Halogen-bonding-induced hydrogen transfer to C=N bond with hantzsch ester

Article abstract of DOI:10.1021/ol501259q

Several bidentate dihydroimidazolines were prepared and investigated as catalysts for hydrogen transfer reduction of C=N bond with Hantzsch ester. Highly efficient reactions were observed for quinolines and imines with low catalyst loading of 2 mol %. The presence of halogen bonding was elucidated using NMR studies and isothermal calorimeric titrations. Binding constants of the XB donors were also measured using isothermal calorimeric titrations (ITC).

Full text of DOI:10.1021/ol501259q

Letter
pubs.acs.org/OrgLett
Halogen-Bonding-Induced Hydrogen Transfer to CN Bond with
Hantzsch Ester
Wei He, Yi-Cen Ge, and Choon-Hong Tan*
School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371
S
* Supporting Information
ABSTRACT: Several bidentate dihydroimidazolines were pre-
pared and investigated as catalysts for hydrogen transfer
reduction of CN bond with Hantzsch ester. Highly efficient
reactions were observed for quinolines and imines with low
catalyst loading of 2 mol %. The presence of halogen bonding
was elucidated using NMR studies and isothermal calorimeric
titrations. Binding constants of the XB donors were also
measured using isothermal calorimeric titrations (ITC).
alogen bonding (XB) is the directional interaction
between a covalently bound halogen atom (X) and a
H
Lewis base.1 This noncovalent interaction was conclusively
revealed by Hassel through X-ray crystallographic studies of
dihalogen molecules with Lewis bases.2 Halogen bonding has
impacted research fields which require control of intermolecular
recognition and self-assembly processes.3 In particular, it has
found applications in crystal engineering and supramolecular
chemistry.4 These observations are generally under thermody-
namic control. Initially, this process is reversible under
experimental conditions, and it will terminate until the assembly
with XB is formed under thermodynamically favorable state.
As it is highly directional, halogen bonding has potential to be
used in catalytic processes.5 Bolm6 and Huber7 were the first to
recognize that XB can be exploited for organocatalysis. Bolm
reported that haloperfluoroalkanes can be used as catalysts for
the reduction of 2-phenylquinoline using a Hantzsch ester.6 N-
Heterocycles such as quinolines are well-known as efficient XB
acceptors in the study of halogen bonding.8 Huber developed
charge-assisted imidazolium XB donors to activate benzhydryl
bromide for a Ritter-type reaction with acetonitrile.7a These
bidentate donors have strong interactions with halogen atom,
with constant binding in the order of 106. Stoichiometric
amounts of these XB donors are required to promote the
reaction. Huber further developed neutral polyfluorinated arenes
as catalysts for the addition of ketene silyl acetal to 1-
chloroisochroman.5a Unlike the previous example, in which the
leaving halide binds to the XB donor, this reaction uses a silyl to
trap the leaving halide, allowing the XB donors to be regenerated
in the reaction.
Figure 1. Halogen bond donors C1−C7.
Scheme 1. Synthesis of Halogen Bond Donor C1
subsequent methylation resulted in the cationic imidazolium C1.
Through similar routes, other XB donors C2, C3, C4, and C5
were also obtained in good yields (see the Supporting
Information for details). These donors were purified with flash
chromatography followed by recrystallization. Notably, the
imidazolium C1 has much better solubility in organic solvents
than imidazolium C4.
Inspired by their work, we designed a series of bidentate
dihydroimidazoline XB donors (Figure 1, C1−C6). The
synthesis of C1 began from commercially available chiral
diamine (Scheme 1). The imidazolidine intermediate was
obtained in high yield through condensation with glyoxylic
acid, followed by oxidative decarboxylation with NBS.9 The
diimidazolidine framework was assembled using m-xylylene
dibromide. Neutral iodoimidazoline was obtained next, and
Received: May 2, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
The structure of C1 was confirmed using the X-ray
crystallographic method (Figure 2). The interaction between
the XB donor with the triflate counterions (2.868 Å) can be
clearly observed, which is below the sum of the van der Waals
radii.7a
GC. The neutral imidazoline C3, nonmethylated variant of C1,
was also unable to complete the reaction within 24 h (entry 3).
