Aminoboranes as compatible iminium ion generators in aminative C-C bond formations

Article abstract of DOI:10.1021/ja045827y

Aminoboranes have been shown to be highly efficient and mild iminium ion generators in the Mannich-type aminative coupling of aldehydes with silyl ketene acetals. By using aminoboranes bearing bulky amino groups, such as a diisopropylamino group, free secondary amines can be successfully used as the amino component in a three-component Mannich reaction with aldehydes and silyl ketene acetals. Copyright

Full text of DOI:10.1021/ja045827y

Published on Web 09/23/2004
Aminoboranes as “Compatible” Iminium Ion Generators in Aminative C-C
Bond Formations
Michinori Suginome,* Lars Uehlin, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
and PRESTO, Japan Science and Technology Corporation (JST), Katsura, Kyoto 615-8510, Japan
Received July 12, 2004; E-mail: suginome@sbchem.kyoto-u.ac.jp
Table 1. Reactions of Silyl Ketene Acetal 7 with Benzaldehyde in
the Presence of Aminoboranes 1-6 or Other Amino Sourcesa
The Mannich reaction is recognized as a highly important method
to access functionalized amines.1,2 The original three-component
protocol uses amines, non-enolizable aldehydes, and active meth-
ylene compounds, including ketones, under rather harsh acidic
conditions. The reaction efficiency is improved by using two-
component systems, which use preformed imines or iminium salts.
Recent developments of asymmetric variants using a two-
component protocol have made the Mannich reaction very valuable.3
However, a two-component system is not always ideal. In the
synthesis of a large number of derivatives, it is preferable to use a
three-component strategy, involving the in situ formation of iminium
intermediates from aldehydes and amines, which are easily available
with wide structural variations. Although new three-component
systems have been reported recently, these mostly involve the use
of primary anilines, which readily form imines.4,5 Exploitation of
new reagents for the efficient generation of iminium intermediates
is crucial to expand the scope of three-component systems.
We recently reported that bis(dialkylamino)boron cyanide6 and
enolates7 react with carbonyl compounds yielding Strecker and
Mannich-type products, respectively, via aminative C-C bond
formation processes. We presumed that a common role of the boron
reagents was in the generation of reactive iminium intermediates,
which undergo further nucleophilic addition of the cyanide or
enolate. This idea prompted us to develop new boron-based iminium
ion generators that would work under mild reaction conditions.
Here, we report a new three-component Mannich-type reaction
using aminoboranes as efficient iminium ion generators that are
compatible with acid-sensitive functionalities (eq 1).
a 7 (1.0 equiv), aldehyde (2.0 equiv), and aminoborane (1.0 equiv) in
N-methylpyrrolidine (0.5 mL) were reacted at 30 °C for 3 h unless otherwise
noted. b NMR yield. c Yields in parentheses were obtained with use of
2-piperidinone (0.2 equiv) at room temperature.
Our proposed mechanism, involving the formation of the iminium
salt with the aminoborane, is supported by the results of NMR
experiments. Upon a 1:1 mixing of 5 with benzaldehyde in DMF-
d7, new distinctive signals were observed at 9.59 and 172.6 ppm
in the 1H and 13C NMR spectra, respectively (eq 2). These chemical
Reactions of benzaldehyde (2.0 equiv) with silyl ketene acetal 7
(1.0 equiv) were carried out in the presence of aminoboranes 1-6
(1.0 equiv) in dry N-methylpyrrolidinone (NMP) at 30 °C (Table
1, entries 1-6). In all cases, the â-amino ester 8 was obtained
selectively, although the yields varied significantly with the structure
of the aminoboranes. It should be noted that no Mannich product
was detected in the presence of the corresponding stannylamine,
silylamine, or free amine in place of the borylamines under
otherwise identical reaction conditions (entries 7-9). Among the
aminoboranes tested, the salicyl alcohol derivative 6 exhibited the
highest reactivity, yielding 8 in a 95% yield. We also found that
the presence of a sub-stoichiometric amount of a secondary amide
(0.2 equiv), such as 2-piperidinone, significantly accelerated the
reaction, lowering the reaction temperature to 20 °C or below
(entries 2, 3, 5, and 6).
shifts can be assigned to the iminium proton and the carbon atom
from previously reported values of 9.18 and 171.3 ppm, respec-
tively, for dimethyl(p-methylbenzylidene)ammonium methoxytri-
