The base-induced fragmentation of N,N-dibenzyl-N'-aryltriazenes

Article abstract of DOI:10.1055/s-2002-31918

Deprotonation of N,N-dibenzyl-N'-aryltriazenes, either in liquid phase or on solid support, by a strong base (n-BuLi or LDA) leads to fragmentation of the N-N single bond to give an imine and a diazenyl anion, which decomposes by loss of nitrogen to the parent aryl anion. The imine is deprotonated to give a 2-aza allyl anion, which is subsequently trapped by electrophiles. As an overall result, this fragmentation of the T1 triazene anchoring group represents a new traceless cleavage mode of this linker. The same mode of fragmentation was observed for the T2 linker leading to 2-aza allyl anions in liquid phase. The dibenzylamino moiety is apparently crucial since pyrrolidinodiazenylarenes can be metallated at the heterocycle without cleavage.

Full text of DOI:10.1055/s-2002-31918

LETTER
915
The Base-Induced Fragmentation of N,N-Dibenzyl-N -aryltriazenes
T
he Base-inducedFrag
a
mentation
t
of N,N
-
t
D
ibenz
h
yl-
N
’-aryltria
i
zenesas E. P. Lormann,a Stefan Dahmen,b Frank Avemaria,a Frank Lauterwasser,a Stefan Bräse*a
a
Kekulé-Institut für Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
Fax +49(228)739608; E-mail: braese@uni-bonn.de
b
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet-Strasse 1, 52074 Aachen, Germany
Received 21 December 2001
N
N
R1
N
Abstract: Deprotonation of N,N-dibenzyl-N'-aryltriazenes, either
in liquid phase or on solid support, by a strong base (n-BuLi or
LDA) leads to fragmentation of the N-N single bond to give an imi-
ne and a diazenyl anion, which decomposes by loss of nitrogen to
the parent aryl anion. The imine is deprotonated to give a 2-aza allyl
anion, which is subsequently trapped by electrophiles. As an overall
result, this fragmentation of the T1 triazene anchoring group repre-
sents a new traceless cleavage mode of this linker. The same mode
of fragmentation was observed for the T2 linker leading to 2-aza al-
lyl anions in liquid phase. The dibenzylamino moiety is apparently
crucial since pyrrolidinodiazenylarenes can be metallated at the
heterocycle without cleavage.
N
N
polystyrene
N
N
R2
R2
1: R1 = Ph
2
R2
N
O
N
N
O
N
N
N
R2
R2
Cl
R2
Key words: triazenes, diazenyl anions, azaallyl anions, umpolung,
solid phase synthesis
4: T2* linker
3: T2 linker (para)
Figure 1 Triazene resins.
Triazenes are an important class of compounds and re-
garded as protected diazonium ions.1 The cleavage of tria-
zenes has been affected by Brønsted acids (various
organic and inorganic acids) or Lewis acids (Me3SiI,
BF3 OEt2 etc.).1 Furthermore, triazenes have been suc-
cessfully applied in the total synthesis of vancomycin2 as
well as linkers in solid phase organic synthesis3 by virtue
of their reputation as base stable functionalities. During
the study of a halogen-metal exchange on solid support
Under basic conditions as presented here, the ionic path-
way should be preferred.
Since we were able to show that the analogous piper-
azenyl linker 2 (Figure 1) is stable towards n-BuLi,5 and,
furthermore, that some pyrrolidinodiazenyl arenes are
also stable under these conditions,6 a likely reason for this
reaction is the enhanced acidity of the benzylic position.7
using the triazene T1 linker 1 (Figure 1) it was observed, Consequently, various triazenes have been subjected to a
in some cases, that the color of the resin, which is normal- range of deprotonation conditions.
ly slightly yellow, became deep red upon treatment with a
strong base such as n-BuLi or LDA.
The same fragmentation was observed with non-polymer
bound triazenes. Using 1.1 equivalents of LDA at 0 °C in
Afterwards, the nitrogen content of the resin was deter- THF, the triazene 8 engaged in a clean fragmentation re-
mined by CHN analysis to have decreased by a factor of action and after quenching with methyl iodide the alkylat-
three. Obviously, a fragmentation of the N-N single bond ed imine 9 was isolated in 80% yield (Scheme 2).
had taken place as shown in the Schemes 1 and 5. To Chlorobenzene (7) was also isolated together with traces
of p-chlorotoluene.
clarify the course of the reaction, several studies on poly-
mer-bound triazenes, as well as on model compounds in
liquid phase, have been undertaken. Here we report the
results of this novel fragmentation reaction.
N
N
Ph
1) n-BuLi, THF, -78 °C
yellow → deep red
2) MeOH
The process is initiated by a selective benzylic deprotona-
tion, followed by elimination of a diazenyl anion.4 This
anion abstracts a proton from the resulting imine (pKa of
diazenyl anions are around 18)4 and decomposes to the
parent hydrocarbon. The diazenyl arenes lose nitrogen
either via the carbanions or the radicals.4
H
N
N
Ph
+
deep red → yellow
Cl
Cl
5
yellow
6
7
yellow
Scheme 1 Metalation and fragmentation of triazene T1 resin 5
Synlett 2002, No. 6, Print: 04 06 2002.
Art Id.1437-2096,E;2002,0,06,0915,0918,ftx,en;G24301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

