Nucleophilic substitution of benzotriazolylalkyl chlorides with Grignard reagents: A direct route to benzotriazoloalkyl(hetero)aromatic compounds

Article abstract of DOI:10.1055/s-1999-3662

Benzotriazolylalkyl chlorides 5 react with (hetero)aromatic Grignard reagents generated from the corresponding halogen derivatives to afford benzotriazoloalkyl(hetero)aromatic compounds 8a-k and 10a-c in good yields.

Full text of DOI:10.1055/s-1999-3662

PAPER
1437
Nucleophilic Substitution of Benzotriazolylalkyl Chlorides with Grignard
Reagents: A Direct Route to Benzotriazoloalkyl(hetero)aromatic Compounds
Alan R. Katritzky,* Ashraf A. A. Abdel-Fattah, Dmytro O. Tymoshenko, Sergei A. Belyakov
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611–7200, USA
Fax +1(352)3929199; E-mail: KATRITZKY@chem.ufl.edu
Received 21 April 1999; revised 14 May 1999
via normal nucleophilic substitution as previously demon-
Abstract: Benzotriazolylalkyl chlorides 5 react with (hetero)aro-
strated for many nucleophiles.13
matic Grignard reagents generated from the corresponding halogen
derivatives to afford benzotriazoloalkyl(hetero)aromatic com-
pounds 8a–k and 10a–c in good yields.
N-(a-Haloalkyl)benzotriazoles 5 were readily obtained
according to the procedure reported earlier.1 We find that
Key words: benzotriazolylalkyl chlorides, Grignard reagents, syn- the nature of the metal in the organometallic reagent de-
thesis, benzotriazoloalkyl(hetero)aromatics
termines the course of the reaction. Thus, N-chlorometh-
ylbenzotriazole with the strongly basic lithio-thiophene
and -benzo[b]thiophene gave deep blue reaction mixtures
(characteristic of a-benzotriazolyl anions) and formed
complex product mixtures (perhaps via carbene species)
with no detectible benzotriazoloalkyl(hetero)aromatics.
The simultaneous activation of a-CH in 8,10 by both the
benzotriazole ring and the (hetero)aromatic ring will facil-
itate deprotonation, as illustrated by syntheses of triaryl-
cyclopropanes,14 diarylacetylenes,15 alkenes and dienes16
and substituted heteroaromatics,17 recently elaborated by
our group. The less reactive analogous organozinc, orga-
nocerium and silyl derivatives of benzo[b]thiophene
caused neither deprotonation nor any other reaction.
Many synthetically useful N-substituted benzotriazoles
are of type Bt-C-X, where X is halogen,1,2 amino-nitro-
gen,3,4 amido-nitrogen,5 oxygen6 or sulfur.7 Such adducts
can react further either by Bt–C bond scission to form
alkyleneonium cations or by C–X bond scission to give
alkylenebenzotriazolium intermediates 3 (Scheme 1).
Species 3 are normally generated from a-haloalkylbenzo-
triazoles (cf. 1)8 in the presence of Lewis acids or alterna-
tively from N-(a-hydroxyalkyl)benzotriazoles (cf. 2)9
with Brønsted acids. However, these methods for the gen-
eration of the benzotriazolyl-stabilized cation 3 have
some limitations. Even with electron-rich (hetero)aromat-
ic systems9,10 some product 4 yields were moderate. Acid-
However, the reactions of N-(a-haloalkyl)benzotriazoles
5 with Grignard reagents (Scheme 2), freshly prepared
from the corresponding aryl halide and Mg turnings, in
anhydrous THF led to the desired benzotriazoloalkyl aro-
matic compounds 8a–k in good yields. Significantly, this
methodology could be extended to the benzotriaz-
oloalkyl(hetero)aromatics 8a–d, k derived from alde-
hydes other than formaldehyde. In particular, this
sequence allowed the syntheses of benzotriazole-substi-
tuted compounds 8a–d (R1 = Me) and 8k (R1 = Et), de-
ic
catalysts
can
dehydrohalogenate
N-(a-
haloalkyl)benzotriazoles derived from aldehydes contain-
ing an a-hydrogen.11 The much greater leaving ability of
chloride, as compared to the benzotriazolyl anion,12 sug-
gested that reactions of N-(a-haloalkyl)benzotriazoles
with organometallic carbanionic species (Scheme 2)
should lead to benzotriazolyl-C-(hetero)aromatics 8,10
N
Lewis acid
N
N
Cl
N
N
N
N
N
N
1
Ar-H (Het-H)
N
N
N
CH2
CH2
Ar(Het)
H+/ -H2O
4
3
N
N
N
OH
2
Scheme 1
Synthesis 1999, No. SI, 1437–1440 ISSN 0039-7881 © Thieme Stuttgart · New York

