B(OMe)3 as a nonacidic iminium ion generator in Mannich- and Ugi-type reactions

Article abstract of DOI:10.1002/ejoc.200801190

Mannich-type reactions of aldehydes with secondary amines and a ketene silyl acetal were promoted by trimethoxyborane in DMSO to afford the corresponding β-amino esters in good yields. B(OMe)₃ also promoted Ugi-type reactions of aldehydes with

Full text of DOI:10.1002/ejoc.200801190

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801190
B(OMe)3 as a Nonacidic Iminium Ion Generator in Mannich- and Ugi-Type
Reactions
Yusuke Tanaka,[a] Kousuke Hidaka,[a] Tomoaki Hasui,[a] and Michinori Suginome*[a]
Keywords: Amination / Nucleophilic addition / Boron / Iminium ions / Amino acids
Mannich-type reactions of aldehydes with secondary amines
and a ketene silyl acetal were promoted by trimethoxybor-
ane in DMSO to afford the corresponding β-amino esters in
good yields. B(OMe)3 also promoted Ugi-type reactions of
aldehydes with secondary amines and isocyanides in 1,2-
dichloroethane, which leads to the formation of α-amino
amides. In these reactions, trimethoxyborane serves as an in-
expensive, commercially available, and virtually nonacidic
iminium ion generator.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
of iminium ions suffers from the requirement of commer-
cially unavailable boron reagents. Although we recently re-
ported new nonacidic, “catalytic” iminium ion genera-
tors,[10,11] these boron-based catalysts were still not easily
available in large quantities. It seems desirable to use com-
mercially available, inexpensive boron compounds as a
practical iminium ion generator. In this paper, we report on
the Mannich- and Ugi-type reactions mediated by B(OMe)3,
which is one of the most inexpensive boron compounds.
Introduction
Aminative C–C bond formation via generation of imin-
ium ion intermediates are widely utilized as reliable, gene-
ral, and efficient methods for the synthesis of amine deriva-
tives. Mannich reactions[1] and Ugi reactions[2] are among
this classification and are utilized frequently in the prepara-
tion of amines. These reactions are typically carried out in
the presence of Brønsted acids or Lewis acids for activation
of carbonyl compounds.[3] The requirement of acidic condi-
tions often makes it difficult to retain acid-sensitive func-
tional groups during the transformations. To avoid this dif-
ficulty, nonacidic reaction systems for the generation of im-
inium ion intermediates have been reported. For example,
iminium ions were generated by α-fragmentation of amine
derivatives bearing a leaving group α to the amino groups.[4]
Although iminium ions are generated under nonacidic reac-
tion conditions with this strategy, it requires preparation of
the α-modified amine precursors. It is highly desirable to
develop new synthesis methods for amine derivatives from
easily available starting materials under functional-group-
tolerable reaction conditions.
Results and Discussion
Reactions of benzaldehyde 2a, diethylamine 3a, and
ketene silyl acetal (4) were carried out in the presence of
BF3·OEt2 and B(OMe)3, both of which are easily available
(Table 1). In the absence of an additive, the reaction af-
forded only a trace amount of aldol product 6 as judged by
1H NMR spectroscopy (Entry 1). The use of boron trifluo-
ride etherate resulted in the formation of β-amino ester 5aa
in 33% yield along with the aldol product 6 in 7% yield
(Entry 2). In the presence of an increased amount of
BF3·OEt2, exclusive formation of the aldol product was ob-
served (Entry 3). We then found that the use of 1–3 equiv.
B(OMe)3 gave the Mannich-type product selectively in 69–
91% yield without any formation of the aldol product (En-
tries 4–6). It should be noted that we previously reported
that a catalytic amount of B(OMe)3 failed to promote the
reaction.[10] The use of 2 equiv. B(OMe)3 afforded the high-
est yield for the Mannich product (Entry 5). The require-
ment of excess B(OMe)3 suggests that it may also serve as
a dehydrating reagent and that the efficiency of the genera-
We previously reported that aminoborane derivative 1
acted as an iminium ion generator under nonacidic condi-
tions,[5] and mediated a Mannich-type reaction,[6] reductive
amination,[7] and Ugi-type reaction.[8,9] The attractive as-
pect of the aminative reactions is that the iminium ions can
be generated directly from secondary amines and carbonyl
compounds without the need for preparation of special pre-
cursors. However, this nonacidic system for the generation
[a] Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University,
Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Fax: +81-75-383-2722
E-mail: suginome@sbchem.kyoto-u.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1148–1151

B(OMe)3 as a Nonacidic Iminium Ion Generator
tion of the iminium ion was not as high as that previously Table 2. Reaction of aldehydes, amines, and silyl ketene acetal in
the presence of B(OMe)3.[a]
reported for the catalytic iminium ion generator
(Ph2BOMe).[10] Among the solvents we examined, DMSO
was found to be the highest-yielding solvent for this reac-
tion (Entries 6–10).
