Formation of Imidazo[1,5-a]pyridine Derivatives Due to the Action of

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Formation of Imidazo[1,5-a]pyridine Derivatives Due to the Action of Fe2+ on Dynamic Libraries of Imines Simone Albano, Giorgio Olivo, Luigi Mandolini, Chiara Massera, Franco Ugozzoli, and Stefano Di Stefano J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Mar 2017 Downloaded from http://pubs.acs.org on March 22, 2017

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The Journal of Organic Chemistry

Formation of Imidazo[1,5-a]pyridine Derivatives Due to the Action of Fe2+ on Dynamic Libraries of Imines Simone Albano,§

Giorgio Olivo,§ Luigi Mandolini,§ Chiara Massera,¶ Franco Ugozzoli,¶ and Stefano Di Stefano§,*

§Dipartimento di Chimica and Istituto CNR di Metodologie Chimiche-IMC, Sezione Meccanismi di Reazione c/o Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy. ¶Dipartimento di Chimica, Università di Parma, Viale delle Scienze 17/a, 43124 Parma, Italy.

ABSTRACT An imidazo[1,5-a]pyridine derivative was unexpectedly obtained through the action of Fe2+ on a dynamic library of imines generated in situ via condensation of benzaldehyde and 2-picolylamine. The reaction product was easily isolated as the only nitrogen-containing product eluted from the chromatographic column. A reaction mechanism is proposed, in which combined kinetic and thermodynamic effects exerted by Fe2+ on the various steps of the complex reaction sequence are discussed. The Fe2+ nature of the added metal cation was found to be pivotal for the achievement of the imidazo[1,5-a]pyridine derivative as well as its amount in the reaction mixture. When the electronic effects were evaluated, gratifying yields were obtained only in the presence of moderately electron-releasing or moderately electron-withdrawing groups on the aldehyde reactant. No traces of imidazo[1,5-a]pyridine derivatives were obtained for p-OCH3 and p-NO2 benzaldehyde.

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Introduction A renewal of interest in imine chemistry is witnessed by the large number of papers published in recent years.1-4 A major reason for this is the reversible character of most of the reactions involving imines, which qualifies them as attractive reagents in the fields of supramolecular and dynamic combinatorial chemistry,1 reaction mechanisms,2 organic synthesis3 and materials science.4 We recently5 reported that the imine based complex 1, quantitatively obtained in a one-pot procedure from a mixture of pyridine-2-carbaldehyde, 2-picolylamine and Fe(CF3SO3)2(CH3CN)2 in a molar ratio of 2:2:1, respectively, eq (1), is an effective catalyst for the oxidation of nonactivated C-H bonds using H2O2 as terminal oxidant.

When pyridine-2-carbaldehyde derivatives X-substituted in γ-position (X = -NO2, -CH3, -OCH3) were used as starting materials, characterization of the resulting complexes was complicated by the transamination reaction of eq (2), which occurred even in the absence of added base other than the 2-picolylamine reactant.5b Obviously, no complications occurred in the case of complex 1, where transamination is degenerate. The reversible nature of the base-catalyzed imine transamination has been known for long.6 Ramström et al.7 recently reported that transamination can be carried out simultaneously with transimination, which is induced by primary amines2e to yield a twodimensional dynamic system, for which the acronym TATI (TransAmination / TransImination) was coined. They showed that reaction of benzyl phenylmethanimines with benzylamines in the presence of a tertiary base led to an equilibrium mixture of nine imines and three amines when all 2 ACS Paragon Plus Environment

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three benzyl groups carry different substituents. They also showed that the complexity of the dynamic system drops to four imines and two amines when two of the three substituents were identical.

Results and Discussion Having in mind the possible use of the two-dimensional dynamic character of TATI for synthetic applications, we carried out a preliminary experiment to verify the generation of a connected TATI system (Scheme 1) from a mixture of benzylidene-2-picolylamine (C) and 2-picolylamine. The results are illustrated by the 1H NMR spectra in Figure 1. Trace a shows the benzylic proton signal of 10 mM C, which was prepared in situ by condensation of benzaldehyde and 2-picolylamine in CD3CN at 50 °C. After 7 h from addition of a 10-fold excess of quinuclidine the signal of transamination product B was clearly visible (trace b). Addition of 1 equiv of 2-picolylamine after 36 h from start triggered the transimination reactions B

A and C

D. The 1H NMR spectrum

taken after 17 h from the addition of 2-picolylamine (trace c) showed the expected mixture of 4 imines (comparison with authentic samples). The benzylic signals of benzylamine and 2picolylamine (not visible in Figure 1) at 3.78 and 3.85 ppm, respectively, were also present.

