Synthesis of novel racemic 3,4-dihydroferroceno[c]pyridines via the Ritter reaction

Article abstract of DOI:10.1016/j.tetlet.2019.02.009

A new approach for the synthesis of functionalized racemic 3,4-dihydroferroceno[c]pyridines via the Ritter reaction of 2-methyl-1-ferrocenylpropan-1-ol with nitriles in the presence of methansulfonic acid was developed. The scope and limitations of the reaction were evaluated. Selected racemic 3,4-dihydroferroceno[c]pyridines were successfully separated by preparative HPLC on a Chiralcel OD-H column. The absolute configuration of the enantiomers was determined by X-ray crystal structure analysis.

Full text of DOI:10.1016/j.tetlet.2019.02.009

Accepted Manuscript
Synthesis of novel racemic 3,4-dihydroferroceno[c]pyridines via the Ritter re-
action
Yuliya S. Rozhkova, Irina V. Plekhanova, Alexey A. Gorbunov, Olga G.
Stryapunina, Evgeny N. Chulakov, Victor P. Krasnov, Marina A. Ezhikova,
Mikhail I. Kodess, Pavel A. Slepukhin, Yurii V. Shklyaev
PII:
S0040-4039(19)30116-9
https://doi.org/10.1016/j.tetlet.2019.02.009
TETL 50603
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 December 2018
29 January 2019
4 February 2019
Please cite this article as: Rozhkova, Y.S., Plekhanova, I.V., Gorbunov, A.A., Stryapunina, O.G., Chulakov, E.N.,
Krasnov, V.P., Ezhikova, M.A., Kodess, M.I., Slepukhin, P.A., Shklyaev, Y.V., Synthesis of novel racemic 3,4-
dihydroferroceno[c]pyridines via the Ritter reaction, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.02.009
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1
Tetrahedron Letters
Synthesis of novel racemic 3,4-dihydroferroceno[c]pyridines via the Ritter reaction
Yuliya S. Rozhkovaa, , Irina V. Plekhanovaa, b, Alexey A. Gorbunova, Olga G. Stryapunina, Evgeny N.
Chulakov c, Victor P. Krasnovc, Marina A. Ezhikovac, Mikhail I. Kodessc, d, Pavel A. Slepukhinc, d, Yurii V.
Shklyaeva, b
aInstitute of Technical Chemistry, Russian Academy of Sciences (Ural Branch), 3 Akademika Korolyeva St., Perm, 614013 Russia
bPerm State University, 15 Bukireva St., Perm, 614990 Russia
cPostovsky Institute of Organic Synthesis, Russian Academy of Sciences (Ural Branch), 22 S. Kovalevskoy St., Ekaterinburg, 620990 Russia
dUral Federal University, 19 Mira St., Ekaterinburg, 620002 Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new approach for the synthesis of functionalized racemic 3,4-dihydroferroceno[c]pyridines
via the Ritter reaction of 2-methyl-1-ferrocenylpropan-1-ol with nitriles in the presence of
methansulfonic acid was developed. The scope and limitations of the reaction were evaluated.
Selected racemic 3,4-dihydroferroceno[c]pyridines were successfully separated by preparative
HPLC on a Chiralcel OD-H column. The absolute configuration of the enantiomers was
determined by X-ray crystal structure analysis.
Available online
Keywords:
3,4-Dihydroferroceno[c]pyridine
Ritter reaction
2018 Elsevier Ltd. All rights reserved.
Nitrilium ion
Cyclization
Chiral HPLC
X-ray diffraction
Due to their unique properties, ferrocene derivatives have
attracted significant attention in the fields of catalysis,1-3 material
science,4-9 and medicinal chemistry.10-14 Among the wide variety
of ferrocene derivatives, ferrocene-fused aza-heterocycles are of
particular interest, because these compounds bearing planar
chirality have been demonstrated to be effective catalysts for a
variety of enantioselective transformations.15-21 Furthermore,
ferrocene-fused aza-heterocycles, being structural analogues of
benzannulated aza-heterocycles, are assumed as potential
bioactive compounds and attract significant interest in medicinal
chemistry.22,23 However, despite the apparent importance of
ferrocene-fused aza-heterocycles, synthetic routes for the
preparation of these compounds are limited to date. Thus, the
development of methods for the construction of ferrocene-fused
aza-heterocycles is an important research area.
The intramolecular Ritter reaction is an effective and
attractive approach for the construction of a variety of aza-
heterocyclic compounds.24,25 In particular, the Ritter reaction is
widely used for the synthesis of 3,4-dihydroisoquinoline
derivatives.26-31 One of the variants for the synthesis of 3,4-
dihydroisoquinolines via the Ritter reaction includes the
condensation of 1-aryl-2-methylpropan-1-oles, serving as a
source of carbocations, with nitriles under strongly acidic
conditions.26, 30, 31 In view of the fact that ferrocene is an aromatic
system, we questioned whether the use of readily available 2-
———
methyl-1-ferrocenylpropan-1-ol instead of 1-aryl-2-
methylpropan-1-oles would lead to an analogous reaction
providing novel racemic 3,4-dihydroferroceno[c]pyridines. It
should be pointed out that there are few reports in the literature
regarding the synthesis of 3,4-dihydroferroceno[c]pyridines,32-35
and to the best of our knowledge the use of the Ritter reaction for
the synthesis of these compounds has not been explored. Herein,
we describe the use of the Ritter reaction for the synthesis of
racemic 3,4-dihydroferroceno[c]pyridines. The separation of
selected racemic 3,4-dihydroferroceno[c]pyridines by chiral
HPLC is also reported.
To evaluate the possibility that 3,4-
dihydroferroceno[c]pyridines could be formed via the Ritter
reaction, we initially investigated the model reaction of 2-methyl-
1-ferrocenylpropan-1-ol (1) with benzonitrile (2a) (Table 1).
Initially, we tested concentrated H2SO4 as a catalyst since it is the
most widely used catalyst for the preparation of 3,4-
dihydroisoquinolines via the Ritter reaction. In this case the
reaction was performed with 8 equivalents of acid and a 1:1 ratio
of 1/2a in DCE at room temperature for 24 h. Disappointingly,
H2SO4 provided the desired 3,4-dihydroferroceno[c]pyridine 3a
in only 8% yield along with various acyclic products, i.e. amide 4
(10%), alkene 5 (11%), arising from deprotonation of the 2-
methyl-1-ferrocenylpropan-1-ylium ion (FcC+HCH(CH3)2), and
amine 6 (16%), arising from the trapping of FcC+HCH(CH3)2
Corresponding author. Tel.: +7-342-237-8287; fax: +7-342-237-8262; e-mail: rjs@mail.ru

