The use of potassium alkynyltrifluoroborates in Mannich reactions

Article abstract of DOI:10.1016/j.tetlet.2003.11.049

Potassium alkynyltrifluoroborates react with amines and salicylaldehydes in the presence of benzoic acid to generate highly functionalized amines. Ionic liquids such as butylmethylimidazolium tetrafluoroborate (BmimBF₄) are suitable solvents fo

Full text of DOI:10.1016/j.tetlet.2003.11.049

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 729–731
The use of potassium alkynyltrifluoroborates in Mannich
reactionsq
George W. Kabalka,* Bollu Venkataiah and Gang Dong
Department of Chemistry, The University of Tennessee, Knoxville, TN 37996-1600, USA
Department of Radiology, The University of Tennessee, Knoxville, TN 37920-1600, USA
Received 14 October 2003; revised 11 November 2003; accepted 12 November 2003
Abstract—Potassium alkynyltrifluoroborates react with amines and salicylaldehydes in the presence of benzoic acid to generate
highly functionalized amines. Ionic liquids such as butylmethylimidazolium tetrafluoroborate (BmimBF4) are suitable solvents for
the reaction.
ꢀ 2003 Elsevier Ltd. All rights reserved.
The Petasis reaction is a modern variation of the Man-
nich reaction involving an amine, a carbonyl compound,
and an organoborane.1 The method has attracted con-
siderable interest because the three-component process
is applicable to a variety of boronic acids, amines, and
carbonyl compounds such as a-ketoacids,2;3 a-hydroxy-
aldehydes,4 and salicylaldehydes.5 a-Heterocyclic alde-
hydes have also been shown to participate.6 Examples of
the Petasis reaction involving alkenylboronates and
arylboronates, are well documented but alkynylboron
derivatives have not been utilized.
esters.9;10 We have discovered that potassium alkynyl-
trifluoroborates are suitable reagents for carrying out
Mannich reactions in ionic liquid media.
Ionic liquids have emerged as alternative solvents
because they have essentially no vapor pressure and
provide good solubility for a wide range of organic,
inorganic, and organometallic compounds.11 In contin-
uation our studies focused on organoboron reactions in
room temperature ionic liquids,12 we examined the
reaction of potassium alkynyltrifluoroborate salts with
formaldehyde and various amines in butylmethyl-
imidazolium tetrafluoroborate (BmimBF4). Propargyl-
amines, 3, were obtained in high yields (Scheme 1). The
resultant products are of biological interest because they
are selective inhibitors of the rat squalene epoxidase
enzyme.13
Alkynylboronic esters are stronger Lewis acids than aryl
and alkenylboronate esters and are easily hydrolyzed.7
Therefore, their use in organic reactions can be prob-
lematic. However, alkynylboronate salts are hydrolyti-
cally stable and readily participate in a number of
carbon–carbon bond forming reactions.8 Recently,
Molander and Genet independently reported Suzuki–
Miyaura cross-coupling reactions using air stable
potassium alkynyltrifluoroborates, which can be easily
In an initial study, the reaction of salicylaldehyde with
potassium 1-hexynyltrifluoroborate and dibenzylamine
in BmimBF4 produced only 10% of desired product
synthesized
from
corresponding
alkynyllithium
reagents.9 It is becoming apparent that trifluoroborate
derivatives can be successfully used in place of boronate
BmimBF4
90 oC, 4 h
R
R
BF3K + R'2NH + HCHO
NR'2
1
2
3
Keywords: Potassium alkynyltrifluoroborates; Mannich reaction; Ionic
liquids; Butylmethylimidazolium tetrafluoroborate; Propargylamines.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.11.049
R
Amine
Yield (%)
n-Butyl
n-Butyl
Phenyl
Dibenzylamine
Morpholine
Piperidine
92
90
83
* Corresponding author. Tel.: +1-865-974-3260; fax: +1-865-974-2997;
e-mail: kabalka@utk.edu
Scheme 1.
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.049

730
G. W. Kabalka et al. / Tetrahedron Letters 45 (2004) 729–731
Table 1. Three-component Mannich reaction in various solventsa;b
(Table 1, entry 1). We then found that the addition of
1 equiv of benzoic acid increased the reaction yields
dramatically (Table 1, entry 2). The benzoic acid pre-
sumably catalyzes the condensation of the aldehyde with
the amine to generate an iminium ion, which then reacts
more efficiently with the borate salt.14 The reaction was
most efficient in BmimBF4 and DMF; whereas, THF,
acetonitrile, 1,4-dioxane, and ionic liquids such as
BmimBr, BmimPF6 were less effective.15
NBn2
CHO
HNBn2
+
n-Bu
BF3K
n-Bu
Solvent
OH
OH
Entry
Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
BmimBF4
BmimBF4
BmimBr
BmimPF6
DMF
10c
81
17
41
73
6
The reactions of a variety of alkynyltrifluoroborates and
carbonyl compounds were then investigated (Table 2).
Benzaldehyde derivatives lacking an o-hydroxy substit-
utent were found to be unreactive. The reaction is lim-
ited to secondary amines, but both aliphatic and
aromatic alkynyltrifluoroborates participate. Under the
reaction conditions utilized, no heterocycle formation
was observed.5a
THF
1,4-Dioxane
Acetonitrile
11
0
a Reactions carried out at 80 ꢁC for 20 h.
b One equivalent of benzoic acid was added to the reaction.
c Reaction run in the absence of benzoic acid.
Table 2. Three-component condensation of potassium alkynyltrifluoroborates, amines, and salicylaldehydes
NR'2
OH
BmimBF4
1 equiv. PhCOOH
CHO
R
BF3K + R'2NH +
R
80 oC, 20 h
OH
X
X
1
2
4
5
Entry
R
Amine (2)
X
H
Yield (%)a
1
n-Butyl
n-Butyl
n-Butyl
n-Butyl
n-Butyl
n-Butyl
Phenyl
Phenyl
p-Tolyl
tert-Butyl
Dibenzylamine
Dibenzylamine
Morpholine
Morpholine
Morpholine
Morpholine
Dibenzylamine
Morpholine
Morpholine
Morpholine
Morpholine
81
83
76
63
76
53
81
79
78
72
78
58b
55c
2
5-NO2
H
3
4
3-Me
5-t-Bu
5-Cl
H
5
6
7
8
5-NO2
5-NO2
H
9
10
11
12
13
1-Cyclohexenyl
1-Cyclohexenyl
Trimethylsilyl
H
Tetrahydroisoquinoline
Morpholine
H
H
a Isolated yields.
b DMF was used as solvent.
c The trimethylsilyl group was removed under the reaction conditions.
+
+
NR'2
NR'2
R
CHO
HNR'2
H
R
BF3K
H
F
PhCOOH
-H2O
B
OH
OH
O
F
NR'2
R
OH
5
Scheme 2.

