Synthesis of novel functional polycyclic chromones through Michael addition and double cyclizations

Article abstract of DOI:10.1039/c0ob01000f

A base-promoted, microwave-assisted one-pot tandem reaction from simple 3-(1-alkynyl)chromones with 2-halobenzylic nitriles (esters or amides) for the synthesis of novel functional polycyclic chromenones has been developed. This tandem process involves multiple reactions, such as Michael addition and double cyclizations without a transition metal catalyst.

Full text of DOI:10.1039/c0ob01000f

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Organic &
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PAPER
Synthesis of novel functional polycyclic chromones through Michael addition
and double cyclizations†
Yang Liu, Liping Huang, Fuchun Xie, Xuxing Chen and Youhong Hu*
Received 9th November 2010, Accepted 1st February 2011
DOI: 10.1039/c0ob01000f
A base-promoted, microwave-assisted one-pot tandem reaction from simple 3-(1-alkynyl)chromones
with 2-halobenzylic nitriles (esters or amides) for the synthesis of novel functional polycyclic
chromenones has been developed. This tandem process involves multiple reactions, such as Michael
addition and double cyclizations without a transition metal catalyst.
Introduction
Tandem reactions provide an efficient way to generate molecular
complexity from readily accessible intermediates.1 2-(1-Alkynyl)-
2-alken-1-one was applied as a special unit in a tandem reaction
catalyzed by transition metals or acids, involving an electrophile-
induced cascade process to form highly substituted furans.2 Under
basic conditions, the cascade reaction of this unit with nucleophilic
substrates proceeded in a different cascade way to generate a
different product.3
Our research group has focused on functionalized 3-(1-alk-
ynyl)chromones to generate diversified natural-product-like scaf-
Scheme 1 Base-promoted tandem reaction to form the functional
polycyclic chromenone 3aa.
folds through cascade reactions.3d–g Recently, we described a base-
promoted one-pot tandem reaction of 3-(1-alkynyl)chromones
under microwave irradiation to generate functionalized amino-
substituted xanthones.3h Continuing our efforts in this area,
various substituted acetonitriles were treated with functional-
ized 3-(1-alkynyl)chromones to generate the diversified amino-
substituted xanthones library for high throughput screening.
Surprisingly, the reaction of 3-(1-phenylethynyl)chromone 1a with
2-(2-bromophenyl)acetonitrile 2a afforded the unexpected novel
compound 3aa containing a benzo seven-membered ring as the
sole product in 71% yield in contrast to the formation of an
aromatic ring for amino-substituted xanthone 4a (Scheme 1).
Fig. 1 ORTEP plot of 3aa shown with ellipsoids at the 50% level.
The structure was unambiguously established by X-ray crystal
structure analysis (Fig. 1).4 This natural-product-like structural
skeleton is reported here for the first time. When Br was changed
to Cl or F for the substrate 2a, the product 3aa was observed in a
Results and discussion
We envisioned that this novel transformation involves a domino
process of a Michael addition-elimination and double cyclizations.
(Scheme 2). Firstly, in the presence of a base and under microwave
irradiation, the 3-(1-alkynyl)chromone 1 as a Michael acceptor
could be attacked by 2 to generate A, along with the opening of
the pyrone ring to form B.5 Subsequently, the phenol group of B
could recyclize with the alkynyl bond to produce the intermediate
C, which could rearrange to D via a 1,5-H shift.3d Then an 8p-
electrocyclization of D6 was possible to form E and followed by
the elimination of bromide to generate the stable seven-membered
polycyclic chromone 3.
similar yield.
State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Science, 555 Zu Chong Zhi Road, Shanghai,
201203, China. E-mail: yhhu@mail.shcnc.ac.cn; Fax: +86-21-5080-5896;
Tel: +86-21-5080-5896
† Electronic supplementary information (ESI) available: Synthesis and 1H
and 13 C NMR spectra of compounds 2, 3 and 4. CCDC reference numbers
755402 and 792937. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob01000f
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aromatic or heteroaryl group on the acetylene moiety and R3 is a
hydrogen, good to excellent yields were obtained (Table 2, entries
1–7). It is noted that an electron-donating group on the aromatic
ring of 3-(1-alkynyl)chromone is beneficial to this domino process
(Table 2, entries 2 and 7). When R3 is a methyl group, the desired
product was formed in low yield (Table 2, entry 8) along with
a dimeric byproduct.3f When R1 is a trimethyl-silyl group, the
desilylated product 3ja was observed in a reasonable yield since
desilylation of 1j easily occurred under basic conditions7 (Table
2, entry 9). In addition, the desired products were produced in
reasonable yields when R1 was an aliphatic group on the acetylene
1
moiety (Table 2, entries 10–12). Interestingly, H NMRs of 3ka
and 3la show the existence of two conformational isomers at room
temperature in d6-DMSO. It is clear from the X-ray structure
that the phenyl substituent on C18 of 3aa is in an axial position
(Fig. 1), which places the phenyl group below and away from
the cyclic units on either side of the seven-membered ring. This
axial orientation of a bulky substituent is evidently the most stable
conformation for this type of polycyclic chromone. Furthermore,
Scheme 2 A proposed mechanism of the tandem reaction.
