Synthesis of Terpyridines: Simple Reactions—What Could Possibly Go Wrong?

The preparation of 24-functionalized 12,22:26,32-terpyridines (4′-functionalized 3,2:6′,3″-terpyridines) by the reaction of three 4-alkoxybenzaldehydes with 3-acetylpyridine and ammonia was investigated; under identical reaction conditions, two (R =nC4H9, C2H5) gave the expected products whereas a third (R = nC3H7) gave only a cyclohexanol derivative derived from the condensation of three molecules of 3-acetylpyridine with two of 4-(n-propoxy)benzaldehyde. A comprehensive survey of “unexpected” products from reactions of ArCOCH3 derivatives with aromatic aldehydes is presented. Three different types of alternative product are identified.

In this paper, we discuss the synthesis of a series of 3,2 :6 ,3 -tpy ligands ( Figure 2) and describe the formation of an unexpected product in one case. The paper also provides a comprehensive review of alternative products which have been obtained from syntheses of terpyridines using the synthetic approaches above. We take this opportunity to issue a caveat: when utilizing these synthetic methods, the terpyridine products should be purified and fully characterized.
Molecules 2019, 24, 1799 3 of 16 synthetic approaches above. We take this opportunity to issue a caveat: when utilizing these synthetic methods, the terpyridine products should be purified and fully characterized.

Strategy and Ligand Design
We have shown that in the 4,2′:6′,4′′-tpy compounds 4a-k (R = n-CnH2n+1, n = 1-10, 12, Figure 2), the length of the alkyl chain on the alkyloxy substituent can influence the packing and the topology of coordination networks generated upon reaction with metal salts [22,[25][26][27][28][29][30]. We are now beginning a systematic investigation of the effect of substituents on the assembly of coordination networks based on 3,2′:6′,3′′-tpy ligands and commenced with the synthesis of derivatives 5a-c. Compound 5d has previously been reported [31]. The synthetic approach was a standard one-pot Scheme 2. Variations on the Kröhnke reaction for the preparation of 4 -aryl-2,2 :6 ,2 -tpy ligands. (a) The classical Kröhnke route in which an enone (chalcone) is prepared from the aldol condensation of 2-acetylpyridine with an aromatic aldehyde followed by reaction with a 2-pyridacylpyridinium salt (obtained from an Ortoleva-King reaction) in the presence of an ammonia source (often ammonium acetate) to give the 4 -aryl-2,2 :6 ,2 -tpy. (b) The simpler one-pot approach in which two equivalents of 2-acetylpyridine and the aromatic aldehyde are reacted directly or sequentially with a source of ammonia. This latter reaction may be in solvent free-conditions by grinding the reactants, use benign solvents such as PEG or conventional solvents. Replacement of the 2-acetylpyridine by 3-acetylpyridine or 4-acetylpyridine allows the synthesis of 4 -aryl-3,2 :6 ,3 -tpy and 4 -aryl-4,2 :6 ,4 -tpy ligands.

