Molecular design of organic superbases, azacalix[3](2,6)pyridines: Catalysts for 1,2-and 1,4-additions

Article abstract of DOI:10.1021/jo3017428

The molecular design, characteristics, and catalytic activity of macrocyclic amino compounds, azacalix[3](2,6)pyridine derivatives, were studied. The introduction of an electron-donating group on the pyridine moiety and bridging amino phenyl group enabled the enhancement of the basicity of azacalix[3](2,6)pyridine up to pKBH⁺ = 29.5 in CD₃CN. These derivatives were shown to be efficient catalysts for 1,4-addition reactions of nitroalkanes or primary alcohols to α,β-unsaturated carbonyl compounds and 1,2-addition reactions of nitroalkanes to aromatic aldehydes.

Full text of DOI:10.1021/jo3017428

Article
pubs.acs.org/joc
Molecular Design of Organic Superbases, Azacalix[3](2,6)pyridines:
Catalysts for 1,2- and 1,4-Additions
Natsuko Uchida, Junpei Kuwabara, Ayako Taketoshi,† and Takaki Kanbara*
Tsukuba Research Center for Interdisciplinary Materials Science (TIMS), Graduate School of Pure and Applied Sciences, University
of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8573, Japan
S
* Supporting Information
ABSTRACT: The molecular design, characteristics, and
catalytic activity of macrocyclic amino compounds, azacalix[3]-
(2,6)pyridine derivatives, were studied. The introduction of an
electron-donating group on the pyridine moiety and bridging
amino phenyl group enabled the enhancement of the basicity
+
of azacalix[3](2,6)pyridine up to pKBH = 29.5 in CD3CN.
These derivatives were shown to be efficient catalysts for 1,4-
addition reactions of nitroalkanes or primary alcohols to α,β-
unsaturated carbonyl compounds and 1,2-addition reactions of
nitroalkanes to aromatic aldehydes.
nitroalkanes is also an extremely useful reaction for organic
synthesis.11 In these reactions, a phosphine-free and nonionic
organic superbase such as proton sponge has attracted interest
as catalyst because of its low toxicity. A proton sponge organic
super base is a promising candidate for the catalyst because the
proton sponge is designed to hold a proton selectively.
However, because the proton sponge organic superbases
generally possess too strong a hold on the proton to serve as
a catalyst,12 most studies involving these compounds are
focused on stoichiometric reactions.1,13 Therefore, both high
basicity and weak holding force are required for a catalyst based
on the proton sponge structure. Alternatively, azacalix[3](2,6)-
pyridine derivatives have a much weaker hold on the proton,
despite being classed as a proton sponge type of organic
superbase. The moderate holding force of the proton is caused
by the high proton affinity and the macrocyclic frameworks of
the azacalix[3](2,6)pyridines. This high basicity and moderate
proton holding force are the reason why azacalix[3](2,6)-
pyridine derivatives 2 and 3 served as effective organic
superbase catalysts for the reported 1,4-additions of nitro-
methane to mesityl oxide and 2-cyclohexenone.7 Thus, it is
expected that the azacalix[3](2,6)pyridine derivatives 2−4 will
be more powerful and more versatile as organic catalysts than
the more commonly used proton sponge organic superbases for
various addition reactions.
INTRODUCTION
■
Organic superbases have received much attention as, owing to
their low environmental burden and the relative ease with
which they can be handled, they are used in many
organocatalytic reactions. One of the major subjects of organic
superbases is enhancement of the basicity.1 For example, the
organic superbase 1,8-bis(hexamethyltriaminophosphazenyl)-
naphthalene (HMPN, MeCNpKBH = 28.35)2 was designed by
+
combining the 1,8-bis(dimethylamino)naphthalene (proton
sponge, MeCNpKBH = 18.2)3 framework with the highly basic
+
hexamethylphosphoramide unit.4 However, in general, enhanc-
ing the basicity of an organic superbase requires organo-
phosphorus moieties that are known to be toxic and have
limited resources.5
We previously reported that the macrotricyclic amino-
pyridine compound azacalix[3](2,6)pyridine derivative 1
(Figure 1) exhibits the synergistic hydrogen bonding ability
of three pyridine nitrogen atoms in a cavity that is appropriate
for capturing a single proton.6 Furthermore, we have also
clarified that the basicities of azacalix[3](2,6)pyridine deriva-
tives 2 and 3 were enhanced by introducing electron-donating
groups on the pyridine units.7 Since 4-methoxyl substituted
aniline (p-anisidine) has a basicity (MeCNpKBH = 11.86)8,9
+
9
higher than that of aniline (MeCNpKBH = 10.62), we can expect
+
that the introduction of an electron-donating group on the
bridging amino phenyl group would enhance the basicity of
azacalix[3](2,6)pyridine. The insight from the investigation
would provide novel and valuable information for the rational
molecular design.
From the viewpoint of atom economy, an addition reaction is
one of the most effective routes for the formation of C−C
bonds. The products of the 1,4-addition reaction of nitro-
alkanes with α,β-unsaturated ketones have been used as raw
materials to prepare azole antifungals,10 and the 1,2-addition of
This study had two aims, the first of which was to achieve
expansion of the molecular design of proton sponge organic
superbases with enhanced basicity. To achieve this, we
investigated newly designed and synthesized the azacalix[3]-
(2,6)pyridine derivative 4 bearing electron-donating groups on
the bridging amino phenyl group. Following this, we assessed
Received: August 30, 2012
Published: November 14, 2012
© 2012 American Chemical Society
10631
dx.doi.org/10.1021/jo3017428 | J. Org. Chem. 2012, 77, 10631−10637

The Journal of Organic Chemistry
Article
Figure 1. Azacalix[3](2,6)pyridine derivatives.
