Point-to-Axial Chirality Transmission: A Highly Sensitive Triaryl Chirality Probe for Stereochemical Assignments of Amines

Article abstract of DOI:10.1021/acs.joc.0c00734

A readily available stereodynamic and the electronic circular dichroism (ECD)-silent 2,5-di(1-naphthyl)-terephthalaldehyde-based probe has been applied for chirality sensing of primary amines. The chiral amine (the inductor) forces a change in the structure of the chromophore system through the point-to-axial chirality transmission mechanism. As a result, efficient induction of optical activity in the chromophoric system is observed. The butterflylike structure of the probe, with the terminal aryl groups acting as changeable wings , allowed for the generation of exciton Cotton effects in the region of 1Bb electronic transition in the naphthalene chromophores. The sign of the exciton couplets observed for inductor-reporter systems might be correlated with an absolute configuration of the inductor, whereas the linear relationship between amplitudes of the specific Cotton effect and enantiomeric excess of the parent amine gives potentiality for quantitative chirality sensing. Despite the structural simplicity, the probe turned out to be unprecedentedly highly sensitive to even subtle differences in the inductor structure (i.e., O vs CH2).

Full text of DOI:10.1021/acs.joc.0c00734

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Article
Point-to-axial chirality transmission – a highly sensitive triaryl
chirality probe for stereochemical assignments of amines
Tomasz M#dry, Agnieszka Czapik, and Marcin Kwit
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00734 • Publication Date (Web): 27 Jul 2020
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Point-to-axial chirality transmission – a highly sensitive triaryl
chirality probe for stereochemical assignments of amines
a
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Tomasz Mądry, * Agnieszka Czapik and Marcin Kwit *
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a) Department of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznanskiego 8, 61 614
Poznan, Poland
b) Center for Advanced Technologies Adam Mickiewicz University, Uniwersytetu Poznanskiego 10,
6
1 614 Poznan, Poland
e-mail: tomasz.madry@amu.edu.pl or marcin.kwit@amu.edu.pl
KEYWORDS: amine, stereodynamic chirality probe, induced optical activity, exciton coupling
ABSTRACT
The readily available stereodynamic and the ECD-silent 2,5-di(1-naphthyl)-
terephthalaldehyde-based probe has been applied for chirality sensing of primary amines. The chiral
amine (the inductor) forces a change in the structure of the chromophore system through the point-
to-axial chirality transmission mechanism. As a result, an efficient induction of an optical activity in the
chromophoric system is observed. The butterfly-like structure of the probe, with the terminal aryl
groups acting as changeable “wings”, allowed for generation of exciton Cotton effects in the region of
1
the B electronic transition in the naphthalene chromophores. The sign of the exciton couplets
b
observed for inductor-reporter systems might be correlated with an absolute configuration of the
inductor, whereas the linear relationship between amplitudes of the specific Cotton effect and
enantiomeric excess of the parent amine gives potentiality for quantitative chirality sensing. Despite
the structural simplicity, the probe turned out to be unprecedentedly highly sensitive to even subtle
differences in the inductor structure (i.e. O vs. CH2).
INTRODUCTION
The stereochemical analysis of chiral molecules, understood as determination of a structure
and/or composition of stereoisomers is crucial in many areas of the chemical synthesis and,
particularly, in the pharmaceutical industry.1-7 The chiroptical methods that are based on a non-
destructive interaction of randomly oriented molecules with linearly or circularly polarized light
constitute convenient and, very often, the only research tools for determining the structure of chiral
entities in a solution. Due to the straightforward response and sensitivity, the electronic circular
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dichroism (ECD) spectroscopy has been widely used in stereochemical studies. To date, a lot of
general, or operating in a very narrow area, correlation rules that bind the main quality of the ECD
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spectrum, namely the Cotton effect (CE) at a given wavelength, with the 3D structure of the chiral
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entity have been proposed. Although, it has been repeatedly demonstrated by us and others, that
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most of the traditional empirical correlation rules are inadequate and often incorrect, the exceptional
exciton chirality method is still highly useful in stereochemical studies. In principle, the geometrical
relationship between the interacting electric dipole transition moments (EDTMs) of allowed (usually)
π−π* electronic transitions, generated in (at least) two isolated chromophores directly reflects the
chirality of the whole system.10-13 As long as the coupling between electric and non-negligible intrinsic
magnetic transition dipole moments (MDTMs), associated with given EDTMs, does not overwhelm the
coupling between electric dipoles, the exciton chirality method works perfectly. Fortunately, these
exceptions of exciton chirality rule are rare and limited to the compounds of the bis-phenanthrene
type or in which the CD spectra are originated from electric forbidden transitions.14-18
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The use of the methods, especially the DFT-based, offered by theoretical chemistry, is an
alternative to the empirical rules. For the ECD, it comes down to solving the Rosenfeld equation of
optically active electron transitions.19-23
While the structure of the majority of optically active compounds allows direct ECD
measurements, there are some compounds, which do not have either a suitable chromophore or their
ECD readouts are difficult to be unequivocal interpreted, even when supported by theoretical
methods. In such circumstances, the structure of a given compound (usually called “inducer” or
“inductor”) can be modified by an attachment of the chromophoric chirality probe (commonly called
“reporter” or “chirality sensor”). The main feature that should characterize the suitable sensor is the
ability to adapt the structure of the probe to the chiral environment. The probe alone is CD-silent but
stereodynamic, and as the result of the dynamic inductor-reporter structural matching, the
appearance of non-zero CEs in the region of the UV absorption of the sensor is observed.24 The
advances in the field of the optical analysis of chiral compounds have been summarized in the recent
reviews.25-31
Among the pool of naturally occurring or artificial chiral compounds, amines seem to be one
of the most important ones as they play the leading role in the biochemical processes, in developing
new synthetic methods and in designing/synthesizing the leading substances, drugs and materials.1,32
Even a cursory review of the available literature precedents led to the conclusion that the
efficiency of the chirality sensing of amines is a function of the mode of an action of the probe and the
method of binding the inductor.33-64 The metaloporphyrin tweezers introduced to stereochemical
analysis by Berova and Nakanishi (Chart 1a) are considered sensitive probes of chirality of non-
covalently bound species. However, for efficient binding to the probe, an analyte requires the presence
of two functional groups in a molecular skeleton. This prerequisite limited the number of potential
analytes to those having already two functional moieties or to those monofunctional ones, into which
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the second, artificial functional group can easily be introduced.43,65 Recently, Borhan and co-workers
have proposed a porphyrin-containing flexible host molecule (called MAPOL, Chart 1a) that binds chiral
monoamines via hydrogen bonding formation. The binding of amine is associated with adapting core
specific P- or M-helical conformation by the biphenyl, which is revealed by the appearance of exciton
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couplets in the region of Soret band. Although the chiroptical response of porphyrin-based sensors
is impressive, their wider applications may be hampered by multistep synthesis, and/or the need to
use a large excess of the guests.
Chart 1. a) The porphyrin-based non-covalent probes for chirality sensing. b) Exemplary sterodynamic
probes for the covalent binding and chirality sensing of amines.
An alternative approach is based on the formation of a covalent bond between the inducer
and chirality sensor. The most common methods for covalent binding of the amine rely on N-
functionalization including N-heterocycle formation, imination or amidation reactions. Some
representative examples of the sterodynamic probes for chirality sensing of amines are presented in
Chart 1b.
The operation simplicity, on one hand, and versality of the sensors, on the other hand, make
the imine-based probes particularly useful in chirality sensing.63,64,66 Widely utilized in the asymmetric
synthesis i.e. allenes, point-to-axial chirality transfer,67-69 recently has gained popularity in chirality
sensing. Now, point-to-axial chirality transfer is efficiently applied as modus operandi of some
chiroptical probes for the stereochemical characterization of optically active amines and other
compounds.39,70 The common denominator of these probes is the presence of at least two aromatic
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fragments capable of twisting relatively to each other upon binding the inducer. The non-planarity of
aromatic parts, in principle, caused appearance of intense CEs, mostly of the exciton character.
Very recently, we have shown that the dinaphthylmethane-based stereodynamic probes were
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turned out to be highly sensitive chirality sensors for optically active secondary alcohols. However,
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some difficulties in the introduction of dinaphthylmethane on the polar functional groups, preclude
wider applicability of these probes.
Feeling that the problem of chirality sensing still has not lost its topicality, we decided to put
some efforts into designing, synthesizing and providing evidence of the efficiency of the new sensitive
stereodynamic reporters for primary amines. We assumed that the probe should be readily available,
simple and of the modular structure. The probe core would consist of two or three directly bound aryl
parts. One of them would serve as the amine-binder whereas the other(s) as supporting chromophore
systems responsible for generating the CEs exciton through the point-to-axial chirality transfer
mechanism. Thus, the energetic barrier of flipping the chromophore(s) conformation should be low
enough not to interfere with the sensing process. The amine would be bound to the receptor
covalently by forming the C=N imine double bond. Last but not least, the solubility of the probe-analyte
systems in hydrocarbons eliminates the possibility to specific interactions with the polar solvents,
which, in some cases, might complicate analysis. The intention behind this idea is illustrated in the
Figure 1.
Figure 1. Schematic representation of the designed stereodynamic triaryl probe. Red arrows indicate
polarizations of electronic transition of the highest oscillator strengths within anthracene and
naphthalene chromophores.
It is worth emphasizing, that in the case of the “flipping” trichromophoric systems, the
operational efficiency may go hand in hand with the complexity of the ECD readout. Looking at this
issue from a different angle and abstracting from the efficiency in chirality sensing, these
chromophores themselves will constitute interesting objects for the ECD study.
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RESULTS AND DISCUSSION
As the substrates for synthesis of probes, we have chosen 2-bromobenzaldehyde and
symmetrical 2,5-dibromoterephthalaldehyde, which in turn can be transformed into respective bi- and
triaryl systems through the Suzuki reaction.72-74 Due to the well-known spectroscopic characteristic,
we limited the number of substrates to the 1-naphthyl- and 9-anthrylboronic acids. The reactions of 2-
bromobenzaldehyde and 2,5-dibromoterephthalic aldehyde with the naphthyl boronic acid smoothly
provided respective probes 1a and 2 (Chart 2a).
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Chart 2. a) Structures of compounds under study. b) The ORTEP drawing showing an X-ray determined
structure of dialdehyde 2 with an atom numbering. c) Torsion angles that characterize a molecular
conformation.
Despite many attempts, the use of 9-anthrylboronic acid and 2,5-dibromoterephthalaldehyde
for the Suzuki coupling did not provide the desired bis-arylated product. However, the 2-(9-
anthryl)benzaldehyde (1b) was obtained under the standard conditions with a reasonable yield (64%).
