Synthesis and conformational analysis of constrained ethylene-bridged bis(hydroxylamino-1,3,5-triazine) compounds as tetradentate ligands; structure of rigid dinuclear Ti(IV) complex

Article abstract of DOI:10.1021/jo800966s

(Chemical Equation Presented) Ethylene-bridged bis(hydroxylamino-1,3,5- triazine) compounds, that may serve as tetradentate ligands, were synthesized in three steps from 2,4,6-trichloro-1,3,5-triazine. These compounds demonstrate different rotation restrictions around the C_Ar-N bonds due to their distinctive electronic structure as apparent from their resonative contributors. A dinuclear complex Ti₂(μ-L)₂(OiPr)₄ (L = bis(triazine)) was synthesized where each octahedral Ti(IV) center is also bound to two isopropoxo groups. The complex rigidity is manifested in a significant deviation from planarity of the aromatic systems, and relatively long Ti-N bonds compared to mononuclear analogous complexes. Increased ligand lability in this complex brings about diminished cytotoxicity toward colon and ovarian cells.

Full text of DOI:10.1021/jo800966s

Synthesis and Conformational Analysis of Constrained
Ethylene-Bridged Bis(hydroxylamino-1,3,5-triazine) Compounds as
Tetradentate Ligands; Structure of Rigid Dinuclear Ti(IV) Complex
Tal Hermon and Edit Y. Tshuva*
Institute of Chemistry, The Hebrew UniVersity of Jerusalem, 91904 Jerusalem, Israel
tshuVa@chem.ch.huji.ac.il
ReceiVed May 7, 2008
Ethylene-bridged bis(hydroxylamino-1,3,5-triazine) compounds, that may serve as tetradentate ligands,
were synthesized in three steps from 2,4,6-trichloro-1,3,5-triazine. These compounds demonstrate different
rotation restrictions around the CAr-N bonds due to their distinctive electronic structure as apparent
2 2 4
from their resonative contributors. A dinuclear complex Ti (µ-L) (OiPr) (L ) bis(triazine)) was synthesized
where each octahedral Ti(IV) center is also bound to two isopropoxo groups. The complex rigidity is
manifested in a significant deviation from planarity of the aromatic systems, and relatively long Ti-N
bonds compared to mononuclear analogous complexes. Increased ligand lability in this complex brings
about diminished cytotoxicity toward colon and ovarian cells.
Introduction
,3,5-Triazine-based compounds have been studied for de-
SCHEME 1
1
cades and have been employed for various applications of
organic synthesis, including those relating to construction of
1
–5
supramolecular composites.
One particularly interesting
feature of 2,4,6-triamino substituted 1,3,5-triazine compounds,
also known as melamine derivatives, is the high electron density
of the triazine nitrogen atoms, which results from the resonative
contribution of electrons of the amino substituents (Scheme 1).
This contribution is also pronounced by the observed high
7
–13
metals.
Particularly, we have recently introduced bis(hy-
droxylamino)triazine ligands, featuring two covalent ami-
noalkoxo donors in addition to a coordinative triazine nitrogen
2
planarity of this compound and thus the large sp character of
6
the substituting nitrogen atoms. This feature makes the triazine
nitrogen atoms especially good ligands to various transition
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(
*
To whom correspondence should be addressed. Fax: +972 2 6584282. Tel.:
972 2 6586084.
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0.1021/jo800966s CCC: $40.75  2008 American Chemical Society
J. Org. Chem. 2008, 73, 5953–5958 5953
Published on Web 06/24/2008

Hermon and Tshuva
SCHEME 3
FIGURE 1. ORTEP drawing of 4b shown from two angles at 50%
probability ellipsoids (H atoms and solvent were omitted for clarity).
the inert complex 3b (Scheme 2) exhibits some cytotoxicity
against colon HT-29 and ovarian OVCAR-1 cells, despite
3
5
SCHEME 2
having no labile groups (Cl, OR) generally assumed to be
3
6,37
essential for activity.
