Cleavage of immobilized disubstituted triazenes with electrophiles: Solid-phase synthesis of alkyl halides and esters

Article abstract of DOI:10.1016/S0040-4039(01)02019-6

An efficient, selective cleavage of polymer-bound disubstituted triazenes with trimethylsilyl halides produces alkyl chlorides, bromides and iodides in good to excellent purities and yields. Similarly, alkyl esters are formed upon cleavage with carboxylic

Full text of DOI:10.1016/S0040-4039(01)02019-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9179–9181
Cleavage of immobilized disubstituted triazenes with
electrophiles: solid-phase synthesis of alkyl halides and esters
Claudine Pilot,a Stefan Dahmen,a Frank Lauterwasserb and Stefan Bra¨seb,*
aRWTH Aachen, Institut fu¨r Organische Chemie, Professor-Pirlet-Strasse 1, D-52074 Aachen, Germany
bKekule´-Institut fu¨r Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universita¨t Bonn,
Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany
Received 14 September 2001; accepted 25 October 2001
Abstract—An efficient, selective cleavage of polymer-bound disubstituted triazenes with trimethylsilyl halides produces alkyl
chlorides, bromides and iodides in good to excellent purities and yields. Similarly, alkyl esters are formed upon cleavage with
carboxylic acids. © 2001 Elsevier Science Ltd. All rights reserved.
The reaction of diazoalkanes1 with nucleophiles is a
frequently used process to synthesize carboxylic esters2
and alkyl and aryl ethers.3 However, the parent com-
pound for this transformation, diazomethane, and its
higher homologues are considered to be highly toxic
and explosive.1 Similarly, the well-known precursors for
diazomethane (such as Diazald®) are also irritants.4
from the diazonium resin 19 or, more conveniently,
from the room temperature stable diazonium resin T2*
(2),10,11 which are both available in two steps from
Merrifield resin (1–2% cross-linked with DVB, 100–200
mesh, approx. 1 mmol/g loading). Coupling with vari-
ous primary aliphatic amines 3 proceeds smoothly to
give disubstituted triazenes 4 or 5, respectively.12
During the investigation of the synthesis of amides on
solid support using the triazene T2 linker family,5 we
observed that in some cases the acyl coupling was not
effective. When the subsequent cleavage was performed
with trimethylsilyl chloride, alkyl chlorides were pro-
duced in good yields and excellent purities. These pre-
liminary results6–8 prompted us to investigate this
reaction in more detail.
Reaction of the triazene resins 4,5 with trimethylsilyl
chloride (10% in dichloromethane) was found to pro-
ceed smoothly at room temperature within a few min-
utes. Filtration and evaporation of the solvent (ca. 1.0
mbar) afforded the alkyl chlorides 8-Cl in 70–95% yield
and over 90% purity without any further purification
(NMR, GC, and GC–MS).13 Similarly, trimethylsilyl
bromide and trimethylsilyl iodide are suitable to result
in the formation of alkyl bromides and iodides, respec-
tively. Interestingly, the formation of alkenes, a general
The transformation depicted in Scheme 1 can be used
for the synthesis of alkyl halides. The synthesis starts
Me3SiX
(X = Br, Cl, I)
H
N
RNH2
3
+
N
−
NH2
R
+
N N BF4
N
X-R
CH2Cl2, rt
1,2
4,5
6,7
8-X
−
N2+ BF4
O
−
O
N2+ BF4
Cl
1
2
Scheme 1. Synthesis of alkyl halides.
* Corresponding author. Tel.: +49 228 73 2653; fax: +49 228 73 9608; e-mail: braese@uni-bonn.de
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02019-6

