1,2,3-Triazole-boranes: Stable and efficient reagents for ketone and aldehyde reductive amination in organic solvents or in water

Article abstract of DOI:10.1039/b915361f

Air, moisture and thermally stable 1,2,3-triazole-borane complexes were developed as new practical reagents for ketone/aldehyde amination with high efficiency and excellent substrate diversity.

Full text of DOI:10.1039/b915361f

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1,2,3-Triazole-boranes: stable and efficient reagents for ketone and
aldehyde reductive amination in organic solvents or in waterw
Wenyan Liao,a Yunfeng Chen,a Yuxiu Liu,b Haifeng Duan,a Jeffrey L. Petersena and
Xiaodong Shi*a
Received (in Cambridge, UK) 29th July 2009, Accepted 16th September 2009
First published as an Advance Article on the web 28th September 2009
DOI: 10.1039/b915361f
Air, moisture and thermally stable 1,2,3-triazole-borane complexes
were developed as new practical reagents for ketone/aldehyde
amination with high efficiency and excellent substrate diversity.
Our interest in developing 1,2,3-triazole-coordinated
complexes was initiated by our recent success with a metal-
free 1,2,3-NH-triazole synthesis8 and post-triazole regio-
selective derivatization.9 Compared to other N-heterocyclic
aromatic compounds, the 1,2,3-triazoles possess unique functions:
high polarity and high electron density on the nitrogen (more
nucleophilic and less basic) allow them to coordinate well with
Lewis acids and a lower LUMO in the aromatic ring enhances
back bonding, giving stable triazole–metal binding. To evaluate
1,2,3-triazoles as potential binding ligands, our group recently
reported triazole-Rh(I) complexes and triazole-Au complexes.10
To our delight, the triazole–metal complexes indeed provided
much better stability toward air, moisture and heat. Therefore,
we wondered whether 1,2,3-triazoles could be applied as
effective ligands for borane. One clear advantage of triazole-
boranes, besides the improved stability of the N–B bond, is
that triazoles are biocompatible, non-toxic ligands (unlike
pyridine), which is crucial for bio-related transformations.
With the presence of an acidic proton, the NH-triazoles
would likely bind to other Lewis acids as anionic ligands. The
N-substituted triazoles, on the other hand, could serve as
neutral ligands. But the different substitution patterns, N-1
or N-2 positions, might also influence the overall coordination
properties. With this concern in mind, to prepare the triazole-
borane complexes, different NH-triazoles and N-substituted
triazoles were applied to react with BH3ÁTHF. The results are
summarized in Table 1.
Borane compounds are important reagents in organic synthesis
with a long history.1 The key function of these compounds is
donating hydride in reductive processes.2 In the past, different
borane compounds have been developed in order to promote
attractive transformations.3 Among those borane compounds,
nitrogen coordinated borane complexes are particularly
attractive to chemists due to their unique reactivity.4 However,
one big concern regarding these complexes is their stability,
especially at high temperature and in reactions in protic
solvents (H2 formation).
Amine-coordinated borane complexes suffer from poor
stability, thus limiting their application in synthesis.5 On the other
hand, N-heteroaromatic compound-coordinated boranes, such as
PyBH3, provide improved stability and have been applied to
several interesting transformations recently.6 Some reported
N-heteroaromatic boranes include pyridine boranes and pyridine
derivative boranes, imidazole boranes and 1,2,4-triazole-boranes
as shown in Scheme 1A.7 However, to the best of our knowledge,
1,2,3-triazole-boranes have never been explored. Herein, we
report the first 1,2,3-triazole-borane complexes (TAB) and their
application as highly efficient reagents in ketone and aldehyde
reductive amination, both in organic solvents and in water.
The reactions between NH-triazoles (1a and 1f) and
BH3ÁTHF gave complex mixtures, whose structure could not
be identified. This was probably due to the multiple nitrogen
binding sites on the triazoles and possible formation of a
B–H–B 3c2e bond. The N-2 substituted benzyl triazoles
(1c, 1e and 1h) indicated no complex formation even when
treated at a higher temperature (50 1C). This lack of coordination
was likely caused by the steric hindrance of the N-2 substituted
groups. The 1,4-disubstituted triazole 1g is the major triazole
derivative product prepared from ‘‘click-chemistry’’.11
Unfortunately, the reaction between 1g and BH3ÁTHF gave
multiple complexes with low reaction rate (more than 12 h at
room temperature) and the complexes decomposed during
attempts at isolation.
Scheme 1
a C. Eugene Bennett Department of Chemistry,
West Virginia University, Morgantown, WV 26506, USA.
