Full Paper
Tong, J. Tu, X. Qi, M. Wang, Y. Wang, H. Fu, C. U. Pittman Jr, A. Zhou, Tet-
of the required building blocks, the reduced reaction time, and
the easy extension to a catalytic asymmetric version recom-
mend this method for both combinatorial and medicinal
chemistry applications.
c) D. I. Tasgin, C. Unaleroglu, Appl. Organomet. Chem. 2010, 24, 33–37.
[5] a) M. W. Bedore, N. Zaborenko, K. F. Jensen, T. F. Jamison, Org. Process
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Bꢂez, J. Oliver, M. Cynamon, M. Gꢃtschow, M. D. Mertens, O. Delgado,
[7] For recent reviews on isocyanide-based multicomponent reactions, see:
b) L. Banfi, A. Basso, L. Moni, R. Riva, Eur. J. Org. Chem. 2014, 2014,
B. Westermann, F. P. J. T. Rutjes, Eur. J. Org. Chem. 2012, 2012, 3543–
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[8] a) I. Ugi, U. Fetzer, U. Eholzer, H. Knupfer, K. Offermann, Angew. Chem.
estingly, the most important isocyanide, tert-butyl isocyanide, is a partic-
ular case: both tert-butyl amine and the isocyanide are prepared indus-
trially from the same precursor, N-tert-butyl formamide: b) K. Eller, E.
Henkes, R. Rossbacher, H. Hçke in “Amines Aliphatic” in Ullmann’s Ency-
clopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2000.
[9] a) T. Y.-W. Jen, C. Kaiser, US3952101, 1976; b) T. Jen, J. Frazee, M.
Experimental Section
An isocyanide (1.2 equiv, 1 mmol) was added to a solution (2 mL
AcOEt, normal grade) of an aldehyde (1 mmol), hexamethylphos-
phoramide (0.1 equiv, 0.1 mmol), and SiCl4 (1.1 equiv, 1.1 mmol) at
0–58C. After stirring for one hour at 0–58C, technical-grade BH3NH3
(1.5 equiv, 1.5 mmol) was added. The ice bath was removed and
the reaction mixture was stirred for another 3 h. Next, the mixture
was diluted (in three portions) with CH2Cl2 (10 mL) and transferred
(cautiously on account of gas evolution) to an aqueous solution of
Na2CO3 (10 wt%, 20 mL). The mixture was stirred for 30 min at
room temperature. The solution was filtered, and the filter was
washed with more CH2Cl2 (10 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (20 mL) in two por-
tions. The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The product was isolated
after column chromatography on silica gel or by precipitation as
the hydrochloride salt from tert-butyl methyl ether.
Acknowledgements
The research for this work received funding from the Innova-
tive Medicines Initiative joint undertaking project CHEM21
which are composed of financial contributions from the Euro-
pean Union’s Seventh Framework Programme (FP7/2007–2013)
and EFPIA companies in-kind contribution. We thank Florentine
Veenstra for her contribution to the experimental part.
not all aspects of this reaction are in line with green chemistry princi-
ples, solvents have a major impact on the overall sustainability of
a chemical process, thus making the use of ethyl acetate a green
option.
[13] Within one hour in ethyl acetate at 0–58C, the uncatalyzed isocyanide
addition yielded 57% of the N-(tert-butyl)-2-hydroxy-2-(p-tolyl)aceta-
mide after aqueous workup. Lewis bases screened for the isocyanide
addition: triphenylphosphine oxide (71%), N,N’-dimethylpropyleneurea
(70%), pyridine oxide (76%).
Keywords: aldehydes · amino alcohols · isocyanide · Lewis
bases · salbutamol
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[14] See the Supporting Information for details.
[15] Ammonia borane has been intensively studied as hydrogen-storage
material and is less-known as a reducing agent in organic synthesis,
but it shows several advantages for this purpose, including good solu-
bility in both organic solvents and water: G. C. Andrews, S. F. Neelamka-
vil, Borane-Ammonia in e-EROS Encyclopedia of Reagents for Organic Syn-
thesis Wiley, Hoboken, 2008.
[16] Assuming all three hydrogen atoms are available for the reaction, and
because two hydrides are required for the imidoyl chloride reduction,
this corresponds to a 2.25-fold excess amount.
[17] Technical-grade (90%) ammonia borane was chosen because it has
a significantly reduced price relative to the high-purity grade reagent.
[18] Ketones are not good substrates for the isocyanide addition under
these conditions. Only trace amounts of product were observed with
cyclopentanone.
[19] Unreacted aldehydes are converted to the corresponding alcohols by
BH3NH3.
[20] An SN1 mechanism is also plausible and, according to our observations,
both pathways are viable.
[22] Purification of these compounds on a silica gel column proved difficult.
Chem. Eur. J. 2015, 21, 1 – 7
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