Rh-Catalyzed domino synthesis of 4-hydroxy-3-methylcoumarins via branch-selective hydroacylation

Article abstract of DOI:10.1039/c9ob01972c

A Rh-catalyzed domino synthesis of 4-hydroxy-3-methylcoumarins via branch-selective hydroacylation of acrylates and acrylamides using salicylaldehydes is described. This protocol under phosphine-free Rh-catalyzed conditions provided 4-hydroxy-3-methylcoum

Full text of DOI:10.1039/c9ob01972c

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Rh-Catalyzed domino synthesis of 4-hydroxy-
3-methylcoumarins via branch-selective
hydroacylation†‡
Cite this: Org. Biomol. Chem., 2019,
17, 9275
Received 9th September 2019,
Accepted 8th October 2019
Maddali L. N. Rao, * Boddu S. Ramakrishna
and Sachchida Nand
DOI: 10.1039/c9ob01972c
rsc.li/obc
A
Rh-catalyzed domino synthesis of 4-hydroxy-3-methyl- ation of the C–H bond of aldehydes10a and (ii) a decarbonyl-
coumarins via branch-selective hydroacylation of acrylates and ative coupling process (Scheme 1b).10b,c Herein, we disclose
acrylamides using salicylaldehydes is described. This protocol the highly branch-selective hydroacylation of acrylates and
under phosphine-free Rh-catalyzed conditions provided 4-hydroxy- acrylamides using salicylaldehydes under phosphine-free
3-methylcoumarins in high yields with excellent functional group Rh-catalysis in the base-mediated tandem preparation of
tolerance and high selectivity.
4-hydroxy-3-methylcoumarins in high yields (Scheme 1c).
4-Hydroxycoumarins11 are present in numerous natural
products11b with varied biological applications such as anti-
coagulant,12 anthelmintic,13 antioxidant and antitumor14
activities. Some of these molecules are shown in Scheme 2.
Introduction
In recent years, rhodium-catalyzed hydroacylation reactions
with excellent atom-economy have played a major role in
organic synthesis.1–3 The introduction of a chelating group
adjacent to the aldehyde has made the intermolecular hydro-
acylation process very successful by reducing the competitive
decarbonylation pathway.1,2 However, a few reactions have also
been reported under rhodium-catalyzed conditions with non-
chelated aldehydes.3 In the present context, aldehydes featur-
ing N,4 O,5 P6 and S7 chelating groups are known with promis-
ing reactivity in the olefin hydroacylation process. Dong et al.
have reported Rh(I)-catalyzed coupling of salicylaldehydes with
acrylates and acrylamides to generate hydroacylation products
with modest to excellent linear-selectivities (Scheme 1a).5c
Recently, Yang et al. have achieved the hydroacylation of para-
quinone methides with salicylaldehydes to form α,α-diaryl-2-
hydroxy acetophenones.5d However, branch-selectivity was
achieved by additional co-ordination of olefin, nitrile, sul-
phide, phosphinite and with other catalytic systems.8,9 In par-
ticular, Zhang and Bolm have reported the branch-selective
hydroacylation of salicylaldehydes with enamides.9g Our group
has been exploring the reactivity of salicylaldehyde under Rh-
catalyzed conditions and developed (i) a method for the aryl-
Scheme 1 Salicylaldehydes under Rh-catalysis.
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP, India.
E-mail: maddali@iitk.ac.in; Fax: +91 512 259 7532; Tel: +91512 259 7532
†Dedicated to Professor Vinod K. Singh, IIT Kanpur on the occasion of his 60th
birthday.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob01972c
Scheme 2 Biologically important molecules with a 4-hydroxycoumarin
scaffold.
