Efficient synthesis of substituted 3-acyl-3,4-dihydrobenzo[d][1,2,3]triazines

Article abstract of DOI:10.1016/j.tetlet.2009.02.184

Acylated o-triazenylbenzylamines were cyclized to give 3-acyl-3,4-dihydrobenzo[d][1,2,3]triazines in good yields. Thus, a novel cyclization via a Jacobsen indazole-type reaction to aminoindazoles is observed in this context.

Full text of DOI:10.1016/j.tetlet.2009.02.184

Tetrahedron Letters 50 (2009) 3439–3442
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Tetrahedron Letters
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Efficient synthesis of substituted 3-acyl-3,4-dihydrobenzo[d][1,2,3]triazines
Rüdiger Reingruber a,b, Sylvia Vanderheiden a,b, Thierry Muller a,b, Martin Nieger c, Mazen Es-Sayed d,
Stefan Bräse a,b,
*
a Institute of Organic Chemistry, University of Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
b Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
c Laboratory of Inorganic Chemistry, University of Helsinki 00014 Helsinki, Finland
d Bayer CropScience AG, CS – R Dis I, Alfred-Nobel-Str. 50, 40789 Monheim, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Acylated o-triazenylbenzylamines were cyclized to give 3-acyl-3,4-dihydrobenzo[d][1,2,3]triazines in
good yields. Thus, a novel cyclization via a Jacobsen indazole-type reaction to aminoindazoles is observed
in this context.
Received 13 January 2009
Revised 21 February 2009
Accepted 23 February 2009
Available online 27 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Heterocycles play a pivotal role in drug discovery and as crop
protection agents.1 Benzoannelated nitrogen heterocycles, in par-
ticular, often display highly specific biological activities, designat-
ing this class of compounds as a source of many privileged
structures.2 Over the last decade, we have shown that triazenes
serve as remarkably versatile starting materials for the liquid and
solid phase synthesis of numerous nitrogen heterocycles.3 More-
over, highly functionalized benzotriazoles,4 cinnolines,5 benzotria-
zines,6 benzothiadiazoles,7 and various other heterocycles8 can be
formed through intramolecular cyclization of diazonium salts. The
latter can easily be generated from the corresponding triazenes,
which act as stable intermediates. Recently, we have shown that,
above all, diisopropyltriazenes are particularly stable toward
strongly basic and even Lewis acidic conditions, thus constituting
extremely versatile templates for the synthesis of functionalized
heterocyclic compounds.9
1. The anticipated heterocycles 1 should be obtained via cyclization
of acylated amines 3 bearing a triazene function as a protected dia-
zonium group. The latter compounds can be prepared from the cor-
responding 2-aminobenzonitriles 4 in good yields.9,14
The last step of the reaction sequence, the generation of the dia-
zonium salt followed by the in situ cyclization reaction, occurs
most probably via a von Richter5 or Widman–Stoermer reaction-
type mechanism. The required acylbenzylamines 3 were prepared
through acylation of benzylamines 5 and delivered, in all cases ex-
cept one, good to excellent yields (Table 1).15 The synthesis of com-
pounds 5 has been previously described in detail.9,13
In order to broaden the applicability of the synthesis of 3-acyl-
3,4-dihydrobenzo[d][1,2,3]triazines (1) to a maximum of different
substrates, various parameters were investigated. Cyclizations
were attempted with acetylated or benzoylated amines, the
In this Letter, we describe the synthesis of 3-acylbenzotriazines10
based on this methodology. In marked contrast to benzotriazinones,
which account for a few thousand examples,11,12 for example,
Azinphos methyl (Guthion) a formerly used crop protection agent,
3,4-dihydrobenzo[d][1,2,3]triazines are far less abundant (fewer
than 100 examples).10 All in all, 4-alkyl-3-acylbenzotriazines have
only once been reported as a byproduct whereas 4-dialkyl-3-
acylbenzotriazines (R2, R3 = alkyl or aryl, Fig. 1) have been unmen-
tioned in the literature up until now.13
R2 R3
N
O
O
H2N
R4
N
N
N
N
X
3-Acyl-3,4-dihydro-
benzo[ ][1,2,3]triazine (1)
Batracylin (2)
d
Figure 1. Generic structure of benzotriazines 1, Batracyclin (2).
