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

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).

Introduction

The stereochemical analysis of chiral molecules, understoon class="Chemical">d 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 nondestructive 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, electronic circular dichroism (ECD) spectroscopy has been widely used in stereochemical studies.[8] To date, a lot of general, or operating in a very narrow area, correlation rules that bind the main quality of the ECD spectrum, namely, the Cotton effect (CE) at a given wavelength, with the three-dimensional (3D) structure of the chiral entity have been proposed.[8] Although it has been repeatedly demonstrated by us and others that most of the traditional empirical correlation rules are inadequate and often incorrect,[9] 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 circular dichroism (CD) spectra are originated from electric forbidden transitions.[14−18]

The use of the methods, especially the n class="Chemical">density functional theory (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 compounn class="Chemical">ds allows direct ECD measurements, there are some compounds that 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 an “inducer” or “inductor”) can be modified by an attachment of the chromophoric chirality probe (commonly called a “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 a result of the dynamic inductor–reporter structural matching, the appearance of nonzero 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, n class="Chemical">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 len class="Chemical">d to the conclusion that the efficiency of the chirality sensing of amines is a function of the mode of action of the probe and the method of binding the inductor.[33−64] The metalloporphyrin tweezers introduced to a stereochemical analysis by Berova and Nakanishi (Chart a) are considered sensitive probes of the chirality of noncovalently 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 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 a) that binds chiral monoamines via hydrogen-bonding formation. The binding of amine is associated with adapting a core-specific P- or M-helical conformation by biphenyl, which is revealed by the appearance of exciton couplets (ECs) in the region of the Soret band.[39] 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 guests.

Chart 1

(a) Porphyrin-Based Noncovalent Probes for Chirality Sensing and (b) Exemplary Sterodynamic Probes for the Covalent Binding and Chirality Sensing of Amines

An alternative approach is basen class="Chemical">d 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 b.

The operation simplicity, on the one hand, ann class="Chemical">d versatility of the sensors, on the other hand, make the imine-based probes particularly useful for 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 the 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 fragments capable of twisting relatively to each other upon binding the inducer. The nonplanarity of aromatic parts, in principle, caused the appearance of intense CEs, mostly of the exciton character.

Very recently, we have shown that the dinaphthylmethane-basen class="Chemical">d stereodynamic probes were turned out to be highly sensitive chirality sensors for optically active secondary alcohols.[71] However, some difficulties in the introduction of dinaphthylmethane on the polar functional groups preclude the wider applicability of these probes.

Feeling that the problem of chirality sensing still has not lost its topicality, we decin class="Chemical">ded to put some efforts into designing, synthesizing, and providing evidence for the efficiency of new sensitive stereodynamic reporters for primary amines. We assumed that the probe should be readily available, simple, and have a 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 CE 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 of specific interactions with polar solvents, which, in some cases, might complicate the analysis. The intention behind this idea is illustrated in Figure .

Figure 1

Schematic representation of the designed stereodynamic triaryl probe. Red arrows indicate polarizations of the electronic transition of the highest oscillator strengths within anthracene and naphthalene chromophores.

Schematic representation of the designen class="Chemical">d stereodynamic triaryl probe. Red arrows indicate polarizations of the 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 hann class="Chemical">d 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.

Results and Discussion

As the substrates for the synthesis of probes, we have chosen 2-bromobenzaldehyde ann class="Chemical">d 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 characteristics, we limited the number of substrates to 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 a).

Chart 2

(a) Structures of Compounds under Study, (b) Oak Ridge Thermal Ellipsoid Plot (ORTEP) Drawing Showing an X-ray-Determined Structure of Dialdehyde 2 with Atom Numbering, and (c) Torsion Angles That Characterize a Molecular Conformation

Despite many attempts, the use of n class="Chemical">9-anthrylboronic acid and 2,5-dibromoterephthalaldehyde for Suzuki coupling did not provide the desired bis-arylated product. However, 2-(9-anthryl)benzaldehyde (1b) was obtained under the standard conditions with a reasonable yield (64%). 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.

As the X-ray diffrn class="Chemical">action study revealed that in the crystal structure of 2 (Chart b) both naphthyl groups (denoted here A and C) are twisted relative to the central aromatic moiety (denoted B). The values of both twist α1 and α2 angles (defined here as C2–C1–C2′–C1′ and C4′–C5′–C1″–C2″, see Chart c) are equal to 121.7°. This in turn excludes the possibility for electron delocalization within the whole chromophoric system; therefore, each unit might act independently. One should keep in mind that the sign and magnitude of exciton CEs are 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 n class="Chemical">(R)-3,3-dimethylbutan-2-amine. The amine is characterized by a large spatial diversity and, therefore, may constitute the point of reference in stereochemical studies. The ECD measurements run in cyclohexane clearly showed the advantage of 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 and Table ). 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 in the higher-energy region. None of the ECD spectra exhibit the CE 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.

Figure 2

UV (upper panels) and ECD (lower panels) spectra of (a) 3a (solid black lines) and 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 185–350 nm region is shown. Experimental and calculated ECD spectra of 4f were multiplied by a factor of 4 to increase their visibility.

Table 1

ECD Data Measured in Cyclohexane and Sensitivity Factors G = |A|/ε × 10–4 Estimated for Imines 3a, 3b, and 4a–j and Amines 6a–j

compd.a	Δε (nm)	G	compd.a	Δε (nm)	G
3a (R)	–6.6 (224); –2.8 (209); 9.5 (189)	n.d.	4j (R)	–16.2 (297); –6.6 (266); –57.4 (241); 118.2 (226); –120.7 (213); 63.3 (200)	15.62
3b (R)	–14.2 (258); 1.2 (231); 4.4 (218); 5.2 (192)	n.d.	6a (R)	–5.2 (232); 7.1 (212)	1.07
4a (R)	–3.8 (289); –6.1 (238); 19.4 (227); –18.0 (215); 18.0 (188)	3.08	6b (S)	8.3 (231); –7.2 (218); 9.7 (192)	1.32
4b (S)	2.9 (286); 3.8 (238); –12.8 (227); 16.0 (215); –16.1 (189)	2.32	6c (R)	–7.1 (233); 8.3 (215); –6.6 (189)	1.32
4c (R)	–3.7 (289); 8.9 (227); –15.0 (215); 11.2 (188)	1.91	6d (R)	–11.4 (232); 14.0 (218); –12.8 (190)	1.37
4d (R)	–8.2 (289); –4.1 (234); 11.9 (227); –20.0 (214); 14.0 (192)	2.59	6e (S)	–2.1 (240)b	n.d.
4e (S)	–4.5 (310); –4.3 (245); 1.6 (232); –5.0 (226); 9.9 (211); –2.4 (188)	1.28	6f (R)	5.8 (232); –5.8 (215); 4.0 (190)	1.03
4f (R)	1.6 (296); –1.1 (266); –2.9 (221); 4.1 (203); 1.6 (188)	0.70	6g (R)	–11.8 (237); 42.1 (217); –19.8 (195)	4.80
4g (R)	11.7 (309); –13.6 (276); 21.3 (236); 19.4 (232); 48.8 (225); –27.0 (208); 84.0 (194)	6.20	6h (R)	–24.4 (233); 48.6 (222); –43.0 (193)	6.74
4h (R)	–18.4 (278); 39.7 (226); –20.9 (208); 96.5 (189)	4.93	6i (R)	2.6 (286); –47.4 (233); 4.2 (222); 56.2 (206)	2.85
4i (R)	–28.6 (288); –11.3 (255); –37.0 (229); 28.2 (217); 62.4 (201)	4.36	6j (R)	–3.5 (301); 10.6 (235); –36.4 (216); 16.8 (193)	n.d.

