Convenient Access to Ferrocene Fused aza -Heterocycles via the Intramolecular Ritter Reaction: Synthesis of Novel Racemic Planar-Chiral 3,4-Dihydroferroceno[ c ]pyridines and 1 H -Ferroceno[ c ]pyrroles

: An efﬁcient and easy approach to the synthesis of novel racemic planar-chiral 3,4-dihydrofer-roceno[ c ]pyridines and 1 H -ferroceno[ c ]pyrroles via the intramolecular Ritter reaction of 2-ferrocenyl-3,3-dimethylbutan-2-ol with nitriles and thiocyanates in the presence of MeSO 3 H was developed. Aromatic and aliphatic nitriles, phenylacetonitriles, and β -oxonitriles produced exclusively 3,4-dihydroferroceno[ c ]pyridines. The condensation of 2-ferrocenyl-3,3-dimethylbutan-2-ol with various thiocyanates, including alkyl thiocyanates, benzyl thiocyanate, and ethyl 2-thiocyanatoacetate, yielded not only 3,4-dihydroferroceno[ c ]pyridines but also 1 H -ferroceno[ c ]pyrroles. The selectivity of these reactions depended on the temperature and the order of addition. The size of substituents at the α -position to the sulfur atom of thiocyanates also had a signiﬁcant effect on the distribution of products.

In our preliminary work, we demonstrated for the first time the application of αferrocenyl alkyl alcohols as substrates for Ritter reaction by an example of the reaction of 1-ferrocenyl-2-methylpropan-1-ol [FcCH(OH)CH(CH 3 ) 2 ] with nitriles [48]. It was found that, in most cases, the nitriles were not nucleophilic enough to react with the secondary αferrocenyl carbocation FcCH + CH(CH 3 ) 2 generated from FcCH(OH)CH(CH 3 ) 2 under acidic conditions. Instead, the more reactive tertiary β-ferrocenyl carbocation FcCH 2 C + (CH 3 ) 2 , formed by a 1,2-shift of the α-carbocation, readily reacted with nitriles to give the corresponding β-nitrilium cations. The latter underwent intramolecular cyclization with the formation of novel 3,4-dihydroferroceno[c]pyridines. These structures, being analogous of 3,4-dihydroisoquinolines, are assumed to be potentially bioactive compounds and attract sufficient interest in medicinal chemistry. It should be pointed out that the synthetic routes for the preparation of 3,4-dihydroferroceno[c]pyridines to date are limited, and there are only a few reports in the literature on their synthesis [49][50][51][52].
To expand the range of α-ferrocenyl alkyl alcohols suitable to be used as substrates in the intramolecular Ritter reaction, herein we studied the reaction of 2-ferrocenyl-3,3dimethylbutan-2-ol (1) with nitriles under acidic conditions.
The reaction of alcohol 1 with 1.2 equivalent of nitrile 2a in the presence of MeSO 3 H at room temperature provided the desired ferroceno[c]pyridine 3a in 59% yield within 5 h ( Table 1, entry 1). In addition, amide 4a (6%) was also isolated. The structure of compound 3a was unambiguously confirmed by X-ray crystallography ( Figure 1). Performing the reaction at higher temperatures led to the improved product yield and significantly shorter reaction times (Table 1, entries [2][3][4][5]. In these cases, 60 • C was found to be the most optimal temperature both in terms of product yield and reaction time, resulting in compound 3a in 73% yield within 15 min (Table 1, entry 3). It turned out that the use of 1.5 equivalent of nitrile 2a did not lead to the improvement in the product yield (Table 1, entry 6). The reaction at 60 • C in DCE or toluene resulted in a longer reaction time and decreased yield of compound 3a compared to the same reaction without solvent (Table 1, entries 7, 8 vs. entry 3). In addition to ferroceno[c]pyridine 3a the inseparable mixtures of alkenes 5 and 6 were also isolated. Reactions of alcohol 1 with nitrile 2a in H 2 SO 4 or CF 3 COOH at 60 • C also gave product 3a, but in lower yields and after longer reaction times (Table 1, entries 9, 10), indicating that these acids were inferior to MeSO 3 H when inducing the studied reaction. No reaction occurred when CH 3 COOH was used, and only starting alcohol 1 along with alkene 5 were isolated in 42% and 32% yields, respectively (Table 1, entry 11). Thus, based on the results obtained, the following reaction conditions were chosen as optimal: MeSO 3 H, 60 • C, a ratio of 1a/2a = 1:1.2, without solvent.   1 Reagents and conditions: 1 (0.35 mmol, 1 equiv.), 2a (0.42 mmol, 1.2 equiv.), acid (8 equiv.). 2 Isolated yields after silica gel column chromatography. 3 According to 1 H NMR analysis of the fractions of chromatography. 4 1.5 equiv. of 2a. 5 0.5 mL of solvent. 6 Only alkene 5 was isolated. With the optimized conditions identified, the reaction of alcohol 1 with a variety of nitriles and thiocyanates was further explored.