As tetradentate [2-] ligands may
38
coordinatively saturate a bis(alkoxo) Ti(IV) center and may
thus allow the exploration of the labile ligand effect, we became
interested in the synthesis of more complex bis(triazine)
compounds featuring two particularly electron-rich coordinative
N-atoms (Scheme 3).
Several examples of the synthesis of diamino-bridged 1,3,5-
3
9–47
triazine rings were reported;
however, bridged hydroxy-
lamino-1,3,5-triazine compounds were never synthesized. Herein
we present in particular the synthesis of tetradentate bis(triazine)
compounds, 5a-7a, which vary in the substituents of the N
donors (Scheme 3), and discuss their dynamic behavior in
solution. The structure and properties of a resulting Ti(IV)
complex is compared to those of the homoleptic complexes of
tridentate triazine ligands.
1
4
donor, for Ti(IV) metal (Scheme 2). We reported formation
of homoleptic [ONO]2Ti-type mononuclear complexes, which
exhibit exceptionally short Ti-N coordinative bonds owing to
the ligand distinctive electronic features, pronounced by espe-
1
4
cially high hydrolytic stability.
The recent interest in identifying new cytotoxic non-Pt based
and the promising results observed with
prompt us to investigate our ami-
noalkoxo complexes for biological applications. Surprisingly,
Results and Discussion
1
5–26
metal compounds,
1
8,19,27–34
The synthesis of 4a (Scheme 2) was achieved by reacting
Ti(IV) complexes,
2
,4,6-trichloro-1,3,5-triazine (cyanuric chloride) with excess
amounts of diethylamine in THF as a solvent in an ice bath
and stirring them for 0.5 h, after which the colorless precipitate
was filtered and discarded and the solution was evaporated. The
crude product was recrystallized from 2-propanol. The formation
(
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of the monosubstituted product was verified by H NMR, and
consequently, double substitution with methylhydroxylamine
was undertaken by employing excessive amounts of N-meth-
ylhydroxylamine hydrochloride previously stirred with NaOH
in water, and refluxing the solution mixture overnight. Evaporat-
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20) Desoize, B. Anticancer Res. 2004, 24, 1529.
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Des. 2003, 9, 2078.
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23) Ott, I.; Gust, R. Arch. Pharm. Chem. Life Sci. 2007, 340, 117.
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2007, 12, 825.
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97.
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2005, 3, 317.
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(
(
(
25) Kostova, I. Curr. Med. Chem. 2006, 13, 1085.
26) Evangelou, A. M. Crit. ReV. Oncol. Hemat. 2002, 42, 249.
27) Mel e´ ndez, E. Crit. ReV. Oncol. Hemat. 2002, 42, 309.
(38) Tshuva, E. Y.; Versano, M.; Goldberg, I.; Kol, M.; Weitman, H.;
Goldschmidt, Z. Inorg. Chem. Commun. 1999, 2, 371.
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2006, 8, 1541.
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69.
(
(
29) K o¨ pf-Maier, P.; K o¨ pf, H. Struct. Bonding (Berlin) 1988, 70, 103.
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Chem. Soc. 2004, 126, 10044.
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Struct. Bonding (Berlin) 1991, 78, 97.
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Diez, S.; Navarrete, E.; Cingolani, A.; Marchetti, F.; Pettinari, C. J. Med. Chem.
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2002, 43, 6783.
(
(43) Yang, X.; Lowe, C. R. Tetrahedron Lett. 2003, 44, 1359.
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000, 43, 3665.
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J. Am. Chem. Soc. 2007, 129, 12098.