The probe 1b turned out to be slightly light sensitive, therefore separation, storage and further
operations on this compound had to be conducted with limited light.
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As X-ray diffraction study revealed, in the crystal structure of 2 (Chart 2b) both naphthyl groups
(dented here as A and C) are twisted relatively to the central aromatic moiety (denoted as B). The
values of both twist α and α angles (defined here as C2-C1-C2’-C1’ and C4’-C5’-C1’’-C2’’, see Chart
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chromophoric system, therefore, each unit might act independently. One should keep in mind that the
sign and the magnitude of exciton CE is primarily the function of the dihedral angle and the distance
between the interacting EDTMs. On the other hand, the perpendicular or parallel mutual orientations
of chromophores may cause disappearance of the exciton Cotton's effects and, thus, inefficiency of a
given chirality probe.
For preliminary tests on the efficiency of the probes in chirality sensing, we have chosen (R)-
3,3-dimethylbutan-2-amine. The amine is characterized by a large spatial diversity, therefore may
constitute the point of reference in sterochemical studies. The ECD measurements run in cyclohexane,
clearly showed the advantage of the probe 2 over the remaining two. As one can see, the tested imine
systems 3a and 3b gave ECD output that might provide structural information, if some efforts are put
into extracting them from the spectral data (see Figure 2 and Table 1). The ECD spectra of 3a and 3b
are characterized by the presence of one well-distinguished ECD band, appearing at 224 and 258,
respectively, and two bands of smaller intensity at the higher energy region. None of the ECD spectra
exhibits CEs pattern typical of exciton coupling. Having taken into account the fact that the UV pattern
for anthracene chromophore seemed to be the most promising in the context of probe designing, the
ECD readout for 3b can be considered disappointing.
On the contrary, the ECD spectrum measured in cyclohexane for 4a is characterized by the high
amplitudes of CEs, especially at the higher-energy region, when compared to the ECD spectra of 3a
and 3b (see Figure 2 and Table 1). In particular, the ECD spectrum of 4a exhibits long wavelength
negative CE at 290 nm and well-distinguished positive/negative/positive couplet appearing between
2
30 and 188 nm. While the long-wavelength CE might be attributed to electronic transitions involving
the central chromophoric unit (B), we assumed that the shape of ECD spectrum at the higher energy
region is the result of exciton interactions between both extreme naphthyl chromophores (AC
interactions) as well as interactions of each of the naphthyl groups with an aromatic diimino linker (AB
and BC interactions, vide infra).
The most promising probe 2 was subsequently used for further studies. Among the available
primary amines, we have chosen arbitrarily those that seemed representative for this class of
compounds. In general, condensations between the amines and 2 proceed smoothly in toluene,
provided almost quantitatively the respective imines (4b-4j). Although most of the compounds thus
obtained were crystalline, in fact, no additional purification of the crude reaction mixtures was
necessary. Note, compound 5 constitutes a model used for theoretical studies.
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Taking advantage of good solubility of these compounds in non-polar solvents, we have
measured their UV and ECD spectra in cyclohexane (see the exemplary UV and ECD spectra in Figure
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c and 2d). For easier comparison of the given chromophoric system with others, and to measure
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sensitivity in chirogenesis, we used the so-called sensitivity factor G defined as G = |A|/ε. For the
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purpose of this work, the sensitivity factor combines the absolute value of the amplitude |A| (A = Δεlong
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Δεshort) of the couplet observed in the region of the high intensity electronic transition ( B ) in
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naphthalene chromophore (ca. 220 nm), which may be the result of exciton interactions, with the
extinction coefficient (ε at ca. 220 nm). The experimental ECD data along with estimates for imines 4b-
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j sensitivity factors G have been juxtaposed in the Table 1.
Figure 2. The UV (upper panels) and the ECD (lower panels) spectra of a) 3a (solid black lines), 3b
dashed black lines), b) 4a c) 4c, and d) 4f (blue lines), measured in cyclohexane and calculated at the
TD-CAM-B3LYP/6-311++G(d,p) level and ΔΔG-based Boltzmann averaged UV and ECD spectra of 4a, 4c
and 4f (red lines). The calculated spectra were wavelength corrected to match the UV maximum. Only
the region 185-350 nm is shown. Experimental and the calculated ECD spectra of 4f were multiplied
by the factor of 4 to increase their visibility.
(
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Table 1. The ECD data measured in cyclohexane and sensitivity factors G = |A|/ε × 10 estimated for
imines 3a-3b, 4a-4j and amines 6a-6j.
Compd.a Δε (nm)
G
Compd.a Δε (nm)
G
3
a (R)
-6.6 (224); -2.8 (209); 9.5 (189)
n.d.
4j (R)
-16.2 (297); -6.6 (266); -57.4 (241); 15.62
18.2 (226); -120.7 (213); 63.3
200)
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b (R)
-14.2 (258); 1.2 (231); 4.4 (218); n.d.
5.2 (192)
-3.8 (289); -6.1 (238); 19.4 (227); - 3.08
18.0 (215); 18.0 (188)
2.9 (286); 3.8 (238); -12.8 (227); 2.32
16.0 (215); -16.1 (189)
6a (R)
6b (S)
6c (R)
6d (R)
6e (S)
6f (R)
6g (R)
6h (R)
-5.2 (232); 7.1 (212)
1.07
1.32
1.32
4a (R)
4b (S)
4c (R)
4d (R)
4e (S)
4f (R)
4g (R)
8.3 (231); -7.2 (218); 9.7 (192)
-7.1 (233); 8.3 (215); -6.6 (189)
-3.7 (289); 8.9 (227); -15.0 (215); 1.91
11.2 (188)
-11.4 (232); 14.0 (218); -12.8 (190) 1.37
-8.2 (289); -4.1 (234); 11.9 (227); - 2.59
20.0 (214); 14.0 (192)
-4.5 (310); -4.3 (245); 1.6 (232); - 1.28
5.0 (226); 9.9 (211); -2.4 (188)
1.6 (296); -1.1 (266); -2.9 (221); 0.70
4.1 (203); 1.6 (188)
-2.1 (240)b
n.d.
5.8 (232); -5.8 (215); 4.0 (190)
1.03
-11.8 (237); 42.1 (217); -19.8 (195) 4.80
-24.4 (233); 48.6 (222); -43.0 (193) 6.74
11.7 (309); -13.6 (276); 21.3 (236); 6.20
19.4 (232); 48.8 (225); -27.0 (208);
8
4.0 (194)
-18.4 (278); 39.7 (226); -20.9 4.93
208); 96.5 (189)
-28.6 (288); -11.3 (255); -37.0 4.36
229); 28.2 (217); 62.4 (201)
4
4
h (R)
i (R)
6i (R)
6j (R)
2.6 (286); -47.4 (233); 4.2 (222); 2.85
56.2 (206)
-3.5 (301); 10.6 (235); -36.4 (216); n.d.
16.8 (193)
(
(
[
a] In parentheses the absolute configuration at the nitrogen-containing stereogenic center is indicated. [b]
Short-wavelength CEs are undistinguishable due to the high noise level.
The process of point-to-axial chirality induction in imines is revealed by generating CEs of
amplitudes ranging from small but visible ones to strong ones – in dependence on the structure of the
inductor. As it can be clearly seen, the probe is sensitive to all inductor systems, even to that
characterized by very little structural diversity. Additionally, we have noticed some straightforward
correlation between the size of substituents flanking stereogenic center and the magnitude of CEs. For
example, a stepwise deterioration of steric congestion in imines 4a-4c manifests itself in a similar
systematic reduction of the amplitude of the respective CEs, appearing in the spectral range 230-180
nm, as well as a reduction of the G factors values. The observed relationship between G values and the
size of the substituent at the stereogenic center is not linear, however. The increase of bulkiness of
cyclohexyl substituent, as in the case of imine 4d, revealed in the increase of the CEs magnitude. On
the other hand, more sterically congested bornyl skeleton affects the resulted ECD spectrum even less
than ethyl and methyl groups in 4c.
The imine 4f constitutes the most challenging task for the probe 2. The parent compound (3R)-
aminotetrahydrofurane is characterized by a very small steric diversity. For the efficient work, the
probe 2 must distinguish the oxygen atom from the methylene group, both involved into five-
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membered ring. Although the observed, easily detectable CEs are not larger than those registered
ones, e.g. for 4c, their appearance clearly confirms the point-to-axial chirality transfer occurring in this
and in the other compounds under study. Consequently, the sensitivity factor, which equals to 0.7×10-
5,
is the smallest of the all estimated.
1
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For 4a-4f is seen direct correlation between the shape of ECD spectrum and absolute
configuration at the stereogenic center. In the spectral region 230-180 nm, the
positive/negative/positive (+/-/+) sequence of CEs corresponds to the R absolute configuration,
whereas -/+/- sequence of CEs is characteristic for the S absolute configuration. However, when one
of the aliphatic substituents at the stereogenic center is replaced by an aromatic group, as in the case
of imines 4g and 4h, the found relationship between sequence of CEs and absolute configuration at
stereogenic center is reversed.
The ECD spectra of 4i and 4j are difficult to interpret. Due to the observed induction of optical
activity, there are no doubts that the presence of the dynamically adapting probe fragment is crucial
for the appearance of intense Cotton effects. However, the experimental spectra of 4i and 4j are
superpositions of contributions originating from the interactions within the chromophores that make
up the probe as well as between the probe, taken as a whole, and the naphthyl or phthalimide
chromophores.
The imines 4 could be smoothly transferred into the corresponding amines 6. Lack of imine
chromophores made the central unit CD-silent in the analytical higher energy region. On the other
hand, after the reduction of imine bonds, one can expect increasing flexibility of the whole system, at
least within the inductor moiety. In fact, the ECD spectra of amines 6 are less complex than that
measured for imines 4. At the same time, we noticed decreasing CEs magnitudes, thus, decreasing the
sensitivity factors values.
When the ECD spectra measured for 4a-4h and their reduced counterparts were compared, it
1
turned out that in the diagnostic region of B electronic transitions in naphthalene chromophore, they
b
are almost the mirror images (neglecting details of the shape of the curves and the amplitude of the
effects). As expected, the ECD spectra of amine systems having additional chromophoric systems,
although deprived of some elements, are still difficult to interpret. A more serious disadvantage of the
amine derivatives is their lower solubility in non-polar solvents. For some derivatives, for which the
ECD spectra are measured in the acetonitrile, the solvent effect is clearly visible. This is particularly
seen in the cases of inductors characterized by either not a very diverse structure of substituents at
the stereogenic center or by the presence of aryl substituents.
