Structural characterization of copper complexes with chiral 1,2,4-triazine-oxazoline ligands

Article abstract of DOI:10.1515/hc-2016-0103

The crystal structure determination of oxazoline-1,2,4-triazine ligand 1f and pyridine-oxazoline ligand 2g was used to analyze their conformational preferences when forming complexes with metals. Proton nuclear magnetic resonance (¹H NMR), electrospray ionization mass spectrometry and UV-vis spectroscopy as well as theoretical calculation using molecular mechanics (MM) were adopted to study the composition and geometry of oxazoline-1,2,4-triazine ligands 1 complexes with copper(II) acetate monohydrate. The study revealed that during the complexation, (i) Cu(II) ion is reduced to Cu(I) upon the ligand-to-metal charge transfer transition and (ii) the ligands form with copper(I) 2:1 (L:Cu) complexes of tetrahedral geometry. On the basis of the findings, the catalytic cycle and the active transition state for the enantioselective nitroaldol reaction (the Henry reaction) catalyzed by 1-Cu are proposed.

Full text of DOI:10.1515/hc-2016-0103

Heterocycl. Commun. 2016; aop
ESwtarWuolcińtsukar*,aZbligcnhiewaKraarcczmtaerzryikzaandtWioaldnemoarfWcysoocpkiper complexes
with chiral 1,2,4-triazine-oxazoline ligands
DOI 10.1515/hc-2016-0103
ring. The enantiocontrolling abilities of the ligands have
been assessed in the asymmetric nitroaldol reaction of a
series of aromatic and aliphatic aldehydes which provide
the β-nitro alcohols with optical purity of up to 92% and
chemical yields up to 95%. It has been shown that the
enantioselectivity of the nitroaldol reaction is controlled
by the substituent on the oxazoline ring, while the chemi-
cal yield depends on the substituents in 1,2,4-triazine ring.
The ligands with 1,2,4-triazine rings possessing a phenyl
substituent in the C-5 position and unsubstituted at C-6
appear the most promising in the asymmetric nitroaldol
reaction. Among them the ligand 1f with a phenyl sub-
stituent in the oxazoline ring and ligand 1n with a fused
indane moiety exhibit the highest activity. Ligand 1p with
two stereocenters catalyzes the nitroaldol reaction with
enantioselectivity comparable to that obtained by using
ligand 1f possessing one stereocenter in the oxazoline
ring. This indicates that an additional stereocenter at the
C-5 position of the oxazoline ring in ligands 1n, 1o and 1p
does not have any influence on the stereochemistry of the
Received June 29, 2016; accepted July 30, 2016
Abstract: The crystal structure determination of oxazo-
line-1,2,4-triazine ligand 1f and pyridine-oxazoline ligand
2g was used to analyze their conformational preferences
when forming complexes with metals. Proton nuclear
magnetic resonance (1H NMR), electrospray ioniza-
tion mass spectrometry and UV-vis spectroscopy as well
as theoretical calculation using molecular mechanics
(MM) were adopted to study the composition and geom-
etry of oxazoline-1,2,4-triazine ligands 1 complexes with
copper(II) acetate monohydrate. The study revealed that
during the complexation, (i) Cu(II) ion is reduced to Cu(I)
upon the ligand-to-metal charge transfer transition and
(ii) the ligands form with copper(I) 2:1 (L:Cu) complexes
of tetrahedral geometry. On the basis of the findings, the
catalytic cycle and the active transition state for the enan-
tioselective nitroaldol reaction (the Henry reaction) cata-
lyzed by 1–Cu are proposed.
Keywords: asymmetric catalysis; chiral 1,2,4-triazine- Henry reaction.
oxazoline ligands; enantioselective nitroaldol reaction;
X-ray diffraction analysis.
Ligands of type 2 can be considered as analogues of
ligands of type 1 in which the 1,2,4-triazine ring is replaced
by a pyridine, pyrimidine or pyrazine ring. They are much
less active in the enantioselective Henry reaction in com-
parison to ligands 1. The use of ligands 2a–2d in the
nitroaldol reaction allows β-nitro alcohols to be obtained
with optical purity not exceeding 34% and chemical yield
varying within the range of 10%–80%. Among ligands 2,
the highest enantioselectivities have been achieved with
ligands 2g and 2h for the reactions of ortho-substituted
benzaldehydes. The β-nitro alcohols are formed with
enantiopurity of 63%–67%, but with low chemical yields
of 22%–44% [5]. The results obtained for ligands 2 indi-
cate that the presence of a 1,2,4-triazine ring in the ligand
structure is essential in promoting high yields and enan-
tioselection. This statement is further confirmed by the
results received in reactions conducted in the presence
of ligands 4a and 4b (Figure 2) in which the 1,2,4-triazine
ring is replaced by phenyl rings. Very low enantioselec-
tion, not exceeding 33% and yield up to 44%, has been
observed in these reactions [3].
