Synthesis, characterization, and catalytic reactivity of a highly basic macrotricyclic aminopyridine

Article abstract of DOI:10.1021/ol102236f

The synthesis methods, physicochemical and structural characteristics, and catalytic reactivity of new macrocyclic proton chelators, N,N′,N″- tris(p-tolyl)azacalix[3](2,6)(4-pyrrolidinopyridine) and N,N′,N″- tris(p-tolyl)azacalix[3](2,6)(4-piperidinopyridine), are studied. The introduction of pyrrolidino and piperidino groups into the pyridine unit enables the enhancement of the synergistic proton affinity of the cavity of the macrotricycle giving a high basicity (pK_BH+ = 28.1 and 27.1 in CD₃CN), resulting in a catalytic activity for the Michael addition of nitromethane with α,β-unsaturated carbonyl compounds.

Full text of DOI:10.1021/ol102236f

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5242-5245
Synthesis, Characterization, and
Catalytic Reactivity of a Highly Basic
Macrotricyclic Aminopyridine
Natsuko Uchida,† Ayako Taketoshi,† Junpei Kuwabara,† Toshihide Yamamoto,‡
Yoshiaki Inoue,‡ Yu Watanabe,‡ 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, and Yokkaichi Research Laboratory, Tosoh Corporation,
1-8 Kasumi, Yokkaichi 510-8540 Japan
kanbara@ims.tsukuba.ac.jp
Received September 23, 2010
ABSTRACT
The synthesis methods, physicochemical and structural characteristics, and catalytic reactivity of new macrocyclic proton chelators, N,N′,N′′-
tris(p-tolyl)azacalix[3](2,6)(4-pyrrolidinopyridine) and N,N′,N′′-tris(p-tolyl)azacalix[3](2,6)(4-piperidinopyridine), are studied. The introduction of
pyrrolidino and piperidino groups into the pyridine unit enables the enhancement of the synergistic proton affinity of the cavity of the macrotricycle
giving a high basicity (pKBH+ ) 28.1 and 27.1 in CD3CN), resulting in a catalytic activity for the Michael addition of nitromethane with r,ꢀ-
unsaturated carbonyl compounds.
The design and synthesis of neutral organic bases and
superbases have recently attracted much attention in organic
chemistry.1,2 Strong nonionic bases such as proazaphospha-
tranes are useful in a number of important organic transfor-
mations such as dehydrohalogenation and nitroaldol reaction,
and the high pKBH+ of superbases enables them to effectively
facilitate reactions previously restricted to ionic inorganic
bases.2 We previously reported that the macrotricyclic
aminopyridine compound azacalix[3](2,6)pyridine, 1, in
Figure 1 exhibits the synergistic hydrogen bonding ability
Figure 1. Azacalix[3](2,6)pyridine derivatives.
† University of Tsukuba.
‡ Tosoh Corporation.
(1) Superbases for Organic Synthesis: guanidines, amidines and phos-
phazenes and related organocatalysts; Ishikawa, T., Eds.; Wiley: New York,
of three pyridine nitrogen atoms (Npy atoms) in a cavity,
which is appropriate for capturing a single proton.3 However,
the estimated pKBH+ of 1 (23.1 ( 0.1 in CD3CN) is still
2009
(2) (a) Verkade, J. G.; Kisanga, P. B. Tetrahedron 2003, 59, 7819. (b)
Verkade, J. G.; Kisanga, P. B. Aldrichimica Acta 2004, 37, 3
.
.
10.1021/ol102236f  2010 American Chemical Society
Published on Web 10/27/2010