The above studies only allow for the statement of the fact of the point-to-axial chirality transfer
and the qualitative associations of this phenomenon with the structure of the inducer. Therefore, we
have decided to expand these studies to include solid-state structural analysis of some derivatives,
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with a particular emphasis put on the imine 4a. Using the propensity to form crystals suitable for X-ray
diffraction analysis, we have determined solid-state structures of imines 4a-4d, and 4f and amines 6a-
6
c and 6f (details are provided in SI). We expected that X-ray analysis would allow for an easy and
explicit correlation of the observed CEs with the structure of the molecule, especially with the
conformation of the chromophore.
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A special opportunity to examine the effect of a substituent on the chromophore structure is
given by a direct comparison of the structures of the respective pairs: 4a-6a, 4b-6b, 4c-6c and 4f-6f
(Figure 3). The molecular structure of compounds in the crystal structure is unchangeable and, in our
opinion, closely related to the molecular packing and weak intermolecular interactions. Surprisingly,
the general tendency observed in these compounds, regardless of their chemical character, is the
pursuit of pseudocentrosymmetry in the solid state, when neglecting the presence of chiral
substituents at the nitrogen atoms. This structural feature is associated with the opposite signs of the
α and α angles and, by this way, with (almost) antiparallel orientation of naphthalene rings. Hence,
1
2
for such conformations, we cannot expect any optical activity originated from naphthyl-naphthyl (AC)
interactions.
Figure 3. Overlays of X-ray diffraction determined solid-state structures of: a) 4a (green) and 6a
(orange); b) 4b (aquamarine) and 6b (red); c) 4c (deep yellow) and 6c (blue); d) 4f (deep yellow) and 6f
(deep blue). For the disordered molecules, the fragments with lower occupancy factors are shown as
a thin line. C-Bound hydrogen atoms have been omitted for clarity, the nitrogen and the oxygen atoms
are shown as balls.
The crystallographic studies, although interesting from the crystal engineering point of view,
have not provided any ultimate answer regarding the origin of the induced optical activity observed
for the studied compounds. Therefore, to cast some light on the problem of the dynamic chirality
induction, we have carried out theoretical studies on the structure-chiroptical property relationships
for all of the imines 4a-4j, with a special emphasis put on the arbitrary chosen representative example
1
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a (discussed later) as well as for the model compound 5.75-78 In the latter case, the chiral substituents
at imine nitrogen atoms were replaced with methyl groups, which significantly facilitate calculations.
In particular, we were interested whether the observed ECD spectra, in the higher energy region, result
from the long-range naphthyl-naphthyl (AC) or short-range naphthyl-imine (AB and BC) interactions.
In the other words, we would answer the question to what extent the terminal naphthalenes flip is
responsible for the ECD response.
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At first, we have established the conformational freedom of the model compounds 5.
Calculated at the B3LYP/6-311++G(d,p) level the potential energy surface (shown in the Figure 4a) for
the systematic change of angles α and α clearly indicates that the low-energy conformers are
1
2
characterized by the values of α angles ranging from ±70° to ±120°. A significant increase of energy is
noticed for conformers in which at least one of the aryl-aryl moiety is pointed towards planarity. By
analogy to the B-A-B type triads, the low-energy conformers of the imine 5 and its real congeners can
be considered as C or S (see Scheme 1).79-81
Scheme 1. Low-energy C- and S-type conformers of imine 5 and relationship between the twist of the
α angles and symmetry of the molecule.
The lowest energy, chiral conformers of 5 have C -symmetry and both naphthyl groups deviate
2
by 10° from perpendicularity (α = α = 100° or -100°). A little bit higher in energy conformers of parallel
1
2
or antiparallel orientation of naphthyl rings are achiral and characterized either by the opposite values
of α and α angles, or one α angle is twisted by ±100°, whereas the second amounts to ±80°. However,
1
2
the calculated energy differences between C -, C - and C -symmetrical minimum-energy conformers
2
s
1
are negligible. Thus, given the method error all the conformers that are characterized by twist angles
ranging from ±100° to ±110° are equally probable.
In the next step, for each low-energy conformer of 5, the ECD spectrum was calculated at the
TD-CAM-B3LYP/6-311++G(d,p) level. This allowed for the calculations of the three-dimensional
surfaces that connect the predicted long- and short-wavelength rotatory strengths (respectively for
1
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CEs experimentally observed at around 230 and 215 nm) with the conformation of the probe. In this
particular spectral region between 230 and 200 nm is expected to see exciton couplets originated from
1
interactions between B electronic transitions within naphthalene chromophores.
b
The exemplary surfaces estimated for long- and short-wavelength rotatory strengths that were
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shown in the Figure 4b (see the remaining results in the Supporting Information) approximately remain
in relation: an object to its mirror image. As it has been supposed, the C -symmetrical conformers of 5
i
1
are ECD-silent in the spectral region of B electronic transitions in naphthalene. These studies suggest,
b
but still do not constitute compelling evidence, the dominant contribution of interactions between
terminal naphthyl chromophores to the overall rotatory strength.
Figure 4. a) Molecular energy of 5 as a function of angles α and α . b) Computed at the TD-CAM-
1
2
B3LYP/6-311++G(d,p) level long (Rlong) and short-wavelength (Rshort) rotatory strengths corresponding
1
to experimental exciton couplets of the B electronic transition as a function of angles α and α . c)
b
1
2
Deconvolution of the ECD spectrum of the low-energy conformer of 5. The ECD spectrum calculated
for the whole conformer is in black, the spectrum calculated for the AB part is represented by blue
solid line, the spectrum calculated for the AC part of the molecules is shown as red line and the effect
of summation (S = 2×AB + AC) is shown as a brown, dashed line. Wavelengths were not corrected.
Inserts indicate the position of the low-energy electronic transition in 5. d) Main molecular orbitals
involved in the low-energy electronic transitions in the low-energy conformer of 5.
To further confirm this hypothesis, we have chosen the low-energy C -symmetrical conformer
2
of 5, characterized by the values of α and α angles equal to -100° and we have divided it into two
1
2
moieties. The first of them, mapping AB and BC interactions between nearest chromophores,
consisted of the naphthalene and the imine part of the molecule (the remaining naphthalene fragment
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was replaced by the hydrogen atom). The second one reflected the AC interactions between terminal
naphthyl groups. For each of the sub-structures the ECD spectrum was calculated at the TD-CAM-
B3LYP/6-311++G(d,p) level (see Figure 4c). Finally, the calculated for the “whole” low-energy
conformer of 5 the ECD spectrum was compared with the one being the result of summation S = 2×AB
+ AC.
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It is clearly seen that both calculated for isolated AC system and compiled (S) spectra are
almost undistinguishable. The only differences are slightly higher magnitudes of the respective CEs
found in the compiled spectrum S. This analysis confirms that in the region 230-200 nm, the observed
CEs are mainly due to the AC exciton-type interactions. The contribution of AB and BC interactions to
the overall rotatory strength at this particular spectral region seemed negligible. However, these AB
and BC interactions are gaining importance in the higher energy region of ECD spectrum, i.e. below
2
00 nm. The comparison of the compiled spectrum S with that calculated for the low-energy conformer
of 5 shows a significant degree of the overall similarity. However, in the latter case (the ECD spectrum
of 5) a red-shift (ca 10 nm) of the respective rotatory strengths is noted. To establish the physical
reasons behind this small discrepancy, we have taken a look into orbitals involved in the electronic
transitions in the low-energy conformer of 5. As expected, the lowest energy electronic transitions
engaged orbitals come from the central imine unit B. Going to higher energies – the rotatory strengths
between 230-200 nm originated mainly from the orbitals centered in the naphthalene units (Figure
4
d). It should be noted that some contribution from electronic transitions involving HOMO-1 and
HOMO-3 orbitals from naphthalene and LUMO orbital centered at the central unit B, to the overall
rotatory strengths, were also established. As an effect of approximation and then summation of
Gaussian functions for each of the individual rotatory strengths, the red shift of the absorption bands
is observed. Finally, the higher energy region of the ECD spectrum of the low-energy conformer of 5 is
again dominated by transitions involving molecular orbitals from the central unit B. In the case of the
AC representing degenerate coupled-oscillator system, the calculated rotatory strengths originate
solely from transitions involving orbitals centered in the naphthalene. Hence, the deconvolution
approach does not allow to capture all the details of the spectrum, at least it leads to a qualitative
estimation of the factors affecting the observed effects.
It is worth noting that the direct correlation of the sign of the exciton couplet with the twist of
the α angles is not straightforward. However, keeping in mind that highest intensity the EDTM in
naphthalene is polarized along the long axis of the chromophore, one may feel entitled to use the ω
angle, defined as ω = C8-C1-C1’’-C8’’, as the angle between interacting EDTMs. To be precise, the sign
of the given exciton CE is a function of the product of the sine of a torsional angle between EDTMs as
well as the sine and cosine (the latter for non-degenerated systems) functions of in-plane angles
between the given electric dipole and the line connected the midpoints of interacting electric
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dipoles.11-13 Thus, assuming the dominant contribution of A/C interactions to the ECD spectrum, and
polarization of EDTM’s close to (or even) parallel to the long axis of the naphthalene chromophore,
the sign of exciton CE will depend on the angle ω. Note that even if the orientation of the EDTMs is
tilted off the long axis of the naphthalene chromophore, this does not affect the sign but only the
magnitude of the excitonic rotatory strength.
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For the above-discussed low-energy conformer of 5, the negative sign of the exciton couplet
remains in agreement with the negative sign of the ω angle (ω = -36°).11-13
To establish the mechanism of the optical activity in the real system, we applied a similar
procedure (see Calculation details in the Supporting Information) to the imines 4a-4j. Since the
detailed elaboration of each calculated structure may obscure the problem, we have decided to limit
the in-depth discussion to the representative example 4a. The remaining results will be briefly
commented, and all the theoretical results were skipped to SI.
There are four low-energy conformers of 4a found by calculations at the B3LYP/6-311++G(d,p)
level of the theory (Table 2, Figure 5a). The conformers are characterized by deviation of the α angles
from perpendicularity by ±11 ÷ ±20°, with a reasonable agreement with the X-ray data obtained for
the real compound. Conformation of the imine groups, described by the β and β angles (see Chart
1
2
2c) in all the cases is synperiplanar.
-1
Table 2. Relative Gibbs free energies (ΔΔG, in kcal mol ), ΔΔG-based percentage populations (Pop.),
values of α , α , β , β and ω angles (in degrees) and predicted sign of the exciton couplet (EC),
1
2
1
2
calculated at the B3LYP/6-311++G(d,p) level of theory for individual low-energy conformers of 4a.
Conf.a ΔΔG Pop.
