10.1002/chem.201903414
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preparation of densely substituted amines by reaction between a
C–H containing pronucleophile, a sulfonamide and an acetal.
The use of this latter in overheated THF was found to be
essential to overcome the detrimental release of water during
imine formation and to ensure efficiency of the multicomponent
approach. These conditions were successfully applied to either
Rh(III)-catalyzed sp2 C–H bond activation or Cu(II)-catalyzed sp3
C–H bond activation, opening the way to a renewal of
multicomponent Mannich reactions.
Experimental Section
Scheme 2. Mechanism of the reaction.
General procedure: In air, an oven-dried 10 mL reaction tube equipped
with a stir bar was charged with [Cp*RhCl2]2 (3.9 mg, 6.2 μmol, 2.5
mol%), AgSbF6 (17.2 mg, 0.05 mmol, 20 mol%) and sulfonamide 2 (0.5
mmol, 2.0 equiv), closed with a septum and flushed with Ar. THF (0.5 mL,
C = 0.5 M), 2-aryl pyridine 1 (0.25 mmol, 1.0 equiv) and aryl aldehyde
dimethyl acetal 5 (0.5 mmol, 2.0 equiv) were successively added and the
tube was sealed with a screw stopper. The reaction was stirred at 120 °C
(external temperature) for 16 h. Then, the reaction mixture was filtered
through a plug of Celite (thoroughly rinsed with EtOAc) and the filtrate
was evaporated. The crude material was purified by FC to afford the
desired product 4.
As the formation of the imine is supposed to be independent of
the C–H bond activation step, it was anticipated that the present
approach should be applicable to other transformations, such as
the multicomponent Mannich reaction through sp3 C–H bond
activation.[25] This approach being previously described by
Manolikakes using a Brønsted acid catalyst,[26] we focused on
the use of Cu(OTf)2 as a Lewis acid catalyst. We thus
investigated the reaction between 2,6-lutidine 6, tosylamide 2a
and benzaldehyde 3a or its dimethyl acetal 5a in THF at 120 °C
(Table 5). Even if no beneficial effect of using an excess of the
imine precursors was detected (entries 1 and 2), the use of 5a
revealed superior to the use of 3a in each case: 68% instead of
62% when using an excess of 6 (entries 3 and 4).
Acknowledgements
The financial support of this work by the CNRS (Master grant to
T. X.), the University Paris-Est Créteil and the University Paris-
Est is gratefully acknowledged. Dr M. Rivard (UPEC) is
acknowledged for helpful discussions.
Table 5. Extension to sp3 C–H bond functionalization.[a]
Keywords: Multicomponent reactions
Mannich reactions • Synthetic methods
• C–H activation •
[1]
[2]
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Entry
Reagent
x:y
Yield (%)[b]
58%
[3]
[4]
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1
2
3
4
3a
5a
3a
5a
1:2.5
1:2.5
2.5:1
2.5:1
62%
Multicomponent Reaction in Organic Synthesis (Eds.: J. Zhu, Q. Wang,
M.-X. Wang), Wiley-VCH, Weinheim, 2015.
62%
[5]
[6]
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68%
[a] Yields of isolated products. Reaction conditions (0.3 mmol scale): 6
(x equiv), 2a (y equiv), 3a or 5a (y equiv), Cu(OTf)2 (5 mol%), 1,10-
phenanthroline (5 mol%), THF (1.5 M), 120 °C, 14 h. [b] Isolated yields.
[7]
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1219. b) M. Moselage, J. Li, L. Ackermann, ACS Catal. 2016, 6, 498–
525. c) T. Yoshino, S. Matsunaga, Adv. Synth. Catal. 2017, 359, 1245–
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Conclusions
[8]
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In conclusion, we have developed multicomponent Mannich
reactions through transition metal-catalyzed C–H bond
functionalization. This reaction allows the straightforward
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