Vicarious nucleophilic substitution of (chloroalkyl)heterocycles with nitroarenes

Article abstract of DOI:10.1002/ejoc.200300806

The vicarious nucleophilic substitution of potassium carbanions of the (chloromethyl)pyridines 1a and 1b, (chloromethyl)benzothiazole 1c, (chloromethyl)thiazole 1d, (chloroethyl)thiazole 1e and (chloroethyl) benzothiazole 1f wit nitroarenes, leading to ni

Full text of DOI:10.1002/ejoc.200300806

FULL PAPER
Vicarious Nucleophilic Substitution of (Chloroalkyl)heterocycles with
Nitroarenes
Saverio Florio,*[a] Patrizia Lorusso,[b] Renzo Luisi,[a] Catia Granito,[b] Ludovico Ronzini,[b]
and Luigino Troisi*[b]
Keywords: Heterocycles / Vicarious nucleophilic substitution / Arenes / Regioselective synthesis
The vicarious nucleophilic substitution of potassium car-
nitroarenes, leading to nitrobenzyl heterocycles 2 and 4−14
banions of the (chloromethyl)pyridines 1a and 1b, (chloro- has been studied.
methyl)benzothiazole 1c, (chloromethyl)thiazole 1d, (chloro-
ethyl)thiazole 1e and (chloroethyl)benzothiazole 1f with
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
of potassium tert-butoxide (3 equiv.) in dimethyl sulfoxide
(DMSO) a dark red solution resulted. An acidic quench
Nucleophilic substitution of hydrogen in an aromatic sys- (satd. aq. NH4Cl) gave, with poor regioselectivity, the
tem is a versatile tool for functionalizing carbon and hetero- (nitrobenzyl)pyridines 2a and 3a, which likely originated
cyclic arenes.[1Ϫ3] Among the many variants which have from the nucleophilic attack of the anion of 1a at the posi-
been developed for the nucleophilic substitution of arenes tions ortho and para to the nitro group of the nitrobenzene.
with hydrogen, vicarious nucleophilic substitution (VNS), Comparable results were obtained when a mixture of nitro-
developed by Makosza and co-workers, has become a good benzene and 2-(chloromethyl)pyridine (1b), 2-(chloro-
method for the introduction of carbon, oxygen and nitrogen methyl)benzothiazole (1c) or 2-(chloromethyl)-4-methyl-
functional groups by the displacement of hydrogen from thiazole (1d) was added to a suspension of potassium tert-
electron-deficient aromatic and heteroaromatic systems.[4Ϫ6]
Vicarious nucleophilic substitution usually occurs when the
nucleophile has a good leaving group at the nucleophilic
Table 1. Reactions of nitrobenzene with 1aϪf
centre.
In a previous paper we reported that carbanions of
(chloroalkyl)oxazolines couple efficiently with nitroarenes
to furnish (nitrobenzyl)oxazolines according to a VNS pro-
cess.[7] In order to ascertain the generality of the VNS reac-
tion of metallated (chloroalkyl)heterocycles, we embarked
in a study focused on the reaction of carbanions of chlo-
roalkyl derivatives of thiazole, benzothiazole and pyridine
with nitroarenes.
Results and Discussion
When a mixture of nitrobenzene (1.1 equiv.) and 4-(chloro-
methyl)pyridine (1a, 1 equiv.) was added to a suspension
[a]
Dipartimento Farmaco-Chimico, University of Bari and
Istituto di Chimica dei Composti Organometallici ‘‘ICCOM’’,
Sezione di Bari
Via E. Orabona 4, 70126 Bari, Italy
Fax: (internat.) ϩ39-080-5442231
E-mail: florio@farmchim.uniba.it
[b]
Dipartimento di Scienze
e
Tecnologie Biologiche ed
Ambientali, University of Lecce,
Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
E-mail: lugino.troisi@unile.it
[a] Yields of isolated products. [b] Determined by GC and 1H NMR
spectroscopy
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300806
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Vicarious Nucleophilic Substitution of (Chloroalkyl)heterocycles with Nitroarenes
FULL PAPER
Scheme 1
butoxide (3 equiv.) in DMSO. Quenching of the reaction ronitrobenzene afforded mixtures of regioisomers 5b ϩ 6b,
mixture with satd. aq. NH4Cl afforded (nitrobenzyl)- 5c ϩ 6c ؉ 7c, and 5d ϩ 6d ϩ 7d, respectively, whereas the
heterocycles 2b ϩ 3b, 2c ϩ 3c, and 2d ϩ 3d, respectively, reaction of 1a led regioselectively to compound 5a. In the
although with poor regioselectivity (Table 1).
case of 4-(chloromethyl)pyridine (1a), the para-substituted
In contrast, the reaction of nitrobenzene with the anions isomer 5a was the exclusive product, and in the cases of 1b,
of 2-(1-chloroethyl)-4-methylthiazole (1e) and 2-(1-chloro- 1c, and 1d, the para-substituted isomers 5b, 5c, 5d were the
ethyl)benzothiazole (1f), leading to the formation of com- major products. When three isomers were formed, the less
pounds 2e and 2f, respectively, was completely para-regio- hindered ortho isomer predominated over the more hin-
selective. These results can reasonably be accounted for in
terms of a vicarious nucleophilic substitution mechanism,
as illustrated in Scheme 1.
Table 2. Reactions of m-substituted nitrobenzenes with 1aϪf
According to this mechanism, the anion of 1, generated
by deprotonation with tBuOK, would rapidly and reversi-
bly add to the nitrobenzene at the hydrogen-bearing posi-
tion, ortho and/or para to the nitro group, resulting in the
formation of the σH adduct A. Base-induced β-elimination
of HCl from the σH adduct A, which is likely the rate-
limiting step of the reaction,[8,9] would then take place, to
generate the benzylic carbanion B and subsequently com-
pounds 2 and 3 upon acidic quenching. It has already been
reported[10] that the orientation of the substitution is
strongly influenced by the steric factor; inspection of the
data listed in Table 1 shows, indeed, that the introduction
of a methyl group on to the halogen-bearing carbon atom
(as in 1e and 1f) suffices to make the reaction completely
para-regioselective. The poor regioselectivity of the reaction
of anions 1aϪd is intriguing, because the para isomer for-
mation should be favoured both for steric and stability re-
asons. In our case, the formation of the ortho isomer can
be explained by the fact that the addition of 1aϪd to the
ortho position of nitrobenzene proceeds faster than to the
para position (kinetic control). The preferential formation
of the ortho regioisomer (with the respect to the alkoxy
group) in the amination of 1-alkoxy-3,5-dinitrobenzenes
has been ascribed to the higher thermodynamic stability of
the corresponding σH complex.[11Ϫ12]
The above VNS reaction of 1aϪf anions takes place also
with other nitroarenes. As shown in Table 2, treatment of
1,3-dinitrobenzene with the anions of (chloroalkyl)hetero-
cycles 1aϪf afforded (dinitrophenylmethyl)- and (dinitro-
phenylethyl)heterocycles 4aϪf. Unfortunately, chemical
yields were often rather poor, even when the temperature
[a] Yields of isolated products. [b] Determined by GC and 1H NMR
spectroscopy. The Z ϭ NO2 isomers 5 and 6 are identical, and
[c]
was changed. The reactions of 1b, 1c, and 1d with 3-chlo- correspond to 4.
