Synthesis of 1H-benzotriazoles via reductive amination on solid supports

Article abstract of DOI:10.1055/s-2008-1032014

An efficient synthesis of N-benzyl-1H-benzotriazoles utilizing a two-step reductive amination reaction on solid supports has been achieved. The method is suitable for combinatorial synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032014

278
LETTER
Synthesis of 1H-Benzotriazoles via Reductive Amination on Solid Supports
Synthesis of
1
H
-B
i
enzotria
k
zoles via
R
e
t
ductive
o
A
mination
r
on SolidSuppo
Z
rts immermann, Rainhard Müller, Stefan Bräse*
Institute of Organic Chemistry, University of Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@ioc.uka.de
Received 11 September 2007
diazonium ion 2
N
N
Ph
N
Ph
Abstract: An efficient synthesis of N-benzyl-1H-benzotriazoles
utilizing a two-step reductive amination reaction on solid supports
has been achieved. The method is suitable for combinatorial synthe-
sis.
H
THF–MeCN,
pyridine, 4 h
–10 °C
N
R
benzylamino resin
X
1
Key words: solid-phase synthesis, nitrogen heterocycles, imines,
benzotriazoles, reductive amination reaction
N+2
X
3: X = NO2, R = H
5: X = NH2, R = H
4: X = NO2, R = Cl
6: X = NH2, R = Cl
SET-catalyst,
Na2S, K2CO3,
DMF–H2O (9:1), 6 d
80 °C
The benzotriazolyl moiety has shown to be an important,
but still underdeveloped, pharmacophore.1 Recently, we
disclosed a straightforward solid-phase synthesis of 1-
alkyl-1H-benzotriazoles via nucleophilic displacement,2
and of 1-alkyl- and 1-aryl-1H-benzotriazoles via
Hartwig–Buchwald amination.3 The latter reaction allows
a wide range of substituents in 1-position, except for the
1-benzyl substituent, since no reaction could be achieved
between benzylic amines and haloarenes on solid sup-
ports. Thus an alternative entry to 1-alkyl- and 1-benzyl-
1H-benzotriazoles was investigated.
(2a,b)
R
Scheme 1 Attachment of diazonium ions to solid supports
8 were treated with 5–13 equivalents of NaBH3CN, result-
ing in a clean conversion to immobilized secondary
amines 9.
In general, benzaldehydes 7c–l were found to be very
good substrates for the reductive amination reaction.
While cyclohexanone (7a) provided good results, 4-meth-
oxyacetophenone (7b) gave only poor ones. Fluorine,
chlorine and bromine atoms were tolerated, along with ni-
tro, dimethylamino, aceto and etheral oxygen groups.
Electron-withdrawing groups (as in benzaldehydes 7d,j)
as well as electron-donating groups (as in benzaldehyde
7i) were well suitable.
Previously, we reported that stabile imines can be formed
on solid supports with immobilized para-aminoben-
zenes,4 however the formation of ortho-iminobenzenes on
triazene linker and their further modifications with orga-
nometallic reagents have not yet been explored.
In this communication, we disclose the reductive amina-
tion of triazene-bound anilines to give benzotriazoles after
cleavage.
Mild acidic cleavage (5 mol% TFA in CH2Cl2, r.t., 5 min)
of the triazene linker provided ortho-amino-substituted
arene diazonium ions 11, which immediately cyclized to
give the corresponding 1H-benzotriazoles 12 in good to
excellent purities. The results are summarized in Table 1.
The required ortho-nitroarene triazene resins 3 and 4 were
synthesized via optimized procedures from the corre-
sponding anilines and benzylaminomethyl polystyrene
(1), which is available from chloromethylated polystyrene
(1–2% cross-linked).5,6 The anilines were immobilized on
Merrifield resin under standard conditions via their diazo-
nium salts 2a,b (Scheme 1). The loadings were deter-
mined by elemental analysis. The amino resins 5 and 6
were synthesized by reduction of the nitro resins 3 and 4
by sodium sulfide in the presence of SET- and the phase-
transfer catalyst viologen.7
Primary and secondary ortho-amino (nucleophilic) sub-
stituents result in quantitative formation of benzotriazoles
12 due to the quick cyclization reaction. The theoretically
possible hydrolysis of 1-substituted benzotriazoles during
the workup was not observed. Thus, this cleavage proto-
col is suitable for analytical purposes, for example for
rapid gas chromatographic analysis. The resulting purities
of the desired benzotriazoles actually reflect the overall
turnover of the two-step reaction on the solid support.
