Full text of DOI:10.1016/j.tetlet.2018.10.044

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Synthesis of 4-acylcoumarins by NHC-catalyzed nucleophilic substitution
Yumiko Suzuki, Asuka Ando, Mizuki Nakagawa
PII:
S0040-4039(18)31263-2
https://doi.org/10.1016/j.tetlet.2018.10.044
TETL 50354
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Tetrahedron Letters
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22 October 2018
Please cite this article as: Suzuki, Y., Ando, A., Nakagawa, M., Synthesis of 4-acylcoumarins by NHC-catalyzed
nucleophilic substitution, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.10.044
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Tetrahedron Letters
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Synthesis of 4-acylcoumarins by NHC-catalyzed nucleophilic substitution
Yumiko Suzuki,a, * Asuka Ando,a Mizuki Nakagawaa
aDepartment of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku, Tokyo, 102-8554 Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Coumarins are bioactive; consequently their syntheses are of importance to medicinal chemists.
We describe the one-step organocatalytic syntheses of 4-acylcoumarins from 4-chlorocoumarin.
The leaving group at the 4-position of the coumarin was replaced by aroyl groups that originate
from aromatic aldehydes by NHC-catalyzed umpolung. 4-Acylthiocoumarins and 2-
acylquinolin-2-ones were also prepared using this method. These are the first examples of
nucleophilic substitutions at the β-carbons of enones to afford -ketoenones.
Available online
Keywords:
N-heterocyclic carbene
Coumarin
2009 Elsevier Ltd. All rights reserved.
Quinolinone
Acylation
Organocatalysis
N-Heterocyclic carbenes (NHCs) are unique organocatalysts that mediate various types of reactions,1 including umpolung,2-7
transesterification,8 oxidative-esterification,9 homoenoate,10 and Diels–Alder reactions.11 The benzoin condensation,2 Stetter reaction,3
and nucleophilic aroylation4-7 are representative examples of the umpolung reaction. In 1985, Higashino and co-workers reported the
first example of an NHC-catalyzed nucleophilic aroylation.4 Subsequently, aroylation reactions of various N-heteroarenes,5 imidoyl
chlorides,6 and benzene derivatives7 have been reported. The authors envisaged that the substrate scope of this NHC-catalyzed
aroylation reaction could be expanded to include enones bearing leaving groups at their β-carbons, such as 4-chlorocoumarins and 4-
chloroquinolin-2-ones.
These types of bicyclic conjugated enones have received significant attention in the areas of natural products and medicinal
chemistry. Coumarin derivatives with anti-HIV,12 antitumor,13 anticoagulation,14 and anti-inflammatory15 activities have been reported
on numerous occasions. In addition, quinolinone derivatives that exhibit anticancer,16 antithyroid,17 and antibacterial18 properties have
also been reported. Therefore, these enone-bearing heterocycles are attractive as components of chemical libraries, and the syntheses of
a wide variety of quinolinone derivatives are of interest.
To the best of our knowledge, only two methods have been reported for the introduction of aroyl groups at the 4-position of the
coumarin core; one requires five steps starting from 4-hydroxycoumarin,19 while the other involves the direct palladium-catalyzed
aroylation of 4-coumarinylzinc bromide.20 Furthermore, there are no reports that describe the introduction of aroyl groups onto 2-
quinolones.
Reactions of readily available coumarins 1–5 bearing leaving groups at the 4-position with 4-methoxybenzaldehyde (6a) were first
examined under standard NHC-catalyzed aroylation conditions,7 in which 1,3-dimethylimizolium iodide was used as the catalyst
precursor with sodium hydride in DMF at room temperature (Table 1; For reaction mechanism, see Supplementary Data). The desired
ketone 7a was obtained in satisfactory yields in reactions involving either chloride 1 or bromide 2 (entries 1 and 2). Unfortunately,
sulfonyl groups were poor leaving groups (entries 3 and 4), while the methyl ether 5 produced a complex mixture in which 7a was not
detected (entry 5).
