Rapid access to substituted piperazines via Ti(NMe2) 4-mediated C-C bond-making reactions

Article abstract of DOI:10.1021/om300022u

An efficient Ti(NMe₂)₄-mediated C-C bond-forming methodology toward substituted piperazines, the basic skeleton of several biologically active natural products, has been developed. In reactions of tridentate monoanionic ligands beari

Full text of DOI:10.1021/om300022u

Article
pubs.acs.org/Organometallics
Rapid Access to Substituted Piperazines via Ti(NMe2)4‑Mediated C−C
Bond-Making Reactions
Zhou Chen,†,‡ Jian Wu,† Yanmei Chen,† Lei Li,† Yuanzhi Xia,*,§ Yahong Li,*,† Wei Liu,† Tao Lei,‡
Lijuan Yang,† Dandan Gao,‡ and Wu Li‡
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering, and Materials Science,
Soochow University, Suzhou 215123, People's Republic of China
‡Key Laboratory of Salt Lake Resources and Chemistry of Chinese Academy of Sciences, Qinghai Institute of Salt Lakes,
Xining 810008, People's Republic of China
§College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, People's Republic of China
S
* Supporting Information
ABSTRACT: An efficient Ti(NMe2)4-mediated C−C bond-forming methodology toward substituted piperazines, the basic
skeleton of several biologically active natural products, has been developed. In reactions of tridentate monoanionic ligands
bearing a [−HCNCH2−] linkage with Ti(NMe2)4, unusual [3 + 3] dimerized complexes through C−C coupling of the putative
titanium aza-allyl complex intermediate could be obtained. These complexes contain substituted piperazine backbones and could
give rise efficiently to substituted piperazine derivatives via hydrolysis. Treatment of Ti(NMe2)4 with a series of tridentate
dianionic and bidentate monoanionic ligands bearing the [−HCNCH2−] moiety only generated chelated titanium complexes
from ligand exchange reactions. Mechanistic studies using DFT/M06 calculations revealed that the methylene in the
[−HCNCH2−] moiety of titanium complexes bearing tridentate monoanionic ligands could be deprotonated intramolecularly by
dimethylamide anion with an activation energy of about 22 kcal/mol. The resulting titanium aza-allyl complexes from this β-H
abstraction step then undergo a consecutive stepwise [3 + 2] cycloaddition/ring expansion reaction facilely to form the dimerized
complex. However, β-H abstractions for Ti complexes bearing tridentate dianionic and bidentate monoanionic ligands were
energetically demanding, as the negative charges could not be stabilized by the adjacent groups in the possible intermediates,
explaining the experimental outcomes that no C−C coupled products were formed.
of redox reactions mediated by group 4 metals have been
reported so far.5
INTRODUCTION
■
Carbon−carbon bond-making reactions mediated by transition
metals are some of the most important transformations in
organic and organometallic chemistry.1 This process is of great
academic and industrial significance for increasing molecular
complexity and constructing natural products and extended
polymeric structures from small organic compounds.2 It has been
documented that most stoichiometric and catalytic C−C bond-
forming reactions mediated by middle and late transition metals
typically follow oxidative addition, transmetalation and reductive
elimination pathways that involve metal−carbon bonds,3
whereas reactions mediated by group 4 metals occur mainly
through σ-bond metathesis and migratory insertion, without
requiring redox changes at the metal center.4 Very few examples
Piperazine is the basic skeleton of a broad class of organic
compounds,6 which display a wide variety of biological activities,
including antitumor,7 antiviral,8 antifungal,9 and antibacterial.10
In addition, a large number of piperazine compounds have been
found to have anthelmintic action.11 However, the piperazine
is only obtained as a coproduct in the ammoniation of 1,2-
dichloroethane or ethanolamine in industrial production.12 The
efficient synthesis of substituted piperazine often requires
lengthy sequential synthesis, making the developments of diverse
and efficient synthetic approaches highly desirable.
Received: January 12, 2012
Published: August 15, 2012
© 2012 American Chemical Society
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Scheme 1. Syntheses of Compounds 1 and 2
Figure 1. (a) ORTEP representation of the structure of 1·2C7H8 from X-ray diffraction (30% probability). Hydrogen atoms and solvate molecules are
omitted for clarity. (b) Side view of the piperazine skeleton in 1·2C7H8, showing its chair configuration.
Recently Gibson et al. reported the syntheses of a series of
group 4 metal complexes bearing Schiff base ligands and
suggested that a C−C bond could be constructed from coupling
of the [−HCNCH−]− moiety of the ligand without changing the
oxidation state of Ti(IV).13 This reaction leads to a dinuclear
complex that is connected by a central piperazine ring. Despite a
number of advantages of this protocol, the scope of the ligand is
only limited to phenoxy(benzimidazolyl)imine, and the occur-
rence of the C−C bond-forming reaction is somewhat random.
We proposed that the discovery of Gibson et al. could be em-
ployed as an efficient methodology for preparing substituted
piperazines by using suitable tridentate monoanionic ligands.
Thus, aiming at expanding the scope of the ligand, from which the
titanium-mediated C−C bond-making reaction would occur, we
have recently developed a method for the syntheses of substituted
piperazines. By employing a series of rationally designed ligands
containing the [−HCNCH2−] backbone, we have synthesized
two substituted piperazines and a series of titanium complexes.