Scheme 1. Synthesis of Azacalix[3](2,6)pyridine Derivative (4)
the catalytic activity of 2−4 in 1,4- and 1,2-addition reactions in
order to demonstrate their superiority in comparison to other
compounds.
naphthalene (TMGN)15 = 2.717 Å, HMPN2 = 2.823 Å).
Interestingly, the structure of the azacalix[3](3,6)pyridine
derivatives showed that the steric hindrance of the center of
the base is significantly reduced in comparison with other
proton sponge superbases.1 It is therefore likely that the
azacalix[3](2,6)pyridine derivatives will have an enhanced
basicity in addition to a large open space within the molecules.
Since azacalix[3](2,6)pyridine possesses a coplanarity of the
macrocyclic framework with a slight deviation of the three
pyridine rings, the cavity of the compounds should be large
enough to enable access to substrates, such as simple
nitroalkanes. Thus, the azacalix[3](2,6)pyridine derivatives
were expected to be more effective catalysts for reactions
involving sterically hindered substrates than the common
proton sponge organic superbases.
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Azacalix[3](2,6)-
pyridine Derivative 4. The methoxy-substituted azacalix[3]-
(2,6)pyridine derivative 4 was synthesized using a previously
reported method (Scheme 1).7 It was subsequently analyzed
using a variety of techniques including NMR, X-ray diffraction,
mass spectroscopy, and elemental analysis. The 1H NMR
spectrum of 4H·Br exhibited a singlet signal at 21.1 ppm in
CDCl3 (see Supporting Information). This largely downfield-
shifted proton signal reflects the synergistic hydrogen bonding
ability of the Npy atoms in the cavity, which is the same as the
previously mentioned monoprotonated azacalix[3](2,6)-
pyridine derivatives 1−3H·Br.
Basicity MeCNpKBH measurements of 4. To estimate the
+
basicity of 4, transprotonation experiments on 4H·Br with a
1
known organic superbase were carried out using H NMR
Single crystals of 4H·Br suitable for X-ray diffraction study
were obtained by recrystallization from CHCl3 and hexane. The
crystal structure of 4H·Br is shown in Figure 2. There are no
significant interactions between the Br anion and the 4H+
cation. The dihedral angles between the two N acceptor
pyridine rings of 4H·Br, PyN(1)···PyN(5) and PyN(5)···PyN(3), is
twisted by 5.72°. Compared to other previously reported
azacalix[3](2,6)pyridine derivatives (1, 1H·PF6, and 3H·Br), 4
exhibited a nonbonding distance of 2.510−2.566 Å between the
N acceptor atoms N(1)···N(5), N(5)···N(3), and N(1)···N(3),
which is appropriate for capturing a single proton. These
distances are also close to those of other proton sponge
superbases (1,8-bis(dimethylamino)naphthalene (proton
sponge)13,14 = 2.588 Å, 1,8-bis(tetramethylguanidino)-
spectroscopy at room temperature (eq 1). Among the tested
organic bases, tert-butylimino-tri(pyrrolidino)phosphorane
(BTPP, MeCNpKBH = 28.4)16 was found to be the most
+
appropriate compound.
10632
dx.doi.org/10.1021/jo3017428 | J. Org. Chem. 2012, 77, 10631−10637

The Journal of Organic Chemistry
Article
also consistent with a DFT calculation carried out by Maksic
and co-workers.18
́
1,4-Addition of Nitroalkanes to Various α,β-Unsatu-
rated Carbonyl Compounds. Prior to comparing the
catalytic activity of the azacalix[3](2,6)pyridine derivatives,
the appropriate reaction conditions were determined. The 1,4-
addition of nitromethane to mesityl oxide was carried out using
3 as a catalyst in various solvents under a nitrogen atmosphere.
The reaction did not proceed at room temperature (Table 1,
Table 1. 1,4-Addition of Nitromethane to Mesityl Oxide
a
Using 3 as a Catalyst
b
entry
solvent
temp
yield [%]
1
2
3
4
5
6
1,4-dioxane
1,4-dioxane
isobutyronitrile
THF
rt
no reaction
reflux
reflux
reflux
reflux
reflux
74
97
72
CH2Cl2
trace
69
DMSO
a
Reaction conditions: 0.20 mmol of mesityl oxide, 0.21 mmol of
b
nitromethane, 1 mL of solvent, 0.01 mmol of 3, under N2. Isolated
yield.
entry 1); however, it was found to be successful at reflux
temperature in each of the solvents tested (Table 1, entries 2−
6). The desired product of the 1,4-addition, 4,4-dimethyl-5-
nitro-2-pentanone, was obtained in 97% yield when isobutyr-
onitrile was employed as the solvent (Table 1, entry 3).
Under these optimized conditions (Table 1, entry 3), the
catalytic activity of azacalix[3](2,6)pyridines 1−4 for the 1,4-
addition of nitromethane to mesityl oxide was examined (Table
2). The corresponding adducts were obtained in high yield in
Figure 2. ORTEP drawing of 4H·Br with thermal ellipsoids shown at
the 30% probability level. Hydrogen atoms, Br anion, and solvent
molecules are omitted for clarity. The position of the proton in the
cavity could not be determined by difference Fourier synthesis
probably due to the disorder or low quality of crystallographic data.