lower than that of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,
pKBH+ ) 24.3 in CH3CN). Thus, to develop catalytically
active organic superbases, the enhancement of the basicity
of the macrocyclic compounds is desired.
Scheme 1. Synthesis of 2
Maksic´ and co-workers carried out a DFT calculation of
a number of azacalix[3](2,6)pyridine derivatives and pre-
dicted that the introduction of electron-donating substituents
such as a dimethyl amino group into the pyridine units will
enhance the basicity of these derivatives.4
In accordance with Maksic´ and co-workers’ prediction,
we here demonstrate the synthesis and characterization of
new azacalix[3](2,6)pyridine derivatives bearing pyrrolidino
(2a) and piperidino (2b) groups. Since 4-pyrrodinopyridine
(the scale of hydrogen-bond basicity, pKHB ) 2.93) and
4-piperidinopyridine (pKHB ) 2.68) show much higher
basicities than pyridine (pKHB ) 1.86),5 the introduction of
the pyridine unit into the macrocyclic compound is expected
to enhance the hydrogen-bonding ability of Npy atoms in the
cavity. In addition, 4-(dimethylamino)pyridine (DMAP) and
its derivatives are well-known catalysts for various organic
syntheses.6 In this communication, the catalytic activity of
these macrotricyclic compounds for the Michael addition is
also described.
The synthetic strategy for macrotricyclic compounds 2a
and 2b was based on our previous reports.7 2,6-Dibromo-
4-pyrrolidinopyridine (3a) and 2,6-dibromo-4-piperidinopy-
ridine (3b) were prepared via the four-step procedure.8 N,N-
Bis[2-(6-bromo-4-pyrrolidinopyridyl)]-p-toluidine (4a), N,N-
bis[2-(6-bromo-4-piperidinopyridyl)]-p-toluidine (4b), 2,6-
bis(p-tolylamino)-4-pyrrolidinopyridine (5a), and 2,6-bis(p-
tolylamino)-4-piperidinopyridine (5b) were prepared by the
Pd-catalyzed aryl amination9 of 3a or 3b with p-toluidine
(Scheme 1). The macrotricyclic compounds 2a and 2b were
prepared by the Cu-catalyzed aryl amination10 of 4a with
5a and of 4b with 5b, respectively. The macrotricyclic
compounds 2a and 2b were obtained as inner monoproto-
nated forms (i.e., 2aH·Br and 2bH·Br) owing to their high
basicity. It is noteworthy that the reaction at temperature
higher than 195 °C provided 2aH·Br and 2bH·Br in good
yields (72 and 84%) without the necessity of using dilute
conditions. This result indicates that the reaction systems can
be driven to favor the formation of cyclic trimer; it is likely
that the preorganization of the backbone of the intermediates
is induced by the presence of proton as a template.11
Deprotonation with an aqueous solution of NaOH (2.5 wt
%) gave the neutral compounds 2a and 2b, and 2aH·PF6 and
2bH·PF6 were isolated by treatment with NH4PF6. The new
compounds including 2aH·PF6 and 2bH·PF6 were character-
ized by NMR and ESI-MS spectroscopies and elemental
analysis. As expected, the 1H NMR spectra of 2aH·PF6 and
2bH·PF6 exhibit a singlet signal at 20.9 and 21.0 ppm,
respectively, in CDCl3 (Figure 2); the largely downfield-
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Figure 2.
1H NMR spectrum of 2aH·PF6 (400 MHz, CDCl3).
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shifted proton signal reflects the synergistic hydrogen bond-
ing ability of Npy atoms in the cavity.3 The detailed synthetic
procedures and characterization of the compounds are
summarized in the Supporting Information.
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5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (c) Selby,
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Org. Lett., Vol. 12, No. 22, 2010
5243

