DDQ-supported alkoxylation of 2-aza-21-carbaporphyrin and noncatalyzed transetherification of its 3,21-dialkoxy derivatives

Article abstract of DOI:10.1021/jo301573e

An oxidative addition of primary alkoxyls into two sites of Nconfused porphyrin (NCP) has been accomplished by means of alcohols in the presence of a stoichiometric amount of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The resulting aromatic monocationic species 1-R₃ (R = Me, Et) were characterized by the NMR and, in the case of triethoxy-NCP, by monocrystal X-ray diffraction analysis. One alkoxy group is located in position 3, on the macrocycle's perimeter, while two -OR moieties are attached to the internal carbon (position 21) of the conf used pyrrole. The 3-EtO-21-Cl-NCP 2, which is formed as a byproduct, was also structurally characterized by means of X-ray diffraction. Reduction of 3-RO-21-(RO)₂-NCP with hydrazine hydrate gave selectively a neutral and intrinsically chiral 3,21-bis (alkoxy)NCP 3-R₂. Dealkylation of the externally bonded 3-OR fragment under basic conditions leading to a zwitterionic aromatic 3-oxo-species 4-R₂, which still possesses the internal ketal functionality, was established by the NMR and X-ray diffraction methods. An unprecedented transetherification for the internal alkoxyl of 3-R₂ can be achieved under very mild conditions and without catalyst. One of the alkoxyl-exchange products, i.e., 3-ethoxy-21-methoxy-NCP, was characterized by the X-ray diffraction method. The substitution proceeds via an associative (S_N2) mechanism resulting in an inversion of the chirality of 3-RR′, which was shown by means of the NMR and chirooptical methods.

Full text of DOI:10.1021/jo301573e

Article
pubs.acs.org/joc
DDQ-Supported Alkoxylation of 2‑Aza-21-carbaporphyrin and
Noncatalyzed Transetherification of Its 3,21-Dialkoxy Derivatives
Xiaofang Li,*,† Bin Liu,† Xin Xu,† and Piotr J. Chmielewski*,‡
†Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan Province College Key
Laboratory of QSAR/QSPR, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology,
Xiangtan, Hunan 411201, China
‡Department of Chemistry, University of Wrocław, 14 F. Joliot-Curie Street, 50 383 Wrocław, Poland
S
* Supporting Information
ABSTRACT: An oxidative addition of primary alkoxyls into two sites of N-
confused porphyrin (NCP) has been accomplished by means of alcohols in the
presence of a stoichiometric amount of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ). The resulting aromatic monocationic species 1-R3 (R = Me, Et) were
characterized by the NMR and, in the case of triethoxy-NCP, by monocrystal X-ray
diffraction analysis. One alkoxy group is located in position 3, on the macrocycle’s
perimeter, while two −OR moieties are attached to the internal carbon (position
21) of the confused pyrrole. The 3-EtO-21-Cl-NCP 2, which is formed as a
byproduct, was also structurally characterized by means of X-ray diffraction.
Reduction of 3-RO-21-(RO)2-NCP with hydrazine hydrate gave selectively a neutral
and intrinsically chiral 3,21-bis(alkoxy)NCP 3-R2. Dealkylation of the externally
bonded 3-OR fragment under basic conditions leading to a zwitterionic aromatic 3-
oxo-species 4-R2, which still possesses the internal ketal functionality, was
established by the NMR and X-ray diffraction methods. An unprecedented transetherification for the internal alkoxyl of 3-R2
can be achieved under very mild conditions and without catalyst. One of the alkoxyl-exchange products, i.e., 3-ethoxy-21-
methoxy-NCP, was characterized by the X-ray diffraction method. The substitution proceeds via an associative (SN2) mechanism
resulting in an inversion of the chirality of 3-RR′, which was shown by means of the NMR and chirooptical methods.
as reaction with dipolar agents36,37 or active methylene
INTRODUCTION
■
reagents14 allowing introduction of a substituent or substituents
Porphyrins and their analogues and homologues are macro-
on the macrocycle’s perimeter. In the present paper we report
cyclic systems which are very broadly spread in pure and
reactivity of the NCP ring that yields a system bearing alkoxy
applied chemistry owing to their versatile redox, acid−base,
substituents on both external and internal carbon of the
optical, and coordination properties. The attractiveness of
confused pyrrole. A 3-methoxylated derivative has been first
porphyrinoids is inter alia due to their reactivity which allows
obtained by Furuta et al. upon transformation of N-fused
profound modification of the structure or properties of the
porphyrin under basic conditions.16 More recently was reported
system without destruction of the macrocyclic ring.
the formation of externally alkoxylated systems which can be
2-Aza-21-carbaporphyrin, also known as N-confused por-
obtained from the silver(III) complexes of NCP.48 The 21-RO-
phyrin (NCP),1−5 an isomer of porphyrin of the same skeleton
substituted derivatives of N-confused porphyrin have not been
of macrocyclic ring, shares part of the reactivity with its regular
obtained to date, although an efficient method of FeCl3-
congeners6 offering some new features which are related to the
presence of the confused pyrrole. The “unsubstituted” atoms of
supported internal alkoxylation of benzocarbaporphyrin yield-
ing carbaporphyrinoids with ketal functionality has been
this moiety, i.e., external nitrogen (N2),7−10 external carbon
reported by Lash et al.49 Inspired by this, we decided to
(C3),11−18 and internal carbon (C21),9,17−31 are particularly
apply an oxidative addition as a synthetic path of introduction
prone to various types of substitution, addition, oxidation, or
of alkoxyls into NCP.
ring fusion8,13,16−18,32−37 reactions. Also very interesting and
rich is the coordination chemistry of NCP and its derivatives.
The presence of a donor site on the macrocycle's perimeter
allows preparation of a variety of complexes in which both
RESULTS AND DISCUSSION
■
Unlike the case for benzocarbaporphyrins,49,50 upon refluxing
of NCP with ferric chloride in the presence of methanol, a
macrocyclic interior and peripheral atoms can be involved in
dimeric iron(III) complex of 2-aza-21-oxocarbaporphyrin51 is
bond formation with cations8,9,26,38−43 or anions.44−47
In our search for facile modifications resulting in fine-tuned
NCP systems that may serve as ligands in chiral organometallic
complexes, we have applied several synthetic approaches such
Received: July 24, 2012
Published: August 27, 2012
© 2012 American Chemical Society
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formed rather than 21-bis(alkoxy)NCP, which we established
on the basis of mass spectrometry indicating composition of the
product and 1H NMR revealing its paramagnetic character. The
mechanism of the oxidative addition reaction involves the
formation of porphyrin radical species as an active inter-
mediate,50 thus the oxidation potential of the applied agent
should be sufficiently high to oxidize NCP. On the other hand
the oxidant ideally should act “tracelessly”, without introduction
of oxygen atom, metal ion, or other substituent into the
porphyrin. Application of a strong organic oxidant, i.e., 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in place of
FeCl3 allowed overcoming most of these problems. The
syntheses were carried out in the presence of six equivalents of
DDQ in the refluxing THF/ROH mixture (80/20 v/v, R = Me,
Et) for 2 h (Scheme 1). The deep green adducts 1-R3 were
Supporting Information). The 22- and 24-NH resonate at
about 4.2 and 4.4 ppm and were assigned on the basis of the
COSY (coupling with β protons of pyrrole) and NOESY
(through-space contacts with protons of the substituent at
C21) experiments as well as by the deuterium isotope exchange
with CD3OD. The chemical shift of the NH protons in 1-R3 is
strongly affected by the intramolecular hydrogen bond that
involves alkoxylic oxygens as the H-bond acceptors. Thus, the
shielding effect of the aromatic ring which resulted in an upfield
shift of the protons inside the macrocyclic crevice of unaltered
porphyrins (about −2.8 ppm for NH’s in regular tetraaryl
porphyrins or NCP) is competing in 1-R3 with the downfield
shift due to formation of the H-bonds. Integration of the signals
in the 1H NMR spectra revealed the presence of two equivalent
alkoxyls attached to the internal carbon and the one bound on
the macrocycle’s perimeter. The protons of the alkyls located
inside the macrocycle are affected by the aromatic ring current,
and their resonances are shifted upfield to the region from
about −0.1 to nearly −1.8 ppm. The alkoxyl protons attached
to the carbon directly bound to the oxygen correlate in the
1H,13C HMBC spectrum with a carbon resonating near δC 96
ppm which is the sp3-hybridized C21 strongly downfield shifted
due to bonding of two oxygens. The methylene protons of the
“internal” substituents in 1-Et3 are diastereotopically differ-
entiated reflecting lack of “in-plane” symmetry of the
macrocycle. On the other hand, methylene of the “external”
ethoxyl is not diastereotopic indicating equivalence of both
faces of the macrocyclic ring. In both adducts the external
carbon C3 which resonates at about δC 177 ppm correlates in
the HMBC spectrum with the protons of the “external” alkoxyl
unequivocally indicating position of this substituent.
Scheme 1. Alkoxylation of NCP
The cation−anion interaction of the macrocycle and DDQ•−
is apparently strong enough to make both components migrate
together as a tight ion pair through the chromatographic
column. The presence of an organic anion prevents
crystallization of the system, but our efforts to exchange it
into other counterions resulted in lack of reaction or further
alteration of 1-R3 (vide infra). We expected that application of
lower amounts of DDQ would force it to act as a two-electron
oxidant and that the resulting reduction product would be
solely a diamagnetic hydroquinone-type anion. Indeed, the
reaction of NCP carried out under slightly modified conditions,
i.e., with lower than stoichiometric amount of the DDQ oxidant
(4−5 equiv), allowed separation of adducts which are
separated from the red and brownish products of the DDQ
reduction by silica gel column chromatography and charac-
terized by mass spectrometry, which revealed molecular ion
peaks, indicating the presence of three alkoxy groups in each
case.
Initially, we experienced some problems with the NMR
characterization of these products because the 1H NMR spectra
recorded for the CDCl3 or CD2Cl2 solutions consisted of broad
signals without fine structure of the spin−spin coupling (Figure
1A). We suspected that the observed line broadening was due
to the presence of a radical species which was formed upon
reduction of DDQ and interacted with 1-R3. In fact, electron
paramagnetic resonance (EPR) spectra indicated the presence
of a semiquinone-type anion radical DDQ•− at g = 2.0052
(Figure 1) which is a one-electron reduction product of the
quinone.52,53 The interaction between this paramagnetic
species and the macrocycle is likely due to cationic character
of the latter. In more polar solvents like methanol or
acetonitrile the tight ion pair is effectively dissociated and the
well-resolved 13C and 1H NMR spectra can be obtained (Figure
1B).