5
954 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Bis(hydroxylamino-1,3,5-triazine)
TABLE 1. Selected Bond Lengths (Å) and Angles (deg) for 4b
atoms
value
atoms
value
atoms
value
Lengths
Angles
O(1)-Ti
O(2)-Ti
1.9652(13)
1.9556(13)
O(3)-Ti
O(4)-Ti
1.9576(13)
1.9482(13)
N(1)-Ti
N(7)-Ti
2.0186(15)
2.0221(15)
O(4)-Ti-O(2)
O(4)-Ti-O(3)
O(2)-Ti-O(3)
O(4)-Ti-O(1)
O(2)-Ti-O(1)
94.10(6)
146.02(6)
96.48(6)
94.17(6)
145.21(6)
O(3)-Ti-O(1)
N(1)-Ti-N(7)
O(1)-Ti-N(1)
O(2)-Ti-N(1)
O(3)-Ti-N(1)
95.27(6)
167.82(6)
73.36(6)
72.87(6)
96.37(6)
O(4)-Ti-N(1)
O(1)-Ti-N(7)
O(2)-Ti-N(7)
O(3)-Ti-N(7)
O(4)-Ti-N(7)
117.61(6)
113.03(6)
101.71(6)
73.12(6)
73.14(6)
ing the organic solvent and recrystallization from 2-propanol
gave 4a, as verified by H NMR, in a total yield for both steps
of 23%.
well. The final product was recrystallized from 2-propanol in a
total yield of 16%. Interestingly, multiple broad signals were
observed in the H NMR of both the final product and the
1
1
The homoleptic titanium complex 4b was also synthesized
product of the second step, suggesting a dynamic behavior. 2D
HSQC measurements supported this notion.
1
4
similarly to 1b-3b by reacting titanium tetra(isopropoxide)
with 2 equiv of 4a at room temperature in THF. Single crystals
suitable for X-ray crystallography were obtained from THF at
35 °C, and an ORTEP view of the structure is presented in
Figure 1 with a summary of selected bond lengths and angles
given in Table 1.
Dynamic NMR measurements were performed on 3a-7a
(Scheme 2,3) at 190-390 K. Indeed, cooling 7a to 280 K in
1
13
-
d8-THF gave H NMR and C NMR spectra with well separated
signals, where each type of NMe is separated into four different
singlets, the methylene bridge appears as two singlets and two
1
13
The structure features an octahedral Ti(IV) center bound to
two approximately perpendicular tridentate triazine ligands in
a mer-mer geometry similarly to a related complex of this
triplets in the H NMR and as four signals in the C NMR,
and eight different signals are observed for the NCH2CO2Et
group as particularly revealed by HSQS measurements at this
temperature (Figure 2a; Figure S11-S18 in Supporting Infor-
mation). Heating 7a to 390 K revealed complete coalescence
for all signals to give a highly symmetrical molecule (Figure
2b). In contrast, for 5a and 6a, only after cooling to 290 K,
multiple peaks began to appear. We may thus conclude that
14
class. A particularly unique feature of this family of complexes
is exceptionally short Ti-N coordinative bonds of 2.0 Å, which
is in accordance with a large contribution of the resonative
structure presented in Scheme 1 that includes negative charge
on the coordinative N-donors.
The synthesis of compounds 5a-7a was achieved by a three-
step procedure, starting with 2,4,6-trichloro-1,3,5-triazine. The
first step for the synthesis of 5a is similar to the first step in the
preparation of 4a. The monosubstituted product was further
reacted in the second step with 0.5 equiv of ethylenediamine in
the presence of triethylamine as a base in dichloromethane/
acetonitrile at room temp, and after stirring overnight, the
reaction mixture was filtered, evaporated, and the resulting
product was recrystallized from 2-propanol to give a colorless
1
powder. H NMR has confirmed the product to be the ethylene-
bridged compound (Scheme 3).
The bis(triazine) compound as a THF solution was finally
reacted with an excess of N-methylhydroxylamine hydrochloride
previously stirred with NaOH in water, and the mixture was
refluxed for 1 day. Evaporating the organic solvent gave a
colorless powder, which was recrystallized from acetonitrile in
1
a total yield for all steps of 24%. H NMR confirmed the product
to be 5a (Scheme 3), featuring one type of ethyl group and two
additional singlets. It was observed that the hydroxylamino
substituent activates the triazine ring for further substitution and
thus is best to be inserted last.