E-mail: Xiaodong.Shi@mail.wvu.edu; Fax: +1-304-293-4904;
Tel: +1-304-293-3435 x6438
b Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin, China. E-mail: Liuyuxiu@nankai.edu.cn;
Fax: +86-22-2349-9842; Tel: +86-22-2350-4229
It is known that the N-1 and N-3 nitrogens of 1,2,3-triazoles
are more nucleophilic than the N-2 nitrogen. Therefore, to
form stable triazole-borane complexes, the N-1 substituted
triazole, with less steric hindrance on the N-3 position, could
be a good choice. Based on this hypothesis, we examined the
N-1 substituted benzotriazoles 1b and 1d. To our great
w Electronic supplementary information (ESI) available: Experimental
details, X-ray measurement and 1H NMR, 13C NMR for all compounds.
CCDC 741401. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b915361f
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Table 1 Formation of triazole-boranesa
Table 2 Screening of reaction conditionsa
Entry TAB (equiv.) Solvent
T/1C
t/h
Yield (%)b
1
2
3
4
5
6
7
8
2a (0.7)
2b (0.7)
2b (0.7)
2b (0.7)
2b (0.7)
2b (0.7)
2b (0.7)
2b (0.7)
2b (0.7)
2b (0.4)
2b (0.4)
2b (0.4)
CH2Cl2
CH2Cl2
DMSO
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
rt
5
499
499
95
3.5
0.5
5
15 min
1.5
91
THF
72
499
499
499
94
499
499
48
Toluene
CH3CN
MeOH
Neat
DCE
DCE
MeOH
4
2
5 min
3
0.5
1
9
10
11
12
Yield
Triazole Reaction results (%)b
Reaction
Triazole results
Yield
(%)b
a
Reactions were carried out by mixing 3a (1.05 equiv.), 4a (1.0 equiv.)
1a
1b
Complex mixtures n.d.
Stable white solid 2a:
1e
1f
No reaction
Complex
mixtures
Complex
mixtures
No reaction
—
n.d.
b
and 2 (0.4–0.7 equiv.) and monitored by TLC. NMR yields. DCE:
1,2-dichloroethane.
499%c
—
1c
1d
No reaction
1g
1h
n.d.
—
slightly faster reaction rate was observed (entries 1 and 2). The
reaction in THF gave lower yield, which was likely due to
solvent coordination with borane, leading to side reactions.
Notably, these new borane complexes indicated great stability
in protic solvent MeOH or at a higher temperature (entries 8
and 11). Impressively, the reaction gave quantitative yield in
DCE even with only 0.4 equiv. of reductant (a slight increase
of reductant was needed for protic solvent, entries 8 and 12).
Considering that 1 equiv. of water was produced in this
process, the fact that only the theoretical limit amount of
borane was needed indicated the extremely high hydride
transfer efficiency and superior stability of the triazole-borane
reductants. Representative aldehydes and amines were applied
as shown in Table 3.
Stable white solid 2b:
499%
a
Reactions were carried out by mixing triazole 1 (1.1 equiv.) and
c
b
BH3ÁTHF (1.0 M, 1.0 equiv.) at rt. Isolated yields. Structures
determined by X-ray.
pleasure, the triazole-borane complexes 2a and 2b were formed
as white solids in nearly quantitative yields. The structure of
2a was confirmed by X-ray crystallography, with BH3 bound
on the N-3 position as expected. Notably, the triazole-boranes
were very stable toward air and moisture and can even be
purified by column chromatography. In addition, the complexes
were also thermally stable at 80 1C (no decomposition).
With these new triazole-boranes 2a and 2b in hand, we then
explored their reactivity as reductants. The transformation
that particularly interested us was aldehyde and ketone
reductive amination, a very important reaction in organic
synthesis, especially for biological related systems.12 According
to the literature, various reducing reagents, such as NaBH3CN,
pyr–BH3, Bu3SnH/SiO2, PhSiH3/Bu2SnCl2 etc., have been
developed for this conversion.13 As a very attractive approach
for bio-elongation, the key concerns regarding ‘‘good’’ reductive
amination reagents are: (a) good chemoselectivity (selectively
reducing imine rather than aldehydes and ketones); (b) bio-
compatibility (‘‘green’’ reaction conditions), and (c) stability in
protic solvents. Among these factors, the hydride stability
under acidic conditions is particularly challenging, due to H2
formation. As a result, reductive amination of ketones is an
extremely difficult task, since acid activation of ketone is often
required for effective imine formation.