2
Tetrahedron Letters
with ammonia during the aqueous ammonia work-up, together
promoted the hydrolysis of benzonitrile (2a) with the formation
with unreacted carbinol 1 (Table 1, entry 1). Also, H2SO4
of benzamide in 42% yield.
Table 1. Optimization of the reaction conditions.a
Yield (%) b
Recov. 1
(%)
2a
(equiv.)
1
Temp
(°С)
Entry
Acid (equiv.)
Time (h)
Solvent
3a
4
10
-
5
6
1
H2SO4 (8)
MsOH (8)
TfOH (8)
TFA (8)
rt
24
24
24
24
4
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
-
8 c
11
8
16
49
2
rt
1
30
trace
trace
n/i f
11
40
3
rt
1
trace d
6 e
8
-
5
84
4
rt
1
4
10
5
MsOH (8)
MsOH (8)
MsOH (8)
MsOH (8)
MsOH (8)
MsOH (8)
MsOH (8)
MsOH (4)
MsOH (16)
60
80
60
60
60
60
60
60
60
1
50
-
10
12
12
7
10
6
4
1
46
-
n/i f
trace
trace
trace
trace
trace
trace
7
7
4
1.2
2.0
1.2
1.2
1.2
1.2
1.2
56 (56) g
-
13
8
4
54
-
n/i f
n/if
9
6
53
-
16
8
10
11
12
13
4
55
-
n/i f
n/i f
trace
n/i f
4
55
-
trace
4
4
DCE
DCE
28
-
4
53
-
11
trace
а Reagents and conditions:1 (1.0 mmol), 2a (1.0-2.0 mmol), acid (4.0-16.0 mmol), solvent (2.5 mL); 25% aq. NH3 work-up.
b Isolated yield after column chromatography.
c Benzamide was also isolated in 42% yield.
d 2,4,6-Triphenyl-1,3,5-triazine was also isolated in 12% yield.
e 90% of 2a was recovered.
f n/i – not isolated; amine 6 was formed according to GC-MS analysis of the crude reaction mixture, but after column chromatography it was obtained as
an inseparable mixture with unidentified side-products.
g 2.5 mmol scale.
Strong Brønsted acids including MsOH, TfOH and TFA were
then screened as catalysts under the same conditions. The use of
MsOH gave 3,4-dihydroferroceno[c]pyridine 3a in 30% yield
(Table 1, entry 2). In addition to product 3a the starting carbinol
1 (40%) and alkene 5 (8%) were also isolated. Only trace
amounts of 3a were detected when TfOH was used as a catalyst.
In this case amide 4 was obtained in 9% yield along with 5% of
alkene 5 and 84% starting material 1 recovered (Table 1, entry 3).
Moreover, TfOH promoted the cyclotrimerization of 2a to afford
2,4,6-triphenyl-1,3,5-triazine in 12% yield.36 Finally, the reaction
of 1 with benzonitrile (2a) in the presence of TFA gave 3a in
only 6% yield together with alkene 5, amine 6 and unreacted
starting materials (Table 1, entry 4). Having identified MsOH as
the optimal catalyst, we next screened different reaction
parameters in order to improve the yield of the desired product
3a. Performing the reaction at 60 °С for 4 h provided 3,4-
dihydroferroceno[c]pyridine 3a in 50% yield (Table 1, entry 5).
However, further increasing the reaction temperature to 80 °С
caused a slight decrease in the product yield (Table 1, entry 6). A
slight improvement in the yield of 3a was observed when the
reaction was carried out at 60 °С for 4 h with 1.2 equivalents of
2a. In this case 3a was isolated in 56% yield (Table 1, entry 7).
Further prolongation of the reaction time or the use of 2.0
equivalents of 2a did not lead to an improvement in the yield
(Table 1, entries 8, 9). Performing the reaction in toluene or
under solvent-free conditions (60 °С, 4 h, 1.2 equiv. of 2a) gave
yields of the product 3a which were comparable to those using
DCE as a solvent (Table 1, entries 10, 11). Finally, the influence
of catalyst loading was evaluated (60 °С, 4 h, 1.2 equiv. of 2a,
DCE). This revealed that reducing the amount of MsOH to 4
equivalents resulted in a significantly lower yield of
ferroceno[c]pyridine 3a (Table 1, entry 12), whereas the use of
16 equivalents of MsOH had no significant effect on the yield of
3a (Table 1, entry 13). Based on the results of this screening the
optimal reaction conditions were determined as 8 equivalents of
MsOH, 60 °С , 1/2a = 1:1.2 and DCE as a solvent.
Using the optimized conditions the scope and limitations of
the reaction of 2-methyl-1-ferrocenylpropan-1-ol (1) with various
nitriles 2 were evaluated (Table 2).