Scheme 1. Connected TATI system generated through the reaction of benzylidene-2-picolylamine (C) with 2-picolylamine.



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Figure 1. TATI of 10 mM benzylidene-2-picolylamine C and 10 mM 2-picolylamine in CD3CN at 50 °C. 1H NMR benzylic region: (a) benzylidene-2-picolylamine C; (b) 7 h after quinuclidine addition; (c) 17 h after 10 mM 2-picolylamine addition.

Having ascertained the actual occurrence of the TATI process in Scheme 2 under relatively mild conditions, and considering that tridentate nitrogen ligand A is most likely the strongest ligand in the lot, we reasoned that addition of Fe2+ would steer the dynamic library8 towards the quantitative formation of complex 1. Accordingly, a mixture of 2-picolylamine, benzaldehyde, and Fe2+ in the molar ratio of 4:2:1, respectively, should behave as shown in eq (3). Complex 1 had been previously found to be easily removed from a reaction mixture by simple elution through a thin layer of silica.5b If one looks at complex 1 as an easily removable side product, the net transformation is the reductive amination of benzaldehyde to benzylamine, in which the role of reductant is played by 2-picolylamine through the formal isodesmic reaction of eq (4).


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The latter compound undergoes oxidation to pyridine-2-carbaldehyde, which should be found in the reaction mixture in the form of the Fe2+-complexed tridentate nitrogen ligand. Based on the above considerations, we envisaged the possibility of realizing the actual transformation of benzaldehyde to benzylamine according to eq (3) but the results failed to meet our expectation, as shown by the following experiment. A solution of benzaldehyde (15 mmol), 2-picolylamine (30 mmol), Fe(CF3SO3)2(CH3CN)2 (7.5 mmol), and quinuclidine (3 mmol)9 in 150 mL of freeze-pump-thaw degassed acetonitrile was prepared under an argon atmosphere. The mixture was kept at 50 °C under stirring for 40 h. Column chromatography on the crude product yielded a trace amount of benzaldehyde followed by 0.510 g of a yellow solid, mp 92.0-92.5 °C. No other compound was eluted from the column. The remaining materials, presumably strongly bound to Fe2+, were trapped at the head of the column. Two additional runs, carried out under identical conditions, gave exactly the same results. A further experiment, carried out without paying attention to the exclusion of air, but under otherwise identical conditions, yielded again the same amount of yellow solid. Attempts at structure assignment to the isolated compound were based on standard spectrometric and spectroscopic techniques. EI and high resolution ESI mass spectrometry (see SI) were fully consistent with the molecular formula C19H15N3 (MW = 285). The presence of 3 nitrogen atoms in the product of a reaction between two reactants featuring an even number (0 or 2) of nitrogen atoms is consistent with the occurrence of a TATI process along the reaction path. According to the formal stoichiometric eq (5), 0.24 mole of unexpected product 2 per 2 moles of benzaldehyde were obtained.

The 1H NMR spectrum (Figure 2) is complex. The existence of three different spin systems involving 4, 4 and 7 protons was clearly indicated by 2D NMR techniques (COSY, TOCSY and HSQC, see SI), but this information was not sufficient for unequivocal structure assignment, as several isomeric structures compatible with spectroscopic data could be envisaged (see SI). A 5 ACS Paragon Plus Environment


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definite solution to the problem was offered by the preparation of single crystals suitable for X-ray diffraction analysis, which were obtained by slow diffusion of pentane into a concentrated ethyl acetate solution (see the SI for the experimental details of the X-ray data collection and for the crystal structure determination).

Figure 2. 1H NMR spectrum (CD2Cl2, 25 °C) of the unknown compound 2. Three spin systems including 4 ( ), 4 (○) and 7 (Δ) protons respectively are identified through 2D NMR (see SI). The signal at 5.3 is due to CHDCl.