We initiated that a systematic synthesis of this class of com-
pounds can be obtained via the well-known N–C–C–C–N–N cycli-
zation due to their potential to mimic important
pharmacophores found, for example, in Batracyclin (2), an anti-
cancer DNA-binding alkaloid (Fig. 1). The retrosynthetic analysis
of the given 4-dialkyl-3-acylbenzotriazines is depicted in Scheme
R2 R3
R2 R3
N
O
O
CN
R4
R4
N
H
N
N
N
NH2
X
N
R1
X
X
N
R1
1
3
4
* Corresponding author. Tel.: +49 721 608 2902; fax: +49 721 608 8581.
E-mail address: Stefan.Braese@kit.edu (S. Bräse).
Scheme 1. Retrosynthesis of 3-acyl-3,4-dihydrobenzo[d][1,2,3]triazines (1).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.184

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R. Reingruber et al. / Tetrahedron Letters 50 (2009) 3439–3442
Table 1
Synthesis of acylbenzotriazines 1
R2 R3
NH2
R2 R3
O
(R4CO)2O
THF
N
H
R4
N
N
N
X
R1
X
N
R1
N
N
R1
R1
5
3
R2 R3
O
R4
TFA
CH2Cl2
N
N
N
X
1
X = H, CF3
Entry
X
R1
R2
R3
R4
Acylation yield (%)
Cyclization yield (%)
a
b
c
d
e
f
g
h
i
H
H
H
H
CF3
CF3
CF3
CF3
CF3
CF3
CF3
iPr
iPr
iPr
Et
iPr
iPr
Et
iPr
iPr
iPr
iPr
H
H
H
H
H
Me
Ph
H
H
H
Me
Bu
Ph
Me
Me
Ph
Ph
66
Me
Ph
Ph
Ph
Me
Me
Quant
89
90
35
80
87
Quant
89
88
93
— (65)a
12 (44)a
49 (29)a
CH2–CH2
H
H
H
H
H
H
Quant
b
75
67
88
99
j
k
58
93
CH2–CH2
a
A phenol was formed through hydrolysis of the diazonium salt, with the yield in parentheses.
An indazole 6 (Scheme 2, Fig. 4) was isolated as the main product in 93% yield.
b
substituents in the benzylic position were altered and the electron
density of the aromatic cycle was varied (Table 1). The use of
benzylamines bearing an unsubstituted benzylic position and a
3,3-diisopropyl-triazene moiety resulted in the hydrolysis of the
diazonium salts, thus yielding the corresponding phenols as major
products (entries a and b). The latter are frequent byproducts of
these cyclization reactions. In our case, however, hydrolysis was
suppressed by substitution of one benzylic hydrogen by a methyl
group (entry c).
When the benzylic position bore a cyclopropane and the isopro-
pyl groups were replaced by ethyl moieties, hydrolysis was no
longer observed and the desired compound 1 was obtained in
excellent yield (entry d). Modifying the electron density of the aro-
matic cycle by introducing a trifluoromethyl group ortho to the
triazene led to generally better yields as hydrolysis was completely
suppressed in all cases (entries e–k). The structures of 1e and 1k
have been confirmed by X-ray crystallography (Figs. 2 and 3),
which demonstrates that they are co-planar and therefore should
have DNA-intercalating abilities such as those displayed by Batra-
cyclin (2). Biological testing is in progress.
Figure 2. Molecular structure of one of the two independent molecules of 1e in the
crystal (ORTEP drawing showing 50% ellipsoids).
In the case of 3,3-diisopropyltriazene 3f, instead of the antici-
pated benzotriazine 1f (Table 1, entry f, Scheme 2), indazole deriv-
ative 614 was isolated as the sole product in 93% yield. The
structure of compound 6 has been proven by X-ray crystallography
(Fig. 4). This transformation presumably proceeds via a Jacobsen-
type indazole synthesis,16 although the latter generally takes place
in the presence of alkyl groups rather than benzylamines (Scheme
3).15,17 This result is all the more astonishing given that reacting
triazene 3g under identical conditions leads to the desired triazine
1g with no traces of the corresponding indazole (Table 1, entry g,
Scheme 2). For the moment, we are unable to rationalize these
findings. Given that in both cases the corresponding compounds
were obtained as sole products in high yields, an indazole–triazine
equilibrium is unlikely to exist. It seems that switching from
isopropyl to ethyl groups on the triazene moiety induces a com-
pletely different reaction pathway.
