Gold-Catalyzed Dimerization of Diarylalkynes: Direct Access to Azulenes

Article abstract of DOI:10.1002/anie.201805918

We have developed a simple gold-catalyzed procedure for the synthesis of substituted and modifiable azulenes. The azulenes are formed either by the dimerization of push–pull diarylalkynes bearing a fluorine atom in ortho or para position or by the dimeriz

Full text of DOI:10.1002/anie.201805918

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Accepted Article
Title: Direct Access to Azulenes via the Gold-Catalyzed Dimerization of
Diarylalkynes
Authors: Vanessa Weingand, Siegfried Harrer, Michael Schukin,
Matthias Rudolph, Frank Rominger, Abdullah M. Asiri, Jin Xie,
and A. Stephen K. Hashmi
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http://dx.doi.org/10.1002/ange.201805918

Angewandte Chemie International Edition
10.1002/anie.201805918
Direct Access to Azulenes via the Gold-Catalyzed Dimerization of
Diarylalkynes
a
a
a
Vanessa Claus (neé Weingand), Michael Schukin, Siegfried Harrer, Matthias
a
a[+]
b
a
a,b,
Rudolph, Frank Rominger, Abdullah M. Asiri, Jin Xie, A. Stephen K. Hashmi *
[
a] M. Sc. V. Claus, B. Sc. Michael Schukin, B. Sc. Siegfried Harrer, Dr. M. Rudolph,
Dr. F. Rominger, Dr. J. Xie, Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Heidelberg University
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)-6221-54-4205
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
[b] Prof. Dr. A. M. Asiri, Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University, Jeddah 21589, Saudi Arabia
[+] Crystallographic investigation
Keywords: gold catalysis, vinyl cations, azulenes, alkyne dimerization, push-pull
systems
Abstract:
We discovered a simple gold-catalyzed protocol for the synthesis of substituted and
modifiable azulenes. The azulenes are either formed by the dimerization of push-pull
diarylalkynes bearing a fluorine atom in ortho or para position, or by the dimerization
of a symmetric electron-rich diarylalkyne. In the presence of a cationic gold catalyst
the two alkynes can form a highly reactive vinyl cation. Trapping of this high energy
intermediate by an appropriate aryl unit then delivers substituted azulenes in a single
step and in a perfect atom economy.
In the field of gold catalysis,[1] alkynes still dominate as substrates.[2] In addition to
common reactions in which nucleophiles react with one alkyne moiety, intramolecular
cascade reactions involving two or more connected alkynes are gaining in
[
2a]
importance. Substrates with at least one terminal alkyne can be transformed via dual
[
3]
[4]
gold catalysis, giving access to high energy intermediates such as gold vinylidenes
[
5]
and diaurated phenyl cations. If two connected internal alkynes are used, gold
[
6]
[7]
catalysis gives rise to aurated vinyl cation and phenyl cation species that undergo
further transformations. Related intermolecular dimerizations of alkynes are rare. Both
terminal alkynes and iodoalkynes in the presence of a gold catalyst can dimerize in a
head to tail coupling. We recently reported the first gold-catalyzed dimerization
reaction of push pull diaryl alkynes, the first example for the intermolecular formation
of a high energy intermediate by a gold-catalyzed diyne cyclization. The vinyl cation
[
8]
[
9]
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Angewandte Chemie International Edition
10.1002/anie.201805918
intermediates were trapped by the pending aromatic core which led to highly
substituted naphthalenes. Now we discovered a completely different reactivity for
substrates bearing a fluorine atom at the less electron rich aromatic part. Highly
substituted azulene derivatives are obtained in one single step. The synthesis of
substituted azulene derivatives from such simple precursors is remarkable, azulene
syntheses, despite the long history and the potential for organic electronics, are still
[
10]
challenging. Azulene is a non-alternant hydrocarbon with a high dipole moment and
[
11]
a low HOMO-LUMO energy gap. It is reported that the HOMO-LUMO energy gap of
azulenes is strongly dependent on their substitution pattern. Therefore, a variable and
[
12]
step economic synthesis of substituted azulenes would be extremely useful.
The
electronic structure and its photophysical properties make azulenes highly interesting
[
13]
[14]
[15]
for applications in organic electronics,
bioimaging,
medicinal chemistry
and
[
16]
stimuli response materials. The first syntheses of azulenes were established in the
950s by Ziegler, Hafner and Nozoe. The drawbacks are the low atom and step
[
17]
[18]
1
