Ru(II)-catalyzed C-H activation and annulation of salicylaldehydes with monosubstituted and disubstituted alkynes

Article abstract of DOI:10.1039/c6cc07204f

The Ru(ii)-catalyzed C-H activation and annulation reaction of salicylaldehydes and disubstituted alkynes affords chromones in high yields. This reaction also works with terminal alkynes and tolerates a wide range of sensitive functional groups. The selectivity pattern of this Ru(ii)-catalyzed annulation reaction is different from the known Au(i), Rh(iii)-catalyzed annulation reactions of salicylaldehydes and terminal alkynes.

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ARTICLE TYPE
Ru(II)-Catalyzed C-H Activation and Annulation of Salicylaldehydes
with Monosubstituted and Disubstituted Alkynes
Swagata Baruah, Partha Pratim Kaishap, and Sanjib Gogoi*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
skeleton by switching the selectivity of the reaction (eqn 2,
Scheme 1).6b In continuation of our work on the metal catalyzed
C-H/C-C bond activation and functionalization reactions,7 herein,
50 we describe that the newly developed Ru(II) catalytic system
efficiently catalyzes the oxidative alkyne annulation reaction of
dialkyl, diaryl, arylalkyl substituted alkynes with salicylaldehydes
to afford biologically important chromones (eqn 4). Furthermore,
we describe that the terminal alkynes are also suitable substrates
55 for this Ru(II)-catalyzed annulation reaction and the selectivity
pattern of this Ru(II)-catalyzed reaction is different from the
reported Au- with Rh-catalyzed reactions of salicylaldehydes and
terminal alkynes (eqn 3).
The Ru(II)-catalyzed C-H activation and annulation reaction
of salicylaldehydes and disubstituted alkynes affords
chromones in high yields. This reaction works with terminal
alkynes also and tolerates wide range of sensitive functional
10 groups. The selectivity pattern of this Ru(II)-catalyzed
annulation reaction is different from the known Au(I),
Rh(III)-catalyzed annulation reactions of salicylaldehydes
and terminal alkynes.
Chromones represent the core structures of flavonoids,
15 isoflavonoids, wide range of biologically active compounds and
drug molecules.1 Because of their tremendous significance in
medicinal chemistry and drug discovery,1a there is a continuous
interest in the development of simple and general synthetic routes
to access derivatives of this heterocyclic scaffold.1a,2 In recent
20 years, the transition metal catalyzed C-H activation and
annulation reactions have emerged as a powerful tool for the
efficient construction of various important heterocycles.3 The
Rh(III)-catalyzed, Co(I)-diphosphine-catalyzed C-H activation
and annulation reactions of salicylaldehydes with disubstituted
25 alkynes have been reported for the synthesis of 2,3-disubstituted
chromones.4 However, the Rh-catalyzed reaction was very low
yielding when dialkyl and arylalkyl substituted alkynes were used
as the coupling partners.4a Again, the high cost of the Rh(III)
catalyst is a limitation of this approach. The Co(I)-diphosphine-
30 catalyzed method was also not efficient for dialkyl substituted
alkynes, though the reaction condition was suitable to retain a
silyl group of the alkyne in the heterocycle.4b
60
65
70
75
Apart from accelerating the rate of a reaction, a catalyst can
influence the selectivity of a chemical reaction. In nature, the
35 enzymes have the ability to convert the same starting material
into a wide range of products by controlling the reaction
selectivity. Taking the advantage of the reaction selectivity of the
catalysts, chemists have been working on the development of new
catalyst systems which could transform the same simple starting
40 compounds into valuable products similar to the enzymes.5 Very
recently, Li and coworkers developed two catalytic systems to
control the selectivity of the reaction of simple starting materials
salicylaldehydes and terminal aryl alkynes.6 These starting
materials on Au-catalyzed annulation reaction afforded
45 isoflavanone skeleton (eqn 1, Scheme 1),6a whereas replacing Au
with Rh catalyst, the same starting materials provided coumarin
Scheme 1. Synthesis of various important scaffolds controlling the
80
selectivity of the reaction using different catalysts
Initially, the performance of the [RuCl2(p-cymene)]2 catalyst
was studied for the oxidative coupling reaction of salicylaldehyde
1a with phenylacetylene 2a (Table 1). Among the additives tested
for this reaction, only CsOAc provided the highest yield of 3aa
85 (entries 1-4). The reaction did not work in the absence of additive
(entry 5). Screening of other solvents and additives could not
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Table 1. Optimization study for chromone synthesisa
Table 3. Scope of salicylaldehydes with 4aa
40
5
entry
additive
solvent
yield (%)b
45
1
2
Cu(OAc)2
AgOAc
tAmOH
tAmOH
0
23
3
4
CsOAc
CuBr2
tAmOH
tAmOH
90
0
50
5
6
-
tAmOH
MeOH
-
67c
CsOAc
7
8
CsOAc
CsOAc
H2O
58
78
65
73
MeCN
tAmOH
tAmOH
9
CsOAc/KPF6
CsOAc/AgSbF6
10
aReaction conditions: Salicylaldehyde (1a, 1.0 mmol), alkyne (1a, 1.0
mmol), Ru catalyst (2.5 mol %) and additive (1.0 equiv) in solvent (6.0
mL) was heated at 80 oC for 12 h under air.