As a continuation of our ongoing efforts on group 4 metal
mediated C−N and C−C bond construction,14 in the current
paper we describe the synthetic application, limitations, and DFT
mechanistic study of the reactions between Ti(NMe2)4 and a
series of tridentate and bidentate ligands with the
[−HCNCH2−] linkage. This study provides an efficient method
for the synthesis of substituted piperazines and discloses the
factors that may control the reactivity of different proligands
from both experimental and theoretical analysis.
ligands has been well developed, and these complexes have been
proven to be especially useful in mediating C−C and C−N bond
formation.15 The reaction of the pyrrolyl Schiff base ligand HL1
(HL1 = N-((1H-pyrrol-2-yl)methylene)-1-(pyridin-2-yl)-
methanamine),16 which contains the [−HCNCH2−] backbone,
with Ti(NMe2)4 was explored. Treatment of Ti(NMe2)4 with
1 equiv of HL1 in THF generated the unexpected dinuclear bis-
(dimethylamido) titanium complex (NMe2)2Ti(NC(C4H3N)-
HC(C5H4N)HNC(C4H3N)HC(C5H4N)H)Ti(NMe2)2 (1)
(Scheme 1), which was isolated as a pure red solid after
recrystallization in toluene.
The crystal structure of 1·2C7H8 was determined by X-ray
analysis, with an ORTEP representation of the structure of
1·2C7H8 being shown in Figure 1a and selected bond lengths and
angles being summarized in Table 1. This complex exhibits
approximate Ci symmetry and consists of two titanium(IV) ions,
Table 1. Selected Bond Distances (Å) and Angles (deg) from
the X-ray Diffraction Study on 1·2C7H8
Ti−N(1)
Ti−N(4)
Ti−N(5)
N(2)−C(6)
N(4)−Ti−N(5)
N(4)−Ti−N(2)
N(5)−Ti−N(2)
N(4)−Ti−N(3)
N(5)−Ti−N(3)
N(5)−Ti−N(1)
2.181(4)
1.879(5)
1.896(5)
1.452(6)
109.8(2)
123.6(2)
125.6(2)
105.5(2)
97.6(2)
Ti−N(2)
Ti−N(3)
C(6)−C(7)#1
N(2)−C(7)
N(2)−Ti−N(1)
N(3)−Ti−N(1)
C(1)−N(1)−Ti
N(2)−Ti−N(3)
N(4)−Ti−N(1)
1.964(4)
2.036(4)
1.576(6)
1.460(6)
74.14(16)
152.99(16)
122.8(4)
78.86(16)
90.0(2)
RESULTS AND DISCUSSION
■
Synthesis of Substituted Piperazine from Proligand
97.68(18)
HL1. The chemistry of titanium complexes supported by pyrrolyl
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Scheme 2. Plausible Mechanism
four dimethylamido groups, one bridging doubly deprotonated
piperazine ring, and two solvated toluene molecules. The
geometry around each titanium atom can be described as a
distorted trigonal bipyramid, with the pyridyl and pyrrolyl
nitrogens axial and the amido and piperazine nitrogens equa-
torial. As expected, the donor pyridine has the longest
Ti−N(pyridine) bond of 2.186 Å in comparison with the bond
lengths of Ti−N(pyrrolyl) and Ti−N(piperazine) and falls in
the range of the previously reported Ti−N(pyridine) bond
containing compounds (minimum 2.126 Å, maximum 2.450 Å for
317 examples in the CSD). The Ti−N(pyrrolyl) bond distance is
0.08 Å longer than the Ti−N(piperazine) bond.
The doubly deprotonated piperazine ring adopts a chair
configuration (Figure 1b), with the newly formed C−C bond
distance being about 1.58 Å (C6A−C7 = 1.576(6) Å) and a C−N
bond length of 1.46 Å (C7−N2 = 1.460(6) Å), indicating that the
C−C and C−N bonds in 1 are typical single bonds. The four
atoms C6, C7A, C6A, and C7 are strictly coplanar.
aza-allyl complexes by Wolczanski and co-workers,17 but no
dimerization reactions were observed.
Reactions of Ti(NMe2)4 with Other Tridentate Dianionic
and Bidentate Monoanionic Ligands. To expand the
generality of the C−C coupling process, we next attempted the
possible reactions of Ti(NMe2)4 with a variety of ligands con-
taining phenol, benzenyl, furan, and tetrahydrofuran moieties,
respectively, with the results being summarized in Scheme 3.
It is interesting to find that no piperazine derivatives from
Ti-mediated C−C coupling could be observed under these con-
ditions, and only the complexes from ligand exchange reactions
were obtained, as characterized by X-ray diffraction.
Treatment of Ti(NMe2)4 with 1 equiv of H2L2 (H2L2 = 2-
(((1H-pyrrol-2-yl)methylimino)methyl)phenol) resulted in
complex Ti(L2)2 (C-L2), which contains one bis-ligated tita-
nium center. This complex exhibits pseudo-octahedral geometry
with one oxygen atom and one pyrrolyl nitrogen atom of the
mer-L22− ligand trans. No deprotonation of the methylene
moieties of tridentate dianionic ligands was observed.
