In(III)-Catalyzed tandem reaction of chromone-derived Morita–Baylis–Hillman alcohols with amines

Chen Wu ab, Yuliang Liu ab, Hao Zeng a, Li Liu *a, Dong Wang a and Yongjun Chen a
aBeijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail:; Fax: +86 6255 4449
bGraduate School of Chinese Academy of Sciences, Beijing 100049, China

Received 18th August 2010 , Accepted 5th October 2010

First published on 3rd November 2010


The reaction of chromone-derived cyclic Morita–Baylis–Hillman alcohols with amines catalyzed by In(OTf)3 in a one pot process was developed for the convenient and efficient synthesis of 2-substituted-3-aminomethylenechromans. The tandem allylic amination/chromen ring-opening/Michael cyclization reactions were involved in this protocol.


Morita–Baylis–Hillman (MBH) adducts, which possess both allylic hydroxyl and Michael acceptor units in the identical molecule, have been illustrated as valuable synthons and starting materials for the synthesis of various biologically active molecules.1–2 Recently MBH adduct as an electrophilic substrate has achieved fruitful results in the allylic substitution reactions with various nucleophiles, including C-nucleophiles, such as arenes and hetero-nucleophiles, such as the compounds bearing –OH, –SH and –NH groups.3 Among them, the carbon–nitrogen bond formation by N-nucleophilic substitution plays an important role for the diversity of synthetic compounds with biological activities.1–3 Generally, the MBH acetate was employed in the nucleophilic substitutions with amines, because hydroxyl group was usually considered as an inefficient leaving group. However, the advantages of directly using allyl alcohol as an allylic reagent were noteworthy: no further functionalization was required for the activation of hydroxyl group and water was the sole by-product after the reaction.4 Although many synthetic methods could be employed in performing the allylic amination of MBH acetates, the N-nucleophilic substitution of MBH alcohols was seldom reported.5 The reaction of MBH adducts with amines could proceed through two ways: either conjugate addition (Scheme 1, path B),5a–e or allylic amination accompanied with dehydration affording α- and γ-products (Scheme 1, path A).5f–h
The reaction of MBH alcohols with N-nucleophile.
Scheme 1 The reaction of MBH alcohols with N-nucleophile.

Benzopyranyl structural moiety is a common heterocyclic framework that can be found in numerous natural compounds and pharmaceutical molecules.6 3-Aminomethylchromons and their derivatives 3-aminomethylenechromans (Fig. 1) have shown important biological activities,7 such as nonsteroidal aromatase inhibitors, antimicrobial effects, and are also interesting as scaffolds in the synthesis of versatile benzopyranyl heterocycle libraries in drug discovery.8 As the Morita–Baylis–Hillman reaction is becoming an environmentally benign and important C–C bond formation reaction, the application of the allylic amination of chromone-derivatised MBH adducts could be efficient methods to construct diverse 3-aminomethylchromone derivatives.

          3-Aminomethylchromon derivatives.
Fig. 1 3-Aminomethylchromon derivatives.

Although chromone-derived MBH adducts, which exhibited a cyclic structural unit of MBH adduct, have been used in the synthesis of many heterocycles such as quinoline derivatives and azopinoindoles,9 the allylic amination of such substrates has been seldom reported. As an expansion of our research on the nucleophilic substitution of cyclic MBH adduct, we describe herein the preliminary results of the reaction between chromone-derived MBH alcohols and amines in a one pot process, in which an unexpected tandem allylamination/ring-opening/Michael cyclization reactions was observed to provide 3-aminomethylenechromans in high yields.

