Acta Chim. Slov. 2011, 58, 9-13
11
Review
Tele--substitutions in Heterocyclic Chemistry
Miha Tisler
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana * Corresponding author: E-mail: miha.tisler@fkkt.uni-lj.si
Received: 05-01-2011
Abstract
Particular and rare examples of aromatic nucleophilic substitution are described as tele-substitution. Usually strong nuc-leophiles are involved and the entering group is introduced at a position distant from the expected leaving group. Examples of tele-substitution in various heteroaromatic systems are presented.
Keywords: Tele-substitution, heteroaromatic five-, six-membered, bicyclic and polycyclic systems.
1. Introduction
In general, nucleophilic substitution reactions of aromatic or heteroaromatic compounds occur at the same position of the leaving group (ipso-substitution). However, there are some exceptions - a substitution reaction can take place at a position more than one atom away from the atom in which the leaving group was attached and is called a tele-substitution. On the other hand, when the entering group takes up a position adjacent to that occupied by the leaving group, this is called a cine-substitution (IUPAC Gold Book).1 Previously, in the 1980s, such substitutions were designed as "abnormal" substitutions. Moreover, a nucleophilic aromatic substitution can occur in special cases with replacement of a hydrogen atom and not a halogen atom or other leaving group and this kind of reaction is called vicarious nucleophilic substitution (VNS). A more complicated mechanism occurs under the action of a strong nucleophile (e.g. amide anion); ring opening of the heterocyclic ring with subsequent cycliza-tion, representing the ANRORC mechanism (Addition of the Nucleophile, Ring Opening, and Ring Closure).
In this article we like to deal only with tele-substitution involving heterocyclic systems.
2. Five-membered Heterocycles
In the five-membered heterocycles several tele-substitutions were recorded. In an earlier described reaction between a-furfuryl chloride (1, R = CH2Cl) with an aqueous solution of cyanide ion the reaction product was assig-
ned to be an ¿pso-substitution product. Later, however, it was established that the product was actually 5-cyano-2-methylfuran (= 2-cyano-5-methylfuran) (2). Its structure was established after hydrolysis into 5-methylfuroic acid. The reaction with the cyanide is thus an early example of ie/e-substitution.2 The same compound (2) was obtained as the major product when 2-furfuryltrimethylammonium iodide (1, R = CH2NMe3+ I) was treated with sodium cyanide in the absence of solvent at 180-200 °C.3 For this ie/e-substitution a tentative mechanism was proposed. It was also established that related 2-chloromethylthiophene or benzyl chloride are not transformed in this way.4
Cr
--s
NC —^^^— M6
2-(W-methylpyrrolyl)trimethylammonium salts (3, X = CH, R = CH2NMe3+, R1 = H) when treated with sodium cyanide at elevated temperature afforded among other products also 1,2-dimethyl-5-cyanopyrrole (4, X = CH, R = Me, R1 = CN), a product of ie/e-substitution. With variation of temperature and solvent it could be observed that ie/e-substitution is greatly dependent on the reaction medium and yields were in the range of 10-40%.5
When 5-bromo-1-metylimidazole (3, X = N, R = H, R1 = Br) was treated with lithium piperidide and piperidi-ne in boiling ether among other products also 1-methyl-2-piperidinoimidazole (4, X = N, R = NC5H10, R1 = H), a te-/e-substitution product, was formed in 16% yield. The
2
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Acta Chim. Slov. 2011, 58, 9-13
corresponding 5-chloro analog yielded the same product in low yield (3-5%).6
Me	Me
Amination of 2-chloro-3,5-dinitropyridine (11, R = NO2) in liquid ammonia containing potassium permanganate, followed by 13C NMR spectra measurements revealed that at -40 °C addition at C-6 has occurred to give a thermodynamically stable tele-addition intermediate and then 12 (R = NO2) as the end product. At lower temperature (-60 °C) the addition occurred at C-4 to give a kineti-cally controlled tele-adduct.12
3. Six-membered Heterocycles
There are several examples of ie/e-substitution in the pyridine series. 3-Trichloromethylpyridine (5) reacted with various nucleophiles by an attack at position 5 to give 5-sub-stituted pyridines. With sodium phenoxide at elevated temperature a mixture of 2-phenoxypyridine-5-carbaldehyde (6, R = OPh, R1 = CHO) and the corresponding 5-diphenoxy-methyl analogue [6, R = OPh, R1 = CH(OPh)2] were formed in low yield. A similar ie/e-substitution occurred with thiop-henol and methyl thioglycolate to give 6 (R = SPh or SCH2COOMe, R1 = CHCl2) in high yield. Similarly, the reaction with morpholine in acetonitrile under reflux afforded 6 [R = N(CH2)4O, R1 = CHO] whereas at room temperature the trichloromethyl group was attacked. Analogous reactions at position 6 were observed in the case of 3-trichloro-methylpyridine-N-oxide with the N-oxide group remaining unaffected.7 When 2-chloro-3-trichloromethylpyridine (7) was treated with methoxide ion the methoxy group entered at position 6 and the trichloromethyl group was converted either into an acetal or aldehyde [8, R = CH(OMe)2 or CHO].8,9
CCl3
h2n
-nh2
-R
11
12
N-fluoropyridinium tetrafluoroborate (13, R = F, R1 = H, X = BF4) reacted with weakly-basic C-nucleophiles at position 4. Examples of ie/e-substitution, which is influenced by the nature of the carbanion and reaction conditions, involve anions of trinitromethane and ethyl nitroa-cetate [14, R = H, R1 = C(NO2)3 CH(NO2)COOEt]. A reaction mechanism was proposed.13 Although N-fluorop-yridinium salts are used as fluorinating agents they display also other reactivities, among them nucleophilic aromatic ie/e-substitution.14
Cyanation of 1-(N-methylacetamido)-2-methylpyri-dinium iodide [13, R = N(Me)COMe, X = I] in aqueous solution afforded 4-cyano-2-methylpyridine in 88% yield (14, R = Me, R1 = CN).15
13
Ri 14
Cl
CCl3
MeO
2-Bromo-6-alkoxypyridines (9, R = Me, Et) reacted in a solution of the potassium salt of pentanone-3 in liquid ammonia to give among other products also ie/e-substitu-tion products such as the 4-amino (10, R = NH2, R1 = Et) and 4-pentanone substituted derivatives [10, R = CH(Me) COEt, R1 = Et].10 Moreover, 2-bromo-6-ethoxypyridine (9, R = Et) when treated with KNH2/NH3 yielded as byproduct in 14% yield the corresponding ie/e-product,
4-amino-6-ethoxypyridine (10, R = NH2, R1 =
Et).1
RO
O"
R1O
R 10
In the case of pyridazines, 3-a-chlorobenzylpyrida-zine (15) when heated with different sodium alkoxides afforded ie/e-substituted 3-benzyl-6-alkoxypyridazines [16, R = Me, Et, (CH2)2NMe2] with simultaneous dehalogena-tion. Alkoxides were prepared from methanol, ethanol, and dimethylaminoethanol and yields were in the range of 11-77%.16
RO
15
16
Several 4-substituted-5-bromopyrimidines were investigated and treated with strong nucleophiles, but only 5-bromo-4-piperidinopyrimidine [17, R = N(CH2)5] afforded with KNH2/NH3 a ie/e-substitution product, namely 2-amino-4-piperidinopyrimidine [18, R = N(CH2)5] in low yield (4-6%).17
N
R
R
R
R