In parentheses, the absolute configuration at the nitrogen-containing stereogenic center is indicated.

Short-wavelength CEs are undistinguishable due to the high noise level.

UV (upper panels) and ECn class="Chemical">D (lower panels) spectra of (a) 3a (solid black lines) and 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 185–350 nm region is shown. Experimental and calculated ECD spectra of 4f were multiplied by a factor of 4 to increase their visibility.

In parentheses, the absolute configuration at the nitrogen-containing stereogenic center is inn class="Chemical">dicated.

On the contrary, the ECD spectrum measuren class="Chemical">d in cyclohexane for 4a is characterized by the high amplitudes of CEs, especially in the higher-energy region, when compared to the ECD spectra of 3a and 3b (see Figure and Table ). In particular, the ECD spectrum of 4a exhibits long-wavelength negative CE at 290 nm and a well-distinguished positive/negative/positive couplet appearing between 230 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 the ECD spectrum in the higher-energy region is a 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 of this class of compounds. In general, condensations between the amines and 2 proceed smoothly in toluene, provided almost quantitatively the respective imines (4b–j). Although most of the compounds thus obtained were crystalline, in fact, no additional purification of the crude reaction mixtures was necessary. Note that compound 5 constitutes a model used for theoretical studies.

Taking advantage of goon class="Chemical">d solubility of these compounds in nonpolar solvents, we have measured their UV and ECD spectra in cyclohexane (see the exemplary UV and ECD spectra in Figure c,d). For easier comparison of the given chromophoric system with others, and to measure sensitivity in chirogenesis, we used the so-called sensitivity factor G defined as G = |A|/ε.[71] For the purpose of this work, the sensitivity factor combines the absolute value of the amplitude |A| (A = Δεlong – Δεshort) of the couplet observed in the region of the high-intensity electronic transition (1Bb) in the naphthalene chromophore (ca. 220 nm), which may be a result of exciton interactions, with the extinction coefficient (ε at ca. 220 nm). The experimental ECD data along with estimates for sensitivity factors G of imines 4b–j are juxtaposed in Table .

The process of point-to-axial chirality induction in class="Chemical">n 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 the substituents flanking the stereogenic center and the magnitude of CEs. For example, a stepwise deterioration of steric congestion in imines 4a–c 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 factor 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, resulted in an increase of magnitude of CEs. On the other hand, more sterically congested bornyl skeleton affects the resulted ECD spectrum even less than ethyl and methyl groups in 4c.

Imine 4f constitutes the most challenging task for probe 2. The parent compounn class="Chemical">d (3R)-aminotetrahydrofurane is characterized by a very small steric diversity. For the efficient work, probe 2 must distinguish the oxygen atom from the methylene group, both involved in a five-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 0.7 × 10–5, is the smallest of the all estimated.

For 4a–f is seen a direct correlation between the shape of the ECn class="Chemical">D spectrum and absolute configuration at the stereogenic center. In the 230–180 nm spectral region, the positive/negative/positive (+/–/+) sequence of CEs corresponds to the R absolute configuration, whereas the −/+/– sequence of CEs is characteristic of 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 the sequence of CEs and absolute configuration at the stereogenic center is reversed.

The ECD spectra of 4i ann class="Chemical">d 4j are difficult to interpret. Due to the observed induction of optical activity, there is no doubt 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.

Imines 4 couln class="Chemical">d be smoothly transferred into corresponding amines 6. A 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 increased flexibility of the whole system, at least within the inductor moiety. In fact, the ECD spectra of amines 6 are less complex than those measured for imines 4. At the same time, we noticed decreasing magnitudes of CEs and thus decreasing sensitivity factors values.

When the ECD spectra measuren class="Chemical">d for 4a–h and their reduced counterparts were compared, it turned out that in the diagnostic region of 1Bb electronic transitions in the naphthalene chromophore 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 nonpolar solvents. For some derivatives, for which the ECD spectra are measured in 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 fn class="Chemical">act 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, with a particular emphasis on imine 4a. Using the propensity to form crystals suitable for X-ray diffraction analysis, we have determined solid-state structures of imines 4a–d and 4f and amines 6a–c and 6f (details are provided in the Supporting Information (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.

A special opportunity to examine the effect of a substituent on the chromophore structure is given by a n class="Chemical">direct comparison of the structures of the respective pairs: 4a–6a, 4b–6b, 4c–6c, and 4f–6f (Figure ). 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 α1 and α2 angles and, in this way, with the (almost) antiparallel orientation of naphthalene rings. Hence, 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), and (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, and the nitrogen and oxygen atoms are shown as balls.

The crystallographic studies, although interesting from the crystal engineering point of view, have not provin class="Chemical">ded 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–j, with a special emphasis on the arbitrary chosen representative example 4a (discussed later) as well as on 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 other words, we would answer the question to what extent the terminal naphthalenes flip is responsible for the ECD response.

First, we have established the conformational freen class="Chemical">dom of the model compounds 5. Calculated at the B3LYP/6-311++G(d,p) level, the potential energy surface (shown in the Figure a) for the systematic change of angles α1 and α2 clearly indicates that the low-energy conformers are 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 toward planarity. By analogy to the B–A–B-type triads, the low-energy conformers of imine 5 and its real congeners can be considered as C or S (see Scheme ).[79−81]

Figure 4

(a) Molecular energy of 5 as a function of angles α1 and α2. (b) Computed at the TD-CAM-B3LYP/6-311++G(d,p) level, long- (Rlong) and short-wavelength (Rshort) rotatory strengths corresponding to experimental exciton couplets of the 1Bb electronic transition as a function of angles α1 and α2. (c) 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 the blue solid line, the spectrum calculated for the AC part of the molecules is shown as the red line, and the effect of summation (S = 2 × AB + AC) is shown as a brown dashed line. Wavelengths were not corrected. Insets 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.

Scheme 1

Low-Energy C- and S-Type Conformers of Imine 5 and the Relationship between the Twist of the α Angles and Symmetry of the Molecule

(a) Molecular energy of 5 as a function of angles α1 and α2. (b) Computen class="Chemical">d at the TD-CAM-B3LYP/6-311++G(d,p) level, long- (Rlong) and short-wavelength (Rshort) rotatory strengths corresponding to experimental exciton couplets of the 1Bb electronic transition as a function of angles α1 and α2. (c) 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 the blue solid line, the spectrum calculated for the AC part of the molecules is shown as the red line, and the effect of summation (S = 2 × AB + AC) is shown as a brown dashed line. Wavelengths were not corrected. Insets 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.

The lowest-energy, chiral conformers of 5 have C2 symmetry and both n class="Chemical">naphthyl groups deviate by 10° from perpendicularity (α1 = α2 = 100 or −100°). A little bit higher in energy conformers of parallel or antiparallel orientation of naphthyl rings are achiral and characterized either by the opposite values of α1 and α2 angles or one α angle twisted by ±100° and the second amounting to ±80°. However, the calculated energy differences between C2-, C-, and C1-symmetrical minimum-energy conformers are negligible. Thus, given the method error, all of 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 ECn class="Chemical">D 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 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 interactions between 1Bb electronic transitions within naphthalene chromophores.

