Reactions of resin-bound triazenes with dithianylium tetrafluoroborates: Efficient synthesis of α-Azo ketene dithioacetals and related hydrazones

Article abstract of DOI:10.1021/ol4037133

The conversion of dithianylium cations into α-azo ketene dithioacetals via addition of polymer-bound diazonium precursors is shown. This new procedure allows the synthesis of α-azo ketene dithioacetals in one step within 2-90 min at rt and yields highly p

Full text of DOI:10.1021/ol4037133

Letter
pubs.acs.org/OrgLett
Reactions of Resin-Bound Triazenes with Dithianylium
Tetrafluoroborates: Efficient Synthesis of α‑Azo Ketene Dithioacetals
and Related Hydrazones
Nicole Jung,*,†,‡ Bettina Stanek,† Simone Graßle,† Martin Nieger,§ and Stefan Brase*,†,‡
̈
̈
†Karlsruhe Institute of Technology, Campus North, Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
‡Karlsruhe Institute of Technology, Campus South, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
§University of Helsinki, A.I. Virtasen aukio 1, P.O. Box. 55, 00014, Helsinki, Finland
S
* Supporting Information
ABSTRACT: The conversion of dithianylium cations into α-azo
ketene dithioacetals via addition of polymer-bound diazonium
precursors is shown. This new procedure allows the synthesis of
α-azo ketene dithioacetals in one step within 2−90 min at rt and
yields highly pure compounds that do not have to be purified in
most cases. The α-azo ketene dithioacetals obtained have been
shown to be valuable intermediates for the synthesis of
hydrazones, α-halogenated α-azo ketene dithioacetals, and azo-
functionalized dienes.
Scheme 1. Formation of Dithianylium Tetrafluoroborates 2
s 1,3-dithianes and their derivatives are excellent
Aprecursors for the introduction of diverse functional
groups, electro- and nucleophilic dithiane derivatives and
methods for their modification are of high interest in organic
chemistry. Out of the group of 1,3-dithian-containing
compounds, the ketene dithioacetals are very attractive
intermediates1 that have been investigated for their ability to
add electrophiles as halonium ions,2 α,β-unsaturated carbonyls3
(via Pd catalysis4) or acyl chlorides5 for a long time. In addition,
these ylidene-dithioketals offer a wide range of chemical
diversity. They can be e.g. oxidized enantioselectively to their
bissulfoxides,6 fluorinated via oxidative difluorodesulfuration,7
can be derived by C−S bond cleavage, or converted into diverse
heterocycles.8 In addition to various well-known trans-
formations of the α-position, the reaction of the versatile
dithiane moiety with azo-building blocks has been shown to
yield α-azo ketene dithioacetals recently.9 These α-azo ketene
dithioacetals are interesting intermediates for organic syntheses.