6
a (Scheme 3) was synthesized in a similar manner, by
reacting the diethylamino monosubstituted compound with 0.5
equiv of N,N′-dimethylethylenediamine and recrystallization
from acetonitrile, followed by the hydroxylamino substitution
to give 6a in a total of 22% yield following recrystallization
1
from acetonitrile. The H NMR of 6a is consistent with that of
5
a, featuring three singlets in addition to a single type of ethyl
group.
7
a (Scheme 3) was also synthesized in a similar manner,
starting with 1 equiv of diethyliminodiacetate for the first
substitution in the presence of 1 equiv of diisopropylethylamine
FIGURE 2. 1H NMR spectra (500 MHz) of 7a in d
8
-THF at 280 K
6
-DMSO at 390 K
demonstrating restricted rotation (a) and in d
(
DIPEA) as a base, which was employed for the second step as
demonstrating free rotation (b).
J. Org. Chem. Vol. 73, No. 15, 2008 5955

Hermon and Tshuva
SCHEME 4. Schematic Representation of Stereoisomers
Resulting from Restricted Rotation
restricted rotation around the CAr-N bonds, due to the highly
contributing resonative structure where the amino substituents
2
on the triazine rings are of sp character (Scheme 1), results in
FIGURE 3. ORTEP drawing of 7b shown at 50% probability ellipsoids
several conformations in solution that do not interconvert in
the NMR time scale under certain temperature conditions. As
the monotriazine molecules 3a and 4a (Scheme 2) do not show
(
H atoms and ester groups were omitted for clarity) for half of the
molecule (a) and two angles of the molecule in full (b).
q
multiple NMe peaks at temperatures as low as 190 K, with ∆G
Since the tetradentate ligand is too rigid to wrap around a single
Ti(IV) center owing to the planarity of the aromatic systems
-1
for rotation of 36.5-38.5 ( 1.3 kJ mol , we conclude that the
rotation around the CAr-N(OH)Me is relatively free for the
bis(triazine) compounds as well under the conditions employed.
We thus conclude that the rotations around the two CAr-NCH2
bonds in 7a are restricted owing to steric interference giving
altogether three isomers, two symmetrical and one asymmetrical
(
C(12)-C(27): 4.68 Å), two ligand units bridge between the
two Ti(IV) ions. The two triazine rings of each ligand thus bind
to separate Ti(IV) centers through the aminoalkoxo groups and
N-donors of the highest electron density, giving an especially
long Ti-Ti distance of 13.8 Å, and the ligand is constrained in
the asymmetrical conformation (Scheme 4). The rigidity of the
molecule is also pronounced in longer Ti-N coordinative bonds
of 2.3-2.4 Å in comparison to the 2.0 Å value observed for
the mononuclear homoleptic complexes, as well as in the
substantial deviation from planarity of the aromatic moieties
of up to 20°. It is also notable that as one cause for the longer
Ti-N bonds, the Ti(IV) centers are not coplanar with the
aromatic moieties of the triazine systems, unlike the observation
with the homoleptic analogues, which is another obvious
consequence of the ligand rigidity on one hand, and the tendency
of the Ti(IV) center to complete its coordination sphere in an
optimal form on the other. Interestingly, a very planar array of
the ethylene bridges of the two bridging ligands is observed,
with a N(11)-C(27)-C(12′)-N(12′) torsion angle of 176.7°
and a 180.0° angle between the two C-C vectors of the ethylene
bridges of the two ligands. Each Ti(IV) ion thus fills altogether
four coordination sites by donors from the chelating ligand while
the two additional covalent bonds are to isopropoxo ligands to
give two octahedral Ti(IV) centers. Altogether, this complex
includes a total Ti:L (bis(triazine)):OiPr ratio of 1:1:2.