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FULL PAPER
dered orthoЈ isomer (as in the reaction of 1d), whereas both be explained by the well established reactivity of 4-chloroni-
isomers were found in traces in the reaction of 1c. trobenzene with nucleophiles and the reducing ability of
Replacement of hydrogen in 1,2-dinitrobenzene and 2- tBuOK (Table 4).
chloro-1-nitrobenzene could occur at both the para and or-
tho positions with respect to the nitro group, giving two
Table 4. Reactions of p-substituted nitrobenzenes with 1aϪf
isomeric products. The reaction, however, proceeds in a qu-
ite regioselective way, with the prevalence of the para substi-
tuted product. However, the reaction with 2-(chloromethyl)-
benzothiazole (1c) afforded only the ortho-hydrogen substi-
tution product 9c (Table 3).
Table 3. Reactions of o-substituted nitrobenzenes with 1aϪf
[a] Yields of isolated products. [b] Determined by GC and 1H NMR
spectroscopy.
The dehalogenation of the SNAr product has been re-
ported in the reaction of carbanions of (chloromethyl)sul-
fones with fluoronitrobenzenes.[10a] The anion of 2-(chloro-
methyl)benzothiazole (1c) was treated with p-nitroanisole to
generate compound 14c, in accordance with the above-men-
[a] Yields of isolated products. [b] Determined by GC and 1H NMR
spectroscopy.
As expected, when the carbanions of heterocycles 1aϪd tioned pattern for para-substituted nitrobenzenes.
were treated with 4-chloronitrobenzene, the VNS reaction A completely different pattern was observed when the
occurred exclusively ortho to the nitro group to give com- anions of 1aϪf were reacted with 1,4-dinitrobenzene. The
pounds 13aϪd. Exceptionally, the anion of 2-(1-chloro- products, compounds 12 and 2, are very likely to be the
ethyl)-4-methylthiazole (1e) reacted with 4-chloronitroben- SNAr products; one of the two nitro groups could be dis-
zene to generate compound 2e, which is likely to derive placed by the anion of the heterocycle used (the ability of
from an SNAr process involving the replacement of the NO2 to act as a leaving group in a SNAr process is well-
chlorine para to the nitro group followed by the tBuOK- known[1]). Compounds 2 might be the result of the re-
induced reduction of the chlorobenzylic group. All this can duction of 12 by the excess of tBuOK.[13]
2120
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Vicarious Nucleophilic Substitution of (Chloroalkyl)heterocycles with Nitroarenes
FULL PAPER
2-(4-Nitrobenzyl)pyridine (2b): Yield: 85 mg (40%), oil. 1H NMR
(400.13 MHz, CDCl3): δ ϭ 4.23 (s, 2 H), 7.15Ϫ7.17 (m, 2 H), 7.42
(d, J ϭ 8.5 Hz, 2 H), 7.61Ϫ7.65 (m, 1 H), 8.13 (d, J ϭ 8.5 Hz, 2
H), 8.55 (d, J ϭ 3.7 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ
44.7, 122.2, 123.7, 124.2, 130.2, 137.3, 147.1, 147.6, 150.1, 159.4
ppm. GC-MS: m/z (%) ϭ 214 (2) [Mϩ], 213 (12), 197 (35), 196 (28),
169 (77), 168 (100), 167 (96), 169 (77), 166 (74), 139 (66), 92 (46).
IR (film): ν˜ ϭ 3050 cmϪ1, 2920, 1590, 1510, 1430, 1345, 1150, 1050.
Conclusion
In conclusion, the work carried out in this paper shows
that carbanions of (chloroalkyl)heterocycles are VNS re-
agents, and provide the synthetic organic chemist with a
convenient route to α-substituted (nitrobenzyl)pyridines,
(nitrobenzyl)benzothiazoles, and (nitrobenzyl)thiazoles,
which have potential for elaboration to a variety of other
substances and, are therefore useful in synthetic organic
chemistry.
2-(4-Nitrobenzyl)benzothiazole (2c): Yield: 76 mg (28%), oil. 1H
NMR (400.13 MHz, CDCl3): δ ϭ 4.54 (s, 2 H), 7.38 (t, J ϭ 8.1 Hz,
1 H), 7.48 (t, J ϭ 8.1 Hz, 1 H), 7.54 (d, J ϭ 8.7 Hz, 2 H), 7.83 (d,
J ϭ 8.1 Hz, 1 H), 8.00 (d, J ϭ 8.1 Hz, 1 H), 8.20 (d, J ϭ 8.7 Hz,
2 H) ppm. 13C NMR (100.62 MHz): δ ϭ 40.4, 122.0, 123.4, 124.4,
125.7, 126.7, 130.4, 135.9, 144.8, 147.6, 153.6, 168.5 ppm. GC-MS:
m/z (%) ϭ 270 (100) [Mϩ], 269 (90), 240 (61), 224 (80), 223 (91),
111 (83). IR (film): ν˜ ϭ 3050 cmϪ1, 2960, 1600, 1500, 1350, 1100.
Experimental Section
General Remarks: 1H and the 13C NMR spectra were recorded with
a Bruker Avance 400 apparatus (400.13 MHz and 100.62 MHz, for
1H and 13C, respectively) and a Bruker AC200 apparatus (200 MHz
and 50.3 MHz, for 1H and 13C, respectively); with CDCl3 as the
solvent (δ ϭ 7.24 ppm for 1H spectra; δ ϭ 77.0 ppm for 13C spectra)
and TMS as an internal standard. IR spectra were recorded with
a PerkinϪElmer spectrometer Model 283. GC-MS analyses were
performed with a Shimadzu GCϪ17A gas chromatograph (5% di-
phenyl, 95% dimethylpolysiloxane capillary column, 30 m, 0.25 mm
i.d.), equipped with a Shimadzu GCMSϪQP5050A mass-selective
detector operating at 70 eV (EI). TLC analysis was performed on
Merck silica gel plates with FϪ254 indicator; visualization was by
UV light (254 nm). Column chromatography was performed on sil-
ica gel (63Ϫ200 µm), with petroleum ether/ethyl acetate mixtures
as the eluent. All reactions involving air-sensitive reagents were per-
formed under nitrogen in oven-dried glassware using syringe/sep-
tum cap techniques. DMSO was distilled and stored over molecular
4-Methyl-2-(4-nitrobenzyl)thiazole (2d): Yield: 96 mg (41%), oil. 1H
NMR (400.13 MHz, CDCl3): δ ϭ 2.43 (s, 3 H), 4.40 (s, 2 H), 6.80
(s, 1 H), 7.48 (d, J ϭ 8.5 Hz, 2 H), 8.16 (d, J ϭ 8.5 Hz, 2 H) ppm.
13C NMR (100.62 MHz): δ ϭ 16.8, 38.8, 113.7, 123.7, 129.5, 145.1,
146.7, 152.7, 166.4 ppm. GC-MS: m/z (%) ϭ 234 (100) [Mϩ], 233
(85), 204 (30), 187 (70), 89 (50), 71 (96). IR (film): ν˜ ϭ 3100 cmϪ1
,
2950, 2850, 1600, 1510, 1350, 1100, 730.
4-Methyl-2-[1-(4-nitrophenyl)ethyl]thiazole (2e): Yield: 101 mg
1
(41%), oil. H NMR (200 MHz, CDCl3): δ ϭ 1.72 (d, J ϭ 7.1 Hz,
3 H), 2.33 (s, 3 H), 4.50 (q, J ϭ 7.1 Hz, 1 H), 6.70 (s, 1 H), 7.40
(d, J ϭ 8.7 Hz, 2 H), 8.10 (d, J ϭ 8.7 Hz, 2 H) ppm. 13C NMR
(50.3 MHz): δ ϭ 17.0, 21.6, 43.6, 113.2, 123.8, 128.4, 147.3, 151.1,
152.8, 172.3 ppm. GC-MS: m/z (%) ϭ 248 (100) [Mϩ], 233 (16),
215 (21), 201 (36), 187 (90), 126 (63), 112 (37), 71 (60). IR (film):
ν˜ ϭ 3100 cmϪ1, 2960, 2920, 1600, 1510, 1340, 850, 740.