1438
A. R. Katritzky et al.
PAPER
R3
R2
N
R4
MgHal
N
N
N
N
N
N
N
N
Cl
R4
7
R1
Cl
R1
R1
R2
R3
5
8
6
R1
R2
R3
R4
8
Het-MgBr
a
b
c
d
e
f
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
9
Me
H
MeO
N
-CH=CH-CH=CH-
N
N
H
H
H
Me
H
H
Het
g
h
i
R1
H
MeO
H
H
H
Me
10a, R1 = H; Het = thiophene-2-yl
10b, R1 = Me; Het = thiophene-2-yl
10c, R1 = H; Het = benzo-1,3-
thiazol-2-yl
H
H
H
N(Me)2
H
j
H
-OCH2O-
k
Et
H
Me
H
Scheme 2
rived from aldehydes other then formaldehyde, and acid In conclusion, we have described a general method for the
sensitive 8j, which are difficult to obtain using the meth- synthesis of compounds of types 8 and 10 which are valu-
ods described earlier.8,9 Our attempted reaction of 1-(1- able intermediates for benzannulation reactions19 and for
chloro-2-methylpropyl)-1H-1,2,3-benzotriazole
(5, the introduction of complex C-linked substituents into ar-
R1 = i-Pr) with phenyl and o-tolylmagnesium bromide af- omatic and heteroaromatic ring systems.13
forded 1-(2-methylprop-1-enyl)-1H-1,2,3-benzotriazole
in 60% and 63% yields, respectively, because of the com-
Mps were measured with a Kofler hot stage apparatus without cor-
peting dehydrochlorination reaction, which was already
reported for N-(a-haloalkyl)benzotriazoles derived from
aldehydes containing an a-hydrogen.11 Although 1-(1-
1
rection. The H NMR and 13C NMR spectra were recorded on a
Varian Gemini (300 MHz) spectrometer in CDCl3 with TMS as the
internal standard. Elemental analyses were performed using a Carlo
Erba 1106 elemental analyzer.
chloro-2,2-dimethylpropyl)-1H-1,2,3-benzotriazole
5
(R1 = t-Bu) was stable to dehydrochlorination, the nucleo-
philic substitution with phenyl, o-tolyl and methylmagne-
sium bromide did not occur, perhaps because of steric
hindrance of the electrophile.
1-Aryl(heteryl)alkylbenzotriazoles 8a–k and 10a,b; General
Procedure
To a solution of arylmagnesium bromide 7 for 8a–k (4 mmol), or 2-
thienylmagnesium bromide (9) for 10a,b, in Et2O (50 mL) (freshly
prepared from aryl bromide or 2-thienyl bromide and Mg turnings)
was added dropwise a solution of 1-chloroalkylbenzotriazole (4
mmol) in THF under N2. The solution was heated under reflux for 3
h. The mixture was cooled to r.t. and poured into ice/H2O (100 mL).
HOAc (5 mL) was added, and the whole was extracted with Et2O
(2 x 50 mL). The combined organic phases were washed with 20%
aq NaHCO3 (2 x 40 mL) and then H2O, until the aqueous layer re-
mained at pH = 7. The ethereal solution was dried (MgSO4) and
evaporated in vacuo to give the crude product as an oil, which was
subjected to column chromatography (silica gel, CH2Cl2/hexanes,
4:1) to give the products 8a–k or 10a,b.
