10.1002/chem.201801012
Chemistry - A European Journal
COMMUNICATION
The optimized conditions were also applied to a variety of
aldehydes 2 using 6a. It was found that substituted aryl aldehydes
afforded high yields of the desired products (Scheme 3).
Heteroaromatic aldehydes could also be employed, although
yields of the adducts 6 were lower. Simple alkyl aldehydes were
not successful in the formation of the allylic amine products, most
likely due to the formation of enamines rather iminium
intermediates with the silylated amines. Enal 2v and the non-
enolizable aldehyde 2w could also be employed, although in the
latter more sterically hindered case the isolated product yield was
poor.
Experimental Section
General procedure for the synthesis of allylic amines: Aldehyde (0.9
mmol) and CH2Cl2 (2.7 mL) was placed in a flamed dried reaction flask
under N2 atmosphere. TMSOTf (0.9mmol was then added and stirred for
2 min. Silylated amine 6 was then added (0.9mmol). This was left to stir at
room temperature for 4 h. Organaluminum 1 was then added and stirred
for another 4 h at room temperature. The reaction was quenched with a
solution of saturated Rochelle’s salt at 0 °C. This was brought to room
temperature and stirred for 18 hrs. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The combined
organic phases were washed with brine (15 mL) and dried with Na2SO4.
This was concentrated under reduced pressure to provide the crude
material, which was purified by silica gel chromatography (5% MeOH in
CH2Cl2) to provide the desired product.
Variation of the organoaluminum reagent in the alumino-Mannich
reaction was also evaluated. Organoaluminums generated
through known hydroalumination of alkynes afforded the amines
7 in good yields (Scheme 4). Reaction of a Z-alkenylaluminum
reagent 1d10 gave the product amine 7c in low yield, but as a
single alkene stereoisomer (d.r. ≥ 19:1). The addition of more
equivalents of 1d or additives, such as THF or trimethylamine, did
not improve the yield. The use of alkylaluminums is also possible,
generating the product amines in moderate to good yields
(Scheme 4, 7d-7j). These results are in stark contrast to the lack
of reactivity observed for alkylboron reagents [C(sp3) based
nucleophiles] in the Petasis borono-Mannich reaction.11,12
Acknowledgements
The authors thank the University of Toronto and the Natural
Science and Engineering Research Council of Canada (NSERC)
for financial support. A.T. is grateful to the Ontario Ministry of
Education for an Ontario Graduate Scholarship. D.E. is grateful
to NSERC for a NSERC-USRA Scholarship.
Scheme 4. Organoaluminum substrate scope for the alumino-Mannich reaction
using silylated amines and aldehydes.a
Keywords: multicomponent reaction • iminium ions • alanes •
silylated amines • Mannich reaction
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[a] Reactions performed at 0.9 mmol scale under nitrogen as a 0.33 M solution
in CH2Cl2. Isolated yields of purified products. [b] a solution of triethylaluminum
was used (1.0 M in hexanes). [c] a solution of trimethylaluminum was used (2.0
M in hexanes).
In summary, a general method for the construction of tertiary
allylic and other tertiary amines using a three-component method
was investigated. The method extends the substrate scope for
tertiary amine formation, allowing the reaction of aldehydes and
amines that are unreactive in the Petasis borono-Mannich
reaction. The method can also be applied toward the addition of
alkylaluminum reagents, permitting the transfer of alkyl groups, a
process for which there has been limited success with the boron-
based counterpart. Further studies of the alumino-Mannich
addition reaction will be reported in due course.
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