Simple and efficient copper(I)-catalyzed access to three versatile aminocoumarin-based scaffolds using isocyanoacetate

Article abstract of DOI:10.1002/adsc.201000895

An efficient method has been developed for the one-pot copper(I)-catalyzed synthesis of 3-aminocoumarin and its derivatives, such as 3-substituted methylideneaminocoumarins and chromeno[3,4-d]imidazol-4(1H)-ones. Significantly, the strategy presents a straightforward and efficient approach to constructing biologically useful molecular scaffolds.

Full text of DOI:10.1002/adsc.201000895

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DOI: 10.1002/adsc.201000895
Simple and Efficient Copper(I)-Catalyzed Access to Three
Versatile Aminocoumarin-Based Scaffolds using Isocyanoacetate
Tao Meng,a Yiquan Zou,a Oleg Khorev,b Yu Jin,a Huayong Zhou,a
Yongliang Zhang,a Dingyu Hu,a Lanping Ma,a Xin Wang,a and Jingkang Shena,*
a
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu
Chong Zhi Road, Shanghai 201203, Peopleꢀs Republic of China
Fax : (+86)-21-5080-7088; phone: (+86)-21-5080-6600/5407; e-mail: jkshen@mail.shcnc.ac.cn
Division of Nephrology and Hypertension, Inselspital, University of Bern, Bern 3010, Switzerland
b
Received: November 28, 2010; Revised: January 25, 2011; Published online: April 12, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000895.
Abstract: An efficient method has been developed
for the one-pot copper(I)-catalyzed synthesis of 3-
aminocoumarin and its derivatives, such as 3-substi-
tuted methylideneaminocoumarins and chromeno-
thesis of this pharmaceutically useful scaffold and its
derivatives.
Multicomponent reactions (MCRs) are a powerful
tool in the modern drug discovery process in terms of
lead finding and lead optimization, and has gained
considerable and steadily increasing academic, eco-
nomic and ecological interest.[8] As part of our ongo-
ing efforts to prepare novel fused imidazole ring sys-
tems,[9,10] which are of great interest to the pharma-
ceutical industry, we recently focused on the
Groebke–Blackburn–Bienaymꢁ multicomponent reac-
tion or GBB-MCR (Scheme 1).[11] It involves the reac-
tion of 2-aminopyridine, salicylaldehyde and ethyl iso-
cyanoacetate, and is catalyzed by scandium triflate to
ACHTUNGTRENNUNG[3,4-d]imidazol-4(1H)-ones. Significantly, the strat-
egy presents a straightforward and efficient ap-
proach to constructing biologically useful molecular
scaffolds.
Keywords: 3-aminocoumarin; chromenoACTHNUTRGENU[GN 3,4-d]imi-
dazol-4(1H)-ones; copper(I)-catalyzed heterocycle
formation; ethyl isocyanoacetate; 3-substituted
methylidene-aminocoumarins
afford 3-aminoimidazo
(>80%). However, we accidentally found that by
using Cu(OTf)2 as catalyst in this reaction, one strong
ACHTUNGTRNE[NUNG 1,2-a]pyridines in good yields
AHCTUNGTRENNUNG
During the last decades, the study of the biological ac- fluorescent spot was observed in thin layer chroma-
tivities of coumarin derivatives has been the aim of tography (TLC) analysis. Single crystal X-ray diffrac-
many researchers. Coumarin and its derivatives occur tion analysis then showed this compound to be 3-for-
widely in medicinal chemistry, and are considered to mamidocoumarin (Figure 1), obtained in 33% yield
be “privileged structures” in the pharmaceutical and (entry 1, Table 1).
agrochemical industries.[1] A particularly interesting
These results prompted us to turn our attention to
group of coumarins is 3-aminocoumarins, since they optimizing the conditions for the efficient formation
are used as CNS depressant,[2] antitumor,[3] anti-in- of 3-formamidocoumarins, which then could be easily
flammatory,[4] and antimicrobial agents.[5] In addition, deprotected under acidic conditions to afford the
these compounds are also known to exhibit interest- pharmaceutically useful 3-aminocoumarin intermedi-
ing photochemical behavior and have been used as ates.
