Synthesis of aryl azides via post-cleavage modification of polymer-bound triazenes

Article abstract of DOI:10.1055/s-2004-82298

Starting from immobilized arenes on the triazene T1 linker resin, cleavage was achieved by trifluoroacetic acid in the presence of trimethylsilyl azide to obtain aryl azides in good yields and excellent purities. A novel cleavage protocol has been introduced and analytical and preparative applications have been presented.

Full text of DOI:10.1055/s-2004-82298

LETTER
1163
Synthesis of Aryl Azides via Post-Cleavage Modification of Polymer-Bound
Triazenes
Synthesis of
A
r
ryl
A
zid
a
e
s
via Post-
n
C
leavage
M
k
odification Avemaria,a Viktor Zimmermann,a Stefan Bräse*b
a
Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Strasse 1,
53121 Bonn, Germany
b
Institut für Organische Chemie, Universität Karlsruhe, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@ioc.uka.de
Received 19 March 2004
using a soluble polymer18 and with a polystyrene resin.19
The synthesis of a polymer-bound trimethylsilyl azide
was also reported.20
Abstract: Starting from immobilized arenes on the triazene T1
linker resin, cleavage was achieved by trifluoroacetic acid in the
presence of trimethylsilyl azide to obtain aryl azides in good yields
and excellent purities. A novel cleavage protocol has been intro-
duced and analytical and preparative applications have been
presented.
Without any catalysts aryl diazonium salts and azide
transfer reagents immediately react to the aryl azides. In
contrast to the common Sandmeyer reaction, this reaction
does not proceed under cleavage of the carbon–hetero-
atom bond. After addition of the azide onto the diazonium
ion, an open chain pentazene or a cyclic pentazole is
formed, followed by the release of nitrogen to yield the
desired aryl azide.21
Key words: aryl azides, post-cleavage modification, polymer-
bound triazenes
Aryl azides are useful intermediates in organic synthesis.1
They can be used for cycloaddition reactions,2 for the syn-
thesis of anilines and N-alkyl substituted anilines3 as well
as precursors for the generation of nitrenes. Although no
natural product with this functionality has been isolated so
far, several aryl azides with biological activity have been
reported.4 Particularly, the labeling of ligands can be used
for photoaffinity labeling as shown by the synthesis of
combrestatin analogues as molecular probes for the tubu-
line polymerization.5 Some aryl azide derivatives are
commercially available (around 120 azides according to
the Available Chemical Directory) and can be prepared
from diazonium salts with sodium azide or from aryl
halides and azide sources.6 Despite their usefulness, a
combinatorial access using solid phase methods has not
been reported yet.
Diazonium ions are readily available by cleavage of tri-
azenes.22 Moore et al.23 and we24 have demonstrated that
polymer-bound aryl triazenes are useful intermediates in
the solid-phase synthesis of substituted arenes such as
cinnolines,25 alkyl arenes26 and iodoarenes23,24 and for
traceless cleavage.27
Under photochemical and thermal conditions, aryl azides
with a double bond in ortho-position decompose to the
corresponding benzoannelated heterocycles under loss of
dinitrogen. Using this strategy, indenes,28 indazoles,28,29
benzofuroxanes30 and other heterocycles are accessible.
Alternatively, the intra- or intermolecular aza-Wittig reac-
tion might also be envisaged.31
Due to their importance, we developed a solid-phase syn-
thesis of aryl azides. Starting from anilines 2a–c,h–o,s–u
and benzylaminomethyl polystyrene (1), triazene resins
3a–c,h–o,s–u were prepared as outlined in Scheme 1.32
Modification on the bead e.g. by nitro group reduction
furnished immobilized arenes 3a–u (Scheme 2). The
cleavage of the triazene resin was accomplished by 10%
TFA in dichloromethane at room temperature in the
presence of trimethylsilyl azide.33,34 After a few minutes,
the mixture was filtered and the solvent was removed by
evaporation. Without any further purification the aryl
azides 4a–u were isolated mostly in good yields and
excellent purities. Small amounts (<5%) of silyl residues
can be detected by means of NMR spectroscopy. The mild
cleavage conditions allow the synthesis of various
functionalized arenes even with amino and imino func-
tionality (Figure 1).
Aliphatic azides have been synthesized on solid support
earlier. In each case, a polymer-bound electrophile was
treated with an appropriate azide transfer reagent. The
substitution of alkyl halides,7–9 –sulfonates10 and the ring
opening of epoxides11 were investigated using sodium
azide. Jacobsen and coworkers reported that trimethylsilyl
azide was used in the asymmetric ring opening of meso-
epoxides.12 The substitution of hydroxyl groups proceeds
under Mitsunobu conditions using phenoxyphosphoryl-
azide.13,14 The reduction of azides to the corresponding
amines was achieved by use of thiols9,12,15 and phos-
phanes.14,16
Cycloaddition of azides with electron rich alkenes (enol-
ethers, enamines) or alkynes17 leads to the formation of
triazoles. An application of this reaction has been reported
SYNLETT 2004, No. 7, pp 1163–1166
0
3.
0
6.
2
0
0
4
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-82298; Art ID: G20203ST
© Georg Thieme Verlag Stuttgart · New York