Strategy and Ligand Design
We have shown that in the 4,2 :6 ,4 -tpy compounds 4a-k (R = n-C n H 2n+1 , n = 1-10, 12, Figure 2), the length of the alkyl chain on the alkyloxy substituent can influence the packing and the topology of coordination networks generated upon reaction with metal salts [22,[25][26][27][28][29][30]. We are now beginning a systematic investigation of the effect of substituents on the assembly of coordination networks based on 3,2 :6 ,3 -tpy ligands and commenced with the synthesis of derivatives 5a-c. Compound 5d has previously been reported [31]. The synthetic approach was a standard one-pot synthesis, involving the reaction of 3-acetylpyridine with the appropriate 4-alkyloxybenzaldehyde in basic solution, followed by the addition of aqueous ammonia.    The electrospray (ESI) mass spectra of compounds 5a and 5c showed base peaks at m/z 354.08 and 382.16, respectively, arising from the [M + H] + ions (Figures S1 and S2, see Supporting Information). The solution 1 H and 13 C NMR spectra were consistent with the structures shown in Figure 3 and were assigned using COSY, NOESY, HMQC and HMBC methods. Figure 4 displays a comparison of the 1 H NMR spectra, and confirms that the introduction of the different alkyloxy substituents has no significant influence on the spectroscopic signature of the 4′-phenyl-3,2′:6′,3′′-tpy unit. 13 C{ 1 H} NMR spectra are compared in Figure S3. As expected, the solid-state IR spectra of 5a and 5c are very similar ( Figures S4 and S5) and the solution absorption spectra ( Figure 5) show intense absorptions in the UV region arising from spin-allowed π*π and π*n transitions. The electrospray (ESI) mass spectra of compounds 5a and 5c showed base peaks at m/z 354.08 and 382.16, respectively, arising from the [M + H] + ions (Figures S1 and S2, see Supporting Information). The solution 1 H and 13 C NMR spectra were consistent with the structures shown in Figure 3 and were assigned using COSY, NOESY, HMQC and HMBC methods. Figure 4 displays a comparison of the 1 H NMR spectra, and confirms that the introduction of the different alkyloxy substituents has no significant influence on the spectroscopic signature of the 4 -phenyl-3,2 :6 ,3 -tpy unit. 13 C{ 1 H} NMR spectra are compared in Figure S3. As expected, the solid-state IR spectra of 5a and 5c are very similar ( Figures S4 and S5) and the solution absorption spectra ( Figure 5) show intense absorptions in the UV region arising from spin-allowed π*←π and π*←n transitions.

A Reaction that Works with Ethoxy and Butoxy
Homologues, Fails for 4′-(4-propoxyphenyl)-3,2′:6′,3′′-terpyridine During attempts to prepare 4′-(4-propoxyphenyl)-3,2′:6′,3′′-terpyridine (5b, Figure 2) by the reaction of 4-propoxybenzaldehyde with 3-acetylpyridine in the presence of KOH in ethanol, under identical conditions to those for the successful preparation of ligands 5a and 5c, followed by addition of aqueous NH3, we noted that precipitation of a product began before ammonia was added. The white solid that was isolated exhibited IR ( Figure S6) and absorption spectra ( Figure 5) with different profiles from those of 5a and 5c. In particular, the IR spectrum of the product exhibited a sharp

A Reaction that Works with Ethoxy and Butoxy
Homologues, Fails for 4′-(4-propoxyphenyl)-3,2′:6′,3′′-terpyridine During attempts to prepare 4′-(4-propoxyphenyl)-3,2′:6′,3′′-terpyridine (5b, Figure 2) by the reaction of 4-propoxybenzaldehyde with 3-acetylpyridine in the presence of KOH in ethanol, under identical conditions to those for the successful preparation of ligands 5a and 5c, followed by addition of aqueous NH3, we noted that precipitation of a product began before ammonia was added. The white solid that was isolated exhibited IR ( Figure S6) and absorption spectra ( Figure 5) with different profiles from those of 5a and 5c. In particular, the IR spectrum of the product exhibited a sharp