Both the presence of the iodo group and the electron-
withdrawing tendency of the imidazolium cationic core are
essential for the reactivity of the catalyst C1. Solubility of
imidazolinium C4 is poor and may contribute to its
ineffectiveness as a catalyst (entry 4). XB donor C5, the
monodentate version of C1, was able to catalyze the reaction
with some efficiency (entry 5). We were not able to detect any
product when imidazolium C6 was used (entry 6). When a well-
known XB donor pentafluoroiodobenzene was used as the
catalyst, sluggish reactivity was observed (entry 7). To remove
the doubt that the reaction is catalyzed by residual acid present in
the catalyst, 20 mol % of K2CO3 was added to a separate
experiment, which proceeded smoothly (entry 8). In the absence
of catalyst, only a trace amount of product was detected within 19
h (entry 9).
With further optimization, we found that quinoline 1a can be
catalyzed with 2 mol % of C1 (Table 2, entry 1). Under the
Figure 2. X-ray structure analysis of the XB donor C1 (elipsol at 50%
probability); selected bond lengths (Å) and angles (deg): C1−I1
2.088(10), C1−N1 1.309(9), C1−N2 1.322(10), C3−N1 1.499(8);
N1−C1−N2 114.0(8).
Table 2. Transfer Hydrogenation of Quinoline Derivatives in
a
the Presence of C1
The hydrogen-transfer reaction of CN, using Hantzsch
ester as hydrogen source, is a mild method to reduce nitrogen-
containing compounds.10 Brønsted acids were shown to be
particularly good catalysts to promote this reaction.11 XB donors
can act as Lewis acids in the presence of pyridines and
heterocycles; it is likely to be an efficient catalyst for this
reaction. The effectiveness of a XB donor as a catalyst probably
follows the “goldilocks” principle. A weak XB donor might not be
sufficiently Lewis acidic to decrease the HOMO of CN, while a
strong XB donor may bind too tight to the product/reagent of
the reaction and inhibit the catalytic cycle. A suitable XB catalyst
is thus a dynamic XB donor.
We selected the reduction of quinoline 1a as a model for our
initial investigation (Table 1). With 10 mol % of imidazolium C1
as the catalyst, we obtained complete reaction within 1 h, and the
resulting amine was obtained with an isolated yield of 92% (entry
1). For imidazolium C2, the deiodo version of C1, a non-XB
donor, the reaction was not completed after 24 h (entry 2). After
1 h, only about 10% of the reduced adduct was detected using
b
entry
1
[R1,R2,R3,R4]
[H,H,H,H]
C1 (mol %) time (h) yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2
2
5
2
2
2
2
2
5
4.5
24
99
95
95
95
93
95
90
90
90
[Me,H,H,H]
[H,Me,H,H]
48
5
c
[Ph,H,H,H]
[4MeOC6H4, H,H,H]
[Ph,H,Br,H]
5
15
3
1g
1h
1i
[Ph,H,NO2,H]
[Ph,H,Me,H]
24
7
[Me,H,H,OH]
a
b
c
HEH: Hantzsch ester. Isolated yield. The enantiometric excess of
the product is zero.
optimized reaction conditions, a variety of mono and
disubstituted quinolines were reduced with high yields (entries
2−9). Both electron-withdrawing and electron-donating sub-
stituents are suitable.
In the presence of 5 mol % of C1, 1,10-phenanthroline 1j can
be reduced to the corresponding 1,2,3,4-tetrahydro-1,10-
phenanthroline 4j (Scheme 2, eq 1). Reduction of unactivated
pyridine is nontrivial, and there are only a limited number of
reports.12 With our methodology, 3-carbonylpyridine 1k−l can
be reduced in high yield to tetrahydropyridines 4k−l albeit with
long reaction time (Scheme 2, eq 2).
Table 1. Transfer Hydrogenation of Quinolone 1a with
a
Hantzsch Ester in the Presence of Different Catalysts
b
entry
catalyst (mol %)
time (h)
yield (%)
c
1
2
3
4
5
6
7
C1 (10)
C2 (10)
C3 (10)
C4 (10)
C5 (10)
C6 (10)
C7 (10)
C1 (10)
−
1
24
24
19
3
99 (92)
68
Scheme 2. Transfer Hydrogenation of Pyridine Derivatives in
the Presence of C1
45
78
91
21
67
2.5
19
trace
30
d
8
99
9
trace
a
HEH: diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate).
