A complete switch of the directional selectivity in the annulation of 2-hydroxybenzaldehydes with alkynes

Article abstract of DOI:10.1002/anie.201407589

Controlling reaction selectivity is an eternal pursuit for chemists working in chemical synthesis. As part of this endeavor, our group has been exploring the possibility of constructing different natural product skeletons from the same simple starting mat

Full text of DOI:10.1002/anie.201407589

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Chemie
DOI: 10.1002/anie.201407589
Rhodium Catalysis
Hot Paper
A Complete Switch of the Directional Selectivity in the Annulation of
2-Hydroxybenzaldehydes with Alkynes**
Huiying Zeng and Chao-Jun Li*
Abstract: Controlling reaction selectivity is an eternal pursuit
for chemists working in chemical synthesis. As part of this
endeavor, our group has been exploring the possibility of
constructing different natural product skeletons from the same
simple starting materials by using different catalytic systems. In
our previous work, an isoflavanone skeleton was obtained
from the annulation of a salicylaldehyde and an alkyne when
a gold catalyst was employed. In this paper, it is shown that
a coumarin skeleton can be efficiently obtained through an
annulation reaction with the same starting materials, that is,
terminal alkynes and salicylaldehydes, by simply switching to
a rhodium catalyst. A plausible reaction mechanism is
proposed for this new annulation based on isotopic substitu-
tion experiments.
Scheme 1. Controlling the reaction selectivity for the synthesis of
different natural product skeletons with different catalysts.
C
ontrolling reaction selectivity is an ultimate goal for
chemists working in chemical synthesis.[1] Selectivity is
defined as the rate of a reaction along a particular pathway
divided by the sum of the rates along all possible reaction
pathways. In nature, enzymes have miraculous abilities to
control reaction selectivity by converting the same simple
starting materials into a diverse range of products. For
example, squalene, a common intermediate in biosynthesis,
can be transformed selectively into a wide variety of
terpenoids when subjected to different enzymes (Scheme 1a).
Inspired by the abilities of enzymes, chemists have been
developing abiological means to control reaction selectivity,
mimicking nature.[2] As a part of this endeavor, our group has
been exploring the possibility of constructing different natural
product skeletons from the same reaction of salicylaldehydes
and terminal alkynes by employing different catalysts (Sche-
me 1b). Previously, we have developed an expedient route for
the synthesis of isoflavanone skeletons by a gold-catalyzed
annulation of salicylaldehyde with phenylacetylene.[3] Herein,
we report that a complete switch of the reaction selectivity,
which was achieved by replacing the gold with a rhodium
catalyst, in the annulation of the same starting materials
provides a direct and efficient access to coumarin skeletons.
Coumarin and its derivatives are widely found in nature.[4]
They represent important heterocyclic structures with a broad
range of biological activities.[5] Coumarin has also been used
as a medium in dye lasers[6] and as a sensitizer in earlier
photovoltaic technologies.[7] The 3-aryl coumarin moiety is
the key structural motif of many complex natural products
and pharmaceutical compounds with important biological
activities (Scheme 2), such as pachyrrhizine (mosquitocidal
activity),[8] AP2238 (anti-Alzheimer drug candidate),[9] glycy-
coumarin (anti-HIV activity), and licopyranocoumarin (anti-
HIV activity).[10]
Our investigation commenced with the reaction of
salicylaldehyde and phenylacetylene in the presence of
[Rh(PPh3)3Cl] (5 mol%) in acetonitrile at 508C under an
[*] Dr. H. Y. Zeng, Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Centre for Green Chemistry
and Catalysis, McGill University
801 Sherbrooke St. W., Montreal, Quebec H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
Dr. H. Y. Zeng
The Key Laboratory of Coordination Chemistry of Jiangxi Province
and College of Chemistry and Chemical Engineering
Jinggangshan University (China)
[**] We thank the CSC (China Scholarship Council) and FQRNT for
a postdoctoral fellowship (to H.Y.Z.) and NSERC, FQRNT, CFI, and
the Canada Research Chair (to C.J.L.) for their support of our
research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407589.
Scheme 2. Representative natural products and pharmaceutical com-
pounds with a 3-aryl coumarin framework. Bn=benzyl.