aReaction conditions: Salicylaldehyde (1.0 mmol), alkyne (1.0 mmol), Ru
t
catalyst (2.5 mol %), and CsOAc (1.0 equiv) in AmOH (6.0 mL) was
heated at 80 oC for 12 h under air.
Table 2. Scope of terminal alkynesa
further improve the yield of the reaction (entries 6-10). With the
55 optimized reaction conditions in hand, we first tested the scope of
the annulation reaction of salicylaldehyde 1a with terminal
alkynes 2a-m. As shown in Table 2, terminal aryl alkynes
substituted with electron-donating and electron-withdrawing
groups such as methyl, methoxy, fluoro, nitro trifluoromethyl
60 groups at C-4, C-2 positions were well tolerated, providing good
yields of chromones 3aa-af. In contrast to the previously reported
metal catalyzed annulation reactions of salicylaldehydes and
terminal alkynes,2 which worked only with aryl/heteroaryl
substituted alkynes, in the present annulation reaction, the
65 terminal alkynes substituted with cycloalkyl and alkyl
substituents also turned out to be good substrates to provide
chromones 3ai-ak. Similarly, terminal fused aryl and heteroaryl
alkynes also tolerated the reaction conditions to afford 3ag-ah,
3al-am. The electron rich and poor salicylaldehydes 1b-c were
70 also tested with 2a. Both the aldehydes 1b-c reacted well with 2a
irrespective of the substituents present to provide good yields of
3ba-ca.
10
15
20
25
30
Next, the scope of the annulation reaction of aliphatic
disubstituted alkyne 4a, which was not a good substrate in the
75 previously reported annulation reactions6 was studied with
salicylaldehydes 1a-i. As shown in Table 3, salicylaldehydes
substituted with electron-donating and electron-withdrawing
groups such as methyl, methoxy, diethylamino and chloro groups
at C-3, C-4, C-5 positions were well tolerated, providing good
80 yields of
chromones 5ba-ga. Similarly, useful sensitive
fuctional groups such as bromo, nitro and allyl were well
tolerated to provide chromones 5ha-ja, which could be easily
35 aReaction conditions: Salicylaldehyde (1.0 mmol), alkyne (1.0 mmol), Ru
subjected
for
further
transformations.
9-Formyl-8-
t
catalyst (2.5 mol %), and CsOAc (1.0 equiv) in AmOH (6.0 mL) was
hydroxyjulolidine (1k) and 2-hydroxy-1-naphthaldehyde (1l)
heated at 80 oC for 12 h under air.
2
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Table 4. Scope of disubstituted alkynes with 1aa
competition experiment performed between 1a+1a-D (1:1) and
55 2a, provided 1:1.3 mixture of unreacted 1a+1a-D in two hours
(kH/kD = 1.3, eqn 2). Furthermore, the rates of individual reactions
of 1a and 1a-D with alkyne 2a were also determined (kH/kD
=
1.4), which indicates that C-H bond cleavage might be involved
in the rate-limiting step.