(
Scheme 4), where each includes two different ester groups on
q
each triazine ring. The average ∆G calculated based on
coalescence of the two NMe and the two NCH2 signals for
rotation around the CAr-N(Me)CH2CH2 bond is 69.0 ( 1.3 kJ
mol , whereas the ∆G calculated based on coalescence of
NCH2CO2 signals for rotation around the CAr-N(CH2CO2Et)2
bond is 78.7 ( 1.3 kJ mol . Clearly, the compounds 5a and
6
2
-
1
q
-1
q
a demonstrate lower ∆G values of 61.9 ( 1.3 and 64.9 (
-
1
.1 kJ mol , respectively, for rotation around the CAr-N(Me/
H)CH2CH2 bond due to their reduced steric bulk, with higher
restriction in the bulkier compound, as expected.
Reacting 7a with 1 equiv of titanium tetra(isopropoxide) in
THF at room temperature overnight gave a dark-yellow solution.
Single crystals suitable for X-ray crystallography were grown
from diethylether, and an ORTEP view of the structure is
presented in Figure 3 with selected bond lengths and angles
summarized in Table 2.
The structure features a Ci-symmetrical dinuclear species, of
the formula Ti2(µ-L)2(OiPr)4 (L ) bis(triazine)), where the two
Ti(IV) centers are of a highly distorted octahedral configuration.
5
956 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of Bis(hydroxylamino-1,3,5-triazine)
TABLE 2. Selected Bond Lengths (Å) and Angles (deg) for 7b
atoms
value
atoms
value
atoms
N(8)-C(16)
C(16)-N(11)
N(11)-C(28)
N(11)-C(27)
C(12)-C(27)
value
Lengths
Angles
O(1)-Ti
1.931(7)
1.908(7)
1.800(8)
1.794(7)
2.303(8)
N(6)-Ti
2.356(9)
1.300(14)
1.387(14)
1.496(15)
1.480(14)
1.465(16)
O(6)-Ti
O(11)-Ti
O(12)-Ti
N(1)-Ti
N(4)-O(1)
N(9)-O(6)
N(6)-C(15)
C(15)-N(8)
1.342(10)
1.401(10)
1.373(13)
1.349(13)
O(12)-Ti-O(11)
O(12)-Ti-O(6)
O(11)-Ti-O(6)
O(12)-Ti-O(1)
O(11)-Ti-O(1)
O(12)-Ti-N(1)
O(11)-Ti-N(1)
O(6)-Ti-N(1)
95.2(3)
101.7(3)
100.6(3)
97.1(3)
102.0(4)
169.2(3)
93.5(3)
O(1)-Ti-N(1)
O(12)-Ti-N(6)
O(11)-Ti-N(6)
O(6)-Ti-N(6)
O(1)-Ti-N(6)
N(1)-Ti-N(6)
N(6)-C(15)-N(8)
C(15)-N(8)-C(16)
74.7(3)
91.4(3)
171.9(3)
73.4(3)
81.6(3)
80.4(3)
N(8)-C(16)-N(11)
117.1(11)
C(16)-N(11)-C(28)
118.2(11)
117.4(10)
110.2(11)
176.7
88.5
177.0
C(28)-N(11)-C(27)
N(11)-C(27)-C(12)
N(11)-C(27)-C(12)-N(11)
C(28)-N(11)-C(27)-C(12)
N(6)-C(15)-N(8)-C(16)
C(21)-N(10)-C(15)-N(8)
125.3(10)
114.0(10)
82.9(3)
170.6
The cytotoxicity of the dinuclear complex 7b was tested to
which was filtered and recrystallized from acetonitrile to give 5a
as a colorless powder (0.32 g, 71%). The total yield is 24%. Anal.