The structure of the monoprotonated form of 2a was also
elucidated by X-ray crystallography; the ORTEP drawing
of 2aH·Br is shown in Figure 3.12 Although one of the
bases were carried out by 1H NMR spectroscopy.3,13 Among
the organic bases tested, tert-butylimino-tri(pyrrolidino)phos-
phorane (BTPP, pKBH+ ) 28.4 in CH3CN)14 was the most
appropriate base for the transprotonation experiments on
2aH·PF6 and 2bH·PF6 (eq 1). Since the proton exchange
between 2aH·PF6 and BTPP was relatively slow on the NMR
time scale at room temperature, the pKBH+ of 2a was
estimated to be 28.1 ( 0.1 from the 1H NMR spectra of the
mixtures of 2aH·PF6 and BTPP with various molar ratios.
Similar transprotonation experiments on 2bH·PF6 with BTPP
gave the estimated pKBH+ of 2b to be 27.1 ( 0.2. Since these
pKBH+ data are higher than that of 1 by a factor of 104-105,
the introduction of pyrrolidino and piperidino groups into
the pyridine unit allows us to enhance the proton affinity of
Npy atoms in a cavity, resulting in a high basicity.
1
In the H NMR spectrum of 2aH·PF6, the addition of
CD3OD caused the disapperance of the signal at δ ) 20.9
indicating that the proton in the cavity could be replaced in
solution. This result motivated us to utilize 2a and 2b as
catalysts for the Michael addition of nitromethane with
mesityl oxide and 2-cyclohexenone. Table 1 summarizes the
Table 1. Michael Addition of Nitromethane with Mesityl Oxide
and 2-Cyclohexenone Using 2a and 2b, 1, BTPP, and DBU as
the Base Catalysts
Figure 3. ORTEP drawing of 2aH·Br with thermal ellipsoids shown
at the 30% probability level. Hydrogen atoms except for the
captured proton, Br anion, and solvated dichloromethane molecules
are omitted for clarity.
pyrrolidino groups and a solvated dichloromethane molecule
were disordered, the monoprotonation of 2a led to a
coplanarity of the macrocyclic framework with a slight
deviation of the three pyridine rings; the angles between pairs
of these pyridine rings are 2.99° and 6.01°, respectively. The
captured proton is located unsymmetrically within nonlinear
hydrogen-bonded bridges. The short N(1)-H(1) bond length
is 1.33(7) Å, and the long N(3)···H(1) and N(5)···H(1)
hydrogen bond lengths are 1.40(8) and 1.67(8) Å, respec-
tively. These hydrogen bond lengths lie in a similar range
found in 1H·PF6.3
To estimate the basicities of 2a and 2b, transprotonation
experiments on 2aH·PF6 and 2bH·PF6 with known organic
a Yield of isolated analytically pure compound. b The reaction time was
(11) (a) Template Synthesis of Macrocyclic Compounds; Gerbeleu, N. V.,
Arion, C. B., Burgess, J., Eds.; Wiley-VCH: New York, 1994. (b) Cao, Y.;
Wang, L.; Bolte, M.; Vysotsky, M. O.; Bo¨hmer, V. Chem. Commun. 2005,
3132.
12 h. c The reaction time was 6 h. d pKBH+ in CH3CN
(12) Selected data for 2aH·Br·2CH2Cl2: C50H56BrCl4N9, M ) 1044.77,
monoclinic, P21/n, a ) 10.3682(14), b ) 16.537(2), c ) 28.698(4), ꢀ )
90.958(2), V ) 4919.9(12) Å3, Z ) 4, Dcalcd ) 1.356 g cm3, µ ) 1.10
mm-1, T ) 90 K, F(000) ) 2088, observed reflections 10 767 (all data),
variables 573, R1 ) 0.1019 (I > 2σ(I)), R ) 0.1545, Rw ) 0.3464, GOF )
1.361. See the Supporting Information for details.
results of the model reactions using some organic base
catalysts; the reactions were carried out in accordance with
the literature.15 The Michael addition was achieved using
2a and 2b as base catalysts, whereas no catalytic reaction
5244
Org. Lett., Vol. 12, No. 22, 2010

was observed using 1. These results exemplify that the
enhancement of the basicity of the macrotricyclic compound
is efficient for the deprotonation of nitromethane. Although
DBU was reported as a catalyst for the Michael addition of
nitroalkane,16 2a and 2b served as superior catalysts for the
model reactions (Table 1, entries 2, 3, 7, and 8).
As described above, according to Maksic´’s prediction
based on the DFT calculation, we demonstrated the enhance-
ment of the basicity of azacalix[3](2,6)pyridine by the
introduction of pyrrolidino and piperidino groups into the
pyridine unit. Since 2a and 2b served as an efficient base
catalyst for the Michael addition, the method outlined in this
paper is expected to contribute to the molecular design of
neutral organic superbases. To expand their range of ap-
plications, further studies including other catalytic reactions
are in progress.
Tsukuba for X-ray diffraction study, elemental analyses, and
NMR spectroscopy.
Supporting Information Available: Synthesis and char-
acterization of all compounds. NMR and X-ray crystal-
lographic data in CIF format for 2aH·Br. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL102236F
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Acknowledgment. The authors thank Prof. M. Ichinohe
for useful discussion of X-ray analysis. The authors are
grateful to the Chemical Analysis Center of University of
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