Introduction
Compounds that contain the oxazoline ring have been
called privileged ligands for asymmetric catalysis because
of their ability to catalyze various enantioselective pro-
cesses with high enantioselectivity [1, 2]. We have previ-
ously reported the synthesis and asymmetric activity of
chiral oxazoline ligands of classes 1 [3–5], 2 [5] and 3 [6]
(Figure 1). Ligands of class 1 contain in their structure oxa-
zoline and 1,2,4-triazine rings linked by the N-phenylamine
unit. These ligands vary in the type of substituent in the
oxazoline ring and substitution pattern in the 1,2,4-triazine
*Corresponding author: Ewa Wolińska, Department of Chemistry,
Siedlce University, 3 Maja 54, 08-110 Siedlce, Poland,
e-mail: ewol@uph.edu.pl
Zbigniew Karczmarzyk and Waldemar Wysocki: Department of
Chemistry, Siedlce University, 3 Maja 54, 08-110 Siedlce, Poland
Changing the N-phenylamine unit in ligands 1 to pyr-
idine-2-amine or 2-aminopyridine 1-oxide causes the total
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ꢀꢀꢀꢁ
2ꢀ
ꢀE. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligands
R2
R3
N
N
N
R2
R3
N
N
N
N
N
N
N
Ph
N
N
N
N
N
H
H
H
N
N
O
N
O
N
O
H
*
R1
N
O
Ph
Ph
1a - m
1n - o
1p
Ph
1q
1a: R2 = R3 = Ph, R1 = t-Bu (S)
1b: R2 = R3 = Ph, R1 = Ph (S)
1c: R2 = R3 = Ph, R1 = i-Pr (S)
1d: R2 = R3 = Ph, R1 = Bn (R)
1i: R2 = H, R3 = t-Bu, R1 = Ph (S)
1j: R2 = H, R3 = t-Bu, R1 = i-Pr (S)
1k: R2 = H, R3 = t-Bu, R1 = Bn (R)
1l: R2 = Ph, R3 = H, R1 = i-Pr (S)
1m: R2 = Ph, R3 = H, R1 = Ph (S)
1e: R2 = H, R3 = Ph, R1 = t-Bu (S)
1f: R2 = H, R3 = Ph, R1 = Ph (S)
1g: R2 = H, R3 = Ph, R1 = i-Pr (S)
1n
: R2 = H, R3 = Ph
1h: R2 = H, R3 = t-Bu, R1 = t-Bu (S) 1o: R2 = Ph, R3 = H
N
N
H
N
N
O
N
H
N
O
R
2a - f
2g - i
N
=
=
N
N
=
2d: R = i-Pr,
2e: R = Ph,
2a: R = Ph,
2b: R = Ph,
N
N
N
=
2g:
N
N
N
N
N
=
N
2h:
2i:
N
N
=
=
N
N
O
O
N
N
2c: R = Ph,
2f: R = i-Pr,
N
=
N
=
N
N
Ph
Ph
N
N
N
X
N
3a: R1 = t-Bu (S), X = N
3b: R1 = Ph (S), X = N
3c: R1 = i-Pr (S), X = N
3d: R1 = Bn (R), X = N
N
H
O
3e: R1 = t-Bu (S), X =
N
O
*
R1
3f: R1 = Ph (S), X =
N
O
3a - f
Figure 1ꢀChiral oxazoline ligands of the types 1, 2 and 3.
probably does not participate in the copper ion complexa-
tion as lack of enantioselection is observed.
N
H
N
H
In this work, catalytically active complexes for the
nitroaldol reaction were prepared in situ by mixing ligands
1, 2, or 3 and Cu(OAc)2·H2O in 2-propanol or a mixture of
2-propanol/tetrahydrofuran (THF) prior to addition of
substrates. Efforts toward obtaining a crystal of complex
appropriate for X-ray diffraction analysis were unsuccess-
ful. As the isolation of complexes thus formed was not
possible, intensive efforts were made to establish the pref-
O
N
O
N
R
R
4a
4b
Figure 2ꢀLigands 4a and 4b, Rꢁ=ꢁPh.
loss of the stereocontrolling ability of the resultant ligands erential stoichiometry and geometry of complexes and, as
3. The nitroaldol reactions catalyzed by complexes 3–Cu a consequence, to understand the stereoinduction mecha-
produce racemic products, however, with relatively good nism. The crystal structure determination of ligands 1f
yields of up to 79% [6]. A different mode of copper compl- and 2g, UV-vis, nuclear magnetic resonance (NMR) and
exation by ligands 3 in comparison to ligands 1 has been electrospray ionization high resolution mass spectroscopy
postulated. The nitrogen atom of the oxazoline ring in 3 (ESI-HR-MS) studies of the in situ formed complexes as
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ꢁꢀꢀꢀ
E. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligandsꢂ ꢂ3
Figure 3ꢀA view of the X-ray molecular structures of 1f and 2g with the atomic labeling and 50% probability displacement ellipsoids for
non-H atoms.
well as theoretical calculation using molecular mechanics C10–H10…O18 and C13–H13…N2(N1) in 1f and 2g, and
(MM) method were adopted in the research. In this paper, additionally C52–H52…N4 in 1f (Table 1).
we present the results of the work.