Tetrahedron Letters
3
Table 2. Substrate scope of nitriles.a, b
a Reagents and conditions: Unless indicated otherwise, 1 (2.5 mmol), 2 (3.0 mmol), MeSO3H (20 mmol), DCE (5 mL), 60 °C, 4 h; 25% aq. NH3 work-up.
b Isolated yield after column chromatography.
c Alkene 5 containing trace amounts of unidentified side-products was also isolated.
d 2.5 mmol of 2 was used.
e Starting nitrile 2 was recovered.
f Reaction was carried out for 5 h.
g n/i – not isolated; 3j was formed according to GC-MS analysis of the crude reaction mixture, but after column chromatography it was obtained as an inseparable
mixture with unidentified side-products.
h Reaction was carried out for 6 h.
i The complex mixture of unidentified side-products and picolinamide were formed according to GC-MS analysis of the crude reaction mixture.
The reaction between 1 and benzonitriles substituted with electron-donating groups (MeO- or NH2-groups) 2b, e, f, i, m led to
3,4-dihydroferroceno[c]pyridines 3b, e, f, i, m in moderate to good yields (23-60%). The structure of compound 3m was
unambiguously confirmed by X-ray crystallography (Fig. 1, see ESI for details).
Figure 1. Molecular structure of 3m according to XRD data with thermal ellipsoids of the 50% probability level (only the (Rp)-enantiomer
is shown).
In the case of 2-aminobenzonitrile 2j, GC-MS analysis of the crude reaction mixture suggested the formation of product 3j;
however, numerous attempts to isolate 3j were unsuccessful. Some limitations were observed when benzonitriles with electron-