These results were further extended by treatment of 5 with
heterocyclic Grignard reagents under the same conditions
to yield heteroaromatics 10a–c (Scheme 2). Compounds
10a,b were obtained smoothly with no dehydrochlorina-
tion products being detected for 10b, although it is derived
from an aldehyde with an a-hydrogen. Compound 10b
was prone to isomerization and was isolated, according to
1H and 13C NMR, as a mixture of 1- and 2-benzotriazolyl
derivatives in a 5:1 ratio. The generation of Grignard type
heterocyclic carbanions with strongly basic species
(transmetalation of lithiated benzothiaphene, benzothiaz-
1-(1-Phenylethyl)-1H-1,2,3-benzotriazole (8a)
Prism-shaped crystals; mp 59–60 °C; yield: 0.57 g (64%).
1H NMR: d = 8.1 (d, 1H, J = 4.2 Hz), 7.36–7.19 (m, 8H), 6.08 (q,
.
ole and indole was performed with MgBr2 Et2O or by
treatment with EtMgBr or i-PrMgCl) did not afford ben-
zotriazoloalkyl heteroaromatics, probably because of 1H, J = 7.1 Hz), 2.22 (d, 3H, J = 3.2 Hz).
13C NMR: d = 146.2, 140.1, 132.7, 128.9, 128.3, 128.1, 126.3,
deprotonation. The utility of less nucleophilic magnesium
diisopropylamide gave compound 10c in low yield, which
could be explained by the instability of thiazole derived
anions.18
123.8, 119.9, 110.1, 59.0, 21.1.
C14H13N3 calcd
(223.28) found
C
75.31
75.17
H
5.87
5.87
N
18.82
18.99
Synthesis 1999, No. SI, 1437–1440 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Direct Route to Benzotriazoloalkyl(hetero)aromatic Compounds
1439
1-[1-(2-Methylphenyl)ethyl]-1H-1,2,3-benzotriazole (8b)
Prism-shaped crystals; mp 83–85 °C; yield: 0.64 g (68%).
1H NMR: d = 8.07 (d, 1H, J = 8.0 Hz), 7.40–7.33 (m, 3H), 7.19 (d,
2 H, J = 8.0 Hz), 7.13 (d, 2 H, J = 8.2 Hz), 5.81 (s, 2 H), 2.32 (s, 3
H).
1H NMR: d = 8.06 (d, 1H, J = 4.1 Hz), 7.37–7.11 (m, 8H), 6.26 (q,
1H, J = 7.1 Hz), 2.35 (s, 3H), 2.15 (d, 3H, J = 6.8 Hz).
13C NMR: d = 146.1, 138.3, 132.4, 131.7, 129.6, 127.6, 127.3,
123.8, 120.0, 109.8, 52.1, 21.1.
13C NMR: d = 146.2, 137.7, 135.3, 132.3, 130.9, 128.2, 126.9,
126.6, 125.9, 123.8, 119.8, 110.0, 56.1, 20.4, 19.0.
C14H13N3 calcd
(223.28) found
C
75.31
75.15
H
5.87
5.85
N
18.82
19.03
C15H15N3 calcd
(237.3) found
C
75.90
75.86
H
6.37
6.36
N
17.71
17.81
4-(1H-1,2,3-Benzotriazol-1-ylmethyl)-N,N-dimethylaniline (8i)
Prism-shaped crystals; mp 166–168 °C (Lit.21 167–168.5 °C);
yield: 0.66 g (65%).
1H NMR: d = 8.05 (d, 1H, J = 7.9 Hz), 7.39–7.29 (m, 3H), 7.21 (d,
2H, J = 8.0 Hz), 6.68 (s, 1H), 6.67 (d, 1H, J = 7.9 Hz), 5.74 (s, 2H),
2.93 (s, 6H).
1-[1-(3-Methoxyphenyl)ethyl]-1H-1,2,3-benzotriazole (8c)
Light-yellow oil; yield: 0.57 g (56%).
1H NMR: d = 8.08 (d, 1H, J = 6.6 Hz), 7.41–7.25 (m, 4H), 6.92–
6.84 (m, 3H), 6.04 (q, 1H, J = 5.8 Hz), 3.82 (s, 3H), 2.20 (d, 3H,
J = 7.1 Hz).
