10.1002/chem.202004835
Chemistry - A European Journal
COMMUNICATION
2.2 eq. of 4-chlorothiophenol 3a over time (Figure 1A). Under
standard conditions, the reaction proceeded very fast with around
50% conversion after only 5 min. Interestingly, the strong
preference towards formation of the mixed S,S-acetal was
immediately visible. The amount of symmetrical by-products
remained low and constant over the course of the reaction. In a
second experiment, we monitored a reaction between the same
components, however using a 1:1:1 ratio of benzaldehyde and the
two thiols (Figure 1B). As expected based on our optimization
studies, the reaction proceeded slower. While the unsymmetrical
S,S-acetal remained the main product, the selectivity was
reduced compared to the optimized protocol. Most importantly,
the amount of bisaliphatic acetal 4a’’ was substantially increased.
The reaction was monitored until no substantial change could be
observed in the composition of the reaction mixture. Then, we
added another 1.2 eq. of 4-chlorothiophenol, thereby creating the
same overall stoichiometry as in the first experiment. This led to
the consumption of the remaining benzaldehyde. Notably, the
resulting mixture contained substantially higher amounts of the
two symmetric products 4a’’ and 4a’’’ alongside lower amounts of
4a’. Even after allowing for a possible equilibration overnight, no
convergence towards the composition obtained in Figure 1a was
observed.
Considering that in Figure 1a we observed a fast reaction towards
the observed ratios, a thermodynamically controlled reaction
would have converged to the same ratio within this timeframe.[16]
This allowed us to rule out thermodynamic control as the source
of the observed selectivities, leading us to conclude that the
process is kinetically controlled.
The preferential formation of the mixed dithioacetal thus seems to
be a consequence of differences in the reactivity of aromatic and
aliphatic thiols,[17] as well as properties of the catalyst/protocol
which support a kinetically controlled reactivity.
In summary, we have developed a simple and general protocol
for the synthesis of unsymmetrical dithioacetals bearing an
aromatic and an aliphatic thiol. The protocol shows a high
selectivity for the mixed dithioacetals and the isolation of these
major products through common chromatography methods was
shown. In contrast to previous reports, our protocol is suitable for
the construction of large compound libraries tolerating a broad
range of functional groups and heterocycles. The observed
selectivity was shown to result from a kinetically controlled
product formation and renders this protocol attractive for the
generation of a broad spectrum of unsymmetrical dithioacetals.
Acknowledgements
PhCHO
4a'
4a''
A.
100%
80%
60%
40%
20%
0
We gratefully acknowledge financial support from the DFG
(Project: GE 2945/1-1 and Emmy Noether Programme) and
WWU Münster. We thank the members of our NMR and MS
departments for their excellent service, as well as F. Clausen for
preparative HPLC separations. Further thanks go to A. Mondal for
confirming the reproducibility of the protocol. We are indebted to
Prof. Dr. F. Glorius for his generous support.
4a'''
Keywords: (unsymmetrical) dithioacetals • thioacetalization •
Brønsted acid catalysis• aldehydes • thiols
0
1
2
3
4
5
6
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t [h]
B.
PhCHO
4a'
4a''
addition more HS-Ph-4-Cl
100%
80%
60%
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0
4a'''
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Figure 1. Product formation over time, monitored by HPLC with TMB as internal
standard. A. Standard reaction conditions, PhCHO:HSBn:HS-Ph-4-Cl = 1:1:2.2.
B. PhCHO:HSBn:HS-Ph-4-Cl = 1:1:1, 1.2 eq. of HS-Ph-4-Cl added after 10.5 h
when the system had reached a constant composition.
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4
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