First, the use of aromatic and aliphatic nitriles 2b-t, and β-oxonitriles 2u-x, was investigated (Table 2). Alcohol 1 smoothly reacted with benzonitrile (2b) and with ortho-, metha-, and para-substituted benzonitriles containing electron-donating (OMe, 2c-e and NH 2 , 2f) or electron-withdrawing (Br, 2h-j or CF 3 , 2k-m) substituents within 15-50 min to provide novel ferroceno[c]pyridines 3b-f, h-m in good to excellent yields ( Table 2,  entries 2 -6, 8-13). In contrast to the other ortho-substituted benzonitriles (2e, j, m), 2aminobenzonitrile (2g) afforded ferroceno[c]pyridine 3g in a poor yield ( Table 2, entry  7). The reaction of 4-nitrobenzonitrile (2n) with alcohol 1 led to a complex mixture of unidentified products with only trace amounts of compound 3n, probably because of a low nucleophilicity of 2n (Table 2, entry 14). Condensation of alcohol 1 with aliphatic nitriles 2o-s, including sterically hindered 1-adamantanecarbonitrile (2s), gave ferroceno[c]pyridines 3o-s within 15-25 min in high yields. According to 1 H NMR analysis of the crude residue, 3-methoxypropionitrile (2t) gave a complex mixture of products, none of which could be identified and isolated (Table 2, entry 20). Alcohol 1 reacted smoothly with β-oxonitriles 2u-x to afford products 3u-x in 34-87% yields ( Table 2, entries [21][22][23][24]. The NMR spectra clearly indicated that ferroceno[c]pyridines 3u-x existed exclusively in the Z-enamine form, which was stabilized by an intramolecular hydrogen bond. That is, the 1 H NMR spectra of these compounds in CDCl3 contained resonance signals of CH vinyl protons as singlets in the range of 4.74-5.98 ppm, together with resonance signals of NH protons as broad singlets in the range of 8.23-10.99 ppm. Cross peaks between the CH vinyl proton and H7′ proton or protons of unsubstituted Cp ring in the 2D 1 H-1 H NOESY spectra confirmed that compounds 3u-x existed as Z-isomers with respect to the >C=CH-bond ( Figure 2). Phenylacetonitriles 7a-c, like nitriles 2a-m, o-s, u-x, readily reacted with alcohol 1 to afford the corresponding ferroceno[c]pyridines 8a-c. However, products 8a-c could not be isolated in a pure form, since they were unstable. These compounds easily oxidized in air at a benzylic position, resulting in ferroceno[c]pyridines 9a-c (Table 3). Condensation of alcohol 1 with aliphatic nitriles 2o-s, including sterically hindered 1-adamantanecarbonitrile (2s), gave ferroceno[c]pyridines 3o-s within 15-25 min in high yields. According to 1 H NMR analysis of the crude residue, 3-methoxypropionitrile (2t) gave a complex mixture of products, none of which could be identified and isolated (Table 2,  entry 20).
Alcohol 1 reacted smoothly with β-oxonitriles 2u-x to afford products 3u-x in 34-87% yields ( Table 2, entries [21][22][23][24]. The NMR spectra clearly indicated that ferroceno[c]pyridines 3u-x existed exclusively in the Z-enamine form, which was stabilized by an intramolecular hydrogen bond. That is, the 1 H NMR spectra of these compounds in CDCl 3 contained resonance signals of CH vinyl protons as singlets in the range of 4.74-5.98 ppm, together with resonance signals of NH protons as broad singlets in the range of 8.23-10.99 ppm. Cross peaks between the CH vinyl proton and H7 proton or protons of unsubstituted Cp ring in the 2D 1 H-1 H NOESY spectra confirmed that compounds 3u-x existed as Z-isomers with respect to the >C=CH-bond ( Figure 2).