˚
sieves (5 A) prior to use. Starting materials were commercially
available or were prepared by known methods. In particular, 4-
(chloromethyl)pyridine (1a) and 2-(chloromethyl)pyridine (1b) were 2-[1-(4-Nitrophenyl)ethyl]benzothiazole (2f): Yield: 114 mg (40%),
obtained from the corresponding hydrochlorides upon treatment
with 5% NaOH, extraction with diethyl ether, drying (Na2SO4) and
evaporation of the solvent under reduced pressure. Substrates 1c
and 1f were obtained by the reaction of 2-aminothiophenol with
glycolic or lactic acid and subsequent halogenation.[14Ϫ17] Com-
pound 1d was prepared by formylation of 4-methylthiazole, re-
duction of the thiazol-2-carbaldehyde thus obtained, and sub-
sequent halogenation, following reported synthetic protocols.[18] 1e
was obtained by the coupling of 2-(4-methyl)thiazolyllithium with
acetaldehyde and subsequent halogenation.[18]
oil. 1H NMR (400.13 MHz, CDCl3): δ ϭ 1.88 (d, J ϭ 7.1 Hz, 3
H), 4.68 (q, J ϭ 7.1 Hz, 1 H), 7.33 (t, J ϭ 8.0 Hz, 1 H), 7.45 (t,
J ϭ 8.0 Hz, 1 H), 7.53 (d, J ϭ 8.7 Hz, 2 H), 7.81 (d, J ϭ 8.0 Hz,
1 H), 8.0 (d, J ϭ 8.0 Hz, 1 H), 8.17 (d, J ϭ 8.7 Hz, 2 H) ppm. 13C
NMR (100.62 MHz): δ ϭ 21.2, 44.4, 121.5, 122.9, 123.9, 125.1,
126.1, 128.5, 134.9, 147.0, 150.2, 153.0, 173.4 ppm. GC-MS: m/z
(%) ϭ 284 (100), 269 (5), 254 (8), 237 (22), 223 (40), 262 (20). IR
(film): ν˜ ϭ 3050 cmϪ1, 2960, 1600, 1530, 1340, 1100.
4-(2-Nitrobenzyl)pyridine (3a): Yield: 60 mg (28%), oil. 1H NMR
(200 MHz, CDCl3): δ ϭ 4.22 (s, 2 H), 6.97 (d, J ϭ 5.6 Hz, 2 H),
7.24 (d, J ϭ 7.5 Hz, 1 H), 7.36 (dd, J ϭ 7.4, 7.5 Hz, 1 H), 7.50 (dd,
J ϭ 7.4, 7.5 Hz, 1 H), 7.90 (d, J ϭ 7.5 Hz, 1 H), 8.40 (d, J ϭ
5.6 Hz, 2 H) ppm. 13C NMR (50.3 MHz): δ ϭ 37.9, 123.8, 125.0,
128.0, 132.6, 133.2, 133.4, 147.7, 149.8 ppm. GC-MS: m/z (%) ϭ
214 (4) [Mϩ], 213 (15), 197 (100), 184 (20), 168 (31), 167 (25), 139
(40). IR (film): ν˜ ϭ 3050 cmϪ1, 2925, 1595, 1515, 1410, 1340, 850.
General Procedure for the Preparation of α-Substituted (Nitro-
benzyl)heterocycles: A solution of 1aϪf (1 mmol) and the nitroar-
ene (1.1 mmol) in DMSO (2 mL) was added dropwise, under N2,
to a vigorously stirred suspension of powdered tBuOK (3 mmol) in
DMSO (10 mL). The reaction was kept at room temperature for
1 h, quenched with saturated aqueous NH4Cl solution (10Ϫ20 mL)
and extracted with dichloromethane (3 ϫ 20 mL). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo. The
crude products were purified by column chromatography (silica gel;
petroleum ether/EtOAc, 1:1) to afford the α-substituted (nitro-
benzyl)heterocycles in yields of 12Ϫ86%.
2-(2-Nitrobenzyl)pyridine (3b): Yield: 56 mg (26%), oil. 1H NMR
(400.13 MHz, CDCl3): δ ϭ 4.48 (s, 2 H), 7.09Ϫ7.12 (m, 1 H), 7.15
(d, J ϭ 7.8 Hz, 1 H), 7.36Ϫ7.41 (m, 2 H), 7.50Ϫ7.60 (m, 2 H), 8.95
(d, J ϭ 8.1 Hz, 1 H), 8.49 (d, J ϭ 4.4 Hz, 1 H) ppm. 13C NMR
(100.62 MHz): δ ϭ 41.6, 121.9, 123.7, 125.2, 128.1, 133.4, 133.5,
134.5, 137.8, 149.7, 149.8, 159.0 ppm. GC-MS: m/z (%) ϭ 214 (83)
[Mϩ], 213 (100), 197 (8), 196 (10), 184 (18), 183 (23), 168 (70), 167
(93), 166 (72), 92 (7). IR (film): ν˜ ϭ 3050 cmϪ1, 2920, 1530, 1510,
1430, 1350, 1150, 1050.
4-(4-Nitrobenzyl)pyridine (2a): Yield: 80 mg (37%), oil. 1H NMR
(200 MHz, CDCl3): δ ϭ 4.08 (s, 2 H), 7.10 (d, J ϭ 5.9 Hz, 2 H),
7.34 (d, J ϭ 8.7 Hz, 2 H), 8.16 (d, J ϭ 8.7 Hz, 2 H), 8.53 (d, J ϭ
5.9 Hz, 2 H) ppm. 13C NMR (50.3 MHz): δ ϭ 40.8, 123.8, 124.0,
129.7, 146.3, 147.9, 149.8, 150.1 ppm. GC-MS: m/z (%) ϭ 214 (100)
[Mϩ], 197 (5), 184 (17), 168 (78), 139 (19). IR (film): ν˜ ϭ 3060 2-(2-Nitrobenzyl)benzothiazole (3c): Yield: 49 mg (18%), oil. 1H
cmϪ1, 2950, 1600, 1510, 1345, 860.
NMR, 13C NMR, GC-MS, IR are measured on the mixture with
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2c. H NMR (400.13 MHz, CDCl3): δ ϭ 4.80 (s, 2 H), 7.32Ϫ7.53
1
H), 5.29 (q, J ϭ 7.0 Hz, 1 H), 7.37 (t, J ϭ 8.1 Hz, 1 H), 7.46 (t,
(m, 4 H), 7.58 (t, J ϭ 7.8 Hz, 1 H), 7.79 (d, J ϭ 8.1 Hz, 1 H), 7.95 J ϭ 8.1 Hz, 1 H), 7.81Ϫ7.87 (m, 2 H), 7.96 (d, J ϭ 8.1 Hz, 1 H),
(d, J ϭ 8.1 Hz, 1 H), 8.05 (d, J ϭ 8.2 Hz, 1 H) ppm. 13C NMR
(100.62 MHz): δ ϭ 38.0, 121.9, 123.3, 125.4, 125.7, 126.4,0, 126.5,
8.35 (dd, J ϭ 2.1, 8.6 Hz, 1 H), 8.73 (d, J ϭ 2.1 Hz, 1 H) ppm. 13
NMR (100.62 MHz): δ ϭ 21.4, 39.2, 120.0, 121.5, 123.1, 125.4,
C
129.0, 132.5, 133.3, 134.1, 149.1, 153.5, 168.6 ppm. GC-MS: m/z 126.2, 127.1, 131.7, 134.9, 144.1, 147.7, 148.5, 152.9, 172.0 ppm.
