Traceless tosylhydrazone-based triazole formation: A metal-free alternative to strain-promoted azide-alkyne cycloaddition

Article abstract of DOI:10.1002/anie.201108850

Triple-T trick! Traceless tosylhydrazone-based triazole formation is readily achieved by reacting primary amines with functional α,α- dichlorotosylhydrozones under ambient conditions. This fast and efficient alternative affords exclusively 1,4-substituted triazole "click products" with complete retention of configuration. Primary amines, inherent to many natural products, can be modified in this way without protecting group manipulations. Copyright

Full text of DOI:10.1002/anie.201108850

Angewandte
Chemie
DOI: 10.1002/anie.201108850
Metal-Free Click Reaction
Traceless Tosylhydrazone-Based Triazole Formation: A Metal-Free
Alternative to Strain-Promoted Azide–Alkyne Cycloaddition**
Sander S. van Berkel, Sebastian Brauch, Lars Gabriel, Michael Henze, Sebastian Stark,
Dimitar Vasilev, Ludger A. Wessjohann, Muhammad Abbas, and Bernhard Westermann*
The unprecedented impact of the CuI-mediated Huisgen
Table 1: Cyclooctyne-based probes for metal-free triazole formation.
cycloaddition reaction is demonstrated by its manifold
Group
Name
Structure
applications in the life sciences and material sciences.[1,2]
The requirement of a metal catalyst, however, has limited
the utilization of this cycloaddition reaction in areas such as
photophysical chemistry and chemical biology. Consequently,
several metal-free processes have been developed to serve as
orthogonal ligation methods.[3] At present the foremost
method is the strain-promoted azide–alkyne cycloaddition
(SPAAC) as is reflected by the fast growing number of
cyclooctyne derivatives developed by the groups of Ber-
tozzi,[4] Boons,[5] Rutjes,[6] and van Delft[7] (Table 1). In
addition to SPAAC, SPANC,[8] and SPANOC,[9] several
other metal-free click methods relying on cycloaddition
reactions with alkenes have received considerable atten-
tion.[10–13]
Disadvantages of these strategies are: 1) the formation of
equimolar quantities of the 1,4 and 1,5 regioisomers; and
2) the requirement of functional handles on both substrates,
for example, an activated double or triple bond and the
appropriate complementary counterpart. To reduce the
synthetic efforts, one of the functionalities should be readily
available, that is, inherent to a large variety of starting
materials, so that it can be used without further manipulation
in a click-type reaction.
MOFO, X=H
DIFO, X=F
Bertozzi et al.
Bertozzi et al.
van Delft et al.
DIMAC
BCN
Boons et al.
Rutjes et al.
DIBO
DIBAC
In 1986 Sakai et al. described such a reaction for the
elegant formation of triazoles and thiadiazoles.[14] The Sakai
approach relies on the condensation of a primary amine and
an a,a-dichlorotosylhydrazone (1) to form regioselectively
a 1,4-substituted triazole (3) under ambient reaction condi-
tions (Scheme 1). As a result of the highly chemoselective
character of this reaction, protecting group strategies, in
Scheme 1. Proposed mechanism for the Sakai reaction incorporating
the Bamford–Stevens intermediate. Ts=tosyl.
principal, seem to be unnecessary. Surprisingly, this elegant
and mild protocol for the formation of stable 1,2,3-triazoles
has found only infrequent applications.[15]
Despite the evident potential of this reaction, it has not
been fully exploited; that is, neither the mechanism nor the
scope and limitations have been explored. Here we report our
findings concerning the Sakai triazole formation reaction and
demonstrate the suitability of this methodology as a strategy
for metal-free triazole conjugation and an alternative to the
traditional azide–alkyne cycloaddition.
[*] Dr. S. S. van Berkel, Dipl.-Chem. S. Brauch, L. Gabriel,
Dipl.-Chem. M. Henze, Dipl.-Chem. S. Stark, Dipl.-Chem. D. Vasilev,
Prof. Dr. L. A. Wessjohann, Dr. M. Abbas, Prof. Dr. B. Westermann
Department of Bioorganic Chemistry
Leibniz-Institute of Plant Biochemistry
Weinberg 3, 06120 Halle (Germany)
E-mail: bwesterm@ipb-halle.de
Homepage: http://www.ipb-halle.de
Prof. Dr. L. A. Wessjohann, Prof. Dr. B. Westermann
Institute of Chemistry
For the identification of the scope and limitations of the
Sakai reaction, two a,a-dichlorotosylhydrazones (1a[16] and
1b)[15a] were prepared and reacted with a variety of primary
amines (2a–j). The reactions were performed either in
a solvent mixture of acetonitrile and ethanol (1:1 v/v%) or
in methanol, in the presence of six equivalents of N,N-
diisopropylethylamine (DiPEA). These simple reaction con-
Martin-Luther-University, Halle-Wittenberg
Kurt-Mothes-Strasse 2, 06120 Halle (Germany)
[**] The donation of phytosphingosine by T. Bçhmer, Evonik-Industries,
Essen (Germany) is highly appreciated. This work was in part
financed by a WGL-PFI project.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108850.