fluorescent markers.[6] 3-Aminocoumarins are gener-
Initially, we chose salicylaldehyde and ethyl isocya-
ally prepared by utilizing the corresponding salicylal- noacetate as the model substrates to optimize the re-
dehydes and N-acetylglycine, and has been conducted action conditions. After testing various solvents,
in acidic media and at high temperatures, with low methanol was selected to be used in the reaction be-
yields and tedious work-up procedures.[7] Thus, new cause of its ability to dissolve the starting materials
and efficient methods to prepare 3-aminocoumarins but not the products, which precipitated upon reac-
using readily available starting materials under mild tion completion and could be easily isolated by filtra-
reaction conditions are strongly desired. Herein, we tion. Thus, the preliminary investigation (Table 1) was
wish to disclose a new procedure for the efficient syn- carried out in methanol at 40–508C for 5 h. No de-
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Simple and Efficient Copper(I)-Catalyzed Access to Three Versatile Aminocoumarin-Based Scaffolds
Scheme 1. General three-component condensation reaction.
hyde and ethyl isocyanoacetate in the presence of a
secondary amine such as piperidine undergo a three-
component reaction leading to 3-methylideneamino-
coumarins (4a–c). Whereas, in the presence of a pri-
mary amine, the reaction affords an imidzole ring in-
stead of a coumarin, which can then be converted to
a chromenoACTHNUGRTNEUNG[3,4-d]imidazol-4(1H)-one under micro-
wave heating conditions using potassium carbonate as
the base (Scheme 2). The structures of both three-
component condensation (3CC) products were con-
firmed by single-crystal X-ray analysis of representa-
tive compounds 4b and 5a (Figure 2).
To gain insight into the reaction mechanism, we
performed a labeling study with deuterated solvent.
The reaction of ethyl isocyanoacetate in the presence
of CuI/pyridine in CD3OD led to the bideuteration of
the a-position (see Supporting Information for full
details of ee determination), which suggests the pres-
ence of intermediate A (Scheme 3). On the basis of
Figure 1. X-ray crystal structure of 2a.[12]
sired product was observed in the absence of either a this observation, we propose that a possible mecha-
copper source (entries 2 and 10) or 2-aminopyridine nism of the reaction may proceed via the initial for-
(entry 3). While by replacing 2-aminopyridine with mation of the activated Cu(I)-isocyanide complex,[13]
aniline or pyridine, only pyridine led to the formation which is deprotonated by pyridine to form A, which
of the desired product in 35% yield (entry 5). The then attacks the salicylaldehyde to give aldol adduct
nature of the base was found to have a pronounced B. Subsequent intramolecular rearrangement (B!E)
impact on the process. Pyridine and DMAP were and 5-endo-dig ring closure (E!F) generate the 3-
shown to be more effective than DBU and DIPEA formamidocoumarin product G. If carried out in the
(entries 6–8). Among the different copper salts tested, presence of a secondary amine (e.g., piperidine), in-
CuI was the best catalyst for this reaction, and the termediate E is attacked nucleophilically by piperi-
corresponding yield was enhanced up to 81% (en- dine to form H, followed by intramolecular rearrange-
tries 9, 11 and 12).
ment to give a 3-substituted methylideneaminocou-
It is interesting to note, that under the optimized marin (I) as the product. In the presence of a primary
conditions (CuI, pyridine, MeOH, 508C) salicylalde- amine, initial condensation with the salicylaldehyde
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Table 1. Reaction conditions.
Entry
Conditions
Yield [%]
1
2
3
4
5
6
7
8
2-aminopyridine (1.0 equiv.), Cu
(OTf)2 (0.1 equiv.), 508C
33[a]
0
0
2-aminopyridine (1.0 equiv.), 508C
Cu(OTf)2 (0.1 equiv.), 508C
aniline (1.0 equiv.), Cu(OTf)2 (0.1 equiv.), 508C
Pyridine (1.0 equiv.), Cu(OTf)2 (0.1 equiv.), 508C
DMAP (1.0 equiv.), Cu(OTf)2 (0.1 equiv.), 408C
DBU (1.0 equiv.), Cu(OTf)2 (0.1 equiv.), 408C
DIPEA (1.0 equiv.), Cu(OTf)2 (0.1 equiv.), 408C
T
N
0
N
35[a]
30[a]
trace
trace
18[a]
0
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
pyridine (1.0 equiv.), CuCl2 (0.1 equiv.), 508C
pyridine (1.0 equiv.), FeCl3 (0.1 equiv.), 508C
10
11
12
pyridine (1.0 equiv.), Cu
N
25[a]
81[b]
pyridine (1.0 equiv.), CuI (0.1 equiv.), 508C
[a]
Yield [%] of isolated product after column chromatography.