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Table 1: Annulation of salicylaldehyde with phenylacetylene under vari-
With the optimized reaction conditions established, the
substrate scope was explored at 1208C under argon using
[Rh(PPh3)3Cl] (5 mol%) as the catalyst and 4-picoline
N-oxide (1.3 equiv) as the oxidant in acetonitrile for five
hours. As shown in Table 2, the reaction proceeded efficiently
ous conditions.[a]
Table 2: Rhodium-catalyzed annulations of aldehydes with alkynes.[a]
Entry
Oxidant
T [8C]
Ratio[e]
Yield [%]
1
2
3
4
5
6
7
8
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-methoxypyridine N-oxide
4-nitropyridine N-oxide
pyridine N-oxide
isoquinoline N-oxide
2-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
4-picoline N-oxide
50
80
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:1.3
1:1.3:2
15
38
60
60
44
9
58
60
40
3
20
32
39
41
67
87
96
120
150
120
120
120
120
120
120
120
120
120
120
120
120
120
9
10[b]
11[c]
12[d]
13
14
15
16
17
2:1:1.3
1:2:1.3
1:3:1.3
1:4:1.3
[a] All reactions were conducted on a 0.2 mmol scale with [Rh(PPh3)3Cl]
(5 mol%) in a sealed tube in acetonitrile (1 mL); all yields were
determined by 1H NMR spectroscopy using nitromethane as an internal
standard. [b] Cesium carbonate was added. [c] Zinc chloride was added.
[d] Water (1.0 equiv) was added. [e] The ratio of salicylaldehyde, phenyl-
acetylene, and oxidant.
argon atmosphere (Table 1). Gratifyingly, the desired annu-
lation product 3-phenylcoumarin was formed in 15% yield
(Table 1, entry 1). Encouraged by this result, we then
examined different temperatures and found that a higher
temperature was beneficial to this reaction (entries 2–4), with
the best result obtained at 1208C (entry 3). Further increasing
the temperature to 1508C gave a similar result (entry 4). Next,
an investigation of different oxidants revealed that a better
yield can be obtained by utilizing an oxidant with a weakly
electron-donating group, 4-picoline N-oxide (entry 3). Both
more strongly electron-donating groups (entry 5) and an
electron-withdrawing group on the N-oxide (entry 6) resulted
in lower yields. Similar results were obtained when pyridine
N-oxide and isoquinoline N-oxide were used as the oxidants
(entries 7 and 8). When 2-picoline N-oxide was used, the yield
also decreased (entry 9). Addition of either a weak base
(cesium carbonate) or a Lewis acid (zinc chloride) led to
lower yields (entries 10 and 11). The addition of one
equivalent of water to this reaction was detrimental to the
yield (entry 12). Increasing the amount of oxidant was also
harmful to this transformation (entry 13). After optimizing
the ratio of the different reagents, we found that increasing
the amount of phenylacetylene promoted the reaction
tremendously whereas an excess amount of salicylaldehyde
would decrease the yield (entries 14–17). When four equiv-
alents of phenylacetylene were used, the desired annulation
product was obtained in 96% yield. Other solvents and
rhodium catalysts were found to be less effective for this
transformation (see the Supporting Information).
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), [Rh(PPh3)3Cl]
(5 mol%), and 4-picoline N-oxide (0.26 mmol) in acetonitrile (1 mL). All
reactions were carried out at 1208C in a sealed tube under argon for
5 hours; yields of isolated products are given.
with different aryl acetylenes and salicylaldehyde derivatives.
Various substituents on the aryl acetylene had little effect on
the outcome of the reaction, and different 3-aryl coumarins
were obtained in excellent yields in all cases (Table 2, 3a–3h).
It is noteworthy that the use of a heteroaryl alkyne,
3-ethynylpyridine, also led to the corresponding product in
good yield without any complication from the strongly
coordinating pyridinyl nitrogen atom (3i). On the other
hand, the presence of an electron-withdrawing group (3j–3l)
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on the 2-hydroxybenzaldehyde appeared to be more benefi-
cial than the presence of an electron-donating group (3m–
3o). 2-Hydroxy-naphthaldehyde also reacted smoothly with
several acetylenes to afford the corresponding products in
good to high yields (3p–3r). A bulky or an electron-donating
substituent (3s and 3t) at the ortho position of the
2-hydroxybenzaldehyde did not affect the reaction adversely,
and good yields were obtained in both cases. A good yield was
also obtained with a strongly electron-withdrawing group on
the 2-hydroxyaldehyde coupling partner (3u). However,
aliphatic alkynes were not viable substrates for the current
annulation under the standard reaction conditions, which is
similar to what was observed for the gold-catalyzed annula-
tion.[3] For aliphatic alkynes, owing to the absence of the
conjugating effect of the aryl group, the intermediate B or E
(Scheme 4) generated in the process might not survive long
enough to undergo cyclization; instead, protonation of the
intermediate leads to side product formation. For example,
the reaction of salicylaldehyde with 1-decyne under the
standard reaction conditions generated the acylated side
product 2-formylphenyl decanoate in 51% yield.