(%) ϭ 270 (13) [Mϩ], 253 (100), 252 (55), 225 (70), 224 (70), 223 GC-MS: m/z (%) ϭ 330 (4) [Mϩ], 329 (20), 224 (98), 151 (100), 136
(74), 136 (62), 111 (87). IR (film): ν˜ ϭ 3050 cmϪ1, 2960, 1600, 1500,
(70), 135 (72), 123 (40), 77 (75). IR (film): ν˜ ϭ 3060 cmϪ1, 2980,
1350, 1100.
1600, 1520, 1340.
4-Methyl-2-(2-nitrobenzyl)thiazole (3d): Yield: 70 mg (30%), oil. 1H
NMR (400.13 MHz, CDCl3): δ ϭ 2.39 (s, 3 H), 4.64 (s, 2 H), 6.75
(s, 1 H), 7.41Ϫ7.48 (m, 2 H), 7.57 (t, J ϭ 7.6 Hz, 1 H), 8.0 (d, J ϭ
8.1 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 16.8, 36.4, 113.6,
124.9, 128.2, 132.5, 132.7, 133.4, 148.4, 152.3, 166.4 ppm. GC-MS:
m/z (%) ϭ 234 (1) [Mϩ], 217 (100), 187 (29), 100 (43), 89 (56), 71
(90). IR (film): ν˜ ϭ 3080 cmϪ1, 2950, 2850, 1605, 1520, 1350.
4-(2-Chloro-4-nitrobenzyl)pyridine (5a): Yield: 111 mg (45%), oil.
1H NMR (400.13 MHz, CDCl3): δ ϭ 4.20 (s, 2 H), 7.11 (d, J ϭ
4.0 Hz, 2 H), 7.39 (d, J ϭ 8.3 Hz, 1 H), 8.08 (d, J ϭ 8.3 Hz, 1 H),
8.27 (s, 1 H), 8.54 (d, J ϭ 4.0 Hz, 2 H) ppm. 13C NMR
(100.62 MHz): δ ϭ 38.4, 121.8, 123.6, 123.8, 124.6, 125.0, 131.4,
143.9, 146.4, 149.0 ppm. GC-MS: m/z (%) ϭ 248 (100) [Mϩ], 232
(5), 202 (15), 167 (98), 139 (32). IR (film): ν˜ ϭ 3040 cmϪ1, 2920,
1590, 1520, 1350, 1260, 735.
4-(2,4-Dinitrobenzyl)pyridine (4a): Yield: 52 mg (20%), oil. 1H
NMR (400.13 MHz, CDCl3): δ ϭ 4.40 (s, 2 H), 7.06 (d, J ϭ 5.4 Hz,
2 H), 7.53 (d, J ϭ 8.5 Hz, 1 H), 8.40 (dd, J ϭ 2.1, 8.5 Hz, 1 H),
8.51 (d, J ϭ 5.4 Hz, 2 H), 8.83 (d, J ϭ 2.1 Hz, 1 H) ppm. 13C
NMR (100.62 MHz): δ ϭ 37.9, 120.6, 123.9, 127.3, 133.8, 140.3,
145.9, 146.9, 149.0, 150.2 ppm. GC-MS: m/z (%) ϭ 259 (7) [Mϩ],
258 (14), 242 (100), 231 (10) 228 (8); 196 (70), 139 (55). IR (film):
ν˜ ϭ 3050 cmϪ1, 2925, 1595, 1515, 1410, 1340, 850.
1
2-(2-Chloro-4-nitrobenzyl)pyridine (5b): Yield: 87 mg (35%), oil. H
NMR (400.13 MHz, CDCl3): δ ϭ 4.36 (s, 2 H), 7.18Ϫ7.28 (m, 2
H), 7.46 (d, J ϭ 8.5 Hz, 1 H), 7.64 (t, J ϭ 7.7 Hz 1 H), 8.06 (d,
J ϭ 8.5 Hz, 1 H), 8.25 (s, 1 H), 8.55 (d, J ϭ 4.6 Hz, 1 H) ppm. 13
C
NMR (100.62 MHz): δ ϭ 42.2, 122.2, 122.3, 123.8, 125.0, 132.3,
135.5, 137.2, 145.2, 147.5, 150.2, 158.1 ppm. GC-MS: m/z (%) ϭ
248 (1) [Mϩ], 247 (3), 213 (100), 202 (3), 183 (29), 167 (82). IR
(film): ν˜ ϭ 3060 cmϪ1, 1600, 1510, 1340, 1110.
2-(2,4-Dinitrobenzyl)pyridine (4b): Yield: 98 mg (38%), oil. 1H
NMR (400.13 MHz, CDCl3): δ ϭ 4.60 (s, 2 H), 7.15Ϫ7.17 (m, 1
H), 7.28 (d, J ϭ 7.1 Hz, 1 H), 7.64Ϫ7.70 (m, 2 H), 8.37Ϫ8.46 (m,
2 H), 8.81 (s, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 41.5, 120.7,
122.5, 123.9, 127.3, 134.8, 137.3, 141.5, 147.1, 149.6, 150.0, 157.2
ppm. GC-MS: m/z (%) ϭ 259 (1) [Mϩ], 258 (8), 213 (100), 196 (29)
2-(2-Chloro-4-nitrobenzyl)benzothiazole (5c): Yield: 229 mg (75%),
1
oil. H NMR (400.13 MHz, CDCl3): δ ϭ 4.57 (s, 2 H), 7.29Ϫ7.33
(m, 1 H), 7.36Ϫ7.42 (m, 1 H), 7.51 (d, J ϭ 8.6 Hz, 1 H), 7.77 (d,
J ϭ 8.0 Hz, 1 H), 7.95 (d, J ϭ 8.2 Hz, 1 H), 8.00 (dd, J ϭ 2.2,
8.6 Hz, 1 H), 8.19 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR
(100.62 MHz): δ ϭ 37.1, 121.6, 122.1, 123.0, 123.6, 124.9, 126.1,
126.3, 130.6, 134.4, 135.4, 142.2, 152.9, 167.3 ppm. GC-MS: m/z
(%) ϭ 304 (5) [Mϩ], 269 (100), 239 (30), 223 (76) 136 (17). IR
(film): ν˜ ϭ 3040 cmϪ1, 2950, 1600, 1520, 1350, 1250
183 (33); 167 (85), 166 (71), 92 (24). IR (film): ν˜ ϭ 3060 cmϪ1
,
1600, 1510, 1340, 1110
2-(2,4-Dinitrobenzyl)benzothiazole (4c): Yield: 170 mg (54%), oil.
1H NMR (400.13 MHz, CDCl3): δ ϭ 4.90 (s, 2 H), 7.37 (t, J ϭ
7.9 Hz, 1 H), 7.45 (t, J ϭ 7.9 Hz, 1 H), 7.78 (d, J ϭ 8.4 Hz, 1 H),
7.84 (d, J ϭ 7.9 Hz, 1 H), 7.92 (d, J ϭ 7.9 Hz, 1 H), 8.43 (dd,
J ϭ 2.3, 8.4 Hz, 1 H), 8.93 (d, J ϭ 2.3 Hz, 1 H) ppm. 13C NMR
(100.62 MHz): δ ϭ 37.8, 121.2, 122.0, 123.5, 125.9, 126.7, 127.1,
127.9, 134.7, 135.7, 139.1, 147.7, 153.3, 166.1 ppm. GC-MS: m/z
(%) ϭ 315 (8) [Mϩ], 298 (100), 285 (20), 252 (62), 224 (28), 223
(30), 222 (27), 135 (30). IR (film): ν˜ ϭ 3060 cmϪ1, 2920, 1600,
1515, 1340.