The results demonstrated that this transformation is
suitable for a large variety of aldehydes (aromatic, aliphatic
and heteroaromatic) and amines (aromatic, aliphatic and
secondary amines). Excellent yields were obtained for almost
all cases. Meanwhile, the benzotriazole by-product could be
recovered in nearly quantitative yield.
Encouraged by this success, we extended the investigation to
ketones. Since acids were often required for the imine formation,
30% of AcOH was added as the catalyst (no reaction was
observed without acid catalyst at room temperature). Again,
effective reductive amination of ketone was achieved
using triazole-boranes with a slightly higher loading of TAB
(0.8–1.2 equiv.). Moreover, this ketone reductive amination
could also be achieved by increasing the reaction temperature
without further addition of acid catalyst (condition B).
Selected reaction substrates are shown in Table 4.
As shown in Table 4, this reaction was suitable for primary
amines, secondary amine and aniline. Meanwhile, the two
different reaction conditions provided orthogonal approaches
for sensitive substrates. For example, in the synthesis of 7f,
the furanyl ketone decomposed under acidic conditions.
Therefore, using condition A gave 7f in less than 50% yield
along with ketone decomposition by-products. Application of
condition B could help to avoid the decomposition of ketone,
giving 7f in excellent yield. The enone substrate has also been
To evaluate the reactivity of triazole-boranes, aldehyde 3a
and aniline 4a were first applied as shown in Table 2. These
triazole-boranes showed excellent reactivity toward aldehyde
reductive amination in various solvents (Table 1), giving near
quantitative yields in most of the cases. Although both 2a
(TAB-M) and 2b (TAB-P) produced stable triazole-borane
complexes, the N-1-phenyl-benzotriazole-borane 2b showed
improved solubility in the organic solvents. As a result, a
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Table 3 Aldehyde–amine reductive coupling by TABa
Notably, this reaction tolerated functional groups that may
potentially coordinate with borane, such as imidazole and
sulfur (9b and 9c), which further enhanced the synthetic utility
of the reported TAB.
In conclusion, triazole-boranes were successfully prepared
and applied as reductants in ketone/aldehyde reductive
amination. Compared to literature reported systems, the
triazole-boranes showed clear advantages regarding efficiency,
and proton and thermal stability, which made them new
practical reagents for related chemical and biological research.
Detailed studies regarding reaction mechanism (borane
dissociation process) and application of this new reagent
for other important transformations are currently under
investigation in our group.
R1
4
t/h
Yield (%)b
p-ClC6H4
p-MeOC6H4
C6H5
C6H5NH2
C6H5NH2
C6H5NH2
p-MeOC6H4NH2
p-FC6H4NH2
C6H5CH2NH2
p-MeOC6H4CH2NH2
p-MeOC6H4CH2NH2
C4H9NH2
3
3
3
3
6
4
4
3
4
4
3
3
5a: 99
5b: 99
5c: 99
5d: 99
5e: 99
5f: 95
5g: 96
5h: 82
5i: 91
5j: 95
5k: 99
5l: 99
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-NO2C6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
C6H5CH2CH2
Pyrrolidine
C6H5NHCH3
C6H5NH2
We greatly appreciate the West Virginia University,
WV-Nano Initiative and American Chemical Society PRF
for generous financial support.
a
Notes and references
Reactions were carried out by mixing 3 (1.05 equiv.), 4 (1.0 equiv.)
b
and 2b (0.4 equiv.) and monitored by TLC. Isolated yields.
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¨
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a
Reactions were carried out by mixing 6 (1.3 equiv.), 4 (1.0 equiv.)
b
and 2 (0.6-1.2 equiv.) and monitored by TLC. Isolated yields.
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E. Vedejs, J. Am. Chem. Soc., 2008, 130, 8669–8676;
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Scheme 2
investigated (cyclohexenone). A mixture of different reduction
products (including the desired allylic amine) was observed.
The lack of chemoselectivity was likely caused by the harsher
conditions. Overall, to the best of our knowledge, the triazole-
boranes are one of the most efficient metal-free reagents for the
challenging ketone reductive amination. With clear evidence
for improved proton and thermal stability of TAB, we then
applied this reagent in the reductive amination of unprotected
amino acids in water.
To increase the solubility of amino acid in water, 30%
Na2CO3 was added (Scheme 2). This modification helped the
further evaluation of the triazole-borane reductant under
basic conditions. As anticipated, good yields were obtained.
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This journal is The Royal Society of Chemistry 2009
6438 | Chem. Commun., 2009, 6436–6438