G. W. Kabalka et al. / Tetrahedron Letters 45 (2004) 729–731
731
9607; (d) Berree, F.; Debache, A.; Marsac, Y.; Carboni, B.
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The mechanism of the reaction presumably involves the
initial formation of an iminium ion. Coordination of the
borate moiety with the phenolate oxygen10a would form
an intermediate, 6, that would deliver the propargyl-
amine (Scheme 2).5
4. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998,
120, 11798; (b) Prakash, G. K. S.; Mandal, M.; Schweizer,
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7. (a) Soulie, J.; Cadiot, P. Bull. Soc. Chim. Fr. 1966, 3846;
(b) Molander, G. A.; Brown, H. C. Synthesis 1979, 104; (c)
Blanchard, C.; Framery, E.; Vaultier, M. Synthesis 1996,
45.
In conclusion, the efficient benzoic acid promoted, three-
component coupling of potassium alkynyltrifluoro-
borates, amines, and salicylaldehydes in ionic liquid
media has been achieved. The process is simple and
generates functionalized propargylamines in good
yields. The products, 5, can be utilized as precursors to a
variety of functionally substituted heterocycles.16
8. (a) Soderquist, J. A.; Matos, K.; Rune, A.; Ramos, J.
Tetrahedron Lett. 1995, 36, 2401; (b) Furstner, A.; Seidel,
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J. Org. Chem. 2002, 67, 8416; (b) Darses, S.; Michaud, G.;
Genet, J.-P. Eur. J. Org. Chem. 1999, 1875.
Supplementary data
Reaction procedure, 1H and 13C and analytical data.
This supplementary data is available online with the
paper in ScienceDirect.
10. (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.;
Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020; (b) Darses,
S.; Michaud, G.; Genet, J.-P. Tetrahedron Lett. 1998, 39,
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scheid, P.; Kein, W. Angew. Chem., Int. Ed. 2000, 39, 3772;
(c) Sheldon, R. Chem. Commun. 2001, 2399; (d) Dupont,
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3667.
Acknowledgements
We thank the U.S. Department of Energy the National
Institutes of Health (NCI R01CA96128), and the
Robert H. Cole Foundation for support of this research.
12. (a) Kabalka, G. W.; Malladi, R. R. Chem. Commun. 2000,
2191; (b) Kabalka, G. W.; Dong, G.; Venkataiah, B. Org.
Lett. 2003, 5, 893; (c) Kabalka, G. W.; Venkataiah, B.;
Dong, G. Tetrahedron Lett. 2003, 44, 4673; (d) Kabalka,
G. W.; Venkataiah, B.; Das, B. C. Synlett, in press.
13. Musso, D. L.; Clarke, M. J.; Kelly, J. L.; Boswell, G. E.;
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References and notes
1. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993,
34, 583.
2. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
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Tetrahedron 1997, 53, 16463; (c) Thompson, K. A.; Hall,
D. G. Chem. Commun. 2000, 2379; (d) Koolmeister, T.;
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Tetrahedron Lett. 2002, 43, 6845; (f) Naskar, D.; Roy, A.;
Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003, 44,
5819.
3. The Petasis reaction has been applied to the synthesis of
heterocyclic systems: (a) Hansen, T. K.; Schlienger, N.;
Hansen, B. S.; Andersen, P. H.; Bryce, M. R. Tetrahedron
Lett. 1999, 40, 3651; (b) Batey, R. A.; MacKay, D. B.;
Santhakumar, V. J. Am. Chem. Soc. 2000, 121, 5075; (c)
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14. Jun, C.-H.; Lee, D.-Y.; Hong, J.-B. Angew. Chem., Int. Ed.
2000, 39, 3070.
15. Typical experimental procedure: To a mixture of salicyl-
aldehyde (1 mmol) and dibenzylamine (1 mmol) in
BmimBF4 (800 mg), potassium 1-hexynyltrifluoroborate
(1 mmol) and benzoic acid (1 mmol) were added. The
mixture was stirred at 80 ꢁC for 20 h, the product was
extracted into diethyl ether (3 · 5 mL), the solvent re-
moved, and the crude product purified by column chro-
matography (silica gel).
16. (a) Luo, F.-T.; Schreuder, I.; Wang, R.-T. J. Org. Chem.
1992, 57, 2213; (b) Larock, R. C.; Yue, D. Tetrahedron
Lett. 2001, 42, 6011, and references cited therein.