Condensation of alcohol 1 with aliphatic nitriles 2o-s, including sterically hindered 1-adamantanecarbonitrile (2s), gave ferroceno[c]pyridines 3o-s within 15-25 min in high yields. According to 1 H NMR analysis of the crude residue, 3-methoxypropionitrile (2t) gave a complex mixture of products, none of which could be identified and isolated (Table 2, entry 20). Alcohol 1 reacted smoothly with β-oxonitriles 2u-x to afford products 3u-x in 34-87% yields ( Table 2, entries 21-24). The NMR spectra clearly indicated that ferroceno[c]pyridines 3u-x existed exclusively in the Z-enamine form, which was stabilized by an intramolecular hydrogen bond. That is, the 1 H NMR spectra of these compounds in CDCl3 contained resonance signals of CH vinyl protons as singlets in the range of 4.74-5.98 ppm, together with resonance signals of NH protons as broad singlets in the range of 8.23-10.99 ppm. Cross peaks between the CH vinyl proton and H7′ proton or protons of unsubstituted Cp ring in the 2D 1 H-1 H NOESY spectra confirmed that compounds 3u-x existed as Z-isomers with respect to the >C=CH-bond ( Figure 2). Phenylacetonitriles 7a-c, like nitriles 2a-m, o-s, u-x, readily reacted with alcohol 1 to afford the corresponding ferroceno[c]pyridines 8a-c. However, products 8a-c could not be isolated in a pure form, since they were unstable. These compounds easily oxidized in air at a benzylic position, resulting in ferroceno[c]pyridines 9a-c (Table 3). Phenylacetonitriles 7a-c, like nitriles 2a-m, o-s, u-x, readily reacted with alcohol 1 to afford the corresponding ferroceno[c]pyridines 8a-c. However, products 8a-c could not be isolated in a pure form, since they were unstable. These compounds easily oxidized in air at a benzylic position, resulting in ferroceno[c]pyridines 9a-c (Table 3).  Purification of the crude residues by silica gel column chromatography, performed immediately after the work-up of the reaction mixtures, afforded products 8a-c as the mixtures with oxidized compounds 9a-c in ratios of 65:35 to 78:22. Storage of these mixtures at room temperature exposed to air resulted in full conversion of 8a-c to 9a-c within 1-6 days and isolation of ferroceno[c]pyridines 9a-c in 16-35% yields ( Table 3, Method A). Similar results in terms of the oxidation time and yields of 9a-c were obtained after storing the solutions of crude residues in EtOAc at room temperature exposed to air (Table 3, Method B). The rate of the conversion of compounds 8a-c to 9a-c strongly depends on the nature of substituents in the aromatic ring of the benzylic fragments. Thus, the oxidation of ferroceno[c]pyridine 8a, containing MeO groups, proceeded much faster than that of 8c with NO2 groups in the aromatic ring of the benzylic fragment (Table 3, entries 1 and 3).
Further, we investigated the reaction of alcohol 1 with thiocyanates 10a-j. It turned out that the condensation of alcohol 1 with EtSCN (10a) under optimal conditions gave a mixture of products in a 23:77 ratio, one of which was shown to be ferroceno[c]pyridine 11a and the other one ferroceno[c]pyrrole 12a (Table 4, entry 1). After silica gel column chromatography, compounds 11a and 12a were isolated in 18% and 65% yields, respectively. The structures of products 11a and 12a were unambiguously confirmed by X-ray crystallography (Figures 3 and 4). Only a single diastereomer of ferroceno[c]pyrrole 12a was formed, in which the tert-butyl group occupied exo-position with respect to the iron atom, according to X-ray data. Next, we found that the selectivity of the reaction strongly depended on the temperature and the order of addition of the thiocyanate 10a. The reaction at room temperature led to an excellent selectivity for the formation of ferroceno[c]pyrrole 12a (11a/12a = 5:95), which was isolated in 87% yield (Table 4, entry 2). At the same time, addition of thiocyanate 10a to the solution of alcohol 1 preheated to 60 °C gave a 43:57 mixture of products 11a and 12a, which were isolated in 33% and 53% yields, respectively ( Storage of the solutions of the crude residues in EtOAc at rt exposed to air. 2 Isolated yields after silica gel column chromatography. Purification of the crude residues by silica gel column chromatography, performed immediately after the work-up of the reaction mixtures, afforded products 8a-c as the mixtures with oxidized compounds 9a-c in ratios of 65:35 to 78:22. Storage of these mixtures at room temperature exposed to air resulted in full conversion of 8a-c to 9a-c within 1-6 days and isolation of ferroceno[c]pyridines 9a-c in 16-35% yields (Table 3, Method A). Similar results in terms of the oxidation time and yields of 9a-c were obtained after storing the solutions of crude residues in EtOAc at room temperature exposed to air (Table 3, Method B). The rate of the conversion of compounds 8a-c to 9a-c strongly depends on the nature of substituents in the aromatic ring of the benzylic fragments. Thus, the oxidation of ferroceno[c]pyridine 8a, containing MeO groups, proceeded much faster than that of 8c with NO 2 groups in the aromatic ring of the benzylic fragment (Table 3,  entries 1 and 3).