Results and discussion

An initial investigation was performed by employing 3-(hydroxy(phenyl)methyl)-chromone 1a and aniline 2a as substrates in the presence of the catalyst In(OTf)3 (10 mol%) in refluxing THF. To our surprise, unlike the reactions of the Morita–Baylis–Hillman alcohols derived from cycloenone with amines,5f this protocol gave neither α- nor γ-products eventually, but 2-phenyl-3-aminomethylene-chroman 3a in 28% yield (Scheme 2). The experimental results for screening solvent and catalyst are summarized in Table 1. A quantitative yield of 3a can be achieved when toluene was used instead of THF (Table 1, entry 2). Several other Lewis acids were screened. In all cases the product 3a was obtained, but in decreased yields. (Table 1, entries 5–8). No reaction occurred either at room temperature or without catalyst, and the starting materials were recovered (Table 1, entries 9 and 10). Water was also used as a solvent but the yield was decreased to 61% (Table 1, entry 11).
Table 1 Catalytic reaction of 1a with 2aa
Entry Catalyst Solvent T/°C Yield of 3a (%)
a 1a (0.2 mmol), 2a (0.3 mmol), catalyst (0.02 mmol), solvent (2 mL), 72 h. b Without catalyst.
1 In(OTf)3 THF Reflux 28
2 In(OTf)3 Toluene Reflux >99
3 In(OTf)3 MeCN Reflux 41
4 In(OTf)3 DCM Reflux Trace
5 Sc(OTf)3 Toluene Reflux 65
6 FeCl3 Toluene Reflux 69
7 AgOTf Toluene Reflux 90
8 InBr3 Toluene Reflux 16
9 b Toluene Reflux 0
10 In(OTf)3 Toluene r.t. 0
11 In(OTf)3 Water Reflux 61

Reaction of 1a with 2a catalyzed by Lewis acid.
Scheme 2 Reaction of 1a with 2a catalyzed by Lewis acid.

As shown in Table 2, the substrate scope of this tandem reaction is quite broad. An array of anilines (2b–2f) with both electron-withdrawing and electron-donating substituents were employed in the reactions with MBH alcohol 1a under the catalysis of In(OTf)3. Good to excellent yields (78–99%) were obtained (entries 2–6). Besides, several aliphatic amines with either acyclic (2g–2i) or cyclic (2j) substituent were suitable to this reaction, affording the corresponding products (3g–3j) in moderate yields (entries 7–10).

Table 2 In(III)-Catalyzed reaction of MBH alcohols (1) with amines (2)a

Entry MBH Alcohol (R1,R2) Amine (R3) Yield of 3 (%)
a MBH alcohol 1 (0.2 mmol), amine 2 (0.3 mmol), In(OTf)3 (0.02 mmol).
1 1a, R1[double bond, length as m-dash]H, R2[double bond, length as m-dash]Ph 2a, Ph 3a, 99
2 1a 2b, 4-ClC6H4 3b, 99
3 1a 2c, 4-BrC6H4 3c, 99
4 1a 2d, 4-F-C6H4 3d, 78
5 1a 2e, 4-MeOC6H4 3e, 92
6 1a 2f, 4-Me-C6H4 3f, 82
7 1a 2g, Bn 3g, 68
8 1a 2h, n-C8H17 3h, 75
9 1a 2i, n-C12H25 3i, 66
10 1a 2j, Cy 3j, 60
11 1b, R1[double bond, length as m-dash]H,R2 = 2-BrC6H4 2a 3k, 82
12 1c, R1[double bond, length as m-dash]H,R2 = 4-ClC6H4 2a 3l, 83
13 1d, R1[double bond, length as m-dash]Me, R2[double bond, length as m-dash]Ph 2a 3m, 99
14 1e, R1[double bond, length as m-dash]H,R2 = n-C3H7 2a 3n, 55
15 1f, R1[double bond, length as m-dash]H,R2[double bond, length as m-dash]Cy 2a 3o, 85
16 1g, R1[double bond, length as m-dash]H,R2[double bond, length as m-dash]C6H5(CH2)2 2a 3p, 65
17 1e 2g 3q, 68
18 1g 2g 3r, 58
19 1a 2k, Bn2NH 3s, 78

Subsequently, we examined the chromone-derived MBH alcohols bearing different functional groups. Importantly, not only MBH alcohols (1b–1d) derived from aromatic aldehydes can undergo the tandem reaction smoothly to provide corresponding products, 2-aryl-3-aminomethylenechromanes (3k–3m), in very good yields (Table 2, entries 11–13), the ones 1e–1g derived from aliphatic aldehydes were also suitable to the tandem reaction, albeit in slightly decreased yields (Table 2, entries 14–16). Furthermore, the MBH alcohols 1e and 1g can also react with benzylamine (2g) to give desired products (3q–3r) in moderate yields (Table 2, entries 17–18). When secondary amine, dibenzylamine (2k) was used in the reaction with 1a under the same conditions, the tandem reaction product 3s was also obtained in 78% yield (entry 19).

ugraphic, filename = c0ob00604a-u2.gif

The molecular structure of the tandem reaction product 3 was further confirmed by X-ray crystallographic analysis of 3k (Fig. 2).10 The distance between NH and carbonyl is 2.014 Å, which falls into the range of hydrogen bonding interaction.