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reactivity of ethyl acrylate in comparison with other alkyl acry-
lates by delivering the products in high yields. This reaction
Results and discussion
In continuation of our earlier efforts, we explored the hydro- with 3 mmol scale of 1a and 3 mol% lowered catalyst loading
acylation of acrylates with salicylaldehydes. It was initially in the presence of ethyl acrylate afforded 2a in 67% yield.
studied with ethyl acrylate and salicylaldehyde (1a) under
To expand the scope of this work, we next examined the
different reaction conditions (Table 1) to evolve a standardized reactivity of functionalized salicylaldehydes with ethyl acrylate
protocol for the envisioned process. Interestingly, this led to and the results are given in Table 2. The reaction conditions
hitherto unprecedented branch-selective hydroacylation and offered high tolerance to halogens and the variation of the elec-
tandem cyclization to generate 4-hydroxy-3-methylcoumarin tronic properties of salicylaldehydes. For example, electron-
(2a) in 62% yield (entry 1). Furthermore screening other cata- rich salicylaldehydes with methyl and methoxy groups partici-
lysts did not improve the yield (entries 2–4). However, the pated very well to give the corresponding coumarins 2b and 2c
temperature variation studies (entries 5 and 6) had a positive in 62% and 69% yields, respectively. Salicylaldehydes functio-
effect and 2a was isolated in 89% yield at 120 °C (entry 6). nalized with halogens such as fluorine, chlorine and bromine
Bases other than Na2CO3 were less effective as they gave 2a in reacted well to give the corresponding halogenated products
lower yields (entries 7–10). Finally, a control reaction revealed 2d–2h in 52–74% yields. Furthermore, the effect of sterics in
the necessity of the Rh-catalyst for the process (entry 11). This salicylaldehydes was investigated by functionalization of the
screening thus provided a protocol with Na2CO3 in DMF at ring with the methoxy group. These substrates afforded pro-
120 °C and 12 h as the best conditions.
ducts 2i and 2j in 76% and 82% yields, respectively. Under this
Furthermore, the efficiency of different alkyl acrylates was protocol, 2-hydroxy-1-naphthaldehyde also participated well to
investigated as shown in Scheme 3. This study revealed better give the coumarin product 2k in 57% yield. Electron-deficient
salicylaldehydes with acetyl, cyano, methoxycarbonyl and nitro
groups as the ring substituents gave the corresponding pro-
ducts 2l–2o in 61–80% yields. It should be noted that salicyl-
aldehydes with free carbaldehyde and hydroxyl groups were well
tolerated with high selectivity as the corresponding coumarin
products 2p and 2q were formed in 77% and 60% yields. The
overall branch-selectivity and functional group tolerance
derived with our protocol is truly significant. This notably
facilitated the tandem preparation of various functionalized
4-hydroxy-3-methylcoumarin products in good to high yields.
Table 1 Screening conditionsa
Temp.
(°C)
Yield 2a
(%)
Entry
Catalyst
Base
1
2
3
4
5
6
7
8
Rh(CO)2(acac)
RhCl3/2PPh3
RhCl(CO)(PPh3)2
RhCl(PPh3)3
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
—
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
K2CO3
100
100
100
100
80
120
120
120
120
120
120
62
25
43
53
34
89
83
76
41
29
—
Table 2 Scope of functionalized salicylaldehydes with ethyl acrylatea
9
10
11
KOAc
NaOAc
Na2CO3
a Reaction conditions: 1a (0.5 mmol, 1 equiv.), ethyl acrylate (1 mmol,
2 equiv.), catalyst (0.025 mmol, 0.05 equiv.), base (1 mmol, 2 equiv.),
DMF, temp., 12 h.
Scheme 3 Scope of alkyl acrylates. aGeneral reaction conditions: 1a
(0.5 mmol,
1 equiv.), acrylate (1 mmol, 2 equiv.), Rh(CO)2(acac)
(0.025 mmol, 0.05 equiv.), Na2CO3 (1 mmol, 2 equiv.), DMF (2 mL),
120 °C, 12 h. bWith 1a (3 mmol, 1 equiv.), ethyl acrylate (6 mmol,
2 equiv.), Rh(CO)2(acac) (0.09 mmol, 0.03 equiv.), Na2CO3 (6 mmol,
2 equiv.), DMF (10 mL), 120 °C, 12 h.
a Reaction conditions: functionalized salicylaldehyde (0.5 mmol,
1 equiv.), ethyl acrylate (1 mmol, 2 equiv.), Rh(CO)2(acac) (0.025 mmol,
0.05 equiv.), Na2CO3 (1 mmol, 2 equiv.), DMF (2 mL), 120 °C, 12 h.