Moreover, the phenyl ring C19…C24 adopts a similar
gauche conformation with respect to oxazoline ring in
both molecules with the torsion angles N15–C16–C19–C20
of 63.0(3)° in 1f and 52.5(3)° in 2g, but this conformation is
frozen in the indeno[(1,2-d)(1,3)oxazol-2-yl]phenyl tricyclic
system of 2g. The partially saturated five-membered oxa-
Results and discussion
In order to confirm the assumed molecular structures of zoline and cyclopentene rings are slightly distorted from
investigated ligands and to predict their coordination abil- planarity with the maximum deviation from the mean
ities, the X-ray diffraction analysis of 1f and 2g as model plane of 0.083(3) Å and 0.114(3) Å for the oxazoline ring
compounds was performed. The structure and conforma- in 1f and 2g, respectively, and 0.107(2) Å for cyclopentene
tion of the molecules 1f and 2g in the crystal are shown in ring in 2g.
Figure 3.
The presence of intramolecular N7–H7…N15 hydro-
The X-ray diffraction investigations confirmed the gen bond in 1f and 2g determines the geometry of mole-
previously assumed absolute configuration S at C16 atom cule, in which the chelation of a metal is possible between
for 1f, and R at C16 and S at C17 atoms for 2g. The bond
lengths and angles in molecules of 1f and 2g do not differ
Table 1ꢀIntramolecular hydrogen-bond geometry (Å, °) in compounds
significantly from those reported for similar structure of
1f and 2g.
N-{2-[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}-
5,6-diphenyl-1,2,4-triazin-3-amine [7]. In both molecules,
D–H...A
ꢁ
D–Hꢁ
H...Aꢁ
D...Aꢁ
D–H...A
the central secondary N7-amino group is planar with the
sum of the angles around the N-atom of 360.6° in 1f and
359.8° in 2g, and it is co-planar with the triazine (1f) and
pyridine (2g) rings and oxazolylphenyl moiety with the
torsion angles N2(N1)–C3(C2)–N7–C8 of 1.6(4)° and 1.0(3)°,
1f
N7–H7...N15
ꢃ
0.90(4)ꢃ
0.93ꢃ
1.99(4)ꢃ
2.33ꢃ
2.737(3)ꢃ
2.699(4)ꢃ
2.845(4)ꢃ
2.807(4)ꢃ
140(3)
103
C10–H10...O18 ꢃ
C13–H13...N2
C52–H52...N4
ꢃ
ꢃ
0.93ꢃ
2.21ꢃ
125
0.93ꢃ
2.49ꢃ
100
the torsion angles C3(C2)–N7–C8–C9 of 2.2(5)° and −7.5(4)° 2g
N7–H7...N15
ꢃ
0.94(3)ꢃ
0.93ꢃ
0.93ꢃ
1.84(3)ꢃ
2.40ꢃ
2.33ꢃ
2.665(2)ꢃ
2.752(3)ꢃ
2.944(3)ꢃ
146(3)
103
123
and the torsion angles C8–C9–C14–C15 of −2.5(5)° and
−3.1(3)° for 1f and 2g, respectively. This planarity is stabi-
lized by the intramolecular hydrogen bonds N7–H7…N15,
C10–H10...O18 ꢃ
C13–H13...N1
ꢃ
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ꢀꢀꢀꢁ
4ꢀ ꢀE. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligands
N7-amine and N15-oxazoline atoms. This kind of chelation not participate in the complexation. It explains the lack
of the zinc atom is observed in the complex of N-{2-[(4S)- of enantiocontrolling ability of ligand 3a in the nitroaldol
4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}pyridine- reaction [6]. This complexation manner probably occurs
2-amine and ZnCl2 with the change of the position of the for other not active ligands 3 as well. The presence of free
pyridine ring on the opposite with respect to the amine ligands in the analyzed samples indicates that the com-
group and shift of the H7 proton to the pyridyl nitrogen plexes of ligands with Cu(OAc)2·H2O are not stable, and
atom [8]. Moreover, in the conformation observed in the equilibrium between the complex and ligand is shifted
1
the crystal of 1f, an additional (or competitive with the toward free ligand. H NMR spectra were also obtained
N7-amine atom) coordination center at the N4-triazine for complexes with other ligands, but they were usually
atom is possible. On the one hand, this atom can accept difficult to analyze due to paramagnetic broadening of
a proton from the amino group without changing the the signals. More detailed magnetic resonance studies,
position of the triazine ring or, on the other hand, it can e.g. 15N NMR of these complexes, were not conducted due
become an additional coordination center for the metal to low concentrations of the complexes present in the
with proton transfer from the amino group to the nitrogen samples and broadening of 1H NMR signals.
N2 atom of the triazine ring. The N4 and N2 nitrogen atoms
Spectrophotometric investigations of complexes were
of the triazine ring are recognized as being better proton further conducted. The electronic spectrum of ligand 1f
acceptors than the N1 nitrogen atom [9].
shows significant absorption bands at 288 and 325 nm
Proton nuclear magnetic resonance (1H NMR) analy- attributed to π-π* and n-π* transitions, respectively
sis of the mixtures obtained after mixing ligand with (Figure 5). In the presence of copper, the band at 325 nm
Cu(OAc)2·H2O revealed the presence of two sets of signals is shifted to 377 nm, which indicates the formation of
in the spectra: signals of free ligand protons and signals complex. This band is associated with a broad shoulder at
shifted toward lower field attributed to proton of the the red end of the spectrum (>ꢀ420 nm) (Figure 5).