Table 2. Catalytic Performance of Azacalix[3](2,6)pyridine
Bases 1−4 for 1,4-Addition
The basicity of 4 was estimated to be MeCNpKBH = 29.5 from
+
a
1
the H NMR measurements of the mixtures of 4 and BTPP
with various molar ratios (see Supporting Information). As
expected, the MeCNpKBH of 4 was higher than that of 3 because
+
of the enhancement in basicity from the introduction of the
electron-donating methoxy groups into the bridging amino
phenyl groups in the macrocyclic framework. This value means
that the azacalix[3](2,6)pyridine derivative has an enhanced
basicity close to that the strongest known phosphine free
organic superbase, tricyclic 2,4-diaminovinamidine proton
catalyst
b
+
entry
base
MeCNpKBH
yield [%]
1
2
3
4
1
2
3
4
23.1
27.1
28.1
29.5
0
85
97
95
sponge (vinamidine), that has a value of MeCNpKBH = 31.9.17
+
Figure 3 reveals that the basicities of the azacalix[3](2,6)-
pyridine derivatives were systematically enhanced by the
introduction of the electron-donating substitutions, not only
into the pyridine units but also the bridging amino phenyl
groups in the macrocyclic framework. This synthetic strategy is
a
Reaction conditions: 0.20 mmol of mesityl oxide, 0.21 mmol of
nitromethane, 1 mL of isobutyronitrile, 0.01 mmol of base, reflux,
b
under N2. Isolated yield.
Figure 3. Chart of the basicity of organic superbases in acetonitrile. Red values show the basicity level of the azacalix[3](2,6)pyridine derivatives (1−
4). Black values show the previously reported phosphine-free organic superbases proton sponge, TMGN,15 1,5-diazabicyclo[5.4.0]undec-5-ene
(DBU),19 and vinamidine.17 Blue values show the phosphine-containing organic superbases BTPP and Verkade’s base, which are the most basic
structures, P(HNCH2CH2)2NCH2CH2N-i-Pr.1
10633
dx.doi.org/10.1021/jo3017428 | J. Org. Chem. 2012, 77, 10631−10637

The Journal of Organic Chemistry
Article
every case except for compound 1, and the catalytic activity was
found to increase with increasing basicity of the azacalix[3]-
(2,6)pyridine derivatives. Since catalysts 3 and 4 gave
comparable results, it was deduced that the catalytic activity
was saturated at the level of basicity of 3 under these
conditions. This result is supported by previous findings for
other general organic superbases, such as the proazaphospha-
trane base and the phosphazene base.20
were deprotonated by 2.5 wt % aqueous solutions of KOH with
a pH of 13.8 or higher.8 The basicities of such inorganic bases
are satisfactory for deprotonating primary alcohols such as
methanol and allylalcohol.2 4-DMAP, DBU, morpholine (with
basicities lower than those of 2−4), and proazaphosphatrane
have been reported as useful organic base catalysts for the 1,4-
addition of various alcohols to α,β-unsaturated carbonyl
compounds.26,22 However, there are no reports on 1,4-addition
of alcohols using proton sponge base catalysts. Thus, as 2−4
are a versatile model for base catalysts for the 1,4-addition of
primary alcohols, it would be advantageous for the field of
synthetic organic chemistry to optimize them. The 1,4-addition
reactions of alcohols to α,β-unsaturated carbonyl compounds
were carried out using 3 as a catalyst under the same conditions
The 1,4-additions of various nitroalkanes to mesityl oxide
were carried out using 3 as a catalyst under the standard
conditions (Table 3).21 The catalyst 3 promoted each reaction
Table 3. 1,4-Addition of Nitroalkane to Mesityl Oxide Using
a
3 as a Catalyst
that have been reported for utilizing proazaphosphatrane bases
+
(
MeCNpKBH = 32.8−33.63).21 When methanol was used as the
donor, 3 showed high catalytic activity in the reactions of each
of the α,β-unsaturated carbonyl compounds (Table 4, entries 1
and 2). When allyl alcohol was used as the donor, the
corresponding adducts were also obtained in good yields, with
the reaction using 3 being clearly superior to that with the
reference catalyst. Compound 3 satisfies the basicity require-
ment for deprotonation of the proton(s) of the hydroxy groups.
Moreover, given the difference in amounts of catalyst between
3 and the reference, these results indicate that catalyst 3 has
higher catalytic activity.
1,2-Addition of Nitroalkanes to Various Aldehyde
Compounds. The activities of the azacalix[3](2,6)pyridine
derivatives in the catalysis of the 1,2-addition reaction of
nitroalkanes with aromatic aldehydes was also investigated. The
1,2-addition of nitromethane to benzaldehyde was carried out
using 3 as a catalyst, in various solvents, at room temperature,
under a nitrogen atmosphere (Table 5). The desired product,
α-(nitromehyl)benzyl alcohol, was obtained in 97% yield when
a neat condition was employed (Table 5, entry 4). Under the
optimized conditions, the 1,2-addition reaction of nitromethane
with benzaldehyde was carried out using each azacalix[3](2,6)-
pyridine catalyst (Table 5, entries 4−7). Compounds 2, 3, and
4 all successfully gave the corresponding adducts, with the
derivatives with the higher basicities (3 and 4) providing the
best yields. These results are consistent with those obtained for
the 1,4-additions (Table 2).