R
R
R
R
R
Ph
Ph
Cl
9
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Acta Chim. Slov. 2011, 58, 9-13
11
R 17

R 18
romethyl group. It was further reported that phenols reacted in an analogous manner as C-nucleophiles (2,6-di-mehylphenol, resorcinol or 4-hexylresorcinol). Phenols reacted at their ortho- or para-positions in the C-C bond formation with triazines.21' 22
Tele-substitutions were reported also in the pyrazine series. Treatment of 2-chloro-3-dichloromethyl pyrazine (19) with three equivalents of methoxide ion afforded 2,6-dimethoxy-3-methoxymethylpyrazine (20, R, R1 = Me, referred also as 3,5-dimethoxy-2-methoxymethylp-yrazine), the methoxy group entering at position 6. Similarly, the reaction with one equivalent of ethoxide ion afforded as the principal product 2-chloro-3-chloromethyl-6-ethoxypyrazine.

CHCl2
Tele-substitution occurred also in the case of 2-trich-loromethylpyrazine with methoxide ion to give a mixture of di-, tri- and tetrasubstituted products.18 3-Chloro-1-eth-yl-2-morpholinopyrazinium salts [21, Mo = N(CH2)4O] were treated with various C-nucleophiles of the type X-CH2-Y (X,Y = CN, COOEt, COMe) to give 6-substitu-ted derivatives with an alkylidene side chain [22, Mo = N(CH2)4O; X,Y = CN, COOEt, COMe].19 In another case, 2,3-dichloropyrazine (23) when treated with lithio-1,3-dithiane at -70 °C produced tele-substituted product 2-chloro-6-(1',3'-dithian-2'-yl)pyrazine (24). Its structure was confirmed by deuterium labeling and X-ray determi-
nation.2
Et
%-Mo