916
M. E. P. Lormann et al.
LETTER
Ph
N
N
Ph
Pr
N
N
N
N
1) LDA, THF, 0 °C
yellow → deep red
2) MeI
H
N
Me
N
N
1) LDA, THF, -78 °C
2) PrI
Ph
N
Ph
+
deep red → yellow
+
p-ClPh
N
H
Cl
Cl
80%
Cl
Cl
8
9
7
yellow
13
14
37%
15
25%
Scheme 2 Metalation and fragmentation of a dibenzyltriazene 8
Scheme 4 Metalation of a pyrrolidine triazene
Similarly, the T2 and the T2* linker with a dibenzylamine
moiety (3 and 4, Figure 1) fragmented under these condi-
tions and the products trapped with methyl iodide as elec-
trophile (Scheme 3). In both cases, the methylated imine
9 was isolated. As a by-product, the addition of n-BuLi to
the primarily formed imine was found. The analogous
fragmentation of the diethyl derivative proceeded similar-
ly to give the corresponding imine. However, the 2-aza-
allyl anion is not formed due to the low acidity of the
imine.
Aryldiazenes, the second type product from the above-
mentioned fragmentation process,4 are, by comparison
with the diazonium ions, less frequently investigated.
They have been generated by fragmentation, elimination
or reduction processes4 and are allegedly found as inter-
mediates in the reduction of diazonium salts, the Sand-
meyer reaction and related transformations. The fragmen-
tation of carbonyl diazenides, used as linker for solid
phase synthesis by Lowe19 and Waldmann,20 presumably
proceeds via such intermediates. The present route pro-
vides a novel access to this kind of highly reactive inter-
mediate.
In the case of the pyrrolidinodiazenyl arene 13, metalation
with LDA or BuLi at the heterocyclic core was observed
(Scheme 4). The intermediate is somewhat more stable
and subsequent reaction with an electrophile leads, main-
ly, to the substituted pyrrolidinodiazenyl arene 14. How-
ever, partial fragmentation was also observed. The
intermediate 3,4-dihydro-2H-pyrrole was trapped in a
1,2-addition reaction8 with the nucleophile formed by loss
of nitrogen from the aryldiazenyl anion to give pyrrolidine
15.9
Further, this fragmentation reaction allows a general ac-
cess to 2-azaallyl anions, since the analogous N,N-
dibenzylhydrazones21 and N,N-dibenzylsulfonamides22
react similarly.23
In summary, a novel reaction was observed on solid
support for the first time. The fragmentation of dibenzyl-
triazenes opens a new pathway for the basic cleavage of
this type of compounds. The products obtained, 2-azaallyl
anions and diazenylarenes, are generated under mild con-
ditions and with a wide synthetic potential. We are cur-
rently investigating the scope and limitations of this
reaction and trying to establish further experimental evi-
dence for its mechanism.
The elimination of HCl from 1-chloropyrrolidine was in-
vestigated before, leading to 3,4-dihydro-2H-pyrrole.10 In
addition, the thermolysis of tetrazenes also gives rise to
the elimination products.11
The analogous deprotonation of N-sulfonamides12 and N-
nitrosamines13 is well known (the overall reaction is sim-
ilar to an Umpolung reaction14 however, only the frag-
mentation of sulfonamides has been reported so far.12
General Procedure for the Attachment of Secondary Amines to
the T2* Diazonium Resin24
Overall, this metalation/fragmentation protocol provides
a novel route to 1,3-diarylazaanions, which have been
In a three-necked round bottom flask equipped with a mechanical
stirrer was suspended 10.0 g (5.3 mmol, loading 0.53 mmol/g) of
T2* diazonium resin in THF. The mixture was cooled to –5 to
–10 °C (ice-bath) and the secondary amine (2.65–5.3 mmol, 5–10
equiv) added with stirring. After stirring for 0.5–1 h, the ice-bath
was removed and the mixture allowed to warm to r.t.. The resin 4
used in the synthesis of 2,5-diarylpyrrolidines,15
-
lactams16 and other heterocyclic systems.17 In addition, 2-