13C NMR: d = 160.0, 141.7, 129.9, 127.6, 127.0, 123.8, 119.9,
118.5, 114.2, 113.3, 112.2, 110.1, 59.0, 55.2, 21.0.
13C NMR: d = 150.4, 146.3, 132.7, 128.9, 127.0, 123.6, 122.0,
119.8, 112.4, 110.0, 52.2, 40.3.
C15H16N4 calcd
(223.28) found
N
22.21
22.06
C15H15N3O calcd
(253.3) found
C
71.11
71.07
H
5.97
6.37
N
16.60
16.59
1-(1,3-Benzodioxol-4-ylmethyl)-1H-1,2,3-benzotriazole (8j)
Prism-shaped crystals; mp 128–130 °C; yield: 0.71 g (70%).
1H NMR: d = 8.09–8.05 (m, 1H), 7.41–7.34 (m, 3H), 6.83–6.75 (m,
3H), 5.94 (s, 2H), 5.75 (s, 2H).
13C NMR: d = 148.2, 147.8, 146.3, 132.6, 128.4, 127.3, 123.9,
121.3, 120.0, 109.7, 108.4, 108.1, 101.3, 52.1.
1-[1-(1-Naphthyl)ethyl]-1H-1,2,3-benzotriazole (8d)
Plate-shaped crystals; mp 111–113 °C; yield: 0.72 g (66%).
1H NMR: d = 8.15 (d, 1H, J = 7.5 Hz), 8.04 (d, 1H, J = 7.7 Hz),
7.89–7.83 (m, 2H), 7.51–7.41 (m, 4H), 7.26–7.21 (m, 2H), 7.10–
7.07 (m, 1H), 6.88 (q, 1H, J = 6.9 Hz), 2.30 (d, 3H, J = 7.0 Hz).
13C NMR: d = 146.1, 134.8, 133.5, 132.1, 130.2, 128.8, 128.0,
126.6, 125.6, 124.9, 124.3, 123.6, 123.5, 121.9, 119.4, 109.9, 55.5,
20.3.
C14H11N3O2 calcd
(253.26) found
C
66.39
66.44
H
4.39
4.46
N
16.60
16.67
C18H15N3 calcd
(273.13) found
C
79.10
78.70
H
5.53
5.68
N
15.37
15.47
1-[1-(4-Methylphenyl)propyl]-1H-1,2,3-benzotriazole (8k)
Plates; mp 47–49 °C: yield: 0.58 g (57%).
1-Benzyl-1H-1,2,3-benzotriazole (8e)
1H NMR: d = 8.04 (d, 1H, J = 8.0 Hz), 7.37–7.28 (m, 3H), 7.25 (d,
2H, J = 7.7 Hz), 7.11 (d, 2H, J = 7.6 Hz), 5.67 (t, 1H, J = 7.2 Hz),
2.81–2.72 (m, 1H), 2.55–2.46 (m, 1H), 2.28 (s, 3H), 0.95 (t, 3H,
J = 7.2 Hz).
13C NMR: d = 146.19, 138.0, 136.1, 132.7, 129.4, 126.9, 126.7,
123.7, 119.9, 109.9, 65.2, 27.9, 21.0, 11.3.
Prism-shaped crystals; mp 115–117 °C (Lit.8 114–115 °C); yield:
0.59 g (71%).
1H NMR: d = 8.08 (d, 1H, J = 8.0 Hz), 7.44–7.27 (m, 8H), 5.85 (s,
2H).
13C NMR: d = 146.2, 134.7, 132.7, 128.9, 128.3, 127.4, 127.3,
123.8, 119.9, 109.6, 52.1.
C16H17N3 calcd
(251.33) found
C
76.46
76.66
H
6.82
7.12
N
16.72
16.82
1-(2-Methylbenzyl)-1H-1,2,3-benzotriazole (8f)
Prism-shaped crystals; mp 87–89 °C (Lit.20 87 °C); yield: 0.60 g
(67%).
1 H NMR: d = 8.11 (d, 1H, J = 7.2 Hz), 7.42–7.17 (m, 6H), 7.08 (d,
1H, J = 7.4 Hz), 5.88 (s, 2H), 2.38 (s, 3H).