Calcd for C18H N O : C, 47.99; H, 7.61; N, 37.31. Found: C,
34 12 2
evaluate the influence of the labile isopropoxo groups and
3
5
general ligand lability. Employing the MTT assay, we found
that unlike its homoleptic counterpart 3b (Scheme 2), this
complex exhibits essentially no reactivity against colon HT-29
and ovarian OVCAR-1 cells. It therefore appears that the
hydrolytic stability observed for 3b is essential for cytotoxicity,
a parameter that is more important than the existence of
additional particularly labile monodentate groups, despite the
general assumption that such groups are required to allow
1
4
8.00; H, 7.70; N, 37.04. H NMR (Figure S3-S4) (400 MHz;
CDCl
3
(
1
3
; rt) δ 3.6 (4 H, s, NCH
2
), 3.5 (8 H, q, J ) 7.2 Hz, CH
2
CH
). C NMR
3
, rt) δ 167.0, 165.5, 163.9, 41.3, 37.5,
3
),
1
3
.3 (6 H, s, NMe), 1.2 (12 H, t, J ) 7.1 Hz, CH
Figure S5) (400 MHz; CDCl
3.4. Mp 149 °C.
a (Figures S6-S8). The monosubstituted product was obtained
2 3
CH
6
as described above. The two consequent steps are similar to those
undertaken for 5a, where the monosubstituted product (1.0 g, 4.52
mmol) in THF to which triethylamine (0.63 mL, 4.55 mmol) was
added was reacted with N,N′-dimethylethylenediamine (0.24 mL,
2.27 mmol) in THF and stirred overnight. The colorless powder
obtained following filtration and evaporation was recrystallized from
acetonitrile to give the disubstituted product as colorless crystals
3
5
binding to the biological target following their hydrolysis.
Thus, the longer Ti-N bonds in 7b, which lead to substantially
increased hydrolytic instability, appear to play a significant role
in abolishing the biological activity.
(
0.67 g, 65%). The crystals (0.67 g, 1.48 mmol) in dichloromethane
were refluxed overnight with N-methylhydroxylamine hydrochloride
0.74 g, 8.83 mmol) previously contradicted with NaOH (0.35 g,
.83 mmol) in water, and evaporation of the dichloromethane and
recrystallization from acetonitrile gave 6a as a colorless powder
0.36 g, 51%). The total yield is 22%. Anal. Calcd for C20
C, 50.19; H, 8.00; N, 35.12. Found: C, 50.37; H, 8.14; N, 34.87.
Experimental Section
(
8
4
a (Figures S1-S2). Diethylamine (5.6 mL, 54.13 mmol) in
THF was added dropwise to a solution of cyanuric chloride (2,4,6-
trichloro-1,3,5-triazine) (5.0 gr, 27.11 mmol), in THF at 0 °C after
which the reaction mixture was stirred for an additional 0.5 h. The
colorless solid was filtered, and the THF solution was evaporated
to dryness. The crude product was recrystallized from 2-propanol
to give the monosubstituted product as crystalline solid (4.1 gr,
(
38 12 2
H N O :
1
H NMR (Figure S6-S7) (400 MHz; CDCl
3
; rt) δ 3.7 (4 H, s,
NCH CH N), 3.5 (8 H, q, J ) 6.8 Hz, CH CH
2
2
2
3
), 3.3 (6 H, s, NMe),
1
3
6
7%). This product (1.5 gr, 6.78 mmol) was redissolved in THF;
3.1 (6 H, s, NMe), 1.2 (12 H, t, J ) 7.0 Hz, CH
2
CH
3
). C NMR
N-methylhydroxylamine hydrochloride (2.27 gr, 27.12 mmol)
previously contradicted with NaOH (1.09 gr, 27.12 mmol) in water
was added, and the reaction mixture was refluxed overnight. The
THF was evaporated to yield a colorless precipitate, which was
filtered and recrystallized from 2-propanol to give 4a as a colorless
powder (0.55 g, 34%). The total yield is 23%. Anal. Calcd for
(Figure S8) (500 MHz; CDCl ; rt) δ 167.9, 164.7, 163.6, 46.2, 41.3,
3
37.3, 35.1, 13.3; mp 99 °C.
