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

Article abstract of DOI:10.1039/c0ob00604a

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 allyli

Full text of DOI:10.1039/c0ob00604a

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In(III)-Catalyzed tandem reaction of chromone-derived
Morita–Baylis–Hillman alcohols with amines
Chen Wu,a,b Yuliang Liu,a,b Hao Zeng,a Li Liu,*a Dong Wanga and Yongjun Chena
Received 18th August 2010, Accepted 5th October 2010
DOI: 10.1039/c0ob00604a
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.
Introduction
Morita–Baylis–Hillman (MBH) adducts, which possess both al-
lylic 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
Scheme 1 The reaction of MBH alcohols with N-nucleophile.
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 a- and
g-products (Scheme 1, path A).5f–h
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.
Fig. 1 3-Aminomethylchromon derivatives.
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 scaf-
folds in the synthesis of versatile benzopyranyl heterocycle libraries
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.
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:
lliu@iccas.ac.cn; Fax: +86 6255 4449
bGraduate School of Chinese Academy of Sciences, Beijing 100049, China
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Table 1 Catalytic reaction of 1a with 2aa
Table 2 In(III)-Catalyzed reaction of MBH alcohols (1) with amines (2)a
Entry
Catalyst
Solvent
T/◦C
Yield of 3a (%)
1
2
3
4
5
6
7
8
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
Sc(OTf)3
FeCl3
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
28
>99
41
Trace
65
69
90
16
0
0
Toluene
MeCN
DCM
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Water
Entry MBH Alcohol (R1,R2)
Amine (R3)
Yield of 3 (%)
AgOTf
InBr3
1
2
3
4
5
6
7
8
1a, R1 H, R2 Ph
2a, Ph
3a, 99
3b, 99
3c, 99
3d, 78
b
1a
2b, 4-ClC6H4
2c, 4-BrC6H4
2d, 4-F-C6H4
9
10
11
—
1a
In(OTf)3
In(OTf)3
1a
Reflux
61
1a
2e, 4-MeOC6H4 3e, 92
a 1a (0.2 mmol), 2a (0.3 mmol), catalyst (0.02 mmol), solvent (2 mL), 72 h.
1a
2f, 4-Me-C6H4
3f, 82
3g, 68
3h, 75
3i, 66
3j, 60
3k, 82
3l, 83
3m, 99
3n, 55
3o, 85
3p, 65
3q, 68
3r, 58
3s, 78
b Without catalyst.
1a
2g, Bn
1a
2h, n-C8H17
9
1a
2i, n-C12H25
10
11
12
13
14
15
16
17
18
19
1a
2j, Cy
2a
Results and discussion
1b, R1 H,R2 = 2-BrC6H4
1c, R1 H,R2 = 4-ClC6H4
1d, R1 Me, R2 Ph
1e, R1 H,R2 = n-C3H7
1f, R1 H,R2 Cy
2a
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 a- nor g-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).
2a
2a
2a
1g, R1 H,R2 C6H5(CH2)2 2a
1e
1g
1a
2g
2g
2k, Bn2NH
a MBH alcohol 1 (0.2 mmol), amine 2 (0.3 mmol), In(OTf)3 (0.02 mmol).
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). Further-
more, 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).
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 A,
˚
Scheme 2 Reaction of 1a with 2a catalyzed by Lewis acid.
which falls into the range of hydrogen bonding interaction.
Based on the results of X-ray analysis, cis-configuration of the
newly formed double bond could be determined.
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).
Subsequently, we examined the chromone-derived MBH alco-
hols bearing different functional groups. Importantly, not only
MBH alcohols (1b–1d) derived from aromatic aldehydes can
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 g-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.
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Conclusions
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.
Experimental
Fig. 2 ORTEP drawing of 3k with thermal ellipsoids at 30% probability
levels.
General Methods
1
The H 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 spec-
trometer. 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 mL, 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.
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 a-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).
(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 mmax (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.
Acknowledgements
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.
Scheme 4 Reaction of 1a with diphenylamine 2l.
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◦
˚
˚
406.27, Monoclinic, a = 15.7458(9) A, a = 90 , b = 5.1545(2) A, b =
◦
◦
92.048(2) , c = 20.8004(10) A, g = 90 , V = 1687.12(14) A 3, T =
173(2) K, space group = P21/c, Z = 4, Number of Reflections = 6168,
Independent reflections = 3846, [R(int) = 0.0554], Final R indices [I >
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256 | Org. Biomol. Chem., 2011, 9, 253–256
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The Royal Society of Chemistry 2011
©