Based on the above results, different bases such as DBU, t-
BuOK, MeONa and K2CO3 were tested (Table 1, entries 1–4).
DBU and t-BuOK generally performed better. Since the 8p-
electrocyclization might need more energy, the reaction temper-
ature was increased to 130 ◦C to improve the yields a little (Table
1, entries 5 and 6). By decreasing the amount of t-BuOK from 3
equiv to 1 equiv, the reaction proceeded well and gave 82% yield
(Table 1, entry 8). Among the different solvents (Table 1, entries
8–10), DMF was best. In the absence of microwave irradiation,
the reaction at 130 ◦C in an oil bath took longer to give 3aa
in 70% yield (Table 1, entry 11). There was no big difference
whether the reaction was catalyzed by palladium or copper for
the activation of aryl bromide (Table 1, entries 12 and 13). The
optimized conditions were defined as carrying out the reaction in
DMF at 130 ◦C for 10 min in the presence of 1 equiv t-BuOK
under microwave irradiation.
8
the X-ray crystal study of 3ka (see supporting information†)
shows the substitution is in the axial position too. We speculate that
the seven-membered ring should have a degree of conformational
flexibility, which could orientate an axial group into an equatorial
position for substituents of certain size in solution. Insertion
of a methylene unit between C18 and the phenyl ring, as in
3ka or 3la, may achieve that, and the interconversion of the
two conformational isomers on the NMR timescale at room
temperature may occur. Further study of the NMR of 3ka at
variant temperature was carried out in d6-DMSO over a range of
20–70 ◦C (Fig. 2). At 70 ◦C, the broadening of peaks indicates
the conformational flexing of the seven-membered ring system
at higher temperature. At various temperatures, no difference of
NMR spectra of 3aa was found. This means that substituents of
a certain size on the C18 position is critical to the conformational
flexibility of the seven-membered ring system.
By using the optimized reaction conditions, various substituted
3-(1-alkynyl)chromones 1 were treated with 2aa for generating
more functional polycylic chromones (Table 2). When R1 is an
Table 1 Optimization of the one-pot tandem reaction of 1aa
Entry
Solvent
Base
Temp/time
Yield (%)c
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMSO
DMF
DMF
DMF
3 equiv DBU
90 ◦C, 10 min
90 ◦C, 10 min
90 ◦C, 10 min
90 ◦C, 10 min
130 ◦C, 10 min
130 ◦C, 10 min
130 ◦C, 10 min
130 ◦C, 10 min
130 ◦C, 10 min
130 ◦C, 10 min
130 ◦C, 3 h
71
68
57
33
72
75
77
82
66
73
70
80
64
3 equiv t-BuOK
3 equiv MeONa
3 equiv K2CO3
3 equiv DBU
3 equiv t-BuOK
1 equiv DBU
1 equiv t-BuOK
1 equiv t-BuOK
1 equiv t-BuOK
1 equiv t-BuOK
1 equiv t-BuOK
1 equiv t-BuOK
9
10
11b
12d
13e
130 ◦C, 10 min
130 ◦C, 10 min
a Unless otherwise noted, the reactions were carried out under microwave irradiation. b Reactions were carried out in an oil bath. c Yield of isolated
product based on 1a. d 5% equiv PdCl2(PPh3)2 catalyst was added. e 5% equiv CuI catalyst was added.
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Table 2 Tandem reaction of 2aa with various 3-(1-alkynyl) chromonesa
Table 3 Tandem reaction of 1a with various substrates 2a
Entry
1
Substrate
Product
Yield(%)b
51
Entry
1
Substrate
Product
Yield(%)b
88
2
85
2
3
4
66
62
63
3
4
65
62
5
6
60
45
5
43
7
8
77
28
6
7
NAc
91
9
52
63
a Unless otherwise noted, the reactions were carried out under standard
10
conditions. b Yields of isolated products based on 1a. c No desired product.