The exemplary surfaces estimaten class="Chemical">d for long- and short-wavelength rotatory strengths shown in Figure b (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 are ECD-silent in the spectral region of 1Bb electronic transitions in naphthalene. These studies suggest, but still do not constitute compelling evidence, the dominant contribution of interactions between terminal naphthyl chromophores to the overall rotatory strength.

To further confirm this hypothesis, we have chosen the low-energy C2-symmetrical conformer of 5, characterizen class="Chemical">d by the values of α1 and α2 angles equal to −100° and we have divided it into two moieties. The first of them, mapping AB and BC interactions between nearest chromophores, consisted of naphthalene and the imine part of the molecule (the remaining naphthalene fragment was replaced by the hydrogen atom). The second one reflected the AC interactions between terminal naphthyl groups. For each of the substructures, the ECD spectrum was calculated at the TD-CAM-B3LYP/6-311++G(d,p) level (see Figure c). Finally, the ECD spectrum calculated for the “whole” low-energy conformer of 5 was compared with the one being the result of summation S = 2 × AB + AC.

It is clearly seen that both the calculated spectrum for the isolaten class="Chemical">d AC system and the compiled (S) spectrum 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 230–200 nm region, the observed CEs are mainly due to the AC exciton-type interactions. The contribution of AB and BC interactions to the overall rotatory strength in this particular spectral region seemed negligible. However, these AB and BC interactions are gaining importance in the higher-energy region of the ECD spectrum, i.e., below 200 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 coming from the central imine unit B. Going to higher energies, the rotatory strengths between 230 and 200 nm originated mainly from the orbitals centered in the naphthalene units (Figure d). It should be noted that some contribution from electronic transitions involving highest occupied molecular orbital (HOMO) – 1 and HOMO – 3 from naphthalene and the lowest unoccupied molecular orbital (LUMO) orbital centered at the central unit B to the overall rotatory strengths was 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 a 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 of 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 n class="Gene">twist of the α angles is not straightforward. However, keeping in mind that the highest intensity of 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 nondegenerated systems) functions of in-plane angles between the given electric dipole and the line connected the midpoints of interacting electric 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 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.

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 applien class="Chemical">d a similar procedure (see Calculation details in the Supporting Information) to imines 4a–j. 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 on, and all of the theoretical results are skipped to the SI.

Four low-energy conformers of 4a are found by calculations at the B3n class="Gene">LYP/6-311++G(d,p) level of the theory (Table and Figure a). The conformers are characterized by the deviation of α angles from perpendicularity by ±11 to ±20°, with a reasonable agreement with the X-ray data obtained for the real compound. The conformation of the imine groups, described by β1 and β2 angles (see Chart c), in all of the cases is synperiplanar.

Table 2

Relative Gibbs Free Energies (ΔΔG, in kcal mol–1); ΔΔG-Based Percentage Populations (Pop.); Values of α1, α2, β1, β2, and ω Angles (in deg) and Predicted Sign of the Exciton Couplet (EC), Calculated at the B3LYP/6-311++G(d,p) Level of Theory for Individual Low-Energy Conformers of 4a

conf.a	ΔΔG	Pop.	α1b	α2b	β1c	β2c	ωd	CE
1	1.77	3	105	105	178	178	29	(+)
2	1.12	10	101	101	179	179	21	(+)
4	0.00	65	104	–104	176	–178	180	0
6	0.64	22	–111	–111	–171	–171	–41	(−)

Conformers are numbered according to their appearance during the conformational search.

α1 = C2–C1–C2′–C1′; α2 = C2″–C1″–C5′–C4′.

β1 = C2′–C1′–C=N; β2 = C5′–C4′–C=N.

ω = C8–C1–C1″–C8″.

Figure 5

(a) Overlay of low-energy conformers of 4a calculated at the B3LYP/6-311++G(d,p) level 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.

(a) Overlay of low-energy conformers of 4a calculated at the B3n class="Gene">LYP/6-311++G(d,p) level 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.

While three of these structures are characterizen class="Chemical">d by the same signs of both α angles and by C2 symmetry, one of the lowest energy (conf. no. 4) closely resembles the 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 α1 and α2 angles equal to −104 and 104°, respectively. The population of this conformer, estimated on the basis of relative Gibbs energies, amounts to 65%.

Since the interacting n class="Chemical">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 b) in the spectral region dominated by naphthalene–naphthalene interactions. Hence, the contribution of this conformer does not affect the overall ECD spectrum, in accordance with 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-energy, conformer nos. 1 and 2 on the overall ECD spectrum seems to be negligible.

The reproduction of experimental n class="Chemical">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 c), although the good agreement between experimental and theoretical data, obtained for the most demanding imine 4f, is worth mentioning (see Figure d).

For the particular case of imine 4c, the percentage relation of conformers charn class="Chemical">acterized by the positive value of the ω angle to that of the negative value of the ω angle and optically inactive conformers (ω ≈ 180°) amounts to 41% (+): 31% (−): 28% (0). In other cases, even if the 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 transferren class="Chemical">d to the probe. The analysis of the available structural data led to the conclusion that both steric and electrostatic interactions take part in chirality transfer. The latter is easier to demonstrate. The (N=C)H···π interactions between an electron cloud of the naphthalene and positively charged methine proton fix the anti conformation of β angles (see Chart c 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 the synperiplanar orientation of C*H and CH=N protons, allowed for interaction of nitrogen 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, naphthalene is tilted toward 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 Figure , the low-energy but optically active conformers of 4d (conf. no. 14) and 4h (conf. no. 1) are shown, which 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 conformer no. 2 of 4h is positive (ω = 31°), and the naphthalene rings are tilted toward 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.

Figure 6

Top (upper panel) and side (lower panel) views of the low-energy conformers of (a) 4d (conf. no. 14) and (b) 4h (conf. no. 1). The naphthyl rings closer to the observer are in green, whereas the naphthyl rings away from the observer are in red.

The calculated ann class="Chemical">d 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 wouln class="Chemical">d check the possibility of the quantitative chirality sensing with probe 2.[26,33] Thus, we experimentally determined the chiroptical response of nonracemic crude products 4a, obtained by condensation of 2 with 3,3-dimethylbutan-2-amine varied in optical purity. We observed linear relationships between the enantiomeric excess (ee) of the free amine and the CEs appearing at 227 and 215 nm (Figure ). It is worth noting that we found the same linear response for all optically active ECD bands. This feature might be useful for samples where the intrinsic rotatory strengths from the inductor obscure the induced circular dichroism resulting from the point-to-axial chirality transmission.

Figure 7

(a) ECD spectra of the crude imine samples, obtained from 2 and 3,3-dimethylbutan-2-amine of varying ee. (b) Linear relationships between CE amplitude at 227 nm (blue line) and 215 nm (red line) and the sample ee.

Conclusions

In conclusion, we have designen class="Chemical">d 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 nonexpensive 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 nonspecialists in organic synthesis. Hence, the cost of synthesis, compared to, e.g., the synthesis of porphyrin-based probes is small.