1
diamagnetic and can be characterized by H and 13C NMR
also in less polar solvents (e.g., CDCl3, Figure 2A). Obviously,
the yield is lower than upon application of the stoichiometric
amount of DDQ (about 50%), but a benefit of this is
crystallization ability of the obtained product.
The X-ray diffraction data analysis was performed for a single
crystal of 1-Et3 confirming all the structural features of the
systems in the solid that were derived from the NMR data in
solution (Figure 3, Table S1 in Supporting Information). The
presence of two ethoxyls attached to C21 and located on
opposite sides of the porphyrin plane as well as one EtO group
attached to C3 is apparent. The macrocyclic ring is flat, and a
mean deviation from the plane defined by 24 heavy atoms of
the porphyrin (P24) is only 0.12 Å. The distances between
internal C21 and neighboring C1 or C4 are 1.527(6) or
1.508(5) Å, respectively revealing single bonds. The sum of the
bond angles around C21 is 657.2(3)°, which is the value
expected for a pyramidal geometry of carbon environment (6 ×
109.5° = 657°). Despite pyramidal environment of C21, the
The 1H NMR spectra in CD3CN indicate aromaticity of 1-R3
and the presence of two protons located on the inner nitrogens
of the porphyrinoid in line with the proposed structure of the
monocation (Scheme 1). An indication for the monocationic
character of these species comes from the mass of the
molecular ion in the high-resolution ESI mass spectra showing
no additional proton attached upon ionization to 1-R3 (see
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Figure 1. 1H NMR spectrum (600 MHz, 300 K) of 1-Me3 in CDCl3 (A) and in CD3CN (B). The inset A′ comprises an EPR spectrum (1st and 2nd
derivatives) of the 1-Me3 solution in chloroform recorded at room temperature. Note the presence of a five-component hyperfine structure which is
clearly seen on the second derivative of the EPR signal and which is due to the unpaired electron coupling with two 14N nuclei of the DDQ•−. Signal
of the dissolved water, residual proton solvent, and solvent impurity in the NMR spectra are denoted w, s, and *, respectively.
In fact, much more pronounced deviation from the coplanarity
with the macrocycle is observed for the two “regular” pyrroles
which are cis with respect to that confused. Thus, N22 lies 0.19
Å under the P21, while N24 lies 0.33 Å over the plane. Such a
deviation is clearly due to formation of the intramolecular H-
bonds with the oxygens attached to C21 (Table S2 in
Supporting Information). The hydrogen bond formation forces
nitrogen and, consequently, the whole pyrrole unit to tip
toward one of the oxygen atoms. Formation of the H-bonds
1
involving internal protons is in line with the H NMR data
given above. A cyanide counteranion can be identified in the
crystal lattice disordered over two nonequivalently occupied
positions. The source of this ion can be DDQ, for which a
transfer of the cyano group onto the NCP has been reported.54
Under oxidant-deficient conditions (5 equiv of DDQ, 1.5 h
of reflux) we also observed formation of a product which
included a covalently bound substituent derived from the
DDQ, namely, 3-ethoxy-21-chloro-NCP 2 (Chart 1). This
olive-green derivative was formed with about 20% yield and
accompanied the main product 1-Et3. The composition of 2
was derived from ESI HRMS (m/z 749.3030, calcd 749.3042
for [M + H]+), and its optical and NMR spectra revealed its
aromaticity. The UV−vis spectrum of 2 is very similar to that of
Figure 2. Comparison of the 1H NMR spectra (600 MHz, CDCl3, 300
NCP1 or its 21-alkylated derivatives21,25,31 and clearly differs
K) of 1-Et3 (A), 3-Et2 (B), and 4-Et2 (C). Labeling of the signals: pyrr,
1
(21)
β-pyrrole protons; CH2(3), CH3(3), CH2(21), CH3
signals of
from that of 1-Et3 (Figure 4). The H NMR of 2 comprises
neither 21-H nor ethoxyl signals in the high-field region. The
only feature in this region is a very broad signal centered at
about δ 0 ppm (CDCl3, 300 K), which splits into two much
narrower resonances located at −2.56 and −2.85 ppm when the
spectrum is recorded at 213 K. These signals are attributed to
22- and 24-NH, i.e., internal protons of the 21-Cl-substituted
macrocycle. The six β-pyrrole protons resonate in the region of
δ 8.3−8.9 ppm characteristic for the aromatic NCP derivatives.
methylene- and methyl-protons of the ethoxyls bound to carbon 3
or 21, respectively.
confused pyrrole is planar (mean deviation from the
C1N2C3C4C21 plane is 0.014 Å) and it is almost coplanar
with the rest of the macrocycle. A dihedral angle between its
mean plane and P21, that is, a mean plane defined by 21 heavy
atoms of the ring, i.e., all except N2, C3, and C21, is only 7.1°.
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There is a lack of signal of proton 3, and instead, there are three
resonances of an ethyl group of the ethoxyl attached to this
position: the triplet at δ 0.85 ppm represents methyl, while two
multiplets (doublets of quartets) at δ 4.32 and 3.69 ppm
(CDCl3, 300 K) are signals of a diastereotopic methylene
fragment. Both methylene protons correlate in the 1H,13C
HMBC with a carbon resonating at δC 155.1 ppm which can be
assigned to C3. Diastereotopic differentiation of the periph-
erally bound methylene protons clearly indicates nonplanarity
of the porphyrin and, thus, its intrinsic chirality. Intriguingly,
despite electronegative chlorine substituent bound to it, the
internal carbon C21 resonates at δC 93.8 ppm, i.e., about 6 ppm
upfield with respect to that in the unsubstituted NCP.7 Such an
upfield shift may indicate some inclination of C21 toward a
pyramidal geometry.
The single crystal X-ray diffraction analysis of 2 confirmed
both composition and the structure of this species (Figure 5,
Figure 3. Perspective views and atom numbering of the molecular
structure of 1-Et3 drawn with the 50% thermal displacement ellipsoids.
Only the more occupied site of the anion is shown. In the lower view
all hydrogen atoms and meso-tolyl substituents have been omitted for
clarity.
Chart 1
Figure 5. Perspective views and atom numbering of the molecular
structure of 2 drawn with the 50% thermal displacement ellipsoids. In
the lower view all hydrogen atoms and meso-tolyl substituents have
been omitted for clarity. Arbitrarily, only enantiomer R is presented.
Table S1 in Supporting Information). The most striking
structural feature of 2 is a very strong deviation of the confused
pyrrole from the mean plane of the macrocycle. A dihedral
angle between the mean plane of the confused pyrrole and that
defined by the heavy atoms of the rest of the macrocycle (P21)
is 44.8°. Thus, chlorine is located 1.61 Å above P21, while O1
2.15 Å, and the terminal ethyl carbon C32, 3.37 Å under this
plane. The confused pyrrole is planar with a mean displacement
of 0.004 Å. Also O1 attached to C3 lies in this plane with
deviation of only 0.074 Å, while internally bound Cl1 resides
0.455 Å above the mean plane of the confused pyrrole indicating
some pyramidal distortion of the trigonal C21. Also torsion
angles C3C4C21Cl1 (−161.8(5)°) and N2C1C21Cl1
Figure 4. Optical spectra (dichloromethane, 298 K) of 1-Et3 (red), 2
(black), 3-Et2 (green), and 4-Et2 (blue).
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Scheme 2. Reduction and Dealkylation of Tris(alkoxy)NCP and Transetherification of Bis(alkoxy)NCP
(161.8(5)) strongly deviate from the value of 180° expected
for the planar arrangement. For comparison, the torsion angles
C1N2C3O1 and C21C4C3O1 are 176.7(6) and −176.0(6) in
line with the in-plane situation of the oxygen attached to C3
and trigonal hybridization of this carbon. Unlike in 1, the
hydrogen-bearing pyrrole nitrogens are tipped to opposite
direction than the substituent on C21 which makes H-bond
formation with chlorine unlikely (Table S2 in Supporting
Information). The molecule is chiral, but it crystallizes in a
centrosymmetric space group, thus the crystal is a racemate and
the unit cell contains a symmetry-related pair of enantiomers.
An analogous chlorine-substituted derivative has been
previously obtained and structurally characterized by Lash for
benzocarbaporphyrin.50 The structural features revealed for
chlorinated carbaporphyrin are similar to those of 2 except for
chirality and substitution pattern on the macrocyclic perimeter.
The case of 2 indicates that DDQ can also act as a source of
chlorine, though it seems much less obvious than it is for FeCl3.
Although ketal 1-R3 is formally a derivative of the cyclic
ketone, i.e., 21-oxo-2-aza-21-carbaporphyrin, and liberation of
this species upon application of a strong acid should be
possible, our attempt to hydrolyze 1-R3 with trifluoroacetic acid
or concentrated hydrochloric acid yielded, after neutralization,
two new products but none of them with CO functionality
on C21. These products appeared also upon our other attempt
aiming on the anion exchange with chloride by means of
shaking of 1-R3 in dichloromethane solution with brine
(Scheme 2). The mass spectrometry revealed that product 3-
R2 contained two alkoxyls, while product 4-R2 comprised two
alkoxyls and one oxo functionality.