In contrast to acylbenzotriazines, sulfur-substituted benzotria-
zines are virtually unknown.11,18 Starting from the N-tert-
butylsulfinylamine 7—prepared as a diastereomeric mixture (ap-
prox. 1:1) in 58% yield through 1,2-addition to the corresponding
N-tert-butylsulfinyl-amide9—cyclization led to the formation of
the novel heterocycle 8, which, when the reaction time was
extended, underwent complete deprotection and cleavage of
the tert-butylsulfinyl group to form 4-methyl-4-phenyl-3,4-dihy-
drobenzo[d][1,2,3]triazine (9) in almost quantitative yield
(Scheme 4).
In summary, we have presented an efficient synthesis of benzo-
triazines based on functionalized triazenes. Moreover, our group is
conducting ongoing studies to further investigate the unexpected
formation of an indazole during the reaction of a 3,3-diisopropyl-
triazene derivative.

R. Reingruber et al. / Tetrahedron Letters 50 (2009) 3439–3442
3441
O
O
O
HN
Ph
N
H
Ph
N
N
Ph
N
+
N
H
N
N
N
CF3
R1
CF3
CF3
N
R1
1g
6
+ H+
- HNR1
2
O
O
N
H
Ph
N
H
Ph
N+
N
N+
NH
CF3
CF3
Scheme 3. Proposed mechanism for the formation of the indazole 6.20
Figure 3. Molecular structure of 1k in the crystal (ORTEP drawing showing 50%
ellipsoids).
O
S
O
S
Ph Me
Ph Me
N
TFA
CH2Cl2
N
H
-Bu
-Bu
t
t
O
N
O
O
N
N
HN
Ph
N
8
7
N
H
Ph
TFA
N
N
Ph
N
+
N
CH2Cl2
N
N
N
N
H
Ph Me
NH
CF3
R1
CF3
CF3
N
R1
N
quant
N
3f (R1 = Pr)
(R = Et)
-
(93%)
-
6
i
1
1g
(75%)
9
3g
Scheme 4. Formation of 4-methyl-4-phenyl-3,4-dihydrobenzo[d][1,2,3]-triazine (9).
Scheme 2. Synthesis of benzotriazine 1g and indazole 6.
Table 2
Crystallographic data, structure solution, and refinement of 1e, 1k, and 6
1e
1k
6
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
a (Å)
C10H8F3N3O
243.19
123(2)
Monoclinic
P21/c (No. 14)
14.5127(5)
20.2533(6)
7.3614(2)
90
C12H10 F3N3O
269.23
123(2)
Monoclinic
P21/c (No. 14)
7.7501(5)
20.1213(12)
7.9161(5)
90
C15H10F3N3O
305.26
123(2)
Monoclinic
P21/c (No. 14)
4.864(1)
9.539(2)
27.379(6)
90
b (Å)
c (Å)
a
(°)
b (°)
100.487(2)
90
2127.59(11)
8
1.518
0.138
111.821(3)
90
1146.00(12))
4
1.560
0.136
94.66(3)
90
1266.1(5))
4
1.601
0.134
c
(°)
V (Å3)
Z
Dcalcd (g cmÀ3
)
Abs. coeff. (mmÀ1
F(000)
)
992
552
624
Crystal size (mm)
2hmax. (°)
0.45 Â 0.25 Â 0.15 0.30 Â 0.10 Â 0.05 0.40 Â 0.20 Â 0.10
50
50
50
Limiting indices
À16 ꢀ h ꢀ 17
À22 ꢀ k ꢀ 24
À8 ꢀ l ꢀ 8
15,276
3745
0.0485
À9 ꢀ h ꢀ 8
À22 ꢀ k ꢀ 23
À9 ꢀ l ꢀ 9
7640
2021
0.0674
À5 ꢀ h ꢀ 5
À11 ꢀ k ꢀ 11
À32 ꢀ l ꢀ 32
11,325
2205
0.0686
Reflections collected
Unique reflections
Rint
Figure 4. Molecular structure of 6 in the crystal (ORTEP drawing showing 50%
ellipsoids).
