Nickel-catalyzed cycloaddition of salicylic acid ketals to alkynes via elimination of ketones

Article abstract of DOI:10.1021/ja904068p

(Chemical Equation Presented) An intermolecular nickel-catalyzed addition reaction has been developed where salicylic acid ketals react with alkynes to afford substituted chromones. A mechanistic rationale is proposed, implying β-elimination of ketone fro

Full text of DOI:10.1021/ja904068p

Published on Web 09/01/2009
Nickel-Catalyzed Cycloaddition of Salicylic Acid Ketals to Alkynes via
Elimination of Ketones
Akihiro Ooguri, Kenichiro Nakai, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 615-8510, Japan
Received May 19, 2009; E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp; matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
New methodology for rapid transformation from readily available
starting materials into a complex molecule is in constant demand
in modern organic synthesis. The transition metal catalyzed insertion
reaction of an unsaturated carbon-carbon bond into a carbon-oxygen
bond of an oxacyclic compound is a useful transformation to prepare
more complicated oxacyclic compounds in a single step. Recently,
we demonstrated that an oxidative addition of phthalic anhydrides
to a Ni(0) complex and subsequent decarbonylation afford oxa-
nickelacycle A, which allows insertion of alkynes to provide
isocoumarins (Scheme 1a).1 The result encouraged us to investigate
the formation of an isomeric oxa-nickelacycle B, which leads to
an isomeric compound of isocoumarins (e.g., chromones) by
insertion of alkynes.2 Although a direct oxidative addition of a Ni(0)
complex to benzpropiolactone or a decarbonylative oxidative
addition of a Ni(0) complex to benzofurandione would provide
access to the oxa-nickelacycle B (Scheme 1b), such starting
oxacyclic compounds are rather unstable and/or not readily avail-
able.3 We postulated that an oxidative addition of a six-membered
salicylic acid ketal 1,4 which can be readily prepared from salicylic
acids and ketone, to a Ni(0) complex would give a seven-membered
oxa-nickelacycle;5 the advantage of seven-membered ring strain
relief would enhance the ꢀ-elimination of a ketone to furnish the
oxa-nickelacycle B.6 Thus, we attempted the cycloaddition of
salicylic acid ketal 1 to alkyne 2 using Ni(0) catalyst to form
chromones 3; this is an unprecedented substitution reaction of a
ketone by an alkyne. That is, we can prepare heterocyclic
compounds from readily available heterocyclic compounds.
reaction with salicylic acid acetal 1b gave 3aa in 24% yield via
elimination of acetone (entry 2). Among the ligands examined, PCy3
gave the best result. Trace or lower amounts of 3aa were obtained
in the cases using PMe3, PPh3, and IPr in place of PCy3 (entries
3-5). Further examination of the reaction conditions revealed that
an addition of 20 mol % of pyridine improved the yield of 3aa to
56% (entry 6). On addition of 100 mol % of pyridine, the reaction
proceeds to furnish the product in 99% and benzophenone 4 in
99% yield, respectively (entry 7). More basic or bulky amines, such
as DMAP and DABCO, were not as efficient as pyridine (entries
8 and 9). Addition of a Lewis acid inhibits the reaction completely
(entry 10).
Table 1. Optimization of the Reaction Conditionsa
additive
(mol %)
conversion
1 (%)
yield
3aa (%)
entry
R1
R2
1
ligand
1
2
3
4
5
6
7
8
9
10
Ph
Ph
1a PCy3
s
s
s
s
s
42
29
12
19
15
60
>99
48
38
24
9
10
13
56
99
43
13
<1
Me Me 1b PCy3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a PMe3
1a PPh3
1a IPrb
1a PCy3
1a PCy3
1a PCy3
1a PCy3
1a PCy3
pyridine (20)
pyridine (100)
DMAPc (100)
DABCOd (100)
ZnCl2 (20)
21
<1
Scheme 1. Nickel-Catalyzed Cycloaddition via Oxa-Nickelacycle
Intermediates
a Reactions were carried out using Ni(cod)2 (10 mol %), ligand (10
