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prove some of the yields, the residence time was increased or a
higher temperature was employed. This sometimes increased the
yield as in the cases of ethyl methacrylate (entries 7 and 8) and
crotononitrile (entries 10 and 11), but not with ethyl crotonate (en-
tries 5 and 6) and methacrylonitrile (entries 12 and 13). Methacr-
ylonitrile (entry 12) gave a relatively high mass recovery after
chromatography, but this was due to impurities.
11. TFA (0.1 equiv), CH2Cl2: (a) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem.
Pharm. Bull 1985, 33, 896; CsF, TMSOTf, THF, 60 °C, 20 h (b) Hosomi, A.; Sakata,
Y.; Sakurai, H. Chem. Lett. 1984, 1117; (c) TFA (0.2 equiv), Et3 N (1 equiv),
toluene, 20 °C, 20 h, Pfizer unpublished work.; LiF (1.5 equiv), MeCN, 20 °C: (d)
Padwa, A.; Dent, W. J. Org. Chem 1987, 52, 235; . Org. Synth., Coll 1993, 8, 231;
cat. B(C6F5)3: (e) Srihari, P.; Yaragorla, S. R.; Basu, D.; Chandrasekhar, S.
Synthesis 2006, 2646.
12. An attractive alternative has been described for generating the azomethine
ylide via decarboxylation, for example, N-benzylglycine, paraformaldehyde,
toluene, reflux, see: Joucla, M.; Mortier, J. Bull. Soc. Chim. Fr 1988, 579;
Rodriguez Sarmiento, R. M.; Wirz, B.; Iding, H. Tetrahedron: Asymmetry 2003,
14, 1547.
For comparison, the reaction of 1 with methacrylonitrile under
batch conditions in acetonitrile was conducted with TFA and LiF at
room temperature (Scheme 2).
The yield of the TFA-catalysed reaction in batch mode was
slightly superior to the corresponding heated reaction in flow (en-
try 12) and purification of the product was less difficult. Under LiF-
promoted conditions, the yield was even higher, suggesting that
the slow rate of generation of the azomethine ylide increases trap-
ping efficiency. However, owing to the insolubility of LiF, these
conditions are unsuitable for flow, but the reactions also present
less of a hazard as there was no noticeable exotherm.
To demonstrate the viability of performing the cycloaddition in
flow on a reasonable scale, the Vapourtec™ R2+/R4 was equipped
with four heated reaction loops (total volume 40 ml) so that we
could react compound 1 with ethyl acrylate under the previously
optimised conditions (0.5 M overall in MeCN, 70 °C, 10 min). From
a reaction on 30 g scale, we obtained compound 3a in 87% yield,
after chromatography in only 1 h.
We have described the feasibility of a potentially hazardous
cycloaddition reaction under conditions of continuous flow. After
optimisation, uniformly high yields of cycloadducts were obtained
for certain reactive electron-deficient alkenes, and a multi-gram
synthesis was demonstrated for compound 3a. For less reactive
dipolarophiles such as methacrylonitrile, lithium fluoride-pro-
moted batch conditions are probably preferable.
13. There have been two incidents of thermal runaway of which the authors are
aware. (a) N-methylmaleimide (40 g, 1 equiv) and
1 (103 g, 1.2 equiv) in
CH2Cl2 (600 ml) at À20 °C were treated with a solution of TFA (4.1 g, 0.1 equiv),
dropwise. On completion of the addition, the reaction temperature rose very
quickly and the contents of the flask were ejected. (b) A mixture of trans-
methyl crotonate (1 equiv), 1 (1536 g, 1.05 equiv) in CH2Cl2 (ꢀ12 L) at 0 °C was
treated with a solution of TFA (0.1 equiv) dropwise. There was then a delayed
exotherm and the contents of the flask were ejected.
14. (a) Wiles, C.; Watts, P. Expert Opin. Drug Discovery 2007, 2, 1487–1503; (b)
Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Chem Eur. J. 2006, 12, 8434–8442; (c)
Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.
Rev. 2007, 107, 2300–2318; (d) Styring, P.; Parracho, A. I. R. Beilstein J. Org. Chem
2009, 5, 29.
15. For selected examples of chemistry conducted in flow, including those where
flow has been used to overcome intrinsic hazards, see: Kulkami, A. A.; Kalyani,
V. S.; Joshi, R. A.; Joshi, R. R. Org. Proc. Res. Dev 2009, 13, 999–1002 (nitration);
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D. Org. Biomol.
Chem 2008, 6, 1587–1593; Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.;
Smith, C. D.; Tierney, J. P. Org. Biomol. Chem 2008, 6, 1577–1586 (Curtius
rearrangement); Hübner, S.; Bentrup, U.; Budde, U.; Lovis, K.; Dietrich, T.;
Freitag, A.; Küpper, L.; Jähnisch, K. Org. Proc. Res. Dev 2009, 13, 952–960
(ozonolysis); Sugimoto, A.; Sumino, Y.; Takagi, M.; Fukuyama, T.; Ryu, I.
Tetrahedron Lett 2006, 47, 6197–6200 (photolysis); McPake, C. B.; Murray, C. B.;
Sandford, G. Tetrahedron Lett 2009, 50, 1674–1676 (epoxidation); Ahmed-
Omer, B.; Barrow, D. A.; Wirth, T. Tetrahedron Lett 2009, 50, 3352–3355 (Heck
reaction); Tinder, R.; Farr, R.; Heid, R.; Zhao, R.; Rarig, R. S.; Storz, T. Org. Process
Res. Dev. 2009, 13, 1401–1406 (azide [3+2] cycloaddition); Malet-Sanz, L.;
Madrzak, J.; Holvey, R. S.; Underwood, T. Tetrahedron Lett. 2009, 50, 7263–7267
(iodo-deamination of anilines).
16. Palmieri, A.; Ley, S. V.; Hammond, K.; Polyzos, A.; Baxendale, I. R. Tetrahedron Lett.
17. Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed.
2009, 48, 4017–4021; Baxendale, I. R.; Ley, S. V. In New avenues to efficient
chemical synthesis: emerging technologies. Ernst Schering foundation symposium
proceedings 2006-3; Seeberger, P. H., Blume, T., Eds.; Springer: Berlin,
Heidelberg, 2007; pp 151–185; Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C.
M.; Ley, S. V.; Saaby, S.; Tranmer, G. K. Chem. Commun. 2006, 24, 2566–2568;
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