A. J. Clark et al. / Tetrahedron Letters 50 (2009) 6311–6314
6313
Figure 1. Structures of compounds 18a–i and 19a–i.
were isolated. This is in keeping with the observation that carrying
out the reaction at lower temperature increases the amount of
reduction observed.3 Thus, treating 15d–f with 2 equiv of CuBr/2
in CH2Cl2 at rt for 6 h furnished both 16e–f:18e–f in the ratios
(15d = 3:1, 15e = 4:1 and 15f = 6:1,8 respectively). With the excep-
tion of the electron-rich aryl analogue 15c, all the reactions pro-
ceeded to give 1,4-aryl transfer products 16 in average to high
yields (50–99%).
Scheme 5. Radical cyclisation of 20 with 1,4-DMP.
Recently, Ishibashi reported radical cyclisations of trichloroace-
tamides under reductive conditions using 1,4-dimethylpiperazine
(1,4-DMP) as a reactant/solvent.9 No other additives were required.
Organic amines can act as electron donors in single electron transfer
reactions and 1,4-DMP was shown to generate radicals from trichlo-
roacetamides by cleavage of a carbon–chlorine. We showed that
heating trichloroacetamide 12a in 1,4-DMP to 130 °C facilitated a
1,4-aryl transfer to give 14a in low yield (40%), Scheme 4.4 Interest-
ingly, only traces of the corresponding reduced 13a and hydrolysed
11 products were isolated (compared to 13a:14a:11 = 54:34:12
ratio at rt in CH2Cl2), presumably due to the increased temperature
at which the reactions were carried out. To our knowledge, only
trichloroacetamide substrates have been used in successful 1,4-
DMP-mediated radical reactions. We were intrigued therefore to
see if the same approach could be used to generate radicals from
bromodimethylacetamides (e.g., 12d) where radical initiation
through cleavage of the carbon–halogen bond would be more
difficult.
Initially, we were encouraged when we discovered that heating
20 in dry 1,4-DMP at 70 °C in a sealed tube led to the two cyclised
products 22a and 22b in a 60% combined yield (ratio of 22a:22b =
1:8). Presumably 22a is produced via a conventional atom transfer
cyclisation with intermediate radical 21 abstracting a bromine atom
from a molecule of starting material 20, while the major product 22b
arises from abstraction of a hydrogen atom from the solvent. The
reaction was quite capricious and we found that scrupulous drying
(over 4 Å MS followed by reduced pressure distillation) of 1,4-DMP
was required for success. Trace amounts of water led not to cyclisa-
tion, but elimination to give 23. This result is important as it shows
that it is possible to generate radicals from tertiary bromides using
1,4-DMP under conditions that do not lead to elimination of the ter-
tiary bromide. Unfortunately, for slower cyclisations, such as that of
24 these conditions were not successful. Instead, the reaction was
sluggish and 73% of starting material 24 was recovered along with
6% of eliminated product 25 after three days. Facilitating the reac-
tion in a mixed solvent of DMSO:1,4-DMP (1:1) at 65 °C improved
the conversion but the eliminated product 25 was the sole product
isolated in 75% yield after three days, Scheme 5. Hence, it came as
no surprise that the elimination pathway to give 26 was also ob-
served when 1,4-aryl transfer precursor 12d was heated with 1,4-
DMP under the same reaction conditions, Scheme 6.
Scheme 6. Attempted 1,4-aryl rearrangement of 12d mediated by 1,4-DMP.
In conclusion, we have shown that the reaction of sulfonamides
12a–d, and 15a–i, with either CuCl or CuBr and amine ligand 2
furnishes rearranged amides 14a–d, and 16a–i via radical genera-
tion (8), 1,4-aryl migration (with loss of SO2) and reduction of
the intermediate amidyl radical 10. For dichloroacetyl 12b and
monobromoacetyl 12c derivatives the reaction yield is often com-
promised by competitive reduction of the initial carbon radical 8
by the solvent to give 13b–c and by decomposition to give 11 with
the relative amount of 1,4-aryl transfer increasing with increasing
substitution of the initiating radical 12c > 12b. Changing the nature
of the initiating radical from a 1° or 2° radical to a 3° radical (e.g.,
12a,d) facilitates 1,4-aryl transfer over the other competing reac-
tion pathways, presumably through the Thorpe–Ingold effect. The
selectivity for 1,4-aryl migration is marginally better for the more
nucleophilic radical 12d compared to 12a. Thus, N-alkyl-N-(2-bro-
mo-2-methylpropionyl)-sulfonamides 15a–i furnish 2-aryl propi-
onamides in synthetically acceptable yields (40–99%). While
attempts to facilitate the rearrangement of 12d reductively using
1,4-DMP failed, it was possible to mediate a 5-exo radical cyclisa-
tion of bromo substrate 20, indicating that 1,4-DMP can generate
radicals not only from reactive trichloroacetamide derivatives,
but also from other tertiary halides.
Acknowledgement
We thank the EPSRC for DTA studentships (P.W. and N.P.M.).
References and notes
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Scheme 4. Reaction of 12a with 1,4-DMP.