7a (Figures S9-S18). 7a was synthesized similarly to 5a and
6a starting from cyanuric chloride (2.0 gr, 10.84 mmol) in THF
previously mixed with DIPEA (1.88 mL, 10.79 mmol), at 0 °C
where a color change to light yellow was observed, and dieth-
yliminodiacetate (1.94 mL, 10.83 mmol) in THF. The product of
the first step was recrystallized from 2-propanol (1.73 g, 47%). For
the second step, the first product (1.5 g, 4.45 mmol) in THF mixed
with DIPEA (0.78 mL, 4.48 mmol) was reacted with N,N′-
dimethylethylenediamine (0.24 mL, 2.24 mmol) to give a colorless
powder that was recrystallized from 2-propanol (0.84 g, 54%). This
compound (0.84 g, 1.22 mmol) was further reacted in THF with
N-methylhydroxylamine hydrochloride (0.61 g, 7.32 mmol) previ-
ously contradicted with NaOH (0.29 g, 7.32 mmol) in water.
Refluxing the product in water following THF evaporation gave
6a as a colorless powder that was recrystallized from 2-propanol
(0.55 g, 63%) with a total yield of 16% for all three steps. Anal.
9 18 6 2
C H N O : C, 44.62; H, 7.49; N, 34.69. Found: C, 44.60; H, 7.75;
1
N, 34.61. H NMR (Figure S1) (500 MHz; CDCl
q, J ) 7.1 Hz, CH CH ), 3.4 (6 H, s, NMe), 1.2 (6 H, t, J ) 7.1
). C NMR (Figure S2) (500 MHz; CDCl ; rt) δ 162.9,
62.2, 41.7, 37.0, 13.1; mp 146 °C.
a (Figures S3-S5). The monosubstituted product was obtained
3
; rt) δ 3.5 (4 H,
2
3
13
Hz, CH
2
CH
3
3
1
5
as described above. This product (1.0 g, 4.52 mmol) was redissolved
in acetonitrile and triethylamine (0.63 mL, 4.52 mmol) was added.
Ethylenediamine (0.15 mL, 2.26 mmol) dissolved in dichlo-
romethane was added dropwise at rt, and consequently the reaction
mixture was stirred overnight. The precipitate was filtered, and the
solution was evaporated to give a colorless solid, which was
recrystallized from 2-propanol to give the disubstituted product as
a colorless powder (0.50 g, 52%). The powder (0.43 g, 1.01 mmol)
was dissolved in THF; N-methylhydroxylamine hydrochloride (0.51
g, 3.04 mmol) previously contradicted with NaOH (0.24 g, 3.04
mmol) in water was added, and the reaction mixture was refluxed
for 1 day. The THF was evaporated to give a white precipitate,
Calcd for C28
47.19; H, 6.53; N, 23.40. H NMR (Figure S9-S10) (500 MHz;
-DMSO; 390 K) δ 4.4 (8 H, s, NCH CO), 4.2 (8 H, q, J ) 7.0
Hz, CH CH ), 3.7 (4 H, s, NH2), 3.3 (6 H, s, NMe), 3.1 (6 H, s,
NMe), 1.2 (12 H, t, J ) 7.0 Hz, CH
S11-S13) (500 MHz; d -THF; 280 K) δ 168.0, 167.9, 167.9, 167.8
46 12
H N O10: C, 47.32; H, 6.52; N, 23.65. Found: C,
1
d
6
2
2
3
1
3
2
3
CH ). C NMR (Figure
8
J. Org. Chem. Vol. 73, No. 15, 2008 5957

Hermon and Tshuva
1
2
(
1
(
4
1
CO), 165.7, 165.7, 165.6, 165.5 (Ar ), 163.3, 163.3, 163.3 (Ar ),
The crude yellow product was crystallized from diethylether at rt
3
-1
-1
63.0, 163.0, 163.0, 162.9 (Ar ), 58.3, 58.3, 58.2, 58.2, 58.1
CH CH ), 47.2, 47.1, 47.0, 46.9, 46.8, 46.8 (NCH CO ), 44.1, 44.0,
3.9, 43.8 (NMeCH ), 163.3, 163.3, 163.3 (NMe), 163.1, 163.0,
63.0, 162.9 (NMe), 11.8, 11.8 (CH CH ); mp 117 °C.
