990, 31, 5289; (b) Jeong, N.; Chung, Y. K.;
Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204; (c)
Kerr, W. J.; Lindsay, D. M.; Rankin, E. M.; Scott, J. S.;
Watson, S. P. Tetrahedron Lett. 2000, 41, 3229.
3
/cm ) 3062, 2972, 1689, 1570,
) −0.17 (9H, s, CH ), 1.05
H
3
3
2
3
2
c
3
+
4
. (a) Primary amines: Sugihara, T.; Yamada, M.; Ban, H.;
Yamaguchi, M.; Kaneko, C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2801; (b) Sulfides: Sugihara, T.; Yamada,
M.; Yamaguchi, M.; Nishizawa, M. Synlett 1999, 771; (c)
Phosphine oxides: Billington, D. C.; Helps, I. M.; Pau-
son, P. L.; Thomson, W.; Willison, D. J. Organomet.
Chem. 1988, 354, 233; (d) Sulfoxides: Chung, Y. K.; Lee,
B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L.
Organometallics 1993, 12, 220.
C, 71.50; H, 8.31%, C13
8.30%.
H18OSi requires C, 71.60; H,
10. The exo:endo ratios were calculated from characteristic
1
signals in the H NMR spectra after the crude reaction
mixture was purified by flash column chromatography.
No attempt was made to separate the diastereomers,
however, the ratios given must be considered approxi-
mate.
1
11. All new compounds were fully characterised by H NMR
13
5
. (a) Ultrasound: Gair Ford, J.; Kerr, W. J.; Kirk, G. G.;
Lindsay, D. M.; Middlemiss, D. Synlett 2000, 1415; (b)
Ultraviolet irradiation: Pagenkopf, B. L.; Livinghouse, T.
J. Am. Chem. Soc. 1996, 118, 2285; (c) Dry state absorp-
tion: Smit, W. A.; Simonyan, S. O.; Tarasov, V. A.;
Mikaelian, G. S.; Gybin, A. S.; Ibragimov, I. I.; Caple,
R.; Froen, D. E.; Kreager, A. Synthesis 1989, 472.
. (a) Caddick, S. Tetrahedron 1995, 51, 10403; (b) Loupy,
A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault,
P.; Math e´ , D. Synthesis 1998, 1213; (c) Perreux, L.;
Loupy, A. Tetrahedron 2001, 57, 9199; (d) Lidstr o¨ m, P.;
and C NMR spectroscopic techniques by microanalysis
and/or high resolution mass spectroscopy.
12. Khand, I. U.; Pauson, P. L. J. Chem. Res. (M) 1977, 168.
13. (a) Antras, F.; Ahmar, M.; Cazes, B. Tetrahedron Lett.
2001, 42, 8153 and references cited therein; (b) Ahmar,
M.; Antras, F.; Cazes, B. Tetrahedron Lett. 1999, 40,
5503.
14. For a discussion on the use of open and closed systems
see: Stadler, A.; Pichler, S.; Horeis, G.; Kappe, C. O.
Tetrahedron 2002, 58, 3177.
6
15. Kuhnert, N. Angew. Chem., Int. Ed. Engl. 2002, 41, 1863.