It was found that complex 1 retained its structure in CDCl3
The reaction of the bidentate monoanionic ligand HL3 (HL3 =
N-((1H-pyrrol-2-yl)methylene)-1-phenylmethanamine),18 in
which the pyridine donor of HL1 was replaced by a phenyl
group, with Ti(NMe2)4 gave Ti(L3)(NMe2)3 (C1-L3), which is a
five-coordinate tris-amido complex with trigonal-bipyramidal
geometry.
1
solution. The H NMR spectrum of 1 showed two doublets in
the region of 4.18−4.22 and 4.38−4.40 ppm, which are assigned
to the two groups of hydrogen atoms of the piperazine ring. A
signal for the hydrogen of the R(H)CNR fragment in L1− was
not observed, indicating the absence of a CN bond in the
complex.
To explore if the pyridine in proligand HL1 could be replaced
by other donors, HL4 (HL4 = N-(furan-2-ylmethylene)-1-(1H-
pyrrol-2-yl)methanamine) and HL5 (HL5 = (S,E)-N-((1H-
pyrrol-2-yl)methylene)-1-(tetrahydrofuran-2-yl)methanamine)
were synthesized. It was found that the furan and tetrahydrofuran
moieties in these ligands did not coordinate to the titanium
centers in the formed complexes Ti(L4)(NMe2)3 (C1-L4) and
Ti(L5)(NMe2)3 (C1-L5). The trigonal-bipyramidal geometries
show that one dimethylamido nitrogen atom and the imine
nitrogen atom occupy the axial sites. Thus, both HL4 and HL5
serve as bidentate proligands similar to HL3. These suggest that
the β-H abstraction step (Scheme 2) should be more favorable in
the presence of tridentate monoanionic ligands.
Hydrolysis of 1 followed by filtering away the precipitate,
drying the filtrates, and recrystallizing the resulting solid in
ethanol gave the substituted piperazine 2,5-bis(pyridin-2-yl)-3,6-
bis(1H-pyrrol-2-yl)piperazine (2) (Scheme 1). Compound 2
was characterized by NMR spectroscopic techniques and
elemental analysis.
We propose that the dimerized complex 1 is formed via the
plausible mechanism shown in Scheme 2. The hexacoordinated
complex C1 should be first formed from Ti(NMe2)4 and HL1.
Then a β-H abstraction from the methylene moiety will generate
IN1, which could be described as a titanium aza-allyl complex of
mesomeric form ii or a structure of mesomeric form iii with a
dearomatized pyridine moiety. Finally a [3 + 3] cyclodimeriza-
tion of intermediate IN1 forms complex 1. Similar β-H abstrac-
tions were reported in the preparation of late-transition-metal
Synthesis and Structure of 2,2′-(3,6-Bis(pyridin-2-
yl)piperazine-2,5-diyl)diphenol (4). The above results
show that no β-H abstraction occurred for titanium complexes
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Scheme 3. Syntheses of Complexes C-L2, C1-L3, C1-L4, C1-L5 and Their Structures from X-ray Diffraction
Scheme 4. Synthesis of 4
bearing tridentate dianionic and tridentate monoanionic
ligands, and the only tridentate monoanionic ligand with a
[−HCNCH2−] backbone is reactive toward the formation of a
piperazine skeleton. To test this, proligands HL6 (HL6 =
2-((pyridin-2-ylmethylimino)methyl)phenol)19 and HL7 (HL7 =
2-((pyridin-2-ylmethyleneamino)methyl) phenol) were synthe-
sized and subjected to the standard conditions. These com-
pounds form tridentate monoanionic ligands by deprotonation
of the phenol moiety.
Treatment of Ti(NMe2)4 with 1 equiv of HL6 (or HL7) gen-
erated a mixture of several indeterminable titanium complexes.
Gratifyingly, both reactions generated the same substituted
piperazine, 2,2′-(3,6-bis(pyridin-2-yl)piperazine-2,5-diyl)-
diphenol (4), after hydrolysis (Scheme 4). This indicates that
the same dinuclear titanium aza-allyl complex 3 was formed in
both reactions of proligands HL6 and HL7. The solid-state
structure of product 4·2EtOH (Scheme 4) revealed that the
central piperazine ring has a chair conformation with the four
carbon atoms perfectly coplanar.
Mechanistic Insights from DFT Calculations. DFT
calculations20 at the M06/6-31+G* (LANL2DZ for Ti) level21
were carried out to better understand the experimental out-
comes. This section will address the mechanistic problems of (1)
how the β-H abstraction and [3 + 3] cyclodimerization occur, (2)
the regiochemistry of the cyclodimerization process, and (3) why
no similar piperazine derivatives were formed in the reactions of
Ti(NMe2)4 with the bidentate monoanionic and tridentate
dianionic ligands.
According to the plausible mechanism in Scheme 2, we first
present the detailed mechanism for the reaction of HL1 with
Ti(NMe2)4. Theoretically, the β-H abstraction of C1 could
be completed via both inter- and intramolecular processes.