5
60
10
15
20
25
65
Scheme 2. Experiments with isotopically labeled compounds
A plausible mechanism for formation of 3aa through formation
70 of Ru complex A and seven membered ruthenocycle B (eqn 1,
Scheme 3) is ruled out as retention of deuterium atom was not
observed when the reaction between 1a and 2a-D was performed
under standard conditions (eqn 2, Scheme 2). Another possibility
of formation of 3aa through intermediate D (eqn 2, Scheme 3) is
75 also ruled out as the D/H exchange in the product 3aa was not
observed when the reaction between 1a and 2a was performed in
CD3OD (eqn 1, Scheme 2). These studies suggest a greater level
of mechanistic complexity of this annulation reaction.
aReaction conditions: Salicylaldehyde (1.0 mmol), alkyne (1.0 mmol),
t
Ru-catalyst (2.5 mol %), and CsOAc (1.0 equiv) in AmOH (6.0 mL) was
heated at 80 oC for 12 h under air.
were also found to be good substrates for this reaction. The
30 annulated product 5ka is
a promising compound in the
production of laser-compatible NIR marker dyes.8
Subsequently, the scope of disubstituted alkynes (4b-o) was
studied for the annulation reaction with 1a (Table 4). All the
tested symmetrical dialkyl, diaryl and diheteroaryl substituted
35 alkynes were found to be good substrates for this annulation
reaction (5ab-af). Except alkyne 4g, all other tested
unsymmetrical alkynes 4h-i provided both the isomers of
chromones 5ah-ah′, 5ai-ai′ with 1a, which were easily separated
by silica gel column chromatography. The major isomers formed
40 with these unsymmetrical alkynes possess the electron rich
substituents closer to the oxygen atom of the heterocycle. The
arylalkyl disubstituted alkynes 5j-l provided only one isomer of
the product (5aj-al).4e Free hydroxyl group containing alkynes
4m-n and dialkyne 4o tolerated the reaction conditions to provide
45 chromones 5am-ao.6b The reaction of 1a with 1-phenyl-2-
trimethylsilylacetylene under the optimized reaction conditions
provided the silyl deprotected product 3aa. The reaction between
1a and 2a performed under standard conditions in CD3OD using
an excess of 1a did not show D/H exchange in the aldehyde C-H
50 of the recovered starting material 1a (eqn 1, Scheme 2), which
indicates an irreversible C-H bond ruthenation step. Furthermore,
the product 3aa obtained from this reaction did not show H/D
exchange in the C-H of the pyranone ring. The intermolecular
80
Scheme 3. Plausible reaction mechanism
In summary, we have developed a novel Ru(II)-catalyzed
85 annulation reaction of salicylaldehydes with disubstituted and
terminal alkynes. The dialkyl and arylalkyl substituted alkynes
which were not suitable substrates for the reported Rh- and Co-
catalyzed reactions with salicylaldehydes, turned out to be good
substrates for this inexpensive Ru(II)-catalyzed reaction. Unlike
90 the previously reported Au(I)- and Rh(III)-catalyzed reactions of
salicylaldehydes with terminal aryl alkynes which afford
isoflavanones and coumarins, this Ru(II)-catalyzed reaction
affords chromones. Moreover, the Ru(II)-catalyzed reaction
works with terminal aliphatic alkynes. Because of some of the
95 noteworthy features of this reaction, such as the broad substrate
scope, valuable products, high functional group tolerance, less
catalyst loading and high regioselectivity with unsymmetrical
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alkynes, this reaction should be of synthetic utility.
Acknowledgements
Authors thank SERB, New Delhi, for financially supporting us
with GPP-0303 (YSS/2014/001018) project. P. P. Kaishap thanks
UGC for the fellowship. We are grateful to the Director, CSIR-
NEIST for his keen interests.
5
Notes and references
Applied Organic Chemistry, Chemical Science & Technology Division,
10 CSIR-North East Institute of Science and Technology, Jorhat-785006,
AcSIR, India, Fax: +913762370011 Tel.: +91 3762372948;
skgogoi1@gmail.com
.† Electronic Supplementary Information (ESI) available: Experimental
procedures, characterization data, 1H and 13C NMR spectra of
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