The ECD spectra measuren class="Chemical">d 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 nonpolar solvents of the hydrocarbon type and easy 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 probe 2 is its high sensitivity toward 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 shouln class="Chemical">d be noted that this approach does not provide values regarding the absolute size of the substituent. Instead, it allows us to estimate the steric power for dynamic induction of chirality of one substituent relative to the other flanking the stereogenic 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–d increases 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 stereogenic center in the cycle, these relationships are −C*(Me)– > −CH2–; −CH2O– > −CH2CH2–; −C(Ar)– > −CH2–, respectively, for 4e–g. The larger steric power of the methyl group with respect to phenyl and naphthyl groups in 4h and 4i, respectively, is apparently the reason for the reversal of correlation between the sign of exciton couplet and the absolute configuration of aliphatic vs aromatic substituents.

To make this analysis more comprehensive, we have compared sensitivity fn class="Chemical">actors 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 the 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–reporter systems used in this analysis are shown in Chart .

Chart 3

Exemplary Sterodynamic Inductor–Reporter Systems and Their Calculated Sensitivity Factors G

As one can see, all of the probes shown in Chart are characterizen class="Chemical">d 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 toward decreasing sensitivity in the following order: 7 > 11 > 4a > 10 > 9 > 8.

Although on the basis of X-ray results the direct correlation between the chromophore structure ann class="Chemical">d experimentally observed induced optical activity is not visible, 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 on the structure of a given compound in solution, based on crystallographic data solely, may lead to erroneous results.

Even in the case of inductor charn class="Chemical">acterized 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 the absolute configuration of the inducers.

Finally, we have demonstraten class="Chemical">d a 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.

Experimental Section

General Information

Unless otherwise noted, all ren class="Chemical">actions were carried out in air. Deuterated chloroform (CDCl3), solvents, and other chemicals were purchased from commercial suppliers and used 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 ann class="Chemical">d 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 CDCl3 residual solvent peak). Data is described as follows: chemical shift, multiplicity (s = singlet, d = doublet, 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 a 254 nm fluorescence indicator).

Melting points were measured on a BUCHI B-545 apparatus. High-resolution mass spectra (HRMS) were measured using a Bruker Impact HD spectrometer. Optical rotations were recorded on a Jasco P-2000 polarimeter at 20 °C.

The ECD ann class="Chemical">d 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 0.1 cm optical lengths. The concentration of analytes ranged from 1.0 to 2.0 × 10–4 mol L–1. Background spectra of the pure solvents were recorded from 400 to 185 nm with a scan speed of 100 nm min–1. The ECD spectra of analytes were measured with eight accumulations.

IR spectra were recorded on a Jasco FT-IR 4600 spectrophotometer with ATR PRO ONE using a diamond crystal.

2-(1-Naphthyl)-benzaldehyde (1a)

In a 50 mL round-bottom flask, n class="Chemical">K2CO3 (1.310 g, 9.46 mmol, 2.5 equiv) was dissolved in 20 mL of H2O and the resulting solution was sparged with argon for 30 min. A 100 mL round-bottom flask containing a mixture of toluene (30 mL) and EtOH (20 mL) was sparged with argon for 30 min. Then, 2-bromobenzlaldehyde (0.44 mL, 3.78 mmol, 1 equiv), 1-naphthyl boronic acid (0.780 g, 4.54 mmol, 1.2 equiv), Pd(PPh3)4 (0.306 g, 0.27 mmol, 7 mol %), and water solution of K2CO3 were added to the flask. The resulting mixture was refluxed overnight under an argon atmosphere and using a heating mantle. Then, the dark mixture was cooled to room temperature, diluted with CHCl3, and filtered through Celite. The filtrate was washed twice with water and brine, dried (Na2SO4), and concentrated under reduced pressure, resulting in dark thick oil. The product was separated using column chromatography (CHCl3/n-hexane 1:1). Yellow oil, 88% yield (772 mg).

IR (thin film, cm–1): 3368, 3054, 2840, 2749, 1943, 1823, 1740, 1690, 1596, 1504, 1479, 1447, 1387, 1337, 1298, 1261, 1246, 1194, 1159, 1119, 1039, 1014, 957, 926, 883, 870, 836, 817, 802, 780, 765, 738, 704, 636, 618, 578, 565, 477, 444, 419.

1H NMR (400 MHz, CDCl3): 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), 7.69 (td, J = 7.5, 1.5 Hz, 1H), 7.63–7.37 (m, 7H).

13C{H} NMR (101 MHz, CDCl3): δ 192.0, 192.0, 144.2, 135.4, 134.7, 133.6, 133.3, 132.6, 131.7, 128.6, 128.3, 128.1, 127.0, 126.7, 126.1, 125.7, 125.0.

HRMS (electrospray ionization quadrupole time-of-flight (ESI-Q-TOF)), m/z: [M + Na]+ calcd for C17H12NaO, 255.0786; found, 255.0796.

2-(9-Anthracene)-benzaldehyde (1b)

In a 50 mL round-bottom flask, n class="Chemical">K2CO3 (1.310 g, 9.46 mmol, 2.5 equiv) was dissolved in 20 mL of H2O and the resulting solution was sparged with argon for 30 min. A 100 mL round-bottom flask containing a mixture of toluene (30 mL) and EtOH (20 mL) was sparged with argon for 30 min. Then, 2-bromobenzaldehyde (0.44 mL, 3.78 mmol, 1 equiv), 9-anthraceneboronic acid (1.010 g, 4.54 mmol, 1.2 equiv), Pd(PPh3)4 (0.306 g, 0.27 mmol, 7 mol %), and water solution of K2CO3 were added to the flask. The resulting mixture was refluxed overnight in an argon 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. The filtrate was washed twice with water and brine, dried (Na2SO4), and concentrated under reduced pressure, resulting in dark thick oil. The product was separated using column chromatography (CHCl3/n-hexane 9:1). Isolation of 2-(9-anthracene)-benzaldehyde should not be unnecessarily prolonged due to its highly light-sensitiveness. The pure product should be stored in covered glassware in a dark place. Solidifying yellow-green oil, 64% yield (682 mg).

IR (thin film, cm–1): 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, 859, 849, 838, 820, 793, 760, 736, 694, 655, 630, 610, 576, 553, 467, 442, 407.

1H NMR (400 MHz, CDCl3): δ 9.32 (d, J = 0.9 Hz, 1H), 8.56 (s, 1H), 8.26–8.19 (m, 1H), 8.10–8.04 (m, 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).

13C{H} NMR (101 MHz, CDCl3): δ 191.9, 142.8, 135.6, 134.0, 132.6, 131.5, 131.1, 131.0, 128.5, 128.5, 127.7, 127.2, 126.3, 126.1, 125.3.

HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C21H14NaO, 305.0942; found, 305.0947.

2,5-Di-(1-naphthyl)-terephthalaldehyde (2)

The general synthesis method was basen class="Chemical">d on the procedure described by Prusinowska et al. and Frederickson et al.[72,84] In a 50 mL round-bottom flask, K2CO3 (2.49 g, 17.99 mmol, 5 equiv) was dissolved in 30 mL of H2O and the resulting mixture was sparged with argon for 30 min. A 250 mL round-bottom flask containing a mixture of toluene (40 mL) and EtOH (30 mL) was sparged with argon for 30 min. Then, 2,5-dibromoterephthalaldehyde (1.05 g, 3.6 mmol, 1 equiv), 1-naphthyl boronic acid (1.56 g, 8.99 mmol, 2.5 equiv), Pd(PPh3)4 (416 mg, 0.36 mmol, 10 mol %), and water solution of K2CO3 were added to the flask. The resulting mixture was refluxed overnight in an argon atmosphere and with the use of a heating mantle as the heat source. The dark mixture was cooled to room temperature, diluted with CHCl3, and filtered through Celite. The filtrate was washed twice with water and brine, dried (Na2SO4), and concentrated under reduced pressure, resulting in dark thick oil. The product was separated using column chromatography and crystallization.