———
 Corresponding author. Tel.: +81-(0)3-3238-3089; fax: +81-(0)3-3238-3361; e-mail: yumiko_suzuki@sophia.ac.jp

a
Table 1. Leaving-group Scope
OMe
I
N
N
Me
Me
O
L
O
A
NaH
+
H
r.t., DMF
O
O
O
O
OMe
1 5
-
6a
7a
Entry
L
Coumarin
Time (h)
Yield (%)
aReaction conditions: 1–5 (1 mmol), 6a (1.15 mmol), A (10 mol%), NaH (1.6 mmol),
and DMF (10 mL). bNo reaction. cComplex mixture of products.
1
2
3
4
5
Cl
1
2
3
4
5
4
5
7
7
7
67
66
9
The reaction of 1 with 6a was screened under the same conditions but
with various NHC precursors and bases (Table 2). NHCs generated from
imidazolium salts B–E bearing a variety of substituents were as effective
as A, with the exception of the dichloride D, in which the effect of
electron induction presumably lowers the nucleophilicity of the carbene,
leading to slightly decreased yield (entries 1–4). The use of triazolium salt
F resulted in a further decreased yield (entry 5), while a significantly
Br
OMs
OTs
OMe
b
-
c
-
lower product yield was observed when benzimidazolium salt G was used (entry 6), and the NHC derived from thiazolium salt H was
inert (entries 7 and 8). The use of weaker bases such as tBuOK and DBN in the presence of A also afforded very low yields (entries 9
and 10). Hence, the use of A with sodium hydride was determined to be the optimal combination.
a
Table 2. Reaction Optimization: Catalyst and Base.
OMe
A H
-
NHC precursor
base
Cl
O
O
+
H
r.t., DMF
O
O
OMe
O
O
1
6a
7a
Ph
Cl
Ph
Cl
I
I
I
I
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
A
E
B
C
D
H
I
I
N
I
Br
Ph
N
N
N
S
N
N
Me
Me
Me
Me
Me
F
G
Entry
NHC
Precursor
Base
Time (h)
Yield (%) aReaction conditions: 1 (1 mmol), 6a (1.15 mmol), NHC precursor (10 mol%), base
(1.6 mmol), and DMF (10 mL). bNo reaction.
1
2
3
4
5
6
7
8
9
10
B
C
D
E
F
NaH
NaH
NaH
NaH
NaH
NaH
NaH
Et3N
tBuOK
DBN
3
67
Solvents other than DMF were also examined, and reactions were
also performed at a variety of temperatures (Table 3). The product yield
was barely lower than that observed at room temperature when the
reaction was carried out at 20 °C in DMF, (entry 1), while the higher
4
66
7
54
5
63
41
6
temperature (50 °C) did not positively affect the yield of the product
(entry 2). The decreased yield at the higher temperature could be
because of the NaH-absorbed water that is added to the reaction
mixture: the undesired substitution reaction with hydroxide to afford 4-
hydroxycoumarin occurred. The benzoin condensation product was not
detected. The benzoin condensation product was not detected. The same
trend was also observed in other polar solvents, namely DMSO,
acetonitrile, and THF, with product yields comparable or higher than
those obtained in DMF (entries 3–10). The reaction at 50 °C in THF
afforded the product most efficiently (entry 9), while reactions
7
G
H
H
A
A
7.5
7
b
-
b
6
-
6.5
6.5
7
8
performed at temperatures higher than 50 °C did not afford improved yields of the product (entries 4, 7, and 10). Non-polar solvents,
namely 1,4-dioxane and toluene, were unsuitable for this reaction (entries 11 and 12).

a
Table 3. Reaction Optimization: Solvent and Temperature.