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Table 3 Screening conditionsa
Table 4 Scope of salicylaldehydes with N,N-dimethylacrylamide/ethyl
acrylatea
Base
(equiv.)
Temp. Yield (%)
Entry Catalyst
Solvent (°C)
2a (2a′)
1
2
3
4
5
6
7
8
Rh(CO)2(acac)
Na2CO3 (2) DMF
120
120
120
120
120
100
80
32 (6)
61
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
RhCl3/2PPh3
K2CO3 (2)
K3PO4 (2)
DMF
DMF
57 (13)
70 (4)
73 (5)
74 (4)
78 (2)
21
Cs2CO3 (2) DMF
Cs2CO3 (1) DMF
Cs2CO3 (1) DMF
Cs2CO3 (1) DMF
Cs2CO3 (1) DMF
80
9
RhCl(CO)(PPh3)2 Cs2CO3 (1) DMF
80
80
80
80
80
80
12
10
11
12
13
14
RhCl(PPh3)3
Rh(CO)2(acac)
Rh(CO)2(acac)
Rh(CO)2(acac)
—
Cs2CO3 (1) DMF
Cs2CO3 (1) DMA
Cs2CO3 (1) NMP
Cs2CO3 (1) DCE
Cs2CO3 (1) DMF
62 (2)
75 (5)
66 (4)
4 (28)
—
a Reaction conditions: 1a (0.5 mmol, 1 equiv.), N,N-dimethylacrylamide
(1 mmol, 2 equiv.), catalyst (0.025 mmol, 0.05 equiv.), base, solvent,
temp., 12 h.
a Reaction conditions: 1a or functionalized salicylaldehyde (0.5 mmol,
1 equiv.), N,N-dimethylacrylamide/ethyl acrylate (1 mmol, 2 equiv.),
Rh(CO)2(acac) (0.025 mmol, 0.05 equiv.), Cs2CO3 (0.5 mmol, 1 equiv.),
DMF (2 mL), 80 °C, 12 h. b With 1a (4 mmol, 1 equiv.), N,N-dimethyl-
acrylamide (8 mmol, 2 equiv.), Rh(CO)2(acac) (0.12 mmol, 0.03 equiv.),
Cs2CO3 (4 mmol, 1 equiv.), DMF (10 mL), 80 °C, 12 h.
Furthermore, we have also studied the reactivity of N,N-di-
methylacrylamide in this reaction (Table 3). Under the above
established protocol conditions but with the N,N-dimethyl-
acrylamide reactant, the coupling reaction with salicylaldehyde
afforded 4-hydroxy-3-methylcoumarin (2a) in 32% yield along methylacrylamide also afforded 2a in 84% yield. In particular,
with a small amount of the linear hydroacylation product 2a′ salicylaldehydes with fluoro, chloro and bromo substituents
(Table 3, entry 1). Screening of different bases indicated reacted normally and furnished the corresponding halo func-
Cs2CO3 as a better choice of base (entry 4) over K2CO3 and tionalized 4-hydroxy-3-methylcoumarins (2d–2f) in reasonably
K3PO4 (entries 2 and 3). With Cs2CO3 as the base the reaction good yields. The reaction of 4-hydroxyisophthalaldehyde also
furnished 2a in 70% yield (entry 4). Furthermore fine tuning furnished 2p as the sole product in 71% yield. This example
by decreasing the amount of base (entry 5) and the reaction demonstrates the highly selective reactivity of the vicinal
temperature led to a higher yield of 2a (entries 6 and 7). Thus hydroxy aldehyde function in the salicylaldehyde. The broad-
the protocol involving Cs2CO3 (1 equiv.) in DMF at 80 °C ness of the protocol was demonstrated with N,N-dimethylacryl-
afforded 2a in 78% yield with a negligible amount of the side amide and functionalized salicylaldehydes containing fluoro,
product (entry 7). Furthermore screening different rhodium chloro, bromo, acetyl, cyano and carbaldehyde groups. These
catalysts led to inferior reactivity (entries 8–10). Different sol- reactions afforded the corresponding 4-hydroxy-3-methyl-
vents investigated for their suitability including DMA, NMP coumarins in good yields.