9180
C. Pilot et al. / Tetrahedron Letters 42 (2001) 9179–9181
with trimethylsilyl halides has not been studied before
(Scheme 3).
byproduct of the solvolysis of aliphatic diazonium salts
due to elimination reactions,2 has only being detected in
traces (Scheme 2).
The reaction mechanism also explains the rearrange-
ment of homobenzyl residues 5e to the corresponding
phenylpentenyl residue 8f (Scheme 4), which has also
been observed earlier during the diazotation of a-amino
acids.17 Complex triazenes such as the acetal 4d or the
ephedrine derivative 5c undergo elimination reactions
to produce ketones 14 or aldehydes 13, respectively.
Mechanistically, this reaction proceeds via cleavage of
the disubstituted triazene to the corresponding aniline
resin 6,78 and an aliphatic diazonium ion, which
decomposes in the presence of a nucleophile to give the
alkyl halides. The reaction of alkyl diazonium salts with
halides to give alkyl halides is a commonly used trans-
formation. The general entry into this reaction is the
use of azoalkanes, which are cleavable with HCl,14,15
HBr16 or HI to give the corresponding alkyl halides. To
the best of our knowledge, the reaction of azoalkanes
The cleavage with carboxylic acids was also examined
in this context.18 It is known that disubstituted triazenes
can be used for the alkylation of sensitive acids.19 Thus,
treatment of the disubstituted triazene 5a, as demon-
strated above resulted in the formation of esters 8a-
OAc,OTfa and 8b-OAc,OTfa, respectively, in good
yields. Similarly, homobenzyl resins 5g,h were cleaved
to give the esters 8g,h-OAc,OTfa without detectable
amounts of styrenes caused by elimination. Interest-
ingly, even the less nucleophilic trifluoroacetic acid can
be used for this transformation (Scheme 4).
Me3SiX (X = I, Br, Cl)
Ph
or HX (X = OAc, OTfa)
CH2Cl2, 25 ˚C, 30 min
O
N
N
O
N
H
ca. 80% yield
ca. 95% purity
O
+
5a
General procedure for the cleavage of the T2 linker: A
suspension of the resin (200 mg) in dichloromethane
was treated with 4 equiv. of trimethylchlorosilane and
the mixture was stirred at room temperature for 5 min.
The mixture was filtered and the solvent was removed.
This reaction can also performed in a pipette or fritted
syringe filled with the resins.
X
Ph
Ph
O
O
X
O
O
80:20 − 65:35
8b-Cl: X = Cl
8a-Cl: X = Cl
8b-Br: X = Br
8b-I: X = I
8b-OAc: X = OAc
8b-OTfa: X = OTfa
8a-Br: X = Br
8a-I: X = I
8a-OAc: X = OAc
8a-OTfa: X = OTfa
In conclusion, a novel technique20 for the synthesis of
alkyl halides using solid-phase methods21 was devel-
oped, giving rise to products in high yield and purity.
The method was also successfully applied to the synthe-
sis of alkyl esters.22
Scheme 2. Cleavage of phenylalanine esters.
H
N
O
SiMe3
O
N
N
H
N
Me3SiX, CH2Cl2
5-30 min
O
N
O
O
N
O
Cl
Ph
Cl
Ph
5a
9
O
N
NHSiMe3
+
N
O
O
Cl
Ph
11
10
X−
X
X−
O
O
O
O
O
O
Ph
X
Ph
8b-X
Ph
8a-X
12
Scheme 3. Mechanistic rationale for the cleavage of disubstituted triazenes.

C. Pilot et al. / Tetrahedron Letters 42 (2001) 9179–9181
9181
O
H
N
OH
Me3SiCl, CH2Cl2
rt, 5 min
Ph
N
O
N
Ph
CH3
CH3
85%
Cl
13
5c
4d
Ph
O
Me3SiCl, CH2Cl2
rt, 5 min
OH
O
N
O
O
N
N
H
Ph
90%
14
H
N
Me3SiX, CH2Cl2
rt, 5 min
N
Ph
O
N
Ph
Ar
X
90%
Cl
5e
8f-X: X = Cl
8f-X: X = Br
H
N
TFA, CH2Cl2
rt, 5 min
N
TfaO
O
N
Ar
>99%
Cl
5g: Ar = 2-Benzyloxyphenyl
5h: Ar = 3,4-Dimethylphenyl
8g-OTfa
8h-OTfa
Scheme 4. Cleavage of resins 4d, 5c,e,g,h.
Acknowledgements
10. Dahmen, S.; Bra¨se, S. Angew. Chem., Int. Ed. 2000, 39,
3681–3683.
This work was supported by the Deutsche Forschungs-
gemeinschaft (BR 1750/2-3) and the Fonds der Chemis-
chen Industrie (Liebig Stipend to St. B.). The
companies Bayer AG, BASF AG, Gru¨nenthal GmbH,
and Calbiochem-Novabiochem AG are acknowledged
for the donation of chemicals. We thank K. Hennig for
technical assistance.
11. Commercially available from Calbiochem-Novabiochem.
12. The polymeric compounds were characterized by IR and
elemental analysis; the products 8-X were characterized
by NMR methods, GC–MS, and comparison with
authentic samples. The purity and yields were determined
directly and by GC and GC–MS measurements.
13. This allows, in principle, the recycling of the resins, since
the anilin resins 6,7 are the precursors of the diazonium
resins 1,2.
14. (a) Perrey, D. A.; Scannell, M. P.; Narla, R. K.; Uckun,
F. M. Bioorg. Med. Chem. Lett. 2000, 6, 551–552; (b)
Sapi, A.; Fetter, J.; Lempert, K.; Kajtar-Peredy, M.;
Czira, G. Tetrahedron 1997, 37, 12729–12738.
15. Landais, Y.; Planchenault, D. Tetrahedron 1997, 53,
2855–2870.
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