The bis(alkoxy)NCP product 3-R2 can be readily obtained
by reduction of 1-R3 with aqueous hydrazine hydrate. Right
after mixing of the tris(alkoxy) derivative solution in dichloro-
methane with a drop of 40% solution of N2H4, the organic layer
turned brown-red, and the olive-green color of it can be
recovered by washing with several portions of water. The
bis(alkoxy)NCP is practically the only product of the reaction,
thus it can be obtained with a high yield. We performed the
reduction for both alkoxy derivatives (Scheme 2) and
characterized the products by high-resolution mass spectrom-
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etry and UV−vis and NMR spectroscopies. Integration of the
interpreted as a contribution of a carbonyl-containing canonical
form for which the delocalization path of the π-electrons is
broken due to inclusion of one electron pair into CO double
bond, and which is consequently nonaromatic (Scheme 2). The
observed ring current, though much weaker than in the case of
cationic 1-R3, along with the presence of two protons inside the
porphyrin crevice implies zwitterionic character of 4-R2 with a
negative charge localized on the external oxygen. The weak
aromaticity of this derivative is responsible for a poor shielding
of the porphyrin interior, and thus, the 22,24-NH’s resonate at
δ 6.75 and 6.47 ppm. It is also likely that deshielding due to
formation of H-bonds with oxygens at C21 contributes to the
downfield shift of these signals. Both internal protons seem to
be held firmly at their positions which can be inferred from the
fine structure of the appropriate signals of β-pyrrole protons (7,
8, 17, and 18) due to spin−spin coupling with 22- and 24-NH
which is observed even at room temperature. Thus, apparently
the alternative tautomeric forms involving N2 or the oxygen
bound to C3 as a proton sites do not occur at all in this system
(Scheme 2).55,56
1
signals in H NMR spectra revealed that the porphyrinoids 3-
R2 consisted of one alkoxyl bound to C3 and the other attached
to C21, which means that reduction was combined with an
abstraction of −OR group from the inner carbon. Protons of
the alkoxyls located on C21 are shielded by the ring current of
the porphyrin and resonate in a region of δ −0.5 to −2.0 ppm,
while resonances of the externally bound substituent appear
around δ 4.1 ppm (Figure 2B). The methylene protons of
ethoxyls located both inside and outside the porphyrin crevice
are diastereotopic, indicating chirality of the system due to its
nonplanarity (Figure 2B). The aromaticity of 3-R2 is enhanced
with respect to that of 1-R3, which is indicated by wider
spreading of the proton signals with Δδ 11 ppm for
bis(ethoxy)NCP as compared to Δδ 10 ppm for tris(ethoxy)-
NCP (Figure 2). In fact, positions of β-pyrrole protons are
1
similar to those in the H NMR spectrum of 2 or NCP. The
signals of 22,24-NH are hardly seen at room temperature due
to a fast chemical exchange causing their considerable
broadening. At lower temperature, however, they appear as
reasonably narrow singlets at δ −1.19 and −1.69 ppm (3-Et2,
CDCl3, 223 K). Significantly, they are more than 1 ppm less
shifted upfield than the signals of analogous protons in 2, likely
due to intramolecular H-bond formation with oxygen attached
to C21 in 3-Et2. The signal of C21 in the 13C NMR spectrum of
3-R2 can be assigned on the basis of correlations with alkoxyl
protons observed in the HMBC experiment. It appears at δC
131.3 ppm in the spectrum of 3-Et2 and at δC 133.1 ppm in that
of 3-Me2, which is more than 30 ppm downfield with respect to
the signal of the unsubstituted C21 of NCP.7 Certainly, a major
contribution to such deshielding influence has a binding of
electronegative oxygen atom, but it is also likely that downfield
shift is caused in part by less effective shielding of C21 by the
ring current due to out-of plane position of this carbon with
respect to the aromatic macrocycle. The signal of C3 can be
found at δC 158.5 ppm, which is only 2 ppm more downfield
than in the case of NCP7 despite the presence of the oxygen-
containing substituent at this carbon in 3-Et2. Optical spectra of
3-R2 resemble those of 2 or NCP (Figure 4).
X-ray single crystal diffraction analysis performed for 4-Me2
reveals almost planar structure of the porphyrin ring, presence
of two −OMe substituents attached to C21, and lack of an alkyl
bound to O3 (Figure 6, Table S1 in Supporting Information).
The C3−O3 distance is very short (1.175(5) Å) and definitely
not compatible with a single bond formulation, for which a
distance of about 1.30 Å is expected. Moreover, the N2−C3
distance (1.453(5) Å) is considerably longer than that in 1-Et3
The product 4-R2 can also be effectively obtained simply by
passing solution of 1-R3 in dichloromethane through a basic
alumina column of low activity (Brockman III). In fact, we
intended to obtain 1-R3 in a neutral form by abstracting one of
the internal NH’s, but instead, a dealkylation of the external
oxygen occurred, while both 22- and 24-NH remained inside
the porphyrin core (Scheme 2). The optical spectrum of 4-R2
to some extent resembles that of 1-R3 in particular in the Q-
band region (Figure 4), thus similar electronic structure for
both derivatives could be anticipated. An integral intensity of
1
the H NMR signal of the alkoxyl substituents indicates the
presence of two −OR groups and their magnetic equivalence,
while the upfield position of these resonances is in line with the
location of them onto C21 as it took place in 1-R3 (Figure 2C).
The aromatic ring current effect in 4-R2 is severely reduced
with respect to that of 1-R3. Signals of the β-pyrrole protons
appear in a narrow region of 7.2−7.6 ppm, and the most
downfield shifted signal is due to one of the ortho-protons of
the meso-tolyl substituent (δ 7.7 ppm, CD2Cl2, 300 K), while
the most upfield shifted signal attributed to 21-methoxyl can be
found at δ 0.79 ppm in the spectrum of 4-Me2 and in the case
of 4-Et2 the triplet of terminal methyl is observed at δ −0.82
ppm (Figure 2C). Thus, the signals are spread over the region
of only about 8.5 ppm. The aromaticity decrease can be
Figure 6. Perspective views and atom numbering of the molecular
structure of 4-Me2 drawn with the 50% thermal displacement
ellipsoids. Only the more populated form out of two present in the
crystal lattice due to C3−N2 and O3 disorder is shown. Solvent
(chloroform) molecules are omitted in both projections. In the lower
view all hydrogen atoms and meso-tolyl substituents have been omitted
for clarity.
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(1.356(5) Å) or 2 (1.294(7) Å), which suggests weaker bond
between these atoms in 4-Me2. Thus, the lactam functionality12
can rather be assigned to this fragment of the confused pyrrole
in the solid state. The structure of the macrocycle is otherwise
close to that of 1-Et3. That includes the bond distances around
C21 indicating sp3 hybridization of this carbon (Table S1 in
Supporting Information), planarity of the confused pyrrole, and
its coplanarity with the rest of the porphyrin. Also the
intramolecular H-bonds between internal nitrogens N22, N24
and O1, O2 are formed similarly effective to those observed in
the structure of 1-Et3 (Table S2 in Supporting Information).
The structures of 2 and 3-R2 can also be subjected to further
alteration. 21-Cl can be partially substituted with ethoxy group
by 12 h reflux of 2 in the dichloromethane/EtOH (20:80)
mixture resulting in about 50% conversion into 3-Et2. On the
other hand, substitution of 21-OR in 3-R2 by other akoxyl is
surprisingly facile. In some instances it can be accomplished at
room temperature just by adding the incoming R′OH to the
solution of 3-R2 (Scheme 2). For example, the complete
exchange of the “internal” ethoxyl into methoxyl was observed
about 8 h after addition of 70 equiv of MeOH to the solution of
3-Et2 in chloroform. The product 3-EtMe can be transformed
back to 3-Et2 by addition of an aliquot of ethanol (Figure 7).
Figure 8. Perspective views and atom numbering of the molecular
structure of 3-EtMe drawn with the 50% thermal displacement
ellipsoids. Arbitrarily, the enantiomer R has been chosen for
presentations. In the lower view all hydrogen atoms and meso-tolyl
substituents have been omitted for clarity.
porphyrin ring with the mean plane of the confused pyrrole
tipped by 39.2° out of P21 with N2 and C3 lying more than 1 Å
over the P21, and C21 about 0.3 Å under the plane. That causes
chirality of the system, and the unit cell consists of a symmetry-
related pair of enantiomers due to racemic character of the
phase crystallizing in a centrosymmetric space group. The
structure resembles that of 2 with one exception concerning
much more in-plane situation of O1 with respect to the
confused pyrrole in 3-EtMe than it was in the case of C21-
bound chlorine (vide supra). The displacement of O1 from the
mean plane of the pyrrole is 0.049 Å while mean displacement
of the atoms defining this plane is 0.034 Å. That is in line with a
trigonal geometry of C21 in 3-R2 which seemed to be
considerably pyramidally distorted in 2. The distances between
O1 and N22 or N24 as well as appropriate bond angles suggest
interaction of the intramolecular H-bond-type in this system,
though it seems to be weaker than in the case of 1-R3 or 4-R2
(Table S2 in Supporting Information).
1
Figure 7. A high-field fragment of the H NMR spectra (600 MHz,
CDCl3, 300 K) of 3-EtMe obtained from 3-Et2 by recrystallization
from methanol (A), 3-Et2 obtained in situ from 3-EtMe by addition of
ethanol to the previous sample (B), and 3-Et(sBu) obtained from 3-
Et2 by addition of 2-(S)-butanol (C). Note two sets of signals in C due
to the presence of equally populated diastereomers.
Also some of the secondary alcohols can react with 3-R2
substituting internal alkoxyl, though the apparent reaction rate
is significantly lower than in the case of the primary alcohols.
For example, in the case of 2-butanol the full exchange of 21-
EtO into 21-sBuO required altogether about 18 h of heating to
50 °C of the solution containing 3-Et2 in chloroform with 120
equiv of the secondary alcohol to achieve reaction complete-
ness. Due to the intrinsic chirality of 3-R2 in the case of chiral
alcohols such as 2-butanol or 1-phenylethanol a mixture of
diastereomers is formed upon addition of pure enantiomer or
The 1H NMR spectral characteristic of 3-EtMe indicates
unequivocally the presence of methoxyl substituent attached to
C21 and ethoxyl group bound to C3. The rest of the spectrum
is typical for the bis(alkoxy)NCP system 3-R2.
The single-crystal X-ray diffraction analysis of 3-EtMe
(Figure 8, Table S1 in Supporting Information) confirms the
presence of different substituents inside and outside the
porphyrin ring. It also indicates a nonplanar structure of the
1
racemic mixture of the alcohol. Thus, in the H NMR spectra
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Article
two sets of signals can be observed which are particularly
strongly differentiated in the high-field part of the spectrum
where resonances of the internal substituent can be found.
Owing to that, the signal assignment to a particular stereo-
isomer in this region is feasible (Figure 7C) allowing also an
assessment of the component molar ratios.