Scheme 4. Tentative mechanism for the rhodium-catalyzed annulation
of salicylaldehyde with phenylacetylene.
To explore the reaction mechanism, deuterium-labeled
salicylaldehyde [D]-1[11] (58% D) was used as the substrate
under the standard reaction conditions. We found that the
isolated product also possesses 58% deuterium at the C4
position (Scheme 3a), which unambiguously demonstrated
3-phenylcoumarin and regenerates the rhodium catalyst.
Alternatively, it is also possible that oxidation of vinylidene
intermediate A occurs in the second step to give a rhodium
ketene intermediate D, as proposed by Lee and co-workers.[15]
Then, nucleophilic addition of salicylaldehyde to rhodium
ketene D forms intermediate E, which also undergoes an
intramolecular Aldol-type reaction followed by dehydration
to give the desired product 3-phenylcoumarin.
The products readily generated by this method are very
useful in synthesizing natural products and bioactive mole-
cules. For example, compounds 3n and 3p can be readily
transformed into the natural product (S)-equol and bioactive
molecule 4, respectively (Scheme 5).[16] To test whether the
Scheme 3. Investigation of the mechanism for the annulation of 2-
hydroxycarbonyl compounds with phenylacetylene.
À
that no C H/D insertion of salicylaldehyde occurred in this
reaction,[12] and that the carbon atom of the C4 position
originated from the carbonyl moiety of the salicylaldehyde.
This conclusion was further supported by the reaction of
2’-hydroxyacetophenone with phenylacetylene under the
standard reaction conditions, which gave a 4-methylcoumarin
derivative (also a very useful structural motif; Scheme 3b),
while the corresponding annulation product was obtained in
a lower yield.
Scheme 5. 3-Aryl coumarins for the synthesis of natural products and
bioactive compounds.
Based on these experimental results, a tentative mecha-
nism was proposed (Scheme 4). Initially, phenylacetylene
reacts with the rhodium catalyst to form vinylidene inter-
mediate A.[13] Subsequently, nucleophilic addition of salicyl-
aldehyde to A generates intermediate B, which undergoes an
intramolecular Aldol-type reaction immediately followed by
dehydration, which then results in metal carbene intermedi-
ate C. Finally, oxidation of C[14] produces the desired product
reaction could be readily scaled up, compound 3n was
synthesized on a 1.35 gram scale in 80% yield. The product
crystallized from the reaction mixture upon cooling, and thus
this transformation provides a convenient large-scale syn-
thesis of this compound.
In conclusion, we have developed a novel annulation of
simple ortho-hydroxybenzaldehydes with terminal alkynes
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[11] M. von Delius, C. M. Le, V. M. Dong, J. Am. Chem. Soc. 2012,
134, 15022 – 15032.
catalyzed by a rhodium species. The cyclization generated
products with a 3-aryl coumarin motif, which have many
applications in the synthesis of pharmaceutical compounds
and photosensitizers. The reaction perfectly complements the
gold-catalyzed annulation, as an endeavor to control the
selectivity of reactions with the same starting materials to
construct different natural product skeletons by using differ-
ent metal catalysts. An extension of this catalytic method to
broaden its scope and further mechanistic studies are in
progress.
À
[12] For selected examples of C H insertion reactions of the
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Experimental Section
Typical experimental procedure:
A solution of [Rh(PPh3)3Cl]
(9.25 mg, 0.01 mmol), 4-picoline N-oxide (29 mg, 0.26 mmol), salicyl-
aldehyde (0.2 mmol), and alkyne (0.8 mmol) in distilled acetonitrile
(1 mL) was stirred in a sealed tube at 1208C for 5 hours under argon.
The reaction mixture was cooled to room temperature, and the
solvent was evaporated in vacuo. The residue was purified by
preparative thin-layer chromatography (TLC) on silica gel with the
appropriate mixture of hexane and ethyl acetate to give the 3-aryl
coumarin derivative.
Received: July 24, 2014
Revised: September 4, 2014
Published online: && &&, &&&&
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Keywords: alkynes · annulation · coumarins ·
homogeneous catalysis · rhodium
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Rhodium Catalysis
H. Y. Zeng, C.-J. Li*
&&&& — &&&&
A Complete Switch of the Directional
Selectivity in the Annulation of 2-
Hydroxybenzaldehydes with Alkynes
Rodeo rhodium: Different natural prod-
uct skeletons can be obtained from the
same simple starting materials by using
different catalytic systems. The gold-cat-
alyzed annulation of terminal alkynes and
salicylaldehydes yielded isoflavanones,
whereas the rhodium-catalyzed version
led to coumarin skeletons.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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www.angewandte.org
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