They are formal precursors for α-arylazo-carbonyls10 or
hydrazones11 which are very famous building blocks in organic
chemistry, as they can be used for the formation of heterocycles
(e.g., via the Fischer indole synthesis). As far as we know, only
two procedures for the synthesis of α-azo ketene dithioacetals
from diazonium precursors have been described,9,12 both
suffering from the mandatory presence of an α-carboxy
functionality and additional electron-withdrawing groups. In
addition, a related procedure from dithiafulvene has been
described.13
and Ketene Dithioacetals 315
dithioacetals 3,15 we were interested in their use for the
formation of α-arylazo ketene dithioacetals. The necessary
diazonium ion for the α-arylazo ketene formation has been
added in the form of solid-supported triazenes 4 (see Table 1)
that act as a protecting group for diazonium ions.16
While the reactions of triazene linkers with ketene
dithioacetals 3 were not successful, the reaction of the
dithianylium tetrafluoroborate salts 2 (as activated form of
the ketene dithioacetals) with several immobilized triazenes in
dichloromethane gave excellent results without any additives
within short reaction times. These results encouraged us to
develop an efficient protocol for the diazo-transfer to dithiane
building blocks yielding α-azo ketene dithioacetals in a very
simple manner (Table 1). The synthesis of the starting
materials has been performed according to well-established
protocols for the synthesis of dithianylium salts 2 by reaction of
propanedithiol with acyl chlorides 1 in tetrafluoroboric acid or
boron trifluoride (Scheme 1).15 Depending on the aromatic or
aliphatic residue R1, the corresponding dithianylium tetra-
The benefits of dithianylium tetrafluoroborates 2 (Scheme 1)
for transformations in organic syntheses are of current concern
in our group.14 As the latter ones are highly reactive
compounds and precursors for the formation of ketene
Received: December 22, 2013
Published: February 11, 2014
© 2014 American Chemical Society
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Table 1. Synthesis of α-Azo Ketene Dithioacetals 5 from Dithianylium Tetrafluoroborates 2 and Resin-Bound Triazenes 4
2
4
5
R1
R2
R3
R4
yield [%]
1
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2d
2d
2d
2d
2d
2e
2e
2e
2e
2f
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
I
99
74
2
H
CH2OH
OMe
benzo
H
H
H
ab
,
3
H
quant
93
4
benzo
H
Br
5
F
99
6
H
H
OPh
H
97
a
7
4g
4h
4e
4f
5g
5h
5i
Me
H
Cl
98
a
8
H
CO2Et
F
96
9
H
H
quant
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
5j
H
H
H
OPh
I
88
a
4a
4f
5k
5l
H
H
H
93
CO2Me
H
H
OPh
F
99
b
4e
4g
4e
4c
4a
4f
5m
5n
5o
5p
5q
5r
CO2Me
H
H
87
a
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CO2Me
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
Me
H
Cl
H
86
a
H
F
90
a
H
OMe
H
H
83
a
H
I
78
a
H
H
OPh
H
97
4c
4e
4g
4f
5s
5t
H
OMe
H
75
b
H
F
quant
a
5u
5v
5w
5x
5y
Me
H
Cl
H
90
H
OPh
F
90
a
4e
4g
4f
H
H
81
b
2f
CH3
Me
H
Cl
H
94
2f
CH3
H
OPh
96
a
b
Purification via column chromatography has been performed. Up to 3.8 equiv of the resin have been added (see details in Supporting
Information).
fluoroborates 2 were obtained as crystals or as highly viscous
oils that could be isolated via separation of the organic layers in
a separation funnel. In both cases, no further purification of the
starting material was necessary. The formation of the protected
diazonium-electrophile 4 has been achieved via diazotization of
diverse amines and following immobilization on amino benzyl-
modified Merrifield resin according to published procedures.16
The combination of these stable, less toxic immobilized
triazenes 4 (Scheme 2) with highly reactive dithianylium
cations 2 resulted in an α-azo ketene dithioacetal synthesis with
several beneficial aspects. The synthesis of the target
compounds 5 (Table 1) is independent of additional
electron-withdrawing groups or the presence of carboxylic
acid functionalities in α-position to the starting dithiane moiety.
The reaction can be conducted at rt without the addition of
acids, and the product can be easily obtained by filtration of the
crude material. For less reactive substrates 2 (bearing electron-
withdrawing substituents in α-position), an excess of solid-
supported triazene can be added without loss of purity as
unreacted resin-bound material is removed by filtration. All of
the substances were obtained in good to excellent yields very
often without the need for further purification (Table 1). All
reactions have been performed in small scale according to a
combinatorial application (using ∼0.1 mmol of starting material
2a−f), and the applicability for synthesis in mmol scale has
been proven as well. The reaction has been performed with 2.6
Scheme 2. Proposed Mechanism of the α-Azo Ketene
Dithioacetal Formation
mmol of the starting material 2a furnishing the target
compound 5e with a slightly diminished yield of 96% (in
comparison to 99% in 0.1 mmol scale) (Table 1, entry 5).