Chirality of 3-R2 is defined by an orientation of the atoms of
confused pyrrole with respect to the direction of its deviation
from the porphyrin plane (Figure 9). The configuration of such
a configuration R can be assigned to the enantiomer of 3-Me2
displaying negative sign of the Cotton effect at a lower-energy
part of the major CD signal. (Note the opposite configuration
definition used in ref 31 due to a lack of the substituent at C3.)
A much more effective separation of the stereoisomers can be
achieved for the derivative with a chiral substituent attached to
C21, namely, for 3-Me(sBu). With an enantiomerically pure
(S)-sec-butanol the substitution at C21 yields a mixture of
diastereomers which differ only in configuration of the
porphyrin ring, so their quantitative relations and optical
activity are strictly related to the planar chirality of the
1
macrocycle. In Figure 11 partial H NMR and CD spectra of
Figure 9. Definition of absolute configuration of 3-R2.
systems is stable as long as a substituent on C21 prevents
flipping of the confused pyrrole, thus an attempt to separate the
enantiomers was considered to be feasible. However, a chiral-
phase HPLC of 3-Me2 resulted in a poor resolution despite
several mobile and stationary phases tested. Nevertheless, an
early fraction collected with dichloromethane/ethyl acetate as a
mobile phase is optically active containing some excess of one
of the enantiomers. Its CD spectrum consisted of several
features, but the most pronounced Cotton effect appears at the
wavelength of the Soret-type band, i.e., at about 445 nm
(Figure 10). The spectrum pattern is very close to that
observed previously for one of the enantiomers of 21-
methylated NCP31 for which absolute configuration has been
established on the basis of TDDFT calculation and NMR and
further confirmed by X-ray method applied for the dimeric
derivatives.57 Considering these structural and spectral
similarities and according to the definition given in Figure 9,
Figure 11. High-field fragments of the 1H NMR spectra (CDCl3, 300
K) of diastereomer RS of 3-Me(sBu) (A), mixture containing 39% de
of diastereomer SS (B), and the solution before separation consisting
of an equimolar mixture of both diastereomers (C). In the insets
associated with NMR traces the CD spectra recorded for each of the
solutions are presented.
the major fractions obtained upon a chiral-phase HPLC of 3-
Me(sBu) are presented. The diastereomer RS contained in the
fastest migrating band can be obtained in a practically pure
form, while the other stereoisomer, SS, can be separated only
partially (diastereomer excess 39% or diastereomer ratio
1:0.44). Their configuration can be assigned on the basis of
the CD spectra which are of the same pattern as the spectrum
of nonracemic 3-Me2. The solution before the stereoisomer
separation is optically inactive in the visible region (Figure
11C) because absorption of the chiral 2-butoxyl occurs in the
far UV and does not interfere with that of the porphyrin ring.
Chirality of the system allows exploring some details of the
mechanism of the transetherification in 3-R2. Usually the
exchange of an −OR group requires an acidic catalyst and
proceeds via a dissociative mechanism (SN1) involving a
relatively stable carbocation,58−62 and in some instances an
alkoxide anion facilitates ether bond cleavage.63−65 Apparently,
upon transetherification of 3-R2 no external catalyst is involved,
thus the reagents need to activate each other in some way by a
specific interaction involving structural fragments in the vicinity
of the reaction site, i.e., C21. Such an interaction may also
suggest an associative mechanism of the alkoxyl exchange.
Figure 10. Comparison of the UV−vis (upper traces) and CD (lower
traces) spectra of the enantiomer R of 3-Me2 (solid red line) and 21-
methylated derivative of NCP (black dashed line).31
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1H NMR-monitored titration of 3-Me2 with 1-(S)-
Article
A
phenylethanol (CDCl3, 300 K) resulted in a splitting of certain
peaks into two components, and the difference of their
chemical shifts grew as the concentration of alcohol increased
with apparently no changes of their relative intensities. This
behavior indicates formation of a supramolecular adduct
between the alcohol and the porphyrin. Since both reagents
are chiral, and 3-Me2 solution is racemic, the differentiation is
due to the presence of RS and SS diastereomers of adduct
which are expected to be NMR-distinguishable. No such effect
is observed with sec-butanol as a titrant. We suppose that the
source of the differentiation is the phenyl ring of phenylethanol
and its distinct orientation in each diastereomer with respect to
these β-pyrrole protons that are close to the alcohol binding
site. Significantly, the strongest effect is observed for the proton
in position 18, which is in the closest vicinity of the external
nitrogen N2; the effect is much weaker for 17-H located on the
same pyrrole unit, but does not occur for the other β-pyrrole
protons, for which only a small downfield shift takes place over
the alcohol concentration range of 0−120 equiv (Figure 12). It
may suggest N2 as the alcohol binding site.
1
Figure 13. The high-field parts of the H NMR spectra (CDCl3, 300
K) recorded after 1 h (A), 24 h (B), 48 h (C), and 6 days (D) after
mixing 3-Me2 with 120 equiv of 1-(S)-phenylethanol. The spectral
intensities were normalized with respect to the signals of the SS
isomer. The insets present CD spectra of the initial and final solutions.
mixture of diastereomers of 3-Me(PhEt). Since the config-
uration inversion is precluded in 3-R2 by the presence of the
substituent at C21 which cannot be threaded through the
porphyrin crevice, observation of an excess of one of the
diastereomers suggests that one of the following processes
occurred. (1) Dissociation of the C21−O1 bond which
liberates the confused pyrrole to move C21 onto the opposite
side before an attack of the incoming alkoxyl. Such a process,
however, should result in a stochastic 1:1 mixture rather than
induction of the diastereomeric excess as the attack from each
of the sides of the porphyrin plane is equally probable.25 (2)
Formation of the ketal-type intermediate with different −OR
groups on the opposite sides of the planar porphyrin ring and
subsequent dissociation of the outgoing alkoxyls. In this case an
inversion rather than racemization can be expected as long as a
consecutive substitution is slow enough and an effective
racemization is kinetically prevented.
1
Figure 12. H NMR spectral changes in the low-field region of the
spectra of 3-Me2 (CDCl3, 300 K) recorded upon titration with 1-(S)-
phenylethanol (0−120 equiv from the top to the bottom). The
assignment of signals given on the top was made on the basis of low-
temperature COSY and NOESY experiments.
Spectral changes due to substitution of 21-OMe with
phenylethanol can be observed by 1H NMR almost
immediately after addition of the incoming alcohol, though
reaction is complete after several days. The reaction is
stereoselective, although the selectivity is rather poor and,
surprisingly, opposite on the early and final stages. In the
beginning (after 1 h of the reaction) the diastereomer RS has
higher concentration, while in the final reaction mixture
stereoisomer SS dominates (de 8%, Figure 13). That
domination allowed assignment of the NMR signals to the
certain isomers on the basis of the CD spectra of the
diastereomer mixtures. The diastereomeric excess in the early
stages of the reaction reflects an affinity of the alcohol
enantiomer toward one of the enantiomers of 3-Me2 and is
likely kinetic in its origin as no steric preference in porphyrin−
alcohol adduct formation has been observed (vide supra).
However, domination of one of the diastereomers when
reaction is completed implies change of the porphyrin
configuration in a part of the reacting molecules. Otherwise,
reaction for racemic mixture of 3-Me2 would result in a 1:1
To check which one of these mechanisms is operative in the
present case we performed a series of exchange experiments for
the optically active 3-RR′ systems. Initially, we attempted
substitution of the chiral sec-butoxyl of the pure diastereomer
RS of 3-Me(sBu) in the reaction with methanol. However, the
reaction proceeded very slowly even at 60 °C, and we were
unable to achieve the full exchange of the alkoxyls, which
prevented analysis of the optical activity of the formed
compound. Moreover, the much faster consecutive reaction
of the formed 3-Me2 with excess of methanol causes effective
racemization. The convincing results were derived from an
experiment carried out for the solution containing an excess of
the R enantiomer of 3-Me2 reacting with 2-(S)-butanol. The
1
progress of the reaction was monitored by H NMR. After
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Article
Figure 14. Top row: CD spectrum of the solution chloroform containing an excess of the R enantiomer of 3-Me2 (left) and of the same solution
after 24 h of heating at 60 °C with 80 equiv of 2-(S)-butanol (right). Lower row: the mechanism of the transetherification of 3-R2 and the final step
of formation of 1-RR1R2.
Figure 15. Mass spectrum (ESI-TOF) of the mixture formed upon addition of DDQ to the 3-Me2 + EtOH system.
about 24 h of heating of the solution to 50 °C, NMR indicated
an excess of the SS diastereomer (de about 19%). The CD
spectrum of this solution displays Cotton effects of opposite
signs to those observed for the starting R-3-Me2 (Figure 14).
Clearly, the transetherification causes inversion of the
porphyrin configuration, and that implies formation of an
intermediate T whose structure consists of a planar ring and
two alkoxyls attached simultaneously to C21 (Figure 14). Thus,
the reaction mechanism is associative and the process can be
described as SN2.