α
1
b
α
2
b
β
1
c
β
2
c
ωd CE
1
2
4
6
1.77
3
105 105 178 178 29 (+)
1.12 10 101 101 179 179 21 (+)
0.00 65 104 -104 176 -178 180
0.64 22 -111 -111 -171 -171 -41 (-)
0
[
a] Conformers are numbered according to their appearance during conformational search. [b] α
1
= C2-C1-C2’-
C1’; α = C2’’-C1’’-C5’-C4’. [c] β = C2’-C1’-C=N; β = C5’-C4’-C=N. [d] ω = C8-C1-C1’’-C8’’.
2
1
2
While three of these structures are characterized by the same signs of both α angles and by C2
symmetry, the one of the lowest energy (conf. no 4) closely resembles X-ray determined crystal
structure of 4a, at least in the context of the preferred chromophore conformation. Namely, the C1-
symmetrical conformer No 4 is characterized by the values of α and α angles equal to -104° and 104°,
1
2
respectively. The population of this conformer, estimated on the basis on relative Gibbs energies,
amounts to 65%.
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Figure 5. a) Overlay of the calculated at the B3LYP/6-311++G(d,p) structures of individual conformers
of 4a. b) ECD spectra calculated at the TD-CAM-B3LYP/6-311++G(d,p) level for the individual low-
energy conformers of 4a. Wavelengths were not corrected. Structural and spectral data for a given
conformer are shown in the same color: conf. no 1 – green; conf. no 2 – blue; conf. no 4 – black and
conf. no 6 – red.
Since the interacting EDTMs in naphthyl chromophores are orientated antiparallelly (ω ≈ 180°)
there is no possibility for optically active AC exciton interactions. Thus, the ECD spectrum, calculated
for the conformer No 4, is almost flat (see Figure 5b) in the spectral region dominated by naphthalene-
naphthalene interactions. Hence, the contribution of this conformer does not affect the overall ECD
spectrum, in accordance to the empirical estimation. The second low-energy conformer No 6 is much
less populated (22%), but in fact, this particular conformer determines the sign and the pattern of the
averaged ECD spectrum. Due to the small contribution to the conformational equilibrium, the effect
of the remaining, higher in energy, conformers No 1 and 2 on the overall ECD spectrum seems to be
negligible.
The reproduction of experimental data by DFT calculation is satisfactory for most of the cases,
with the exception of 4i, which, indeed, represents a very complex problem. In fact, the best
agreement between the experimental ECD spectrum and that calculated is noticed for one of the
difficult cases, namely 4c (see Figure 2c), although, the good agreement between experimental and
theoretical data, obtained for the most demanding imine 4f is worth mentioning (see Figure 2d).
For the particular case of imine 4c, the percentage relation of conformers characterized by the
positive value of ω angle to that of negative value of ω angle and optically inactive (ω ≈ 180°) amount
to 41% (+) : 31% (-) : 28% (0). In other cases, even if abundance of optically inactive conformers prevails,
there is the conformer (or conformers) in the population, whose contribution to the ECD spectrum is
dominant. This seemingly high conformational dynamics is not uncommon for stereodynamic chirality
probes and results directly from the principles on which their mode of action is based. Finally, by
neglecting the contribution of optically inactive conformers, the mode of action of probe 2 also
determines the most typical equilibrium between P- and M-helical diasteroisomers.
The naturally emerging question is how the chirality of the inducer is transferred to the probe.
The analysis of the available structural data led to the conclusion, that both steric and electrostatic
interactions take part in the chirality transfer. The latter are easier to demonstrate. The (N=C)H∙∙∙π
1
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interactions between an electron cloud of the naphthalene and positively charged methine proton fix
the anti conformation of β angles (see Chart 2c for definition). In all cases, the β angles adapt anti
conformation. The syn conformation of H-C=N-C* moieties, typical of imines, associated with
synperiplanar orientation of C*H and CH=N protons, allowed for an interaction of nitrogens lone pairs
with aromatic protons in ortho positions of the central unit B. The tilting of naphthalene units is
determined by very weak sterical interactions with substituents flanking the stereogenic centers. In
general, the naphthalene is tilted towards a less bulky substituent. For example, the opposite-sign
exciton CEs in 4d and 4h point to opposite helicity of the chromophore. As both compounds are
characterized by the same R configuration of stereogenic centers, the reversal of the signs is associated
with steric demands of the chiral substituent. In the Figure 6 the low-energy, but optically active
conformers of 4d (conf. No 14) and 4h (conf. No 1) are shown, whose contribute the most to the
overall, respective, ECD spectra. The conformer No 14 of 4d is characterized by a negative value of the
ω angle (ω = -31°), and the naphthalene rings are tilted towards methyl groups. On the contrary, the
ω angle found for the conformer No 2 of 4h is positive (ω = 31°), and the naphthalene rings are tilted
towards the phenyl substituents. Thus, the steric power of the methyl groups for induction of dynamic
chirality in 4h is larger than that of the phenyl rings.
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Figure 6. Top (upper panel) and side (lower panel) views on the low-energy conformers of a) 4d (conf.
No 14) and b) 4h (conf. No 1). The naphthyl rings closer to the observer are green-colored, whereas
the naphthyl ring away from the observer are in red.
The calculated and ΔΔG-based and Boltzmann averaged ECD spectrum of 4i did not reproduce
well the experimental one. This is due to the complexity of the system and problems with a correct
mapping of energy relationships between conformers.
At the final stage of our study, we would check the possibility of the quantitative chirality
sensing with the probe 2.26,33 Thus, we experimentally determined the chiroptical response of non-
racemic crude products 4a, obtained by condensation of 2 with the 3,3-dimethylbutan-2-amine varied
in optical purity. We observed linear relationships between ee of the free amine and the CEs appearing
at 227 and 215 nm (Figure 7). It is worth noting that we found the same linear response for all optically
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active ECD bands. This feature might be useful for samples, where the intrinsic rotatory strengths from
the inductor obscure the induced circular dichroism resulted from the point-to-axial chirality
transmission.
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Figure 7. a) The ECD spectra of the crude imine samples, obtained from 2 and 3,3-dimethylbutan-2-
amine of the varying ee. b) The linear relationships between CE amplitude at 227 nm (blue line) and
2
15 nm (red line) and the sample ee.
CONCLUSIONS
In conclusion, we have designed and proven the usefulness of stereodynamic 2,5-di(1-
naphthalene)-terephthalaldehyde (2) for qualitative chirality sensing of amines. The sensor is readily
available from non-expensive and commercial substrates and is smoothly converted into
corresponding diimines through simple condensation reactions. In fact, there are only three simple
synthetic steps from terephtalaldehyde to the imine, approachable to even non-specialists in organic
synthesis. Hence, the cost of synthesis, compared to e.g. synthesis of porphyrin-based probes is small.
The ECD spectra measured for crude and purified by crystallization samples did not show any
visible differences. Thus, purification of the condensation product is not necessary, which further
simplifies the whole procedure. The additional values of the studied compounds are their solubility in
non-polar solvents of the hydrocarbon type and easily transformation into more chemically resistant
amines by reduction. The latter provide the ECD active products as well, however, the chiroptical
response of amines is smaller than that established for the parent imines.
The most important feature of the probe 2 is its high sensitivity towards inductors
characterized by the very small structural diversity at the stereogenic center.
In principle, taken into account the G values, it is possible to estimate the relative size of groups
flanking stereogenic center. It should be noted that this approach does not provide values regarding
the absolute size of the substituent. Instead, it allows to estimate the steric power for dynamic
induction of chirality of one substituent relative to the other flanking the sterogenic center(s). The
weak point of this approach is its limitation to aliphatic amines and those in which the aryl substituent
does not interfere with the induced circular dichroism. The results obtained from the analysis suggest
that the relative size of the substituents in structurally similar imines 4a-4d rises as follows: t-Bu > Cy
>
i-Pr > Et > Me. For compounds of this type, the positive exciton couplet observed at around 220 nm
corresponds to R absolute configuration and vice versa. For imines characterized by the presence of
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stereogenic center in the cycle, these relationships are: -C*(Me)- > -CH -; -CH O- > -CH CH -; -C - > -
2
2
2
2
(Ar)
CH -, respectively for 4e-4g. The larger steric power of the methyl group with respect to phenyl and
2
naphthyl groups in 4h and 4i, respectively, is apparently the reason for the reversal of correlation
between sign of exciton couplet and absolute configuration for aliphatic vs. aromatic substituents.
To make this analysis more comprehensive, we have compared sensitivity factors calculated
from the data available in the literature with the results obtained in this study.39,50,51,62,82 We have
chosen only the data, which are given in ε and Δε units, since their expressions include both,
concentration and path length. For the reasons given above, only inducers with high structural
variability (preferably 2-amino-3,3-dimethylbutane) were selected. The structures of inductor-
reported systems used in this analysis are shown in Chart 3.
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As one can see, all of the probes shown in Chart 3 are characterized by comparable values of
sensitivity factors. Among the analyzed systems, none of the sensors definitely outperforms the others,
however, there is a slight advantage of probes containing extended chromophoric systems.
Hence, we can rank these compounds towards decreasing sensitivity in the following order: 7 > 11 >
4
a > 10 > 9 > 8.
Chart 3. Exemplary sterodynamic inductor-reporter systems and their calculated sensitivity factors G.
Although on the basis on X-ray results is not visible the direct correlation between the
chromophore structure and experimentally observed induced optical activity, one can bear in mind
that the solid state structure of flexible compounds is determined by the way of packing of individual
molecules in the crystal lattice. Hence, the direct inference about the structure of a given compound
in solution, based on crystallographic data solely, may lead to erroneous results.
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Even in the case of inductor characterized by low structural diversity, the agreement between
experimental and calculated ECD spectra is good to excellent. Thus, this alternative theoretical
approach can be used for determining absolute configuration of the inducers.
Finally, we have demonstrated linear relationship between ee of the amine and ECD signal,
thus, the probe might be used for screening purposes, e.g. for quick checking of optical activity of
product of stereoselective processes.
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EXPERIMENTAL SECTION
General Information.
Unless otherwise noted, all reactions were carried out in air atmosphere. Deuterated
chloroform (CDCl ), solvents and other chemicals were purchased from commercial suppliers and used
3
as received without further purification. Intermediates: 2,5-dibromoterephthalaldehyde and (1R,2R)-
N-phthaloyl-1,2-diaminohexane were synthesized according to the literature procedures.72,83-85
1H and 13C{H} NMR spectra were recorded on a Varian 400 MHz spectrometer at room
temperature. Chemical shifts are reported in parts per million (ppm). Spectra are referenced using an
internal reference (trimethylsilane or CDCl residual solvent peak). Data is described as follows:
3
chemical shift, multiplicity (s = singlet, d = dublet, t = triplet, q = quartet, quint = quintet, h = sextet, m
= multiplet, dd = doublet of doublets, dt = doublet of triplets, dq = doublet of quartets, td = triplet of
doublets, tt = triplet of triplets, qd = quartet of doublets, quintd = quintet of doublets, ddd = doublet
of doublets of doublets and br = broad), coupling constants (Hz) and integration. Column
chromatography was performed on silica-gel of pore size 60 Å, 70-230 mesh, 63-200 µm. (Fluka). Thin
layer chromatography (TLC) was carried out using Sigma-Aldrich precoated TLC plates (60 Å medium
pore diameter with fluorescent indicator 254 nm).