and DCE offered mixed results (entries 11–13) and were
To check the generality of the reaction conditions, we next
inferior to that obtained with the DMF solvent (entry 7). A examined the reactivity of functionalized salicylaldehydes with
control reaction without the rhodium catalyst did not provide ethyl acrylate under these conditions. Interestingly, this proto-
the coumarin product (entry 14). Overall, the above investi- col also offered general reactivity with ethyl acrylate to give the
gation showed that the conditions with Cs2CO3 (1 equiv.) in corresponding 4-hydroxy-3-methylcoumarins (2a, 2c, 2e, 2f, 2l,
DMF at 80 °C are the best choice to obtain high product yields 2m and 2p) in good to high yields.
(entry 7) and these conditions were employed in our further
study.
To gain mechanistic insight into the reaction, simple benz-
aldehyde and 2-methoxybenzaldehyde were allowed to react
The scope of the reaction was further investigated using with ethyl acrylate under the optimized conditions. In this
N,N-dimethylacrylamide in combination with different functio- case, unreacted benzaldehyde was recovered (Scheme 4a). This
nalized salicylaldehydes (Table 4). The substitution of elec- demonstrated the necessity of the ortho-hydroxy group for the
tron-rich and electron-deficient groups in salicylaldehyde was reaction to proceed to give the product.
well tolerated to give the corresponding functionalized
Two parallel reactions were conducted with n-butyl acrylate
4-hydroxy-3-methylcoumarin products (2a–2f and 2l–2q) in in combination with salicylaldehyde (h-1a) and its deuterium
good to excellent yields. This reaction with 4 mmol scale of 1a derivative (d-1a) (Scheme 4b) under the optimized conditions.
and 3 mol% lowered catalyst loading in the presence of N,N-di- This delivered the corresponding coumarin products h-2a and
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undergoes reductive elimination to generate the branched
product D along with the regeneration of the rhodium catalyst.
Product D undergoes base-mediated intramolecular trans-
esterification to form 4-hydroxy-3-methylcoumarin (d-2a).16
Selective formation of intermediate C leading to branch-
selectivity is probably due to the influence of ligand on
rhodium and such a selectivity was earlier reported in the lit-
erature under varied ligand conditions.8a,9a
Conclusions
In summary, we have described efficient catalytic protocols for
the synthesis of 4-hydroxy-3-methylcoumarins involving
branch-selective hydroacylation of acrylates and acrylamides
using salicylaldehydes. The rhodium protocol with Na2CO3
was proved to be effective for reactions with acrylates, while
the protocol with Cs2CO3 showed efficient reactivity both with
acrylates and acrylamides. The high branch-selectivity coupled
with efficient functional group tolerance enabled the pot-
economical direct synthesis of several functionalized 4-hydroxy-
3-methylcoumarins in high yields.
Scheme 4 Control experiments.
d-2a in 79% and 52% yields with the coumarin product d-2a
showing 100% deuterium incorporation. The calculated KH/KD
of 1.5 indicated that the oxidative addition step is not the rate
determining step and the reductive elimination step is
expected to be the turnover limiting step.15 Furthermore, a
cross-over experiment carried out between the deuterium-
labeled salicylaldehyde-d1 (d-1a) and 5-acetyl salicylaldehyde
(h-1l) did not show any deuterium scrambling between the
substrates (Scheme 4c). Furthermore the possibility of the
intramolecular hydroacylation process was investigated using
the salicylaldehyde derivative 3 (Scheme 4d) and product 2a
was not obtained. This effectively ruled out the intramolecular
pathway.
From the above control experiments and literature
reports,5c,8b a mechanistic proposal is depicted in Scheme 5
for the branch-selective hydroacylation of salicylaldehyde and
tandem formation of 4-hydroxy-3-methylcoumarin (d-2a). The
rhodacycle A is generated by oxidative insertion of rhodium
into the C–H bond of the aldehyde. This is followed by olefin
co-ordination to give complex B which in turn involves branch-
selective hydride insertion to form complex C. This further
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
The financial support from the SERB under DST, New Delhi is
gratefully acknowledged (SR/S1/OC-20/2012). B. S. R and S. N
thank the CSIR, New Delhi for research fellowships.
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