Further, we investigated the reaction of alcohol 1 with thiocyanates 10a-j. It turned out that the condensation of alcohol 1 with EtSCN (10a) under optimal conditions gave a mixture of products in a 23:77 ratio, one of which was shown to be ferroceno[c]pyridine 11a and the other one ferroceno[c]pyrrole 12a (Table 4, entry 1). After silica gel column chromatography, compounds 11a and 12a were isolated in 18% and 65% yields, respectively. The structures of products 11a and 12a were unambiguously confirmed by X-ray crystallography (Figures 3 and 4). Only a single diastereomer of ferroceno[c]pyrrole 12a was formed, in which the tert-butyl group occupied exo-position with respect to the iron atom, according to X-ray data. Next, we found that the selectivity of the reaction strongly depended on the temperature and the order of addition of the thiocyanate 10a. The reaction at room temperature led to an excellent selectivity for the formation of ferroceno[c]pyrrole 12a (11a/12a = 5:95), which was isolated in 87% yield (Table 4, entry 2). At the same time, addition of thiocyanate 10a to the solution of alcohol 1 preheated to 60 • C gave a 43:57 mixture of products 11a and 12a, which were isolated in 33% and 53% yields, respectively ( Table 4, entry 3). The reaction under similar conditions at 80 • C resulted in a predominant formation of ferroceno[c]pyridine 11a (11a/12a = 74:26), isolated in 57% yield (Table 4, entry 4). Increasing the reaction temperature to 100 or 120 • C provided an even greater selectivity toward ferroceno[c]pyridine 11a, resulting in products 11a and 12a in the ratios of 88:12 and 91:9, respectively (Table 4, entries 5, 6). However, lower yields of compound 11a were obtained compared to the reaction at 80 • C, likely due to its partial decomposition.   4 Addition of 10a to the solution of 1 in MeSO3H preheated to the indicated temperature. 5 Not isolated in an analytically pure form, only as a mixture with ferroceno[c]pyridine 11a. 6 Considerable tar formation was observed. 7 Not isolated.  Further, we investigated the reaction of alcohol 1 with thiocyanates 10b-f both at room temperature and at 80 °C (Table 5). Thiocyanates 10b-f, similar to EtSCN (10a), afforded ferroceno[c]pyrroles 12b-f as the main products at room temperature, with 11/12 ratios of 16:84 to 2:98, in moderate to good yields, as single diastereomers (Table 5, entries 1, 3, 5, 7, 9 and 11). At 80 °C thiocyanates 10c-f reacted with alcohol 1 with a predominant formation of ferroceno[c]pyridines 11c-f with ratios of 11c-f to 12c-f in the range of 67:23 to 92:8 (Table 5, entries 6, 8, 10 and 12). In these cases, products 11c-f were isolated in 42-61% yields. When MeSCN (10b) was used, the reaction proceeded with no selectivity to give a 52:48 mixture 11b and 12b, and ferroceno[c]pyridine 11b was obtained only in 35% yield (   4 Addition of 10a to the solution of 1 in MeSO3H preheated to the indicated temperature. 5 Not isolated in an analytically pure form, only as a mixture with ferroceno[c]pyridine 11a. 6 Considerable tar formation was observed. 7 Not isolated.  Further, we investigated the reaction of alcohol 1 with thiocyanates 10b-f both at room temperature and at 80 °C (Table 5). Thiocyanates 10b-f, similar to EtSCN (10a), afforded ferroceno[c]pyrroles 12b-f as the main products at room temperature, with 11/12 ratios of 16:84 to 2:98, in moderate to good yields, as single diastereomers (Table 5, entries 1, 3, 5, 7, 9 and 11). At 80 °C thiocyanates 10c-f reacted with alcohol 1 with a predominant formation of ferroceno[c]pyridines 11c-f with ratios of 11c-f to 12c-f in the range of 67:23 to 92:8 (Table 5, entries 6, 8, 10 and 12). In these cases, products 11c-f were isolated in 42-61% yields. When MeSCN (10b) was used, the reaction proceeded with no selectivity to give a 52:48 mixture 11b and 12b, and ferroceno[c]pyridine 11b was obtained only in 35% yield (Table 5, entry 4).   4 Addition of 10a to the solution of 1 in MeSO3H preheated to the indicated temperature. 5 Not isolated in an analytically pure form, only as a mixture with ferroceno[c]pyridine 11a. 6 Considerable tar formation was observed. 7 Not isolated.  