complex. Figure 4 presents spectra of ligand 1f and 1f–Cu
The Yoe and Jones’ mole-ratio method at constant con-
complex obtained after mixing ligand 1f and Cu(OAc)2·H2O. centration of Cu(II) (2ꢀ×ꢀ10−3 m) and varying concentrations
In the spectra of 1f–Cu, diagnostic signals of the free- (0.0 m to 5.2ꢀ×ꢀ10−3 m) of ligand 1f was applied to determine
ligand oxazoline-ring protons are present at 4.26, 4.83 and the stoichiometry of complex 1f–Cu (Figure 6). As can be
5.66 ppm. The signals at 5.95, 6.52 and 6.70 ppm are attrib- seen, the absorption of the d-d band at 669 nm, assigned
uted to the respective oxazoline protons of complex 1f–Cu. to copper(II) acetate, is decreasing with increasing ligand
The shift toward the lower field must be a result of concentration, but it is not accompanied by shifting of the
deshielding caused by transferring the electron pair from band (Figure 6C). This obviously indicates that Cu(II) ion
the oxazoline nitrogen to the copper ion. That shifting is is reduced to Cu(I) upon ligand-to-metal charge transfer.
not observed in the spectra of 3a–Cu. Signals from the oxa-
zoline protons of 3a–Cu complex and free ligand overlap,
which may suggest that the oxazoline nitrogen atom does
Figure 4ꢀ1H NMR spectra (CDCl3, 400 MHz) of ligand 1f (A) and
complex 1f–Cu formed in situ by mixing 1f and Cu(OAc)2·H2O (B).
Figure 5ꢀUV-vis spectra of ligand 1f (4ꢁ×ꢁ10−5 m) in THF and complex
1f–Cu formed in situ by mixing 1f and Cu(OAc)2·H2O in THF.
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ꢁꢀꢀꢀ
E. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligandsꢂ ꢂ5
Figure 6ꢀ(A) Stoichiometry studies for 1f–Cu complex at 520 nm using copper concentration of 2ꢁ×ꢁ10−3 m and varying concentrations (0.0 m
to 5.2ꢁ×ꢁ10−3 m) of ligand 1f. (B) Plot of the absorption at 520 nm as a function of L:Cu mole ratio. (C) Decreasing absorption of the d-d band of
Cu(II) with increasing concentration of ligand.
The low-energy absorption, broad shoulder, present in the 1n–Cu. Complex 2g–Cu formed by the ligand with a pyri-
complex spectra (Figure 5) can be assigned to metal-to- dine ring instead of a 1,2,4-triazine ring was also investi-
ligand charge transfer (MLCT) transitions, which is a char- gated by ESI mass spectroscopy. The spectra indicate the
acteristic for Cu(I) complexes [10]. The absorption of the formation of the Cu(II) complex predominantly by showing
shoulder measured at 520 nm is increasing with increas- the signal for ion with m/z 716.1953 being nearly identi-
+
ing amount of ligand. The highest absorption is observed cal with the mass calculated for [2(2g-H)ꢀ+ꢀCu(II)ꢀ+ꢀH] .
at a 2:1 ratio of L:Cu and it does not change on addition of The presence of 2g–Cu(I) complex cannot be definitely
larger amounts of ligand (Figure 6B). This study reveals a excluded as the signal corresponding to it may be hidden
2:1 (L:Cu) stoichiometry in the complex formed between under the signal of the Cu(II) complex. It can be suggested
ligand 1f and Cu.
that the presence of Cu(I) ions could be a result of a redox
The complexes of ligands 1 with Cu(OAc)2·H2O were process which typically occurs with ESI conditions during
also studied by ESI-HR-MS. ESI is a sensitive ionization the study [12]. However, the findings obtained from the
mode and thus considered as a very appropriate method UV-vis study suggest that Cu(I) ions originally exist in the
for the investigation of complexes, although the ions in samples subjected to ESI-MS analysis. The intensities of
the gas phase can be different from those present in solu- the peaks for ions of the complexes are very low in com-
+
tion [11]. As the attempted isolation of complexes failed, parison with those of the free ligand ions (Lꢀ+ꢀH) , which
samples obtained by mixing ligand with Cu(OAc)2·H2O in are the most abundant peaks in the spectra. Peaks for ions
2-propanol were subjected to mass spectrometry analy- corresponding to complexes composed of one molecule
sis after evaporation of 2-propanol. Thus, ESI-HR mass of ligand are not present in the spectra of the analyzed
spectra of several complexes 1–Cu were obtained. In all samples. The mass spectrometry study confirms 2:1 (L:Cu)
+
spectra, the presence of ions [2Lꢀ+ꢀCu(I)] was observed. stoichiometry of complexes formed between ligands 1 and
The mass spectrum of the 1f–Cu complex shows signal Cu(OAc)2·H2O and the existence of Cu(I) species in solu-
at m/z 849.2462 corresponding to the calculated mass tions of the samples.