b (Figures S19-S20). 4a (100 mg, 0.41 mmol) was reacted
with Ti(OiPr)
(204 mg, 69%). λmax(ether)/nm 320 (ꢀ/M cm 11000). See Figure
1
2
3
2
2
S21 for H NMR of the crystals in d -THF measured at 400 MHz
8
2
in air. Additional characterization by NMR was impeded by the
complex hydrolytic instability.
Crystal Data. 7b was crystallized from diethylether at rt. The
asymmetric unit contains half of the molecule and disorder.
2
3
4
4
(62 µL, 0.21 mmol) in THF for 3 h at rt. The orange
solution was evaporated, and the product was crystallized from THF
34 54 12 2
(C H N O12Ti) , M ) 870.79, triclinic, a ) 10.580(3), b )
at -35 °C as fine needles (95 mg, 90%). λmax(THF)/nm 378 (ꢀ/
1
8
2.585(3), c ) 18.065(4) Å, R ) 89.161(5), ꢀ ) 76.392(5), γ )
-1
-1
M
cm 6000) Anal. Calcd for C18
H
32
N O
12 4
Ti: C, 40.91; H, 6.10,
3
2.305(5)°, U ) 2316.2(10) Å , T ) 173(1) K, space group P1 j,
1
N; 31.81. Found: C, 41.43; H, 6.36; N, 31.58. H NMR (Figure
S19) (400 MHz; CDCl CH ), 3.4
). C NMR
; rt) δ 164.1, 159.5, 42.1, 36.0, 13.2.
Crystal Data. 4b was crystallized from THF at -35 °C. The
asymmetric unit contains one molecule of the complex and a half-
molecule of THF solvent. C18
-1
Z ) 2, µ(Mo KR) ) 0.251 cm , 27170 reflections measured, 10718
3
; rt) 3.6 (8 H, q, J ) 7.0 Hz, CH
2
1
3
2
unique (Rint ) 0.1459). R(F
2σ(I)] ) 0.4253.
°
) for [I > 2σ(I)] ) 0.1618, Rw for [I
3
(
12 H, s, NMe), 1.2 (12 H, t, J ) 7.0 Hz, CH
2 3
CH
>
(Figure S20) (400 MHz; CDCl
3
Acknowledgment. We thank Dr. Roy Shenhar for fruitful
discussions, Dr. Roy Hoffman and Yair Ozeri for NMR advice,
and Dr. Shmuel Cohen for crystallography.
H
32
N
12
O
4
Ti · 0.5(C
4
H
8
O), M )
1
2
129.02, monoclinic, a ) 14.0304(9), b ) 14.6037(9), c )
3
5.6883(16) Å, ꢀ ) 92.9260(10)°, U ) 5256.6(6) Å , T ) 173(1)
-
1
K, space group I2/a, Z ) 4, µ(Mo KR) ) 0.380 cm , 29915
Supporting Information Available: Spectra for 4a,b 5a, 6a,
and 7a,b and crystallographic data for 4b and 7b. This material
is available free of charge via the Internet at http://pubs.acs.org.
2
reflections measured, 6265 unique (Rint ) 0.0347). R(F
σ(I)] ) 0.0505, Rw for [I > 2σ(I)] ) 0.1140.
b (Figure S21). 7a (120 mg, 0.17 mmol) was added to Ti(OiPr)
50 µL, 0.17 mmol) in THF, and the reaction was stirred overnight.
°
) for [I >
2
7
4
(
JO800966S
5
958 J. Org. Chem. Vol. 73, No. 15, 2008