13C NMR: d = 146.2, 136.5, 132.9, 132.5, 130.9, 128.6, 128.5,
127.3, 126.4, 123.8, 120.0, 109.8, 50.7, 19.2.
1-(Thien-2-ylmethyl)-1H-1,2,3-benzotriazole (10a)
Prism-shaped crystals; mp 101–103 °C (Lit.22 103–104 °C);
yield:0.59 g (69%).
1H NMR: d = 8.06 (d, 1H, J = 8.4 Hz), 7.47–7.35 (m, 3H), 7.25 (s,
1H), 7.11 (d, 1H, J = 3.1 Hz), 6.98–6.96 (m, 1H), 6.0 (s, 2H).
13C NMR: d = 146.2, 136.6, 132.6, 127.4, 127.1, 126.4, 123.9,
119.8, 109.5, 46.8.
C14H13N3 calcd
(223.28) found
C
75.31
75.21
H
5.87
5.96
N
18.82
19.07
C11H9N3S calcd
(215.28) found
C
61.37
61.80
H
4.22
4.41
1-(3-Methoxybenzyl)-1H-1,2,3-benzotriazole (8g)
Prism-shaped crystals; mp 52–54 °C; yield:0.58 g (60%).
1H NMR: d = 8.09 (d, 1H, J = 8.2 Hz), 7.43–7.36 (m, 3H), 7.27 (t,
1H, J = 7.9 Hz), 6.86 (m, 3H), 5.83 (s, 2 H), 3.76 (s, 3H).
1-[1-(Thien-2-yl)ethyl]-1H-1,2,3-benzotriazole (10b) and its 2H-
Isomer
Prism-shaped crystals; mp 65–67 °C; yield:0.62 g (68%).
13C NMR: d = 160.0, 146.2, 136.2, 132.7, 130.0, 127.3, 123.8,
1H NMR: d = 8.08 (d, J = 8.0 Hz, 1H), 7.44–7.32 (m, 3H), 7.29–
7.25 (m, 1H), 7.06 (s, 1H), 6.99–6.95 (m, 1H), 6.44 (q, J = 6.9 Hz,
1H), 6.26 [(q, J = 6.9 Hz)], 2.22 (d, J = 7.2 Hz, 3H) [2.15 (d, J = 7.2
Hz)].
13C NMR: d = 146.5, 142.9, 131.8, 127.1 [127.0], 126.9 [126.3],
125.7, 125.5, 123.9 [120.1], 120.0, 110.2, 54.8 [55.1], 21.5 [20.7].
119.9, 119.7, 113.8, 113.2, 109.7, 55.2, 52.1.
C14H13N3O calcd
(239.11) found
C
70.26
70.19
H
5.48
5.55
N
17.57
17.75
1-(4-Methylbenzyl)-1H-1,2,3-benzotriazole (8h)
Prism-shaped crystals; mp 107–109 °C (Lit.20 108–109 °C); yield:
C12H11N3S calcd
(229.31) found
N
18.32
18.30
0.63 g (70%).
Synthesis 1999, No. SI, 1437–1440 ISSN 0039-7881 © Thieme Stuttgart · New York

1440
A. R. Katritzky et al.
PAPER
1-(1,3-Benzothiazol-2-ylmethyl)-1H-1,2,3-benzotriazole (10c)
Under N2, diisopropylamine (0.404 g, 4 mmol) was added to a mix-
ture of 1.0 M dibutylmagnesium in heptane (2 mL, 2 mmol) and an-
hyd THF (5 mL). The mixture was stirred at r.t. for 5 h.
Benzothiazole (0.54 g, 4 mmol) was added to the mixture, and stir-
ring was continued at r.t. for 3 h. N-Chloromethylbenzotriazole
(0.67 g, 4 mmol) in anhyd THF (10 mL) was added, and the mixture
was stirred at r.t. for 12 h. and then at boiling temperature for 4 h.