mol %), 1 (0.5 mmol), and 2 (1.0 mmol) in 2 mL of toluene at 120 °C
for
6 h
in sealed tube. b 1,3-Bis(2,6-diisopropyl)imidazol-2-ylidene.
c N,N-Dimethyl-4-aminopyridine. d 1,4-Dizabicyclo[2,2,2]octane.
With the optimized conditions in hand, we next investigated the
use of other alkynes in this reaction. The reaction of 1a with
unsymmetrical alkynes such as 2-octyne (2b) and 4-methyl-2-
pentyne (2c) gave the products consisting of regioisomers in a 1/1
ratio in 84 and 98% yields (Table 2, entries 1 and 2). Bulky tert-
butyl- or trimethylsilyl-substituted alkynes such as 2d, 2e, and 2f
reacted with 1a to provide adducts with complete regiocontrol in
good yields (entries 3-5). However, terminal alkynes, such as
1-octyne and phenylacetylene, failed to participate in the reaction,
presumably due to rapid oligomerization of alkynes. A range of
electron-donating or -withdrawing ring substitutents tolerated the
reaction conditions well enough to furnish the corresponding adducts
in good to excellent yields (entries 5-11). The addition of 1i to 2a
gave the product in 38% yield even with prolonged reaction time
(entry 12). The reaction with 1j with 2a provided the corresponding
adducts 3jk in 99% yield (entry 13).
Our initial experiments began with finding a ketone that is
capable of ꢀ-elimination. We discovered that an addition of salicylic
acid derivative 1a, which eliminates benzophenone through the
reaction, to 4-octyne (2a) with 10 mol % of Ni(0)/PCy3 catalyst
led to chromone 3aa in 38% yield (Table 1, entry 1), while the
A plausible reaction pathway to account for the formation of
chromone 3 based on the observed results is outlined in Scheme 2.
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13194 J. AM. CHEM. SOC. 2009, 131, 13194–13195
10.1021/ja904068p CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Plausible Reaction Mechanism
Table 2. Nickel-Catalyzed Cycloaddition of 1 to 2 via Elimination
of Benzophenonea
8, which undergoes reductive elimination to give 3 and regenerates
the starting Ni(0) complex.
In conclusion, we have developed a new nickel-catalyzed
cycloaddition of salicylic acid ketals to alkynes, which opens the
way for divergent synthesis of chromones. We also demonstrated
that ketones are capable of ꢀ-elimination, which allows formation
of the key oxa-nickelacycle intermediate. Further efforts to expand
the scope of the chemistry and studies of the detailed mechanism
are currently underway in our laboratories.
Acknowledgment. This work was supported by Grants-in-Aid
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. T.K. also acknowledges Novartis Foundation
(Japan) for the Promotion of Science, and the Takeda Pharmaceuti-
cal Company Award in Synthetic Organic Chemistry, Japan.
Supporting Information Available: Experimental procedures in-
cluding spectroscopic and analytical data of new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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a All reactions were carried out using Ni(cod)2 (10 mol %), PCy3 (10
mol %), pyridine (100 mol %), 1 (0.5 mmol), and 2 (1.0 mmol) in 2 mL
of toluene at 120 °C for 24 h in sealed tube. b Isolated yields. c Reaction
time: 72 h.
In view of the mechanism of the previously reported nickel-
catalyzed addition reaction of phtahlic anhydrides with alkynes,2
it is reasonable to consider that the catalytic cycle of the present
reaction should consist of the oxidative addition of an ester CO-O
bond to a Ni(0) complex. Subsequent elimination of benzophenone
(4a) and coordination of alkyne 2 take place, in which the steric
repulsive interaction is minimal between the bulkier R1 and the
PCy3 ligand on the nickel, to give nickel(II) intermediate 7a. The
alkyne would then insert into the C-Ni bond to give nickelacycle
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