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Article
3
3
3
(d, J = 7.7 Hz, 2H), 7.90 (d, J = 7.7 Hz, 2H), 7.86 (d, J = 7.8 Hz,
2H), 7.63 (d, 3J = 7.8 Hz, 2H), 7.62 (d, 3J = 7.7 Hz, 2H), 7.61 (d, 3J =
7.8 Hz, 2H), 7.59 (d, 3J = 7.7 Hz, 2H), 4.45 (s, 3H), 4.18 (b, 1H), 4.01
It is also likely that a similar transient species is formed
during synthesis of 1-R3 and the two-electron oxidation of T-R3
by DDQ (formally a hydride abstraction) yields cationic ketal
product. In fact, identification of 2 in the reaction mixtures
indicates position 3 as a primary target of alkoxylation. Reaction
may go further through 21-monoalkoxylated NCP with the final
quenching of the equilibrium between 3-RR2 and T by
oxidation. To check if such a synthetic path indeed occurs we
add 1 equiv of DDQ to the solution of 3-Me2 in THF/EtOH
mixture (80/20) at room temperature. The solution color
changed immediately from olive-green to grass-green, which is
1
(b, 1H), 2.65 (s, 3H), 2.64 (s, 6H), 2.63 (s, 3H), −0.47 (s, 6H). H
NMR (600 MHz, CDCl3, 300 K) δH = 8.23 (dd, J = 4.7 Hz, 4J = 1.1
3
Hz, 1H), 8.17 (dd, 3J = 4.7 Hz, 4J = 1.4 Hz, 1H), 8.11 (d, 3J = 4.5 Hz,
1H), 8.02 (dd, 3J = 4.6 Hz, 4J = 1.2 Hz, 1H), 7.97 (dd, 3J = 4.7 Hz, 4J =
1.1 Hz, 1H), 7.96 (d, 3J = 4.5 Hz, 1H), 7.95 (d, 3J = 7.8 Hz, 2H), 7.91
3
3
3
(d, J = 7.8 Hz, 2H), 7.90 (d, J = 7.8 Hz, 2H), 7.75 (d, J = 7.6 Hz,
2H), 7.56 (d, 3J = 7.6 Hz, 2H), 7.55 (d, 3J = 7.8 Hz, 2H), 7.54 (d, 3J =
7.6 Hz, 2H), 7.51 (d, 3J = 7.7 Hz, 2H), 4.52 (s, 3H), 4.16 (b, 1H), 3.97
(b, 1H), 2.64 (s, 9H), 2.61 (s, 3H), −0.40 (s, 6H); 13C NMR (150
MHz, CDCl3, 300 K) δC = 175.3, 174.5, 172.7, 171.3, 171.1, 161.8,
157.2, 155.4, 152.5, 146.0, 141.8, 141.6, 140.2, 140.2, 139.7, 138.9,
138.8, 138.2, 137.9, 136.8, 136.8, 136.5, 136.1, 135.0, 135.0, 134.9,
134.4, 133.8, 133.8, 133.7, 131.8, 129.7, 129.2, 129.0, 128.4, 128.4,
128.3, 118.6, 117.2, 113.1, 96.7, 89.0, 59.1, 49.0, 21.6, 21.5, 21.5; UV−
vis (CH2Cl2, 298 K) λ/nm (ε/M−1 cm−1) = 256 (sh), 288 (26900),
318 (sh), 363 (sh) 441 (80500), 477 (50700), 571 (sh), 594(sh), 644
(sh), 678 (19300), 734 (17400); HRMS (ESI-TOF) m/z = 761.3479
(obsd), 761.3486 (calcd for C51H45N4O3, [M]+).
1
typical for 1-R3. The products were analyzed by H NMR and
ESI-MS (Figure 15), which indicate, among others (i.e., 1-Me3,
1-MeEt2, 3-MeEt), the presence of the cationic product 1-
Me2Et comprising both methoxyl and ethoxyl substituent
bound to C21 confirming occurrence of the intermediate T
both in substitution process 3-R2 and in the formation reaction
of the triply alkoxylated NCP 1-R3.
Selected data for 1-Et3: mp >300 °C; 1H NMR (600 MHz,
CD3CN, 300 K) δH = 8.23 (dd, 3J = 5.0 Hz, 4J = 1.81 Hz, 1H), 8.14 (d,
3J = 4.7 Hz, 1H), 8.10 (dd, 3J = 4.9 Hz, 4J = 2.0 Hz, 1H), 8.05 (dd, 3J =
4.7 Hz, 4J = 2.0 Hz, 1H), 8.01 (d, 3J = 8.1 Hz, 2H), 8.00 (dd, 3J = 4.6
CONCLUSION
■
Introduction of three primary alkoxy groups to the confused
pyrrole of NCP appears to be an efficient and easy to conduct
modification of this porphyrinoid. Reactivity of the ketals 1-R3
allows further alteration of the macrocycle’s structure and
substitution pattern. The noncatalytic transetherification of 3-
R2 occurring under very mild conditions is of special interest.
The process is reversible and can be described as an example of
dynamic covalent chemistry (DCC).60,66−68 This reactivity can
be exploited in the construction of more complex structures
involving NCP derivatives such as oligomers or various types of
complexes. The studies on these subjects are underway in our
laboratories.
4
3
3
Hz, J = 2.3 Hz, 1H), 7.97 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 7.8 Hz,
2H), 7.91 (d, 3J = 7.8 Hz, 2H), 7.83 (d, 3J = 7.8 Hz, 2H), 7.616 (d, 3J =
3
3
7.8 Hz, 2H), 7.614 (d, J = 7.8 Hz, 2H), 7.611 (d, J = 7.8 Hz, 2H),
7.57(d, 3J = 7.9 Hz, 2H), 4.92 (q, 3J = 7.2 Hz, 2H), 4.46 (b, 1H), 4.26
(b, 1H), 2.64 (s, 9H), 2.62 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), −0.36
3
(dq, 2J = 9.0 Hz, 3J = 7.0 Hz, 2H), −0.47 (dq, 2J = 9.0 Hz, 3J = 7.0 Hz,
2H), −1.79 (t, 3J = 7.0 Hz, 6H); 13C NMR (150 MHz, CDCl3, 300 K)
δC = 174.0, 172.8, 161.6, 157.0, 156.9, 152.9, 141.7, 141.1, 140.2,
140.1, 140.0, 139.6, 138.8, 138.7, 137.9, 137.8, 136.7, 136.5, 136.2,
135.1, 134.9, 134.7, 134.2, 133.8, 133.7, 131.5, 129.6, 129.2, 128.9,
128.5, 128.3, 118.1, 114.6 94.7, 68.4, 57.4, 31.6, 22.6, 21.5; UV−vis
(CH2Cl2, 298 K) λ/nm (ε/M−1 cm−1) = 258 (sh), 288 (27900), 317
(sh), 356 (sh) 440 (81100), 477 (51600), 576 (sh), 594(sh), 643 (sh),
678 (11600), 734 (18200); HRMS (ESI-TOF) m/z = 803.3953
(obsd), 803.3956 (calcd for C54H51N4O3, [M]+).
EXPERIMENTAL SECTION
■
General Methods. Applied dichloromethane was freshly distilled
from calcium hydride. Optical and circular dichroism spectra were
recorded in dichloromethane. NMR spectra were recorded in CD3CN,
CDCl3, or CD2Cl2 and referenced with residual solvent signals (1.94,
7.24, or 5.31, respectively). 2D experiments were performed by means
of standard software. The low-temperature NOESY spectra were
recorded with 2048 × 512 data blocks and with 400 ms mixing time.
Resolution of stereoisomers was performed at room temperature by
means of a Chirex 3010 analytical column (25 cm length, 4.6 mm i.d.)
packed with 5 μm silica gel coated with covalently bound (S)-valine
and dinitroaniline. The HPLC-grade solvents were applied. EPR
spectra were recorded at room temperature for chloroform or
acetonitrile solutions contained in capillary test tubes using X-band
microwave radiation (9.752 GHz) with modulation frequency and
amplitude 100 kHz and 0.2 G, respectively.
Separation of 3-Ethoxy-21-chloro-meso-(p-tolyl)-2-aza-21-
carbaporphyrin 2. 60 mg of NCP (0.09 mmol) and 100 mg of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.44 mmol) dissolved in a
mixture of THF/EtOH (50 mL, 80/20 v/v) was refluxed for 1.5 h.
Solvents were then removed, and solid residuum was dissolved in
dichloromethane and passed down a silica gel column. The initial red
and brown bands migrating with dichloromethane were discarded, and
an olive-green fraction eluted with 5% of ethyl acetate in dichloro-
methane containing 2 was collected. The solution volume was
reduced, and the product was precipitated as a dark green powder by
addition of hexane. Yield: 18 mg (27%).
Selected data for 2: mp 240−245 °C; 1H NMR (600 MHz, CDCl3,
300 K) δH = 8.82 (d, 3J = 4.9 Hz, 1H), 8.62 (d, 3J = 4.7 Hz, 1H), 8.45
Synthesis of Precursor. Starting porphyrin NCP was synthesized
3
3
3
as previously described.3
(d, J = 4.7 Hz, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 4.7 Hz,
1H), 8.30 (d, 3J = 8.0 Hz, 2H), 8.30 (d, 3J = 4.7 Hz, 1H), 8.20 (d, 3J =
Alkoxylation of NCP. In a typical synthesis of 1-R3 a solution
containing 100 mg of NCP (0.15 mmol) and 203 mg of 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (0.9 mmol) dissolved in a mixture of
THF/ROH (50 mL, 80/20 v/v, R = Me, Et) was refluxed for 2 h.
Solvents were then removed, and solid residuum was dissolved in
dichloromethane and passed down a silica gel column. The initial red
and brown bands migrating with dichloromethane were discarded, and
a grass-green fraction eluted with 20% of ethyl acetate in dichloro-
methane was collected. The solution volume was reduced, and the
product was precipitated by addition of hexane as dark green powder.
Yields: 1-Me3, 73 mg (68%); 1-Et3, 85 mg (71%).
3
3
7.7 Hz, 3H), 8.03 (d, J = 7.6 Hz, 1H),7.94 (d, J = 7.3 Hz, 1H),7.88
3
3
3
(d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.6 Hz, 3H), 7.57 (d, J = 7.9 Hz,
3H), 7.51 (d, 3J = 7.7 Hz, 2H), 7.48 (d, 3J = 7.7 Hz, 2H), 4.32 (dq, 2J =
4
2
4
10.2 Hz, J = 7.2 Hz, 1H), 3.69 (dq, J = 10.2 Hz, J = 7.2 Hz, 1H),
2.66 (s, 3H), 2.65 (s, 3H), 2.64 (s, 3H), 2.62 (s, 3H), 0.85 (t, 3J = 7.0
Hz, 3H); 13C NMR (150 MHz, CDCl3, 300 K) δC = 158.3, 155.4,
155.1, 144.8, 140.6, 139.0, 138.4, 138.2, 138.1, 137.6, 137.4, 137.2,
137.0, 136.9, 136.7, 135.9, 135.0, 134.9, 134.6, 134.4, 133.7, 128.4,
128.37, 128.0, 127.7, 127.6, 127.5, 126.8, 125.3, 125.1, 124.1,121.4,
121.3, 116.5, 93.8, 63.4, 21.55, 21.49, 21.45,13.9; UV−vis (CH2Cl2,
298 K) λ/nm (ε/M−1 cm−1) = 295 (21500), 350 (sh), 438 (sh), 458
(108000), 559 (10700), 602 (10900), 723 (8700); HRMS (ESI-TOF)
m/z = 749.3030 (obsd), 749.3042 (calcd for C50H42ClN4O, [M +
H]+).