2-(2-Chloro-4-nitrobenzyl)-4-methylthiazole (5d) and 2-(4-Chloro-2-
nitrobenzyl)-4-methylthiazole (6d): Inseparable mixture of isomers:
1
83:17. Overall yield: 171 mg (64%), oil. H NMR, 13C NMR, GC-
MS, IR were measured on the mixture of the isomers. 1H NMR
(200 MHz, CDCl3): δ ϭ 2.43 (d, J ϭ 0.8 Hz, 3 H), 4.50 (s, 2 H),
6.80 (q, J ϭ 0.8 Hz, 1 H), 7.52 (d, J ϭ 8.5 Hz, 1 H), 8.06 (dd,
J ϭ 2.2, 8.5 Hz, 1 H), 8.25 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR
(100.62 MHz): δ ϭ 16.8, 16.9, 35.8, 36.7, 113.7, 113.8, 121.8, 121.9,
124.6, 125.0, 131.4, 131.5, 133.4, 133.6, 134.8, 134.9, 142.9, 143.0,
152.9, 153.0, 164.9, 165.1 ppm. GC-MS: m/z (%) ϭ 268 (2) [Mϩ],
238 (5), 233 (100), 203 (72), 187 (56), 140 (13), 71 (43). IR (film):
ν˜ ϭ 3090 cmϪ1, 2920, 1520, 1345, 1120, 890, 730.
2-(2,4-Dinitrobenzyl)-4-methylthiazole (4d): Yield: 56 mg (20%), oil.
1H NMR (200 MHz, CDCl3): δ ϭ 2.39 (s, 3 H), 4.76 (s, 2 H), 6.82
(s, 1 H), 7.73 (d, J ϭ 8.5 Hz, 1 H), 8.42 (dd, J ϭ 2.3, 8.5 Hz, 1 H),
8.87 (d, J ϭ 2.3 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 17.4,
36.7, 114.6, 121.0, 127.8, 134.4, 140.0, 147.5, 153.4, 155.5, 164.3
ppm. GC-MS: m/z (%) ϭ 279 (2) [Mϩ], 262 (100), 216 (90), 187
(43), 186 (40), 115 (66), 71 (90). IR (film): ν˜ ϭ 3100 cmϪ1, 2920,
2850, 1670, 1600, 1420, 1350, 830.
2-(4-Chloro-2-nitrobenzyl)pyridine (6b): Yield: 15 mg (6%), oil. 1H
NMR, 13C NMR, GC-MS, IR were measured on the mixture with
1
5b. H NMR (400.13 MHz, CDCl3): δ ϭ 4.45 (s, 2 H), 7.18Ϫ7.28
(m, 2 H), 7.39 (d, J ϭ 8.3 Hz, 1 H), 7.52 (d, J ϭ 8.3 1 H), 7.55 (t,
2-[1-(2,4-Dinitrophenyl)ethyl]-4-methylthiazole (4e): Yield: 35 mg
(12%), oil. 1H NMR (400.13 MHz, CDCl3): δ ϭ 1.87 (d, J ϭ
7.1 Hz, 3 H), 2.41 (s, 3 H), 5.17 (q, J ϭ 7.1 Hz, 1 H), 6.83 (s, 1 H),
7.77 (d, J ϭ 8.7 Hz, 1 H), 8.37 (dd, J ϭ 2.2, 8.7 Hz, 1 H), 8.73 (d,
J ϭ 2.2 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 17.1, 21.8,
38.4, 113.6, 119.1, 127.1, 128.9, 130.7, 131.7, 145.1, 153.2, 170.0
ppm. GC-MS: m/z (%) ϭ 293 (3) [Mϩ], 276 (17), 262 (25), 245 (32),
234 (56), 230 (30), 200 (44), 188 (58), 71 (100). IR (film): ν˜ ϭ 3100
cmϪ1, 2920, 2850, 1600, 1430, 1350, 900, 710.
J ϭ 7.7 Hz, 1 H), 7.96 (s, 1 H). 8.48 (d, J ϭ 4.5 Hz, 1 H) ppm. 13
C
NMR (100.62 MHz): δ ϭ 41.1, 122.1, 123.7, 125.6, 128.8, 133.5,
134.6, 137.0, 147.7, 149.9, 153.0, 158.4 ppm. GC-MS: m/z (%) ϭ
248 (1) [Mϩ], 247 (2), 202 (85), 183 (11), 167 (100). IR (film): ν˜ ϭ
3060 cmϪ1, 1600, 1510, 1340, 1110.
2-(4-Chloro-2-nitrobenzyl)-4-methylthiazole
(6d):
1H
NMR
(200 MHz, CDCl3): δ ϭ 2.39 (d, J ϭ 0.8 Hz, 3 H), 4.60 (s, 2 H),
6.76 (q, J ϭ 0.8 Hz, 1 H), 7.40Ϫ7.55 (m, 2 H), 7.99 (d, J ϭ 2.1 Hz,
1 H) ppm. GC-MS: m/z (%) ϭ 268 (1) [Mϩ], 251 (100), 238 (60),
2-[1-(2,4-Dinitrophenyl)ethyl]benzothiazole (4f): Yield: 83 mg (25%),
oil. 1H NMR (400.13 MHz, CDCl3): δ ϭ 1.96 (d, J ϭ 7.0 Hz, 3 164 (40), 71 (65). 13C NMR and IR see 5d.
2122
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2118Ϫ2124

Vicarious Nucleophilic Substitution of (Chloroalkyl)heterocycles with Nitroarenes
FULL PAPER
2-(2-Chloro-6-nitrobenzyl)-4-methylthiazole (7d): Yield: 14 mg (5%),
4-(3-Chloro-4-nitrobenzyl)pyridine (10a): Yield: 99 mg (40%), oil.
1
oil. H NMR (200 MHz, CDCl3): δ ϭ 2.39 (d, J ϭ 0.8 Hz, 3 H), 1H NMR (400.13 MHz, CDCl3): δ ϭ 4.04 (s, 2 H), 7.11 (d, J ϭ
4.77 (s, 2 H), 6.72 (q, J ϭ 0.8 Hz, 1 H), 7.42 (t, J ϭ 8.2 Hz, 1 H),
5.0 Hz, 2 H), 7.22 (d, J ϭ 8.3 Hz, 1 H), 7.37 (s, 1 H), 7.85 (d, J ϭ
7.69 (dd, J ϭ 1.2, 8.2 Hz, 1 H), 7.86 (dd, J ϭ 1.2, 8.2 Hz, 1 H) 8.3 Hz, 1 H), 8.56 (d, J ϭ 5.0 Hz, 2 H) ppm. 13C NMR
ppm. 13C NMR (50.3 MHz): δ ϭ 17.0, 33.4, 113.2, 123.5, 128.8, (100.62 MHz): δ ϭ 40.2, 123.9, 125.9, 127.3, 127.9, 132.0, 145.2,
131.1, 134.2, 147.0, 152.5, 165.2 ppm. GC-MS: m/z (%) ϭ 268 (1) 147.1, 150.0, 167.5 ppm. GC-MS: m/z (%) ϭ 248 (100) [Mϩ], 232
[Mϩ], 251 (100), 238 (35), 164 (30), 71 (50). IR (film): ν˜ ϭ 3040
(5), 218 (30) 202 (12), 183 (21), 167 (72), 139 (45). IR (film): ν˜ ϭ
cmϪ1, 2905, 1520, 1250, 730.
3050 cmϪ1, 2920, 1585, 1515, 1350, 1040, 740.