Further, we investigated the reaction of alcohol 1 with thiocyanates 10b-f both at room temperature and at 80 °C (Table 5). Thiocyanates 10b-f, similar to EtSCN (10a), afforded ferroceno[c]pyrroles 12b-f as the main products at room temperature, with 11/12 ratios of 16:84 to 2:98, in moderate to good yields, as single diastereomers (Table 5, entries 1, 3, 5, 7, 9 and 11). At 80 °C thiocyanates 10c-f reacted with alcohol 1 with a predominant formation of ferroceno[c]pyridines 11c-f with ratios of 11c-f to 12c-f in the range of 67:23 to 92:8 (Table 5, entries 6, 8, 10 and 12). In these cases, products 11c-f were isolated in 42-61% yields. When MeSCN (10b) was used, the reaction proceeded with no selectivity to give a 52:48 mixture 11b and 12b, and ferroceno[c]pyridine 11b was obtained only in 35% yield (Table 5, entry 4). Further, we investigated the reaction of alcohol 1 with thiocyanates 10b-f both at room temperature and at 80 • C (Table 5). Thiocyanates 10b-f, similar to EtSCN (10a), afforded ferroceno[c]pyrroles 12b-f as the main products at room temperature, with 11/12 ratios of 16:84 to 2:98, in moderate to good yields, as single diastereomers (Table 5, (Table 5, entries 6, 8, 10 and 12). In these cases, products 11c-f were isolated in 42-61% yields. When MeSCN (10b) was used, the reaction proceeded with no selectivity to give a 52:48 mixture 11b and 12b, and ferroceno[c]pyridine 11b was obtained only in 35% yield (Table 5, entry 4).  The selectivity of the reaction is influenced by substituents at the α-position to the sulfur atom of thiocyanates 10a-f. An increase in the substituent size results in a higher selectivity toward ferroceno[c]pyridines 11, versus ferroceno[c]pyrroles 12. For example, in the case of reactions at 80 °C, the most sterically hindered isopropyl thiocyanate (10d) afforded ferroceno[c]pyridine 11d and ferroceno[c]pyrrole 12d in a ratio of 92:8, whereas the reaction with a less sterically constrained MeSCN (12b) gave products 11b and 12b in a ratio of 52:48 (Table 5, entries 8 and 4). When the reaction of alcohol 1 with isopropyl thiocyanate (10d) was carried out at room temperature, 11d/12d ratio was 16:84, while when using MeSCN (12b) under the same conditions, a 2:98 11b/12b ratio was observed ( Table 5, entries 7 and 3).
Ethyl 2-thiocyanatoacetate (10g) reacted with alcohol 1 the same way as thiocyanates 10a-f (Table 6, entries 1, 2). The use of thiocyanate 10g at room temperature led to the formation of a 4:96 mixture of compounds 11g and 12g, which were isolated in 6% and 73% yields, respectively ( Table 6, entry 1), whilst at 80 °C products 11g and 12g were formed in a ratio of 59:41, and purification by silica gel column chromatography gave 27% of ferroceno[c]pyridine 11g and 26% of ferroceno[c]pyrrole 12g (Table 6, entry 2). In both cases the 1 H NMR spectra of ferroceno[c]pyridine 11g recorded immediately after its isolation indicated that this compound contained trace amounts of ferroceno[c]pyridine 3u with 11g/3u ratios of 99:1 and 96:4, respectively. 1 H NMR analyses showed that ferroceno[c]pyridine 11g was very slowly converted to compound 3u when stored at room temperature, both neat and in solution. Compound 3u has not been isolated in a pure form in these cases. The results of the 1 H NMR monitoring of the transformation of thioimine 11g to enaminone 3u are performed in Supplementary Materials ( Figure S1, Table  S1). The formation of ferroceno[c]pyridine 3u likely occurred due to the extrusion of sulfur from thioimine 11g. This reaction is a typical for thioimines, containing CH2C(O)R fragment at the sulfur atom, and is the basis of such a synthetic method as Eschenmoser The selectivity of the reaction is influenced by substituents at the α-position to the sulfur atom of thiocyanates 10a-f. An increase in the substituent size results in a higher selectivity toward ferroceno[c]pyridines 11, versus ferroceno[c]pyrroles 12. For example, in the case of reactions at 80 • C, the most sterically hindered isopropyl thiocyanate (10d) afforded ferroceno[c]pyridine 11d and ferroceno[c]pyrrole 12d in a ratio of 92:8, whereas the reaction with a less sterically constrained MeSCN (12b) gave products 11b and 12b in a ratio of 52:48 (Table 5, entries 8 and 4). When the reaction of alcohol 1 with isopropyl thiocyanate (10d) was carried out at room temperature, 11d/12d ratio was 16:84, while when using MeSCN (12b) under the same conditions, a 2:98 11b/12b ratio was observed ( Table 5, entries 7 and 3).