The 1,2-addition reactions of nitromethane with various
aromatic and heterocyclic aldehydes were carried out using 3 as
a catalyst (Table 6). Even when aldehydes with electron-
donating groups were used as the substrates (p-anisaldehyde
and o,m,p-tolualdehyde), the corresponding adducts were
obtained in good yields (Table 6, entries 1−4). Since the
yields of the reactions with the o,m,p-tolualdehydes were
comparable, it was clear that the catalytic activity was not
affected by steric hindrance of the methyl group. When an
aldehyde with electron-withdrawing groups was used as the
substrate (p-trifluoromethylbenzaldehyde), 3 showed good
catalytic activity. Specifically, the reactions of nitromethane
with heterocyclic aldehydes show significant advantages over
the results of the reference base (Table 6, entries 6 and 7).27,28
These results suggest that 3 allows approach of heterocyclic
aldehydes to the catalytic site because of the high basicity.
a
Reaction conditions: 0.20 mmol of mesityl oxide, 0.21 mmol of
nitroalkane, 1 mL of isobutyronitrile, 0.01 mmol of 3, 12 h, reflux,
under N2. Isolated yield.
b
with nitroalkanes to give the corresponding 1,4-addition
adducts. The reaction of 2-nitropropane was slower than that
of nitromethane (Table 3, entries 2 and 4). The yield of the
reaction with nitromethane was higher than that with
nitroethane (entries 1 and 4). From the viewpoint of acidity
of the substrates, nitroethane (DMSOpKa = 16.7) has an
advantage in the reaction in comparison with nitromethane
(
DMSOpKa = 17.2). Therefore, steric hindrance of the substrates
is likely to determine the reaction efficiency; the reaction with
the nitroalkane with a bulky substituent, nitrocyclohexane,
provided a moderate yield (entry 5). When 4 was used as a
catalyst for the 1,4-addition of nitrocyclohexane, a better yield
was obtained compared to that of 3 (Table 3, entry 6). These
results indicate that higher basicity of the catalyst 4 promotes
the 1,4-addition of nitrocyclohexane smoothly. Therefore, the
molecular design of azacalix[3](2,6)pyridine in the present
work is effective for the 1,4-addition of nitromethane.
1,4-Addition of Primary Alcohols to Various α,β-
Unsaturated Carbonyl Compounds. The alcohol is
arguably the most versatile compound in the field of organic
synthesis and is used in the Williamson ether synthesis with
inorganic bases used for its deprotonation.25 The proton
adducts of the azacalix[3](2,6)pyridine derivatives (2−4H·Br)
CONCLUSION
■
In conclusion, we designed and synthesized a new organic
superbase, 4, that has the highest basicity out of the
azacalix[3](2,6)pyridine derivatives described. The introduc-
10634
dx.doi.org/10.1021/jo3017428 | J. Org. Chem. 2012, 77, 10631−10637

The Journal of Organic Chemistry
Article
a
Table 4. 1,4-Addition of Alcohols to α,β-Unsaturated Carbonyl Compounds Using 3 as a Catalyst
a
b
Reaction conditions:; 2.0 mmol of α,β-unsaturated carbonyl compounds, 1 mL of alcohol, 0.2 mmol of 3, neat, under N2. Isolated yield.
c
d
e
Reference 21; cat. 10 mol % of P(i-PrNCH2CH2)3N, 0.5 h, 50 °C. Reference 21; cat. 10 mol % of P(i-BuNCH2CH2)3N, 3 h, 50 °C. Reference 21;
f
cat. 20 mol % of P(i-PrNCH2CH2)3N, 3 h, 70 °C. Reference 21; cat. 20 mol % of P(i-BuNCH2CH2)3N, 3 h, 70 °C.
tion of an electron-donating group on the bridging amino
Table 5. Optimization of Reaction Conditions for the 1,2-
Addition of Nitromethane to Benzaldehyde Using
Azacalix[3](2,6)pyridine Catalysts
phenyl group enhanced the basicity of azacalix[3](2,6)pyridine.
This novel strategy is a promising tool in the development of
efficient organic superbase catalysts. Owing to the high basicity,
2−4 showed catalytic activities comparable to those of the
reported high-performance organic superbases in various 1,4-
and 1,2-additions, and 4 exhibited the highest catalytic activity.
The experimental results were in accordance with our
hypothesis that the level of catalytic activity for these addition
reactions is associated with the basicity of the azacalix[3](2,6)-
pyridine catalyst used. The major factors involved in achieving
high catalytic activity are the high basicities and the moderate
holding forces of protons by the macrocyclic framework of the
azacalix[3](2,6)pyridine. Thus, catalysts 3 and 4 appear to be
well suited to 1,4- and 1,2-addition reactions of various
substrates. These results have significant implications concern-
ing novel possibilities for proton sponge organic superbases.
a
catalyst
b
entry
base
MeCNpKBH
solvent
THF
yield [%]
+
1
2
3
4
5
6
7
3
3
3
3
1
2
4
28.1
28.1
28.1
28.1
23.1
27.1
29.5
56
trace
62
97
0
1,4-dioxane
DMSO
neat
neat
neat
75
92
neat
a
Reaction conditions: 1 mmol of benzaldehyde, nitromethane 1 mL,
b
rt, 8 h, under N2. Isolated yield.