Table 1. Reaction of benzaldehyde, diethylamine, and silyl ketene
acetal in the presence of boron compounds.[a]
Entry Boron
compound[b]
Solvent
Yield (5aa)
Yield (6)
[%][c]
[%][c]
1
2
3
4
5
6
none
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
0
33
0
69
91
80
55
42
30
43
trace
7
77
0
0
0
0
0
0
BF3·OEt2 (1)
BF3·OEt2 (2)
B(OMe)3 (1)
B(OMe)3 (2)
B(OMe)3 (3)
B(OMe)3 (3)
B(OMe)3 (3)
B(OMe)3 (3)
B(OMe)3 (3)
7[d]
8[d]
9[d]
10[d]
toluene
THF
DCE[e]
0
[a] Benzaldehyde (0.30 mmol), diethylamine (0.20 mmol), and silyl
ketene acetal (0.30 mmol) were treated with boron compounds at
room temperature for 5 h unless otherwise noted. [b] Number of
equivalents in parentheses. [c] NMR yield. [d] 23 h. [e] 1,2-Dichloro-
ethane.
[a] Aldehyde 2 (0.60 mmol), amine 3 (0.40 mmol), and silyl ketene
acetal 4 (0.60 mmol) were treated with B(OMe)3 (0.80 mol) at room
temperature unless otherwise noted. [b] Isolated yield. [c] Use of
0.80 mmol 4. [d] Isolated yield for 10 mmol-scale reaction in paren-
Under the optimized conditions, various aldehydes 2 and
amines 3 were treated with ketene silyl acetal 4 (Table 2).
Diethylamine and diallylamine gave the corresponding theses. [e] Use of 0.40 mmol B(OMe)3. [f] Paraformaldehyde
(1.2 mmol) was used.
Mannich-type products in high yield (Entries 1 and 2). Re-
actions of dibenzylamine and N-methyl aniline also af-
forded β-amino esters 5ac and 5ad (Entries 3 and 4). Cyclic Mannich-type product, but gave imines in the reactions
amines such as pyrrolidine (3e), piperidine derivatives (3f with benzaldehyde. As postulated in our previous re-
and 3h), hexamethyleneimine (3g), and tetrahydroisoquin- ports,[8,10] our reaction system can hardly activate imine de-
oline (3i) afforded the corresponding amino esters in good rivatives, because of the nonacidic nature of the reaction
yields, although reaction of tetrahydroquinoline (3j), an ani- conditions. This fact can be utilized for selective C–C bond
line derivative like 3d, gave the Mannich-type product only formation at the iminium carbon rather than at the imino
in moderate yield (Entries 5–10). In the reaction of amine carbon atom. Secondary amine 3l bearing an NH2 group
derivative 3h, the acetal group was compatible with the re- was treated with 4 under the B(OMe)3-mediated Mannich-
action conditions (Entry 8). p-Substituted benzaldehydes type reaction conditions (Scheme 1). The Mannich reaction
(2b and 2c) and 1-naphthaldehyde 2d afforded the desired proceeded at the iminium carbon, which was generated with
products in their reactions with diethylamine (Entries 11– the secondary amine moiety, with conversion of the NH2
13). No remarkable reactivity difference was observed group into the imino group to give 7a. This result clearly
among these aldehydes. B(OMe)3-mediated Mannich-type indicates that trimethoxyborane is not acidic enough to me-
reactions were also applicable to the aliphatic aldehydes 2e– diate addition of the ketene silyl acetal to aldimines. This
2g (Entries 14–16). Acid-sensitive protective groups such as prompted us to examine the selective Mannich-type reac-
THP and trityl groups could tolerate the reaction condi- tion of amine–imine conjugates 3m and 3n. The secondary
tions (Entries 15 and 16). Paraformaldehyde (2h) also af- amines 3m and 3n, bearing imine moieties, were subjected
forded the corresponding Mannich-type product 5hk in the to reaction with benzaldehyde and ketene silyl acetal in the
reaction with dicyclohexylamine (Entry 17).
presence of B(OMe)3 (Scheme 2). Mannich reaction took
In sharp contrast to the reaction of the secondary place selectively at the secondary amine moiety to provide
amines, the primary amines did not give the corresponding the β-amino esters 7a and 7b bearing an imine moiety.
