C. J. Cobley et al. / Tetrahedron Letters 42 (2001) 7481–7483
7483
In conclusion, we have confirmed that NBD precata-
lysts can give faster initial reaction rates than the
corresponding COD precatalysts. However, as catalyst
loadings are reduced to levels more conducive to eco-
nomic manufacture, the difference between the use of
COD and NBD precatalysts becomes increasingly
insignificant. Furthermore, with certain substrates and
conditions we see no induction period with the COD
precatalyst. We suggest that generally the more readily
available COD precatalysts are appropriate for use
under industrial conditions, at least in the case of
rhodium-DuPHOS catalysts. For other rhodium–bis-
phosphine–diolefin precatalysts, it is possible that an
unacceptable induction period could occur with the
COD precatalyst3 such that appropriate comparative
characterisation is recommended. The absence or pres-
ence of any induction period depending on the sub-
strate or conditions may be associated with effects of
hydrogen availability at the catalyst and in particular
by the rate of uptake of hydrogen by the COD pre-cat-
alyst relative to that of the substrate–catalyst complex.
This aspect is currently being explored further.
room temperature; GC analysis: DEX-CB column, 60°C
for 5 min, then 5°C/min to 150°C, 17.0 min (S), 17.2 min
(R).
6. In a typical experiment a 600 mL Parr hydrogenation
vessel is charged with a MeOH solution of the substrate
and pressurised with nitrogen to 10 bar under vigorous
stirring. The system is allowed to equilibrate over 20 min
before releasing the pressure. This procedure is repeated
three times with nitrogen and three times with hydrogen.
A solution of the catalyst in deoxygenated MeOH is
introduced via syringe. The vessel is quickly purged a
further three times with hydrogen (less than 20
s
required) and pressurised to the required reaction pres-
sure (gauge reading). The amount of hydrogen uptake is
monitored at standard intervals and the pressure con-
stantly maintained within 0.5 bar of the initial pressure
reading. When no further hydrogen consumption is
detected the pressure is released and samples taken for
conversion and selectivity analysis. The curves of hydro-
gen uptake versus time are normalised to 100% uptake.
7. Methyl acetamidocinnamate 3 (10.0 g, 27 mL, 45.6
mmol) in MeOH (200 mL), precatalyst (0.023 mmol) in
MeOH (2 mL), 3 bar H2, 26°C; GC analysis: DEX-CB
column, 150°C for 25 min, then 5.0°C/min to 200°C, 20.3
min (R), 21.0 min (S).
Acknowledgements
8. Dimethyl itaconate 4 (30.0 g, 190 mmol) in MeOH (250
mL), precatalyst (0.019 mmol) in MeOH (3 mL+20 mL,
total reaction volume: 300 mL), 5 bar H2, 23°C; GC
analysis: G-TA column, 40–130°C at 5°C/min, then to
170°C at 15°C/min, 21.8 min (S), 22.05 min (R).
9. 31P{1H} and 1H NMR experiments indicated that no
reaction occurred between dimethyl itaconate and (R,R)-
6b or (S,S)-7b in MeOH-d4. This demonstrates that no
significant displacement of COD or NBD occurs in the
absence of hydrogen gas.
We are grateful to Dr. Steve Challenger and Pfizer Ltd
for supporting this work through their supply of the
Candoxatril precursor and useful discussion. We also
thank Natasha Cheeseman of the ChiroTech analytical
team for her skilled technical assistance.
References
10. Candoxatril precursor 5 (29.5 g, 84.3 mmol) in MeOH
(350 mL), precatalyst (0.020 mmol) in MeOH (2 mL), 5
bar H2, 26°C; work up and analysis as reported in Ref. 4.
11. The 600 mL Parr hydrogenation vessel is configured with
two impellers. When the upper impeller is positioned just
below the surface of the reaction solution, a more
efficient transfer of hydrogen into solution is achieved
(Fig. 3, curves a and b) than when the impeller is placed
deep within the bulk of the solution (Fig. 3, curves c and
d).
1. Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372.
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