The reductive amination of various carbonyl compounds
7 with triazene-linked 2-aminobenzenes 5 and 6 was per-
formed via a two-step reaction (Scheme 2). At first, the
corresponding immobilized imines 8 were formed by
heating the reaction mixture at 80 °C in toluene in the
presence of a drying agent. In the second step, the imines
In conclusion, the solid-phase synthesis of diverse N-sub-
stituted benzotriazoles using the two-step reductive
amination9 reaction starting from readily available com-
pounds is shown. The products were obtained in high pu-
rities. The presented work substantially extends the
chemical transformations to be carried out on solid sup-
ports to give the desired benzotriazoles. This route to the
SYNLETT 2008, No. 2, pp 0278–0280
x
x.
x
x.
2
0
0
7
Advanced online publication: 04.01.2008
DOI: 10.1055/s-2008-1032014; Art ID: G29007ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1H-Benzotriazoles via Reductive Amination on Solid Supports
279
Table 1 Results of the Two-Step Reductive Amination Reaction8
(continued)
N
N
Ph
N
N
Ph
1. 7a–l,
toluene,
80 °C, 3 d
N
N
Resin
Reactant
Benzotriazole
Puritya
12%
H
NH2
N
(formation of imine 8)
R2
OMe
2. NaBH3CN,
toluene,
80 °C, 3 d
N
N
N
R1
5 (R1 = H)
5
7b
R1
9a–h (R1 = H)
10g–l (R1 = Cl)
6 (R1 = Cl)
12b
N2+
NMe2
N
N
N
N
H
TFA,
N
N
rapid
cyclization
N
N
CH2Cl2,
R2
R2
5
5
7c
99%
95%
r.t., 5 min
R1
R1
12c
12a–h (R1 = H)
H
N
11a–l
N
12g–l (R1 = Cl)
N
O
7d
Reagents:
O
OMe
NMe2
12d
Ph
O
O
O
N
N
7a
7c
7b
Ph
7e
Cl
N
5
5
5
5
7e
7f
95%
95%
71%
95%
H
N
F
12e
O
O
O
O
7d
7f
F
N
N
N
N
Br
OMe
7i
O
O
7h
7g
12f
Br
Cl
Br
Cl
NO2
N
N
O
O
O
7g
7h
7l
7j
7k
Scheme 2 Reductive amination with immobilized amines
12g
N
N
immobilized N-substituted 2-anilines allows a larger set
of substitution pattern of the N-substituents and gives a
prospect on a straightforward synthesis of novel 1H-ben-
zotriazoles. In comparison to the straightforward alkyla-
tion of benzotriazoles in solution, the presented method
offers the significant advantage of being applicable as a
useful step in a multistep combinatorial synthesis strategy
on solid support, giving access to diverse compound li-
braries.
N
12h
N
N
N
6
6
7g
7h
95%
95%
Cl
Table 1 Results of the Two-Step Reductive Amination Reaction8
12i
Cl
N
N
Resin
Reactant
Benzotriazole
Puritya
93%
N
N
N
N
5
7a
Cl
12j
12a
Synlett 2008, No. 2, 278–280 © Thieme Stuttgart · New York

280
V. Zimmermann et al.
LETTER
(6) Dahmen, S.; Bräse, S. In Handbook of Combinatorial
Table 1 Results of the Two-Step Reductive Amination Reaction8
(continued)
Chemistry; Nicolaou, K. C.; Hanko, R.; Hartwig, W., Eds.;
Wiley-VCH: Weinheim, 2002, Chap. 4.
Resin
Reactant
Benzotriazole
Puritya
(7) Zimmermann, V.; Avemaria, F.; Bräse, S. J. Comb. Chem.
2007, 9, 200.