EXPERIMENTAL SECTION
General Information. 2,6-Dibromo-4-pyrrolidinopyridine and 1−
3 were prepared according to previous methods.7,8 The reagents and
solvents were used after distillation.
■
Table 6. 1,2-Addition of Nitroalkane with Aldehyde Using 3
as a Catalyst
Synthesis. Synthesis of N,N-Bis[2-(6-bromo-4-pyrrolidinopyrid-
yl)]-p-anisidine (Dibromide). A mixture of 2,6-dibromo-4-pyrrolidi-
nopyridine (1.20 g, 4.0 mmol), p-anisidine (123 mg, 1.0 mmol),
sodium-tert-butoxide (480.5 mg, 5.00 mmol), tris(dibenzylidene-
acetone)dipalladium(0) [Pd2(dba)3] (45.7 mg, 0.050 mmol), and
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS)
(86.8 mg, 0.15 mmol) was dissolved in toluene (40 mL). The
reaction mixture was stirred for 18 h at 100 °C under a nitrogen
atmosphere. After cooling to rt, the mixture was filtered through Celite
and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (ethyl acetate/hexane, 1:5) to afford
a
b
entry
R =
yield [%]
yield [%]
c
1
2
3
4
5
6
7
p-MeO-Ph-
p-CH3-Ph-
o-CH3-Ph-
m-CH3-Ph-
p-CF3-Ph-
2-pyridinyl-
2-furanyl-
93
82
91
88
87
91
86
99
98
62
55
1
dibromide (298.1 mg, 52%) as a white solid. H NMR (400 MHz,
CDCl3): δ 1.93−1.96 (m, 8H), 3.18 (t, J = 6.4 Hz, 8H), 3.81 (s, 3H),
5.99 (d, J = 2.0 Hz, 2H), 6.25 (d, J = 1.6 Hz, 2H), 6.85−6.87 (m, 2H),
7.04−7.12 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 25.2, 47.3,
55.4, 97.9, 105.2, 114.5, 128.9, 137.6, 140.3, 154.3, 157.2, 157.8. Anal.
Calcd for C25H27Br2N5O: C, 52.37; H, 4.75; N, 12.22. Found: C,
a
b
Isolated yield. Reference 27; cat. 5 mol % of Cyclen, in THF, 24 h,
rt. Reference 28; cat. 10 mol % of P(i-PrNCH2CH2)3N,29 MeCNpKBH
c
+
= 33.63, 40 min, rt.
10635
dx.doi.org/10.1021/jo3017428 | J. Org. Chem. 2012, 77, 10631−10637

The Journal of Organic Chemistry
Article
52.40; H, 4.92; N, 12.16. ESI-MS positive: 574.12 (m/z). Melting
point: 212 °C.
1,4-adduct (239.5 mg, 92%). The spectral data of the obtained 1,4-
adducts were identical to those in previous references.22,26
General Method of 1,2-Addition of Nitromethane to
Aromatic Aldehydes. A mixture of 3 (37.7 mg, 0.050 mmol),
nitromethane (1.0 mL, 18.7 mmol), and benzaldehyde (101.9 μL, 1.0
mmol) was stirred under a nitrogen atmosphere. After being stirred
under room temperature for 8 h, the solvent was removed. The crude
product was purified by column chromatography on silica gel
(chloroform) to afford the corresponding 1,2-adduct (162.2 mg,
97%). The spectral data of the obtained 1,2-adducts were identical to
Synthesis of 2,6-Bis(p-anisylamino)-4-pyrrolidinopyridine (Dia-
mine). A mixture of 2,6-dibromo-4-pyrrolidinopyridine (198 mg, 0.65
mmol), p-anisidine (398 mg, 3.2 mmol), sodium-tert-butoxide (311
mg, 3.2 mmol), [Pd2(dba)3] (29.6 mg, 0.030 mmol), and
XANTPHOS (56.2 mg, 0.090 mmol) was dissolved in toluene (15
mL). The reaction mixture was stirred for 18 h at 100 °C under a
nitrogen atmosphere. After cooling to rt, the mixture was filtered
through Celite. The crude product was purified by column
chromatography on aminopropylated silica gel (gradient, ethyl
acetate/hexane, 5:1 → 2:1) to afford diamine (233.5 mg, 92%) as a
purple solid. 1H NMR (400 MHz, CDCl3): δ 1.89−1.92 (m, 4H), 3.17
(t, J = 6.6 Hz, 4H), 3.79 (s, 6H), 5.38 (s, 2H), 5.98 (s, 2H), 6.85 (dd, J
= 6.4 Hz, 2 Hz, 4H), 7.22 (dd, J = 6.4 Hz, 2 Hz, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ 25.3, 47.2, 55.5, 81.3, 114.4, 121.9, 123.9, 134.1,
155.6, 156.6. Anal. Calcd for C23H26N4O2: C, 70.75; H, 6.71; N, 14.35.
Found: C, 70.35; H, 6.70; N, 14.14. ESI-MS positive: 391.78 (m/z).