Yield of crystalline compound isolated by filtration (no recovery from mother liquor), hence the total yield may be
higher.
[b]
Scheme 2. Multicomponent synthesis of 3-substituted methylideneaminocoumarins and chromenoACTHNUTRGNEU[GN 3,4-d]imidazol-4(1H)-ones.
forms an imine (J) which is then attacked by A to nally, removal of the formyl group using 5 equivalents
form intermediate K. Subsequent 5-endo-dig ring clo- of concentrated HCl in methanol afforded the pure 3-
sure and protonation form the imidazoline L. The aminocoumarins (3a–j) in excellent yields.
latter is rapidly oxidized to imidazole M.
In Table 3, pyrrolidine, piperidine, and morpholine
With the identification of the optimal reaction con- were selected as the substrates in the 3CC reaction, to
ditions, we wished to extend the utility of the reac- afford the 3-substituted methylideneaminocoumarins
tion. As shown in Table 2, seven commercially avail- (4a–c, Table 3) in moderate yields. Meanwhile, vari-
able substituted salicylaldehydes (1a–g, entries 1–7), ous primary amines were used in the construction of
two 2’-hydroxyacetophenones (1h and i, entries 8 and imidazole derivatives (5a–f). The reaction was found
9), and 2’-hydroxypropiophenone (1j, entry 10) bear- to proceed with a range of R3 groups, including ali-
ing electron-withdrawing and electron-donating sub- phatic groups and aromatic rings. Subsequent ring-
stituents were selected. The simplicity of a one-pot closing reaction furnished the polycyclic products 6a–f
procedure is perfectly amenable to automation for in moderate overall yields. Notably, such benzopyrani-
combinatorial synthesis. Likewise, all the syntheses midazolones were revealed as PDE7 inhibitors, but
were performed on a 12-reaction set-up in a parallel no synthetic method was disclosed.[14]
synthesizer (Radleys Discovery Technology, Carousel
In summary, by using ethyl isocyanoacetate as a
12 Place Reaction Station) to give the key 3-formami- glycine equivalent, an efficient avenue for the facile
docoumarin intermediates 2a–j (Table 2). According and atom-economic synthesis of two types of 3-ami-
to Table 1, the reaction rate appeared to be sensitive nocoumarin derivatives under mild conditions was de-
to steric effects: reactions with larger R2 groups re- veloped. Furthermore, the same conditions can be
quired longer times for completion (entries 8–10). Fi- used to generate N-substituted chromenoACTHUNRTGNE[GNU 3,4-d]imi-
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Simple and Efficient Copper(I)-Catalyzed Access to Three Versatile Aminocoumarin-Based Scaffolds
Figure 2. X-ray crystal structures of 4b and 5a.[12]
dazol-4(1H)-ones. The protocol uses readily available (100 MHz) spectra were recorded using Varian Mercury-400
starting materials, and the corresponding target prod- High Performance Digital FT-NMR. The LC-MS were car-
ucts are obtained in moderate to high yields. The ried out on Thermo Finnigan LCQDECAXP and low-reso-
copper catalyst used was active without additional co- lution EI-MS was measured on a MAT-95 spectrometer and
ordinating ligands. 3-Aminocoumarins are well-known HR-EI-MS on a MAT-77 spectrometer. Purity was recorded
as biologically and pharmaceutically active molecules, on Gilson high-performance liquid chromatography (HPLC)
as well as chromophores of many fluorescent proteins, (306 pump, UV/vis-156 Detector, 215 liquid handle). TLC
therefore, the present method will be of wide applica- was carried out with glass pre-coated silica gel GF254 plates.
tion in organic and medicinal chemistry.
TLC spots were visualized under UV light. All the solvents
and reagents were used directly as obtained commercially
unless otherwise noted. A Biotage Initiator microwave reac-
tor was used for microwave reactions. Irradiation was initiat-
ed at 300 W to raise the temperature to the set point and
then power was applied at intervals and levels to maintain
the desired temperature. Reactions were run in sealed ves-
sels.