I
OMe
N
N
Me
Me
O
Cl
O
O
A
NaH
+
H
r.t., solvent
O
OMe
O
O
1
6a
7a
Entry
1
Solvent
DMF
Temperature (°C)
Time (h)
Yield (%)
aReaction conditions: 1 (1 mmol), 6a (1.15 mmol), A (10 mol%), base (1.6 mmol),
and solvent (10 mL). bNo reaction.
20
50
6.5
3
63
49
63
57
33
65
34
54
77
63
Table 4. Aldehyde Scope.a
2
DMF
I
3
DMSO
DMSO
CH3CN
CH3CN
CH3CN
THF
r.t.
6.5
3
N
N
O
R
Me
Me
Cl
O
A
4
80
O
6
NaH
+
H
R
5
r.t.
6.5
6
r.t., DMF
O
O
O
1
7
6
50
OMe
OMe
7
reflux
r.t.
3
OMe
OMe
OMe
Cl
O
O
O
O
8
6
9
THF
50
6
O
O
O
O
O
O
O
O
10
11
12
THF
reflux
5
7b
7c
7d
7e
b
55% (4 h)
54% (4 h)
56% (6 h)
62% (5.5 h)
1,4-dioxane r.t.
toluene 50
6
-
Cl
Br
b
5.5
-
Br
Cl
O
O
O
O
O
O
O
O
O
O
O
O
7f
7g
7h
7i
63% (24 h)b
70% (24 h)b
35% (5.5 h)
66% (2.5 h)
N
O
O
O
S
O
O
O
O
O
O
O
O
O
O
7j
7k
88% (5 h)
7l
7m
40% (24 h)b
50% (5.5 h)
43% (5 h)
aStandard conditions: 1 (1 mmol), 6a (1.15 mmol), A (10 mol%), NaH (1.6 mmol), and DMF (10 mL) at r.t. bThe reaction was carried out in THF (10 mL) at 50
°C instead of DMF at r.t.
The aldehyde scope was next explored (Table 4). Reactions with benzaldehydes bearing a variety of substituents, as well as 2-
naphthaldehyde and heteroaryl aldehydes afforded the corresponding products in good-to-moderate yields, except for a few examples.
The reactivities of the furan moieties in 3-furancarboxaldehyde and the product 7l are believed to be factors responsible for the lower
yield. However, the reasons for the low yields observed in the reactions of 4-bromobenzaldehyde and nicotinaldehyde, which gave
ketones 7f and 7m, respectively, remain uncertain.
Substrates other than 4-chlorocoumarin were also reacted with 4-methoxybenzaldehyde (Table 5). The desired product 8 was
obtained in 71% yield from 4-chlorothiocoumarin, while 4-chloroquinolinones bearing methyl and benzyl groups at their 1-positions
afforded products 9 and 10 in yields of 66% and 79%, respectively.

Table 5. Further Substrate Scope.a
OMe
I
N
N
Me
Me
Cl
X
O
O
A
NaH
H
+
r.t., DMF
O
OMe
X
O
8-10
1
6a
OMe
OMe
OMe
O
O
O
N
O
N
O
S
O
Bn
Me
10
8
9
79%, 5 h
71%, 7.5 h
66%, 5 h
aReaction conditions: 1 (1 mmol), 6a (1.15 mmol), A (10 mol%), NaH (1.6 mmol), and DMF (10 mL) at r.t.
In conclusion, a straightforward organocatalytic synthesis of 4-aroylcoumarins has been developed. A structurally related
thiocoumarin and quinolinone derivatives bearing aroyl groups at their 4-positions are also accessible using this method. NHCs
generated from imidazolium salts are the most effective in this transformation compared to those formed from triazolium or
benzthiazolium salts, while the thiazolium-salt-based NHC failed to catalyze this reaction. To the best of our knowledge, these reactions
represent the first examples of nucleophilic substitutions at the β-carbons of enones to furnish the corresponding aroyl-substituted
systems. The method facilitates rapid access to this type of -ketoenone.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from The Ministry of Education, Culture, Sports, Science and Technology, Japan.
