ropyridine, presumably through an SNAr reaction mechanism.
Lithium aminoborohydrides (LABs) are used as the amina-
tion reagents. This reaction is generally applicable to the
introduction of a variety of secondary amines and comple-
mentary to existing synthetic methods. The activation of
carbon-fluorine bonds is of importance since this reaction
contributes to the fundamental understanding of the reactivity
of such very stable bonds.12
Scheme 2. LAB-Promoted SNAr of 2-Fluoropyridine
LAB reagents are a new class of powerful yet selective
reducing agents that reproduce, in air, virtually all of the
transformations for which lithium aluminum hydride is used.
LAB reagents are nonpyrophoric and are readily prepared
from any primary or secondary amine, thus allowing precise
electronic and steric control of their reactivity by substituents
on the nitrogen atom. It was recently found that in some
circumstances, LABs preferentially transfer their amine
functionality over a hydride. During a screening of the
reducing capabilities of LAB reagents, a unique tandem
amination-reduction reaction between LABs and 2-haloben-
zonitriles was discovered.13 During this reaction, reduction
of the nitrile is accompanied by amination at the carbon
bearing the halogen, and 2-aminobenzylamines (2) are
obtained (Scheme 1). The amination capabilities of LAB
The progress of these reactions was monitored by TLC,
which indicated complete consumption of starting material
after a 2 h period. Still, the isolated product yields were only
moderate. To account for the loss in yield, the reaction with
lithium dimethylaminoborohydride was repeated and exam-
ined for side-product formation. It was discovered that 33%
of the desired product was lost in the form of the 2-(di-
methylamino)pyridine-borane complex (6 and 7), which
remained in the neutral layer during workup. The workup
procedure was thus modified accordingly. Heating the
reaction mixture in acidic methanol liberates the product from
the borane complex, and 2-(dimethylamino)pyridine was
isolated in 85% yield after workup.
After these initial findings, attempts were made to optimize
the reaction conditions further. It was discovered that elevated
reaction temperatures were unnecessary and only 1.1 equiv
of LAB reagent were required for the desired transformation.
When 2-fluoropyridine was reacted at room temperature with
1.1 equiv of LAB reagent for 1 h, 2-(hexamethyleneimino)-
pyridine was isolated in 97% yield after employing the
modified workup procedure.
Scheme 1. LAB-Promoted Tandem Amination-Reduction
Table 1 lists the products obtained from reaction of various
LAB reagents with 2-fluoropyridine. The optically active
LAB reagent prepared from (S)-(+)-2-methylpiperidine
(entry 9) gave the lowest yield (60%), presumably as a result
of increased sterics.
reagents have now been extended to effect the transformation
of 2-fluoropyridine to 2-(dialkylamino)pyridines.
The direct amination of 2-fluoropyridine via LAB was first
attempted to determine if an amination reaction analogous
to that of 2-fluorobenzonitrile (1) was indeed possible. The
same reaction conditions that had been optimized for the
amination of 2-fluorobenzonitrile were employed, and 2-flu-
oropyridine (3) was treated with 1.5 equiv of lithium
dimethylaminoborohydride at 65 °C for 2 h. Upon addition
of 2-fluoropyridine to the LAB reagent, the colorless solution
turned deep red in color. Meisenheimer complexes, the
anionic intermediates formed during an SNAr reaction, are
known to form highly colored solutions. In fact, a similar,
deep red color change in the SNAr reactions of LABs with
2-halobenzonitriles had been observed. Gratifyingly, 2-(di-
methylamino)pyridine (4) was isolated in 59% yield under
these reaction conditions (Scheme 2). The same reaction was
attempted with a cyclic LAB reagent to see if similar results
would be obtained. When lithium homopiperidinoborohy-
dride was used as the LAB reagent in this reaction, com-
parable results were observed and 2-(hexamethyleneimino)-
pyridine (5) was isolated in 68% yield (Scheme 2).
It is important to note that when 2-fluoropyridine is treated
with a free amine such as homopiperidine at reflux temper-
ature, the substrate remains intact even after extended reflux.
Other amines, specifically lithium amides such as LDA, do
not promote amination of 2-halopyridines. Rather, these
reagents result in ortho lithiation.14 Clearly, the LAB reagent
is essential for promoting the amination of 2-fluoropyridine.
To gain insight into the kinds of boron species that are
formed during this reaction, an aliquot of the reaction mixture
was analyzed by 11B NMR. Among the observed signals were
found two aminopyridine-borane monomers at δ -16.23 (q)
and δ -12.89 (q), attributed to the pyridinoborane (6) and
aminoborane complexes (7) of 2-(amino)pyridine, respec-
tively (Figure 1). The dominant 11B NMR signal is a sharp
peak at δ 3 (t, J ) 113 Hz). This signal may indicate that
the majority of the aminopyridine product exists as an
aminopyridine-borane dimer (8) in solution before workup.15
Acyclic aminopyridine dimer complexes with borane are
(14) (a) Choppin, S.; Gros, S.; Fort, Y. Eur. J. Org. Chem. 2001, 3,
603. (b) Radinov, R.; Khaimova, M.; Simova, E. Synthesis 1986, 11, 886.
(15) BH2 compound shown in Figure 1 may be cyclic or acyclic. The
exact identity of this species is not forthcoming at this moment and is under
further investigation.
(12) Hudlicky, M. Chemistry of Organic Fluorine Compounds; Prentice
Hall: New York, 1992.
(13) Thomas, S.; Collins, C. T.; Cuzens, J. R.; Spiciarich, D.; Goralski,
C. T.; Singaram, B. J. Org. Chem. 2001, 66, 1999.
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Org. Lett., Vol. 5, No. 21, 2003
Thomas, Shannon