A Reaction that Works with Ethoxy and Butoxy
Homologues, Fails for 4 -(4-propoxyphenyl)-3,2 :6 ,3 -terpyridine During attempts to prepare 4 -(4-propoxyphenyl)-3,2 :6 ,3 -terpyridine (5b, Figure 2) by the reaction of 4-propoxybenzaldehyde with 3-acetylpyridine in the presence of KOH in ethanol, under identical conditions to those for the successful preparation of ligands 5a and 5c, followed by addition of aqueous NH 3 , we noted that precipitation of a product began before ammonia was added. The white solid that was isolated exhibited IR ( Figure S6) and absorption spectra ( Figure 5) with different profiles from those of 5a and 5c. In particular, the IR spectrum of the product exhibited a sharp absorption at 3495 cm -1 attributable to an OH group. These observations were unexpected since we have previously reported the successful synthesis of the analogous series of 4,2 :6 ,4 -tpy derivatives 4a-4k (Figure 2) by the Hanan one-pot strategy [25]. The ESI mass spectrum of the product showed a base peak at m/z 656.31 ( Figure S7) suggesting the formation of the cyclic product 6 shown in Figure 6.
Molecules 2019, 24, 1799 6 of 16 absorption at 3495 cm -1 attributable to an OH group. These observations were unexpected since we have previously reported the successful synthesis of the analogous series of 4,2′:6′,4′′-tpy derivatives 4a-4k ( Figure 2) by the Hanan one-pot strategy [25]. The ESI mass spectrum of the product showed a base peak at m/z 656.31 ( Figure S7) suggesting the formation of the cyclic product 6 shown in Figure  6. The solution 1 H NMR spectrum of 6b is shown in Figure 7 and is consistent with the presence of three pyridine environments (rings A, B and C) and two 4-propoxyphenyl environments (rings D and E). The spectrum was assigned using COSY, NOESY ( Figure S8), HMQC ( Figure S9) and HMBC ( Figure S10)   The spectroscopic characterization confirms the formation of 6b although it offers no indication as to why this product precipitates from solution only in the case of the propoxy substituent. We noted that the reaction only involves the aldehyde and the 3-acetylpyridine and were prompted to The solution 1 H NMR spectrum of 6b is shown in Figure 7 and is consistent with the presence of three pyridine environments (rings A, B and C) and two 4-propoxyphenyl environments (rings D and E). The spectrum was assigned using COSY, NOESY ( Figure S8), HMQC ( Figure S9) and HMBC ( Figure S10) (Figure 2) by the Hanan one-pot strategy [25]. The ESI mass spectrum of the product showed a base peak at m/z 656.31 ( Figure S7) suggesting the formation of the cyclic product 6 shown in Figure  6. The solution 1 H NMR spectrum of 6b is shown in Figure 7 and is consistent with the presence of three pyridine environments (rings A, B and C) and two 4-propoxyphenyl environments (rings D and E). The spectrum was assigned using COSY, NOESY ( Figure S8), HMQC ( Figure S9) and HMBC ( Figure S10)   The spectroscopic characterization confirms the formation of 6b although it offers no indication as to why this product precipitates from solution only in the case of the propoxy substituent. We noted that the reaction only involves the aldehyde and the 3-acetylpyridine and were prompted to The spectroscopic characterization confirms the formation of 6b although it offers no indication as to why this product precipitates from solution only in the case of the propoxy substituent. We noted that the reaction only involves the aldehyde and the 3-acetylpyridine and were prompted to perform the reactions in the absence of ammonia. We repeated the reaction of 4-propoxybenzaldehyde with 3-acetylpyridine at a 1:2 molar ratio in ethanol with KOH but without the addition of NH 3 . This led to the formation of 6b (confirmed by NMR spectroscopy, Figure 8b) in 42.0% yield. We then performed the analogous reactions of 4-ethoxybenzaldehyde or 4-butoxybenzaldehyde with 3-acetylpyridine in the presence of KOH in ethanol, but without NH 3 . In both cases, white precipitates formed within 5 min. The ESI mass spectra of the products were consistent with their being analogues of 6b. Base peaks at m/z = 628.29 and 684.35 were assigned to [6a + H] + and [6c + H] + , respectively (Figures S11 and S12). The 1 H NMR spectra of 6a and 6c are shown in Figure 8a,c, and the similarity to that of 6b (Figure 8b) is immediately apparent. The 1 H and 13 C NMR spectra of 6a and 6c (see Experimental Section) were assigned using routine 2D methods. perform the reactions in the absence of ammonia. We repeated the reaction of 4-propoxybenzaldehyde with 3-acetylpyridine at a 1:2 molar ratio in ethanol with KOH but without the addition of NH3. This led to the formation of 6b (confirmed by NMR spectroscopy, Figure 8b) in 42.0% yield. We then performed the analogous reactions of 4-ethoxybenzaldehyde or 4-butoxybenzaldehyde with 3-acetylpyridine in the presence of KOH in ethanol, but without NH3. In both cases, white precipitates formed within 5 min. The ESI mass spectra of the products were consistent with their being analogues of 6b. Base peaks at m/z = 628. 29 Figures S11 and S12). The 1 H NMR spectra of 6a and 6c are shown in Figure 8a,c, and the similarity to that of 6b (Figure 8b) is immediately apparent. The 1 H and 13 C NMR spectra of 6a and 6c (see Experimental Section) were assigned using routine 2D methods.