economy which leads to a lack of variability and accompanying high costs (1 g azulene
costs 285,50 € at Sigma Aldrich (29.04.18)). Only two direct one step syntheses of
azulenes are known. In the presence of palladium complexes, diaryl alkynes can
dimerize to azulenes, but yields are very low and high loadings are needed (yield up
[
19]
to 30% if 1.2 eq. palladium are used).
Non-terminal ynamides dimerize to
[
20]
cyclopentadiene derivatives in most cases in the presence of a gold catalyst, with
aryl ynamides provide azulenes, but only in an unselective fashion and with only poor
yields. Due to the lack of versatile protocols towards azulenes from pre-functionalized
precursors, the most common strategy towards substituted azulenes is the post-
synthetic functionalization of the azulene skeleton.
Scheme 1: Previous study and the discovery of a one-step azulene synthesis.
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Figure 1: Solid state molecular structure of 2a´
Table 1: Screening with substrate 1a
Entry
1
Catalyst
[(IPr )Au(NCMe)]SbF
solvent
DCE
time conversion
2a
57%
2a´
28%
*
[b]
[b]
6
6
1 d
1 d
2 d
100%
1,4
*
-[c]
15%[b] 2%[b]
0%[d] 0%[d]
8%
60%
4%
33%
12%
1%
2
[(IPr )Au(NCMe)]SbF
dioxane
DMSO
acetonitrile 2 d
*
[d]
3
4
5
6
7
8
9
[(IPr )Au(NCMe)]SbF
[(IPr )Au(NCMe)]SbF
[(IPr )Au(NCMe)]SbF
6
6
6
67%
77%
*
[e]
0%
9%
1%
4%
2%
0%
0%
0%
0%
*
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1 d
3 d
3 d
3 d
3 d
3 d
3 d
5 d
100%
[
[
[
[
[
[
e]
e]
e]
e]
e]
e]
[(IPr)Au(NCMe)]SbF
[(Johnphos)Au(NCMe)]SbF
SPhosAuCl/AgSbF
TediiAuCl/AgSbF
PhosphiteAuCl/AgSbF
PPh AuCl/AgSbF
(RO) PAuCl/AgSbF
6
42%
64%
27%
35%
87%
17%
6
6
6
10
11
12
6
4%
1%
0%
3
6
[
e]
3
6
8%
1
[
a] 250 µmol scale; H NMR yields determined with hexamethylbenzene as internal
standard if not otherwise noted; [b] isolated yield; [c] could not be determined; [d] an
oxidation to the 1,2-diketone is observed; [e] unselective conversion.
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A screening with alkyne 1a (Table 1) initially used the optimized conditions from the
naphthalene synthesis, which delivered a combined yield for both isomers of 85% in a
[
21]
ratio of 2:1. In DMSO only the diketone as oxidation product was observed (entry 3).
A low conversion in acetonitrile or 1,4-dioxane significantly reduced the yield of the
desired product (entry 2 and 4). Toluene reduced the overall yield but the selectivity
towards the desired product 2a was higher. Staying in toluene but switching the ligands
to Buchwald-type ligands or electron-poor phosphite ligands, did not lead to an
improvement, even after prolonged reaction times, only the cationic Johnphos gold
catalyst converted more than 60% of the starting material but only gave a low yield
[
22]
(entry 7). Only the IPr* ligand
fully converted the starting material, leading to a
moderate yield of 2a after one day (entry 5). To proof the connectivity of the obtained
[
23]
isomers, crystals of 2a´ were analyzed by X-ray diffraction (see Figure 1).
Table 2: Substrate scope
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Angewandte Chemie International Edition
10.1002/anie.201805918
R2
R2
F
F
2.5 mol% [(IPr*)Au(NCMe)]SbF6]
toluene, 100°C
R1
R1
F
R1
R2
1b-1j
2b-2j
OMe
OTBS
OMe
F
F
F
F
F
F
OMe
OTBS
OMe
2b, 68%
2c, 45%
2d, 80%
OMe
OMe
OMe
F
OMe
F
F
F
F
F
F
F
MeO
OMe
OMe
OMe
2e, 48%
2f, 61%
2g, 78%
OMe
OMe
OMe
F
F
F
F
F
Br
Br
F
F
F
OMe
OMe
OMe
2h, 54%
2i, 50%
2j, 36%
limitations:
Cl
OMe
OMe
OMe
S
Br
F
1
k,
1l,
unselective reaction
1m,
unselective reaction
1n,
no reaction
unselective reaction
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Scheme 2: Gold-catalyzed dimerization of symmetric alkyne 1k
Then we evaluated the scope of the reaction (Table 2). With a fluorine substituent on
the ortho position, the yield of the azulene 2b raised to 67%, exclusively one isomer
was obtained. A silyl-protected alcohol (2c) delivered a slightly lower yield. The
introduction of additional methyl groups (2d, 2e) or a methoxy group (2f) in meta
position was well tolerated, providing moderate to good yields. A second fluoro
substituent in ortho-position significantly increased the yield (2g). Additional fluoro (2h)
and bromo substituent (2i) in para-position led to acceptable yields as well. Particularly
2i, bearing the bromo substituent in 6-position deserves a special note, since it can be
used for further functionalization using cross coupling strategies. An electron-donating
methyl group in para-position (2j) led to a massive drop in yield. If the para-fluoro
substituent was replaced by a chloro (1k), bromo (1l) or methyl group (1m), only