As similar α-azo ketene dithioacetals have been isolated as
not only six- but also five-membered derivatives and in the form
of the noncyclic acetals before,9 we decided to show the scope
of the reaction by using dithiolanylium tetrafluoroborates (2*)
instead of dithanylium tetrafluoroborates (2) as starting
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material (Scheme 1). The corresponding five-membered ketene
dithioacetals have been isolated in 64−72% yield after
chromatographic purification proving the utility of the herein
presented concept for the formation of five-membered α-azo
ketene dithioacetals as well.17
excess of BH3·Me2S was added. All reactions have been
completed after heating of the reaction mixture for 2−60 min at
80 °C, giving (E)-1-(1-(1,3-dithian-2-yl)ylidene)-2-phenyl-
hydrazines 9 in moderate to good yields over one or two
steps (Table 2).
The addition of the diazonium moiety to the α-position of
dithianylium tetrafluoroborates as shown in Table 1 gave
exclusively the E-isomer which has been proven via the crystal
structures of compounds 5a and 5h. The molecular structure of
(E)-1-((1,3-dithian-2-ylidene)(phenyl)methyl)-2-(4-iodo-
phenyl) diazene 5a (Scheme 2) shows exemplarily the almost
flat core of the α-azo ketene dithioacetal which the phenyl
residue (R1) is stacked to orthogonally (Figure 1).
Table 2. Reduction of α-Azo Ketene Dithioacetals 5 to Their
Corresponding Hydrazones 9
sm
9
R1
R2
R3
R4
yield [%]
49
1
2
3
4
5
6
7
5i
9a
9b
9c
9d
9e
9f
Ph
Ph
H
H
H
Cl
H
H
I
F
a
5f
H
OPh
H
58
a
5u
5t
CH2CH3
CH2CH3
COOMe
CH2CH3
Me
H
68
F
51
50
5m
2e
2c
H
F
b
H
Me
H
67
b
9g
COOMe
Me
Cl
46
a
b
Yield calculated over 2 steps. Yield of a one-pot procedure: reaction
of dithianylium tetrafluoroborates 2c and 2e with triazenes 4i (R2 = H;
R3 = I; R4 = Me) and 4g and following reduction with BH3·Me2S; sm
= starting material.
Figure 1. Molecular structure of (E)-1-((1,3-dithian-2-ylidene)-
(phenyl)methyl)-2-(4-iodophenyl)diazene 5a (one of the two
crystallographic independent molecules is shown; displacement
parameters are drawn at the 50% probability level). Crystallographic
data (excluding structure factors) have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
nos. CCDC-972508 (5a) and CCDC-972509 (5h)21 and are available
as data of the Chemotion repository via DOI: 10.14272/QPYBP-
CGVZSEXOY-FMQUCBEESA-N/Xray (5a) and DOI: 10.14272/
OHDRPYNAGNRNNM-QURGRASLSA-N/Xray (5h).
To provide an access to the novel compound class of (E)-1-
((1,3-dithian-2-ylidene)halomethyl)-2-phenyldiazenes (10), the
reaction of the cleaved azo-derivatives 5 with N-iodo- and N-
bromosuccinimide has been successfully shown (Table 3).
Table 3. Synthesis of (E)-1-((1,3-Dithian-2-
ylidene)halomethyl)-2-phenyl Diazenes (10)
In accordance with previous investigations18 we proposed the
following mechanism for the formation of α-azo ketene
dithioacetals 5 (Scheme 2). The dissolved dithianylium salts
2 form, to some extent, free tetrafluoroboric acid that is known
to cleave the acid labile triazene linkage of the T1-linker.19 At
rt, the released diazonium ions 6 react with the in situ generated
ylidene-dithianes 3 to give dithianylium tetrafluoroborates 8.
The latter ones decompose immediately to α-azo ketene
dithioacetals 5 with elimination of HBF4. Due to the presence
of solid supported benzylamine as a side product of the
reaction, the resulting HBF4 reacts to form an immobilized salt
and is removed via filtration of the crude reaction mixture.