Introduction
Although the Claisen-Schmidt condensation is presented as a simple reaction with a hydroxyketone intermediate and a single enone product in many chemistry text books, the reality is often far more complex. Although this paper is concerned with the use of acetylpyridines in the Claisen-Schmidt reaction, it is instructive to review the broader literature regarding the condensation of aromatic aldehydes with aromatic ketones.
The enone products of the Claisen-Schmidt reaction are electrophilic and can react with nucleophilic enols or enolates at either the carbonyl carbon or by conjugate addition. The formation of the enone 1:1 products (1:1 ratio of ketone to aldehyde) involves the nucleophilic attack of an enol or enolate derived from the aromatic ketone upon the aromatic aldehyde. A number of publications have provided overviews of the reaction space and the types of products that are to be expected. If the rates of the subsequent reactions are significantly faster than the initial ones leading to the enone, domino [32][33][34] or tandem [35] reactions are expected, leading to the selective formation of one (or more) of a range of potential reaction products. In this section, we present a comprehensive overview of the products other than terpyridines that have been obtained from Kröhnke and related syntheses. We have already considered products of this type implicitly-the pentane-1,5-diones (7)

Introduction
Although the Claisen-Schmidt condensation is presented as a simple reaction with a hydroxyketone intermediate and a single enone product in many chemistry text books, the reality is often far more complex. Although this paper is concerned with the use of acetylpyridines in the Claisen-Schmidt reaction, it is instructive to review the broader literature regarding the condensation of aromatic aldehydes with aromatic ketones.
The enone products of the Claisen-Schmidt reaction are electrophilic and can react with nucleophilic enols or enolates at either the carbonyl carbon or by conjugate addition. The formation of the enone 1:1 products (1:1 ratio of ketone to aldehyde) involves the nucleophilic attack of an enol or enolate derived from the aromatic ketone upon the aromatic aldehyde. A number of publications have provided overviews of the reaction space and the types of products that are to be expected. If the rates of the subsequent reactions are significantly faster than the initial ones leading to the enone, domino [32][33][34] or tandem [35] reactions are expected, leading to the selective formation of one (or more) of a range of potential reaction products. In this section, we present a comprehensive overview of the products other than terpyridines that have been obtained from Kröhnke and related syntheses. We have already considered products of this type implicitly-the pentane-1,5-diones (7) arise from the addition of a second equivalent enol or enolate to the enone, giving products of 2:1 (ketone to aldehyde) stoichiometry ( Figure 9). arise from the addition of a second equivalent enol or enolate to the enone, giving products of 2:1 (ketone to aldehyde) stoichiometry ( Figure 9). Figure 9. The structure of the 2:1 (ketone:aldehyde) pentane-1,5-dione that can arise from the reaction of acetophenone with benzaldehyde and the proposed structure of Kostanecki's triketone the 3:2 adduct that formally arises from the nucleophilic addition of the enol of enolate of the pentane-1,5-dione on the 1:1 enone.

The 3:2 Products
The most common of the products that have been isolated from attempted terpyridine syntheses have a reactant stoichiometry of 3:2 ketone-aldehyde. In one respect, this is an old story dating back to 1892 when the compound claimed to be Kostanecki's triketone (8) was isolated as a product from the reaction of benzaldehyde and acetophenone [36]. Over the years, a number of materials purporting to be 8, but possessing different physical properties have been reported [37,38]. A definitive report of the preparation and structural characterization of 8 describing the history of this compound together with an analysis of the various products isolated from the reaction of acetophenone with benzaldehyde appeared recently [39]. A large number of 3:2 condensation products have now been fully characterized by structural and spectroscopic means and shown to be cyclohexanols 9 arising from formally from the internal condensation of intermediate triketones.
To summarize, the formation of 3:2 condensation products is well-established with the stereochemistry at four of the five stereogenic centres defined. Examples of diastereoisomers with the 4-substituent in the axial or equatorial positions have been described and the less stable axial R diastereoisomer may be converted to the more stable equatorial S form with base [58]. To summarize, the formation of 3:2 condensation products is well-established with the stereochemistry at four of the five stereogenic centres defined. Examples of diastereoisomers with the 4-substituent in the axial or equatorial positions have been described and the less stable axial R diastereoisomer may be converted to the more stable equatorial S form with base [58].