Determined using GC−MS. Isolated yield in parentheses. 20 mol %
b
c
d
K2CO3 added.
B
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Organic Letters
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Next, we examined the reduction of imine derivatives in the
presence of C1 (Table 3). In most cases, the imines can be
reduced in good yields within 2 h (entries 1−5). For imines with
highly electron-withdrawing substitution, no reduction was
observed (entry 6).
Isothermal titration calorimetry (ITC) was developed by
Huber to determine the halogen bond strength of XB donors.7d
Using a similar approach, we measured the binding constants of
C1 and C4 with bromide (Table 4); they are 3.29 × 104 and 4.57
× 105 M−1, respectively.
Table 3. Transfer Hydrogenation of Imine Derivatives in the
Presence of C1
Table 4. Isothermal Calorimetric Titrations of Halogen Bond
Donors with Halide
a
a
entry
2
[Ar,R1,R2]
[Ph,H,H]
C1 (mol %) time (h) yield (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
2
5
2
2
2
2
5
1
90
92
90
86
90
n.r.
93
[4ClC6H4,H,H]
1
[4MeC6H4,H,H]
[1-naphthyl,H,H]
[4NO2C6H4,H,Me]
[4NO2C6H4,H,NO2]
1
2
0.2
b
24
24
2g
[Ph,Me,H]
a
b
HEH: Hantzsch ester. Isolated yield. No reaction.
entry
guest
1a
host
K (mol−1
)
ΔH (kJ/mol) TΔS (kJ/mol)
In order to verify the presence of the proposed N-halogen
interaction, we conducted several NMR experiments (Figure 3).
1
2
3
C1
C1
C4
Bu4NBr
Bu4NBr
3.29E4
4.57E5
−18.0
−22.6
7.8
9.7
a
Conditions: halogen bond donors (0.2 mM), halide (2 mM).
In conclusion, we have prepared a series of novel halogen-
bonding donors based on a bidentate dihydroimidazoline core.
One of these donors, imidazolium C1, was found to be an
efficient catalyst for the hydrogen-transfer reduction of the C
N bond with Hantzsch ester. Highly efficient reactions were
observed for quinolines and imines with low catalyst loading of 2
mol %. The presence of halogen bonding was elucidated using
NMR studies and isothermal calorimeric titrations. Binding
constants of the XB donors were also measured using isothermal
titration calorimetry (ITC).
Figure 3. 13C NMR spectra of C1 and 1a in CD2Cl2: (a) C1; (b) C1 +
1a (1:1); (c) 1a.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details and characterization data, X-ray
structural analysis, and ITC spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Through DEPT and 2D NMR (HMQC and HMDC), we
concluded that the iodine-carrying carbon of C1 has a δ = 136.7
ppm in the 13C NMR (Figure 3, Spectra a). When 1.0 equiv of 1a
is added to C1, the peaks of 1a were much reduced (spectra b).
On closer inspection, it seems that the peaks of 1a had broaden,
indicating a presence of a number of nonequivalent con-
formations. At the same time, the iodine-carrying carbon of C1
shifts upfield by 14.5 ppm. Such an observation was not present
when triflic acid (TfOH) was added to 1a (see the Supporting
Information for details). The NMR experiments provide an
indication that there is a clear interaction between the nitrogen
atom of 1a and iodine atom of C1. Resnati and co-workers
reported the 19F NMR study of the halogen bonding between
haloperfluorocarbons (XB donor) and a heteroatom (XB
acceptor).13 Because of the halogen-bonding interaction, it was
also observed that the 19F peak of the XB donor shifted upfield
significantly. Huber and co-workers also made similar observa-
tions in the 13C NMR spectra of the imidazolium XB donor with
its acceptor.7a
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: choonhong@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Huaqiang Zeng (National University of
Singapore) for his assistance with the ITC measurement. We
also thank Dr. Rakesh Ganguly and Dr. Li Yongxin (Nanyang
Technological University) for X-ray crystallographic analysis. We
thank NTU for funding support (M4080946.110, RG 6/12
M4011018.110) and scholarship awards (W.H. and Y.G.).
C
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Letter
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