4-(3,4-Dinitrobenzyl)pyridine (8a): Yield: 88 mg (34%), oil. 1H
NMR (400.13 MHz, CDCl3): δ ϭ 4.20 (s, 2 H), 7.22 (d, J ϭ 5.6 Hz,
2 H), 7.70 (d, J ϭ 7.5 Hz, 1 H), 7.93 (s, 1 H), 8.02 (d, J ϭ 7.5 Hz,
1 H), 8.55 (d, J ϭ 5.6 Hz, 2 H) ppm. 13C NMR (100.62 MHz): δ ϭ
39.5, 122.9, 124.2, 124.5, 129.8, 132.8, 145.7, 145.8, 148.8, 149.8
ppm. GC-MS: m/z (%) ϭ 259 (100) [Mϩ], 229 (2), 211 (11), 168
(15), 167 (20), 154 (25), 139 (18). IR (film): ν˜ ϭ 3050 cmϪ1, 2925,
1595, 1515, 1410, 1340, 850.
2-(3-Chloro-4-nitrobenzyl)pyridine (10b): Yield: 99 mg (40%), oil.
1H NMR (200 MHz, CDCl3): δ ϭ 4.16 (s, 2 H), 7.13Ϫ7.26 (m, 2
H), 7.28 (d, J ϭ 8.3 Hz, 1 H), 7.43 (s, 1 H), 7.63 (dd, J ϭ 7.6,
7.8 Hz, 1 H), 7.80 (d, J ϭ 8.3 Hz, 1 H), 8.55 (d, J ϭ 4.4 Hz, 1 H)
ppm. 13C NMR (50.3 MHz): δ ϭ 43.7, 121.9, 123.2, 125.8, 127.2,
128.2, 132.2, 136.9, 146.1, 149.8, 153.0, 158.0 ppm. GC-MS: m/z
(%) ϭ 248 (31) [Mϩ], 247 (100), 218 (41) 202 (11), 201 (47), 167
(48). IR (film): ν˜ ϭ 3060 cmϪ1, 2920, 1590, 1520, 1350, 1050.
2-(3-Chloro-4-nitrobenzyl)benzothiazole (10c): Yield: 85 mg (28%),
oil. H NMR (400.13 MHz, CDCl3): δ ϭ 4.45 (s, 2 H), 7.35Ϫ7.56
2-(3,4-Dinitrobenzyl)pyridine (8b) and 2-(2,3-Dinitrobenzyl)pyridine
(9b): Inseparable mixture of isomers: 93:7. Overall yield: 176 mg
(68%). 1H NMR, 13C NMR, GC-MS, IR were measured on the
1
(m, 4 H), 7.81Ϫ7.86 (m, 2 H), 7.99 (d, J ϭ 8.0 Hz, 1 H) ppm. 13C
NMR (100.62 MHz): δ ϭ 39.4, 121.6, 123.0, 125.4, 126.0, 126.2,
126.3, 128.2, 129.7, 132.3, 135.4, 143.3, 153.2, 167.1 ppm. GC-MS:
m/z (%) ϭ 304 (4) [Mϩ], 287 (100), 274 (20), 224 (23), 223 (40),
136 (24), 111 (20). IR (film): ν˜ ϭ 3050 cmϪ1, 2905, 1590, 1525,
1350, 730.
1
mixture of the isomers. H NMR (400.13 MHz, CDCl3): δ ϭ 4.30
(s, 2 H), 7.22 (t, J ϭ 5.7 Hz 1 H), 7.28 (d, J ϭ 7.6 Hz, 1 H),
7.68Ϫ7.63 (m, 2 H), 7.86 (s, 1 H), 7.92 (d, J ϭ 8.3 Hz, 1 H). 8.55
(d, J ϭ 4.6 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 43.7, 43.8,
122.5, 123.1, 123.8, 124.2, 124.9, 125.5, 125.6, 125.7, 126.1, 129.1,
137.7, 134.1, 134.5, 137.5, 137.8, 137.9, 147.6, 149.1, 149.9, 150.1,
157.7, 157.8 ppm. GC-MS: m/z (%) ϭ 259 (27) [Mϩ], 258 (100),
242 (30), 212 (25), 166 (86). IR (film): ν˜ ϭ 3050 cmϪ1, 2930, 1600,
1450, 1350, 1020.
2-(3-Chloro-4-nitrobenzyl)-4-methylthiazole (10d): Yield: 94 mg
1
(35%), oil. H NMR (200 MHz, CDCl3): δ ϭ 2.44 (s, 3 H), 4.34 (s,
2 H), 6.81 (s, 1 H), 7.35 (dd, J ϭ 1.6, 8.5 Hz, 1 H), 7.50 (d, J ϭ
1.6 Hz, 1 H), 7.85 (d, J ϭ 8.5 Hz, 1 H) ppm. 13C NMR (50.3 MHz):
δ ϭ 16.9, 38.5, 113.9, 125.9, 127.9, 129.4, 131.0, 132.1, 144.1, 153.1,
165.2 ppm. GC-MS: m/z (%) ϭ 268 (100) [Mϩ], 238 (72), 203 (34),
187 (61), 140 (34), 71 (99). IR (film): ν˜ ϭ 3100 cmϪ1, 2910, 1580,
1520, 1340, 730.
2-(3,4-Dinitrobenzyl)-4-methylthiazole (8d): Yield: 70 mg (25%),
oil.1H NMR (400.13 MHz, CDCl3): δ ϭ 2.44 (s, 3 H), 4.44 (s, 2
H), 6.84 (s, 1 H), 7.70 (d, J ϭ 8.2 Hz, 1 H), 7.76 (s, 1 H), 7.91 (d,
J ϭ 8.2 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 16.9, 38.4,
114.2, 125.2, 125.4, 131.0, 133.4, 136.9, 145.0, 153.5, 164.3 ppm.
GC-MS: m/z (%) ϭ 279 (42) [Mϩ], 262 (12), 232 (21), 186 (30), 71
(100). IR (film): ν˜ ϭ 3100 cmϪ1, 2960, 2850, 1540, 1380, 1350,
1100.
2-[1-(3-Chloro-4-nitrophenyl)ethyl]-4-methylthiazole (10e): Yield:
1
85 mg (30%), oil. H NMR (200 MHz, CDCl3): δ ϭ 1.78 (d, J ϭ
7.2 Hz, 3 H), 2.43 (s, 3 H), 4.49 (q, J ϭ 7.2 Hz, 1 H), 6.80 (s, 1 H),
7.35 (dd, J ϭ 1.5, 8.3 Hz, 1 H), 7.51 (d, J ϭ 1.5 Hz, 1 H), 7.84 (d,
J ϭ 7.3 Hz, 1 H) ppm. 13C NMR (50.3 MHz): δ ϭ 17.1, 21.5, 43.3,
113.3, 125.9, 126.7, 127.1, 128.0, 130.9, 150.0, 153.0, 171.5 ppm.
GC-MS: m/z (%) ϭ 282 (93) [Mϩ], 260 (62), 252 (35), 237 (39), 201
(44), 126 (44), 113 (45), 71 (100). IR (film): ν˜ ϭ 3050 cmϪ1, 2920,
1580, 1520, 1340, 1260, 730.
