of iminium ion intermediates, thus leading to the success of
a variety of amination reactions in nonacidic media. These
successful examples of the amination reaction prompted us
to use aminoboranes as a promoter for secondary amine-
based Ugi reactions.
Scheme 2. Reaction of Benzaldehyde, Diethylamine, and
tert-Octyl Isocyanide in the Presence of Aminoborane 1
In the presence of aminoborane 1, benzaldehyde (2a) was
reacted with diethylamine (3a) and tert-octyl isocyanide (4a)
in THF at room temperature (Scheme 2). When a reagent
ratio of 1:1:1:1.5 was used, the reaction successfully gave
the Ugi product, N,N-diethylphenylglycine amide 5a, in 86%
yield (Table 1, entry 1). The formation of the product 5a
Table 1. Reactions of Benzaldehyde (2a) with Diethylamine
(3a) and tert-Octyl Isocyanide (4a) in the Presence of
Aminoborane 1a (Scheme 2)
are able to accept the acyl group through amide formation.
This mechanism-based requirement makes it difficult to use
secondary amines as the amine component in the Ugi
reaction, although the use of secondary amines has partly
been achieved by the use of excess dimethylamines5 or by
the use of secondary amines that carry additional functional
groups, such as OH and NHR groups, which serve as
intramolecular acyl group receptors.6 Secondary amines also
took part in a certain Ugi-type reaction, where formaldehyde
was used as a highly reactive carbonyl component.7 Because
R-dialkylamino acid derivatives, including those with cyclic
amino groups, attract much attention as potential drugs or
biologically active substances,8 it is highly desirable to
develop entirely new reaction conditions that allow utilization
of secondary amines.
equiv
of 1
equiv
of 3a
equiv
of 4a
% yield
of 5ab,c
% yield
of 6b
entry
1
2
3
4
5
1
1
1
1
1.2
1.5
0
1
1.5
2
1.5
1.2
1.5
2
1.5
1.5
1.5
2
1.5
1.5
1.5
86
94
89
77
94
88 (6a/6b ) 4:1)
89 (6a/6b ) 3:1)
59 (6b)
67 (6a/6b ) 1:4)
90 (6a/6b ) 4:1)
89 (6a/6b ) 4:1)
0
6
7d
99 (82)
0
a
Benzaldehyde (0.2 mmol), Et2NH, and t-octyl isocyanide were reacted
b
c
with aminoborane 1 in THF at rt, unless otherwise noted. NMR yield.
Isolated yield in the parentheses. At 80 °C.
d
was accompanied by the formation of o-(dialkylaminometh-
yl)phenol byproducts 6, which were derived from the salicyl
alcohol-derived ligand of aminoborane 1. We optimized the
reaction conditions of the new Ugi-type reaction by varying
the molar ratios of the reagents used (Table 1). Although no
remarkable difference was found among the reaction condi-
tions examined, the use of a slight excess of aminoborane,
amines, and isocyanide afforded the desired 5a in excellent
yields (entries 5 and 6). It should be also noted that no
reaction took place in the absence of 1 even at 80 °C (entry
7).
Recently, we reported that dialkylaminoboranes serve as
iminium ion generators under mild reaction conditions.9 The
use of these aminoborane derivatives has allowed Strecker-
type reaction,10a Mannich-type â-amino ketone and ester
synthesis,10b,c and reductive amination using NaBH410d under
nonacidic reaction conditions. In these reactions, the use of
secondary amines gave more satisfactory results than the use
of primary amines. We have so far presumed that the
aminoborane derivatives efficiently promote the generation
(4) (a) Portal, C.; Launary, D.; Merritt, A.; Bradley, M. J. Comb. Chem.
2005, 7, 554-560. (b) Zech, G.; Kunz, H. Chem.-Eur. J. 2004, 10, 4136-
4149. (c) Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4,
1167-1170. (d) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin,
T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7277-7230. (e) Strocker,
A. M.; Keating, T. A.; Tempest, P. A.; Armstrong, R. W. Tetrahedron Lett.
1996, 37, 1149-1152.
Under the optimized reaction conditions, various aldehydes
were reacted with secondary amines in the presence of 1
and isocyanides (Scheme 3). Benzaldehydes with electron-
(5) McFarland, J. W. J. Org. Chem. 1963, 28, 2179-2181.
(6) (a) Giovenzana, G. B.; Tron, G. C.; Paola, S. D.; Menegotto, I. G.;
Pirali, T. Angew. Chem., Int. Ed. 2006, 45, 1099-1102. (b) Diorazio, L.
J.; Motherwell, W. B.; Sheppard, T. D.; Waller, R. B. Synlett 2006, 2281-
2283.
Scheme 3. Acid-Free Ugi-Type Reaction of Aldehydes,
Secondary Amines, and Isocyanides in the Presence of
Aminoborane 1
(7) (a) Ugi, I.; Cornelius, S. Chem. Ber. 1961, 94, 734-742. (b)
Kreutzkamp, N.; La¨mmerhirt, K. Angew. Chem. Int., Ed. Engl. 1968, 7,
372-373.
(8) (a) Sexton, K. E.; Lee, H. T.; Massa, M.; Pedia, J.; Patt, W. C.; Liao,
P.; Pontrello, J. K.; Roth, B. D.; Spahr, M. A.; Ramharack, R. Bioorg. Med.
Chem. 2003, 11, 4827-4645. (b) Beguin, C.; LeTiran, A.; Stables, J. P.;
Voyksner, R. D.; Kohn, H. Bioorg. Med. Chem. 2004, 12, 3079-3096.
(9) Suginome, M. Pure. Appl. Chem. 2006, 78, 1377-1387.
(10) (a) Suginome, M.; Yamamoto, A.; Ito, Y. Chem. Commun. 2002,
1392-1393. (b) Suginome, M.; Uehlin, L.; Yamamoto, A.; Murakami, M.
Org. Lett. 2004, 6, 1167-1169. (c) Suginome, M.; Uehlin, L.; Murakami,
M. J. Am. Chem. Soc. 2004, 126, 13196-13197. (d) Suginome, M.; Tanaka,
Y.; Hasui, T. Synlett 2006, 1047-1050.
withdrawing (Table 2, entries 1 and 2) or electron-donating
(entries 3 and 4) groups at their para-positions afforded the
4408
Org. Lett., Vol. 9, No. 22, 2007