Intermolecular N-heterocyclic carbene catalyzed hydroacylation of arynes

Article abstract of DOI:10.1002/anie.201005490

A formal introduction: The conceptually new N-heterocyclic carbene catalyzed formal insertion of arynes into the C_formyl-H bond of aldehydes demonstrates the compatibility of nucleophilic NHCs with electrophilic arynes. This NHC-catalyzed hydroacylation of arynes allows the conversion of aliphatic, α,β-unsaturated, and aromatic aldehydes into aryl ketones; 27 examples and a preliminary mechanistic investigation are provided. Copyright

Full text of DOI:10.1002/anie.201005490

Angewandte
Chemie
DOI: 10.1002/anie.201005490
Organocatalysis
Intermolecular N-Heterocyclic Carbene Catalyzed Hydroacylation of
Arynes**
Akkattu T. Biju and Frank Glorius*
Arynes are highly reactive intermediates endowed with
numerous applications in organic synthesis.[1] The introduc-
tion of 2-(trimethylsilyl)aryl triflates as mild aryne precursors
led to a rapid growth of this field.[2] Arynes have been utilized
extensively in transition-metal-catalyzed reactions[3] and,
recently, efforts have been devoted to transition-metal-free
reactions, which include the initial addition of nucleophiles to
arynes and subsequent trapping with electrophiles.[4] This
approach allows the formal insertion of arynes into carbon–
carbon, carbon–heteroatom, and heteroatom–hydrogen
chemoselectivity observed in this process are especially
intriguing.
Our present study commenced with the NHC-catalyzed
reaction of 4-bromobenzaldehyde (1a) with the aryne gen-
erated in situ from 2-trimethylsilylaryl triflate (2a) and
2.0 equivalents each of KF and [18]crown-6. Reacting these
substrates in the presence of the carbene generated from 4[8,11]
by deprotonation using K2CO3 resulted in the formation of
4-bromobenzophenone (3a) in 60% yield (based on GCMS;
Table 1, entry 1). Remarkably, in contrast to this NHC, other
common NHCs derived from 5–8 are far less effective
(entries 2–5). The use of DBU and NaH as the base resulted
in no conversion (entries 6 and 7), while KOtBu promoted the
bonds.[1c,5] Interestingly, the insertion of arynes into the
[6]
À
Cformyl H bond of aldehydes is unknown. This reaction
would not only be mechanistically interesting, but would also
provide an attractive transition-metal-free synthetic strategy
to a wide range of aryl ketones [Eq. (1)]. In connection with
Table 1: Optimization of the reaction conditions.[a]
our recent success in the N-heterocyclic carbene (NHC)
catalyzed[7] intramolecular hydroacylation of unactivated
alkenes and alkynes,[8] we envisioned that arynes could
serve as an acceptor for acyl-anion intermediates generated
from aldehydes by a NHC-catalyzed umpolung reaction.[9]
Herein, we report the NHC-organocatalyzed formal insertion
Entry Variation of the standard conditions[a]
Yield of 3a [%][b]
1
none
60
5
4
0
12
0
2
5 instead of 4
3
6 instead of 4
4
7 instead of 4
5
8 instead of 4
À
of arynes into the Cformyl H bond of aldehydes—the inter-
6
7
8
9
10
11
12
13
14
15
16
DBU instead of K2CO3
NaH instead of K2CO3
KOtBu instead of K2CO3
TBAF as the fluoride source
CsF and CH3CN instead of KF and THF
1,4-dioxane instead of THF
DME instead of THF
10 mol% K2CO3 instead of 20 mol%
molecular hydroacylation[10] of arynes. The high levels of
0
78
13
30
27
49
75
[*] Dr. A. T. Biju, Prof. Dr. F. Glorius
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Organisch-Chemisches Institut
10 mol% KOtBu instead of 20 mol% K2CO3 83
15 mol% 4 and 15 mol% K2CO3
15 mol% 4 and 15 mol% KOtBu
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax: (+49)251-833-3202
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
index.html
90
98 (92)[c]
[a] Standard conditions: 1a (0.25 mmol), 2a (0.3 mmol), NHC·HX
(10 mol%), K2CO3 (20 mol%), KF (0.5 mmol), [18]crown-6 (0.5 mmol),
THF (1.0 mL), 258C, 4 h. Bn=benzyl, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DME=1,2-dimethoxyethane, Mes=2,4,6-trimethyl-
phenyl. [b] The yields were determined by GCMS analysis of the crude
reaction mixture using mesitylene as the internal standard. [c] Yield of
the isolated product is given in parentheses.
[**] Generous financial support by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, and the Alexander von
Humboldt Foundation (fellowship for A.T.B.) is gratefully acknowl-
edged. The research of F.G. is supported by the Alfried Krupp Prize
for Young University Teachers of the Alfried Krupp von Bohlen und
Halbach Foundation. We thank Nadine Kuhl for skillful experimental
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005490.
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9761