Cl
22
aci - cx r
23
24
6-Aryl-3-trichloromethyl-1,2,4-triazines (25, Ar = phenyl, 4-chlorophenyl or 4-methylphenyl) were transformed with indole or 1-methylindole in the presence of a catalytic amount of hydrochloric or trifluoroacetic acid into 6-aryl-3-dichloromethyl-5-(indol-3-yl or 1-methylindol-3-yl)-1,2,4-triazines [26, Ar1 = 3-indolyl or 3-(1-methylin-dolyl)] in 60-70% yield. Tele-substitution is accompanied by elimination of one of the chlorine atoms in the trichlo-
INK 25
Ar Ar,
INK 26
4. Bi- and Polycyclic Heterocyclic Compounds
There are also several cases reported for bicyclic heterocyclic compounds. For 3-bromoimidazo[1,2-a] pyridine (27) ie/e-substitutions were observed. With ethylamine anion as a minor product 6-bromo-7-ethyla-minoimidazo[ 1,2-a]pyridine (28, R1 = Br, R2 = EtNH, R, R3 = H, 2.5 %) was identified. Its formation is explained by postulating electrophilic substitution at position 6 followed by ie/e-substitution of the bromine atom at position 3. In a similar reaction with lithium diethylamide several ie/e-substituted products were obtained: the 5- (28, R = NEt2, R1, R2, R3 = H, 4%), 7- (28, R2 = NEt2, R, R1, R3 = H, 13%), 8-diethylamino compound (28, R3 = NEt2, R, R1, R2 = H, 9%), and the 5,7-bis(diethylamino) compound (28, R = R2 = NEt2, R1, R3 = H, 1%). With KNH2 compound 27 yielded among other products 6-aminoimi-dazo[1,2-a]pyridine (28, R1 = NH2, R, R2, R3 = H) in 50%
yield.23
-Br
27
28
5-Bromo-s-triazolo[4,3-a]pyrazine (29) reacted with sodium methoxide at room temperature to give a mixture of the ¿^^-substitution product and the 8-methoxy derivative (30) as an example of ie/e-substituted product.24
OMe

29
30
Also 5-bromo-s-triazolo[1,5-a]pyrazine (31) when treated with hydrazine, hydroxylamine or liquid ammonia afforded the corresponding 8-substituted derivatives (32, R = NH2, NHOH, NHNH2 ) as a result of tele-substitu-
tion.
25
NH
2
Br
N
N
N
N
CCl
CHCl
3
2
N
N
Cl
RO
OR
CH OR
'1
R
N
X
Mo
R
Y
N
N
N
N
N
N
N
N
Br
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Acta Chim. Slov. 2011, 58, 9-13	11

Br
31
32
8-Chloropurine (33, R = Cl) when treated with potassium amide in liquid ammonia yielded adenine (34, R = H) as the main product (30%) together with 8-chlo-roadenine (34, R = Cl, 10%). In a similar manner 8-(methylthio)purine (33, R = SMe) afforded 8-methylthi-oadenine (34, R = SMe) in 80% yield.26