Green-to-yellow crystals, mp 245–247 °C, 65% yield (601 mg).

IR (thin film, cm–1): 3352, 3060, 3041, 3012, 2881, 2749, 1746, 1679, 1592, 1509, 1483, 1438, 1406, 1396, 1365, 1267, 1239, 1146, 1114, 1021, 1008, 977, 911, 870, 855, 799, 772, 658, 632, 522, 456, 426.

1H NMR (400 MHz, CDCl3): δ 9.77 (s, 2H), 8.23 (s, 2H), 8.06–7.94 (m, 4H), 7.71–7.47 (m, 10H).

13C{H} NMR (101 MHz, CDCl3): δ 191.3, 143.4, 143.4, 137.7, 137.7, 134.0, 133.5, 133.4, 132.5, 132.4, 130.6, 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 C28H18NaO2, 409.1204; found, 409.1196.

The 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(PPh3)4 (624 mg, 0.54 mmol, 5 mol %). The reaction time was prolonged to 36 h. After workup and purification, the pure product was obtained with 62% yield (2.58 g).

General Procedure for the Synthesis of Imines 3a and 3b

To a 25 mL round-bottom flask containing n class="Chemical">aldehyde 1a or 1b (1 equiv, 0.44 mmol) and chiral amine (1.2 equiv, 0.53 mmol), toluene (8 mL) was added. The resulting mixture was stirred overnight under reflux using a Dean–Stark apparatus and a heating mantle as the heat source. Then, the solvent was removed in vacuo and the product was used as received.

Imine 3a

Yellow oil, 98% yield (137 mg).

IR (thin film, cm–1): 3262, 3058, 2958, 2901, 2866, 2825, 2606, 1933, 1814, 1739, 1638, 1594, 1506, 1477, 1455, 1392, 1367, 1269, 1248, 1202, 1158, 1119, 1083, 1056, 1017, 964, 915, 863, 801, 777, 760, 695, 635, 620, 569, 462, 439, 420.

1H NMR (400 MHz, CDCl3): δ 8.24–8.14 (m, 1H), 7.97–7.86 (m, 2H), 7.78 (s, 0.5H), 7.73 (s, 0.5H), 7.61–7.45 (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, 0.5H), 0.88 (d, J = 6.5 Hz, 1.5H), 0.81 (s, 4.5H), 0.76 (s, 4H).

13C{H} NMR (101 MHz, CDCl3): δ 157.7, 157.7, 157.4, 140.8, 140.7, 137.6, 137.5, 135.6, 135.5, 133.3, 133.3, 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, 126.7, 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 C23H26N, 316.2065; found, 316.2061.

Optical rotation [α]D20 −33.4 (c 1.00, CHCl3).

Imine 3b

White crystals, mp 117–118 °C, 62% yield (80 mg).

IR (thin film, cm–1): 3053, 2958, 2902, 2865, 1947, 1821, 1697, 1637, 1596, 1519, 1442, 1409, 1392, 1355, 1312, 1268, 1201, 1155, 1141, 1121, 1057, 1039, 1012, 963, 936, 888, 845, 822, 792, 761, 735, 630, 611, 553, 455, 416.

1H NMR (400 MHz, CDCl3): 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 (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).

13C{H} NMR (101 MHz, CDCl3): δ 157.2, 138.8, 136.6, 133.9, 131.8, 131.2, 130.7, 130.5, 129.8, 128.3, 128.2, 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 C27H28N, 366.2222; found, 366.2225.

Optical rotation [α]D20 −29.2 (c 1.07, CHCl3).

General Procedure for the Synthesis of Imines 4a–4j

To a 25 mL round-bottom flask containing n class="Chemical">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 a Dean–Stark apparatus and a heating mantle as the heat source. Then, the solvent was removed in vacuo and the product was crystallized if necessary.

Imine 4a

White crystals, mp 289–291 °C, 77% yield (110 mg).

IR (thin film, cm–1): 3057, 3038, 2961, 2868, 1945, 1822, 1696, 1631, 1592, 1507, 1478, 1454, 1392, 1377, 1367, 1337, 1262, 1204, 1180, 1116, 1057, 1017, 965, 915, 800, 776, 740, 661, 564, 429.

1H NMR (400 MHz, CDCl3): δ 8.21 (s, 0.5H), 8.18 (s, 0.5H), 8.16 (s, 0.5H), 8.11 (s, 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), 0.93 (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).

13C{H} NMR (101 MHz, CDCl3): δ 157.7, 157.4, 157.2, 157.0, 140.4, 140.4, 140.3, 137.3, 137.3, 137.2, 137.1, 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, 128.2, 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 C40H45N2, 553.3583; found, 553.3570.

Optical rotation [α]D20 −116.1 (c 0.96, CHCl3).

Imine 4b

White crystals, mp 267–268 °C, 74% yield (100 mg).

IR (thin film, cm–1): 3054, 2956, 2869, 1936, 1827, 1695, 1631, 1592, 1508, 1454, 1376, 1338, 1263, 1241, 1138, 1112, 1055, 1018, 966, 913, 801, 776, 740, 662, 554, 430.

1H NMR (400 MHz, CDCl3): δ 8.24–8.10 (m, 2H), 8.02–7.89 (m, 4H), 7.87–7.78 (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).

13C{H} NMR (101 MHz, CDCl3): δ 157.7, 157.5, 157.3, 157.3, 140.5, 140.5, 140.4, 137.1, 137.0, 136.7, 136.7, 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, 72.5, 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 C38H41N2, 525.3270; found, 525.3264.

Optical rotation [α]D20 +83.7 (c = 0.97, CHCl3).

Imine 4c

White crystals, mp 264–265 °C, 77% yield (99 mg).

IR (thin film, cm–1): 3054, 2963, 2924, 2868, 1940, 1747, 1632, 1592, 1508, 1488, 1454, 1376, 1325, 1267, 1241, 1141, 1021, 966, 913, 887, 803, 778, 741, 694, 662, 549, 526.

1H NMR (400 MHz, CDCl3): δ 8.21–8.17 (m, 1H), 8.15 (dd, J = 8.8, 1.5 Hz, 1H), 7.99–7.89 (m, 4H), 7.88–7.83 (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).

13C{H} NMR (101 MHz, CDCl3): δ 157.7, 157.6, 157.4, 157.4, 140.6, 140.6, 140.5, 140.4, 137.0, 137.0, 136.9, 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, 125.2, 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 C36H37N2, 497.2957; found, 497.2949.

Optical rotation [α]D20 −60.2 (c 0.95, CHCl3).

Imine 4d

White crystals, mp 249–250 °C, 76% yield (120 mg).

IR (thin film, cm–1): 3053, 2918, 2851, 1935, 1826, 1632, 1592, 1507, 1446, 1377, 1332, 1263, 1242, 1116, 1019, 966, 912, 800, 776, 737, 694, 662, 558, 430.