Communications
reaction more efficiently than K2CO3, and afforded 3a in
benzophenone formation. Gratifyingly, challenging aldehydes
such as ferrocenecarboxaldehyde as well as heterocyclic and
aliphatic aldehydes also furnished moderate to good yields of
the desired products, further expanding the scope of this
78% yield (entry 8). The use of other fluoride sources such as
tetrabutylammonium fluoride (TBAF) and CsF were not
found to be beneficial (entries 9 and 10, respectively), and
solvents other than THF were not efficient (entries 11 and
12). The use of a 1:1 ratio of 4 and the base improved the yield
(entries 13 and 14). Finally, increasing the catalyst loading to
15 mol% and using 15 mol% KOtBu improved the reactivity,
with 3a obtained in 92% yield (entry 16). Under optimized
conditions, no products from the direct addition of either the
nucleophilic NHC to the electrophilic arynes or of aldehydes
to arynes[6] were observed.
À
aryne C H insertion reaction (3s–u). In addition, a,b-
unsaturated aldehydes can also be employed in this umpolung
reaction, leading to the formation of a,b-unsaturated ketones
in moderate yield (3v,w).
Next, we examined the effect of varying the substituents
on the aryne precursor 2 (Table 2). Electronically different
4,5-disubstituted symmetrical aryne precursors 2b and 2c
With these optimized reaction conditions in hand, we then
examined the substrate scope of this novel aryne insertion
reaction (Scheme 1). The unsubstituted parent system
worked well, and a variety of electron-donating and elec-
tron-withdrawing groups at the 3- and 4-positions of the
aromatic ring were well tolerated, and led to benzophenones
in 69–93% yield (3a–l). As often observed in NHC organo-
catalysis, 2-substituted benzaldehydes result in significantly
lower yields. However, gratefully, 2-fluoro- and 2-chloroben-
zaldehyde still provide significant amounts of product (3m,
3n), with 3n requiring a higher reaction temperature of 608C.
Furthermore, disubstituted aldehydes as well as 2-naphthal-
dehyde worked well (3o–q). Interestingly, the transformation
of terephthalaldehyde resulted in the smooth formation of the
disubstituted 1,4-dibenzoylbenzene 3r in 75% yield. More-
over, this novel transformation is not only limited to
Table 2: Variation of the aryne moiety.[a]
Entry Aryne precur-
sor
Product(s), yield [%]
1
2
R=Me: 9b, 70%
R=O(CH2)O: 9c, 77%
3
4
[a] General conditions: 1a (0.5 mmol), 2 (0.6 mmol), 4 (15 mol%),
KOtBu (15 mol%), KF (1.0 mmol), [18]crown-6 (1.0 mmol), THF
(2.0 mL), 258C, and 4 h. Yields of the isolated products are given.
readily afforded the benzophenones 9b and 9c in good yields.
Additionally, the reaction of the unsymmetrical aryne gen-
erated from 2d resulted in the formation of separable
regioisomers 9d/9d’ in a 1:1 ratio (entry 3). Moreover, the
unsymmetrical naphthalyne 2e underwent hydroacylation to
afford separable regioisomers 9e and 9e’ in 75% overall yield
(entry 4). The observed regioisomeric ratio in this case
revealed the preferential attack of the Breslow intermediate
at the less sterically hindered carbon atom of the aryne.
Interestingly, competition experiments carried out using
electronically dissimilar aryne precursors 2a and 2c revealed
no preference for either 2a or 2c. Hence, it is reasonable to
assume that the electronic nature of the aryne is not involved
in the rate-determining step.[12]
Further insightful experiments have shed light on the
mechanism of this novel transformation. Competition experi-
ments carried out on the coupling of the unsubstituted
benzyne formed from 2a with electronically different aro-