Melting points were measured on a BUCHI B-545 apparatus. High-resolution mass spectra
(HRMS) were measured in a Bruker Impact HD spectrometer. Optical rotations were recorded on a
Jasco P-2000 polarimeter at 20 °C.
The ECD and UV spectra were measured using a Jasco J-810 spectropolarimeter at room
temperature in cyclohexane and acetonitrile solutions and with the use of a quartz cell of optical
-4
-1
lengths 0.1 cm. The concentration of analytes ranged from 1.0 to 2.0 × 10 mol L . Background spectra
-1
of the pure solvents were recorded from 400 to 185 nm with the scan speed of 100 nm min . The ECD
spectra of analytes were measured with 8 accumulations.
IR spectra were recorded on Jasco FT-IR 4600 spectrophotometer with ATR PRO ONE using the
diamond crystal.
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2
-(1-naphthyl)-benzaldehyde (1a):
In a 50 mL round bottom flask, K CO (1.310 g, 9.46 mmol, 2.5 eq) was dissolved in 20
2
3
mL of H O and the resulting solution was sparged with argon for 30 minutes. A 100 mL
2
round bottom flask containing a mixture of toluene (30 mL) and EtOH (20 mL) was sparged with argon
for 30 minutes. Then the 2-bromobenzlaldehyde (0.44 mL, 3.78 mmol, 1 eq), 1-naphthylboronic acid
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(0.780 g, 4.54 mmol, 1.2 eq), Pd(PPh ) (0.306 g, 0.27 mmol, 7 mol%) and water solution of K CO were
3
4
2
3
added to the flask. The resulting mixture was refluxed overnight under the argon atmosphere and
using a heating mantle. Then, the dark mixture was cooled to room temperature, diluted with CHCl3
and filtered through Celite. Filtrate was washed twice with water and brine, dried (Na SO ) and
2
4
concentrated under reduced pressure resulting dark thick oil. The product was separated using column
chromatography (CHCl / n-hexane 1:1). Yellow oil, 88% yield (772 mg).
3
-1
IR (thin film, cm ): 3368, 3054, 2840, 2749, 1943, 1823, 1740, 1690, 1596, 1504, 1479, 1447, 1387,
337, 1298, 1261, 1246, 1194, 1159, 1119, 1039, 1014, 957, 926, 883, 870, 836, 817, 802, 780, 765,
1
738, 704, 636, 618, 578, 565, 477, 444, 419.
1
H NMR (400 MHz, CDCl ): δ 9.63 (d, J = 0.8 Hz, 1H), 8.11 (dd, J = 7.8, 1.1 Hz, 1H), 7.97 – 7.88 (m, 2H),
3
7
.69 (td, J = 7.5, 1.5 Hz, 1H), 7.63 – 7.37 (m, 7H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 192.0, 192.0, 144.2, 135.4, 134.7, 133.6, 133.3, 132.6, 131.7, 128.6,
3
1
28.3, 128.1, 127.0, 126.7, 126.1, 125.7, 125.0.
+
HRMS (ESI-Q-TOF), m/z: [M + Na] calcd for C H NaO, 255.0786; found, 255.0796.
1
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2-(9-anthracene)-benzaldehyde (1b):
In a 50 mL round bottom flask, K CO (1.310 g, 9.46 mmol, 2.5 eq) was dissolved in 20
2
3
mL of H O and the resulting solution was sparged with argon for 30 minutes. A 100 mL
2
round bottom flask containing a mixture of toluene (30 mL) and EtOH (20 mL) was
sparged with argon for 30 minutes. Then the 2-bromobenzaldehyde (0.44 mL, 3.78 mmol, 1 eq), 9-
anthraceneboronic acid (1.010 g, 4.54 mmol, 1.2 eq), Pd(PPh ) (0.306 g, 0.27 mmol, 7 mol%) and water
3
4
solution of K CO were added to the flask. The resulting mixture was refluxed overnight in the argon
2
3
atmosphere in the dark and with the use of a heating mantle as the heat source. Then, the dark mixture
was cooled to room temperature, diluted with toluene and filtered through Celite. Filtrate was washed
twice with water and brine, dried (Na SO ) and concentrated under reduced pressure resulting dark
2
4
thick oil. The product was separated using column chromatography (CHCl / n-hexane 9:1). Isolation of
3
2
-(9-anthracene)-benzaldehyde should not be unnecessary prolonged due to its highly light-
sensitiveness. Pure product should be stored in covered glassware in dark place. Solidifying yellow-
green oil, 64% yield (682 mg).
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IR (thin film, cm ): 3380, 3056, 2858, 2763, 1950, 1928, 1843, 1821, 1787, 1725, 1695, 1621, 1595,
1517, 1474, 1440, 1396, 1354, 1287, 1265, 1221, 1199, 1168, 1141, 1092, 1037, 1013, 957, 936, 896,
8
59, 849, 838, 820, 793, 760, 736, 694, 655, 630, 610, 576, 553, 467, 442, 407.
1
H NMR (400 MHz, CDCl ): δ 9.32 (d, J = 0.9 Hz, 1H), 8.56 (s, 1H), 8.26 – 8.19 (m, 1H), 8.10 – 8.04 (m,
3
1
1
1
1
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2H), 7.78 (td, J = 7.5, 1.5 Hz, 1H), 7.68 (tt, J = 7.8, 1.1 Hz, 1H), 7.51 – 7.41 (m, 5H), 7.37 (dd, J = 6.3, 1.2
Hz, 1H), 7.35 (dd, J = 6.4, 1.3 Hz, 1H).
13
C{H} NMR (101 MHz, CDCl ): δ 191.9, 142.8, 135.6, 134.0, 132.6, 131.5, 131.1, 131.0, 128.5, 128.5,
3
127.7, 127.2, 126.3, 126.1, 125.3.
+
HRMS (ESI-Q-TOF), m/z: [M + Na] calcd for C H NaO, 305.0942; found, 305.0947.
2
1 14
2
,5-Di-(1-naphthyl)-terephthalaldehyde (2):
The general synthesis method was based on the procedure described by
Prusinowska et al. and Frederickson et al.72,84 In a 50 mL round bottom flask K CO
2
3
(
2.49 g, 17.99 mmol, 5 eq) was dissolved in 30 mL of H O and the resulting mixture
2
was sparged with argon for 30 minutes. A 250 mL round bottom flask containing a mixture of toluene
40 mL) and EtOH (30 mL) was sparged with argon for 30 minutes. Then the 2,5-
(
dibromoterephthalaldehyde (1.05 g, 3.6 mmol, 1eq), 1-naphthyl boronic acid (1.56 g, 8.99 mmol, 2.5
eq), Pd(PPh ) (416 mg, 0.36 mmol, 10 mol%) and water solution of K CO were added to the flask. The
3
4
2
3
resulting mixture was refluxed overnight in the argon atmosphere and with the use of a heating mantle
as the heat source. The dark mixture was cooled to room temperature, diluted with CHCl and filtered
3
through Celite. Filtrate was washed twice with water and brine, dried (Na SO ) and concentrated under
2
4
reduced pressure resulting dark thick oil. The product was separated using column chromatography
and crystallization.
Green-to-yellow crystals, mp 245-247 °C, 65% yield (601 mg).
-1
IR (thin film, cm ): 3352, 3060, 3041, 3012, 2881, 2749, 1746, 1679, 1592, 1509, 1483, 1438, 1406,
1
396, 1365, 1267, 1239, 1146, 1114, 1021, 1008, 977, 911, 870, 855, 799, 772, 658, 632, 522, 456, 426.
1
H NMR (400 MHz, CDCl ): δ 9.77 (s, 2H), 8.23 (s, 2H), 8.06 – 7.94 (m, 4H), 7.71 – 7.47 (m, 10H).
3
1
3
C{H} NMR (101 MHz, CDCl ): δ 191.3, 143.4, 143.4, 137.7, 137.7, 134.0, 133.5, 133.4, 132.5, 132.4,
3
1
30.6, 130.6, 129.2, 128.6, 128.6, 128.5, 128.4, 127.2, 127.1, 126.4, 126.4, 125.4, 125.4, 125.1.
+
HRMS (ESI-Q-TOF), m/z: [M + Na] calcd for C H NaO , 409.1204; found, 409.1196.
2
8
18
2
Larger scale synthesis was repeated starting from 3.15 g of 2,5-dibromoterephthalaldehyde (10.8
mmol), 1-naphthyl boronic acid (4.68 g, 27 mmol) and reduced amount of Pd(PPh ) (624 mg, 0.54
3
4
mmol, 5 mol%). The reaction time was prolongated to the 36 hours. After the work-up and purification,
the pure product was obtained with 62% yield (2.58 g).
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General procedure for the synthesis of the imines 3a and 3b:
To a 25 mL round-bottom flask containing aldehyde 1a or 1b (1 equiv, 0.44 mmol) and chiral amine
(1.2 equiv, 0.53 mmol), toluene (8 mL) were added. The resulting mixture was stirred overnight under
reflux using Dean-Stark apparatus and a heating mantle as the heat source. Then, the solvent was
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removed in vacuo and the product was used as received.
Imine 3a:
Yellow oil, 98% yield (137 mg).
-1
IR (thin film, cm ): 3262, 3058, 2958, 2901, 2866, 2825, 2606, 1933, 1814, 1739, 1638,
1
9
594, 1506, 1477, 1455, 1392, 1367, 1269, 1248, 1202, 1158, 1119, 1083, 1056, 1017,
64, 915, 863, 801, 777, 760, 695, 635, 620, 569, 462, 439, 420.
1
H NMR (400 MHz, CDCl ): δ 8.24 – 8.14 (m, 1H), 7.97 – 7.86 (m, 2H), 7.78 (s, 0.5H), 7.73 (s, 0.5H), 7.61
3
–
0
7.45 (m, 5H), 7.43 – 7.31 (m, 3H), 2.52 (dq, J = 16.8, 6.5 Hz, 1H), 0.98 (d, J = 6.5 Hz, 1.5H), 0.92 (s,
.5H), 0.88 (d, J = 6.5 Hz, 1.5H), 0.81 (s, 4.5H), 0.76 (s, 4H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 157.7, 157.7, 157.4, 140.8, 140.7, 137.6, 137.5, 135.6, 135.5, 133.3,
3
1
1
33.3, 132.5, 132.4, 130.9, 130.8, 129.7, 129.6, 128.1, 128.0, 128.0, 127.9, 127.9, 127.8, 127.5, 126.7,
26.7, 126.4, 126.3, 126.3, 126.2, 125.9, 125.9, 125.1, 125.1, 75.2, 75.1, 34.2, 34.2, 26.6, 26.5, 17.2,
17.1.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N, 316.2065; found, 316.2061.