Melting point: 181 °C.
previous results.31
1
Estimation of MeCNpKBH of 4 by H NMR Transprotonation
+
Studies. The basicity of MeCNpKBH of 4 was estimated by H NMR
1
+
transprotonation measurements at 20 °C with BTPP (MeCNpKBH
=
+
28.4) and 4H·Br. The thermodynamic equilibrium constant (K) was
determined from integration of the signals of 4 and monoprotonated 4
with several amounts of the organic bases in the spectra. For example,
1
from the H NMR experimental data of a 1.61:3.14 mixture of 4H·Br
and BTPP, a 0.38:0.62 mixture of 4 and 4H+, K for the equilibrium is
calculated as
Synthesis of N,N′,N″-Tris(p-anisyl)azacalix[3](2,6)(4-pyrrolidino-
pyridine) Hydrogen Bromide (4H·Br). A mixture of dibromide (24.2
mg, 0.042 mmol) and diamine (16.5 mg, 0.042 mmol), CuBr (7.90
mg, 0.055 mmol), and K2CO3 (70.6 mg, 0.51 mmol) was dissolved in
nitrobenzene (5 mL). The reaction mixture was stirred for 3 h at 190
°C (oil bath temp; 240 °C) under a nitrogen atmosphere. The solvent
was removed under reduced pressure. The crude product was purified
by column chromatography on aminopropylated silica gel (gradient,
ethyl acetate/hexane 3:7 → chloroform → acetonitrile) to afford
4H·Br as a brown solid. 4H·Br was purified by recrystallization from a
chloroform/hexane to give white solid (31.9 mg, 86%). 1H NMR (400
MHz, CDCl3): δ 1.84−1.87 (m, 12H), 2.90−2.93(m, 12H), 3.94 (s,
9H), 4.92 (s, 6H), 7.13−7.15 (m, 6H), 7.29−7.31 (m, 6H), 21.1 (s,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 24.9, 47.2, 55.8, 88.5,
116.1, 131.1, 132.1, 152.4, 154.4, 199.9. Anal. Calcd for
C48H52BrN9O3: C, 65.30; H, 5.94; N, 14.28. Found: C, 65.01; H,
5.81; N, 14.25. ESI-MS positive: 883.65 (m/z). The melting point of
4H·Br was not observed by melting point apparatus from room
temperature to 300 °C.
K = [4][BTPP·H+]/[4·H+][BTPP] = 0.0839
The basicity of 4 is estimated as
MeCNpKBH (4) = MeCNpKBH (BTPP) − log K
= 28.4 − log(0.0839) = 29.475 ≅ 29.5
+
+
These data reveal that 4 has a basicity stronger than that of BTPP.
The average value of MeCNpKBH was defined by several attempts.
+
X-ray Crystal Structure Determinations, Crystal Data. The
crystal structure of 4H·Br was determined by an X-ray diffractional
study. Transparent single crystals of 4H·Br were obtained by the slow
diffusion of hexane into a solution in chloroform. Intensity data was
collected on a Bruker-APEX-II CCD diffractometer with Mo Kα
radiation (λ = 0.71069 Å). A crystal was mounted on MicroMounts.
Crystallographic data and details of refinement of the complex are
summarized in the CIF data (see Supporting Information). A full
matrix least-squares refinement was used for non-hydrogen atoms with
anisotropic thermal parameters method by a Direct Methods
(SHELXD) program. Hydrogen atoms were placed at the calculated
positions and were included in the structure calculation without
further refinement of parameters. Crystallographic data (excluding
structure factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-887269.
Synthesis of N,N′,N″-Tris(p-anisyl)azacalix[3](2,6)(4-pyrrolidino-
pyridine) (4). 4H·Br (5.0 mg, 0.0060 mmol) was dissolved in
chloroform (1 mL) under a nitrogen atmosphere. The solution was
washed with 5.0 wt % NaOH aq (1 mL × 2). After the organic layer
was separated, the solvent was removed under reduced pressure. The
1H NMR spectrum of the residual red solid indicates a quantitative
1
formation of 4. H NMR (600 MHz, CD3CN): δ 1.76 (t, J = 6.6 Hz,
Selected data for 4H·Br·3CHCl3: C57H69BrCl9N9O3, M = 1327.21,
monoclinic, P21/c, a = 10.364(3) Å, b = 30.543(9) Å, c = 19.545(6) Å,
β = 101.745(4)°, V = 6057(3) Å3, Z = 4, Dcalcd = 1.455 g/cm3, μ =
1.129 mm−1, T = 120 K, F(000) = 2744.00, observed reflections 31777
(all data), variables 573, R1 = 0.1979 (I > 2.00σ(I)), R = 0.3537, Rw =
0.5033, GOF = 1.277.
12H), 2.77−2.79 (m, 12H), 3.83 (s, 9H), 4.87 (d, J = 2.4 Hz, 6H),
7.08 (d, J = 9.0 Hz, 6H), 7.32−7.33 (m, 6H). 13C{1H} NMR (100
MHz, CDCl3): δ 14.1, 22.6, 24.9, 31.6, 47.2, 55.7, 88.6, 116.1, 131.1,
132.1, 152.4, 154.5, 199.9.
Because this compound was protonated in air moisture immediately
due to its high basicity, we could not complete other analyses.