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Scheme 5. Energies for Possible β-H Abstraction Pathways
Scheme 6. Mechanism for the Cyclodimerization of IN1
The results in Scheme 5 indicate that intramolecular H abstrac-
tion by one of the dimethylamino anions via TS1 requires an
activation barrier of 21.6 kcal/mol, while intermolecular H
abstraction by one HNMe2 molecule in the reaction media via
TS1′ has an activation barrier of about 5 kcal/mol higher. The
geometry of TS1′ indicates that a hydrogen bond is formed
between the HNMe2 molecule and the nitrogen atom of one
dimethylamino anion. The formation of the titanium aza-allyl
complex IN1 is exergonic by 8.4 kcal/mol, indicating that the
H-abstraction step is thermodynamically favorable. The geo-
metric structure shows that IN1 is closer to mesomeric form iii
(Scheme 2) with a dearomatized pyridine ring, as the N(pyridine)−
Ti distance (2.074 Å) is quite close to the N(pyrrole)−Ti distance
(2.065 Å), while both are much shorter than the N(imine)−Ti
distance (2.176 Å).
cycloaddition/ring expansion pathway. In the first step, the
coupling between C1 and C3′ is realized via TS2, which is only
5.9 kcal/mol higher in energy than two IN1 complexes, leading
to IN2 being slightly endergonic by 0.7 kcal/mol. IN2 could
undergo a C3−N2′ formation reaction via TS3 to generate the
[3 + 2] cycloaddition intermediate IN3, which would undergo a
facile ring-expansion reaction via TS4 to generate the dimerized
complex 1. This last step is driven forward by the thermodynamic
instability of IN3, and the formed intermediate 1 is 28.6 kcal/mol
lower in energy than the starting complex C1. From IN2, the
possible N2−C1′ coupling was also calculated, but a much higher
activation energy is required.
The above results show that, after the β-H abstraction step,
IN1 could be transformed into the cross-coupled complex 1 very
easily through C1−C3′ and C3−C1′ couplings. We wonder if it
is possible to form a homocoupled complex from the C1−C1 and
C3−C3′ couplings. To understand the observed regiochemistry
of the cyclodimerization, the results for the possible homocou-
pling pathway are shown in Scheme 7, which shows that the
For reasons of orbital symmetry, no concerted or stepwise [3 + 3]
cycloaddition between two IN1 complexes could be found to
generate complex 1. Instead, the results in Scheme 6 indicate that
the cyclodimerization of IN1 follows a consecutive stepwise [3 + 2]
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Scheme 7. Results Accounting for the Regioselectivity of the Cyclodimerization
relative energies for the transition states in reactions initiated by
C3−C3′ coupling are relatively lower than those in Scheme 6,
although we failed to locate TS4′ for connecting IN3′ and 1′.
IN2′ would be formed more easily via TS2′ than the formation of
IN2 via TS2, and TS3′ is lower in energy than TS3. These
indicate the homocoupling pathway is more kinetically favorable.
However, 1′ is less stable relative to 1, with the latter being 9.9
and 4.5 kcal/mol lower in energy in the gas phase and in THF
solution, respectively, suggesting the homocoupling pathway is
less favorable than the cross-coupling pathway for thermody-
namic reasons.
While the tridentate monoanionic proligands HL1, HL6, and
HL7 could be efficiently transformed into substituted piper-
azines, it is interesting to find that the proligands H2L2, HL3,
HL4, and HL5 only form ligand-exchanged complexes with
Ti(NMe2)4, and no reactions from the β-H abstraction and
[3 + 3] cyclodimerization occurred. The energies in Scheme 8 show
that the possible β-H abstractions for the Ti complexes formed
from H2L2, HL3, and HL4 and Ti(NMe2)4 are energetically
demanding, being consistent with the experimental outcomes.
As H2L2 is a tridentate dianionic ligand, the pentacoordinated
complex C1-L2 will be first formed in the reaction with
Ti(NMe2)4 (Scheme 8a). The intramolecular β-H abstraction
from C1-L2 requires a barrier of 44.6 kcal/mol. We proposed
that the barrier may be lowered by incorporation of one neutral
HNMe2 ligand into C1-L2 to form the hexacoordinated com-
plex C1′-L2; however, the activation energy is still as high as
36.8 kcal/mol.
Scheme 8b shows that the intramolecular β-H abstraction of
the monoanionic bidentate ligand from HL3 is difficult, with an
activation free energy of 33.9 kcal/mol. Similarly, β-H abstraction
of the pentacoordinated complex C1-L4 from HL4 is also
difficult, with an activation free energy of 39.7 kcal/mol. Notably,
the results in Scheme 8c show that the hexacoordinated complex
C1′-L4 is 13.6 kcal/mol higher in energy than C1-L4, explaining
why the furan oxygen is not coordinated with the metal in this
reaction. This suggests that the coordination of the tridentate
monoanionic ligand with titanium is sensitive to subtle
electronic and steric factors. Similar results should be
expected for the reaction of HL5. Notably, the negative
charges in the formed intermediates in Scheme 8 could be not
stabilized by the adjacent groups, suggesting the importance
of pyridine dearomatization for facilitating the β-H abstrac-
tion step.22
CONCLUSIONS
■
An efficient method was developed for the synthesis of sub-
stituted piperazine derivatives based on Ti(NMe2)4-mediated
C−C bond coupling reactions, and a better understanding of the
experimental results was achieved by DFT calculations. It was
found that the methylene on the [−HCNCH2−] linkage of
the tridentate monoanionic ligand could be deprotonated intra-
molecularly via β-H abstraction to form a titanium aza-allyl
complex, which undergoes consecutive [3 + 2] cycloaddition and
ring-expansion reactions facilely to generate a dinuclear complex
with a piperazine skeleton. No such reaction could be observed
for titanium complexes bearing tridentate dianionic and
bidentate monoanionic ligands, as calculations revealed the
β-H abstractions in these systems are energetically demanding.