23 26
Optical rotation [훼] 2퐷 0 -33.4 (c 1.00, CHCl3).
Imine 3b:
White crystals, mp 117-118 °C, 62% yield (80 mg).
-1
IR (thin film, cm ): 3053, 2958, 2902, 2865, 1947, 1821, 1697, 1637, 1596, 1519, 1442,
409, 1392, 1355, 1312, 1268, 1201, 1155, 1141, 1121, 1057, 1039, 1012, 963, 936,
1
888, 845, 822, 792, 761, 735, 630, 611, 553, 455, 416.
1
H NMR (400 MHz, CDCl ): δ 8.53 (s, 1H), 8.33 – 8.26 (m, 1H), 8.05 (dd, J = 8.5, 2.6 Hz, 2H), 7.61 – 7.50
3
(m, 4H), 7.49 – 7.42 (m, 3H), 7.36 – 7.29 (m, 3H), 2.31 (q, J = 6.5 Hz, 1H), 0.78 (d, J = 6.5 Hz, 3H), 0.68
(s, 9H).
1
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C{H} NMR (101 MHz, CDCl ): δ 157.2, 138.8, 136.6, 133.9, 131.8, 131.2, 130.7, 130.5, 129.8, 128.3,
3
1
28.2, 127.0, 126.8, 126.8, 126.7, 125.7, 125.7, 125.2, 75.0, 34.0, 26.4, 17.1.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N, 366.2222; found, 366.2225.
2
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Optical rotation [훼] -29.2 (c 1.07, CHCl ).
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General procedure for the synthesis of the imines 4a-4j:
To a 25 mL round-bottom flask containing dialdehyde 2 (1 equiv, 0.26 mmol) and chiral amine (2.3
equiv, 0.60 mmol), toluene (8 mL) was added. The resulting mixture was stirred overnight under reflux
using Dean-Stark apparatus and a heating mantle as the heat source. Then, the solvent was removed
in vacuo and product was crystallized if necessary.
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Imine 4a:
White crystals, mp 289-291 °C, 77% yield (110 mg).
-1
IR (thin film, cm ): 3057, 3038, 2961, 2868, 1945, 1822, 1696, 1631, 1592, 1507,
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478, 1454, 1392, 1377, 1367, 1337, 1262, 1204, 1180, 1116, 1057, 1017, 965,
15, 800, 776, 740, 661, 564, 429.
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H NMR (400 MHz, CDCl ): δ 8.21 (s, 0.5H), 8.18 (s, 0.5H), 8.16 (s, 0.5H), 8.11 (s,
3
0
0
.5H), 8.02 – 7.90 (m, 4H), 7.83 (d, J = 4.3 Hz, 1H), 7.79 – 7.39 (m, 11H), 2.51 (dq, J = 18.9, 6.4 Hz, 2H),
.93 (dd, J = 9.9, 6.5 Hz, 3H), 0.83 (dd, J = 6.5, 3.4 Hz, 3H), 0.72 (dd, J = 13.9, 10.9 Hz, 18H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 157.7, 157.4, 157.2, 157.0, 140.4, 140.4, 140.3, 137.3, 137.3, 137.2,
3
1
1
37.1, 136.8, 136.7, 136.5, 133.4, 133.3, 133.3, 132.5, 132.5, 132.5, 132.4, 129.1, 129.0, 128.9, 128.9,
28.2, 128.2, 128.2, 128.1, 128.1, 127.6, 127.6, 126.7, 126.7, 126.4, 126.3, 126.3, 126.3, 126.0, 125.9,
125.9, 125.2, 75.4, 75.4, 75.3, 34.2, 34.2, 34.2, 34.2, 26.6, 26.5, 17.2, 17.1, 17.0, 17.0.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 553.3583; found, 553.3570.
40 45
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Optical rotation [훼] 2퐷 0 -116.1 (c 0.96, CHCl3).
Imine 4b:
White crystals, mp 267-268 °C, 74% yield (100 mg).
-1
IR (thin film, cm ): 3054, 2956, 2869, 1936, 1827, 1695, 1631, 1592, 1508, 1454,
376, 1338, 1263, 1241, 1138, 1112, 1055, 1018, 966, 913, 801, 776, 740, 662,
1
554, 430.
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H NMR (400 MHz, CDCl ): δ 8.24 – 8.10 (m, 2H), 8.02 – 7.89 (m, 4H), 7.87 – 7.78
3
(m, 2H), 7.75 – 7.39 (m, 10H), 2.60 – 2.49 (m, 2H), 1.66 – 1.51 (m, 2H), 0.99 (dd, J = 10.0, 6.4 Hz, 3H),
0.91 (d, J = 6.4 Hz, 3H), 0.86 – 0.66 (m, 9H), 0.62 (dd, J = 6.6, 3.3 Hz, 3H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 157.7, 157.5, 157.3, 157.3, 140.5, 140.5, 140.4, 137.1, 137.0, 136.7,
3
1
36.7, 136.6, 136.5, 133.3, 132.6, 132.5, 132.5, 132.4, 129.0, 128.9, 128.9, 128.8, 128.2, 128.2, 128.1,
128.1, 128.0, 127.9, 127.8, 126.6, 126.6, 126.4, 126.4, 126.3, 126.3, 125.9, 125.9, 125.9, 125.2, 125.2,
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2.5, 72.5, 72.4, 34.0, 34.0, 19.8, 19.7, 19.6, 19.5, 19.4, 19.4, 19.4, 19.2, 19.2, 19.2.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 525.3270; found, 525.3264.
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Optical rotation [훼]2 +83.7 (c = 0.97, CHCl3).
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Imine 4c:
White crystals, mp 264-265 °C, 77% yield (99 mg).
-1
IR (thin film, cm ): 3054, 2963, 2924, 2868, 1940, 1747, 1632, 1592, 1508, 1488,
454, 1376, 1325, 1267, 1241, 1141, 1021, 966, 913, 887, 803, 778, 741, 694, 662,
549, 526.
H NMR (400 MHz, CDCl ): δ 8.21 – 8.17 (m, 1H), 8.15 (dd, J = 8.8, 1.5 Hz, 1H), 7.99 – 7.89 (m, 4H), 7.88
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0
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–
7.83 (m, 2H), 7.71 (m, 1H), 7.64 (m, 1H), 7.61 – 7.39 (m, 8H), 2.75 (h, J = 6.6, 5.8 Hz, 4H), 1.49 – 1.32
(m, 4H), 1.07 – 0.98 (m, 3H), 0.98 – 0.92 (m, 3H), 0.67 (q, J = 7.7 Hz, 3H), 0.55 (t, J = 7.4 Hz, 3H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 157.7, 157.6, 157.4, 157.4, 140.6, 140.6, 140.5, 140.4, 137.0, 137.0,
3
1
36.9, 136.7, 136.6, 136.5, 136.5, 133.4, 133.3, 132.5, 132.5, 132.5, 132.4, 128.9, 128.9, 128.8, 128.2,
128.2, 128.1, 128.0, 128.0, 127.9, 127.9, 126.5, 126.4, 126.4, 126.4, 126.3, 126.3, 125.9, 125.9, 125.9,
1
25.2, 125.2, 68.0, 68.0, 68.0, 30.4, 30.4, 22.1, 22.0, 22.0, 11.0, 10.9, 10.9.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 497.2957; found, 497.2949.
Optical rotation [훼]2 -60.2 (c 0.95, CHCl3).
3
6
37
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퐷
Imine 4d:
White crystals, mp 249-250 °C, 76% yield (120 mg).
-1
IR (thin film, cm ): 3053, 2918, 2851, 1935, 1826, 1632, 1592, 1507, 1446, 1377,
1
332, 1263, 1242, 1116, 1019, 966, 912, 800, 776, 737, 694, 662, 558, 430.
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H NMR (400 MHz, CDCl ): δ 8.19 – 8.08 (m, 2H), 8.02 – 7.84 (m, 4H), 7.79 (d, J =
3
4
.4 Hz, 2H), 7.74 – 7.36 (m, 10H), 2.54 (h, J = 6.3 Hz, 2H), 1.68 – 1.40 (m, 10H), 1.36
0.84 (m, 14H), 0.80 – 0.60 (m, 3H), 0.43 (pd, J = 12.8, 12.1, 3.0 Hz, 1H).
–
1
3
C{H} NMR (101 MHz, CDCl ): δ 157.6, 157.4, 157.3, 140.5, 140.5, 140.4, 140.4, 137.1, 137.1, 137.1,
3
1
37.1, 136.8, 136.6, 136.6, 133.3, 133.3, 133.3, 132.6, 132.5, 132.5, 128.9, 128.8, 128.2, 127.9, 127.8,
126.6, 126.5, 126.3, 126.3, 126.3, 125.9, 125.9, 125.9, 125.2, 125.2, 71.8, 71.7, 71.7, 43.5, 43.4, 43.4,
4
3.3, 29.9, 29.9, 29.8, 29.5, 29.5, 26.5, 26.4, 26.4, 26.2, 26.2, 26.1, 26.0, 19.7, 19.6, 19.6, 19.6.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 605.3896; found, 605.3898.
Optical rotation [훼]2 -67.8 (c 0.94, CHCl3).
4
4
49
2
0
퐷
Imine 4e:
White crystals, mp 307-308 °C, 85% yield (144 mg).
-1
IR (thin film, cm ): 3057, 3042, 2946, 2871, 1630, 1592, 1507, 1454, 1368, 1263,
1
112, 1059, 1018, 942, 800, 776, 664, 554, 430.
1
H NMR (400 MHz, CDCl ): δ 8.24 – 8.17 (m, 1H), 8.15 – 8.10 (m, 1H), 7.95 (dd, J =
3
7.7, 2.3 Hz, 4H), 7.82 – 7.39 (m, 12H), 3.01 – 2.91 (m, 1H), 2.78 – 2.71 (m, 1H), 2.06
–
1.69 (m, 3H), 1.68 – 1.52 (m, 4H), 1.46 – 1.31 (m, 2H), 1.24 – 1.17 (m, 1H), 1.14
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0.81 (m, 7H), 0.80 – 0.68 (m, 9H), 0.57 – 0.48 (m, 3H), 0.44 (m, 1.5H), 0.33 (d, J = 2.5 Hz, 1.5H).