1164
F. Avemaria et al.
LETTER
This method is also suitable for in situ cleavage. The
increased stability of aryl azides in comparison to diazo-
nium salts can favorably be used for analytic purposes by
performing the cleavage into a NMR tube.
N
N
Ph
NH2
1) BF3·OEt2, R´ONO
THF, CH2Cl2
–15 to 5 °C
N
In this case, a mixture of deuterated TFA and CDCl3 was
used. This transformation enables the fast and direct
monitoring for reactions of the triazene T1 linker on solid
supports.
2)
N
Ph
R
1
R
H
3a−c,h−o,s−u
2a−c,h−o,s−u
Pyridine, CH2Cl2
–15 to 25 °C
Scheme 1 Synthesis of the triazene resins
As an example for an application of the method to post-
cleavage synthesis of heterocycles, the cyclization of
2-nitroaryl azides based on the ortho-nitro resins like
3a, performed at approx. 100 °C, yields benzofuroxane
5a in high purities (Scheme 3). Benzofuroxanes are
biologically active compounds35 with broad potential
application.
N3
N
N
Ph
TFA, Me3SiN3
CH2Cl2, 5 min, r.t.
N
R
R
3a–u
4a–u
N
N
Ph
1) TFA, CH2Cl2
Me3SiN3
2) ∆ (ca. 100 °C)
O
N
N+
Scheme 2 Cleavage of aryl azides from solid support
O-
N
NO2
quant.
N3
N3
N3
O
N3
N3
NO2
Ph
5a
3a
CO2Me
Scheme 3 Synthesis of benzofurazone 5a
NO2
NH2
NO2
O
OMe
4d
4a
(96%)
4b
4c
4e
Reaction of azides with bromomagnesium acetylides and
an electrophile provides 1,5-disubstituted-1,2,3-triazoles
in high yields.36 Analogously, the cycloaddition of the
azides with olefins like norbornene yields triazolines 6,
which can be directly transferred into aziridine derivatives
7 by heating or irradiation.37
(96%)
(85%)
(96%)
(96%)
N3
N3
N3
N3
N3
NO2
OMe
CO2Me
NH2
HN
O
NO2
OEt
NO2
The suitability of this method was proved by reaction of
water-washed cleavage solution of 2-bromoazide 4t with
norbornene at 25 °C, yielding the corresponding triazo-
line 6t as the sole product after recrystallization.38 In con-
trast, azide 4k gave at 40 °C the triazoline 6k besides
aziridine 7k (Scheme 4).
4f
(96%)
4h
(94%)
4l
(96%)
4g
(96%)
4k
(96%)
N3
N
N3
N3
O
N3
N3
Me
MeO
O
N
O
NO2
1) TFA, CH2Cl2
O
NH2
Me3SiN3, 5 min
2) washing with water
3) norbornene,
N
N
N
N
Ph
N
N
MeO
OMe
25 °C, 3 d
Br
Br
OMe
4mb
(96%)
4n
(96%)
4p
(96%)
4o
(60%)
4q
(96%)
quant.
3t
6t
N3
N3
N3
N3
Cl
Br
NO2
N
N
N
N
N3
norbornene
18 h, 40 °C
HN
O
Cl
+
OMe
OMe
OMe
O
CDCl3
75%
4r
4s
(96%)
4t
(96%)
4u
(96%)
(96%)
6 : 1
NO2
NO2
NO2
4k
Figure 1 Aryl azides prepareda
6k
7k
a Purities determined by 1H NMR spectroscopy. Identification by 1H/
13C NMR spectroscopy, IR and/or MS.
Scheme 4 Reaction of azides with olefins
b A piperazine resin was used.24a
Synlett 2004, No. 7, 1163–1166 © Thieme Stuttgart · New York