The molecular structure of 2 shown in Figure 3 is characterized by the presence of the imidazo[1,5a]pyridine nucleus.10 Synthetic strategies targeting a variety of imidazo[1,5-a]pyridine derivatives have received considerable attention, in view of potential applications in pharmaceutical and materials chemistry as well as N-rich ligands for metal coordination.11


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Figure 3. X-ray molecular structure of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine (2). The three spin systems are easily seen.

We suggest the mechanism outlined in Scheme 2 for the transformation of the metal complex of the tridentate ligand into the final product. The key step a is the base-catalyzed aldol-type condensation of benzaldehyde with the methylene group of the tridentate ligand, whose acidity is enhanced by metal complexation. The hemilability of one of the pyridine ligands depicted in step b5b opens the way to the Fe2+-activated intramolecular nucleophilic addition of the pyridine nitrogen to the imine carbon atom (step c).12 Step d is a prototropic rearrangement leading to a Fe2+ complex in which the ligand conformation suitable for metal chelation is disfavored by steric repulsion between hydrogen atoms of the pyridine units, as also suggested by the X-ray molecular structure (Figure 3) where the given hydrogen atoms are seen on opposite sides. It seems reasonable, therefore, that the complex loses the metal (step e), thus allowing the elution of the free ligand from the chromatographic column.



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Scheme 2. Proposed mechanism for the formation of the unexpected imidazo[1,5-a]pyridine derivative 2.

A decrease in yield was observed when shorter reaction times were applied, namely a 12% yield after 32 h to be compared with the 24% yield after 40 h, while longer reaction times did not afford any significant improvement (25% yield after 64 h). The yield of the imidazo[1,5-a]pyridine derivative obtained in the presence of a sub-stoichiometric amount of Fe2+ (Table 1, entry 1) was lower than that obtained in the presence of the amount required by eq (3) (entry 2), but no traces of the expected product were found when the amount of Fe2+ was doubled (entry 3). Replacement of Fe2+ with Zn2+ 13or Co2+ (entries 4 and 5) was completely unsuccessful, whereas Fe3+ (entry 6) turned out to be effective, albeit to a lower degree than Fe2+.


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Table 1. Effect of the amount

and nature of the

metal

ion on the

yield

of

3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine obtained from a mixture of benzaldehyde (1.0 mmol) and 2-picolylamine (2.0 mmol) in 10 mL of CH3CN held at 50 °C for 40 h. Entry

Metal ion (mmol)

Yield (%)a

1

Fe2+ (0.1)b

10

2

Fe2+ (0.5)b

24

3

Fe2+ (1)b

nil

4

Zn2+ (0.5)c

nil

5

Co2+ (0.5)d

nil

6

Fe3+ (0.5)b

12

a

Calculated according to eq (5). bTriflate salt. cBromide salt. dChloride salt.

In order to expand the scope of the procedure, a series of para-X-substituted benzaldehyde derivatives were reacted with 2-picolylamine in the presence of Fe2+ triflate. The results listed in Table 2 show that no traces of imidazo[1,5-a]pyridine derivatives were eluted from the chromatographic column when X was –OCH3 and –NO2 (3 and 4 respectively). However, significant amounts of the expected products, comparable to that related to the parent benzaldehyde, were obtained when X was –CH3 and –Cl (5 and 6 respectively). The adverse effect of both strong electron-releasing and strong electron-withdrawing substituents is well precedented in the field of imine chemistry.2d Thus, it is not unreasonable to believe that this is also the case in one or more of the steps involved in the multistep sequence of reversible exchange reactions of the TATI process. Furthermore, when X = –OCH3 a strong retarding effect on the rate of aldol condensation (Scheme 2, step a) is expected. Unfavorable effects arising from strong resonance interactions can possibly operate also in steps b, c and d of Scheme 2.