1H NMR (400 MHz, CDCl3): δ 8.19–8.08 (m, 2H), 8.02–7.84 (m, 4H), 7.79 (d, J = 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).

13C{H} NMR (101 MHz, CDCl3): δ 157.6, 157.4, 157.3, 140.5, 140.5, 140.4, 140.4, 137.1, 137.1, 137.1, 137.1, 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, 43.3, 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 C44H49N2, 605.3896; found, 605.3898.

Optical rotation [α]D20 −67.8 (c 0.94, CHCl3).

Imine 4e

White crystals, mp 307–308 °C, 85% yield (144 mg).

IR (thin film, cm–1): 3057, 3042, 2946, 2871, 1630, 1592, 1507, 1454, 1368, 1263, 1112, 1059, 1018, 942, 800, 776, 664, 554, 430.

1H NMR (400 MHz, CDCl3): δ 8.24–8.17 (m, 1H), 8.15–8.10 (m, 1H), 7.95 (dd, J = 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), 1.14–0.81 (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).

13C{H} NMR (101 MHz, CDCl3): δ 157.8, 157.7, 157.6, 157.5, 157.4, 157.4, 157.4, 156.3, 156.2, 156.1, 156.1, 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, 137.4, 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, 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, 128.2, 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, 126.6, 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, 50.7, 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, 36.4, 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 C48H53N2, 657.4209; found, 657.4220.

Optical rotation [α]D20 −51.5 (c 1.01, CHCl3).

Imine 4f

White crystals, mp 292–294 °C, 67% yield (91 mg).

IR (thin film, cm–1): 3055, 2944, 2918, 2863, 1941, 1714, 1626, 1591, 1508, 1488, 1436, 1380, 1361, 1325, 1266, 1241, 1170, 1123, 1076, 1021, 964, 912, 805, 779, 742, 693, 661, 572, 540, 501, 470, 440, 421, 405.

1H NMR (400 MHz, CDCl3): δ 8.23–8.20 (m, 2H), 7.99–7.92 (m, 4H), 7.90 (s, 2H), 7.70–7.39 (m, 10H), 3.94–3.85 (m, 2H), 3.80–3.50 (m, 8H), 2.04–1.71 (m, 4H).

13C{H} NMR (101 MHz, CDCl3): δ 158.8, 158.7, 158.7, 158.6, 140.8, 140.8, 140.7, 136.6, 136.6, 136.3, 136.2, 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, 127.9, 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 C36H33N2O2, 525.2542; found, 525.2541.

Optical rotation [α]D20 +23.1 (c 1.06, CHCl3).

Imine 4g

Colorless crystals, mp 250–252 °C, 87% yield (146 mg).

IR (thin film, cm–1): 3053, 3015, 2925, 2863, 2834, 1746, 1683, 1628, 1508, 1488, 1450, 1375, 1264, 1239, 1115, 1072, 966, 877, 803, 776, 738, 549, 433.

1H NMR (400 MHz, CDCl3): δ 8.26–8.19 (m, 2H), 8.03–7.87 (m, 6H), 7.76–7.44 (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), 1.99–1.72 (m, 5H), 1.70–1.56 (m, 3H).

13C{H} NMR (101 MHz, CDCl3): δ 159.3, 159.1, 158.9, 158.8, 140.9, 140.9, 140.8, 140.7, 136.9, 136.9, 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, 129.0, 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, 127.7, 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, 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, 19.7.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C48H41N2, 645.3270; found, 645.3284.

Optical rotation [α]D20 +161.1 (c 1.04, CHCl3).

Imine 4h

White crystals, mp 199–201 °C, 67% yield (102 mg).

IR (thin film, cm–1): 3056, 3027, 2964, 2925, 2867, 1940, 1868, 1630, 1591, 1507, 1489, 1446, 1377, 1336, 1264, 1241, 1117, 1080, 1017, 968, 907, 880, 801, 776, 761, 695, 664, 616, 577, 530, 469, 430.

1H NMR (400 MHz, CDCl3): δ 8.31–8.19 (m, 2H), 8.00–7.90 (m, 6H), 7.70 (dd, J = 26.1, 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).

13C{H} NMR (101 MHz, CDCl3): δ 158.1, 158.0, 157.9, 157.9, 144.8, 144.5, 144.4, 140.7, 140.7, 136.9, 136.9, 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, 128.2, 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, 126.3, 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 C44H37N2, 593.2957; found, 593.2952.

Optical rotation [α]D20 +3.2 (c 0.96, CHCl3).

The larger-scale synthesis was repeated starting from 1 g of n class="Chemical">2,5-di-(1-naphthyl)-terephthalaldehyde (2, 2.44 mmol) and 2 equiv 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 a 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 the chloroform/ethanol mixture reduced the yield to 1 g (69%).

Imine 4i

White crystals, mp 131–133 °C, 89% yield (160 mg).

IR (thin film, cm–1): 3044, 1631, 1594, 1508, 1441, 1371, 1257, 1229, 1167, 1119, 1072, 1013, 960, 911, 862, 795, 772, 733, 661, 559, 466, 429.

1H NMR (400 MHz, CDCl3): δ 8.34–8.27 (m, 2H), 8.11–8.04 (m, 2H), 8.00–7.80 (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).

13C{H} NMR (101 MHz, CDCl3): δ 158.2, 158.2, 158.1, 140.8, 140.8, 140.7, 140.4, 140.3, 136.9, 136.9, 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, 130.5, 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, 128.0, 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, 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, 65.0, 24.6, 24.5, 24.3, 24.2.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C52H41N2, 693.3270; found, 693.3255.

Optical rotation [α]D20 −172.3 (c 1.07, CHCl3).

Imine 4j

White crystals, mp 325–326 °C, 86% yield (187 mg).

IR (thin film, cm–1): 3058, 2931, 2859, 1766, 1704, 1633, 1506, 1467, 1453, 1383, 1362, 1265, 1153, 1088, 1050, 1015, 998, 946, 907, 878, 800, 775, 715, 637, 561, 530, 428.

1H NMR (400 MHz, CDCl3): δ 7.95–7.86 (m, 4H), 7.81 (s, 0.4H), 7.78 (d, J = 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).

13C{H} NMR (101 MHz, CDCl3): δ 168.2, 168.1, 160.0, 159.7, 159.6, 159.2, 140.4, 140.2, 136.5, 136.5, 136.4, 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, 128.6, 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, 125.6, 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, 25.5, 24.0, 24.0.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C56H47N4O4, 839.3597; found, 839.3603.

Optical rotation [α]D20 −117.0 (c 1.00, CHCl3).

General Procedure for the Reduction of Imines 4a–j to Amines 6a–j

To a 25 mL round-bottomen class="Chemical">d flask containing a solution of respective imine (0.08 mmol, 1 equiv) in CHCl3 (6 mL), MeOH was added (6 mL) and then NaBH4 (0.4 mmol, 5 equiv) was added. The mixture was stirred overnight at room temperature and quenched with 6 N solution of HCl till pH ≈ 1. Then, the mixture was neutralized with a saturated water solution of K2CO3 to basic pH. The whole mixture was diluted with CHCl3 (20 mL) and washed twice with water and brine, dried (Na2SO4), and concentrated under reduced pressure, giving a white solid. The crude product was further crystallized or used as such.

Amine 6a

Pale orange crystals, mp 172–173 °C, 69% yield (44 mg).