References and notes
1.
(a) Enders D, Balensiefer T. Acc, Chem. Res. 2004; 37: 534-541; (b) N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; WILEY-VCH GmbH &
KGaA: Weinheim, 2006;
2.
3.
4.
5.
6.
7.
8.
9.
(c) Marion N, Die-Gonzale S, Nolan SP. Angew. Chem., Int. Ed. 2007; 46: 2988-3000;
(d) Enders D, Niemeier O, Henseler, A. Chem. Rev. 2007; 107: 5606-5655;
(e) Hopkinson MN. Richter C. Schedler M, Glorius F. Nature. 2014; 510: 485-496;
(f) Flanigan DM, Michailidis FR, White NA, Rovis T. Chem. Rev. 2015; 115: 9307-9387.
(a) Ukai T, Tanaka S, Dokawa S. J. Pharm. Soc. Jpn. 1943; 63: 269–300;
(b) Breslow R. J. Am. Chem. Soc. 1958; 80: 3719-3726.
(a) Stetter H. Angew. Chem. Int. Ed. 1976; 15: 639-647.
(b) Stetter H, Kuhlmann H. Org. React. 1991; 40: 407-496.
10. Higashino T, Takemoto M, Miyashita A, Hayashi E. Chem. Pharm. Bull. 1985; 33: 1395-1399.
11. (a) Miyashita A, Suzuki Y, Iwamoto K, Oishi E, Higashino T. Chem. Pharm. Bull. 1990; 38: 1147-1152.
12. (b) Miyashita A, Suzuki Y, Iwamoto K, Oishi E, Higashino T. Heterocycles, 1998; 49: 405-413.
13. (a) Miyashita A, Matsuda H, Higasmno T. Chem. Pharm. Bull. 1992; 40: 2627-2631.
14. (b) Suzuki Y, A. Bakar Md. Tanoi T, Nomura N, Sato M. Tetrahedron 2011; 67: 4710-4715.
15. (a) Suzuki Y, Toyota T, Imada F, Sato M, Miyashita A. Chem. Commun. 2003; 1314-1315.
16. (b)Suzuki Y, Toyota T, Miyashita A, Sato M. Chem. Pharm. Bull. 2006; 54: 1653-1658.
17. (a) Grasa GA, Kissling RM, Nolan SP. Org. Lett. 2002; 4: 3583-3586.
18. (b) Nyce GW, Lamboy JA, Connor EF, Waymouth RM, Hedrick JL. Org. Lett. 2002; 4: 3587-3590.
19. (c) Connor EF, Nyce GW, Myers M, Möck A, Hedrick JL. J. Am. Chem. Soc. 2002; 124: 914-915.
20. (a) Chow KYK, Bode JW. J. Am. Chem. Soc. 2004, 126, 8126-8127.
21. (b) Reynolds NT, de Alaniz JR, Rovis T. J. Am. Chem. Soc. 2004; 126: 9518-9519.
22. (c) De Sarkar S, Grimme S, Studer A. J. Am. Chem. Soc. 2010; 132: 1190-1191.
23. (a) Sohn SS, Rosen EL, Bode JW. J. Am. Chem. Soc. 2004; 126: 14370-14371.
24. (b) Burstein C, Glorius F. Angew. Chem. Int. Ed. 2004; 43: 6205-6208.
25. (c) He M, Bode JW. Org. Lett. 2005; 7: 3131-3134.
26. (d) Chan A, Scheidt KA. J. Am. Chem. Soc. 2008; 130: 2740-2741.
27. (a) He M, Struble JR, Bode JW. J. Am. Chem. Soc. 2006; 128: 8418-8420.
28. (b) He M, Uc GJ, Bode JW. J. Am Chem, Soc. 2006; 128: 15088-15089.
29. (a) Dayam R, Gundla R, Al-Mawsawi LQ, Neamati N. Med. Res. Rev. 2008; 28: 118-154.