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3
C{H} NMR (101 MHz, CDCl ): δ 157.8, 157.7, 157.6, 157.5, 157.4, 157.4, 157.4, 156.3, 156.2, 156.1,
3
1
1
56.1, 156.1, 156.0, 140.3, 140.3, 140.3, 140.3, 140.2, 140.2, 140.1, 140.1, 137.6, 137.5, 137.5, 137.5,
37.4, 137.4, 136.7, 136.6, 136.6, 136.5, 136.5, 136.4, 136.4, 136.4, 136.4, 136.3, 133.4, 133.4, 133.4,
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133.4, 133.3, 133.3, 133.3, 132.6, 132.5, 132.5, 129.3, 129.3, 129.2, 129.2, 129.1, 129.1, 129.1, 129.0,
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28.2, 128.2, 128.1, 128.1, 128.0, 128.0, 128.0, 127.9, 127.9, 127.9, 127.8, 127.8, 127.8, 127.7, 126.6,
26.6, 126.5, 126.5, 126.5, 126.4, 126.4, 126.4, 126.3, 126.3, 126.3, 126.3, 126.2, 126.0, 126.0, 125.9,
125.9, 125.3, 125.3, 125.3, 125.2, 79.0, 78.9, 78.9, 78.9, 78.8, 78.8, 75.4, 75.4, 75.4, 75.3, 75.3, 50.7,
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0.7, 50.7, 50.6, 50.6, 50.5, 48.2, 48.2, 46.9, 46.9, 45.5, 45.4, 38.5, 38.5, 38.5, 37.1, 37.1, 36.9, 36.9,
6.4, 36.3, 28.4, 28.2, 28.2, 27.5, 27.4, 20.7, 20.6, 20.6, 20.6, 20.6, 19.6, 19.6, 18.7, 13.3, 13.3, 13.3,
13.1, 12.7, 12.7.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 657.4209; found, 657.4220.
Optical rotation [훼] 2퐷 0 -51.5 (c 1.01, CHCl3).
4
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2
Imine 4f:
White crystals, mp 292-294 °C, 67% yield (91 mg).
-1
IR (thin film, cm ): 3055, 2944, 2918, 2863, 1941, 1714, 1626, 1591, 1508, 1488,
1
436, 1380, 1361, 1325, 1266, 1241, 1170, 1123, 1076, 1021, 964, 912, 805, 779,
42, 693, 661, 572, 540, 501, 470, 440, 421, 405.
7
1
H NMR (400 MHz, CDCl ): δ 8.23 – 8.20 (m, 2H), 7.99 – 7.92 (m, 4H), 7.90 (s, 2H),
3
7
.70 – 7.39 (m, 10H), 3.94 – 3.85 (m, 2H), 3.80 – 3.50 (m, 8H), 2.04 – 1.71 (m, 4H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 158.8, 158.7, 158.7, 158.6, 140.8, 140.8, 140.7, 136.6, 136.6, 136.3,
3
1
1
36.2, 136.2, 133.4, 132.5, 132.5, 132.4, 132.4, 129.1, 129.0, 129.0, 128.4, 128.3, 128.3, 128.2, 128.0,
27.9, 127.8, 126.5, 126.4, 126.4, 126.3, 126.2, 126.2, 126.1, 126.1, 126.0, 126.0, 125.3, 125.3, 125.2,
73.7, 73.7, 73.7, 69.8, 69.7, 69.7, 67.8, 67.8, 34.4, 34.4, 34.3.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N O , 525.2542; found, 525.2541.
Optical rotation [훼]2 +23.1 (c 1.06, CHCl3).
3
6
33
2
2
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퐷
Imine 4g:
Colorless crystals, mp 250-252 °C, 87% yield (146 mg).
-1
IR (thin film, cm ): 3053, 3015, 2925, 2863, 2834, 1746, 1683, 1628, 1508, 1488,
1450, 1375, 1264, 1239, 1115, 1072, 966, 877, 803, 776, 738, 549, 433.
1
H NMR (400 MHz, CDCl ): δ 8.26 – 8.19 (m, 2H), 8.03 – 7.87 (m, 6H), 7.76 – 7.44
3
(
m, 10H), 7.08 – 6.88 (m, 6H), 6.70 (dd, J = 17.3, 7.4 Hz, 1H), 6.47 (t, J = 8.3 Hz, 1H),
4.09 (q, J = 5.9 Hz, 1H), 4.02 (dt, J = 12.3, 5.9 Hz, 1H), 2.79 – 2.59 (m, 4H), 1.99 –
.72 (m, 5H), 1.70 – 1.56 (m, 3H).
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C{H} NMR (101 MHz, CDCl ): δ 159.3, 159.1, 158.9, 158.8, 140.9, 140.9, 140.8, 140.7, 136.9, 136.9,
3
136.8, 136.8, 136.8, 136.8, 136.7, 136.6, 136.6, 136.6, 133.4, 133.4, 133.3, 132.6, 132.5, 132.5, 132.4,
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29.0, 129.0, 129.0, 128.9, 128.9, 128.9, 128.8, 128.7, 128.5, 128.4, 128.3, 128.3, 128.3, 128.1, 128.0,
27.7, 127.6, 126.7, 126.7, 126.7, 126.6, 126.6, 126.5, 126.4, 126.4, 126.4, 126.3, 126.0, 125.9, 125.6,
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125.5, 125.5, 125.2, 125.2, 125.2, 68.5, 68.3, 68.2, 67.9, 31.2, 31.1, 31.1, 29.3, 29.3, 19.9, 19.8, 19.7,
9.7.
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 645.3270; found, 645.3284.
1
+
4
8
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Optical rotation [훼]2 +161.1 (c 1.04, CHCl3).
0
퐷
Imine 4h:
White crystals, mp 199-201 °C, 67% yield (102 mg).
-1
IR (thin film, cm ): 3056, 3027, 2964, 2925, 2867, 1940, 1868, 1630, 1591, 1507,
1
489, 1446, 1377, 1336, 1264, 1241, 1117, 1080, 1017, 968, 907, 880, 801, 776,
61, 695, 664, 616, 577, 530, 469, 430.
7
1
H NMR (400 MHz, CDCl ): δ 8.31 – 8.19 (m, 2H), 8.00 – 7.90 (m, 6H), 7.70 (dd, J =
3
2
6.1, 8.2 Hz, 1H), 7.63 – 7.43 (m, 8H), 7.40 – 7.30 (m, 1H), 7.25 – 7.05 (m, 10H),
4
.13 – 4.02 (m, 2H), 1.36 (t, J = 6.7 Hz, 3H), 1.27 (t, J = 6.2 Hz, 3H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 158.1, 158.0, 157.9, 157.9, 144.8, 144.5, 144.4, 140.7, 140.7, 136.9,
3
1
1
1
36.9, 136.6, 136.6, 136.6, 136.5, 133.4, 133.3, 132.6, 132.5, 132.4, 129.1, 129.0, 129.0, 128.3, 128.2,
28.2, 128.2, 128.1, 128.0, 127.9, 127.8, 126.7, 126.6, 126.6, 126.5, 126.5, 126.5, 126.4, 126.4, 126.4,
26.3, 126.0, 126.0, 125.3, 125.2, 69.7, 69.7, 69.6, 69.5, 24.9, 24.8, 24.4, 24.2.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 593.2957; found, 593.2952.
Optical rotation [훼]2 +3.2 (c 0.96, CHCl3).
44 37
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퐷
Larger scale synthesis was repeated starting from 1 g of 2,5-di-(1-naphthyl)-terephthalaldehyde (2,
2.44 mmol) and 2 equivalents of (R)-1-phenylethylamine (0.592 g, 0.63 mL, 4.89 mmol) in toluene (65
mL) The resulting mixture was stirred overnight under reflux using Dean-Stark apparatus and a heating
mantle as the heat source. Then, the solvent was removed in vacuo and the crude product was used
as received (yield 1.44 g, 99%). Further crystallization from chloroform/ethanol mixture reduced the
yield to 1 g (69%).
Imine 4i:
White crystals, mp 131-133 °C, 89% yield (160 mg).
-1
IR (thin film, cm ): 3044, 1631, 1594, 1508, 1441, 1371, 1257, 1229, 1167, 1119,
1
072, 1013, 960, 911, 862, 795, 772, 733, 661, 559, 466, 429.
1
H NMR (400 MHz, CDCl ): δ 8.34 – 8.27 (m, 2H), 8.11 – 8.04 (m, 2H), 8.00 – 7.80
3
(m, 6H), 7.80 – 7.41 (m, 15H), 7.41 –7.22 (m, 7H), 4.97 (q, J = 6.6 Hz, 1H), 4.88 (dt,
J = 11.4, 6.4 Hz, 1H), 1.55 – 1.43 (m, 3H), 1.43 – 1.36 (m, 3H).
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C{H} NMR (101 MHz, CDCl ): δ 158.2, 158.2, 158.1, 140.8, 140.8, 140.7, 140.4, 140.3, 136.9, 136.9,
3
136.8, 136.8, 136.7, 136.7, 136.6, 136.5, 133.8, 133.7, 133.4, 133.3, 132.6, 132.5, 132.4, 132.3, 130.5,
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30.5, 130.4, 130.3, 129.2, 129.2, 129.1, 128.8, 128.8, 128.7, 128.3, 128.3, 128.2, 128.2, 128.1, 128.1,
28.0, 128.0, 127.9, 127.2, 127.1, 127.0, 126.5, 126.4, 126.4, 126.4, 126.2, 126.0, 126.0, 126.0, 125.6,
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9
0
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125.6, 125.5, 125.3, 125.1, 125.1, 123.8, 123.8, 123.7, 123.7, 123.3, 123.3, 123.2, 123.1, 65.5, 65.1,
5.0, 24.6, 24.5, 24.3, 24.2.
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 693.3270; found, 693.3255.
6
+
5
2
41
2
Optical rotation [훼]2 -172.3 (c 1.07, CHCl3).
0
퐷
Imine 4j:
White crystals, mp 325-326 °C, 86% yield (187 mg).
-1
IR (thin film, cm ): 3058, 2931, 2859, 1766, 1704, 1633, 1506, 1467, 1453,
1
383, 1362, 1265, 1153, 1088, 1050, 1015, 998, 946, 907, 878, 800, 775, 715,
37, 561, 530, 428.
6
1
H NMR (400 MHz, CDCl ): δ 7.95 – 7.86 (m, 4H), 7.81 (s, 0.4H), 7.78 (d, J =
3
1
.6 Hz, 0.6H), 7.76 (s, 0.8H), 7.73 (s, 0.2H), 7.70 – 7.62 (m, 5H), 7.61 – 7.27
m, 12H), 7.11 – 6.89 (m, 1.6H), 6.79 – 6.74 (m, 1.2H), 4.27 – 4.13 (m, 2H), 3.66 – 3.44 (m, 2H), 2.06
qd, J = 13.0, 4.1 Hz, 2H), 1.76 – 1.43 (m, 9H), 1.40 – 1.21 (m, 5H).