Ethyl 2-thiocyanatoacetate (10g) reacted with alcohol 1 the same way as thiocyanates 10a-f (Table 6, entries 1, 2). The use of thiocyanate 10g at room temperature led to the formation of a 4:96 mixture of compounds 11g and 12g, which were isolated in 6% and 73% yields, respectively ( Table 6, entry 1), whilst at 80 • C products 11g and 12g were formed in a ratio of 59:41, and purification by silica gel column chromatography gave 27% of ferroceno[c]pyridine 11g and 26% of ferroceno[c]pyrrole 12g (Table 6, entry 2). In both cases the 1 H NMR spectra of ferroceno[c]pyridine 11g recorded immediately after its isolation indicated that this compound contained trace amounts of ferroceno[c]pyridine 3u with 11g/3u ratios of 99:1 and 96:4, respectively. 1 H NMR analyses showed that ferroceno[c]pyridine 11g was very slowly converted to compound 3u when stored at room temperature, both neat and in solution. Compound 3u has not been isolated in a pure form in these cases. The results of the 1 H NMR monitoring of the transformation of thioimine 11g to enaminone 3u are performed in Supplementary Materials ( Figure S1, Table S1). The formation of ferroceno[c]pyridine 3u likely occurred due to the extrusion of sulfur from thioimine 11g. This reaction is a typical for thioimines, containing CH 2 C(O)R fragment at the sulfur atom, and is the basis of such a synthetic method as Eschenmoser sulfide contraction [53,54]. The proposed mechanism for the transformation of thioimine 11g to enaminone 3u is performed in Supplementary Materials (Scheme S1). sulfide contraction [53,54]. The proposed mechanism for the transformation of thioimine 11g to enaminone 3u is performed in Supplementary Materials (Scheme S1).  3 Isolated as a mixture of 11g and 3u. According to 1 H NMR analysis of the fraction of chromatography 11g/3u ratios were found to be 99:1 (entry 1) and 96:4 (entry 2). 4 According to 1 H NMR analysis of the crude residues. 5 According to 1 H NMR analysis of the fraction of chromatography. 6 A complex mixture of unidentified products.
In contrast to ethyl 2-thiocyanatoacetate (10g), the reactions of alcohol 1 with β-oxothiocyanates 10h-j at room temperature did not proceed (Table 6, entries 3, 5, and 7). In these cases the starting alcohol 1 together with alcohol 13 and inseparable mixtures of alkenes 5 and 6 were isolated. Among thiocyanates 10h-j only 10i was recovered in 38% yield. According to the 1 H NMR analysis of the crude residue, the condensation of 1 with 2-thiocyanatoacetamide (10h) at 80 °C resulted in the formation of a complex mixture of unidentified products, which were not isolated (  Table 6, entry 6), along with a mixture of alkenes 5 and 6 in a 42% overall yield, and 63% of recovered thiocyanate 10i. It should be noted that the yield of the product 3w remained at the same level upon an increase in the reaction time up to 1.5 h. According to the 1 H NMR spectrum of the crude residue, 2-oxopropyl thiocyanate (10j) at 80 °C gave trace amounts of ferroceno[c]pyridine 3x, which was not isolated. Only an inseparable mixture of alkenes 5 and 6 in 20% yield together with 38% of starting alcohol 1 were isolated ( In contrast to ethyl 2-thiocyanatoacetate (10g), the reactions of alcohol 1 with βoxothiocyanates 10h-j at room temperature did not proceed (Table 6, entries 3, 5, and 7). In these cases the starting alcohol 1 together with alcohol 13 and inseparable mixtures of alkenes 5 and 6 were isolated. Among thiocyanates 10h-j only 10i was recovered in 38% yield. According to the 1 H NMR analysis of the crude residue, the condensation of 1 with 2-thiocyanatoacetamide (10h) at 80 • C resulted in the formation of a complex mixture of unidentified products, which were not isolated ( Table 6, entry 4). Reaction with phenacyl thiocyanate (10i) at 80 • C within 40 min afforded 8% of ferroceno[c]pyridine 3w ( Table 6, entry 6), along with a mixture of alkenes 5 and 6 in a 42% overall yield, and 63% of recovered thiocyanate 10i. It should be noted that the yield of the product 3w remained at the same level upon an increase in the reaction time up to 1.5 h. According to the 1 H NMR spectrum of the crude residue, 2-oxopropyl thiocyanate (10j) at 80 • C gave trace amounts of ferroceno[c]pyridine 3x, which was not isolated. Only an inseparable mixture of alkenes 5 and 6 in 20% yield together with 38% of starting alcohol 1 were isolated ( Table 6, entry 8). Similar to the formation of 3u from 11g, products 3w and 3x, are assumed to be formed via sulfur extrusion from thioimines 11i and 11j, respectively. However, we could neither isolate nor detect ferroceno[c]pyridines 11i and 11j by 1 H NMR and GS-MS analysis of the crude residues.