General Method of 1,4-Addition of Nitromethane to α,β-
Unsaturated Carbonyl Compounds. A mixture of 3 (75.4 mg, 0.10
mmol), nitromethane (112.7 μL, 2.1 mmol), and mesityl oxide (228.8
μL, 2.0 mmol) in dehydrated isobutyronitrile (1 mL) was stirred under
a nitrogen atmosphere. After stirring under reflux for 12 h, the mixture
poured into water and extracted with ethyl acetate. The crude product
was purified by column chromatography on silica gel (gradient, ethyl
acetate/hexane = 1:10 to 1:4) to afford corresponding 1,4-adduct
(308.8 mg, 97%). The spectral data of the obtained 1,4-adducts were
identical to the previous references.30
General Method of 1,4-Addition of Primary Alcohol to α,β-
Unsaturated Carbonyl Compounds. A mixture of 3 (150.8 mg,
0.20 mmol) and mesityl oxide (228.8 μL, 2.0 mmol) in dehydrated
methanol (1 mL) was stirred under a nitrogen atmosphere. After being
stirred for the time and temperature indicated in Table 4, the mixture
was poured into brine and extracted with diethylether. The crude
product was purified by column chromatography on silica gel
(gradient, ethyl acetate/hexane = 1:10 to 1:5) to afford corresponding
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of X-ray crystalographic data, NMR spectra, Trans-
porotonations data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kanbara@ims.tsukuba.ac.jp.
■
Present Address
†Department of Applied Chemistry, Graduate School of Urban
Environmental Sciences, Tokyo Metropolitan University, 1−1
minami-osawa, Hachioji, Tokyo 192-0397, Japan.
Notes
The authors declare no competing financial interest.
10636
dx.doi.org/10.1021/jo3017428 | J. Org. Chem. 2012, 77, 10631−10637

The Journal of Organic Chemistry
Article
Schlemper, H.; Walz, L..; Peters, E.-M.; Peters, K.; von Schnering, H.
G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1361.
(17) Schwesinger, R.; Miβfeldt, M.; Peters, K.; von Schnering, H. G.
ACKNOWLEDGMENTS
■
This study was supported in part by University of Tsukuba
Research Infrastructure Support Program. Additional support
was provided by grant from the Sasakawa Scientific Research
Grant from The Japan Science Society. The authors are grateful
to the Chemical Analysis Center of University of Tsukuba for
X-ray diffraction study, elemental analyses, and NMR spectros-
copy.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1165.
(18) (a) Despotovic,
9, 1101. (b) Despotovic,
2007, 9, 4709. (c) Despotovic,
52, 6263.
́
I.; Kovace
I.; Kovace
I.; Maksic,
̌
vic,
́
B.; Maksic,
vic, B.; Maksic,
Z. B. Tetrahedron Lett. 2011,
́
Z. B. Org. Lett. 2007,
́
̌
́
́
Z. B. Org. Lett.
́
́
(19) Hermann, O.; Moeller; Friedrich, M. Angew. Chem., Int. Ed. Engl.
1967, 6, 76.
(20) (a) Ye, W.; Xu, J.; Tan, C.-T.; Tan, C.-H. Tetrahedron Lett.
2005, 46, 6875. (b) Pahadi, N. K.; Ube, H.; Terada, M. Tetrahedron
Lett. 2007, 48, 8700.
(21) Kisanga, P. B.; Ilankumaran, P.; Fetterly, B. M.; Verkade, J. G. J.
Org. Chem. 2002, 67, 3555.
REFERENCES
■
(1) (a) Superbases for Organic Synthesis: Guanidines, Amidines and
Phosphazenes and Related Organocatalysts; Ishikawa, T., Ed.; Wiley:
New York, 2009. (b) Chambron, J.-C.; Meyer, M. Chem. Soc. Rev.
2009, 38, 1663. (c) Verkade, J. G.; Kisanga, P. B. Tetrahedron 2003,
59, 7819. (d) Verkade, J. G.; Kisanga, P. B. Aldrichimica Acta 2004, 37,
1. (e) Pozharskii, A. F.; Ozeryaskii, V. A.; Filatova, E. A. Chem.
(22) Bordwell, F. G.; Vanier, N. R.; Matthews, W. S.; Hendrickson, J.
B.; Skipper, P. L. J. Am. Chem. Soc. 1975, 97, 7160.
(23) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006.
(24) Bordwell, F. G.; Bartmess, J. E.; Hautala, J. A. J. Org. Chem.
1978, 43, 3113.
(25) (a) Williamson, W. Liebigs Ann. Chem. 1851, 77, 37.
(b) Williamson, W. J. Chem. Soc. 1852, 106, 229. (c) Dermer, O. C.
Chem. Rev. 1934, 14, 385.
(26) References for 1,4-addition of alcohols: (a) Rulev, A. Y.; Azad,
S.; Kotsuki, H.; Maddaluno, J. Eur. J. Org. Chem. 2010, 33, 6423.
(b) Murtagh, J. E.; McCooey, S. H.; Connon, S. J. Chem. Commun.
2005, 2, 227. (c) Hauser, M. Chem. Rev. 1963, 63, 311. (d) Ramachary,
D. B.; Mondal, R. Tetrahedron Lett. 2006, 47, 7689. (e) Hayashi, Y.;
Nishimura, K. Chem. Lett. 2002, 3, 296.
(27) Bray, C. V.-L.; Jiang, F.; Wu, X.-F.; Sortais, J.-B.; Darcel, C.
Tetrahedron Lett. 2010, 51, 4555.
(28) Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 2002, 67, 426.
(29) (a) Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 2000, 65, 5431.
(b) Tang, J.; Dopke, J.; Verkade, J. G. J. Am. Chem. Soc. 1993, 115,
5015.
(30) References for 1,4-addition of nitroalkanes: (a) Kisanga, P. B.;
Verkade, J. G. Tetrahedron 2001, 57, 467. (b) Ramachary, D. B.;
Mondal, R. Tetrahedron Lett. 2006, 47, 7689.