Selected data for 1-Me3: mp >300 °C; 1H NMR (600 MHz,
3
CD3CN, 300 K) δH = 8.26 (d, 3J = 4.7 Hz, 1H), 8.15 (d, J = 4.7 Hz,
1H), 8.13 (d, 3J = 4.5 Hz, 1H), 8.05 (d, 3J = 4.7 Hz, 1H), 8.03 (d, 3J =
7,8 Hz, 2H), 7.97 (d, 3J = 4.5 Hz, 1H), 7.96 (d, 3J = 4.5 Hz, 1H), 7.93
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Reduction of Tris(alkoxy)-NCP. In a typical procedure a sample
of 1-R3 (30 mg, 0.04 mmol) dissolved in dichloromethane (5 mL) was
shaken with aqueous hydrazine hydrate (0.5 mL, 40% solution) for 2
min, whereupon the organic phase turned brown-red. The reaction
mixture was then washed with six portions of water (10 mL) until the
organic phase turned olive-green. After chromatographic workup
(silica gel column with dichlomethane/ethyl acetate as a mobile phase)
the product 3-R2 was precipitated with hexane as an olive powder.
Yields: 3-Me2, 25 mg (85%); 3-Et2, 27 mg (84%).
127.7, 127.52, 127.48, 127.44, 126.6, 125.3, 125.2, 123.5, 121.3, 120.0,
115.9, 115.3, 62.9, 56.6, 21.5, 21.4, 13.8; MS (ESI-TOF) m/z =
745.3522 (obsd), 745.3537 (calcd for C51H45N4O2, [M + H]+)
1
Selected data for 3-Et(sBu): H NMR (600 MHz, CDCl3, 300 K)
δH = 8.74 (d, 3J = 4.7 Hz, 1H), 8.50 (d, 3J = 4.7 Hz, 1H), 8.37 (d, 3J =
4.7 Hz, 1H), 8.35 (d, 3J = 4.7 Hz, 1H), 8.29 (d, 3J = 4.6 Hz, 1H), 8.25
(d, 3J = 4.7 Hz, 1H), 8.11 (dd, 3J = 7.9 Hz, 4J = 1.9 Hz, 1H), 8.08 (b,
3
1H),7.97 (d, 3J = 7.9 Hz, 2H),7.86 (d, 3J = 7.5 Hz, 1H), 7.79 (d, J =
7.9 Hz, 1H), 7.49 (d, 3J = 7.9 Hz, 2H), 7.48 (d, 3J = 7.9 Hz, 2H), 4.35
(dq, 2J = 10.4 Hz, 3J = 7.2 Hz, 1H), 3.84 (dq, 2J = 10.4 Hz, 3J = 7.1 Hz,
1H), 2.64 (s, 3H), 2.63 (s, 3H), 2.61 (s, 3H), 2.59 (s, 3H), 0.85 (t, 3J =
Selected data for 3-Me2: mp >260 °C; 1H NMR (600 MHz,
3
3
CDCl3, 300 K) δH = 8.73 (d, J = 4.9 Hz, 1H), 8.54 (d, J = 4.6 Hz,
1H), 8.40 (d, 3J = 4.6 Hz, 1H), 8.36 (d, 3J = 5.0 Hz, 1H), 8.32 (d, 3J =
4.6 Hz, 1H), 8.29(d, 3J = 4.6 Hz, 1H), 8.10 (b, 1H),8.08 (dd, 3J = 7.8
3
7.3 Hz, 3H), −0.45 (m, 1H), −1.60 (m, 1H), −1.75 (t, J = 7.6 Hz,
3H), −1.76 (d, 3J = 6.5 Hz, 3H), −2.02 (m, 1H) diastereomer RS; 8.73
3
3
3
4
3
3
(d, J = 4.9 Hz, 1H), 8.50 (d, J = 4.6 Hz, 1H),8.37 (d, J = 4.6 Hz,
1H), 8.35 (d, 3J = 4.9 Hz, 1H), 8.30 (d, 3J = 4.6 Hz, 1H), 8.26 (d, 3J =
4.6 Hz, 1H), 8.09 (dd, 3J = 7.9 Hz, 4J = 2.0 Hz, 1H), 7.97 (d, 3J = 7.9
Hz, 2H), 7.94 (d, 3J = 7.9 Hz, 1H), 7.89 (d, 3J = 7.9 Hz, 1H),7.83 (dd,
Hz, J = 1.8 Hz, 1H), 8.03 (d, J = 7.8 Hz, 2H),7.98 (d, J = 7.6 Hz,
3
4
3
1H), 7.88 (dd, J = 7.7 Hz, J = 1.8 Hz, 1H),7.50 (d, J = 7.9 Hz,
3
3
3
4H),7.47 (d, J = 7.9 Hz, 1H),7.46 (d, J = 7.9 Hz, 1H), 7.45 (d, J =
7.9 Hz, 1H), 3.66 (s, 3H), 2.64 (s, 3H), 2.63 (s, 3H), 2.62 (s, 3H),
2.60 (s, 3H), −0.54 (s, 3H); 13C NMR (126 MHz, CDCl3, 300 K) δC
= 158.3, 158.2, 154.7, 140.4, 139.5, 139.2, 138.4, 137.5, 137.3, 137.1,
137.04, 136.98, 136.93, 136.8, 136.7, 136.2, 135.7, 134.8, 134.3,
134.23, 134.17, 134.1, 133.4, 132.7, 128.2, 128.1, 127.8, 127.52,
127.50, 127.4, 126.66, 125.61, 125.3, 123.5, 121.3, 119.8, 115.3, 115.2,
56.5, 54.8, 21.48, 21.472, 21.469, 21.45; UV−vis (CH2Cl2, 298 K) λ/
nm (ε/M−1 cm−1) = 270 (20100), 407 (sh), 430 (sh), 446 (105700),
518 (sh), 548 (7300), 597 (8900), 651 (sh), 716 (7500); HRMS (ESI-
TOF) m/z = 731.3365 (obsd), 731.3381 (calcd for C50H43N4O2, [M +
H]+).
3J = 7.9 Hz, 4J = 1.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.48 (d, J =
3
3
2
3
2
7.9 Hz, 2H), 4.35 (dq, J = 10.6 Hz, J = 7.2 Hz, 1H), 3.85 (dq, J =
10.6 Hz, 3J = 7.7 Hz, 1H), 2.64 (s, 3H), 2.63 (s, 3H), 2.61 (s, 3H),2.59
3
(s, 3H), 0.85 (t, J = 7.6 Hz, 3H), −0.50 (m, 1H), −1.19 (m, 1H),
−1.36 (t, 3J = 6.7 Hz, 3H), −1.55 (m, 1H), −2.27 (t, 3J = 6.7 Hz, 3H)
diastereomer SS; 13C NMR (150 MHz, CDCl3, 300 K) δC = 158.1,
157.98, 157.94, 154.6, 140.1, 139.7, 139.4, 138.9, 137.7, 137.1, 137.0,
136.8, 136.75, 136.69, 134.8, 134.5, 134.2, 134.12, 134.06, 133.2,
130.8, 128.8, 128.0, 127.8, 127.7, 127.46, 127.40, 127.3, 126.4, 125.0,
123.4, 123.3, 121.1, 117.5, 117.4, 115.2, 76.3, 68.2, 26.8, 24.0, 23.8,
23.2, 23.0, 22.7, 21.5, 21.3, 14.1, 13.8, 11.0, 6.0; HRMS (ESI-TOF) m/
z = 787.4001 (obsd), 787.4007 (calcd for C54H51N4O2, [M + H]+).
Selected data for 3-Me(sBu): 1H NMR (600 MHz, CDCl3, 300 K)
δH = 8.71 (d, 3J = 4.9 Hz, 1H), 8.51 (d, 3J = 4.6 Hz, 1H), 8.37 (d, 3J =
4.6 Hz, 1H), 8.34 (d, 3J = 4.6 Hz, 1H), 8.29 (d, 3J = 4.9 Hz, 1H), 8.25
(d, 3J = 4.6 Hz, 1H), 8.10 (dd, 3J = 7.5 Hz, 4J = 2.2 Hz, 1H), 8.00 (d, 3J
Selected data for 3-Et2: mp >260 °C; 1H NMR (600 MHz, CDCl3,
300 K) δH = 8.75 (d, 3J = 5.0 Hz, 1H), 8.52 (d, 3J = 4.7 Hz, 1H), 8.40
3
3
3
(d, J = 4.7 Hz, 1H), 8.37 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 4.6 Hz,
1H), 8.28 (d, 3J = 4.7 Hz, 1H), 8.09 (dd, 3J = 7.6 Hz, 4J = 1.8 Hz, 1H),
8.07 (b, 1H), 7.98 (d, 3J = 7.9 Hz, 2H), 7.88 (b, 1H), 7.8 (dd, 3J = 7.6
4
Hz, J = 1.8 Hz, 1H), 7.50−7.45 (overlapping multiplets, 8H), 4.36
3
3
(dq, 2J = 10.5 Hz, 3J = 7.1 Hz, 1H), 3.86 (dq, 2J = 10.5 Hz, 3J = 7.1 Hz,
1H), 2.64 (s, 3H), 2.63 (s, 3H), 2.61 (s, 3H), 2.59 (s, 3H), 0.86 (t, 3J =
7.1 Hz, 1H), −0.34 (dq, 2J = 9.9 Hz, 3J = 6.9 Hz, 1H), −0.51 (dq, 2J =
= 8.0 Hz, 2H), 7.93 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H),
7.80 (dd, 3J = 7.5 Hz, 4J = 2.2 Hz, 1H), 7.50 (d, 3J = 8.0 Hz, 4H), 7.49
(d, 3J = 7.9 Hz, 4H), 3.67 (s, 3H), 2.64 (s, 3H), 2.63 (s, 3H), 2.62 (s,
3H), 2.60 (s, 3H), −0.45 (m, 1H), −1.63 (m, 1H), −1.73 (d, 3J = 6.1
Hz, 3H), −1.76 (t, 3J = 7.5 Hz, 3H), −2.05 (m, 1H) diastereomer RS;
9.9 Hz, J = 6.9 Hz, 1H), −2.10 (t, J = 6.9 Hz, 1H); 13C NMR (126
MHz, CDCl3, 300 K) δC = 158.5, 157.9, 154.6, 140.0, 139.6, 139.3,
138.8, 137.9, 137.6, 137.1, 137.1, 136.9, 136.8, 136.74, 136.67, 136.2,
135.6, 134.7, 134.6, 134.3, 134.2, 134.1, 134.0, 133.3, 131.4, 128.04,
127.97, 127.7, 127.5, 127.43, 127.41, 126.5, 1253, 125.2, 123.4, 121.2,
120.0, 116.7, 115.3, 65.1, 62.8, 21.49, 21.47, 21.4, 13.8, 10.7; UV−vis
(CH2Cl2, 298 K) λ/nm (ε/M−1 cm−1) = 270 (20100), 402 (sh), 428
(sh), 448 (101900), 517 (sh), 551 (8100), 598 (9100), 648 (sh), 715
(7800); HRMS (ESI-TOF) m/z = 759.3682 (obsd), 759.3694 (calcd
for C52H47N4O2, [M + H]+).