IR (thin film, cm–1): 3052, 2953, 2866, 2817, 1739, 1591, 1508, 1453, 1392, 1364, 1333, 1203, 1112, 1017, 971, 903, 802, 775, 738, 660, 561, 469, 438.

1H NMR (400 MHz, CDCl3): δ 8.01–7.86 (m, 4H), 7.76–7.61 (m, 2H), 7.61–7.39 (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).

13C{H} NMR (101 MHz, CDCl3): δ 139.2, 139.1, 139.1, 139.1, 138.9, 138.9, 138.7, 138.0, 137.9, 137.7, 133.7, 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, 127.7, 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, 14.4, 14.3, 14.3

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C40H49N2, 557.3896; found, 557.3885.

Optical rotation [α]D20 −60.4 (c 0.99, CHCl3).

Amine 6b

Pale yellow crystals, mp 156–157 °C, 75% yield (40 mg).

IR (thin film, cm–1): 3307, 3053, 2956, 2926, 2870, 2824, 1939, 1714, 1590, 1508, 1493, 1458, 1405, 1381, 1365, 1337, 1260, 1218, 1142, 1113, 1091, 1018, 972, 906, 803, 776, 739, 724, 660, 569, 514, 477, 439.

1H NMR (400 MHz, CDCl3): δ 8.00–7.89 (m, 4H), 7.75–7.63 (m, 2H), 7.61–7.41 (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).

13C{H} NMR (101 MHz, CDCl3): δ 139.3, 139.2, 139.2, 138.9, 138.8, 138.8, 138.0, 137.9, 137.9, 137.9, 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, 127.0, 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, 57.4, 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 C38H45N2, 529.3583; found, 529.3561.

Optical rotation [α]D20 +30.3 (c 1.00, CHCl3).

Amine 6c

White crystals, mp 152–153 °C, 73% yield (40 mg).

IR (thin film, cm–1): 3312, 3052, 2961, 2924, 2874, 2824, 1941, 1590, 1508, 1494, 1455, 1406, 1373, 1331, 1260, 1223, 1163, 1120, 1079, 1019, 974, 906, 804, 778, 740, 660, 568, 512, 472, 437.

1H NMR (400 MHz, CDCl3): δ 8.01–7.84 (m, 4H), 7.74–7.62 (m, 2H), 7.62–7.30 (m, 10H), 3.64–3.29 (m, 4H), 2.23–2.08 (m, 2H), 1.18–0.93 (m, 5H), 0.71–0.48 (m, 11H).

13C{H} NMR (101 MHz, CDCl3): δ 139.3, 139.3, 139.2, 138.8, 138.7, 137.9, 137.8, 137.8, 133.8, 133.7, 133.7, 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, 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, 29.3, 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 C36H41N2, 501.3270; found, 501.3262.

Optical rotation [α]D20 −19.0 (c 1.02, CHCl3).

Amine 6d

Colorless oil, 71% yield (51 mg).

IR (thin film, cm–1): 3340, 3043, 2919, 2847, 1929, 1812, 1592, 1507, 1446, 1405, 1371, 1214, 1154, 1111, 1017, 966, 891, 864, 797, 775, 567, 471, 430.

1H NMR (400 MHz, CDCl3): δ 8.17–7.82 (m, 4H), 7.79–7.28 (m, 12H), 3.66–3.35 (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).

13C{H} NMR (101 MHz, CDCl3): δ 139.1, 139.1, 138.7, 138.6, 138.6, 137.8, 137.8, 137.7, 137.7, 133.7, 133.7, 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, 127.7, 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, 125.3, 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, 27.5, 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 C44H52N2Na, 631.4028; found, 631.4041.

Optical rotation [α]D20 −21.3 (c 0.97, CHCl3).

Amine 6e

White crystals, mp 219–220 °C, 77% yield (59 mg).

IR (thin film, cm–1): 3327, 3059, 2980, 2943, 2871, 2820, 1591, 1509, 1446, 1386, 1327, 1243, 1210, 1117, 1096, 1075, 1017, 986, 901, 866, 801, 778, 741, 660, 567, 430.

1H NMR (400 MHz, CDCl3): δ 8.00–7.85 (m, 4H), 7.77–7.63 (m, 2H), 7.61–7.28 (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).

13C{H} NMR (101 MHz, CDCl3): δ 139.1, 139.1, 139.1, 139.0, 138.9, 138.9, 138.9, 138.8, 138.8, 138.7, 138.0, 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, 127.1, 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, 126.2, 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, 65.6, 65.6, 65.5, 65.5, 65.4, 65.4, 62.5, 62.5, 62.4, 62.3, 62.3, 62.1, 51.0, 50.8, 50.2, 50.1, 50.1, 50.0, 50.0, 48.5, 48.4, 48.4, 48.2, 48.1, 48.1, 48.1, 48.1, 46.6, 46.5, 46.5, 45.2, 45.1, 45.1, 44.8, 44.8, 44.8, 38.3, 38.2, 38.1, 38.1, 38.0, 37.9, 37.9, 37.3, 37.3, 37.1, 37.0, 36.8, 36.8, 36.7, 28.2, 28.1, 28.0, 28.0, 27.3, 27.2, 27.1, 27.1, 20.5, 20.5, 20.4, 20.4, 20.3, 20.2, 19.7, 19.7, 18.6, 18.6, 14.0, 11.8, 11.7, 11.7, 11.7, 11.6, 11.6, 11.5.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C48H57N2, 661.4522; found, 661.4510.

Optical rotation [α]D20 −6.6 (c 0.99, CHCl3).

Amine 6f

Colorless crystals, mp 184–185 °C, 68% yield (34 mg).

IR (thin film, cm–1): 3304, 3053, 2932, 2857, 1935, 1746, 1590, 1508, 1494, 1455, 1435, 1405, 1360, 1334, 1216, 1135, 1109, 1073, 1054, 1019, 974, 907, 804, 779, 741, 660, 568, 519, 434.

1H NMR (400 MHz, CDCl3): δ 8.00–7.88 (m, 4H), 7.68–7.41 (m, 12H), 3.65–3.42 (m, 10H), 3.19–3.02 (m, 4H), 1.78–1.63 (m, 2H), 1.31–1.17 (m, 2H), 1.06 (br, 2H).

13C{H} NMR (101 MHz, CDCl3): δ 139.4, 139.4, 138.5, 138.5, 137.4, 137.4, 137.4, 133.7, 132.4, 132.3, 132.3, 131.4, 131.4, 131.3, 128.5, 128.5, 128.5, 128.1, 128.1, 128.0, 127.0, 127.0, 127.0, 126.4, 126.4, 126.4, 126.1, 126.1, 126.1, 126.0, 126.0, 126.0, 125.5, 125.4, 125.4, 73.3, 73.3, 73.3, 67.1, 67.0, 57.8, 57.8, 57.8, 57.7, 50.1, 50.0, 50.0, 32.8, 32.8, 32.7.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C36H37N2O2, 529.2855; found, 529.2872.

Optical rotation [α]D20 +3.3 (c 1.06, CHCl3).

Amine 6g

Colorless oil, 98% yield (49 mg).

IR (thin film, cm–1): 3849, 3330, 3054, 3012, 2925, 2854, 2359, 2119, 2101, 2068, 2023, 1990, 1941, 1744, 1681, 1634, 1592, 1488, 1445, 1377, 1260, 1092, 1017, 904, 801, 775, 734, 422.