EXPERIMENTAL SECTION
■
General Methods. All manipulations of air-sensitive compounds
were carried out in an MBraun drybox under a purified nitrogen
atmosphere. THF was purchased from commercial suppliers and dried
over purple sodium benzophenone ketyl. Ti(NMe2)4 was purchased
from commercial sources. Elemental analyses (C, H, N) were performed
with a Carlo-Erba EA 1110 CHNO-S microanalyzer. Crystal deter-
mination was performed with a Bruker SMART APEX II CCDC
diffractometer equipped with graphite-monochromated Mo Kα
1
radiation (λ = 0.710 73 Å). H and 13C spectra were recorded on a
Varian Inova-300 or VXR-500 spectrometer. HRMS spectra were
obtained by TOF-MS.
Computational Details. All calculations were carried out with the
Gaussian 09 suite of computational programs.20 All stationary points
along the reaction coordinate were fully optimized at the DFT level
using the M06 hybrid functional.21 The 6-31+G* basis set23 was applied
for all the atoms except Ti, which was described by the LANL2DZ basis
set.24 Frequencies were analytically computed at the same level of theory
to obtain the gas-phase free energies and to confirm whether the
structures are minima (no imaginary frequency) or transition states
(only one imaginary frequency). Intrinsic reaction coordinate (IRC)
calculations were carried out to conform that all transition-state
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geometrical restraints. A full-matrix least-squares refinement on F2 was
carried out using SHELXL-97.27
Scheme 8. Prediction for the Possible β-H Abstraction of the
Ti Complexes from H2L2, HL3, and HL4
Syntheses of the Ligands and the Complexes. Preparation of
N-((1H-Pyrrol-2-yl)methylene)-1-(pyridin-2-yl)methanamine (HL1).
To a solution of 2-pyrrolaldehyde (0.951 g, 10 mmol) in water
(10 mL) was added 2-aminomethylpyridine (1.081 g, 10 mmol) and
1 drop of acetic acid. After the mixture was stirred at room temperature
overnight, a pale yellow solid precipitated, which was collected by
filtration and dried in vacuo. Yield: 1.700 g (92%). 1H NMR (300 MHz,
DMSO): δ 11.50 (s, 1H, NH), 8.50 (d, 1H, CHN), 8.24 (s, 1H,
2-C5H4N), 7.73 (t, 1H, 4-C5H4N), 7.38 (d, 1H, 5-C5H4N), 7.23 (t, 1H,
3-C5H4N), 6.90 (s, 1H, 2-C4H3N), 6.51 (s, 1H, 4-C4H3N), 6.13 (s, 1H,
3-C4H3N), 4.75 (s, 2H, CH2N) ppm. 13C NMR (75 MHz, DMSO): δ
160.2 (CHN), 154.2, 149.6, 137.3, 130.7, 123.1 (C5H4N), 122.9,
122.7, 114.7, 109.7 (C4H3N), 66.3 (CH2N) ppm. Anal. Calcd for
C11H11N3: C, 71.33; H, 5.99; N, 22.69. Found: C, 71.51; H, 5.96; N,
22.51.
Preparation of 2-(((1H-Pyrrol-2-yl)methylimino)methyl)phenol
(H2L2). To a solution of 2-aminomethylpyrrole (0.961 g, 10 mmol) in
water (30 mL) was added salicylaldehyde (1.221 g, 10 mmol) and 1 drop
of acetic acid. After the mixture was stirred at room temperature for 2 h, a
yellow solid precipitated, which was collected by filtration and dried in
1
vacuo. Yield: 1.802 g (90%). H NMR (300 MHz, DMSO): δ 13.43
(s, 1H, OH), 10.86 (s, 1H, NH), 8.54 (s, 1H, CHN), 7.40 (d, 1H,
3-C6H5O), 7.30 (t, 1H, 6-C6H5O), 6.89−6.83 (2H, 4,5-C6H5O), 6.68
(s, 1H, 2-C4H3N), 5.94 (s, 2H, 3,4-C4H3N), 4.68 (s, 2H, CH2N) ppm.
13C NMR (75 MHz, DMSO): δ 166.5 (CHN), 161.3, 133.0, 132.4,
128.6, 119.4, 119.2 (C6H5O), 118.5, 117.1, 108.1, 107.3 (C4H3N), 55.5
(CH2N) ppm. Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99.
Found: C, 71.82; H, 6.09; N, 14.09.