An interesting example provided the reaction at position 3 deuterated 2-bromo-1,8-naphthyridine (40) which was after treatment with KNH2/NH3 transformed in 40 % yield into 7-amino-3-deuterio- (actually 2-ami-no-6-deuterio) -1,8-naphthyridine (41) thus presenting a clear evidence for tele-substitution.32 From NMR evidence it became clear that the intermediate o-adduct occurred at position 7 giving the tele-substituted product. Also in the case of the related deuterated 2-chloro derivative it was established that replacement of the chlorine atom with the amino group occurred partly (~8%) via a tele-substitution process.33 In the last mentioned publication (ref. 7) it was stated that upon amination of 2-bromo-7-deuterio-1,8-naphthyridine tele-substitution proceeded with 27%. However, more exact method of calculation revealed later that the extent of this transformation was 45%.32
33
34
4-Halogenoisoquinolines (35, R = Cl, Br, I) after treatment with KNH2 in liquid ammonia were transformed into 1-aminoisoquinoline (36, R = NH2) in 4-17% yield. In an analogous transformation with piperidine 1-piperidi-noisoquinoline [36, R = N(CH2)5] was obtained in 3-17% yield.27
35
36
Extensive investigations were performed with 1,7- (37), 1,8- (38) and 2,6-naphthyridines (39). 8-Chloro-1,7-naphthyridine afforded after treatment with KNH2/ NH3 a small amount of the te/e-substituted 2-amino-1,7-naphthyridine in low yield (5%).28, 29 On the other hand, 2-chloro- or 2-bromo-1,7-naphthyridine upon treatment with KNH2/NH3 yielded two te/e-substitution products, 4-amino-1,7-naphthyridine (1,2% from the chloro and 3.6% from the bromo starting compound) and 8-amino-1,7-naphthyridine (9.4% from the chloro and 1.0% from the bromo starting compound).30 5-Bromo- or 5-chloro-1,7-naphthyridine underwent te/e-amination with KNH2 in liquid ammonia to give 8-amino-1,7-naphthyridine (42% from the bromo and 1% from the chloro starting compound) and 2-amino-1,7-naphthyridine (17% from the bromo starting compound) as well as 8-amino-5-chlo-ro-1,7-naphthyridine (4% from the chloro starting compound). The reaction with the chloro analogue proceeded very slowly.31
7N
e
N 2
40
N^	^ N
D D 41
1-Bromo- (42, R = Br) or 1-chloro-2,6-naphthyridi-ne (42, R = Cl)) when treated with KNH2 in liquid ammonia afforded among other products also 5-amino-2,6-naphthyridine (= 1-amino-2,6-naphthyridine (43) as a te-/e-substitution product in 28% or 20% yield. From NMR evidence it was suggested that as intermediate adduct at position 5 is formed. Without this evidence the reaction would formally appear as normal ipso-substitution. Experiments involving deuterated and undeuterated starting 1-chloro compound revealed from the kinetic isotope effect that te/e-amination of the undeuterated compound proceeded about 13 times faster than the normal ipso-substitution. In both cases also the 1,5-diamino compound was formed (17% or 14% yield).34
--5
42
43
37
38
39
Investigations of te/e-substitution were performed also with the tricyclic benzo[c]cinnoline system (44). 1-Chlorobenzo[c]cinnoline when treated with lithiated dimethylamine afforded a mixture of 1-chloro-4-di-methylamino- and 1-chloro-7-dimethylamino derivatives together in 72% yield. Similarly, te/e-substitution was observed with 2-chlorobenzo[c]cinnoline to give 2,4,7-tris(dimethylamino)benzo[c]cinnoline in 33% yield.35,36 Also 4-chlorobenzo[c]cinnoline afforded with KNH2/NH3 as te/e-product 2-aminobenzo[c]cinnoline in low yield (5%).37
R
N
N
N
N
N
N
N
N
NH
2
N
R
R
N
NH
H2N
NH
R
R
R
NH
2
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Acta Chim. Slov. 2011, 58, 9-13
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^ ^Ns
N
6
44
5.	Conclusion
Increasing knowledge and detailed investigations concerning (hetero)aromatic nucleophilic substitutions have lead to discovery of several kinds of unusual reaction paths. Among them, tele-substitution has been found to occur with several heterocyclic systems and a summary of them is presented in the present review article.
6.	References
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16.	G. Heinisch, T. Huber, Liebigs Ann. Chem., 1992, 19-22.
17.	C. A. H. Rasmussen, H. C. van der Plas, P. Grotenhuis, A. Koudijs: J. Heterocycl. Chem., 1978, 15, 1121-1125.
18.	E. J. J. Grabowski, E. W. Tristram, R. Tull, P. I. Pollak, Tetrahedron Lett., 1968, 5931-5934.
19.	P. A. Slepukhin, G. I. Rusinov, V. N. Charushin, M. I. Ko-dess, O. N. Chupakhin, Russ. Chem. Bull., Int. Ed., 2003, 52, 689-694.
20.	J. E. Torr, J. M. Large, P. N. Horton, M. B. Hursthouse, E. McDonald, Tetrahedron Lett., 2006, 47, 31-34.
21.	D. N. Kozhevnikov, V. N. Kozhevnikov, V. I. Rusinov, O. N. Chupakhin, Chem. Heterocycl. Compd. 1999, 35, 13771378.
22.	D. N. Kozhevnikov, N. N. Kataeva, V. L. Rusinov, O. N. Chupakhin, Russ. Chem. Bull., Int. Ed., 2004, 53, 12951300.
23.	E. S. Hand, W. W. Paudler, J. Org. Chem, 1978, 43, 29002906.
24.	J. Bradac, Z. Furek, D. Janezic, S. Molan, I. Smerkolj, B. Stanovnik, M. Tisler, B. Vercek, J. Org. Chem., 1977, 42, 4197-4201.
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Povzetek
Posebne in redke primere aromatske nukleofilne substitucije predstavljajo reakcije iefe-substitucije. Običajno potekajo pri uporabi jakih nukleofilov tako, da se ne zamenja pričakovana izstopajoča skupina, ampak se veže nukleofil na bolj oddaljeno mesto. Prikazani so znani primeri tefe-substitucije na heteroaromatskih sistemih.
Tisler: Tele-substitutions in heterocyclic chemistry