2-[1-(3,4-Dinitrophenyl)ethyl]-4-methylthiazole (8e): Yield: 111 mg
(38%), oil. 1H NMR (400.13 MHz, CDCl3): δ ϭ 1.82 (d, J ϭ
7.2 Hz, 3 H), 2.40 (s, 3 H), 4.62 (q, J ϭ 7.2 Hz, 1 H), 6.83 (s, 1 H),
7.70Ϫ7.90 (m, 3 H) ppm. 13C NMR (50.3 MHz): δ ϭ 17.0, 21.6,
43.2, 113.5, 124.1, 125.1, 125.4, 132.3, 133.5, 150.9, 153.3, 170.4
ppm. GC-MS: m/z (%) ϭ 293 (100) [Mϩ], 292 (43), 276 (69), 246
2-[1-(3-Chloro-4-nitrophenyl)ethyl]benzothiazole
(10f):
Yield:
203 mg (64%), oil. 1H NMR (400.13 MHz, CDCl3): δ ϭ 1.87 (d,
J ϭ 7.2 Hz, 3 H), 4.63 (q, J ϭ 7.2 Hz, 1 H), 7.37 (t, J ϭ 7.5 Hz, 1
H), 7.43 (dd, J ϭ 1.8, 8.7 Hz, 1 H), 7.47 (t, J ϭ 7.5 Hz, 1 H), 7.57
(d, J ϭ 1.8 Hz, 1 H), 7.83 (d, J ϭ 8.7 Hz, 1 H), 7.85 (d, J ϭ 7.5 Hz,
1 H), 8.00 (d, J ϭ 7.5 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ
21.1, 44.1, 121.6, 123.1, 125.3, 126.0, 126.3, 126.9, 127.5, 131.0,
134.9, 142.1, 149.2, 153.1, 172.7 ppm. GC-MS: m/z (%) ϭ 318 (100)
[Mϩ], 283 (30), 257 (28), 236 (33), 162 (48), 136 (12), 135 (13). IR
(film): ν˜ ϭ 3060 cmϪ1, 2970, 1590, 1510, 1340, 1110.
(78), 200 (90), 186 (74), 126 (72), 71 (93). IR (film): ν˜ ϭ 3090 cmϪ1
,
2960, 2910, 1540, 1350, 840, 730.
2-(2,3-Dinitrobenzyl)pyridine (9b): 1H NMR (400.13 MHz, CDCl3):
δ ϭ 4.20 (s, 2 H), 7.36 (d, J ϭ 7.8 Hz, 1 H), 7.49Ϫ7.53 (m, 1 H),
7.60Ϫ7.68 (m, 2 H), 7.90 (d, J ϭ 8.3 Hz, 1 H), 7.96 (d, J ϭ 6.9 Hz,
1 H), 8.60 (d, J ϭ 4.4 Hz, 1 H) ppm. GC-MS: m/z (%) ϭ 259 (1)
[Mϩ], 242 (3), 224 (5), 212 (65), 166 (100), 139 (35). 13C NMR and
IR see 8b.
2-(2-Chloro-6-nitrobenzyl)-4-methylthiazole (11d): Yield: 27 mg
1
2-(2,3-Dinitrobenzyl)benzothiazole (9c): Yield: 95 mg (30%), oil. H
1
(10%), oil. H NMR (200 MHz, CDCl3): δ ϭ 2.42 (s, 3 H), 4.28 (s,
NMR (400.13 MHz, CDCl3): δ ϭ 4.81 (s, 2 H), 7.35 (t, J ϭ 7.6 Hz,
1 H), 7.42Ϫ7.58 (m, 2 H), 7.60 (t, J ϭ 7.6 Hz, 1 H), 7.80 (d, J ϭ
8.0 Hz, 1 H), 7.96 (d, J ϭ 8.1 Hz, 1 H), 8.24 (d, J ϭ 7.4 Hz, 1 H)
ppm. 13C NMR (100.62 MHz): δ ϭ 37.6, 121.5, 122.8, 125.1, 125.3,
126.1, 128.6, 132.0, 132.9, 133.7, 135.4, 140.2, 152.9, 168.3 ppm.
GC-MS: m/z (%) ϭ 315 (1) [Mϩ], 253 (100), 225 (35), 224 (29),
2 H), 6.80 (s, 1 H), 7.35Ϫ7.58 (m, 3 H) ppm. 13C NMR
(50.3 MHz): δ ϭ 16.9, 34.6, 114.2, 125.1, 128.3, 129.5, 131.0, 133.5,
145.0, 153.1, 165.0 ppm. GC-MS: m/z (%) ϭ 268 (1) [Mϩ], 251
(85), 187 (22), 100 (33), 90 (39), 71 (100). IR (film): ν˜ ϭ 3050 cmϪ1
,
2910, 1600, 1520, 1350, 1260, 730.
223 (36), 111 (17). IR (film): ν˜ ϭ 3050 cmϪ1, 2960, 1600, 1510, 2-[Chloro-(4-nitrophenyl)methyl]pyridine (12b): Yield: 151 mg
1340, 1100.
(61%), oil. 1H NMR (400.13 MHz, CDCl3): δ ϭ 6.22 (s, 1 H), 7.25
Eur. J. Org. Chem. 2004, 2118Ϫ2124
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2123

S. Florio, P. Lorusso, R. Luisi, C. Granito, L. Ronzini, L. Troisi
FULL PAPER
(dd, J ϭ 4.8, 7.4 Hz 1 H), 7.58 (d, J ϭ 7.9 Hz, 1 H), 7.67 (d, J ϭ 2-(5-Methoxy-2-nitrobenzyl)benzothiazole (14c): Yield: 105 mg
1
8.8 Hz, 2 H), 7.73Ϫ7.77 (m, 1 H), 8.18 (d, J ϭ 8.8 Hz, 2 H), 8.57 (35%), oil. H NMR (400.13 MHz, CDCl3): δ ϭ 3.87 (s, 3 H), 4.83
(d, J ϭ 4.8 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 62.7, (s, 2 H), 6.91 (dd, J ϭ 2.7, 9.1 Hz, 1 H), 6.98 (d, J ϭ 2.7 1 H),
121.9, 123.2, 123.6, 128.7, 137.3, 146.7, 147.8, 149.3, 158.0 ppm.
GC-MS: m/z (%) ϭ 248 (3) [Mϩ], 213 (99), 167 (100), 166 (30), 139
(13). IR (film): ν˜ ϭ 3050 cmϪ1, 2960, 1530, 1510, 1345, 1100.
7.32Ϫ7.36 (m, 1 H), 7.42Ϫ7.46 (m, 1 H), 7.80 (d, J ϭ 7.8 Hz, 1
H), 7.96 (d, J ϭ 8.2 Hz, 1 H), 8.18 (d, J ϭ 9.1 Hz, 1 H) ppm. 13C
NMR (100.62 MHz): δ ϭ 38.4, 55.9, 113.3, 117.9, 121.6, 122.8,
125.0, 126.0, 128.2, 135.1, 135.5, 153.0, 163.5, 168.3 ppm. GC-MS:
m/z (%) ϭ 300 (1) [Mϩ], 283 (68), 270 (17), 267 (28), 254 (100), 240
2-[Chloro-(4-nitrophenyl)methyl]benzothiazole (12c): Yield: 34 mg
1
(40), 210 (53), 136 (40), 106 (39), 77 (28). IR (film): ν˜ ϭ 3020 cmϪ1
,
(11%), oil. H NMR (400.13 MHz, CDCl3): δ ϭ 6.46 (s, 1 H), 7.44
(t, J ϭ 8.1 Hz, 1 H), 7.50 (t, J ϭ 8.0 Hz, 1 H), 7.76 (d, J ϭ 8.7 Hz,
2 H), 7.88 (d, J ϭ 8.0 Hz, 1 H), 7.99 (d, J ϭ 8.1 Hz, 1 H), 8.24 (d,
J ϭ 8.7 Hz, 2 H) ppm. 13C NMR (100.62 MHz): δ ϭ 59.6, 122.2,
124.2, 124.5, 126.5, 127.1, 129.4, 136.0, 145.4, 148.5, 153.3, 169.6
ppm. GC-MS: m/z (%) ϭ 304 (20) [Mϩ], 269 (85), 240 (44), 223
(100), 207 (35), 106 (30). IR (film): ν˜ ϭ 3050 cmϪ1, 2920, 1600,
1515, 1350, 730.
2940, 1610, 1510, 1350, 1100.