The mixture was cooled to r.t., poured into an ice/H2O mixture (100
mL) and treated with HOAc (5 mL); the whole was extracted with
Et2O (2 x 50 mL). The combined organic phases were washed with
20% aq NaHCO3 (2 x 40 mL) and then H2O, until the aqueous layer
remained at pH = 7. The ethereal solution was dried anhyd
(MgSO4) and evaporated in vacuo to give the crude product as an
oil, which was subjected to column chromatography (silica gel,
CH2Cl2/hexanes, 3:2) to give the product 10c (0.16 g, 15%) as
prism-shaped crystals; mp 122–123 °C.
(5) Katritzky, A. R.; Drewniak, M. J. Chem. Soc., Perkin Trans.
1 1988, 2339.
(6) Katritzky, A. R.; Rachwal, S.; Rachwal, B. J. Org. Chem.
1989, 54, 6022.
(7) Katritzky, A. R.; Perumal, S.; Kuzmierkiewicz, W.; Lue, P.;
Greenhill, J. Helv. Chim. Acta 1991, 74, 1924
(8) Katritzky, A. R.; Gordeev, M. F.; Greenhill, J. V.; Steel, P. J.
Chem. Soc., Perkin Trans.2 1992, 1111.
(9) Katritzky, A. R.; Lan, X.; Lam, J. N. Chem. Ber. 1991, 124,
1809.
(10) Katritzky, A. R.; Xie, L.; Cundy, D. Synth. Commun. 1995,
25, 539.
(11) Katritzky, A. R.; Ignatchenko, A. V.; Lang, H. Heterocycles
1995, 41, 131.
(12) Richard, J. P.; Nagorski, R. W.; Rudich, S.; Amyes, T. L.;
Katritzky, A. R.; Wells, A. P. J. Org. Chem. 1995, 60, 5989.
(13) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko O. V. Chem.
Rev. 1998, 98, 409.
(14) Katritzky, A. R.; Gordeev, M. F. Synlett 1993, 3, 213.
(15) Paventi, M.; Elce, E.; Jackman, R. J.; Hay, A. S. Tetrahedron
Lett. 1992, 33, 6405.
1H NMR: d = 8.13–8.06 (m, 2H), 7.83–7.81 (d, 1H, J = 8.0 Hz),
7.64–7.52 (m, 1H), 7.50–7.47 (m, 2H), 7.44–7.30 (m, 2H), 6.29 (s,
2H).
13C NMR: d = 164.0, 152.7, 146.2, 135.5, 132.8, 128.0, 126.5,
125.8, 124.3, 123.4, 121.8, 120.1, 109.6, 50.1.
(16) Katritzky, A. R.; Cheng, D.; Henderson, S. A.; Li, J. J. Org.
Chem. 1998, 63, 6704.
(17) Katritzky, A. R.; Chen, J.; Yang, Z. J. Org. Chem. 1995, 60,
5638.
C14H10N4S calcd
(266.33) found
C
63.13
63.09
H
3.79
3.77
N
21.04
20.95
(18) Beraud, J.; Metzger, J. Bull. Soc. Chim. Fr. 1962, 2072.
(19) Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, in press.
(20) Gibson, M. S. J. Chem. Soc. 1956, 1076.
(21) Katritzky, A. R.; Lan, X.; Lam, J. N. Synthesis 1990, 341.
(22) Katritzky, A. R.; Serdyuk, L.; Xie, L.; Ghiviriga I. J. Org.
Chem. 1997, 62, 6215.
References
(1) Katritzky, A. R.; Kuzmierkiewicz, W.; Rachwal, B.; Rachwal,
S.; Thomson, J. J. Chem. Soc., Perkin Trans. 1 1987, 811.
(2) Katritzky, A. R.; Szajda, M.; Lam, J. N. Pol. J. Chem. 1993,
67, 1243.
Article Identifier:
1437-210X,E;1999,0,SI,1437,1440,ftx,en;C02899SS.pdf
(3) Smith, J. R. L., Sadd, J. S. J. Chem. Soc., Perkin Trans. 1
1975, 1181.
(4) Katritzky, A. R.; Borowiecka, J.; Fan, W.-Q. Synthesis 1990,
1173.
Synthesis 1999, No. SI, 1437–1440 ISSN 0039-7881 © Thieme Stuttgart · New York