3
3
3
3
3
8.70 (d, J = 4.9 Hz, 1H), 8.51 (d, J = 4.6 Hz, 1H), 8.37 (d, J = 4.6
Hz, 1H), 8.34 (d, 3J = 4.9 Hz, 1H), 8.29 (d, 3J = 4.6 Hz, 1H), 8.26 (d,
3J = 4.6 Hz, 1H), 8.08 (dd, 3J = 7.5 Hz, 4J = 1.9 Hz, 1H), 8.00 (d, 3J =
7.9 Hz, 2H), 7.92 (d, 3J = 7.9 Hz, 1H), 7.90 (d, 3J = 8.0 Hz, 1H), 7.84
(dd, 3J = 7.7 Hz, 4J = 1.9 Hz, 1H), 7.50 (d, 3J = 7.9 Hz, 2H), 7.49 (d, 3J
3
= 8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 3.67 (s, 3H), 2.64 (s, 3H),
2.63 (s, 3H), 2.61 (s, 3H), 2.60 (s, 3H), −0.51 (m, 1H), −1.17 (m,
1H), −1.36 (t, 3J = 7.4 Hz, 3H), −1.53 (m, 1H), −2.29 (d, 3J = 6.1 Hz,
Exchange of the Alkoxyl Substituent at C21 (Trans-
etherification). In a typical procedure, to the solution of 3-R2 (5
mg) in chloroform (0.7 mL) was added an excess of alcohol (20−200
equiv). The reaction progress was monitored by 1H NMR. For
primary alcohols the reaction was complete after 12 h. In the cases of
secondary alcohols (2-butanol, 1-phenylethanol) the solution was
heated to 50 °C for three days. The solvents were then removed, and
solid residue was dissolved in a minimum amount of dichloromethane
and precipitated by addition of hexane as an olive powder. Yields:
quantitative.
3H) diastereomer SS; 13C NMR (150 MHz, CDCl3, 300 K) δC
=
175.0, 158.4, 158.3, 158.1, 158.0, 154.7, 140.20, 140.19, 139.70,
139.69, 139.34, 139.33, 138.6, 137.67, 137.65, 137.26, 137.25, 137.23,
137.22, 137.06, 137.05, 136.95, 136.94, 136.85, 136.81, 136.79, 136.2,
136.1, 135.7, 135.6, 134.8, 134.6, 134.22, 134.16, 134.13, 134.11,
134.10, 134.06, 133.3, 128.2, 127.9, 127.8, 127.5, 127.43, 127.37,
126.5, 125.6, 125.5, 125.2, 125.13, 123.43, 123.37, 121.17, 121.15,
119.97, 119.91, 116.8, 116.7, 115.3, 76.29, 76.26, 54.8, 26.7, 24.0, 23.8,
21.48, 21.47, 21.46, 21.45, 14.1, 13.9, 5.9, 5.4; HRMS (ESI-TOF) m/z
= 773.3848 (obsd), 773.3850 (calcd for C53H49N4O2, [M + H]+).
Selected data for 3-Me(PhEt): 1H NMR (600 MHz, CDCl3, 300 K)
1
Selected data for 3-EtMe: mp 205−210 °C; H NMR (600 MHz,
3
3
3
3
δH = 8.80 (d, 3J = 4.9 Hz, 1H),8.54 (d, J = 4.7 Hz, 1H),8.41 (d, J =
CDCl3, 300 K) δH = 8.76 (d, J = 5.0 Hz, 1H), 8.54 (d, J = 4.6 Hz,
1H), 8.41 (d, 3J = 4.6 Hz, 1H), 8.38 (d, 3J = 5.0 Hz, 1H), 8.33 (d, 3J =
4.6 Hz, 1H), 8.29 (d, 3J = 4.6 Hz, 1H), 8.09 (dd, 3J = 7.5 Hz, 4J = 2.2
Hz, 1H), 8.01 (d, 3J = 8.1 Hz, 2H),7.99 (b, 1H), 7.88 (dd, 3J = 7.2 Hz,
3
3
4.9 Hz, 1H),8.37 (d, J = 4.6 Hz, 1H), 8.32 (d, J = 4.6 Hz, 1H),8.30
(d, J = 4.9 Hz, 1H),8.15 (d, J = 7.5 Hz, 1H),8.01 (d, J = 7.8 Hz,
3
3
3
3
3
2H), 7.95 (d, J = 7.3 Hz, 2H),7.83 (d, J = 7.3 Hz, 2H), 7.52−7.44
overlapping doublets of both diastereomers, 6.83 (t, 3J = 7.2 Hz, 1H),
6.58 (t, 3J = 7.2 Hz, 2H), 4.66 (d, 3J = 7.2 Hz, 2H), 3.57 (s, 3H), 2.65
(s, 3H), 2.65 (s, 3H), 2.62 (s, 3H), 2.58 2.62 (s, 3H), 0.13 (q, 3J = 6.6
Hz, 1H), −2.43 (t, 3J = 6.6 Hz, 3H) major (x = 0.54) diastereomer SS;
3
3
4J = 2.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.1 Hz,
1H),7.49 (d, 3J = 8.1 Hz, 2H), 7.49 (d, 3J = 7.9 Hz, 2H), 7.47 (d, 3J =
7.2 Hz, 1H), 7.45 (d, 3J = 8.1 Hz, 1H), 7.44 (d, 3J = 8.0 Hz, 1H), 4.34
(dq, 2J = 10.4 Hz, 3J = 7.0 Hz, 1H), 3.84 (dq, 2J = 10.4 Hz, 3J = 7.0 Hz,
1H), 2.64 (s, 3H), 2.63, (s, 3H), 2.61 (s, 3H), 2.60, (s, 3H), 0.86 (t, 3J
= 7.0 Hz, 3H), −0.55 (s, 3H); 13C NMR (150 MHz, CDCl3, 300 K)
δC = 158.1, 158.0, 154.7, 140.3, 139.6, 139.2, 138.7, 137.6, 137.2,
137.1, 137.0, 136.92, 136.87, 136.8, 136.2, 135.7, 134.8, 134.7, 134.3,
134.2, 134.1, 134.0, 133.3, 129.1, 129.1, 128.7, 128.6, 128.1, 127.9,
3
3
3
8.70 (d, J = 5.0 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 4.6
Hz, 1H), 8.32 (d, 3J = 5.0 Hz, 1H), 8.29 (d, 3J = 4.4 Hz, 1H), 8.25 (d,
3J = 4.6 Hz, 1H),8.09 (d, J = 8.0 Hz, 2H),7.91 (d, J = 7.6 Hz, 1H),
3
3
3
7.87 (d, 3J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.52−7.44
overlapping doublets of both diastereomers, 6.67 (t, 3J = 7.2 Hz, 1H),
8217
dx.doi.org/10.1021/jo301573e | J. Org. Chem. 2012, 77, 8206−8219

The Journal of Organic Chemistry
Article
6.33 (t, 3J = 7.3 Hz, 2H), 4.34 (d, 3J = 7.3 Hz, 2H), 3.60 (s, 3H), 2.65
(s, 3H), 2.64 (s, 3H), 2.62 (s, 3H), 2.59 (s, 3H), 0.25 (q, 3J = 6.6 Hz,
1H), −2.04 (t, J = 6.6 Hz, 3H) minor (x = 0.46) diastereomer RS;
X-ray quality crystals of 1-Et3 were obtained by slow diffusion of an
ethyl acetate solution of 3-Et3 into hexane at room temperature.
Crystal data for 1-Et3: C55H51N5O3, Mr = 830.01, T = 100(2) K, Cu
3
13C NMR (150 MHz, CDCl3, 300 K) δC = 158.7, 158.0, 154.7, 140.0,
139.75, 139.67, 139.4, 139.3, 138.5, 137.8, 137.51, 137.46, 137.1,
137.0, 136.9, 136.8, 136.7, 136.4, 136.3, 135.9, 135.0, 134.9, 134.6,
134.5, 134.2, 134.15, 134.10, 133.3, 133.2, 128.5, 128.4, 128.3, 128.0,
127.9, 127.8, 127.6, 127.5, 127.4, 127.3, 127.0, 126.6, 126.4, 125.4,
125.2, 125.1, 124.9, 124.7, 123.5, 123.3, 121.2, 120.9, 119.8, 115.3,
78.1, 54.73, 54.68, 25.1, 21.5, 17.8, 14.1; HRMS (ESI-TOF) m/z =
821.3832 (obsd), 821.3850 (calcd for C57H49N4O2, [M + H]+).
Dealkylation of Tris(alkoxy)-NCP. In a typical procedure a
sample of 1-R3 (15 mg, 0.02 mmol) was dissolved in dichloromethane.
The solution was then put on the top of the chromatographic column
filled with basic aluminum oxide (Brockman III). The column was
then charged with dichloromethane, and the first band containing a
small amount (less than 10%) of 3-R2 was collected. The mobile phase
was than changed to a 1% mixture of ROH and dichloromethane, and
a grass-green solution was eluted. The solvents were evaporated. The
black-green crystals of the product 4-R2 were obtained by slow
diffusion of hexane into dichloromethane solution. Yields: 4-Me2, 13
mg (87%); 4-Et2, 12 mg (77%).