withdrawing groups were used. While 4-, 3- and 2-(trifluoromethyl)benzonitriles (2c), (2g) and (2k) provided 3,4-
dihydroferroceno[c]pyridines 3c, 3g and 3k, respectively, in moderate to good yields (33-53%), less nucleophilic 4-, 3- and 2-
nitrobenzonitriles (2d), (2h) and (2l) were less reactive and gave either no product or only trace amounts of product, with recovered
starting nitrile and alkene 5 obtained in each case. The reaction between carbinol 1 and 2-pyridinecarbonitrile (2n) was also
unsuccessful with no 3,4-dihydroferroceno[c]pyridine 3n obtained, presumably due to the low nucleophilicity of nitrile 2n. In this
case the complex mixture of unidentified products and picolinamide, arising from the hydrolysis of 2-pyridinecarbonitrile (2n),
were formed according to GC-MS analysis of the crude reaction mixture. As expected, in the 13C NMR spectra of compounds 3c, 3g
and 3k with the (trifluoromethyl)phenyl substituent at the C1 atom, 13C-19F couplings were observed. Moreover, apart from the
usual coupling across one, two and three bonds, a small splitting of the C-7 carbon (6JC,F = 1.3 Hz) in the spectrum of 3k with a CF3
group in ortho-position was observed. This splitting is likely attributed to long-range through-space 13C-19F coupling; hence the
fluorine nucleus is spatially in close proximity to the C-7 carbon nucleus (Fig. 2).
Figure 2. Long-range through-space 13C-19F coupling for 3k.
The reaction proceeded well with aliphatic nitriles such as acetonitrile (2o) and propionitrile (2p) providing 3,4-
dihydroferroceno[c]pyridines 3o and 3p in 60% and 62% yields, respectively. In addition to 3p the oxidized product 3p' was also
isolated in 5% yield. Compound 3p' presumably arises from silica-gel assisted oxidation of the ethyl group in ferroceno[c]pyridine
3p to an acetyl group by oxygen during purification by column chromatography on SiO2. Carbinol 1 reacted with ethyl 2-
cyanoacetate (2q) to give product 3q in 37% yield along with the small amount of compound 3o (6%), which was formed from 3o
via hydrolysis of the ester group with concomitant decarboxylation during the course of the reaction. The NMR and IR spectra
clearly indicated that compound 3q existed exclusively in the enamine tautomeric form which is most likely due to stabilization of
the enamine form by intramolecular hydrogen bonding. The reaction of 1 with methyl thiocyanate (2r) gave not only the expected
3,4-dihydroferroceno[c]pyridine 3r in 50% yield but also ferroceno[c]pyrrole 7 in 10% yield as a single diastereomer. The
stereochemistry of compound 7 was determined by 2D 1H-1H NOESY experiments, in which the cross-peak between the H-3 proton
and equivalent protons of the unsubstituted Cp ring was observed. Therefore, the isopropyl group in compound 7 occupied the exo-
position with respect to the iron atom.
The proposed reaction mechanism is described in Scheme 1. The ionization of 2-methyl-1-ferrocenylpropan-1-ol (1) under acidic
condition leads to the formation of secondary carbocation A, which is in equilibrium with isomeric tertiary carbocation B.
Subsequent trapping of cation B by nitrile 2 gives nitrilium ion C, which then undergoes intramolecular electrophilic cyclization to
form ferroceno[c]pyridines 3. In the case of MeSCN (2r), not only does the reaction take place with carbocation B, but also with
carbocation A, which gives nitrilium ion D, with subsequent intramolecular cyclization affording product 7. The formation of
ferroceno[c]pyrrole 7 may be rationalized in terms of HSAB theory. Carbocation A, due to extensive delocalization of the positive
charge, is expected to be significantly softer than carbocation B. Due to the presence of an S atom, MeSCN (2r) is a softer N-
nucleophile compared to the other nitriles 2. Therefore, it has a greater affinity for soft carbocation A than other nitriles 2, which
leads to the formation of product 7.