Eur. J. Org. Chem. 2009, 1148–1151
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. Tanaka, K. Hidaka, T. Hasui, M. Suginome
SHORT COMMUNICATION
Table 3. Reaction of benzaldehyde, diethylamine, and tert-octyl iso-
cyanide in the presence of B(OMe)3.[a]
Entry
Solvent
Temperature [°C] Yield [%][b]
Scheme 1. Selective Mannich-type reaction of secondary amines
bearing a primary amine.
1
2
3
4
5
6
7
THF
THF
DMSO
MeOH
toluene
ClCH2CH2Cl
B(OMe)3
r.t.
80
80
80
80
80
80
trace
68
25
17
61
70
42
[a] Benzaldehyde (2a, 0.20 mmol), diethylamine (3a, 0.30 mmol),
and tert-octyl isocyanide (8, 0.30 mmol) were treated with tri-
methoxyborane (0.60 mmol) in the solvent (0.5 mL). [b] NMR
yield.
products in high yields (Entries 7 and 8). α-Amino amides
containing acid-sensitive THP ether was obtained in 78%
yield (Entry 9).
Table 4. Reactions of aldehydes, amines, and isocyanide in the pres-
ence of B(OMe)3.[a]
Scheme 2. Selective Mannich-type reaction of amine–imine conju-
gates.
We then examined the Ugi-type reaction using B(OMe)3
as an iminium ion generator. In the presence of B(OMe)3,
reaction of benzaldehyde (2a), diethylamine (3a), and tert-
octyl isocyanide (8) in THF proceeded at 80 °C to give the
corresponding phenylglycine derivative 9aa in 68% yield,
while no reaction took place at room temperature (Table 3,
Entries 1 and 2). Among the solvents tested for the Ugi-
type reaction, nonpolar solvents such as THF, toluene, and
1,2-dichloroethane gave good yields of the α-amino amides
(Entries 2, 5, and 6), while DMSO, which was the solvent
of choice in the Mannich-type reaction, resulted in a lower
yield (Entry 3). The use of B(OMe)3 as a solvent resulted
in a lower yield for the formation of 9aa (Entry 7).
Reactions of 2a with isocyanide 8 and secondary amines
in 1,2-dichloroethane afforded the corresponding Ugi-type
products in good yields (Table 4, Entries 1 and 2). The pres-
ent reaction conditions with trimethoxyborane were also ef-
fective for the aliphatic aldehydes. Reaction of 3-phenylpro-
panal (2e) with 3a and 8 afforded the corresponding Ugi-
type product in 79% yield (Table 4, Entry 3). The successful
use of the aliphatic aldehydes is the significant advantage
of the present system over the previously reported amino-
borane system that uses 1,[8] in which the aliphatic alde-
hydes gave poor yields in the Ugi-type reactions. Secondary
amines such as dibutylamine, piperidine, and hexamethyl-
eneimine are involved in the Ugi-type reactions with 3-
[a] Aldehyde (2, 0.40 mmol), amine (3, 0.60 mmol), and tert-octyl
isocyanide (8, 0.60 mmol) were treated with trimethoxyborane
(1.2 mmol) in dichloromethane (1.0 mL). [b] Isolated yield. [c]
0.80 mmol of the amine was used.
Conclusions
In summary, we have demonstrated nonacidic Mannich-
phenylpropanal, which give the corresponding α-amino and Ugi-type amination reactions mediated by 1–3 equiv.
amides in good yields (Entries 4–6). The reactions of butyr- trimethoxyborane as an iminium ion generator. Because tri-
aldehyde and propionaldehyde also afforded the Ugi-type methoxyborane is inexpensive, commercially available, and
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Eur. J. Org. Chem. 2009, 1148–1151

B(OMe)3 as a Nonacidic Iminium Ion Generator
virtually nonacidic, the present reaction system offers a new
access to amine derivatives through generation of iminium
ions under mild reaction conditions.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
Experimental Section
[1]
[2]
[3]
a) E. D. Kleinman in Comprehensive Organic Synthesis (Eds.:
B. M. Trost), Peramon, Oxford, 1991, vol. 2. pp. 893; b) M.
Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998,
37, 1044.