To prove the potential of the furnished α-azo ketene
dithioacetals 5 for the formation of precursors for e.g.
heterocycle synthesis or the construction of complex
conjugated systems, some key transformations into common
building blocks for cyclization and cross-coupling reactions
have been disclosed for the first time. As one of the most
popular name reactions for the formation of heterocycles, the
Fischer indole reaction uses hydrazones as starting material; we
developed a very fast protocol for the reduction of α-azo ketene
dithioacetals 5 to highly functionalized hydrazones 9. Upon
reaction with several reducing agents, the freshly prepared
target substances 5 have been shown to be stable against
sodium borohydride, lithium aluminum hydride, and many
other reducing agents. The desired hydrazones 9 have been
obtained only via treatment with BH3·Me2S. In a typical
procedure, the starting material 5 was dissolved in THF and an
sm
5i
10
X
R2
R3
R4
yield [%]
1
2
3
4
5
6
10a
10b
10c
10d
10e
10f
Br
I
H
H
H
H
H
H
Cl
F
99
99
60
50
72
5i
H
F
5j
Br
I
H
OPh
OPh
I
5j
H
5k
I
H
a
2b/4g
I
Me
H
57
a
Yield of a one-pot procedure from reaction of 2-2-methyl-5,6-
dihydro-4H-1,3-dithianyliumtetrafluoroborate (2b) with triazene 4g
and following iodination with NIS; sm = starting material.
According to similar procedures that are known for the
halogenation of ketene dithioacetals, the functionalized target
compounds 10 have been isolated in good to excellent yields by
addition of 1.0−1.5 equiv of NBS or NIS and stirring in
acetonitrile at rt for 60 min (Table 3).
While electron-withdrawing groups on the aromatic residue
of the α-azo ketene dithioacetal core seem to stabilize the
halogenated products and high yields could be reached, the
reaction of derivatives bearing electron-donating substituents
(entries 3, 4, and 6) gave lower yields. The reaction proceeded
cleanly with only small amounts of side products, but the
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Letter
chromatographic purification was accompanied with partly
decomposition of the target substances 10. The reaction to
chloro-substituted derivatives 10 was successful as well (GC-
MS analysis of the crude product), but the chlorinated products
decomposed immediately during the chromatographic purifi-
cation.
ACKNOWLEDGMENTS
This work was supported by the Helmholtz Program
Biointerfaces. We thank Bekir Bulat (University Dusseldorf),
Pia Lang, Angelika Kernert, Ingrid Rossnagel, and Dominic
■
̈
Lutjohann (all KIT) for their kind support.
̈
The new halogenated α-azo ketene dithioacetals 10 offer a
wide range of possible transformations of which we chose the
Suzuki cross-coupling reaction to demonstrate exemplarily the
utility to synthesize functionalized dienes 11a and 11b in good
yields (Scheme 3). As the precursors 2, 5, and 10 could be
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ASSOCIATED CONTENT
* Supporting Information
■
S
(18) Copies of the data can be obtained free of charge on application
to: The Director, CCDC, 12 Union Road, GB-Cambridge CB2 1EZ
(Fax int. +1223/336033; E-mail: deposit@ccdc.cam-ak.uk).
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Syntheses of dithianylium tetrafluoroborates 2a−f; general
procedures for resins 4a−i, α-azo ketene dithioacetals 5a−y,
hydrazones 9a−g, α-halo-azo ketene dithioacetals 10a−f, and
dienes 11a,b; analytical data for all synthesized compounds and
crystallographic data for 5a and 5h (including cif files).20 This
material is available free of charge via the Internet at http://
pubs.acs.org.
(20) The T1 linker has been used to immobilze anilines (via
formation of diazonium salts and addition to benzylamino-modified
Merrifield resin).
AUTHOR INFORMATION
Corresponding Authors
■
(21) http://www.chemotion.net/.
*E-mail: nicole.jung@kit.edu.
*E-mail: stefan.braese@kit.edu.
Notes
The authors declare no competing financial interest.
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