(31) References for 1,2-addition of nitroalkanes: (a) Kisanga, P. B.;
Verkade, J. G. J. Org. Chem. 1999, 64, 4298. (b) Han, J.; Xu, Y.; Su, Y.;
She, X.; Pan, X. Catal. Commun. 2008, 9, 2077. (c) Jin, W.; Li, X.;
Wan, B. J. Org. Chem. 2011, 76, 484.
Heterocycl. Compd. 2012, 48, 200. (f) Galeta, J.; Potac
Chem. 2012, 77, 1010. (g) Kunetskiy, R. A.; Polyakova, S. M.; Vavrí
J.; Císarova, I.; Saame, J.; Nerut, E. R.; Koppel, I.; Koppel, I. A.; Kutt,
A.; Leito, I.; Lyapkalo, I. M. Chem.Eur. J. 2012, 18, 3621.
(h) Zachova, H.; Man, S.; Taraba, J.; Potac k, M. Tetrahedron 2009,
65, 792.
(2) Raab, V.; Gauchenova, E.; Merkoulov, A.; Harms, K.;
Sundermeyer, J.; Kovacevic, B.; Maksic, Z. B. J. Am. Chem. Soc.
2005, 127, 15738.
̀
e
̌
k, M. J. Org.
̌
k,
̌
́
̈
̀
̀ ̌
e
̌
́
́
(3) (a) Alder, R. W.; Bowman, P. S.; Steele, W. R. S.; Winterman, D.
R. J. Chem. Soc., Chem. Commun. 1968, 723. (b) Alder, R. W. Chem.
Rev. 1989, 89, 1215. (c) Staab, H. A.; Saupe, T. Angew. Chem., Int. Ed.
Engl. 1988, 27, 865. (d) Llamas-Saiz, A. L.; Foces- Foces, C.; Elguero,
J. J. Mol. Struct. 1994, 328, 297. (e) Howard, S. T. J. Am. Chem. Soc.
2000, 122, 8238.
̌ ́ ́
(4) Kovacevic, B.; Maksic, Z. B. Tetrahedron Lett. 2006, 47, 2553.
(5) (a) Phosphorus. The Carbon Copy; Dillon, K. B., Mathey, F.,
Nixon, J. F., Eds.; John Wiley & Sons: New York, 1997. (b) A Guide to
Organophosphorus Chemistry; Quin, L. D., Ed.; John Wiley & Sons:
New York, 2000. (c) Kuroda, A.; Takiguchi, N.; Kato, J.; Ohtake, H. J.
Environ. Biotechnol. 2005, 4, 87.
(6) (a) Suzuki, Y.; Yanagi, T.; Kanbara, T.; Yamamoto, T. Synlett
2005, 263. (b) Kanbara, T.; Suzuki, Y.; Yamamoto, T. Eur. J. Org.
Chem. 2006, 3314. (c) Miyazaki, Y.; Kanbara, T.; Yamamoto, T.
Tetrahedron Lett. 2002, 43, 7945.
(7) Uchida, N.; Taketoshi, A.; Kuwabara, J.; Yamamoto, T.; Inoue, Y.;
Watanabe, Y.; Kanbara, T. Org. Lett. 2010, 12, 5242.
(8) Bordwell, F. G.; Vanier, N. R.; Matthews, W. S.; Hendrickson, J.
B.; Skipper, P. L. J. Am. Chem. Soc. 1975, 97, 7160.
(9) Kaljurand, I.; Kutt, A.; Soovali, L.; Rodima, T.; Maemets, V.;
̈
̈
̈
Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
(10) Lui, K.-H.; Sammes, M. P. J. Chem. Soc., Perkin Trans. 1990, 457.
(11) (a) Henry, L. Compt. Rend. 1895, 120, 1265. (b) Palomo, C.;
Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561.
(12) (a) Chan, J. W.; Hoyle, C. E.; Lowe, A. B.; Bowman, M.
Macromolecules 2010, 43, 6381. (b) Hibbert, F.; Phillips, S. J. Chem.
Res., Synop. 1990, 90.
(13) (a) Pozharskii, A. F. Russ. Chem. Rev. 1998, 67, 1. (b) Truter,
M. R.; Vickery, B. L. J. Chem. Soc., Dalton Trans. 1972, 395.
(c) Wozniak, K.; Krygowski, T. M.; Kariuki, B.; Jones, W.; Grech, E. J.
Mol. Struct. 1990, 240, 111. (d) Kanters, J. A.; Schouten, A.; Kroon, E.;
Grech, E. Acta Crystallogr., Sect. C 1991, 47, 807.
(14) Einspahr, H.; Robert, J. B.; Marsh, R. E.; Roberts, J. D. Acta
Crystallogr. 1973, B29, 1611.
(15) Raab, V.; Kipke, J.; Gschwind, R. M.; Sundermeyer, J. Chem.
Eur. J. 2002, 8, 1682.
(16) (a) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl.
1987, 26, 1167. (b) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.;
Willaredt, J.; Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger.,
M.; Boele, J.; Fritz, H.; Putzas, D.; Rotter., H. W.; Bordwell, F. G.;
Satish, A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; von Schnering, H. G.;
Walz, L. Liebigs Ann. 1996, 1055. (c) Schwesinger, R.; Hasenfratz, C.;
10637
dx.doi.org/10.1021/jo3017428 | J. Org. Chem. 2012, 77, 10631−10637