Angewandte
Chemie
DOI: 10.1002/anie.201300231
Imine Generation
Acid-Catalyzed in Situ Generation of Less Accessible or
Unprecedented N-Boc Imines from N-Boc Aminals**
Taichi Kano, Taiga Yurino, Daisuke Asakawa, and Keiji Maruoka*
Imines are valuable reagents that are capable of producing
a wide variety of nitrogen-containing compounds by addition
reactions, reduction, and cycloaddition in synthetic chemis-
try.[1–9] Among them, imines 1 (Scheme 1) that have an easily
handled Boc group are frequently used in organic synthesis
owing to the high synthetic utility of the resulting product.[10]
However, available Boc-protected imines are limited because
of their high reactivity and the difficulty of their synthesis.
While N-Boc-protected imines 1 are prepared by the
reaction of trimethylsilyl-protected imines 2 with di-tert-butyl
dicarbonate (Boc2O; Scheme 1, method A), this preparation
proceeds in low yield and requires successive distillation of
both imine 1 and 2.[11,12] Sulfinic acid adducts of imines 3 are
obtained from aldehydes, tert-butyl carbamate (BocNH2), and
sulfinic acid sodium salt (or sulfinic acid). These imine
precursors 3 can be converted into imines 1 by treatment with
a base, such as K2CO3 (method B). This procedure also
enables in situ generation of reactive imines 1 and is the most
commonly used in synthetic chemistry.[13,14] The aza-Wittig
reaction between aldehydes and iminophosphorane 4 is an
alternative approach to N-Boc imines (method C).[12,15]
Unfortunately, however, the precursor of iminophosphorane
4, tert-butoxycarbonyl azide, is recognized as being explosive,
and its use is therefore discouraged. While somewhat
stabilized N-Boc imines having an aromatic substituent on
the carbon atom are obtainable by either methods, N-Boc
imines with alkyl substituent are less accessible owing to the
fact that such imines are readily isomerized to the corre-
sponding enecarbamate.[16–21] To the best of our knowledge,
only one N-Boc imine having an alkenyl substituent has been
reported,[22] and furthermore, N-Boc imines with an alkynyl
group are unprecedented.[23] Accordingly, development of the
general method to generate reactive N-Boc imines 1 is of
great significance in synthetic chemistry.
We have recently become interested in the gradual in situ
generation of reactive N-Boc imines 1, and especially those
with an alkynyl group, under the influence of acid cata-
lyst.[14,16–21,24] Slow generation and rapid consumption of
reactive imines would avoid their accumulation and decom-
position. We then focused on N-Boc aminals 5 as an imine
precursor, which could be readily prepared by condensation
of aldehydes and BocNH2.[19] The desired N-Boc imine would
be gradually generated in situ with one BocNH2 departing
with the aid of acid catalyst. In this reaction system, the
neutral byproduct BocNH2 is not expected to affect the
reaction of N-Boc imines with other reagents. Indeed, N-Boc
ꢀ
aminal 5 (R = PhC C) was obtained as a white solid only by
treatment of 3-phenylpropiolaldehyde with BocNH2 in
a dehydrating agent, acetic anhydride in the presence of
a catalytic amount of trifluoroacetic acid and subsequent
filtration (Figure 1). In the presence of copper(II) trifluor-
omethanesulfonate (Cu(OTf)2) as a Lewis acid catalyst, the
reaction between 5 and diethyl malonate proceeded to give
ꢀ
the Mannich-type product 6 (R = PhC C) in good yield
(Table 1, entry 1). This result indicated that the hitherto
Scheme 1. Generation of N-Boc-protected imines 1.
[*] Dr. T. Kano, T. Yurino, D. Asakawa, Prof. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by Orga-
nocatalysts” from MEXT (Japan). T.Y. thanks the Japan Society for
the Promotion of Science for Young Scientists for Research
Fellowships.
Figure 1. Images of the reaction setup of 3-phenylpropiolaldehyde with
BocNH2 in the presence of trifluoroacetic acid (5 mol%) in acetic
anhydride. a) Reaction mixture before mixing all compounds. b) Reac-
tion mixture after mixing all compounds (5 min). c) Reaction mixture
after completion the reaction (15 min).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 4
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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