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Table 2. Yields of 3-(2-pyridyl)-1-(4-X-benzyl)imidazo[1,5-a]pyridine (2-6) obtained from a mixture of 4-X-benzaldehyde (1.0 mmol), 2-picolylamine (2.0 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.5 mmol) in 10 mL of CH3CN held at 50 °C for 40 h. Product 2

Yield (%) 24

3

nil

4

nil

5

14

6

25

Conclusions To sum up a novel imidazo[1,5-a]pyridine derivative (2) was unexpectedly obtained from the reaction of benzaldehyde (2 equiv), 2-picolylamine (4 equiv), and Fe2+ (1 equiv) in the presence of a catalytic amount of quinuclidine. The yield (24 %) is moderate, but the product can be easily isolated in a pure form, and the starting materials are readily available commercial products. Due to its Lewis acid character, a variety of roles are played by the metal cation in the multistep reaction sequence, leading from reactants to product. First of all, generation of the TATI system of imines starting from benzaldehyde and 2-picolylamine is most likely accelerated by Fe2+.14,15In addition to this multiple kinetic effect the high stability of the metal complex of the tridentate nitrogen ligand A 10 ACS Paragon Plus Environment

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is expected to drive the dynamic library toward the formation of 1.16 However, this is not the end of the story, as foreseen in our original project, eq (3). Subsequent acts in which the role of Fe2+ is believed to be crucial are the aldol-type condensation with benzaldehyde (Scheme 2, step a) and closure of the 5-membered imidazo ring (step c). Finally, detachment of the metal ion from the complex (step e) allows the free ligand to be eluted from the chromatographic column. In a sense, therefore, the results reported in this communication may be viewed as a special application of dynamic combinatorial chemistry.8a Stabilization of a specific library member (imine A), through metal coordination does not determine the final composition of the reaction mixture but the generation of a reaction intermediate, which unexpectedly undergoes a series of irreversible transformations leading to the ultimate formation of such a complex structure as that of the isolated imidazo[1,5-a]pyridine derivative. Interestingly, the successful achievement of the imidazo[1,5-a]pyridine derivative was found to be strongly dependent on the nature of the metal cation, that must specifically be Fe2+ and must be added in the right amount, namely 0.5 mol equiv with respect to the aldehyde. When a series of benzaldehydes substituted in the para position were employed in the procedure, satisfactory yields were obtained only in the presence of moderately electron-releasing or electron-withdrawing groups.

Experimental Section General Experimental Methods NMR spectra were recorded with a 300 MHz spectrometer at room temperature and were internally referenced to the residual proton solvent signal. Mass spectra were recorded with an ESI/QTOF mass spectrometer. UV-vis spectra were recorded with a double-beam spectrophotometer using a standard quartz cell (path length: 1 cm) at room temperature. All reagents and solvents were purchased at the highest commercial quality and were used without further purification, unless otherwise stated. The glassware was either flame- or ovendried. 11 ACS Paragon Plus Environment


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Acetonitrile used for the preparation of Fe(CF3SO3)2(CH3CN)2 was distilled over CaH2. Diethyl ether used for the preparation of Fe(CF3SO3)2(CH3CN)2 was distilled over sodium and benzophenone. Zinc bromide was heated at 250 °C under vacuum for 5 h.

Preparation of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine (2) In a round-bottomed flask a solution of quinuclidine (0.33 g, 3 mmol), benzaldehyde (1.59 g, 15 mmol), 2-picolylamine (3.24 g, 30 mmol), and Fe(CF3SO3)2(CH3CN)2 (3.27 g, 7.5 mmol) in 150 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and the dark brown crude material was chromatographed on silica with hexane / AcOEt 9:1 and 0.510 g of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine was obtained (1.8 mmol, 24 %). mp: 92.0-92.5 °C. 1

H NMR (300 MHz, CD2Cl2) δ (ppm): 9.94-9.92 (m, 1H), 8.64-8.63 (m, 1H), 8.34-8.31 (m, 1H),

7.81-7.76 (m, 1H), 7.45-7.42 (m, 1H), 7.35-7.26 (m, 4H), 7.22-7.17 (m, 2H), 6.84-6.79 (m, 1H), 6.74-6.70 (m, 1H), 4.32 (s, 2H).

13

C{1H}NMR (75 MHz, CD2Cl2) δ (ppm): 151.1, 148.0, 140.5,

136.3, 133.9, 132.2, 129.7, 128.4, 128.2, 125.9, 125.8, 121.3, 121.1, 119.0, 117.2, 113.2, 33.7. UV/vis (CH2Cl2)

mol-1 dm3 cm-1): 18700 at 362 nm, 12700 at 250 nm. HRMS (ESI/QTOF) m/z:

[M + H]+ Calcd for C19H16N3 286.1344; Found 286.1331.