OMe
(8) Representative Experimental Procedure:10
N
N
Resin: Resin 6 (0.600 g, 0.384 mmol, 1.0 equiv), 4-
methoxybenzaldehyde (7i; 0.523 g, 3.84 mmol, 10 equiv)
and molecular sieve (2 g) were suspended in anhyd toluene
(15 mL) in a 20-mL glass vial and the vessel was sealed with
a PTFE-coated cap. The mixture was heated at 80 °C for 3 d
and occasionally shaken through. After cooling, the resin
was separated from the molecular sieve, filtered on a
polypropylene plastic frit, subsequently roughly washed
with anhyd acetone, CH2Cl2 and pentane and dried in air
stream for 5 min. The molecular sieve was disposed and the
glass vial was briefly rinsed with anhyd toluene. The resin
was then immediately placed back into the glass vial,
NaBH3CN (0.145 g, 3.84 mmol, 10 equiv) and anhyd
toluene (15 mL) were added and the vessel was sealed. The
mixture was heated at 80 °C for another 3 d and occasionally
shaken through. After cooling, the resin was filtered on a
polypropylene plastic frit, subsequently washed with
MeOH, 2 × [THF, pentane (2 ×)], 3 × [CH2Cl2, pentane
(2 ×)], and dried in vacuo for 12 h, to give the resin 10i.
Cleavage: The resin 10i (0.400 g) was placed into a glass
vial and a solution of trifluoroacetic acid (0.100 mL) in
CH2Cl2 (10 mL) was added. After 5 min, the mixture was
filtered on a glass frit (polypropylene plastic frits are not
suitable) and washed with CH2Cl2 (8 mL). The combined
filtrates were washed with H2O (2 × 10 mL), the solvent was
removed by distillation, and the product was dried in vacuo
to yield the benzotriazole 12k with 95% purity (1H NMR).
(9) For leading references, see: (a) Review: Baxter, E. W.;
Reitz, A. B. Org. React. (N. Y.) 2002, 59, 1. For recent
examples, see: (b) Rodriguez Loaiza, P.; Löber, S.; Hübner,
H.; Gmeiner, P. J. Comb. Chem. 2006, 8, 252.
N
6
7i
95%
Cl
12k
NO2
N
N
N
6
6
6
7j
7k
7l
95%
95%
95%
Cl
12l
N
N
N
Cl
12m
N
N
N
Cl
Cl
12n
a Purity of the water-washed product.
(c) DiCesare, J. C.; White, C. E.; Rasmussen, W. E.; White,
B. M.; McComas, C. B.; Craft, L. E. Synth. Commun. 2005,
35, 663. (d) Groth, T.; Grötli, M.; Lubell, W. D.; Miranda, L.
P.; Meldal, M. J. Chem. Soc., Perkin Trans. 1 2000, 4258.
(10) Spectroscopic data for 12c: 1H NMR (300 MHz, CDCl3):
d = 3.02 (s, 6 H, NMe2), 5.79 (s, 2 H, CH2), 7.12 (br d, 3J = 8.67
Hz, 2 H, 3¢-H, 5¢-H), 7.30 (br d, 3J = 8.67 Hz, 2 H, 2¢-H, 6¢-
H), 7.32–7.45 (m, 3 H, 5-H, 6-H, 7-H), 8.05 (ddd, 3J = 8.10
Hz, 4J = 1.13 Hz, 5J = 0.94 Hz, 1 H, 4-H). 13C NMR (75
MHz, CDCl3): d = 43.5 (+, NMe), 51.7 (-, CH2), 109.6 (+,
CAr), 117.3 (+, 2 × C, CAr¢), 119.9 (+, CAr), 124.3 (+, CAr),
127.7 (+, CAr), 129.3 (+, 2 × C, CAr¢), 129.9 (quart, C-7a),
132.7 (quart, C-1¢), 145.9 (quart, C-4¢), 146.8 (quart, C-3a).
References and Notes
(1) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
(2) (a) Lormann, M. E. P.; Walker, C. H.; Es-Sayed, M.; Bräse,
S. Chem. Commun. 2002, 1296. (b) Bräse, S. Acc. Chem.
Res. 2004, 37, 805.
(3) Zimmermann, V.; Bräse, S. J. Comb. Chem. 2007, 9, 1114.
(4) Avemaria, F.; Zimmermann, V.; Bräse, S. Synlett 2004,
1163.
(5) Merrifield resin (0.93 mmol/g) was obtained from Polymer
Laboratories.
Synlett 2008, No. 2, 278–280 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.