Preparation of N-((1H-Pyrrol-2-yl)methylene)-1-phenylmethan-
amine (HL3). To a solution of 2-pyrrolaldehyde (0.951 g, 10 mmol)
in water (30 mL) was added benzylamine (1.072 g, 10 mmol) and 1 drop
of acetic acid. After the mixture was stirred overnight, a white solid
precipitated, which was collected by filtration and dried in vacuo. Yield:
1.438 g (78%). 1H NMR (300 MHz, DMSO): δ 8.20 (d, 1H, CHN),
7.30 (4H, 2,3,5,6-C6H5), 7.23 (t, 1H, 4-C6H5), 6.88 (s, 1H, 2-C4H3N),
6.49 (s, 1H, 4-C4H3N), 6.12 (s, 1H, 3-C4H3N), 4.64 (s, 2H, CH2N)
ppm. 13C NMR (75 MHz, DMSO): δ 153.2 (CHN), 140.8, 130.6
(2,5-C4H3N), 128.9, 128.8, 127.3, 122.9 (Ph), 114.5, 109.6 (3,4-
C4H3N), 64.4 (CH2N) ppm. Anal. Calcd for C12H12N2: C, 78.23; H,
6.57; N, 15.21. Found: C, 78.36; H, 6.53; N, 15.08.
Preparation of N-(Furan-2-ylmethylene)-1-(1H-pyrrol-2-yl)-
methanamine (HL4). To a solution of 2-aminomethylpyrrole (0.961
g, 10 mmol) in water (30 mL) was added furfural (0.961 g, 10 mmol)
and 1 drop of acetic acid. After the mixture was stirred at room tem-
perature for 2 h, a pale brown product precipitated, which was collected
by filtration and dried in vacuo. Yield: 1.481 g (85%). 1H NMR
(300 MHz, DMSO): δ 10.76 (s, 1H, NH), 8.14 (s, 1H, CHN), 7.82
(s, 1H, 2-C4H3O), 6.92 (d, 1H, 2-C4H3N), 6.66 (d, 1H, 4-C4H3O), 6.61
(d, 1H, 3-C4H3O), 5.93 (d, 1H, 4-C4H3N), 5.90 (s, 1H, 3-C4H3N), 4.62
(s, 2H, CH2N) ppm. 13C NMR (75 MHz, DMSO): δ 151.6 (CHN),
150.0 (5-C4H3O), 145.2 (2-C4H3O), 128.6 (5-C4H3N), 117.4
(2-C4H3N), 114.0 (4-C4H3O), 111.9 (3-C4H3O), 107.3 (4-C6H5N),
106.5 (3-C6H5N), 56.6 (CH2N) ppm. Anal. Calcd for C10H10N2O: C,
68.95; H, 5.79; N, 16.08. Found: C, 68.80; H, 5.81; N, 16.17.
structures connect the proposed reactants and products.25 The solvation
effect was examined by performing single-point self-consistent reaction
field (SCRF) calculations based on the polarizable continuum model
(CPCM) for gas-phase optimized structures.26 Tetrahydrofuran (THF,
ε = 7.4) was used as the solvent, corresponding to the experimental
conditions. Solvation free energies (ΔGTHF) were calculated by adding
the solvation energies to the computed gas-phase relative free energies
(ΔG298).
Preparation of (S,E)-N-((1H-Pyrrol-2-yl)methylene)-1-(tetrahydro-
furan-2-yl)methanamine (HL5). To a solution of 2-pyrrolaldehyde
(0.951 g, 10 mmol) in water (10 mL) was added tetrahydrofurfuryl-
amine (1.011 g, 10 mmol). After the mixture was stirred overnight, a
white solid precipitated. The solid was collected by filtration and dried in
1
vacuo. Yield: 1.301 g (73%). H NMR (300 MHz, DMSO): δ 11.39
(s, 1H, NH), 8.04 (s, 1H, CHN), 6.86 (s, 1H, 2-C4H3N), 6.44 (d, 1H,
4-C4H3N), 6.10 (t, 1H, 3-C4H3N), 4.03 (t, 1H, 5-C4H7O), 3.77−3.56
(2H, 2-C4H7O), 4.51 (t, 2H, CH2N), 1.97−1.56 (4H, 3,4-C4H7O) ppm.
13C NMR (75 MHz, DMSO): δ 152.2 (CHN), 129.4 (5-C4H3N),
121.4 (2-C4H3N), 112.8 (4-C4H3N), 109.1 (3-C4H3N), 77.5 (CH2N),
66.5 (5-C4H7O), 64.3 (2-C4H7O), 28.2 (4-C4H7O), 24.6 (3-C4H7O)
ppm. Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92; N, 15.72. Found: C,
67.52; H, 7.97; N, 15.44.
X-ray Diffraction. Crystals grown from concentrated solutions at
room temperature were quickly selected and mounted on glass fibers in
wax. The data collections were carried out on a Bruker AXS three-circle
goniometer with a CCD detector equipped with graphite-monochro-
mated Mo Kα radiation by using the ϕ/ω scan technique at room
temperature. The structures were solved by direct methods with
SHELXS-97.27 The hydrogen atoms were assigned common isotropic
displacement factors and included in the final refinement by use of
6011
dx.doi.org/10.1021/om300022u | Organometallics 2012, 31, 6005−6013

Organometallics
Article
Preparation of 2-((Pyridin-2-ylmethyleneamino)methyl)phenol
(HL7). To a solution of 2-pyridinecarboxaldehyde (1.071 g, 10 mmol)
in water (10 mL) was added Na2CO3 (1.060 g, 10 mmol). Then
2-hydroxybenzylamine acetate (1.831 g, 10 mmol) in water (40 mL) was
added slowly with stirring. After the mixture was stirred overnight, a pale
yellow solid precipitated, which was collected by filtration and dried in
vacuo. Yield: 1.676 g (79%). 1H NMR (300 MHz, DMSO): δ 9.55 (br s,
1H, OH), 8.61 (s, 1H, CHN), 8.37 (s, 1H, 6-C5H4N), 7.95 (d, 1H,
4-C5H4N), 7.85 (t, 1H, 3-C5H4N), 7.43 (s, 1H, 5-C5H4N), 7.08−7.15
5.91 (s, 1H, 4-C4H3N), 5.03 (s, 2H, CH2), 3.13 (s, 18H, N(CH3)2) ppm.