Acknowledgments
This work was carried out under the framework of the National
Project ‘‘Stereoselezione in Sintesi Organica. Metodologie ed Ap-
plicazioni’’ supported by the Ministero dell’Istruzione, dell’Univer-
`
sita e della Ricerca (MIUR, Rome) and by the University of Bari
4-(5-Chloro-2-nitrobenzyl)pyridine (13a): Yield: 213 mg (86%), oil.
1H NMR (400.13 MHz, CDCl3): δ ϭ 4.30 (s, 2 H), 7.08 (d, J ϭ
5.4 Hz, 2 H), 7.31 (d, J ϭ 2.0 Hz, 1 H), 7.43 (dd, J ϭ 2.0, 8.7 Hz,
1 H), 7.98 (d, J ϭ 8.7 Hz, 1 H), 8.51 (d, J ϭ 5.4 Hz, 2 H) ppm.
13C NMR (100.62 MHz): δ ϭ 37.8, 123.7, 126.6, 128.2, 132.4,
135.5, 139.6, 146.8, 147.1, 149.8 ppm. GC-MS: m/z (%) ϭ 248 (10)
[Mϩ], 247 (11), 231 (100), 218 (23), 196 (79), 168 (42), 167 (38), 139
(60). IR (film): ν˜ ϭ 3060 cmϪ1, 2920, 1595, 1515, 1340, 900, 830.
and University of Lecce and CNR (Rome).
[1]
F. Terrier, Nucleophilic Aromatic Displacement: The Influence
of the Nitro Group, VCH Publishers, Inc., New York, 1991.
O. N. Chupakhin, V. N. Charushin, H. C. Van der Plas, Nucleo-
[2]
philic Aromatic Substitution of Hydrogen, Academic Press, New
York, San Diego, 1994, p. 246.
[3]
M. Makosza, Russ. Chem. Bull. 1996, 531Ϫ542.
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M. Makosza, J. Winiarski, Acc. Chem. Res. 1987, 20, 282Ϫ289.
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M. Makosza, K. Wojciechowski, Liebig Ann. Chem. 1997,
2-(5-Chloro-2-nitrobenzyl)pyridine (13b): Yield: 131 mg (53%), oil.
1H NMR (200 MHz, CDCl3): δ ϭ 4.46 (s, 2 H), 7.08Ϫ7.21 (m, 2
H), 7.33 (dd, J ϭ 2.0, 8.7 Hz, 1 H), 7.40 (d, J ϭ 2.0 Hz, 1 H), 7.60
(dd, J ϭ 7.5, 7.7 Hz, 1 H), 7.92 (d, J ϭ 8.7 Hz, 1 H). 8.48 (d, J ϭ
4.0 Hz, 1 H) ppm. 13C NMR (100.62 MHz): δ ϭ 40.8, 121.6, 123.1,
123.4, 126.1, 127.6, 132.6, 136.0, 136.5, 139.1, 147.3, 149.3, 157.5
ppm. GC-MS: m/z (%) ϭ 248 (1) [Mϩ], 218 (10), 202 (88), 167 (100)
78 (22). IR (film): ν˜ ϭ 3060 cmϪ1, 2920, 1600, 1550, 1350, 1030.
1805.
[6]
D. N. Kozhevnikov, V. L. Rusinov, O. N. Chupakhin, M.
Makosza, A. Rykowski, E. Wolinska, Eur. J. Org. Chem.
2002, 1412Ϫ1416.
S. Florio, P. Lorusso, C. Granito, L. Ronzini, L. Troisi, Eur. J.
[7]
Org. Chem. 2003, 4053Ϫ4058.
M. Makosza, T. Lemek, A. Kwast, F. Terrier, J. Org. Chem.
[8]
2002, 67, 394Ϫ400.
T. Lemek, M. Makosza, D. S. Stephenson, H. Mayr, Angew.
[9]
Chem. Int. Ed. 2003, 42, 793Ϫ2795.
2-(5-Chloro-2-nitrobenzyl)benzothiazole (13c): Yield: 213 mg (70%),
oil. 1H NMR (400.13 MHz, CDCl3): δ ϭ 4.75 (s, 2 H), 7.32 (t, J ϭ
7.9 Hz, 1 H), 7.39 (dd, J ϭ 2.0, 8.8 Hz, 1 H), 7.42 (t, J ϭ 7.9 Hz,
1 H), 7.50 (d, J ϭ 2.0 Hz, 1 H), 7.78 (d, J ϭ 7.9 Hz, 1 H), 7.93
(d, J ϭ 7.9 Hz, 1 H), 8.01 (d, J ϭ 8.8 Hz, 1 H) ppm. 13C NMR
(100.62 MHz): δ ϭ 37.3, 121.4, 122.8, 125.1, 126.0, 126.6, 128.6,
132.6, 133.9, 135.3, 139.9, 146.7, 152.8, 166.9 ppm. GC-MS: m/z
(%) ϭ 304 (1) [Mϩ], 287 (100), 274 (15), 259 (19), 239 (8), 223 (25),
136 (20). IR (film): ν˜ ϭ 3030 cmϪ1, 2950, 1600, 1510, 1340.
[10] [10a] M. Makosza, T. Lemek, A. Kwast, F. Terrier, J. Org. Chem.
[10b]
2002, 67, 394Ϫ400.
N. J. Liddle, L. Lawrence, S. M.
Bushell, D. A. Jackson, J. Org. Chem. 2002, 67, 457Ϫ464.
[11] [11a]
M. Makosza, T. Ziobrowski, M. Serebriakov, A. Kwast,
[11b]
Tetrahedron 1997, 53, 4739Ϫ4750.
Shevelev, I. I. Chervin, A. R. Mitchell, R. D. Schmidt, J. Org.
Chem. 2003, 68, 2498Ϫ2501.
V. V. Rozhkov, S. A.
[12]
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F. Terrier, Chem. Rev. 1982, 82, 77.
M. Prato, U. Quintily, L. Scapol, G. Scorrano, Bull. Soc. Chim.
Fr. 1987, 99.
H. Chikashita, S. Ikegami, T. Okumura, K. Itoh, Synthesis
1986, 5, 375Ϫ377.
V. M. Zubarovskii, Zhur. Obsch. Khim. 1954, 24, 1664Ϫ1674.
M. Altamura, E. Perrotta, J. Org. Chem. 1993, 58, 272Ϫ274.
S. Florio, C. Granito, G. Ingrosso, L. Troisi, Eur. J. Org. Chem.
2000, 3465Ϫ3472 and refs. therein.
[14]
2-(5-Chloro-2-nitrobenzyl)-4-methylthiazole (13d): Yield: 110 mg
1
(41%), oil. H NMR (200 MHz, CDCl3): δ ϭ 2.30 (s, 3 H), 4.53 (s,
[15]
[16]
[17]
2 H), 6.68 (s, 1 H), 7.28 (dd, J ϭ 2.0, 8.6 Hz, 1 H), 7.35 (d, J ϭ
2.0 Hz, 1 H), 7.90 (d, J ϭ 8.6 Hz, 1 H) ppm. 13C NMR (50.3 MHz):
δ ϭ 16.8, 36.2, 113.8, 126.5, 128.3, 132.3, 134.7, 139.7, 152.6, 165.1
ppm. GC-MS: m/z (%) ϭ 268 (1) [Mϩ], 251 (100), 250 (25), 223
(14), 100 (25), 90 (19), 71 (60). IR (film): ν˜ ϭ 3100 cmϪ1, 2950,
2850, 1600, 1570, 1515, 1340, 1090.
[18]
F. Bona, L. De Vitis, S. Florio, L. Ronzini, L. Troisi, Tetra-
hedron 2003, 59, 1381Ϫ1387 and refs. therein.
Received December 22, 2003
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2118Ϫ2124