General Procedure for the B(OMe)3-Mediated Mannich-Type Reac-
tion: A solution of B(OMe)3 (89 µL, 83 mg, 0.80 mmol), secondary
amine (0.40 mmol), and aldehyde (0.60 mmol) in DMSO (1.0 mL)
was stirred for 10 min at room temperature. To the solution was
added ketene silyl acetal 4 (0.60 mmol) at room temperature. The
mixture was stirred at room temperature for 5 h, quenched with ice
water, and extracted with ethyl acetate. The organic layer was
washed with water, and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was dried with Na2SO4 and
filtered, and the solvents evaporated under vacuum. The crude ma-
terial was purified by silica gel column chromatography to give β-
amino esters 5. For the synthesis of 5hk and the 10 mmol-scale
reactions, the products were isolated by acid–base extraction [0.5 
HCl (aq.)/28% NH3 (aq.)]. See Supporting Information for details.
a) I. Ugi, Angew. Chem. Int. Ed. Engl. 1962, 1, 8; Angew. Chem.
1962, 74, 9; b) A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000,
39, 3198; c) M. Suginome, Y. Ito in Science of Synthesis (Eds.:
S.-I. Murahashi), Thieme, Stuttgart, 2004, vol. 19, pp. 445.
a) C. D. Bailey, C. E. Houlden, G. L. Bar, G. C. Lloyd-Jones,
K. I. Booker-Milburn, Chem. Commun. 2007, 2932; b) F. Gao,
G. Zhang, S. Zhang, Y. Cheng, Z. Shi, Y. Li, J. Gao, Tetrahe-
dron 2007, 63, 3973; c) Z. Zhou, F. Xu, X. Han, J. Zhou, Q.
Shen, Eur. J. Org. Chem. 2007, 5265; d) A. K. Bhattacharaya,
T. Kaur, Synlett 2007, 745; e) M. M. Salter, J. Kobayashi, Y.
Shimizu, S. Kobayashi, Org. Lett. 2006, 8, 3533; f) T. Muraki,
K. Fujita, D. Teraoka, Synlett 2006, 2646; g) J.-R. Ela-Menye,
W. Dobbs, M. Billet, P. Klotz, A. Mann, Tetrahedron Lett.
2005, 46, 1897.
[4]
[5]
[6]
W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56, 3817.
M. Suginome, Pure Appl. Chem. 2006, 78, 1377.
M. Suginome, L. Uehlin, M. Murakami, J. Am. Chem. Soc.
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M. Suginome, Y. Tanaka, T. Hasui, Synlett 2006, 1047.
Y. Tanaka, T. Hasui, M. Suginome, Org. Lett. 2007, 9, 4407.
a) M. Suginome, A. Yamamoto, Y. Ito, Chem. Commun. 2002,
1392; b) M. Suginome, L. Uehlin, A. Yamamoto, M. Murak-
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Y. Tanaka, T. Hasui, M. Suginome, Synlett 2008, 1239.
For reviews on the boronic acid based catalysts, see: a) P. J.
Duggan, E. M. Tyndall, J. Chem. Soc. Perkin Trans. 1 2002,
1325; b) K. Ishihara in Boronic Acids (Ed.: D. G. Hall), Wiley-
VCH, Weinheim, 2005, pp. 377.
General Procedure for the B(OMe)3-Mediated Ugi-Type Reaction:
A solution of B(OMe)3 (134 µL, 125 mg, 1.2 mmol), secondary
amine (0.60 mmol), aldehyde (0.40 mmol), and isocyanide
8
(0.60 mmol) in 1,2-dichloroethane (1.0 mL) was stirred at 80 °C for
12 h. The mixture was cooled to room temperature, quenched with
ice water, and extracted with ethyl acetate. The organic layer was
washed with water, and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was dried with Na2SO4 and
filtered, and the solvents evaporated under vacuum. The crude ma-
terial was purified by silica gel column chromatography to give α-
amino amides 9.
[7]
[8]
[9]
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization of the
new compounds are described.
Received: December 1, 2008
Published Online: January 28, 2009
Eur. J. Org. Chem. 2009, 1148–1151
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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