Experimental Section
The 1H NMR (300 MHz) spectra were recorded using
Varian Mercury-300 High Performance Digital FT-NMR
with TMS as internal standard, and the 13C NMR
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Tao Meng et al.
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Scheme 3. Suggested reaction mechanism.
150.08, 130.07, 127.88, 125.26, 124.84, 123.08, 119.48, 116.42;
HR-MS (EI): m/z=189.0422, calcd. for C10H7NO3: 189.0426.
Compound 2a (120 mg, 0.63 mmol) was then treated with
concentated HCl (260 mL, 5 equiv.) in 10 mL of methanol,
and was refluxed for 1 h. The reaction mixture was then
concentrated under vacuum, and the residue was neutralized
to pH ~8, and extracted with dichloromethane (50 mL). The
organic layer was dried over Na2SO4, filtered, and the sol-
vent was removed under vacuum to afford 3a as a yellow
solid; yield: 101 mg (95%); mp 125–1278C; 1H NMR
(300 MHz, CDCl3): d=7.26–7.34 (m, 3H), 7.15–7.25 (m,
1H), 6.71 (s, 1H), 4.27 (bs, 1H); HR-MS (EI): m/z=
161.0474, calcd. for C9H7NO2: 161.0477.
Typical Experimental Procedure for the Preparation
of 2a and 3a (Table 2)
To a mixture of salicylaldehyde (1a, 100 mg, 0.82 mmol),
ethyl isocyanoacetate (93 mg, 0.82 mmol) and pyridine
(65 mg, 0.82 mmol) in MeOH (1 mL) was added CuI
(16 mg, 0.08 mmol). The reaction mixture was stirred at
508C and monitored by TLC. After the reaction was com-
plete (typically 4–8 h), the precipitate was isolated by filtra-
tion and washed with MeOH (2ꢃ1 mL) to give the desired
product 2a as a light yellow solid; yield: 125 mg (81%); mp
182–1858C; 1H NMR (400 MHz, CDCl3): d=8.71 (s, 1H),
8.58 (s, 1H), 8.31 (bs, 1H), 7.43–7.60 (m, 2H), 7.29–7.40 (m,
2H); 13C NMR (100 MHz, CDCl3): d=159.77, 158.38,
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Simple and Efficient Copper(I)-Catalyzed Access to Three Versatile Aminocoumarin-Based Scaffolds
Table 2. Synthesis of 3-aminocoumarins under optimized conditions.
Entry
R1
R2
R3
Compound, yield (%)[a,b]
Compound, yield [%]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
Me
Me
Et
H
2a, 81
2b, 82
2c, 75
2d, 88
2e, 79
2f, 70
2g, 67
2h, 63
2i, 65
2j, 50
3a, 95
3b, 95
3c, 92
3d, 100
3e, 97
3f, 95
3g, 90
3h, 93
3i, 98
3j, 92
3-OMe
4-Et2N
2,4-di-OMe
3,5-di-Cl
3-OMe, 5-NO2
3-Br, 5-NO2
H
6-OMe
7-Et2N
5,7-di-OMe
6,8-di-Cl
6-OMe, 8-NO2
6-Br, 8-NO2
H
4-F
H
7-F
H
10
[a]
Yield of crystalline compound isolated by filtration (no recovery from mother liquor), hence the total yield may be
higher.
[b]
for entries 1–7: reaction times are 5–6 h; for entries 8 and 9: reaction time was prolonged to 24 h; for entry 10: 48 h was
needed for completion of the reaction.
1.57 (m, 4H); 13C NMR (100 MHz, DMSO-d6): d=159.58,
Table 3. Scope of the three-component reaction.
154.04, 150.19, 137.13, 127.99, 126.44, 124.33, 122.80, 121.09,
115.40, 49.69, 42.30, 26.25, 24.67, 24.09; HR-MS (EI): m/z=
256.1217, calcd. for C15H16N2O2: 256.1212.