13C NMR (75 MHz, C6D6): δ 150.6 (CHN), 148.1 (1-C4H3O), 147.0
(5-C4H3O), 138.3 (5-C4H3N), 127.2 (3-C4H3O), 120.7 (2-C4H3N),
112.9 (4-C4H3O), 109.6 (3-C4H3N), 101.0 (4-C4H3N), 54.4 (CH2),
46.2 (N(CH3)2) ppm. Anal. Calcd for C16H27N5OTi: C, 54.40; H, 7.70;
N, 19.82. Found: C, 53.91; H, 7.87; N, 19.51.
Preparation of Ti(L5)(NMe2)3 (C1-L5). To a solution of Ti(NMe2)4
(0.224 g, 1 mmol) in THF (2 mL) was added HL5 (0.178 g, 1 mmol) in
THF (3 mL). After the mixture was stirred at room temperature for
1 day, the solution was evaporated to dryness to give a red powder. Yield:
(2H, 3,6-C7H7O), 6.80 (2H, 4,5-C6H5O), 4.76 (s, 2H, CH2N) ppm. 13
C
1
NMR (75 MHz, DMSO): δ 163.1 (CHN), 155.9, 150.0, 137.6, 130.3,
128.8 (C5H4N), 125.8, 125.5, 121.1, 119.6, 115.7 (C6H5O), 59.2
(CH2N) ppm. Anal. Calcd for C13H12N2O: C, 73.56; H, 5.70; N, 13.20.
Found: C, 73.71; H, 5.66; N, 13.15.
0.296 g (83%). H NMR (300 MHz, C6D6): δ 7.85 (s, 1H, CHN),
7.08 (s, 1H, 2-C4H3N), 6.63 (d, 1H, 4-C4H3N), 6.34 (d, 1H, 3-C4H3N),
3.68 (s, 1H, 2-C4H7O), 3.56−3.44 (2H, 5-C4H7O), 3.13 (s, 18H,
NMe2), 3.05 (s, 2H, CH2N), 1.42 (br s, 4H, 3,4-C4H7O) ppm. 13C NMR
(75 MHz, C6D6): δ 160.4 (CHN), 139.7 (2-C4H3N), 136.2 (5-C4H3N),
115.5 (3-C4H3N), 111.3 (4-C4H3N), 77.2 (CH2N), 67.4 (2-C4H7O), 60.7
(5-C4H7O), 45.6 (NMe2), 29.7 (3-C4H7O), 25.6 (4-C4H7O) ppm. Anal.
Calcd for C16H31N5OTi: C, 53.78; H, 8.74; N, 19.60. Found: C, 53.01; H,
8.45; N, 19.13.
Preparation of (NMe2)2Ti(NC(C4H3N)HC(C5H4N)HNC(C4H3N)CH-
(C5H4N)H)Ti(NMe2)2 (1). To a solution of Ti(NMe2)4 (0.448 g, 2
mmol) in THF (5 mL) was added HL1 (0.370 g, 2 mmol) in THF
(5 mL) dropwise. After the mixture was stirred at room temperature for
3 days or at 60 °C for 16 h, the solution was evaporated to dryness to give
a red solid. The red solid was washed with n-hexane and dried under
reduced pressure to yield 0.549 g (86%) of product. 1H NMR
(300 MHz, CDCl3): δ 7.82 (m, 2H, 5-C5H5N), 7.60 (m, 2H, 4-C5H5N),
7.38 (m, 2H, 3-C5H5N), 7.20 (m, 2H, 2-C5H5N), 7.16 (m, 1H,
5-C4H3N), 7.06 (m, 1H, 5-C4H3N), 6.19 (m, 2H, 4-C4H3N), 5.58 (m,
2H, 3-C4H3N), 4.39 (d, 2H, −CH−), 4.18 (d, 2H, −CH−), 3.36 (s, 12H,
N(CH3)2), 2.98 (s, 12H, N(CH3)2) ppm. Anal. Calcd for C30H42N10Ti2:
C, 56.44; H, 6.63; N, 21.94. Found: C, 55.97; H, 6.45; N, 21.96.
Preparation of 2,2′-(3,6-Bis(pyridin-2-yl)piperazine-2,5-diyl)-
diphenol (4). To a solution of Ti(NMe2)4 (0.448 g, 2 mmol) in THF
(5 mL) was added HL6 (or HL7) (0.424 g, 2 mmol) in THF (5 mL).