Preparation of 3-(2-pyridyl)-1-(4-methylbenzyl)imidazo[1,5-a]pyridine (5) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), 4-methylbenzaldehyde (0.12 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.22 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and the dark green crude material was chromatographed on silica with hexane / AcOEt 9:1 and 0.021 g of 3-(2-pyridyl)-1-(4-methylbenzyl)imidazo[1,5-a]pyridine was obtained (0.07 mmol, 14 %). mp: 95.5-96.0 °C. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.89-9.87 (m, 1H), 8.62-8.61 (m, 1H), 8.36-8.33 (m, 1H), 7.77-7.72 (m, 1H), 7.32-7.08 (m, 6H), 6.75-6.64 (m, 2H), 4.31 (s, 2H), 2.31 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3) δ (ppm): 151.0, 148.0, 137.1, 136.3, 135.4, 133.8, 132.5, 12 ACS Paragon Plus Environment

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129.6, 129.0, 128.4, 125.7, 121.7, 121.4, 118.9, 117.5, 113.2, 33.7, 20.9. UV/vis (CH2Cl2) 1

mol-

dm3 cm-1): 12200 at 361 nm, 11500 at 251 nm. HRMS (ESI/QTOF) m/z: [M + H]+ Calcd for

C20H18N3 300.1501; Found 300.1527.

Preparation of 3-(2-pyridyl)-1-(4-chlorobenzyl)imidazo[1,5-a]pyridine (6) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), 4-chlorobenzaldehyde (0.14 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.22 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and the dark grey crude material was chromatographed on silica with hexane / AcOEt 9:1 and 0.041 g of 3-(2-pyridyl)-1-(4-chlorobenzyl)imidazo[1,5-a]pyridine was obtained (0.13 mmol, 25 %). mp: 109.8-110.3 °C. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.90-9.88 (m, 1H), 8.63-8.61 (m, 1H), 8.33-8.31 (m, 1H), 7.78-7.72 (m, 1H), 7.31-7.15 (m, 6H), 6.78-6.66 (m, 2H), 4.30 (s, 2H). 13

C{1H}NMR (75 MHz, CDCl3) δ (ppm): 150.9, 148.1, 138.6, 136.3, 134.1, 131.7, 131.5, 129.8,

129.6, 128.4, 125.8, 121.7, 121.3, 119.3, 117.1, 113.3, 33.3. UV/vis (CH2Cl2)

mol-1 dm3 cm-1):

17400 at 359 nm, 14500 at 250 nm. HRMS (ESI/QTOF) m/z: [M + H]+ Calcd for C19H15ClN3 320.0955; Found 320.0938.

Preparation of Fe(CF3SO3)2(CH3CN)2 Fe(CF3SO3)2(CH3CN)2 was prepared according to a laboratory procedure.5b In a three-neck roundbottomed flask equipped with a dropping funnel and containing freeze-pump-thaw degassed acetonitrile (40 ml), FeCl2 was added (2.48 g, 20 mmol) under argon atmosphere. Then trimethylsilyl trifluoromethanesulfonate (8.1 ml, 45 mmol) was slowly added through the dropping funnel to the FeCl2 solution under magnetic stirring. Then the reaction mixture was kept at room temperature under inert atmosphere for 15 h. The solvent was evaporated in a rotavapor previously flushed with N2. The solid obtained was redissolved in degassed acetonitrile (8 ml). Then the mixture was filtered under argon atmosphere and freeze-pump-thaw degassed diethyl ether was 13 ACS Paragon Plus Environment


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added (16 ml) to the filtered solution, that was subsequently kept under argon atmosphere in a freezer for 16 h. A solid precipitate was collected by filtration of the mixture under argon atmosphere and dried under high vacuum, providing Fe(CF3SO3)2(CH3CN)2 as a white solid (6.34 g, 15 mmol, 74 %).

Preparation of compound 2 (reaction time 32 h) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), benzaldehyde (0.11 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.22 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 32 h at 50 °C. The solvent was evaporated and the dark brown crude material was chromatographed on silica with hexane / AcOEt 9:1 and 0.017 g of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine was obtained (0.06 mmol, 12 %).