+
1
of [2(1f)ꢀ+ꢀCu(I)] . The signal of ion of m/z 873.2457 is
The results of MS, UV-vis and H NMR spectroscopic
observed in the spectrum of 1n–Cu, which matches the studies indicate that ligands 1, 2 and 3 form different
value expected for [2(1n)ꢀ+ꢀCu(I)] . Analogous signals for catalytic species with copper acetate. This may explain
+
ions with m/z 1001.3078 and m/z 809.3077 are present in different behavior between the ligands in the asymmetric
the spectra of 1b–Cu and 1i–Cu, respectively. The mass nitroaldol reaction: ligands 1 possess the highest enan-
spectra of the investigated complexes indicate the exist- tiocontrolling ability, ligands 2 show significantly lower
+
ence of [2(L-H)ꢀ+ꢀCu(II)ꢀ+ꢀH] ions corresponding to Cu(II) activity, while ligand 3 is not stereo-active in the reac-
complexes as well, but the intensity is lower and is varied tion. The colors of 2-propanol solutions of complexes
depending on the ligand. The lowest intensity of [2(L- formed from ligands 1, 2 and 3 suggest the oxidation state
+
H)ꢀ+ꢀCu(II)ꢀ+ꢀH] ion is observed for complexes 1f–Cu and of the copper ion and the formation of different species.
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ꢀꢀꢀꢁ
6ꢀ ꢀE. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligands
Thus, the solution of complexes 1–Cu is reddish brown, study. More sterically hindered ligands 1 tend to form tet-
while the solutions obtained by mixing ligands 2 or 3 and rahedral four-coordinated complexes with copper(I) ions.
copper acetate monohydrate are typically green due to the Less-crowded ligands 2 with an unsubstituted six-mem-
color of Cu(II) ions.
bered heterocyclic ring support square-planar geometry
1
Based on the UV-vis, H NMR and MS studies, we of complexes with copper(II), as suggested for complex
propose the following complexation mode of ligands 1 and 2g–Cu on the basis of its MS spectrum. Formation of
Cu. Two ligand molecules coordinate to the copper(II) ion species with Cu(II) of different geometries can explain the
with the amino and the oxazoline nitrogen atoms, initially lower enantiocontrolling activity of ligands 2.
forming sterically crowded square planar complex which
Taking into account the above findings, the catalytic
undergoes reduction of Cu(II) to Cu(I) and rearranges nitroaldol reactions for several aldehydes were rerun
to a distorted tetrahedral four-coordinated geometry, using a 2:1 ratio of ligand 1f and Cu(OAc)2·H2O (Table 2,
typical of Cu(I) complexes [10, 13]. The process is associ- enries 1–10).
ated with the secondary amino-group proton shift to the
The results thus obtained are comparable to those
six-membered heterocycle nitrogen atom. The shifting is obtained in reactions conducted with 1:1 ratio of ligand
more favorable for ligands 1 with the 1,2,4-triazine ring 1f and Cu [3]. As the yields and enantioselectivities were
where the N2 and N4 nitrogen atoms are the most likely to not improved using 2:1 ratio of ligand 1f and Cu(OAc)2·H2O,
accept the proton. Due to the lack of suitable crystals for it can be suggested that under both conditions the same
X-ray diffraction analyses of 1f–Cu and 2g–Cu complexes, catalytic complex is formed. On the basis of the UV-vis and
molecular modeling studies were undertaken to confirm MS studies, a complex of stoichiometry 2:1 (1f:Cu) is pos-
their predicted molecular structures from MS investiga- tulated. Under both conditions, the complex is formed in
tions. The molecular structures of complexes (Figure 7) the amount sufficient to catalyze the nitroaldol reaction
were obtained using molecular mechanics calculations with the same efficiency. According to the equilibrium
with the MM+ force field. In both complexes, the copper established between ligand and complex, free ligand is
ion is coordinated to two N-atoms of the central secondary
amine groups and two N-atoms of the oxazoline rings of
Table 2ꢀThe catalytic enantioselective Henry reaction with 2:1 ratio
the two bidentate 1f and 2g ligands. The CuN4 unit adopts
of ligand 1f and Cu(OAc)2·H2O and without Cu(OAc)2·H2O.a
a slightly distorted tetrahedral geometry with Cu–N bonds
within the range 1.823–1.832 Å in 1f and 1.823–1.827 Å in
Cu(OAc)2·H2O
ligand 1f
OH
O
2g. The N–Cu–N angles are between 101.10° and 116.13° in
1f and 100.50° and 116.32° in 2g. This calculated geometry
for 1f–Cu and 2g–Cu complexes is the result of the para-
metrization used for the Cu-atom in the MM+ force field.
However, these calculations show the possibility of the
formation of stable complexes 1f–Cu and 2g–Cu with rea-
sonable geometry for the nitroaldol reaction conditions.