30. (b) Ong EBB, Watanabe N, Saito A, Futamura Y, Abd El Galil KH, Koito A, Najimudin N, Osada H. J. Biol. Chem. 2011; 286: 14049-14056.
31. (a) Emami S, Dadashpour S. Eur. J. Med. Chem. 2015; 102: 611-630.
32. (b) Huang XY, Shan ZJ, Zhai HL, Su L, Zhang XY. Chem. Biol. Drug Des. 2011; 78: 651-658.
33. Cravotto G, Nano GM, Palmisano G, Tagliapietra S. Tetrahedron: Asymmetry 2001; 12: 707-709.
34. (a) Nakamura T, Kodama N, Oda M, Tsuchiya S, Arai Y, Kumamoto T, Ishikawa T, Ueno K, Yano S. J. Nat. Med. 2009; 63:15-20.
35. (b) Gosselin F, Britton RA, Davies IW, Dolman SJ, Gauvreau D, Hoerrner RS, Hughes G, Janey J, Lau S, Molinaro C, Nadeau C, O’Shea PD, Palucki
M, Sidler R. J. Org. Chem. 2010; 75: 4154-4160.
36. (a) Muscia GC, Bollini M, Bruno AM, Asis SE. J. Chil. Chem. Soc. 2006; 51: 859-863.
37. (b) Vukanovic J, Passaniti A, Hirata T, Traystman RJ, Hartley-Asp B, Isaacs JT. Cancer Res. 1993; 53: 1833-1837.
38. a) Ukrainets IV, Taran SG, Kodolova OL, Gorokhova OV, Kravchenko VN. Chem. Heterocycl. Compd. 1997; 33: 959-963.
39. (b) Ukrainets IV, Taran SG, Gorokhova OV, Marusenko NA, Turov AV. Chem. Heterocycl. Compd. 1997; 33: 600-604.

40. (a) Azad M, Munawar MA, Siddiqui HL. J. Applied Sci. 2007; 7: 2485-2489.
41. (b) Melliou E, Magiatis P, Mitaku S, Skaltsounis A.-L, Chinou E, Chinou I. J. Nat. Prod. 2005; 68: 78-82.
42. (c) Chen YL, Chung CH, Chen IL, Chen PH, Heng HY. Bioorg. Med. Chem. 2002; 10: 2705-2712.
43. Kay, T. Glue SEJ Tetrahedron Lett. 1986; 27: 113-116.
44. Rieke RD, Kim SH. Tetrahedron Lett. 2011; 52: 3094-3096.Lyle, F. R. U.S. Patent 5 973 257, 1985; Chem. Abstr. 1985, 65, 2870.
Supplementary Material
Supplementary data related to this article can be found at.
Highlights
Synthesis of 4-acylcoumarins by NHC-catalyzed nucleophilic substitution
Yumiko Suzuki,a, * Asuka Ando,a Mizuki Nakagawaa
aDepartment of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku, Tokyo, 102-8554 Japan



Nucleophilic substitutions at the β-carbons of enones to afford -ketoenones
Synthesis of 4-aroylcoumarins, 4-aroylthiocoumarins, and 4-aroylquinolin-2-ones
Imidazole-based N-heterocyclic carbenes effectively catalyze the substitutions
Graphical Abstract
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Synthesis of 4-acylcoumarins by NHC-catalyzed
nucleophilic substitution
Leave this area blank for abstract info.
Yumiko Suzuki,a,*Asuka Ando,a Mizuki Nakagawaa
aDepartment of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-
ku, Tokyo, 102-8554 Japan
O
Ar
Cl
NHC
O
+
H
Ar
O
X
O
X
X = O, S, N-R'
Fonts or abstract dimensions should not be changed or altered.
———
 Corresponding author. Tel.: +81-(0)3-3238-3089; fax: +81-(0)3-3238-3361; e-mail: yumiko_suzuki@sophia.ac.jp