1H NMR (400 MHz, CDCl3): δ 8.03–7.91 (m, 4H), 7.78–7.41 (m, 12H), 7.10–6.82 (m, 7H), 6.59 (dd, J = 24.6, 7.6 Hz, 1H), 3.72 (dd, J = 13.0, 3.8 Hz, 1H), 3.56 (d, J = 13.0 Hz, 1H), 3.45 (dq, J = 21.6, 4.9 Hz, 2H), 2.71–2.50 (m, 4H), 1.75–1.36 (m, 10H).

13C{H} NMR (101 MHz, CDCl3): δ 139.6, 139.5, 139.1, 139.0, 138.9, 138.8, 138.7, 138.6, 137.9, 137.8, 137.8, 137.7, 137.3, 137.3, 137.3, 133.7, 133.7, 133.7, 133.6, 132.6, 132.5, 132.5, 131.9, 131.9, 131.9, 131.7, 131.7, 131.6, 129.0, 128.9, 128.9, 128.9, 128.8, 128.7, 128.4, 128.4, 127.9, 127.2, 127.2, 127.1, 126.6, 126.5, 126.5, 126.3, 126.3, 126.0, 126.0, 125.6, 125.6, 125.6, 125.5, 125.4, 125.4, 55.1, 55.1, 54.9, 54.9, 54.8, 54.7, 54.4, 54.3, 49.6, 49.5, 49.5, 49.4, 49.3, 49.3, 49.1, 49.1, 49.0, 48.8, 48.8, 48.8, 29.4, 29.3, 29.3, 27.7, 27.7, 27.6, 18.8, 18.8, 18.7, 18.6.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C48H45N2, 649.3583; found, 649.3575.

Optical rotation [α]D20 +5.2 (c 0.90, CHCl3).

Amine 6h

Colorless oil, 64% yield (30 mg).

IR (thin film, cm–1): 3326, 3056, 2959, 2923, 2833, 1942, 1738, 1681, 1591, 1507, 1491, 1449, 1405, 1368, 1200, 1113, 1056, 1016, 907, 865, 799, 775, 759, 698, 569, 541, 434.

1H NMR (400 MHz, CDCl3): δ 7.93 (q, J = 7.7 Hz, 4H), 7.74–7.27 (m, 12H), 7.22–7.00 (m, 6H), 6.99–6.78 (m, 4H), 3.59–3.21 (m, 6H), 1.09–0.83 (m, 6H).

13C{H} NMR (101 MHz, CDCl3): δ 145.2, 145.2, 139.3, 139.3, 139.3, 139.2, 138.8, 138.6, 138.6, 137.8, 137.7, 137.6, 137.6, 133.8, 133.7, 132.7, 132.6, 132.3, 132.3, 132.1, 132.1, 131.9, 131.9, 128.4, 128.4, 128.3, 128.3, 127.9, 127.9, 127.8, 127.0, 127.0, 127.0, 126.7, 126.6, 126.5, 126.3, 126.3, 126.2, 126.2, 126.1, 126.0, 125.4, 57.6, 57.5, 57.4, 57.3, 50.0, 49.9, 49.6, 49.6, 24.3, 24.2.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C44H41N2, 597.3270; found, 597.3251.

Optical rotation [α]D20 +54.3 (c 1.02, CHCl3).

Amine 6i

White foam, 65% yield (52 mg).

IR (thin film, cm–1): 3861, 3849, 3797, 3640, 3566, 3333, 3044, 2963, 2924, 2859, 2414, 2359, 2244, 2116, 1942, 1811, 1746, 1641, 1593, 1507, 1440, 1368, 1257, 1171, 1113, 1057, 1016, 969, 904, 861, 797, 773, 726, 648, 613, 566, 429.

1H NMR (400 MHz, CDCl3): δ 7.97–7.81 (m, 6H), 7.79–7.66 (m, 3H), 7.61–7.30 (m, 15H), 7.29–6.93 (m, 6H), 4.39–4.26 (m, 2H), 3.63 (dd, J = 13.2, 11.2 Hz, 1H), 3.54 (dd, J = 13.2, 2.6 Hz, 1H), 3.45–3.36 (m, 2H), 1.16 (d, J = 6.5 Hz, 2H), 1.13–1.09 (m, 4H).

13C{H} NMR (101 MHz, CDCl3): δ 140.7, 140.7, 140.6, 140.5, 139.4, 139.4, 139.3, 139.2, 138.8, 138.6, 138.6, 137.8, 137.8, 137.7, 133.9, 133.9, 133.7, 133.6, 132.6, 132.5, 132.3, 132.2, 132.2, 132.1, 132.1, 132.0, 132.0, 132.0, 131.9, 131.9, 131.2, 131.2, 128.9, 128.9, 128.4, 127.9, 127.8, 127.1, 127.1, 127.0, 126.9, 126.3, 126.2, 126.1, 126.0, 125.8, 125.6, 125.6, 125.4, 125.4, 125.2, 122.9, 122.7, 122.6, 52.9, 52.6, 52.5, 52.2, 50.0, 49.6, 49.5, 23.7, 23.7.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C52H45N2, 697.3583; found, 697.3576.

Optical rotation [α]D20 +38.2 (c 1.00, CHCl3).

Amine 6j

White foam, 95% yield (57 mg).

IR (thin film, cm–1): 3054, 2925, 2854, 1937, 1766, 1700, 1611, 1592, 1507, 1466, 1373, 1329, 1173, 1153, 1115, 1083, 1016, 952, 903, 870, 800, 776, 715, 638, 569, 530, 423.

1H NMR (400 MHz, CDCl3): δ 7.90–7.83 (m, 2H), 7.78 (dt, J = 8.7, 4.3 Hz, 2H), 7.51–7.27 (m, 14H), 7.26–7.21 (m, 2H), 7.15 (ddd, J = 10.7, 7.0, 1.2 Hz, 1H), 7.10 (ddd, J = 7.0, 2.3, 1.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 3.76–3.61 (m, 2H), 3.43–3.32 (m, 2H), 3.26–3.11 (m, 2H), 3.04–2.90 (m, 2H), 2.15–1.98 (m, 2H), 1.71–1.45 (m, 8H), 1.21–0.82 (m, 6H), 0.70–0.59 (m, 2H).

13C{H} NMR (101 MHz, CDCl3): δ 168.9, 168.9, 168.8, 139.0, 138.9, 138.8, 138.8, 138.7, 138.6, 137.8, 137.7, 137.7, 137.5, 133.5, 133.5, 133.4, 133.3, 133.3, 132.5, 132.4, 132.4, 131.8, 131.7, 131.7, 131.7, 130.8, 130.7, 130.7, 130.5, 128.2, 128.1, 128.1, 128.0, 127.4, 127.4, 127.4, 126.9, 126.9, 126.8, 126.5, 126.4, 126.3, 126.2, 126.1, 126.1, 126.1, 126.0, 125.8, 125.3, 125.2, 125.2, 122.8, 122.7, 122.6, 56.7, 56.5, 56.4, 56.1, 56.1, 56.0, 55.9, 48.0, 47.7, 47.4, 33.0, 32.9, 32.7, 32.6, 29.7, 29.7, 25.7, 25.1, 25.0, 24.9.

HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C56H51N4O4, 843.3910; found, 843.3905.

Optical rotation [α]D20 −54.4 (c 1.00, CHCl3).