LETTER
Synthesis of Aryl Azides via Post-Cleavage Modification
1165
Tetrahedron Lett. 1998, 39, 9293. (c) Kim, J. M.; Bi, Y. Z.;
Paikoff, S. J.; Schultz, P. G. Tetrahedron Lett. 1996, 37,
5305. (d) Savin, K. A.; Woo, J. C. G.; Danishefsky, S. J. J.
Org. Chem. 1999, 64, 4183.
N3
NH2
Br
Br
PS-PPh3, H2O, r.t.
(16) (a) Tang, Z. L.; Pelletier, J. C. Tetrahedron Lett. 1998, 39,
4773. (b) Tremblay, M. R.; Poirier, D. Tetrahedron Lett.
1999, 40, 1277. (c) Osborn, N. J.; Robinson, J. A.
Tetrahedron 1993, 49, 2873. (d) Liang, R.; Yan, L.;
Loebach, J.; Ge, M.; Uozumi, Y.; Sekanina, K.; Horan, N.;
Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still,
W. C.; Kahne, D. Science 1996, 274, 1520.
4t
2t
Scheme 5 Reduction of azides to anilines with immobilized phos-
phine
(17) Melai, V.; Brillante, A.; Zanirato, P. J. Chem. Soc., Perkin
Trans. 2 1998, 2447.
(18) (a) Freeze, S.; Norris, P. Heterocycles 1999, 51, 1807.
(b) Moore, M.; Norris, P. Tetrahedron Lett. 1998, 39, 7027.
(19) Gouault, N.; Cupif, J.-F.; Sauleau, A.; David, M.
Tetrahedron Lett. 2000, 41, 7293.
(20) Missio, A.; Marchioro, C.; Rossi, T.; Panunzio, M.; Selva,
S.; Seneci, P. Biotechnol. Bioeng. 2000, 71, 38.
(21) Butler, R. N.; Fox, A.; Collier, S.; Burke, L. A. J. Chem.
Soc., Perkin Trans. 2 1998, 2243.
(22) Bräse, S.; Lormann, M.; Vogt, H. Scope and Limitation of a
Tin Promoted Amidation on Solid Phase: A New Monitoring
for the T1 Triazene Linker; Proceedings of ECSOC-4, The
Third International Electronic Conference on Synthetic
Organic Chemistry, September 1-30, 2000, see also http://
www.mdpi.org/ecsoc-4.htm.
The reduction of azides to amines using immobilized
phosphines is well-known,39 thereby a catch-and-release
strategy can be implemented. We verified this pathway by
reaction of the water-washed cleavage mixture of 4t with
PPh3-resin in the presence of water. The azide was
completely converted to 2-bromoaniline 2t at room
temperature (Scheme 5).
In conclusion, we have demonstrated a new multifunc-
tional cleavage protocol40 mode for the T1 triazene linker
to yield aryl azides. A catch-and-release strategy for
anilines is as well available. Further applications towards
the combinatorial synthesis of heterocycles are currently
investigated and will be reported in due course.
(23) Nelson, J. C.; Young, J. K.; Moore, J. S. J. Org. Chem. 1996,
61, 8160.
References
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Multidirectional Cleavage for Solid Phase Organic
Synthesis; Proceedings of ECSOC-3, The Third
International Electronic Conference on Synthetic Organic
Chemistry, 1999, see also http://www.mdpi.org/ecsoc-
3.htm.
(1) (a) Patai, S. The Chemistry of Diazonium and Diazo Groups,
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(10) Lee, C. E.; Kick, E. K.; Ellman, J. A. J. Am. Chem. Soc.
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1071; Angew. Chem. 1999, 111, 1139. (b) de Meijere, A.;
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2000, 41, 3813. (b) Bräse, S.; Enders, D.; Köbberling, J.;
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(32) Representative Procedure for Synthesis of a T1-Resin:
The aniline 2n (3.68 g, 20.2 mmol) was dissolved in 100 mL
of CH2Cl2 and BF3·OEt2 (4.26 g, 30.0 mmol) was added at
r.t. The mixture was cooled to –15 °C and isoamyl nitrite
(3.83 g, 32.7 mmol) was added dropwise with stirring for 15
min. After stirring for 4 h the mixture was cooled to –70 °C
and the solid diazonium salt was filtered off, washed with
precooled Et2O and suspended in MeCN at –40 °C. In a
second flask, the benzylamine resin 1 (5.00 g, 4.65 mmol,
Synlett 2004, No. 7, 1163–1166 © Thieme Stuttgart · New York