Preparation of compound 2 (reaction time 64 h) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), benzaldehyde (0.11 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.22 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 64 h at 50 °C. The solvent was evaporated and the dark brown crude material was chromatographed on silica with hexane / AcOEt 9:1 and 0.036 g of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine was obtained (0.13 mmol, 25 %).

Preparation of compound 2 (0.1 molar equivalents of Fe(CF3SO3)2(CH3CN)2 with respect to benzaldehyde) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), benzaldehyde (0.11 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.044 g, 0.1 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and the dark green crude material was chromatographed on silica with hexane / AcOEt 9:1 and 0.014 g of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine was obtained (0.05 mmol, 10 %). 14 ACS Paragon Plus Environment

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Attempt at preparation of compound 2 (1 molar equivalent of Fe(CF3SO3)2(CH3CN)2 with respect to benzaldehyde) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), benzaldehyde (0.11 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.44 g, 1 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and TLC control of the dark green reaction crude showed no presence of 3-(2-pyridyl)-1-benzylimidazo[1,5a]pyridine.

Preparation of compound 2 (0.5 molar equivalents of Fe(CF3SO3)3 with respect to benzaldehyde) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), benzaldehyde (0.11 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)3 (0.25 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and the dark red crude material was chromatographed on silica with hexane / AcOEt 9:1 and 0.017 g of 3(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine was obtained (0.06 mmol, 12 %).

Attempt at preparation of compound 2 (0.5 molar equivalents of ZnBr2 with respect to benzaldehyde) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), benzaldehyde (0.11 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and ZnBr2 (0.11 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and TLC control of the reaction crude showed no presence of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine.



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Attempt at preparation of compound 2 (0.5 molar equivalents of CoCl2 with respect to benzaldehyde) In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), benzaldehyde (0.11 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and CoCl2 (0.065 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and TLC control of the dark blue reaction crude showed no presence of 3-(2-pyridyl)-1-benzylimidazo[1,5-a]pyridine.

Attempt at preparation of compound 3 In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), 4-methoxybenzaldehyde (0.14 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.22 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and the dark brown crude material was chromatographed on silica with hexane / AcOEt mixtures of increasing polarity. No evidence for the presence of 3-(2-pyridyl)-1-(4-methoxybenzyl)imidazo[1,5a]pyridine was found.

Attempt at preparation of compound 4 In a round-bottomed flask a solution of quinuclidine (0.022 g, 0.2 mmol), 4-nitrobenzaldehyde (0.15 g, 1 mmol), 2-picolylamine (0.22 g, 2 mmol), and Fe(CF3SO3)2(CH3CN)2 (0.22 g, 0.5 mmol) in 10 mL acetonitrile was prepared and left stirring for 40 h at 50 °C. The solvent was evaporated and the dark brown crude material was chromatographed on silica with hexane / AcOEt mixtures of increasing polarity. No evidence for the presence of 3-(2-pyridyl)-1-(4-nitrobenzyl)imidazo[1,5a]pyridine was found.

AUTHOR INFORMATION Corresponding Authors 16 ACS Paragon Plus Environment

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*E-mail: [email protected] (S.D.S.).

ORCID Stefano Di Stefano: 0000-0002-6742-0988

Notes The authors declare no competing financial interest.

Funding Thanks are due to the Ministero dell’Istruzione, dell'Università e della Ricerca (MIUR, PRIN 2010CX2TLM). This work was also partially supported by Università di Roma La Sapienza (Progetti di Ricerca 2014).

ASSOCIATED CONTENT Supporting Information Initially hypothesized structures for the unknown compound, characterizations for the isolated compounds (NMR spectra for all compounds, furthermore IR, GC-MS analysis and X-ray diffraction analysis for compound 2)

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(14) Fe2+ was reported to enhance rates of imine formation from primary amine and carbonyl compounds (see ref 5a) as well as rates of transamination (see ref 5b). Transimination reactions are known to be catalyzed by a variety of Lewis acids (see ref 7 and 15). (15) Giuseppone, N.; Schmitt, J.-L.; Lehn, J.-M. Angew. Chem. Int. Ed. 2004, 43, 4902-4906. (16) Whether the actual stoichiometry of the ligand-metal complex is 2:1 or 1:1 is irrelevant to the argument.


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TOC Graphic


Formation of Imidazo[1,5-a]pyridine Derivatives Due to the Action of

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