(
(
1
3
C{H} NMR (101 MHz, CDCl ): δ 168.2, 168.1, 160.0, 159.7, 159.6, 159.2, 140.4, 140.2, 136.5, 136.5,
3
1
1
1
2
36.4, 136.2, 133.7, 133.6, 133.5, 132.4, 132.3, 132.2, 132.1, 131.8, 131.7, 131.7, 129.3, 129.1, 129.0,
28.6, 128.4, 128.3, 128.3, 127.6, 127. 5, 126.6, 126.5, 126.4, 126.4, 126.2, 126.1, 126.0, 125.8, 125.7,
25.6, 125.5, 125.2, 125.1, 123.1, 123.0, 122.9, 69.0, 68.9, 68.6, 55.7, 55.6, 33.7, 33.5, 33.5, 28.6, 28.5,
5.5, 24.0, 24.0.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N O , 839.3597; found, 839.3603.
Optical rotation [훼]2 -117.0 (c 1.00, CHCl3).
5
6
47
4
4
0
퐷
General procedure for the reduction of the imines 4a-4j to amines 6a-6j:
To a 25 mL round-bottomed flask containing a solution of respective imine (0.08 mmol, 1 eq) in CHCl3
(6 mL) MeOH was added (6 mL) and then NaBH (0.4 mmol, 5 eq). The mixture was stirred overnight
4
at room temperature and quenched with 6N solution of HCl till pH ≈ 1. Then the mixture was
neutralized with a saturated water solution of K CO to basic pH. The whole mixture was diluted with
2
3
CHCl (20 mL) and washed twice with water and brine, dried (Na SO ) and concentrated under reduced
3
2
4
pressure giving white solid. The crude product was further crystallized or used as it is.
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Amine 6a:
Pale orange crystals, mp 172-173 °C, 69% yield (44 mg).
-1
IR (thin film, cm ): 3052, 2953, 2866, 2817, 1739, 1591, 1508, 1453, 1392, 1364,
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333, 1203, 1112, 1017, 971, 903, 802, 775, 738, 660, 561, 469, 438.
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H NMR (400 MHz, CDCl ): δ 8.01 – 7.86 (m, 4H), 7.76 – 7.61 (m, 2H), 7.61 – 7.39
3
(m, 10H), 3.74 – 3.56 (m, 2H), 3.48 (dd, J = 13.0, 7.5 Hz, 1H), 3.34 (dd, J = 13.0, 6.0
Hz, 1H), 2.03 – 1.89 (m, 2H), 0.73 – 0.51 (m, 24H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 139.2, 139.1, 139.1, 139.1, 138.9, 138.9, 138.7, 138.0, 137.9, 137.7,
3
1
1
33.7, 133.7, 133.5, 133.5, 132.5, 132.5, 132.4, 132.4, 131.7, 131.7, 131.5, 131.4, 128.2, 128.2, 128.2,
27.7, 127.6, 127.1, 127.0, 126.9, 126.4, 126.2, 126.1, 126.0, 126.0, 125.8, 125.8, 125.8, 125.3, 125.3,
125.2, 61.3, 61.3, 61.2, 60.9, 50.3, 50.2, 50.2, 50.0, 34.2, 34.2, 34.1, 34.0, 26.3, 26.3, 26.2, 26.2, 14.5,
4.4, 14.3, 14.3
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 557.3896; found, 557.3885.
1
+
4
0
49
2
Optical rotation [훼]2 -60.4 (c 0.99, CHCl3).
0
퐷
Amine 6b:
Pale yellow crystals, mp 156-157 °C, 75% yield (40 mg).
-1
IR (thin film, cm ): 3307, 3053, 2956, 2926, 2870, 2824, 1939, 1714, 1590, 1508,
1
9
493, 1458, 1405, 1381, 1365, 1337, 1260, 1218, 1142, 1113, 1091, 1018, 972,
06, 803, 776, 739, 724, 660, 569, 514, 477, 439.
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H NMR (400 MHz, CDCl ): δ 8.00 – 7.89 (m, 4H), 7.75 – 7.63 (m, 2H), 7.61 – 7.41
3
(m, 10H), 3.59 (dd, J = 13.2, 2.6 Hz, 1H), 3.54 (s, 2H), 3.44 (dd, J = 13.1, 9.2 Hz, 1H), 2.18 – 2.04 (m, 2H),
1
.44 – 1.26 (m, 2H), 0.69 – 0.45 (m, 18H).
13
C{H} NMR (101 MHz, CDCl ): δ 139.3, 139.2, 139.2, 138.9, 138.8, 138.8, 138.0, 137.9, 137.9, 137.9,
3
133.8, 133.7, 132.6, 132.5, 132.5, 131.8, 131.8, 131.7, 131.6, 128.4, 128.4, 128.4, 127.8, 127.1, 127.1,
1
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27.0, 127.0, 126.4, 126.3, 126.3, 126.3, 126.2, 126.2, 126.0, 126.0, 126.0, 125.4, 125.4, 57.6, 57.6,
7.4, 57.2, 49.5, 49.4, 49.3, 49.3, 32.0, 31.9, 31.8, 19.4, 19.3, 19.3, 19.2, 17.1, 17.0, 17.0, 16.8, 15.8,
15.6, 15.6, 15.4.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 529.3583; found, 529.3561.
Optical rotation [훼] 2퐷 0 +30.3 (c 1.00, CHCl3).
3
8
45
2
Amine 6c:
White crystals, mp 152-153 °C, 73% yield (40 mg).
-1
IR (thin film, cm ): 3312, 3052, 2961, 2924, 2874, 2824, 1941, 1590, 1508, 1494,
1455, 1406, 1373, 1331, 1260, 1223, 1163, 1120, 1079, 1019, 974, 906, 804, 778,
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H NMR (400 MHz, CDCl ): δ 8.01 – 7.84 (m, 4H), 7.74 – 7.62 (m, 2H), 7.62 – 7.30 (m, 10H), 3.64 – 3.29
3
(m, 4H), 2.23 – 2.08 (m, 2H), 1.18 – 0.93 (m, 5H), 0.71 – 0.48 (m, 11H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 139.3, 139.3, 139.2, 138.8, 138.7, 137.9, 137.8, 137.8, 133.8, 133.7,
3
1
33.7, 132.5, 132.5, 132.4, 131.7, 131.7, 131.6, 128.4, 128.4, 127.9, 127.0, 127.0, 127.0, 127.0, 126.3,
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126.3, 126.2, 126.0, 126.0, 126.0, 125.4, 125.4, 53.8, 53.8, 53.7, 53.5, 49.2, 49.2, 49.1, 49.1, 29.4, 29.3,
2
9.3, 29.2, 19.6, 19.6, 19.6, 19.5, 10.1, 10.1, 10.0, 10.1.
+
HRMS (ESI-Q-TOF), m/z: [M + H] calcd for C H N , 501.3270; found, 501.3262.
Optical rotation [훼]2 -19.0 (c 1.02, CHCl3).
3
6
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2
0
퐷
Amine 6d:
Colorless oil, 71% yield (51 mg).
-1
IR (thin film, cm ): 3340, 3043, 2919, 2847, 1929, 1812, 1592, 1507, 1446, 1405,
1
371, 1214, 1154, 1111, 1017, 966, 891, 864, 797, 775, 567, 471, 430.
1
H NMR (400 MHz, CDCl ): δ 8.17 – 7.82 (m, 4H), 7.79 – 7.28 (m, 12H), 3.66 – 3.35
3
(m, 4H), 2.24 – 1.95 (m, 2H), 1.80 – 1.42 (m, 6H), 1.38 – 0.84 (m, 14H), 0.61 (dt, J
=
21.9, 6.4 Hz, 10H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 139.1, 139.1, 138.7, 138.6, 138.6, 137.8, 137.8, 137.7, 137.7, 133.7,
3
1
1
1
2
33.7, 133.6, 133.6, 132.5, 132.4, 132.4, 132.3, 131.8, 131.7, 131.6, 131.6, 128.2, 128.2, 128.2, 128.2,
27.7, 127.0, 126.9, 126.9, 126.8, 126.2, 126.2, 126.2, 126.1, 126.1, 126.1, 125.9, 125.8, 125.8, 125.8,
25.3, 125.2, 57.2, 57.0, 56.9, 56.5, 49.6, 49.3, 49.2, 49.0, 42.4, 42.3, 29.7, 29.7, 29.5, 29.4, 27.7, 27.6,
7.5, 27.4, 26.7, 26.6, 26.6, 26.5, 26.5, 26.5, 26.4, 16.5, 16.3, 16.1.
+
HRMS (ESI-Q-TOF), m/z: [M + Na] calcd for C H N Na, 631.4028; found, 631.4041.
Optical rotation [훼]2 -21.3 (c 0.97, CHCl3).
44 52
2
0
퐷
Amine 6e:
White crystals, mp 219-220 °C, 77% yield (59 mg).
-1
IR (thin film, cm ): 3327, 3059, 2980, 2943, 2871, 2820, 1591, 1509, 1446, 1386,
327, 1243, 1210, 1117, 1096, 1075, 1017, 986, 901, 866, 801, 778, 741, 660, 567,
1
430.
1
H NMR (400 MHz, CDCl ): δ 8.00 – 7.85 (m, 4H), 7.77 – 7.63 (m, 2H), 7.61 – 7.28
3
(m, 10H), 3.71 – 3.27 (m, 4H), 2.59 – 2.47 (m, 1H), 2.29 – 2.20 (m, 1H), 1.82 – 1.63
(m, 1H), 1.57 – 0.80 (m, 14H), 0.74 – 0.64 (m, 10H), 0.57 – 0.06 (m, 7H).
1
3
C{H} NMR (101 MHz, CDCl ): δ 139.1, 139.1, 139.1, 139.0, 138.9, 138.9, 138.9, 138.8, 138.8, 138.7,
3
1
38.0, 137.9, 137.8, 137.6, 133.7, 133.6, 132.6, 132.5, 132.5, 132.4, 132.3, 132.3, 132.2, 132.2, 132.1,
131.9, 131.8, 131.8, 131.7, 131.6, 131.6, 128.3, 128.2, 128.2, 128.2, 127.7, 127.7, 127.7, 127.6, 127.6,
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27.1, 127.1, 127.0, 127.0, 127.0, 126.9, 126.9, 126.9, 126.8, 126.8, 126.8, 126.7, 126.3, 126.3, 126.3,
26.2, 126.2, 126.2, 126.1, 126.1, 126.0, 126.0, 125.8, 125.8, 125.8, 125.3, 125.3, 125.2, 65.9, 65.7,
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