̅
Kα radiation, triclinic, space group P1, a = 14.124(7) Å, b = 14.642 (6)
Å, c = 16.533(9) Å, α = 113.02(4)°, β = 96.96(4)°, γ = 113.94 (5)°, V
= 2712.1(2) Å3, Z = 2, Dc = 1.016 Mg m−3, λ = 1.54178 Å, μ = 0.498
mm−1, diffractometer with CCD detector, 3.08° ≤ θ ≤ 66.00°, 17283
collected reflections, 9264 independent reflections, 606 parameters,
R1(F) = 0.083, wR2(F2) = 0.2254, S = 1.385, largest difference peak
and hole 0.781 and −0.464 e·Å−3. The external oxygen atom is
disordered, which we modeled by displacing its electron density into
two sites, O3 and O3A. The less occupied site (18%) is located
1.24(1) Å from the N2 site.
X-ray quality crystals of 2 were obtained by slow diffusion of a
chloroform solution of 2 into hexane at room temperature. Crystal
data for 2: C50H41N4O, Mr = 749.32, T = 100(2) K, Mo Kα radiation,
triclinic, space group P1, a = 9.463(1) Å, b = 14.978(1) Å, c =
̅
15.103(2) Å, α = 69.75(9)°, β = 80.70(9)°, γ = 73.91(9)°, V =
1924.7(3) Å3, Z = 2, Dc = 1.293 Mg m−3, λ = 0.71073 Å, μ = 0.144
mm−1, diffractometer with CCD detector, 2.79° ≤ θ ≤ 26.50°, 7868
collected reflections, 1467 independent reflections, 505 parameters,
R1(F) = 0.066, wR2(F2) = 0.0839, S = 0.635, largest difference peak
and hole 0.430 and −0.341 e·Å−3.
Selected data for 4-Me2: mp >300 °C; 1H NMR (600 MHz,
X-ray quality crystals of 4-Me2 were obtained by slow diffusion of a
chloroform solution of 4-Me2 into hexane at room temperature.
Crystal data for 4-Me2: C52H44Cl3N4O3, Mr = 985.61, T = 100(2) K,
Mo Kα radiation, monoclinic, space group P21/c, a = 12.550(7) Å, b =
29.401(1) Å, c = 12.857(7) Å, α = 90.00°, β = 92.94(5)°, γ = 90.00°, V
= 4737.6(4) Å3, Z = 4, Dc = 1.382 Mg m−3, λ = 0.71073 Å, μ = 0.411
mm−1, diffractometer with CCD detector, 3.04° ≤ θ ≤ 27.00°, 10330
collected reflections, 3795 independent reflections, 628 parameters,
R1(F) = 0.059, wR2(F2) = 0.1648, S = 0.734, largest difference peak
and hole 0.442 and −0.436 e·Å−3. The asymmetric unit contains one
molecule of 4-Me2 and two molecules of chloroform solvent, and one
of them is disordered into two sites. The external oxygen of 4-Me2
atom is disordered, which we modeled by displacing its electron
density into two sites, O3 and O3A. The less occupied site (29%) is
located 1.208(8) Å from the N2 site.
X-ray quality crystals of 3-EtMe were obtained by slow diffusion of a
chloroform solution of 3-EtMe into methanol at room temperature.
Crystal data for 3-EtMe: C51H44N4O2, Mr = 744.90, T = 100(2) K, Mo
Kα radiation, monoclinic, space group P21/n, a = 11.5264(2) Å, b =
26.2557(4) Å, c = 13.4965(2) Å, α = 90.00°, β = 91.037 (1) °, γ =
90.00°, V = 4083.8 (1) 3, Z = 4, Dc = 1.212 Mg m−3, λ = 0.71073 Å, μ
= 0.074 mm−1, diffractometer with CCD detector, 2.92° ≤ θ ≤ 27.00°,
49655 collected reflections, 8913 independent reflections, 524
parameters, R1(F) = 0.058, wR2(F2) = 0.2225, S = 0.925, largest
difference peak and hole 0.698 and −0.468 e·Å−3. The external oxygen
atom is disordered, which we modeled by displacing its electron
density into two sites, O2 and O2A. The less occupied site (17%) is
located 1.317(7) Å from the N2 site.
3
3
CDCl3, 300 K) δH = 7.69 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.8 Hz,
2H), 7.64 (d, 3J = 7.9 Hz, 2H), 7.62 (d, 3J = 4.6 Hz, 1H), 7.61 (d, 3J =
7.8 Hz, 2H), 7.60 (d, 3J = 5.2 Hz, 1H), 7.51 (dd, 3J = 5.2 Hz, 4J = 1.6
Hz, 1H), 7.43 (d, 3J = 7.9 Hz, 2H), 7.42 (d, 3J = 7.8 Hz, 2H), 7.41 (d,
3J = 7.8 Hz, 2H), 7.40 (d, 3J = 7.6 Hz, 2H), 7.36 (d, 3J = 4.6 Hz, 1H),
7.28 (dd, 3J = 4.5 Hz, 4J = 2.5 Hz, 1H), 7.25 (dd, 3J = 4.5 Hz, 4J = 2.1
Hz, 1H), 6.75 (b, 1H), 6.46 (b, 1H), 2.57 (s, 3H), 2.55 (s, 3H), 2.54
(s, 3H), 2.53 (s, 3H), 0.79 (s, 6H); 13C NMR (150 MHz, CDCl3, 300
K) δC = 181.1, 172.2, 165.0, 154.9, 151.6, 143.0, 139.1, 138.8, 138.7,
138.5, 138.1, 138.1, 137.9, 137.6, 137.4, 137.1, 136.4, 136.0, 135.3,
133.9, 133.6, 133.5, 132.1, 131.9, 131.7, 131.6, 129.0, 128.8, 128.45,
128.38, 125.0, 123.7, 122.3, 115.7, 108.8, 100.0, 50.4, 21.8, 21.70,
21.66; UV−vis (CH2Cl2, 298 K) λ/nm (ε/M−1 cm−1) = 320 (33800),
359 (30100), 408 (sh), 426 (sh) 450 (107000), 523 (3600), 576
(5400), 627 (sh), 690 (13300), 737 (18600); HRMS (ESI-TOF) m/z
= 747.3337 (obsd), 747.3330 (calcd for C50H43N4O3, [M + H]+).
Selected data for 4-Et2: mp >300 °C; 1H NMR (600 MHz, CDCl3,
300 K) δH = 7.69 (d, 3J = 7.9 Hz, 2H), 7.66 (d, 3J = 8.0 Hz, 2H), 7.62
3
3
3
(d, J = 7.9 Hz, 2H), 7.59 (d, J = 4.6 Hz, 1H), 7.57 (d, J = 8.0 Hz,
2H),7.55 (dd, 3J = 5.2 Hz, 4J = 2.1 Hz, 1H), 7.44 (dd, 3J = 5.2 Hz, 4J =
1.8 Hz, 1H), 7.37 (d, 3J = 7.9 Hz, 2H), 7.36 (d, 3J = 7.9 Hz, 4H),7.35
(d, 3J = 8.0 Hz, 2H),7.33 (d, 3J = 4.6 Hz, 1H), 7.23 (dd, 3J = 4.3 Hz, 4J
3
4
= 2.5 Hz, 1H), 7.19 (dd, J = 4.3 Hz, J = 2.0 Hz, 1H),7.03 (b, 1H),
6.74 (b, 1H), 2.54 (s, 3H), 2.533 (s, 3H),2.529 (s, 3H), 2.48 (s, 3H),
0.89 (dq, 2J = 9.3 Hz, 3J = 7.0 Hz, 2H), 0.86 (dq, 2J = 9.3 Hz, 3J = 7.0
Hz, 2H), −0.82 (t, J = 7.0 Hz, 6H); 13C NMR (150 MHz, CDCl3,
3
300 K) δC = 180.8, 172.4, 164.1, 154.1, 151.2, 142.0, 138.6, 138.3,
137.9, 137.7, 137.6, 137.3, 137.0, 136.6, 136.4, 135.7, 135.0, 134.5,
133.7, 133.1, 133.0, 131.4, 131.2, 131.1, 130.9, 128.5, 128.1, 128.0,
127.7, 124.0, 122.7, 121.5, 116.7, 108.3, 98.1, 58.2, 21.6, 21.41, 21.38,
21.36, 13.0; UV−vis (CH2Cl2, 298 K) λ/nm (ε/M−1 cm−1) = 319
(31600), 358 (27200), 400 (sh), 426 (sh) 450 (105000), 531 (2700),
575 (4500), 626 (sh), 688 (14000), 735 (19000); HRMS (ESI-TOF)
m/z = 775.3634 (obsd), 775.3643 (calcd for C52H47N4O3, [M + H]+).
Reaction of 1-Me3 with Brine. A solution of 1-Me3 (2 mg) in
dichloromethane (5 mL) was stirred vigorously for 2 h with saturated
aqueous NaCl (5 mL). The organic layer was then washed with five
portions of water (10 mL each), and the solvent was evaporated in
vacuum. The conversion and yields were examined by integration of
the 1H NMR signals (CDCl3) revealing the presence of 36% of 4-Me2,
19% of 3-Me2, and 45% of starting 3-Me3.
The crystal structures have been deposited at the Cambridge
Crystallographic Data Center and allocated the deposition numbers
CCDC 896020−896023.
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic data in cif format, selected bond lengths and
hydrogen bond geometries in the crystal structures (Tables S1
and S2), 1D and 2D NMR, and mass spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lixiaofang@iccas.ac.cn; piotr.chmielewski@chem.uni.
wroc.pl.
■
Crystallographic Data. The structures were solved by direct
methods using the SHELXS program.69 All non-hydrogen atoms were
refined anisotropically by full matrix least-squares with SHELXL-97.69
All H atoms were placed in a calculated position and refined as the
riding model with Uiso(H) = 1.2Ueq(C).
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/jo301573e | J. Org. Chem. 2012, 77, 8206−8219

The Journal of Organic Chemistry
Article
(34) Młodzianowska, A.; Latos-Grazyn
Chem. 2008, 47, 6364−6374.
ski, L.; Szterenberg, L. Inorg.
̇
ACKNOWLEDGMENTS
■
This work was supported by National Natural Science
Foundation of China (No. 20971041), the Key Project of
Chinese Ministry of Education (No. 210146).
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