The 3:1 Products
A second type of cyclohexane derivative 10 ( Figure 11) with a 3:1 (ketone-aldehyde) constitution is also known. We first described the formation of cyclohexane-1,3-diols from the condensation of 2-acetylpyridine with benzaldehyde derivatives in 1995 [58]. Although less commonly observed than the 3:2 condensation products, compounds of this type, arising from the aldol condensation of an intermediate pentane-1,5-dione with a third equivalent of ketone, have been isolated with a variety of substituents [32,60,[68][69][70][71][72][73]. The relative stereochemistry in 10, originally proposed on the basis of NMR studies [58], has been crystallographically confirmed [32,69,70,72]. Sequential reaction of the benzaldehyde derivative with two different ketones, Ar 1 COCH 3 and Ar 2 COCH 3 allows the synthesis of compounds 11 via the addition of Ar 2 COCH 3 to the intermediate enone Ar 1 COCH=CHAr. To summarize, the formation of 3:2 condensation products is well-established with the stereochemistry at four of the five stereogenic centres defined. Examples of diastereoisomers with the 4-substituent in the axial or equatorial positions have been described and the less stable axial R diastereoisomer may be converted to the more stable equatorial S form with base [58].

The 3:1 Products
A second type of cyclohexane derivative 10 ( Figure 11) with a 3:1 (ketone-aldehyde) constitution is also known. We first described the formation of cyclohexane-1,3-diols from the condensation of 2-acetylpyridine with benzaldehyde derivatives in 1995 [58]. Although less commonly observed than the 3:2 condensation products, compounds of this type, arising from the aldol condensation of an intermediate pentane-1,5-dione with a third equivalent of ketone, have been isolated with a variety of substituents [32,60,[68][69][70][71][72][73]. The relative stereochemistry in 10, originally proposed on the basis of NMR studies [58], has been crystallographically confirmed [32,69,70,72]. Sequential reaction of the benzaldehyde derivative with two different ketones, Ar1COCH3 and Ar2COCH3 allows the synthesis of compounds 11 via the addition of Ar2COCH3 to the intermediate enone Ar1COCH=CHAr.

Materials and Methods
1 H and 13 C and NMR spectra were recorded on a Bruker Avance iii-500 spectrometer (Bruker BioSpin AG, Fällanden, Switzerland) at 298 K. The 1 H and 13 C NMR chemical shifts were referenced with respect to residual solvent peaks (δ TMS = 0) and all quoted coupling constants J are J HH between protons. A Shimadzu LCMS-2020 instrument (Shimadzu Schweiz GmbH, Roemerstr., Switzerland) was used to record electrospray ionization (ESI) mass spectra; samples were introduced as 200-800 µM solutions in MeCN with the addition of formic acid. PerkinElmer UATR Two (Perkin Elmer, Bahnstrasse 8, 8603 Schwerzenbach, Switzerland) and Cary-5000 (Agilent Technologies Inc., Santa Clara, CA, United States) spectrometers were used to record FT-infrared (IR) and absorption spectra, respectively. Melting points were measured using a Bibby Melting Point Apparatus SMP30. 3-Acetylpyridine was purchased from Acros Organics (Chemie Brunschwig AG, Basel, Switzerland), 4-ethoxybenzaldehyde and 4-butoxybenzaldehyde from Sigma Aldrich (Riedstr. 2, 89555 Steinheim, Germany), and 4-propoxybenzaldehyde from Fluorochem and were used as received.

Conclusions
The preparation of terpyridines from the reactions of acetylpyridines with aromatic aldehydes and ammonia is an established synthetic method. Nevertheless, the reaction can give a variety of products. This paper provides another example of an unexpected product and a systematic survey of the products of such reactions. Although the one-pot synthesis of terpyridines is presented in the literature as an infallible synthetic method, there is ample precedent for the formation of a variety of alternative products. In particular, the assumption that the material precipitating from the reaction mixture is the desired terpyridine is not always correct. As these reactions are commonly used in the coordination chemistry community, this paper serves as a useful caveat. We are currently further investigating these reactions with varying length alkyloxy chains and will report on the constitution of the full reaction space in the future.
Supplementary Materials: The following are available online. Figures S1 and S2: Mass spectra of 5a and 5c; Figure S3: 13