TheexistenceoftwodifferentspeciesofCu(I)andCu(II)
complexes is suggested based on the mass spectrometry
+
H NO
C
3
2
NO2
R
R
H
i-PrOH
rt
5a-j
6
7a-j
ꢁ R
ꢁ Aldehydeꢁ L (%)ꢁ Cu (%)ꢁ Productꢁ Yieldb (%)ꢁ eec (%)
1 ꢃ Ph
ꢃ 5a
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
10ꢃ
10ꢃ
10ꢃ
10ꢃ
10ꢃ
10ꢃ
10ꢃ
10ꢃ
10ꢃ
10ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
5ꢃ
0ꢃ
0ꢃ
0ꢃ
7aꢃ
7bꢃ
7cꢃ
7dꢃ
7eꢃ
7fꢃ
24ꢃ 54 (S)
68ꢃ 59 (S)
81ꢃ 38 (S)
83ꢃ 35 (S)
92ꢃ 74 (S)
13ꢃ 50 (S)
53ꢃ 64 (S)
85ꢃ 75 (S)
57ꢃ 48 (S)
51ꢃ 48 (S)
15ꢃ rac
2 ꢃ 2-NO2C6H4 ꢃ 5b
3 ꢃ 3-NO2C6H4 ꢃ 5c
4 ꢃ 4-NO2C6H4 ꢃ 5d
5 ꢃ 2-ClC6H4 ꢃ 5e
6 ꢃ 3-MeC6H4 ꢃ 5f
7 ꢃ 2-MeOC6H4 ꢃ 5g
8 ꢃ 2-BrC6H4 ꢃ 5h
9 ꢃ 3-MeOC6H4 ꢃ 5i
10ꢃ 2-MeC6H4 ꢃ 5j
11ꢃ 3-NO2C6H4 ꢃ 5c
12ꢃ 4-NO2C6H4 ꢃ 5d
13ꢃ 2-ClC6H4 ꢃ 5e
7gꢃ
7hꢃ
7iꢃ
7jꢃ
7cꢃ
7dꢃ
7eꢃ
5ꢃ
13ꢃ rac
5ꢃ
20ꢃ rac
aAll reactions were performed on a 0.5 mmol scale in 2 mL of i-PrOH
at room temperature for 98 h.
bYields of isolated products.
cEnantiomeric excess was determined by HPLC using the Chiralcel
OD-H column. The absolute configuration was assigned by compar-
ing their specific rotations or the HPLC elution order with data from
Figure 7ꢀThe structures of 1f–Cu and 2g–Cu complexes obtained
after theoretical calculation using the molecular mechanics method. the literature.
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E. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligandsꢂ ꢂ7
present in the reaction mixture and it may therefore affect stronger bases, which activates the unselective reaction
the reaction course as a catalyst. Different amounts of route, (ii) competitive coordination to copper ion or (iii)
free ligand must be present in reaction run with 1:1 and coordination to 1f–Cu complex instead of substrate which
2:1 ligand-to-copper ratios, but as the results obtained causes inactivation. Another disadvantage of using exter-
under both conditions are similar, it can be suggested that nal bases can be promotion of elimination of water from
free ligand does not have any impact on the reaction. To the β-nitro alcohols.
further investigate the issue, the nitroaldol reactions were
In a reaction run without addition of base, the
carried out in the presence of ligand 1f without addition nitromethane must be deprotonated by acetate ion or by
of copper. The β-nitro alcohols thus formed were isolated nitrogen atoms present in the six-membered heterocyclic
as racemic mixtures in low chemical yields of 13%–20% ring of the ligand. Considering the basicity of the nitrogen
(Table 2, entries 11–13), which is consistent with the sug- atoms of the four heterocyclic systems present in ligands 1
gestion that free ligand does not have any influence on the and 2, 1,2,4-triazine is the weakest base among them [14].
stereochemical outcome of the reaction.
As ligands 1 with the lowest basic six-membered hetero-
Thenitroaldolreactionscatalyzedbythe1,2,4-triazine- cyclic ring exhibit the highest enantiocontrolling ability,
oxazoline ligands were run in the absence of base. Addi- the nitrogen atoms of the six-membered heterocyclic ring
tion of an external organic base to the reaction catalyzed cannot be responsible for deprotonation of the nitrometh-
by 1f-Cu has a negative influence on enantioselectivity. ane. Thus, probably the acetate ion plays the role of a base.
1
Weaker bases exhibit lower impact on enantioselectivity
The H NMR, UV-vis and MS studies revealed that
(Table 3, entry 1), while the stronger ones promote forma- the equilibrium between the complexes and ligands is
tion of product with optical purity lower than 20%. The strongly shifted toward free ligands, which indicates that
strongest bases N,N-diisopropylethylamine (DIPEA) and the complexes are not stable. Therefore, all attempts to
1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) direct the reac- obtain single crystals from complexes suitable for X-ray
tion toward racemic product (Table 3, entries 5 and 6).
analysis appeared impossible. Due to the lack of crystal
Unfavorable impact of DIPEA and DBU can be a result structure of complexes, the transition state of the Henry
of (i) deprotonation of not-coordinated nitromethane by reaction is discussed on the basis of the findings obtained
from the 1H NMR, UV-vis, MS studies, the X-ray diffraction
analysis of ligands and the modeled complex obtained
Table 3ꢀThe catalytic enantioselective Henry reaction in the presence
using MM calculations. Theoretical calculation is rec-
of external base.a
ognized as an efficient method to optimize geometry of
O
OH
Cu(OAc)2·H2O (5 mol%)
complexes and to explain the mechanism of stereoinduc-
tion [15–17]. The suggested transition state and the cata-
lytic cycle for the nitroaldol reaction catalyzed by 1-Cu
are shown in Scheme 1A. As the Cu(I) complexes easily
undergo ligand exchange [18, 19], the replacing of one
molecule of ligand with the aldehyde and nitromethane
in 1–Cu complex takes place to generate complex 8. The
nitroalkane is deprotonated by acetate ion, which gives
state 9, and finally, transition state 10 is formed. Then, the
nitroaldol product is released and complex 8 is regener-
ated by binding molecules of nitromethane and aldehyde.