fluoroborate in DMSO-d6.8,9 It should be noted that the iminium
intermediate had not been observed in our previous aminative C-C
bond formations, because the aminoboron reagents inevitably
possesses carbon nucleophiles on their boron atoms.6,7
The reactions of some other aldehydes with silyl ketene acetals
were examined in the presence of aminoborane 2 or 6 acting as
new iminium ion generators (Table 2). Enolizable butyraldehyde
successfully afforded the corresponding Mannich product in a high
yield (entry 1). In a reaction with 5-tetrahydropyranyloxypentanal,
aminoborane 6 gave the corresponding product in a high yield (entry
2). Under the same reaction conditions, Boc-protected aliphatic and
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10.1021/ja045827y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reactions of Aldehydes with Silyl Ketene Acetals in the
Table 3. Aminoborane-Mediated Coupling of Aldehyde, Silyl
Presence of Aminoboranesa
Ketene Acetal, and Secondary Aminea
a Silyl ketene acetals or a silyl enol ether (1.0 equiv), aldehyde (2.0
equiv), and aminoborane (1.0 equiv) with 2-piperidinone (0.2 equiv) in
N-methylpyrrolidine (0.5 mL) were reacted at 20 °C for 1-3 h. b Isolated
yield.
aromatic aldehydes afforded the corresponding Mannich products
(entries 3 and 4). These examples using aldehydes bearing acid-
sensitive functionalities clearly demonstrate the mildness of the
present iminium generation conditions. â,â-Disubstituted silyl
ketene acetal afforded the corresponding â-amino ester in a high
yield (entry 5), and silyl enol ether also successfully afforded the
corresponding â-amino ketone in a high yield (entry 6). The
vinylogous Mannich reaction2 with silyl ketene acetal 9 was also
examined. Only the γ-addition product 10 with trans geometry was
obtained stereoselectively in a high yield with no formation of the
R-adduct (eq 3).
a 7 (1.0 equiv), aldehyde (1.5 equiv), secondary amine (1.0 equiv), and
aminoborane (1.0 equiv) with 2-piperidinone (0.2 equiv) in N-methylpyr-
rolidine (0.5 mL) were reacted at 20 °C for 1-3 h. b Isolated yield. c PMB,
p-methoxybenzyl. d The reaction was carried out at -10 to 20 °C.
ondary amines, and silyl ketene acetals is mediated by common
boron reagents bearing a bulky diisopropylamino group on the boron
atom. Investigation into the application of this reaction system to
other nucleophiles, including organometallic species, is now being
undertaken in our laboratory.
Acknowledgment. We thank Mr. Tomoaki Hasui for his
assistance in the characterization of the products.
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
We then focused our attention on the use of free secondary
amines as the source of the amino group via the in situ formation
of the requisite aminoborane. We prepared the (diisopropylamino)-
borane derivatives 11 and 12, and the bulky aminoboranes
sluggishly afforded Mannich products bearing a diisopropylamino
group using the reaction conditions shown above. However, when
free secondary amines, such as diethylamine (1 equiv), were added
to the reaction mixture, Mannich products derived from the added
amines were isolated in high yields (Table 3, entry 1). In a similar
manner, (p-methoxybenzyl)methylamine, acetal-protected piperidin-
4-one, and pyrrolidine afforded the corresponding products in good
yields (entries 2-4). In the reaction of pyrrolidine with an aliphatic
aldehyde, aminoborane 12 gave a slightly higher yield than 11 did
(94% versus 86%, respectively) (entry 5). In the reaction of optically
pure 2-methoxymethylpyrrollidine, one diastereoisomer was ob-
tained selectively in a high yield (entry 6). It should be noted that
the same strategy was applicable to aliphatic and aromatic aldehyde
bearing acid-sensitive functionalities (entries 7 and 8). A successful
three-component coupling reaction relies upon the amino group
exchange reaction on the boron atom, producing a more reactive,
(i.e., less bulky) aminoborane in a reversible manner. A remarkable
feature of this three-component coupling reaction seems to be the
mildness of the reaction conditions, which results in a high
compatibility with the functional groups. The applicability of the
reaction to enolizable aldehydes is also noteworthy.
References
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In summary, we have established that aminoboranes serve as
efficient iminium ion generators in Mannich-type reactions. The
synthetically useful three-component coupling of aldehydes, sec-
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