Typical Experimental Procedure for the Preparation
of 6a (Table 3)
To a mixture of salicylaldehyde (1a, 100 mg, 0.82 mmol),
ethyl isocyanoacetate (90 mL, 0.82 mmol) and 4-methoxy-
benzylamine (106 mL, 0.82 mmol) in MeOH (3 mL) was
added pyridine (66 mL, 0.82 mmol) and CuI (16 mg,
0.08 mmol). The reaction mixture was stirred at 508C over-
night. The solvent was removed under vacuum, and the resi-
due was purified by a flash column chromatography to
afford the intermediate 5a as a pale white solid; yield:
1
195 mg (70%); mp 199–2028C; H NMR (400 MHz, DMSO-
d6): d=7.88 (s, 1H), 7.28 (t, J=7.6 Hz, 1H), 6.99 (dd, J=
13.9, 7.6 Hz, 2H), 6.84 (t, J=8.0 Hz, 3H), 6.76–6.80 (m,
2H), 4.76–5.12 (m, 2H), 3.68 (s, 3H), 3.56 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d=162.98, 158.72, 155.03, 137.95,
135.61, 132.60, 130.56, 129.34, 128.85 (2ꢃC), 128.65, 118.82,
115.93, 115.48, 113.88 (2ꢃC), 55.10, 50.73, 47.76; HR-MS
Typical Experimental Procedure for the Preparation
of 4b (Table 3)
(EI): m/z=338.1267, calcd. for C19H18N2O4: 338.1267.
A Biotage Microwave Vial (5 mL) was charged with 5a
(150 mg, 0.44 mmol) and potassium carbonate (61 mg,
0.44 mmol) in DMF (1 mL). After sealing the cap, the re-
sulting mixture was irradiated at 1808C for 10 min using a
Biotage Initiator microwave reactor. After the reaction had
cooled to ambient temperature, the crude reaction mixture
was extracted with ethyl acetate (3ꢃ15 mL). The combined
organic phase was washed with water (2ꢃ15 mL), brine
(20 mL), dried with Na2SO4 and concentrated. The residue
was purified by flash column chromatography on Combi-
flashTM to provide the desired product as a white solid;
yield: 120 mg (88%). mp 187–1908C; 1H NMR (400 MHz,
To a mixture of salicylaldehyde (1a, 100 mg, 0.82 mmol),
ethyl isocyanoacetate (90 mL, 0.82 mmol) and piperidine
(243 mL, 2.46 mmol) in MeOH (3 mL) was added pyridine
(66 mL, 0.82 mmol) and CuI (16 mg, 0.08 mmol). The reac-
tion mixture was stirred at 508C overnight. The solvent was
removed under vacuum, and the residue was purified by a
flash column chromatography to afford 4b as a yellow solid;
yield: 155 mg (74%); mp 135–1388C; 1H NMR (400 MHz,
DMSO-d6): d=8.08 (s, 1H), 7.51 (dd, J=7.7, 1.5 Hz, 1H),
7.33–7.40 (m, 1H), 7.23–7.32 (m, 2H), 7.22 (s, 1H), 3.55 (t,
J=5.3 Hz, 2H), 3.33–3.40 (m, 2H), 1.59–1.66 (m, 2H), 1.47–
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Tao Meng et al.
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CDCl3): d=7.77 (s, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.42–7.50
(m, 2H), 7.22 (ddd, J=8.1, 6.4, 2.1 Hz, 1H), 7.10 (d, J=
8.8 Hz, 2H), 6.89–6.95 (m, 2H), 5.59 (s, 2H), 3.80 (s, 3H);
13C NMR (100 MHz, CDCl3): d=159.86, 156.86, 152.19,
143.12, 135.41, 129.70, 127.88 (2ꢃC), 127.80, 125.53, 124.29,
121.33, 118.18, 114.86 (2ꢃC), 112.92, 55.32, 50.62; HR-MS
(EI): m/z=306.1005, calcd. for C18H14N2O3: 306.1004.
[4] G. Melagraki, A. Afantitis, O. Igglessi-Markopoulou,
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Acknowledgements
This work was supported by National Science & Technology
Major Project “Key New Drug Creation and Manufacturing
Program”,
China
(numbers:
2009ZX09301-001,
2009ZX09501-010 and 2009ZX09103-074), the 863 Hi-Tech
Research and Development Program, 863 Program of China
(Grant 2007AA02Z308), and the National Natural Science
Foundation of China (Grant 81001355).
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