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ditions gave triazoles 3aa–3aj and 3ba–3bj (see Scheme 2) in
good to excellent yields when the reaction mixtures were
stirred for up to 16 h at ambient temperatures.[17]
The incorporation of triazoles in peptides and proteins
applied in peptidomimetics[20] is often not possible owing to
the difficult stereoselective synthesis of azides adjacent to the
chiral center of an amino acid. Enantiomerically pure a-
azides can be generated from their corresponding alcohols by
a modified Mitsunobu reaction[21] or by the kinetic resolution
protocol described by Finn and Fokin.[22] The Sakai reaction,
however, would allow the use of readily available chiral a-
amines. As an example, enantiomerically pure (S)-1-phenyl-
ethylamine (2g) was reacted with tosylhydrazones 1a,b
resulting in the formation of triazoles 3ag and 3bg in
quantitative yield after only 30 min or 1a and 1 hour for 1b.
HPLC analysis on a chiral stationary phase indicated that no
racemization had occurred during the reaction.
In continuation of our efforts to determine the scope and
limitations of this procedure, we focused on the use and
modification of different a,a-dichloroketones (Scheme 3). As
Scheme 2. Primary-amine-derived triazole products (3). Segments
from the starting amine 2 are depicted in blue.
Focusing on the formation of Caryl–N-containing struc-
tures, a frequently reoccurring structural motif in pharma-
ceutical compounds, often prepared by metal-catalyzed cross-
coupling reactions,[18] we tested the suitability of various
anilines (2a–e) in the Sakai reaction. Both electron-rich and
electron-poor anilines served as starting material for the
production of various phenyl triazoles (3aa–3ae and 3ba–
3be, starting from 1a and 1b, respectively). The yields of the
isolated products were in most cases good to excellent.[19]
Dicarboxylic acid 2c could be used without protecting groups
and triazole 3ac was obtained smoothly. A fragment fre-
quently used in affinity/activity-based protein profiling is 4-
aminobenzophenone (2e). Facile conjugation of either tosyl-
hydrazone (1a or 1b) to the amino group was readily
achieved, leading to triazoles 3ae and 3be, respectively.
Shifting from anilines to benzyl and aliphatic amines (2 f–
j), also gave the corresponding triazoles in high yields. To
investigate the amine chemoselectivity, tosylhydrazones 1a,b
were reacted with 4-aminophenylethylamine (2 f). In both
cases immediate bis(triazole) formation was observed leading
to products 3af (69%) and 3bf (55%) in good yields. These
results indicate poor chemoselectivity regarding aromatic
amines over aliphatic amines; however, more examples are
required. No restrictions were observed when aliphatic
amines 2h–j were used, including acetal-functionalized
amine 2j, leading to the corresponding triazoles 3ah–3aj
and 3bh–3bj in good to excellent yields (up to 96%).
Scheme 3. A) 1-Aminotriazole formation upon treatment of a,a-
dichloroacetophenone with tosylhydrazine; B) attempted synthesis of
tosylhydrazone 1d; C) formation of functional tosylhydrazones 1e and
1 f.
was also demonstrated by Sakai and co-workers,[14] isolation
of tosylhydrazone 1c obtained from a,a-dichloroacetophe-
none and tosylhydrazine could not be accomplished. Instead,
the N-substituted triazole 4 was isolated after crystallization
(Scheme 3A). This product is presumably generated after
osazone formation of intermediate 1c with a second equiv-
alent of tosylhydrazine.[23] Saponification of the ester moiety
of tosylhydrazone 1b should result in tosylhydrazone 1d
(Scheme 3B), which could then be utilized in further func-
tional group transformations. Unfortunately, under the
employed reaction conditions (mild basic or acidic) the
desired product 1d was not obtained. Most likely, the mild
basic conditions favor the formation of the diazo intermediate
which undergoes decomposition in a subsequent step follow-
ing the Bamford–Stevens mechanism.[24]
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Conversely, mild acidic conditions appeared to give no
hydrolysis at all. With the purpose of obtaining functional
tosylhydrazones, a concise synthetic strategy was employed
(Scheme 3C). In the first step a cooled solution of e-lactone in
CH2Cl2 was treated with lithium diisopropylamide (LDA)
resulting in the formation of the desired a,a-dichloroketone 5
(67%).[25] This compound could then either be transformed
into the corresponding tosylhydrazone 1e (52%), or treated
with periodate and converted into the carboxylic acid
derivative 6 (94%). Finally, a,a-dichloroketone 6 was reacted
with tosylhydrazine to generate tosylhydrazone 1 f in 40%
yield (nonoptimized conditions). The obtained tosylhydra-
zones (1e and 1 f) were subsequently subjected to the Sakai
reaction following the established protocol (see Scheme 4). In
accordance with the observations for 2g, products 3eg and
3 fg were obtained in good yields and with retention of
configuration.
