Communications
doi.org/10.1002/open.202100147
ChemistryOpen
derivatives is less reported and only N-(2-nitrobenzenesulfonyl)-
N-allyl amine derivatives have been described as efficient
nucleophiles for Tsuji-Trost coupling on cyclic electrophilic
substrates.[30] The reported method used complex and not
commercially available ligands[31–35] or multistep addition of
reagents leading to long reactions.[33,36] Iridium complexes were
also explored as catalyst, however only the 1,4-addition
products were obtained in good yields.[37] To avoid such
limitations, we optimized the conditions for the Tsuji-Trost
coupling reaction and obtained a method that allowed to
obtain a wide range of allyl amine derivatives in good to
excellent yields using commercially available ligands and stable
palladium complex. In order to achieve this, we chose the 2-
nitrosulfonyl group (nosyl) as it is a dual protective and
activating group efficiently cleavable in mild conditions and
compatible with allylsulfonamide motifs.[38,39] In addition, 2-
nitrosulfonamide derivatives are stable intermediates that are
obtained upon 2-nitrosulfonylchloride treatment of amines.
To define the most robust conditions for the reaction,
unfavourable substrates were selected: the cinnamyl acetate
1a, as a deactivated electrophile, and 2-nitro-N-phenylbenzene-
sulfonamide 2a, as a hindered electrophile. Based on the most
common conditions for the Tsuji-Trost reaction, catalyst,
solvent, base, time and temperature were then optimized
(Table 1).
were comparable. This is a great advantage for a robust
method, as it allows to apply the reaction to any substrates
even those with poor solubility.
Next, six different bases were screened (Table 1, entries IV–
IX). All bases afforded the desired product, with a lower
efficiency for triethylamine and carbonates. Dibasic potassium
phosphate and sodium hydride provided the best yields.
However, we excluded sodium hydride as it was necessary to
preliminary treat the nosyl derivative with sodium hydride in a
dry solvent under inert atmosphere before addition to the
electrophile substrate and the catalyst. Accordingly, dibasic
potassium phosphate was selected as the most adequate base
(Table 1, entry IV). The temperature and time were then
optimised (Table 1, entries IV and X–XII) following the reaction
by TLC until disappearance of the starting materials. As
expected, the kinetics depended on the temperature. Interest-
ingly, by varying the time of the reaction, the temperature can
be adapted to the reactants and, for instance, take into account
their stability and/or the need to control their isomerisation as
illustrated below.
This optimisation led to a general procedure to obtain allyl
amine derivatives based on the Tsuji-Trost reaction using
sulfonamide derivative and Pd2(dba)3 associated with dppp in
the presence of dibasic potassium phosphate and adapting the
solvent and temperature to the specificity of the reactants. The
robustness of the procedure was demonstrated by the use of a
wide range of electrophiles and nucleophiles (Table 2). In
addition to cinnamyl acetate 1a, commercially available electro-
philes (1b to 1d) bearing aliphatic chain, conjugated diene and
cyclic allyl acetate were selected to cover a broad range of
functionalisation. The acetate group was used as leaving group
because it can be conveniently added to alcohols either
chemically or enzymatically.[40,41] Similarly, seven sulfonamide
derivatives (2a to 2g) were selected to afford a large range of
primary to secondary amines after denosylation. The corre-
sponding nosyl derivatives were obtained by treatment of the
desired amine with 2-nitrosulfonyl chloride in pyridine and
required no purification. The Tsuji-Trost reaction tolerated a
wide range of functionalised electrophiles and sulfonamide
derivatives to afford polysubstituted allyl amines in good to
excellent yields. No reaction was observed between the N-Boc-
sulfonamide 2b and the cyclopentene derivative 1d, probably
because of high steric hindrance. Lower yields were obtained
using 2-nitrosulfonamide 2c as nucleophile due to the
occurrence of disubstituted side products, still yields remained
above 60%. Of note, the reaction with the soft nuclephiles
sulfonamide derivatives[42] proceeded with a double nucleo-
philic substitution, resulting in the conservation of the absolute
configuration.[43–45] No isomerisation was observed except when
using the diene (E,E)-sorbyl acetate 1c. In this case, we observed
the formation of 30% of the (1E,3Z)-pentadienyle 17 when the
Several common complexes of palladium were assessed but
only tris(dibenzylideneacetone) dipalladium(0) [Pd2(dba)3] asso-
ciated with 1,3-Bis(diphenylphosphino)propane (dppp) allowed
the reaction under normal atmosphere and was thus retained
as catalyst.
The effect of the solvent was then evaluated (Table 1,
entries I to IV): THF and dioxane were selected as aprotic low
polar solvents and DMF and NMP as aprotic highly polar
solvents. The polarity of the solvent had little effect and yields
Table 1. Optimization of the condition of reaction.
°
°
reaction was performed at 60 C (80% yield), 12% when at 40 C
°
(78% yield) and less than 5% when at 0 C (72% yield)
(Figure S1 in the Supporting Information). This underlines the
advantage of the procedure, as by varying the temperature it is
possible to control the isomerisation.
[a] 1 mmol scale synthesis, nucleophile (0.3 m), base (1.1 equiv). Yields are
the average of three reactions.
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