A. J. Clark et al. / Tetrahedron Letters 50 (2009) 5609–5612
5611
reduction of the intermediate amidyl radical 11. The reaction yield
is often compromised by the competitive reduction of the initial
carbon radical 9 by the solvent and decomposition (hydrolysis) of
the starting materials under the reaction conditions. Increasing the
temperature generally increases the relative amount of 1,4-aryl
migration at the expense of reduction, and in some cases, leads
to total selectivity for rearrangement (runs 4 and 11, Table 2).
Heating trichloroacetamides 13c and 16a, b in 1,4-DMP at 130 °C
without CuCl also facilitated 1,4-aryl transfer in the trichloroaceta-
mide derivatives. The results described here suggest that if carry-
ing out relatively slow atom transfer or other slow radical
cyclisation reactions on compounds containing suitably pendant
sulfonyl groups, care should be taken to minimise competing aryl
migration by using a low reaction temperature.
Figure 1. Substrates 16a–c.
Table 3
Reaction of 16a–c with CuCl/2 in CH2Cl2
Compound
Temperature
Massa balance
Ratiob 7:18
16a
16a
16b
16b
16c
16c
rt
Reflux
rt
Reflux
rt
Reflux
55% (11%)
51% (8%)
26%
48%
39% (0%)
59% (0%)
88:12
Acknowledgement
66:34
c
We thank the EPSRC for a DTA studentship (P.W. and N.P.M.).
References and notes
c
72:28
38:62
a
Mass of 17:18, figure in parentheses equates to percentage of hydrolysed amide
1. Clark, A. J. Chem. Soc. Rev. 2002, 31, 1.
isolated.
2. (a) Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K. J. Org.
Chem. 1993, 58, 464; (b) Iwamatsu, S.; Matsubara, K.; Nagashima, H. J. Org.
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b
c
Ratio determined by 1H NMR (300 MHz) of the crude mixture.
The crude NMR indicated the presence of many products, the ratios were not
determined but the major product was 17b.
strate 16b was more problematic in that the reactions were not
clean and the only unambiguously assigned product isolated was
that arising from reduction to give 17b irrespective of the
temperature.
Recently, Ishibashi reported radical cyclisations of trichloroace-
tamides under reductive conditions using 1,4-dimethylpiperazine
(1,4-DMP) as the reactant/solvent.12 No other additives were re-
quired. Organic amines can act as electron donors in single-elec-
tron transfer reactions and 1,4-DMP was shown to generate
radicals from trichloroacetamides by cleavage of a carbon-chlorine
bond. As our reactions are reductive in nature we briefly explored
whether it was possible to mediate the 1,4-aryl transfer using this
protocol without the need for copper chloride. Heating 13c, 16a or
16b (0.3 mmol) with 1,4-DMP (2 ml) at 130 °C overnight in a
sealed tube followed by removal of the 1,4-DMP in vacuo and chro-
matography produced the expected 1,4-aryl transfer products 15c,
18a and 18b in 40%, 39% and 37% yields, respectively (Scheme 4).
Interestingly, only traces of the corresponding reduced and hydro-
lysed products were isolated, presumably due to the increased
temperature at which the reactions were carried out. Thus, while
the fluoro-derivative 16b underwent mainly reduction to 17b
using CuCl/2 either at rt or at 50 °C, only the 1,4-aryl transfer prod-
uct 18b was isolated when 1,4-DMP was used at 130 °C.
4. (a) Benedetti, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. M.; Ronzoni, R. Tetrahedron
1997, 41, 14031; (b) Ghelfi, F.; Bellesia, F.; Forti, L.; Ghirardini, G.; Grandi, R.;
Libertini, E.; Montemaggi, M. C.; Pagnoni, U. M.; Pinetti, A.; De Buyck, L.;
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Chem. 2000, 65, 6249; (d) De Buyck, L.; Cagnoli, R.; Ghelfi, F.; Merighi, G.;
Mucci, A.; Pagnoni, U. M.; Parsons, A. F. Synthesis 2004, 10, 1680; (e) Bellesia, F.;
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1999, 40, 4885; (c) Clark, A. J.; De Campo, F.; Deeth, R. J.; Filik, R. P.; Gatard, S.;
Hunt, N. A.; Lastécouères, D.; Thomas, G. H.; Verlac, J.-B.; Wongtap, H. J. Chem.
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B.; Boesten, W. H. J.; Schoemaker, H. E.; Kamphius, J. Tetrahedron Lett. 1992, 33,
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In conclusion, we have shown that reaction of trichloroacetyl-
sulfonamides 4a–c, 13a–e and 16a–c, with CuCl and amine ligands
(1–3) furnishes rearranged amides 6a–c, 15a–e and 18a–c via
radical generation 9, 1,4-aryl migration (with loss of SO2) and
10. A typical procedure is illustrated for compound 13c. A 2.5 M solution of n-
butyllithium (4.4 ml, 12.0 mmol) was added dropwise over 5 min to a stirred
solution of N-butylbenzenesulfonamide 12c (2.13 g, 10 mmol) in anhydrous THF
(100 ml) under nitrogen at À78 °C. After 30 min trichloroacetyl chloride
(1.34 ml, 12.0 mmol) was added and the reaction mixture was allowed to
warm to rt overnight. The reaction was quenched with saturated NH4Cl solution
(10 ml), and the reaction mixture was partitioned between CH2Cl2 (200 ml) and
Scheme 4. Reaction of 13c and 16a–b with 1,4-DMP at 130 °C.