unselective reactions were observed. This might be explained either by the lower push-
pull effect or by the increased sterically hindrance compared to the small fluorine atom.
If an electron-rich thiophene unit (1n) was used instead of the para-methoxybenzene
unit, no reaction took place. Fortunately, we were also able to dimerize a symmetric
substrate bearing methoxy groups in para positions at the aryl units in very good yield
(Scheme 2, 2k).
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Scheme 3: Proposed mechanism
The obtained substitution pattern and the reactivity of the substrates can be explained
by our proposed mechanism (Scheme 3). First, the cationic gold catalyst forms a -
complex with one of the diaryl alkynes 1. The activated triple bond can then be attacked
by the triple bond of the second alkyne giving rise to high energy intermediate II. The
selectivity of the nucleophilic attack of the alkyne is controlled by the stability of the
vinyl cation II, the attack only takes place at the more electrophilic position at the
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second alkyne, which is activated by the gold catalyst bound to the more nucleophilic
carbon. The vinyl cation then is attacked by the electron-poorer aromatic unit bearing
the fluorine in ortho- or para-position to deliver the cationic spiro-compound III.
Compared to the substrates used for the naphthalene synthesis, the fluoro substituent
holds an extremely strong + M effect. Due to the position of the fluorine either in ortho-
or para-position this directs the attack to the carbon directly connected to the alkyne
(the electronically different meta-fluoro derivative only provided a naphthaline). Then
isomerization to the cationic tricyclic species IV and ring expansion leads to aurated
azulene compound V which upon elimination of the cationic gold fragment forms
azulene 2 under release of the active catalyst.
Table 3: Substrate scope for the nucleophilic substitution reaction
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OMe
OMe
NuH
base
MeCN, 50-80 °C
F
F
F
Nu
OMe
OMe
OMe
N
OMe
OMe
O
N
N
F
F
O
N
F
OMe
a, 90%
OMe
OMe
3
3ba, 93%
3bb, 88%
OMe
F
OMe
OMe
F
Br
N
O
S
F
OMe
OMe
OMe
3
bc, 65%
3bd, 86%
3be, 91%
OMe
F
Br
S
Br
S
F
OMe
3
h, 87%
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Angewandte Chemie International Edition
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OMe
OMe
F
OMe
F
HO
F
NH2
O
F
NH in
3
ethylene glycol
1
50 °C
autoclave
OMe
OMe
OMe
2
b
3bf, 83%
3bg, 4%
Scheme 4: Nucleophilic substitution with ammonia
Scheme 5: Bromination of 2b with NBS
For potential applications of azulenes in any field, the possibility for selective
functionalization of the molecule is crucial. As in our case all the positions of the five-
membered ring are blocked, selective functionalization of the seven-membered ring
becomes feasible. Based on the ability of fluorine to act as a leaving group, nucleophilic
[
24]
substitution reactions at the 4- and 6-position were considered (Table 3). Both, the
- and the 6-fluoro azulene reacted well with morpholine, delivering the desired
4
products in excellent yields (3a, 3ba). Since the result for both azulenes was equally
efficient, for the reaction with various nucleophiles 4-fluoro azulene 2b was selected.
Other N-nucleophiles, like 1-methylbenzimidazole (3bb) or carbazole (3bc), delivered
moderate to good yields. In addition, the reaction with ammonia obtaining the primary
amine delivered also good yields (Scheme 4, 3bf). Furthermore, we tested phenol
(
3bd) as the representative of an O-nucleophile and 2-bromothiophenol (3be) of a S-
nucleophile, which both delivered high to excellent yields. Disubstituted 4,6-
difluoroazulene 2h with 2-bromothiophenol as nucleophile gave rise to the
corresponding two-fold substituted azulenes in remarkable yield (3h). With the five-
membered ring blocked, electrophilic substitution with N-bromosuccinimide exclusively
provided 7-bromo-5-fluoroazulene 4b in good yield (Scheme 5).
In conclusion, we developed a simple gold-catalyzed protocol, which gives direct
access to substituted azulenes from ready available starting materials in perfect atom
economy. The ability of fluorine to act as a strong +M donor initiates a completely new
reaction pathway that delivers azulenes in an exceptionally fast way. The simple
reaction protocol combined with the possibility to easily modify the obtained scaffolds
at the seven-membered ring in a selective manner makes the methodology highly
interesting for the use in organic synthesis, electronics or optoelectronics.
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