1166
F. Avemaria et al.
LETTER
loading 0.93 mmol/g) was dissolved in THF at –20 °C and
pyridine (5.87 g, 74.0 mmol) was added. The cooled
suspension of the diazonium salt was added to the
benzylamine resin suspension and the reaction mixture was
stirred slowly for 6 h. It was allowed to warm up to r.t. The
resin was filtered off, washed sequentially with THF,
CH2Cl2, MeOH, pentane, DMF and dried under high
vacuum.
(38) The crude solution of the azide (4t) was washed with H2O to
remove the excess of trimethyl silyl azide, and norbornene
was added. After 3 d at 25 °C the solvent was evaporated and
the residue was recrystallized from petroleum ether/EtOAc
(1:1).
3-(2¢-Bromophenyl)-3,4,5-triazatri-cyclo[5.2.1.02,6]dec-4-
ene (5): >95%. IR (KBr): 3403 (w), 3068 (w), 2968 (s), 2874
(m), 2662 (w), 1921 (w), 1802 (w), 1586 (m), 1503 (m),
1469 (s), 1325 (m), 1310 (m), 1300 (m), 1260 (m), 1247 (m),
1216 (w), 1159 (w), 1124 (m), 1079 (m), 1046 (s), 1028 (m),
1012 (m), 974 (s), 952 (m), 918 (s), 888 (w), 863 (w), 846
(m), 805 (w), 754 (s), 714 (w), 700 (m), 640 (m) cm–1. 1H
NMR (400 MHz, CDCl3): d = 1.08–1.10 (complex, 2 H,
10-H), 1.20 (m, 1 H, 9-H), 1.34 (m, 1 H, 8-H), 1.44 (m, 1 H,
9-H), 1.55 (m, 1 H, 8-H), 2.06 (d, 3J = 4.3 Hz, 1 H, 1-H),
2.70 (d, 3J = 4.4 Hz, 1 H, 7-H), 4.25 (d, 3J = 9.1 Hz, 1 H,
2-H), 4.61 (d, 3J = 9.2 Hz, 1 H, 6-H), 7.07 (ddd, 3J = 8.0 Hz,
3J = 7.3 Hz, 4J = 1.7 Hz, 1 H, 5¢-H), 7.28 (ddd, 3J = 8.0 Hz,
3J = 7.3 Hz, 4J = 1.4 Hz, 1 H, 4¢-H), 7.34 (dd, 3J = 8.0 Hz,
4J = 1.7 Hz, 1 H, 3¢-H), 7.59 (dd, 3J = 8.0 Hz, 4J = 1.4 Hz, 1
H, 6¢-H). 13C NMR (75 MHz, CDCl3): d = 24.9 (-, 9-CH2),
25.4 (-, 8-CH2), 31.8 (-, 10-CH2), 40.1 (+, 1-CH), 40.7 (+,
7-CH), 61.4 (+, 2-CH), 87.0 (+, 6-CH), 116.1 (q, C-2¢),
125.7 (+, C-3¢), 127.1 (+, C-5¢), 128.0 (+, C-4¢), 133.9 (+, C-
6¢), 139.9 (q, C-1¢). MS (FAB): m/z (%) = 292/294 (100/98)
[MH+], 263/265 (26/25) [C13H14NBr+], 234/236 (9/11). MS
(EI): m/z (%) = 263/265 (C13H14NBr+, 20/20) [M+ – N2],
235/236 (96/100), 222/224 (5/5), 208/210 (9/8), 197/199
(22/18), 182/184 (24/33), 171/173 (30/29), 155/157 (27/26),
143 (7), 130 (15), 118 (11), 93 (90), 91 (32), 77 (32). HRMS
(EI): calcd 291.0371 for M+ resp. 263.0310 for (M+ – N2),
found 263.0308. Product undergoes thermal decomposition
while GC and EI measurements are taken.
(33) Representative Procedure for Cleavage of a T1-Resin:
The resin 3n (0.40 g, loading 0.74 mmol/g) was suspended
in 5 mL of CH2Cl2 and trifluoroacetic acid (0.30 mL, 4.0
mmol) was added dropwise at r.t. After 2–5 min,
trimethylsilyl azide (0.15 mL, 1.2 mmol) was added to the
resin and after few minutes (5–10) the mixture was filtered
and the solvent was removed by evaporation.
1-Azido-5-methoxy-2-methyl-4-nitro-benzene (4n): 58.5
mg, 79% yield. GC: Rt = 13.99 min. IR (KBr disk): 2100
cm–1. 1H NMR (400 MHz, CDCl3): d = 2.18 (s, 3 H), 3.99 (s,
3 H), 6.73 (s, 1 H) 7.79 (s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 16.2 (Cp), 56.8 (Cp), 102.9 (Cp), 121.8 (Cq),
128.6 (Cp), 135.5 (Cq), 144.6 (Cq), 152.9 (Cq). MS-DIP:
m/z (%) = 208 (51), 180 (92), 152 (50), 122 (27), 106 (10),
95 (100), 92 (73), 80 (95), 77 (12), 63 (23).
(34) (a) Trimethyl silyl azide is a commercially available
combustible liquid, which has no explosive properties.
(b) Groutas, W. C.; Felker, D. Synthesis 1980, 861.
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11, 305. (b) Cerecetto, H.; Di Maio, R.; Gonzalez, M.; Risso,
M.; Saenz, P.; Seoane, G.; Denicola, A.; Peluffo, G.;
Quijano, C.; Olea-Azar, C. J. Med. Chem. 1999, 42, 1941.
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submitted.
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Nowack, G. P. J. Am. Chem. Soc. 1965, 87, 306.
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Synlett 2004, No. 7, 1163–1166 © Thieme Stuttgart · New York