matic aldehydes showed that the rate of the reaction increases
in the order 1c(4-Me) < 1b(4-H) < 1h(4-CO2Me), with 1h
reacting approximately 11 times faster than 1c under stan-
dard conditions.[12] This finding indicates that the electronic
Scheme 1. NHC-catalyzed hydroacylation of arynes: Scope of alde-
hydes. General conditions: 1 (0.5 mmol), 2a (0.6 mmol), 4 (15 mol%),
KOtBu (15 mol%), KF (1.0 mmol), [18]crown-6 (1.0 mmol), THF
(2.0 mL), 258C, 4 h. Yields of isolated products are given. TMS=
trimethylsilyl, Tf=triflate. [a] The reaction was carried out at 608C.
[b] The reaction mixture was stirred for 6 h. [c] 0.25 mmol scale.
[d] Using 20 mol% of 4 and 20 mol% of KOtBu.
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nature of the aldehydes plays a
prominent role in the rate-determin-
ing step.[13] The fact that electron-
poor aldehydes react faster than the
electron-rich ones seems to indicate
that the electrophilicity of the alde-
hydes is more important than the
nucleophilicity of the Breslow inter-
mediate[14] in the aryne hydroacyla-
tion.
These observations can be sum-
marized in a mechanistic proposal
(Scheme 2). After the reversible for-
mation of the Breslow intermediate
A,[12,15] the in situ formed aryne can
be attacked in a stepwise manner to
give the alkoxide intermediate D via
the intermediate B.[16] Alternatively,
a concerted transition state[8,17] C can
also be invoked in analogy to the
Scheme 2. Proposed mechanism of the reaction.
reaction of 1,3-dipoles with arynes.[18] Both of these steps
seem to be faster than the formation of the Breslow
intermediate.[12] Release of the NHC catalyst closes the
catalytic cycle and results in the formation of the observed
ketone product.
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In conclusion, we have developed a transition-metal-free
NHC-organocatalyzed intermolecular hydroacylation of
arynes to furnish benzophenones as well as a,b-unsaturated
and other aryl ketones. This is the first time that NHCs have
been found to be compatible with arynes, and the present
study reveals an unprecedented formal insertion of arynes
À
into Cformyl H bonds under mild conditions. Further studies on
the mechanistic aspects of this reaction as well as related
NHC-organocatalyzed reactions are ongoing.
Experimental Section
General procedure: The thiazolium salt 4 (27.9 mg, 0.075 mmol), dry
KOtBu (8.4 mg, 0.075 mmol), KF (58.1 mg, 1.0 mmol), and
[18]crown-6 (264.3 mg, 1.0 mmol) were added in a glove box to a
flame-dried screw-capped test tube equipped with a magnetic stir bar.
The aldehyde 1 (0.5 mmol) was then added to this mixture outside the
glove box under argon. The mixture was dissolved in THF (2 mL) and
2-(trimethylsilyl)phenyl triflate 2a (0.179 g, 146 mL, 0.6 mmol) was
added to the stirred solution. The resultant mixture was stirred at
258C for 4 h. The mixture was then diluted with EtOAc (2 mL) and
filtered through a pad of silica gel and eluted with EtOAc (10 mL).
Evaporation of the solvent followed by column chromatography
afforded the corresponding aryl ketone 3.
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Shirakawa, Y. Honda, T. Hiyama, Angew. Chem. 2002, 114, 3381;
Angew. Chem. Int. Ed. 2002, 41, 3247.
Received: September 2, 2010
Published online: November 12, 2010
Keywords: arynes · benzophenones · hydroacylation ·
.
N-heterocyclic carbenes · organocatalysis
=
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Angew. Chem. Int. Ed. 2010, 49, 9761 –9764
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www.angewandte.org 9763

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