Data/restraints/
parameters
3745/0/309
2021/0/173
2205/2/205
Crystal structure studies of 1e, 1k, and 6: Single-crystal X-ray
diffraction studies were carried out on a Nonius KappaCCD diffrac-
tometer (1k), a Bruker–Nonius APEXII diffractometer (1e), and a
Bruker–Nonius KappaCCD diffractometer (6) at 123(2) K using
GOF on F2
1.074
0.0437
0.1064
0.186/À0.239
1.104
0.0626
0.1641
0.387/À0.468
1.146
0.0638
0.1312
0.300/À0.466
R1 [I > 2
r
(I)]
wR2 (all data)
Largest diff. map
peak and hole
MoK radiation (k = 0.71073 Å). The structures were solved by Di-
(e AÀ3
)
a
rect Methods (SHELXS-9719) and refinement was carried out using
SHELXL-9719(full-matrix least-squares refinement on F2). The
hydrogen atoms were localized by difference electron density
determination and were refined using a ‘riding’ model (in 6 H(N)
free). Important data on the data collection and structure solution
and refinement are listed in Table 2. Crystallographic data (exclud-
ing structure factors) for the structures reported in this work have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 715560 (1k), 715561

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R. Reingruber et al. / Tetrahedron Letters 50 (2009) 3439–3442
5. Bräse, S.; Dahmen, S.; Heuts, J. Tetrahedron Lett. 1999, 40, 6201–6203.
6. Gil, C.; Bräse, S. Chem. Eur. J. 2005, 11, 2680–2688.
7. Kreis, M.; Nising, C. F.; Schroen, M.; Knepper, K.; Bräse, S. Org. Biomol. Chem.
(1e), and 715562 (6). Copies of the data can be obtained free of
charge upon application to: The Director, CCDC, 12 Union Road,
Cambridge DB2 1EZ, UK (Fax: int.code+(1223)336-033; e-mail:
deposit@ccdc.cam.ac.uk).
2005, 3, 1835–1837.
8. Knepper, K.; Themann, A.; Bräse, S. J. Comb. Chem. 2005, 7, 799–801.
9. Reingruber, R.; Vanderheiden, S.; Wagner, A.; Nieger, M.; Muller, T.; Es-Sayed,
M.; Bräse, S. Eur. J. Org. Chem. 2008, 3314–3327.
Acknowledgments
10. For the synthesis of benzotriazines: (a) Widermannova, I.; Slouka, J.; Humpa,
O.; Lemr, K. J. Heterocycl. Chem. 2003, 40, 357–358; (b) LaFrance, R. J.; Manning,
H. W.; Vaughan, K. Can. J. Chem. 1987, 65, 292–297; (c) Hooper, D. L.; Manning,
H. W.; LaFrance, R. J.; Vaughan, K. Can. J. Chem. 1986, 64, 250–254; (d)
Grayshan, R.; Miller, D. D. Eur. J. Med. Chem. 1986, 21, 87–90; (e) Vaughan, K.;
LaFrance, R. J.; Tang, Y.; Hooper, D. L. Can. J. Chem. 1985, 63, 2455–2461; (f)
Treppendahl, S.; Jakobsen, P. Acta Chem. Scan. B 1984, B38, 185–187; (g) Faye, P.
L.; Vaughan, K.; Hooper, D. L. Can. J. Chem. 1983, 61, 179–183; (h) Gibson, M. S.;
Murray, A. W. J. Org. Chem. 1962, 27, 4083–4084; (i) Lai, K. K.; Schwalbe, C. H.;
Vaughan, K.; LaFrance, R. J.; Whiston, C. D. Can. J. Chem. 1985, 63, 581–585; (j)
Vaughan, K.; LaFrance, R. J.; Tang, Y.; Hooper, D. L. J. Heterocycl. Chem. 1991, 28,
1709–1713; (k) Fong, H.; Vaughan, K. Can. J. Chem. 1975, 53, 3714–3719.
11. As of January 2009 according to Scifinder.
We
acknowledge
the
financial
support
of
the
Landesgraduiertenförderung Baden Württemberg (fellowship to
R.R.) and the Bayer Cropscience AG. M.N. thanks Professor K. Rissa-
nen, Professor J. Valkonen (Department of Chemistry, Univ. of Jyväs-
kylä), and Professor T. Pakkanen (Department of Chemistry, Univ. of
Joensuu) for data collection time.