ORTEP drawing of 3k with thermal ellipsoids at 30% probability levels.
Fig. 2 ORTEP drawing of 3k with thermal ellipsoids at 30% probability levels.

Based on the results of X-ray analysis, cis-configuration of the newly formed double bond could be determined.

The plausible mechanism of the tandem reaction of MBH alcohol with amine was proposed, and shown in Scheme 3. The MBH alcohol derived from chromone was activated by In(OTf)3. The N-nucleophile attacked γ-position of MBH alcohol to carry out allylic amination reaction accompanied with dehydration, generating an intermediate A. Subsequently, intermediate A. underwent chromone ring-opening9b–c to form an active Michael acceptor B which was followed by intramolecular oxa-Michael cyclization to yield 2-substituted-3-aminomethylenechroman 3.

Proposed mechanism of the reaction of chromone-derived MBH alcohol with amine.
Scheme 3 Proposed mechanism of the reaction of chromone-derived MBH alcohol with amine.

It was interesting to note that if the reaction of MBH alcohol 1a with diphenylamine 2l was carried out under the catalysis of In(OTf)3, the α-regioselective product of Friedel–Crafts alkylation (4) was formed in 43% yield, as well as unexpected indenone 5 was obtained in 38% yield via cascade allylic amination/chromen ring-opening/C-nucleophilic Friedel–Crafts cyclization (Scheme 4).

Reaction of 1a with diphenylamine 2l.
Scheme 4 Reaction of 1a with diphenylamine 2l.


In summary, we developed the reaction of chromone-derived Morita–Baylis–Hillman alcohols with amines under In(OTf)3 catalysis for the synthesis of 2-substituted-3-aminomethylene-chromans. This protocol combined allylic amination, ring-opening, Michael cyclization reactions in a one pot process. A tentative mechanism for the tandem reactions was proposed. Investigation of the tandem reactions and their application in the synthesis of biologically active compounds is ongoing.


General Methods

The 1H and 13C NMR spectra were recorded on Bruker-AV 300 spectrometer and chemical shift reported in CDCl3 or DMSO-d6 with tetramethylsilane as an internal standard. IR spectra were recorded on a Bruker tensor 27 infrared spectrometer. HRMS spectra were recorded on GCT-Mass Micromass spectrometer. Melting points were measured on Beijing-Tiker X-4 apparatus without correction. All reactions were carried out in oven dried flasks. Common reagents were purchased from commercial sources and were used without further purification. The Morita–Baylis–Hillman alcohols were prepared according to literature methods.11 All reactions were performed under nitrogen atmosphere.

Typical experimental procedures for the reaction of MBH alcohol with amine

To a stirred solution of 3-(hydroxy(phenyl)methyl)-chromone (1a, 51 mg, 0.2 mmol) in toluene (2 mL) at room temperature was added aniline (2a, 35 μL, 0.3 mmol) and In(OTf)3 (11 mg, 0.02 mmol) sequentially and the reaction mixture was heated to reflux for 72 h. Upon completion of the reaction as judged by TLC, the reaction was quenched with water and extracted with DCM twice. The combined extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluent: EtOAc/petroleum ether = 1/8) to afford the product 3a.
(Z)-2-Phenyl-3-((phenylamino)methylene)chroman-4-one (3a). Compound 3a was isolated as a yellow solid (65 mg, yield >99%). m.p. 101–104 °C. IR νmax (film, cm−1): 3053, 2960, 2919, 2858, 1649, 1601, 1466, 1277, 1218, 1150, 1100, 1022, 801, 753, 695, 499. 1H NMR (300 MHz, CDCl3): 11.91 (d,1H, J = 12.0 Hz), 7.95 (dd, 1H, J = 1.6 Hz, 7.8 Hz), 7.52–7.35 (m, 6H), 7.28–7.23 (m, 2H), 7.08–6.84 (m, 6H), 6.06 (s, 1H); 13C NMR (75 MHz, CDCl3): 182.2, 158.1, 141.2, 139., 138.0, 133.5, 128.7,127.7, 126.8, 125.6, 122.7, 122.6, 120.7, 116.8, 115.2, 104.6, 80.3. HRMS (EI): m/z calcd for C22H17NO2: 327.1259 (M+), found 327.1262.


We thank the National Natural Science Foundation of China, Ministry of Science and Technology (No. 2009ZX09501-006) and the Chinese Academy of Sciences for the financial support.


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