azaallyl anions and their homologues have been investi-
gated in terms of rearrangement reactions.18
1) n-BuLi, THF, -20 °C
yellow → deep red
2) MeI
Me
N
N
N
Ph
deep red → yellow
X
+
Ph
N
Ph
H
X
Ph
yellow
56-67%
10: T2 (para)
11: T2*
12
9
Scheme 3 Metalation and fragmentation of triazene T2/T2* resins 10 and 11
Synlett 2002, No. 6, 915–918 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Base-Induced Fragmentation of N,N-Dibenzyl-N -aryltriazenes
917
Nu
E
R1
N
E
R1
R1
N
R1
1) Nu-
2) E+
E-X
R1
N
R1
R1
N
N
R1
R1
N
R1
R1
N
N
R1
N
N
N=N−
n-BuLi
-78 °C
N=NH
R2
R2
R2
R2
N2
N2
H
E
E-X
R2
R2
R2
Scheme 5 Mechanistic rationale for the base-induced fragmentation (R1 = Ph; R2 = H, Cl; in boxes: molecules isolated).
was filtered off, washed sequentially with THF, CH2Cl2, and MeOH
and dried in high vacuum.
(3) (a) Nelson, J. C.; Young, J. K.; Moore, J. S. J. Org. Chem.
1996, 61, 8160. (b) Bräse, S.; Köbberling, J.; Enders, D.;
Wang, M.; Lazny, R.; Brandtner, S. Tetrahedron Lett. 1999,
40, 2105.
(4) Kosower, E. M. Acc. Chem. Res. 1971, 4, 193.
(5) Bräse, S.; Enders, D.; Köbberling, J.; Avemaria, F. Angew.
Chem. Int. Ed. 1998, 37, 3413.
(6) Gross, M. L.; Blank, D. H.; Welch, W. M. J. Org. Chem.
1993, 58, 2104.
(7) Since the diethyl derivative is cleavable also (see below), the
stability of the piperazine triazenes might be due to kinetic
reasons.
(8) For the 1,2-addition of 3,4-dihydro-2H-pyrrole: (a) Scully,
F. E. J. Org. Chem. 1980, 45, 1515. (b) Nakamura, M.;
Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 8489.
(9) This reaction is similar to the aza-1,2-Wittig rearrangement
reaction with concurrent loss of nitrogen.
(10) Nutt, R. F.; Joullié, M. M. J. Am. Chem. Soc. 1982, 104,
5852.
(11) Rademacher, P.; Heymanns, P.; Münzenberg, R.; Woell, H.;
Kowski, K.; Poppek, R. Chem. Ber. 1994, 127, 2073.
(12) Bozec-Ogor, S.; Salou-Guiziou, V.; Yaouanc, J. J.; Handel,
H. Tetrahedron Lett. 1995, 36, 6063.
General Procedure for the Metalation of Triazenes on Solid
Support24
a) The resin 3 or 4 (0.90 g, 0.513 mmol, loading 0.57 mmol/g) was
suspended in THF (10 mL). BuLi or LDA (1.54 mmol, 3 equiv) was
added at –20 °C and the mixture was agitated at this temperature.
After 2 h, the electrophile (MeI, 6.0 mmol) was added and the mix-
ture was agitated for another 2 h at –20 °C. The reaction was
quenched by the addition of water (1 mL), the resin filtered off, and
sequentially washed with THF, CH2Cl2, and MeOH and dried in
high vacuum.
b) The resin 2 (0.4 g, 0.32 mmol, loading 0.80 mmol/g) was sus-
pended in THF (30 mL). BuLi (1.2 mmol, 3 equiv) was added at
–40 °C and the mixture agitated at this temperature. After 2 h, the
electrophile (MeOH) was added and the mixture was agitated for
0.5 h at –20 °C and let to warm up to r.t.. The resin filtered off, and
sequentially washed with THF, CH2Cl2 and MeOH and dried in
high vacuum.
Acknowledgement
(13) (a) Seebach, D.; Dach, R.; Enders, D.; Ranger, B.; Jansen,
M.; Brachtel, G. Helv. Chim. Acta 1978, 61, 1622.
(b) Shibata, N.; Katoh, T.; Terashima, S. Tetrahedron Lett.
1997, 38, 619. (c) Schmitz, E.; Sonnenschein, H.;
Gründemann, C. J. Prakt. Chem. 1980, 322, 261.
(14) (a) Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239.
(b) The ‘Umpolung’ was referenced to the change of a a2-
synthon to a d2-synthon similar to the use of N-
nitrosoamines.
We thank the Deutsche Forschungsgemeinschaft (BR 1750), the
Fonds der Chemischen Industrie and the companies Grünenthal,
CalBioChem-NovaBioChem and Bayer for financial support.
References
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M. E. P. Lormann et al.
LETTER
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Synlett 2002, No. 6, 915–918 ISSN 0936-5214 © Thieme Stuttgart · New York