References and notes
12. Döpp, H.; Döpp, D. Science of Synthesis 2004, 17, 223–355.
13. Golik, U.; Taub, W. J. Heterocycl. Chem. 1975, 12, 1155–1158.
14. The cyclopopane derivatives were synthesized via a de Meijere-Kulinkovich
reaction: (a) Wiedemann, S.; Frank, D.; Winsel, H.; de Meijere, A. Org. Lett.
2003, 5, 753–755; (b) de Meijere, A.; Kozhushkov, S. I. In Titanium and
Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp
390–434.
15. To a solution of the benzylamine (0.25 M in THF) was added 2 equiv of the
corresponding acidic anhydride at 25 °C and the mixture was stirred for 24 h.
All new compounds were purified on silica. They exhibit satisfactory spectral
and analytical data (elemental analysis and/or HRMS). The structures of 1e, 1k,
and 6 were unequivocally proven by X-ray spectroscopy.
16. This reaction was discovered by Witt et al.: (a) Witt, O. N.; Nölting, E.;
Grandmougin, E. Ber. Dt. Chem. Ges. 1890, 23, 3635–3644; (b) Jacobson, P.;
Huber, L. Ber. Dt. Chem. Ges. 1908, 41, 660–671; (c) Porter, H. D.; Peterson, W. D.
Org. Synth. 1940, 20; (d) Rüchardt, C.; Hassmann, V. Synthesis 1972, 375–376;
(e) Stadlbauer, W. Sci. Synth. 2002, 12, 227–324.
1. (a) Ziegert, R. E.; Toräng, J.; Knepper, K.; Bräse, S. J. Comb. Chem. 2005, 7, 147–
169; (b) Fürstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.;
Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061–7069; (c) Fürstner, A.; Castanet, A.-
S.; Radkowski, K.; Lehmann, C. W. J. Org. Chem. 2003, 68, 1521–1528; (d)
Kaizerman, J. A.; Gross, M. I.; Ge, Y.; White, S.; Hu, W.; Duan, J.-X.; Baird, E. E.;
Johnson, K. W.; Tanaka, R. D.; Moser, H. E.; Buerli, R. W. J. Med. Chem. 2003, 46,
3914–3929; (e) Wipf, P.; Reeves, J. T.; Balachandran, R.; Day, B. W. J. Med. Chem.
2002, 45, 1901–1917; (f) Trost, B. M.; Crawley, M. L. Chem. Eur. J. 2004, 10,
2237–2252; (g) Fischer, H.-P.; Buser, H.-P.; Chemla, P.; Huxley, P.; Lutz, W.;
Mirza, S.; Ramos Tombo, G. M.; Van Lommen, G.; Sipido, V. Bull. Soc. Chim.
Belges 1994, 103, 565–581; (h) Elsner, J.; Boeckler, F.; Heinemann, F. W.;
Huebner, H.; Gmeiner, P. J. Med. Chem. 2005, 48, 5771–5779; (i) Sperry, J. B.;
Wright, D. L. Curr. Opin. Drug Discov. Devel. 2005, 8, 723–740; (j) Newton, R. F.
PharmaChem 2003, 2, 44–45.
2. (a) Gil, C.; Bräse, S. J. Comb. Chem., ASAP.; (b) Bräse, S.; Gil, C.; Knepper, K. Bioorg.
Med. Chem. 2002, 10, 2415–2437.
3. For a review: Bräse, S. Acc. Chem. Res. 2004, 37, 805–816.
4. (a) Zimmermann, V.; Müller, R.; Bräse, S. Synlett 2008, 278–280; (b)
Zimmermann, V.; Avemaria, F.; Bräse, S. J. Comb. Chem. 2007, 9, 200–203; (c)
Avemaria, F.; Zimmermann, V.; Bräse, S. Synlett 2004, 1163–1166.
17. Bartsch, R. A.; Yang, I. W. J. Heterocycl. Chem. 1984, 21, 1063–1064.
18. Hennart, C. Bull. Soc. Chim. France 1967, 4691.
19. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.
20. Tröndlin, F.; Werner, R.; Rüchardt, C. Chem. Ber. 1978, 111, 367–378.