After the mixture was stirred at room temperature for 1 week, several
drops of water were added. The resulting mixture was stirred for 6 h, and
the precipitate was filtered away. The filtrates were washed with CH2Cl2
and dried under vacuum give a crude product. The pure yellow product
was obtained by recrystallizing or washing the crude product with a
mixture of ethanol and water. Yield: 0.255 g (60%, based on HL6); 0.225 g
Preparation of 2,5-Bis(pyridin-2-yl)-3,6-bis(1H-pyrrol-2-yl)-
piperazine (2). To a solution of 1 in THF was added several drops of
water. After the mixture was stirred at room temperature for 6 h, the
resulting precipitate was filtered. The filtrates were washed with CH2Cl2
and dried in vacuo to give a crude product. The pure red product was
afforded by recrystallizing or washing the crude product with a mixture
1
(53%, based on HL7). H NMR (300 MHz, DMSO): δ 8.48 (d, 2H,
6-C5H4N), 7.55 (t, 2H, 4-C5H4N), 7.17 (t, 2H, 3-C5H4N), 6.98 (d, 2H,
5-C5H4N), 6.93 (d, 2H, 6-C6H5O), 6.68 (d, 2H, 4-C6H5O), 6.52 (br s, 2H,
3-C6H5O), 6.42 (t, 2H, 5-C6H5O), 4.31 (s, 4H, CH) ppm. HRMS (EI): m/
z calcd for C26H24N4O2 424.1899, found 425.1973 (M + H). Anal. Calcd
for C26H24N4O2: C, 73.56; H, 5.70; N, 13.20. Found: C, 73.21; H, 5.79;
N, 13.05.
1
of ethanol and water. Yield: 0.288 g (78%). H NMR (300 MHz,
DMSO): δ 10.69 (s, 2H, NH), 8.44 (d, 2H, 6-C5H4N), 7.57 (t, 2H,
4-C5H4N), 7.17 (t, 2H, 3-C5H4N), 7.10 (d, 2H, 5-C5H4N), 6.50 (s, 2H,
5-C4H3N), 5.73 (s, 2H, 3-C4H3N), 5.67 (s, 2H, 4-C4H3N), 4.12 (t, 2H,
CH), 4.21 (t, 2H, CH) ppm. 13C NMR (75 MHz, DMSO): δ 159.8,
148.3, 135.8, 122.9, 122.0, 116.3, 106.5, 105.2 (Ar), 65.1 (CH), 57.6
(CH) ppm. HRMS: m/z 371.1978 (M + 1). Anal. Calcd for C22H22N6:
C, 71.33; H, 5.99; N, 22.69. Found: C, 71.41; H, 6.06; N, 22.44.
Preparation of Ti(L2)2 (C-L2). To a solution of Ti(NMe2)4 (0.224 g,
1 mmol) in THF (2 mL) was added H2L2 (0.200 g, 1 mmol) in THF
(3 mL). After the mixture was stirred at room temperature for 2 days,
the solution was evaporated to dryness to give a red solid. The red solid
was washed with n-hexane and dried under reduced pressure to yield
0.167 g (75%) of product. 1H NMR (300 MHz, CD2Cl2): δ 8.92 (s, 1H,
CHN), 7.72 (d, 2H, 3-C6H4O), 7.56 (t, 2H, 6-C6H4O), 7.09 (t, 2H,
4-C6H4O), 6.72 (d, 2H, 5-C6H4O), 6.40 (s, 2H, 5-C4H3N), 5.84 (s, 2H,
4-C4H3N), 5.74 (s, 2H, 3-C4H3N), 5.53−5.19 (4H, CH2) ppm. Anal.
Calcd for C24H20N4O2Ti: C, 64.88; H, 4.54; N, 12.61. Found: C, 64.64;
H, 4.63; N, 12.42.
Preparation of Ti(L3)(NMe2)3 (C1-L3). To a solution of Ti(NMe2)4
(0.224 g, 1 mmol) in THF (2 mL) was added HL3 (0.184 g, 1 mmol) in
THF (3 mL). After the mixture was stirred at room temperature
overnight, the solution was evaporated to dryness to yield 0.334 g
(92%) of product. 1H NMR (300 MHz, C6D6): δ 7.29 (s, 1H, CHN),
7.87(s, 2H, −C6H5), 6.77 (d, 2H, −C6H5), 6.66 (s, 2H, 5-C4H3N,
−C6H5), 6.37 (s, 1H, 3-C4H3N), 6.14 (s, 1H, 4-C4H3N), 3.89 (s, 2H,
−CH2−), 2.80 (d, 18H, −N(CH3)2). 13C NMR (75 MHz, C6D6): δ 158.6
(CHN), 139.2, 137.7, 136.4, 129.1, 128.1, 127.1, 115.6, 111.3 (C4H3N,
Ph), 60.1 (CH2), 45.1 (N(CH3)2) ppm. Anal. Calcd for C18H29N5Ti: C,
59.50; H, 8.05; N, 19.28. Found: C, 58.88; H, 7.68; N, 19.85.
ASSOCIATED CONTENT
* Supporting Information
Text, tables, figures, and CIF files giving X-ray crystallographic
data, NMR spectroscopic data, and computational results. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: xyz@wzu.edu.cn (Y.X.); liyahong@suda.edu.cn (Y.L.).
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate the financial support of the Hundreds of Talents
Program (2005012) of CAS, the Natural Science Foundation of
China (20872105 and 21002073), the “Qinglan Project” of
Jiangsu Province (Bu109805), and A Project Funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions. Y.X. thanks the High Performance
Computation Platform of Wenzhou University for providing
the computation facility.
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