otosylhydrozones 1e and 1 f were also utilized in the coupling
reaction with 7. This procedure generated the corresponding
triazole analogues 8b and 8c in high yields (76% and 89%,
respectively) in a single step, starting from the unprotected
phytosphingosine, thus laborious protection and deprotection
steps could be sidestepped.
Psychosine is a glycosphingolipid occurring in the pathol-
ogy of globoid cell leukodystrophy (GLD), a genetic meta-
bolic disorder that results from the absence of the enzyme
galactosyl ceramide.[28] Recently, photoaffinity probes were
employed as useful tools for identifying these yet unknown
receptors.[29] The derivatization presented in Scheme 5 ena-
bles the facile, straightforward synthesis of suitable probes.
The triazole-modified psychosine 10 could be synthesized
from psychosine (9) and tosylhydrazone 1e in a single step in
a moderate 48% yield. Again, thanks to the superior chemo-
selectivity of this protocol, previously unknown modifications
can be incorporated and a highly functionalized molecule can
be prepared without laborious protecting group manipula-
tions.
The examples herein clearly show the versatility of the
Sakai reaction as a strategy for metal-free triazole formation.
In contrast to the strain-promoted azide–alkyne cycloaddition
reaction, this methodology applies readily accessible starting
materials such as amines and a,a-dichlorotosylhydrazones.
The latter can be prepared from cheap and commercially
available starting materials by a two-step procedure. More-
over, highly defined products are obtained as a result of the
regioselective formation of exclusively 1,4-substitued tria-
zoles. Currently investigations are underway in our laborato-
ries regarding the use of the Sakai reaction in bioconjugation
strategies for the modification of complex biological targets
and surfaces.
Scheme 4. Sakai reaction with functional tosylhydrazones 1e and 1 f.
In work on biologically significant targets we focused on
the modification of phytostigmine (7) and psychosine (9;
Scheme 5). The N-acylated phytoceramides, like the analo-
gous N-acylated ceramides, show a pronounced cytotoxic
effect on different cell types.[26] Moreover, corresponding
triazole-modified, metabolically stable ceramides and phyto-
ceramides have previously been synthesized and evaluated
successfully,[27] demonstrating the amide-bond mimicry of Experimental Section
General procedure: A cooled solution (08C) of amine 2 (0.25 mmol)
1,2,3-triazoles. Elaborating on this topic we employed the
Sakai reaction of tosylhydrazone 1a and phytosphingosine (7)
to prepare 4-Me-triazolyl-phytoceramide 8a (77%) in
a single step. In addition to tosylhydrazone 1a, a,a-dichlor-
in ethanol (3 mL) was treated with N,N-diisopropylethylamine
(0.26 mL, 1.50 mmol, 6 equiv). The solution was stirred for 10 min
before a solution of hydrazone 1 (0.33 mmol, 1.3 equiv) dissolved in
acetonitrile (2 mL) was added dropwise. Stirring was continued at
room temperature until the reaction was complete (checked by thin-
layer chromatography). Subsequently, all volatiles were removed
under reduced pressure and the residue was purified by column
chromatography.
Published online: && &&, &&&&
Keywords: bioconjugation · click chemistry ·
.
nitrogen heterocycles · Sakai reaction
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4
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Metal-Free Click Reaction
Triple-T trick! Traceless tosylhydrazone-
based triazole formation is readily ach-
ieved by reacting primary amines with
functional a,a-dichlorotosylhydrozones
under ambient conditions. This fast and
efficient alternative affords exclusively
1,4-substituted triazole “click products”
with complete retention of configuration.
Primary amines, inherent to many natural
products, can be modified in this way
without protecting group manipulations.
S. S. van Berkel, S. Brauch, L. Gabriel,
M. Henze, S. Stark, D. Vasilev,
L. A. Wessjohann, M. Abbas,
B. Westermann*
&&&& — &&&&
Traceless Tosylhydrazone-Based Triazole
Formation: A Metal-Free Alternative to
Strain-Promoted Azide–Alkyne
Cycloaddition
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!