Binding of the aldehyde to the southern position is prob-
ably energetically more favored as the process avoids the
steric repulsion between the phenyl group of the aldehyde
and the substituent in the oxazoline ring. In the nitroaldol
reactions controlled by (S)-configured ligands 1, the (S)-
enantiomers of β-nitro alcohols are formed in excess. To
ensure the stereoinduction, the nitronate must attack
the aldehyde from the Re face (Scheme 1B). Possible π-π
interactions between the 1,2,4-triazine ring or phenyl sub-
stituent in its C-5 position and the aldehyde phenyl ring
keep the aldehyde in a position which makes the Re face
NO2
ligand 1f (5 mol%)
H
+
CH3NO2
Base (10 mol%)
6
i-PrOH
rt
NO2
NO2
5c
7c
ꢁ
Base
ꢁ
pKaꢁ
Yieldb (%)ꢁ
eec (%)
1ꢃ
2ꢃ
3ꢃ
4ꢃ
5ꢃ
6ꢃ
NMM
DABCOꢃ
DMAP ꢃ
TEA
DIPEA ꢃ
DBU
ꢃ
7.4ꢃ
8.8ꢃ
66ꢃ
80ꢃ
79ꢃ
82ꢃ
56ꢃ
74ꢃ
41
16
14
8.5
6
9.2ꢃ
ꢃ
10.8ꢃ
11.4ꢃ
12.5ꢃ
ꢃ
rac
aAll reactions were performed on a 0.5 mmol scale in 2 mL of i-PrOH
at room temperature for 18 h.
bYields of isolated products.
cEnantiomeric excess was determined by HPLC using the Chiralcel
OD-H column. The absolute configuration was assigned by compar-
ing their specific rotations or the HPLC elution order with data from
the literature.
NMM, N-methylmorpholine; DABCO, 1,4-diazabicyclo[2.2.2]octane;
DMAP, 4-(N,N-dimethylamino)pyridine; TEA, threethylamine;
DIPEA, N,N-diisopropylethylamine; DBU, 1,8-diazabicyclo-
[5.4.0]undec-7-ene.
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ꢀꢀꢀꢁ
8ꢀ ꢀE. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligands
A
N
NH
N
O
N
N
Cu(I)
N
N
N
O
+
HN
N
1f-Cu
O
O
N+
O-
R
H
L
O
N
H
R1
O
O
O
H
OH
N
H
NO2
R
N
N
H
AcO-
HN
N
R
O
N+
O
+
O-
AcOH
8
R
H
O
O
N
R1
R1
-O
-O
N+
N+
N
N
N
N
O
O
N
O
H
O
HN
HN
N
H
N
R
R
10
9
B
O
disfavored
O
R1
-O
R1
N
N
N+
H
O
Cu
R
N
N
Cu
O
O
HN
N
(S)-isomer
N
H
O
HN
N
N
π−π
N+
-O
R
10
Re face
favored
Scheme 1ꢀProposed catalytic cycle (A) and transition state (B).
accessible for attack of the nitronate ion. The π-π interac-
tions between the phenyl substituent in the 1,2,4-triazine
Conclusion
C-5 position and the aldehyde phenyl group can also The X-ray diffraction analysis of model compounds 1f
explain the higher activity of ligands with 1,2,4-triazine and 2g confirmed their molecular structures. Based on
substituted in the C-5 position with a phenyl ring.
the geometry and conformation of 1f and 2g in the crys-
The more electron-withdrawing 1,2,4-triazine ring in talline state, the possibility of metal complex formation
complexes 1–Cu makes the copper ion more acidic, which involving the investigated oxazoline-based compounds as
results in better activation of the coordinated aldehyde potential ligands was discussed. Formation of complexes
toward the attack of nitromethane. Ligands 2 possessing between ligands 1 and copper is consistent with the analy-
1
weaker electron-withdrawing heterocyclic rings are less sis of H NMR spectra, where the shifts of ligand proton
activated, which can additionally explain the lower enan- signals are observed as a result of complexation. This
tioselectivity observed in the reactions catalyzed by these conclusion is strongly supported by the analysis of UV-vis
ligands.
spectra. On the basis of the UV-vis and MS studies, the 2:1
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ꢁꢀꢀꢀ
E. Wolińska et al.: Cu complexes with chiral 1,2,4-triazine-oxazoline ligandsꢂ ꢂ9
of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre (CCDC), 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0) 1223 336 033; email: deposit@
ccdc.cam.ac.uk].
(L:Cu) stoichiometry of complexes 1–Cu was established.