The proposed mechanism for the formation of ferroceno[c]pyridines 3, 8, 11 and ferroceno[c]pyrroles 12 is shown in Scheme 1. The reaction includes initial acid-promoted ionization of starting alcohol 1 with the formation of tertiary α-ferrocenyl carbocation A, which is in an equilibrium with isomeric tertiary β-ferrocenyl carbocation B. The latter reacts with nitriles 2, 7, or 10 to give nitrilium ion C (path a), the intramolecular cyclization of which then provides ferroceno[c]pyridines 3, 8, and 11. Thiocyanates 10, being more nucleophilic than nitriles 2 and 7 because of the influence of an electron-donating sulfur atom, may react not only with carbocation B but also with the less electrophilic α-ferrocenyl carbocation A, to form nitrilium ion D (path b which is in an equilibrium with isomeric tertiary β-ferrocenyl carbocation B. The latter reacts with nitriles 2, 7, or 10 to give nitrilium ion C (path a), the intramolecular cyclization of which then provides ferroceno[c]pyridines 3, 8, and 11. Thiocyanates 10, being more nucleophilic than nitriles 2 and 7 because of the influence of an electron-donating sulfur atom, may react not only with carbocation B but also with the less electrophilic α-ferrocenyl carbocation A, to form nitrilium ion D (path b The lower electrophilicity of α-ferrocenyl carbocation A compared to β-ferrocenyl carbocation B is due to the extensive delocalization of the positive charge with the participation of the ferrocenyl moiety. At room temperature an equilibrium between carbocations A and B is shifted towards the thermodynamically more stable α-ferrocenyl carbocation A, which explains the predominant formation of ferroceno[c]pyrroles 12 at these conditions. An increase in the reaction temperature shifts the A↔B equilibrium towards the carbocation B, which causes an increase in the selectivity of the formation of ferroceno[c]pyridines 11.

General Information
Thin-layer chromatography was performed on commercially available Sorbfil silica gel plates, which were visualized under UV light (254 nm). Column chromatography was performed on silica gel 60 (0.063-0.200 mm, Macherey-Nagel). 1 H and 13 C NMR spectra were recorded on a Bruker Avance NEO 400 spectrometer using CDCl3, DMSO-d6, or C6D6 as solvents. Chemical shifts are quoted on the δ scale, parts per million (ppm). The 1 H chemical shifts were measured relative to the internal standard HMDSO (δH 0.055 ppm) for CDCl3 and DMSO-d6, or residual C6H6 (δH 7.16 ppm) for C6D6. The 13 C chemical shifts were measured relative to the solvent signal (δC 77.16 ppm for CDCl3, δC 39.50 ppm for DMSO-d6, δC 128.06 ppm for C6D6). The 19 F chemical shifts were measured relative to the internal standard C6F6. The assignment of primary (CH3), secondary (CH2), tertiary (CH), and quaternary (C) carbon nuclei was made by using DEPT-135 spectra. The signals in the 1 H and 13 C NMR spectra of compounds 3a, 3u-x, 11a, and 12a were assigned based on 2D 1 H- 13 C HSQC, 1 H- 13  The lower electrophilicity of α-ferrocenyl carbocation A compared to β-ferrocenyl carbocation B is due to the extensive delocalization of the positive charge with the participation of the ferrocenyl moiety. At room temperature an equilibrium between carbocations A and B is shifted towards the thermodynamically more stable α-ferrocenyl carbocation A, which explains the predominant formation of ferroceno[c]pyrroles 12 at these conditions. An increase in the reaction temperature shifts the A↔B equilibrium towards the carbocation B, which causes an increase in the selectivity of the formation of ferroceno[c]pyridines 11.

General Information
Thin-layer chromatography was performed on commercially available Sorbfil silica gel plates, which were visualized under UV light (254 nm). Column chromatography was performed on silica gel 60 (0.063-0.200 mm, Macherey-Nagel). 1 H and 13 C NMR spectra were recorded on a Bruker Avance NEO 400 spectrometer using CDCl 3 , DMSO-d 6 , or C 6 D 6 as solvents. Chemical shifts are quoted on the δ scale, parts per million (ppm). The 1 H chemical shifts were measured relative to the internal standard HMDSO (δ H 0.055 ppm) for CDCl 3 and DMSO-d 6 , or residual C 6 H 6 (δ H 7.16 ppm) for C 6 D 6 . The 13 C chemical shifts were measured relative to the solvent signal (δ C 77.16 ppm for CDCl 3 , δ C 39.50 ppm for DMSO-d 6 , δ C 128.06 ppm for C 6 D 6 ). The 19 F chemical shifts were measured relative to the internal standard C 6 F 6 . The assignment of primary (CH 3 ), secondary (CH 2 ), tertiary (CH), and quaternary (C) carbon nuclei was made by using DEPT-135 spectra. The signals in the 1 H and 13 C NMR spectra of compounds 3a, 3u-x, 11a, and 12a were assigned based on 2D 1 H- 13 C HSQC, 1 H- 13 C HMBC and 1 H-1 H NOESY experiments. Copies of NMR spectra for all new compounds are deposited in the Supplementary Materials. Low-resolution mass spectra were obtained with an Agilent 6890N/5975B GC-MS system (column: HP-5ms, 15 or 30 m × 0.25 mm, 0.25 µm; helium as a carrier gas, 1 mL/min, electron impact ionization mode (230 • C, 70 eV)) and Agilent 7890B/5977B GC-MS system (column: HP-5ms UI, 30 m × 0.25 mm, 0.25 µm; helium as a carrier gas, 1 mL/min, electron impact ionization mode (230 • C, 70 eV)). High-resolution mass spectra were recorded with a Bruker maXis HD UHR-QTOF mass spectrometer equipped with an electrospray ionization ion source. Infrared spectra were recorded on a Bruker IFS 66 FT-IR spectrometer. Elemental analysis was carried out on a Vario EL Cube analyzer. Melting points were determined using a PTP apparatus and are uncorrected.