Tetrahedron Letters
3
Scheme 1. Proposed reaction mechanism.
Considering the importance of optically active planar chiral ferrocene derivatives we also investigated the chiral HPLC
resolution of racemic 3,4-dihydroferroceno[c]pyridines obtained using compounds 3a, 3m and 3o as examples (Scheme 2).
Scheme 2. Chiral HPLC resolution of racemic ferroceno[c]pyridines 3a, 3m and 3o.
Preliminary analytical chiral HPLC (Chiralcel OD-H column; 250 4.6 mm, 5 m) demonstrated excellent separation of the (Rp)-
and (Sp)-enantiomers of 3a, 3m and 3o (separation factor: 3a = 1.23, 3m = 1.13, 3o = 1.15, see ESI for details). Next, both
enantiomers of 3a, 3m and 3o of >99% ee were obtained in 17-35% yield, from racemates by preparative chiral HPLC on a
Chiralcel OD-H column (250 20 mm, 5 m) using hexane–i-PrOH–TEA 200:1:0.4 (for 3a, 3o) or hexane–i-PrOH–MeOH 50:0.8:0.2
(for 3m) as eluent followed by crystallization from hexane. The absolute configuration of the separated enantiomers was established
by X-ray crystallography (Fig. 3 and 4, see also Fig. S2-S4 in the ESI).
Figure 3. Molecular structure of (Rp)-3o according to XRD data with thermal ellipsoids of the 50% probability level.

Figure 4. Molecular structure of (Sp)-3o according to XRD data with thermal ellipsoids of the 50% probability level.
In summary, for the first time we have demonstrated the synthesis of novel racemic 3,4-dihydroferroceno[c]pyridines via the
Ritter reaction of 2-methyl-1-ferrocenylpropan-1-ol with nitriles in the presence of methansulfonic acid. The reaction is compatible
with a wide range of nitriles, however, some limitations were observed when benzonitriles containing electron-withdrawing groups
were used. Despite modest yields, the simplicity of the procedure and the availability of starting reagents make this method
convenient for the synthesis of functionalized ferroceno[c]pyridines. Selected racemic 3,4-dihydroferroceno[c]pyridines were
successfully separated by preparative HPLC on a Chiralcel OD-H column, and the absolute configuration of the enantiomers was
determined by X-ray crystal structure analysis. Further studies to extend the scope of this reaction to other ferrocenyl alcohols and
investigation of synthetic transformations of the 3,4-dihydroferroceno[c]pyridines obtained are in progress in our laboratory.
Acknowledgments
The work was financially supported by the Russian Foundation for Basic Research (grant 17-03-00546) and partially by the
Program of the Ural Branch of the Russian Academy of Sciences (project 18-3-3-13).
Appendix A. Supplementary data
Supplementary data related to this article can be found at doi 10.1016/j.tetlet.......
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Graphical Abstract
Synthesis of novel racemic
Leave this area blank for abstract info.
3,4-dihydroferroceno[c]pyridines via the
Ritter reaction
Yuliya S. Rozhkova, Irina V. Plekhanova, Alexey A. Gorbunov, Olga G. Stryapunina, Evgeny N.
Chulakov, Victor P. Krasnov, Marina A. Ezhikova, Mikhail I. Kodess, Pavel A. Slepukhin, Yurii V.
Shklyaev

Tetrahedron
5
Highlights
Racemic 3,4-dihydroferroceno[c]pyridines were
obtained via the Ritter reaction
MsOH-catalysed reaction of 2-methyl-1-
ferrocenylpropan-1-ol with nitriles
Preparative chiral HPLC resolution of the racemic
3,4-dihydroferroceno[c]pyridines
Assignment of absolute configuration of (Rp)- and
(Sp)-enantiomers by X-ray