The study also revealed that Cu(II) ions are reduced to
Cu(I) ions upon ligand coordination via ligand-to-metal
charge transfer. Studies of ligands 1 support the forma-
tion of distorted tetrahedral Cu(I) complexes, while analy-
Crystal data of 1fꢁC24H19N5O, Mꢀ=ꢀ393.44, orthorhombic, space group
sis of the ESI-MS spectra of ligands 2g strongly suggests P212121 aꢀ=ꢀ5.4030(2), bꢀ=ꢀ10.2366(3), cꢀ=ꢀ34.5542(10) Å, Vꢀ=ꢀ1911.15(10)
Å3, Zꢀ=ꢀ4, dcalcꢀ=ꢀ1.367 mg m−3, F(000)ꢀ=ꢀ824, μ(Cu Kα)ꢀ=ꢀ0.699 mm−1,
that these ligands are preferentially involved in chelation
Tꢀ=ꢀ120.01(10) K, 27621 measured reflections (θ range 4.50–76.61°,
with copper(II). The possibility of formation of tetrahedral
3983 unique reflections (Rintꢀ=ꢀ0.077), final Rꢀ=ꢀ0.044, wRꢀ=ꢀ0.107,
complexes is supported by theoretical calculation using
Sꢀ=ꢀ1.079 for 3625 reflections with Iꢀ>ꢀ2σ(I).
the MM method. It is postulated that the higher enan-
tiocontrolling ability of ligands 1 is the result of the high
electron-withdrawing character of the 1,2,4-triazine ring
and their tendency to form complexes with Cu(I) ion of
tetrahedral geometry.
Crystal data of 2gꢁC21H17N3O, Mꢀ=ꢀ327.38, orthorhombic, space group
P212121, aꢀ=ꢀ6.0870(1), bꢀ=ꢀ11.8809(1), cꢀ=ꢀ21.9053(2) Å, Vꢀ=ꢀ1584.17(2)
Å3, Zꢀ=ꢀ4, dcalcꢀ=ꢀ1.373 mg m−3, F(000)ꢀ=ꢀ688, μ(Cu Kα)ꢀ=ꢀ0.687 mm−1,
Tꢀ=ꢀ120.01(10) K, 44278 measured reflections (θ range 4.04–76.24°),
3320 unique reflections (Rintꢀ=ꢀ0.108), final Rꢀ=ꢀ0.045, wRꢀ=ꢀ0.091,
Sꢀ=ꢀ1.153 for 3171 reflections with Iꢀ>ꢀ2σ(I).
Experimental
General procedure for the catalytic enantioselective
Henry reaction
1H NMR spectra were recorded at 400 MHz on a Varian 400 spectrom-
eter. Chemical shifts are reported relative to the solvent resonance as
the internal standard. Mass spectra were obtained by using an LTQ
Orbitrap Velos (Thermo Scientific) spectrometer. UV-vis spectra were
obtained by using a Shimadzu UV-3600 spectrophotometer. Optical
rotation values were measured at room temperature with a Perkin-
Elmer polarimeter. The ee values were obtained by the high per-
formance liquid chromatography (HPLC) (Knauer) analysis using a
chiral stationary phase column (Chiralcel OD-H) eluting with isopro-
panol/hexanes. Thin layer chromatography (TLC) was carried out on
aluminium sheets precoated with silica gel 60 F254 (Merck). Column
chromatography separations were performed using a Merck Kieselgel
60 (0.040–0.060 mm).
A mixture of Cu(OAc)2·H2O (5.5 mg, 0.027 mmol, 5.5 mol%) and
ligand 1f (0.05 mmol, 5 mol%) in anhydrous isopropanol (2 mL)
was stirred at room temperature for 4 h under argon atmosphere
to give a reddish-brown solution. The aldehyde (0.5 mmol) and
nitromethane (270 μL, 5 mmol) were added and the mixture was
allowed to stand at room temperature for 4 days. Then the solvent
was removed under reduced pressure and the product was isolated
by column chromatography. The ee values of the nitroalcohols were
determined by chiral HPLC analysis using the Chiralcel OD-H col-
umn. The absolute configurations of the products were assigned by
comparing their specific rotations or the retention times in HPLC
with the literature data.
X-ray structure determinations of 1f and 2g
Acknowledgments: The authors are grateful to Dr. Anna
Kamecka and Professor Robert Kawęcki for helpful
discussions.
X-ray diffraction data of 1f and 2g were collected at 120 K on the
SuperNova X-ray diffractometer equipped with an Atlas S2 CCD detec-
tor; crystal sizes 0.45ꢀ×ꢀ0.05ꢀ×ꢀ0.02 mm (1f) and 0.32ꢀ×ꢀ0.08ꢀ×ꢀ0.05 mm
(2g), CuKα (λꢀ=ꢀ1.54184 Å) radiation, ω scans. The analytical numeric
absorption correction using a multifaceted crystal model based on
expression derived by Clark and Reid [20] was applied; the ratios
Tmin/Tmax of 0.708/1.000 for 1f and 0.867/0.971 for 2g were obtained.
Both structures were solved by direct methods using SHELXS-2013
[21] and refined by full-matrix least-squares with SHELXL-2014/7
[21]. All H-atoms were located by difference Fourier synthesis. The
N-bound H-atom was refined freely. The remaining H-atoms were
treated as riding on their C-atoms, with C–H distances of 0.93 (aro-
matic), 0.96 (CH3), 0.97 (CH2) and 0.98 Å (CH). All H-atoms were
assigned Uiso(H) values of 1.5Ueq(N,C). The absolute configuration for
both compounds was established from the absolute configuration of
the substrate used for their synthesis and confirmed by anomalous
dispersion effects with the Flackꢀ×ꢀparameter of −0.2(2) and 0.02(12)
for 1331 and 1275 quotients for 1f and 2g, respectively [22]. All calcula-
tions were performed using the WINGX version 2014.1 package [23].
CCDC-1487643 (1f) and CCDC-1487644 (2g) contain the supplementary
crystallographic data for this paper. These data can be obtained free
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