Compound 10g. Well-ground NH 4 SCN (2.09 g, 27.5 mmol) was added portionwise to a stirred solution of ethyl 2-bromoacetate (2.8 mL, 25 mmol) in i-PrOH (3 mL), and the resulting mixture was heated under reflux with stirring for 5 h. The reaction mixture was then cooled to room temperature, diluted with water (10 mL) until the complete dissolution of the precipitate, and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with water, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was dissolved in EtOH (20 mL), and charcoal (2 g) was added. The resulting mixture was stirred at room temperature for 30 min, and the charcoal was removed by filtration and washed with EtOH (5 mL). The combined filtrates were concentrated in vacuo to afford pure product 10g Compound 10j. Well-ground NH 4 SCN (2.09 g, 27.5 mmol) was added portionwise to a stirred solution of chloroacetone (2 mL, 25 mmol) in i-PrOH (3 mL), and the resulting mixture was stirred at room temperature for 20 h. The reaction mixture was then worked up as described for the preparation of compound 10g to afford pure product 10j (2.03 g, 71%) as a light yellow liquid; R f 0.20 (hexane/  3a-m, o-s, u-x (Table 2) General Procedure (GP) . Nitrile 2a-m, o-s, u-x (0.42 mmol) was added to a stirred solution of alcohol 1 (100 mg, 0.35 mmol) in MeSO 3 H (0.18 mL) at room temperature, and the resulting mixture was heated at 60 • C in an oil bath with vigorous stirring for the indicated time (monitored by TLC). The reaction mixture was then cooled to room temperature, neutralized with 10% aq. Na 2 CO 3 solution (3 mL) and extracted with EtOAc (10 mL × 4). The combined organic phases were washed with water, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography.  1608, 1589, 1562, 1513, 1453, 1441, 1372, 1361, 1309, 1251, 1168, 1155, 1108, 1033, 1002, 933 1599, 1568, 1487, 1462, 1435, 1372, 1361, 1305, 1285, 1274, 1238, 1168, 1152, 1108, 1049, 1039 3464, 3433, 3378, 3321, 3204, 3094, 2973, 2931,  2868, 1621, 1609, 1584, 1556, 1518, 1454, 1372, 1361, 1315, 1296, 1171, 1155, 1107, 1002 13 13  . GC-MS analyses of product 3u indicated the presence of a peak in the chromatogram that, based on its MS spectra, belonged to compound 3o. The latter was likely produced by the thermolysis of the parent compound in the GC instrument injector. HRMS-ESI (m/z): [ 13 (Table 3) General Procedure 1 (GP1). Phenylacetonitrile 7a-c (0.42 mmol) was added to the stirred solution of alcohol 1 (100 mg, 0.35 mmol) in MeSO 3 H (0.18 mL) at room temperature, and the resulting mixture was heated at 60 • C in an oil bath with vigorous stirring for the indicated time (monitored by TLC). The reaction mixture was then cooled to room temperature, neutralized with 10% aq. Na 2 CO 3 solution (3 mL), and extracted with EtOAc Table 1, entry 1. Nitrile 2a (0.05 mL, 0.42 mmol) was added to a stirred solution of alcohol 1 (100 mg, 0.35 mmol) in MeSO 3 H (0.18 mL) at room temperature, and the resulting mixture was stirred at this temperature for 5 h. The reaction mixture was then worked up as described in GP. Purification by silica gel column chromatography (petroleum ether/EtOAc

Conclusions
In summary, we demonstrated that 2-ferrocenyl-3,3-dimethylbutan-2-ol was a suitable substrate in the intramolecular Ritter reaction. Condensation of starting alcohol with a variety of nitriles in the presence of MeSO 3 H yielded novel 3,4-dihydroferroceno[c]pyridines. The reaction of 2-ferrocenyl-3,3-dimethylbutan-2-ol with thiocyanates gave not only 3,4dihydroferroceno[c]pyridines but also 1H-ferroceno[c]pyrroles. The selectivity of this reaction depended on the temperature, the order of addition, and the size of substituents at the α-position to the sulfur atom of thiocyanates. The simplicity of the procedure and the availability of starting materials make the reaction of 2-ferrocenyl-3,3-dimethylbutan-2-ol with nitriles and thiocyanates very convenient and attractive to the synthesis of variously functionalized ferrocene-fused aza-heterocycles.