11
12
57
60
a Unless otherwise noted, the reactions were carried out under standard
conditions. b Yield of isolated product based on 1.
Fig. 2 Temperature dependent NMR spectra of 3ka.
To extend the scope of this reaction, various substrates of 2 were
used. Products 3ab–3af were obtained in 43–88% yields (Table 3).
It is noted that an electron-withdrawing group on the aromatic
ring of 2 is beneficial to this domino process for easy removal of
the leaving group, Br-, from the para-position, according to the
proposed mechanism (Table 3, entry 1). When R5 was an ester
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group or amide group, this tandem reaction proceeded smoothly
to give the desired products (Table 3, entries 3–5). In the case
where there was a methyl group adjacent to the cyano group
(2g), no desired product was formed and only the desalicyloylative
dimerization product3e of 1a was obtained (Table 3, entry 6). In
addition, when R5 is a ketone group (2h), the aromatic compound
4b was formed in 91% yield, since the 1,2-addition 3d to the keto
group is more active than the 8p-electrocyclization in this tandem
process.
118.1, 116.1, 114.9, 55.0. HRMS [M]+ Calculated for C25H15NO2
361.1103, found 361.1106.
General procedure for synthesis of xanthone 4b
To a solution of 1-(2-bromophenyl)propan-2-one 2g (44 mg, 0.2
mmol) in dry DMF (1 mL) was added t-BuOK (24 mg, 0.2
mmol) at room temperature under a nitrogen atmosphere. After
stirring for 5 min, compound 1a (50 mg, 0.2 mmol) was added
and the resulting dark red solution was irradiated for 10 min at
130 ◦C (monitored by TLC). The mixture was extracted with ethyl
acetate (10 mL ¥ 3). The combined organic layers were washed
with brine (10 mL), dried over anhydrous Na2SO4, filtered and
concentrated to give the crude product, which was further purified
by column chromatography (petroleum ether/ethyl acetate 10 : 1)
Conclusions
In conclusion, we have developed a novel base-promoted,
microwave-assisted one-pot tandem reaction for the synthesis
of functionalized polycyclic chromenones. Notably, we found
that this tandem process involves the formation of a benzo
seven-membered ring by 8p-electrocyclization. The process effi-
ciently generates novel natural-product-like diversified polycyclic
chromenone scaffolds. The library generation and biological
evaluation of the novel polycyclic chromenones are under investi-
gation.
◦
1
to afford compound 4b as a white solid; m.p. 185–186 C; H
NMR (300 MHz, CDCl3) d: 8.33 (dd, J = 1.7, 7.9 Hz, 1H), 8.15
(s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.63 (td, J = 1.6, 7.7 Hz, 1H),
7.26–7.58 (m, 9H), 7.23 (d, J = 8.8 Hz, 1H), 2.01 (s, 3H). 13C
NMR (100 MHz, CDCl3) d: 177.3, 156.1, 153.0, 143.0, 141.5,
137.9, 135.5, 134.5, 132.6, 131.3, 131.1, 130.3, 130.0, 129.2, 128.4,
128.3, 127.6, 127.4, 126.4, 126.0, 124.0, 123.8, 121.5, 119.5, 118.2,
18.9. HRMS [M]+ Calculated for C26H17BrO2Na 463.0310, found
463.0298
Experimental
General information
Acknowledgements
All reactions were performed under a nitrogen atmosphere.
Dry solvents were distilled prior to use; DMF was dried over
microwave-dried molecular sieve; petroleum ether refers to the
Financial supports of this project, provided by the NST Major
Project “Key New Drug Creation and Manufacturing Program”
(2009ZX09501-010) and SIMM0909KF-04, are gratefully ac-
knowledged.
◦
1
fraction with boiling point in the range 60–90 C. All H NMR
and 13C NMR spectra were measured in CDCl3 or d6-DMSO
with TMS as the internal standard. Chemical shifts are expressed
in ppm and J values are given in Hz. High resolution mass
spectra were recorded on a Finnigan MAT 95 mass spectrometer
(EI). Column chromatography was performed with 200–300 mesh
silica gel using flash column techniques. Melting points are
uncorrected.
References
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General procedure for synthesis of the novel functional polycyclic
chromenones 3
A typical procedure for the preparation of 3aa: To a solution of
2-(2-bromophenyl)acetonitrile 2aa (40 mg, 0.2 mmol) in dry DMF
(1 mL) was added t-BuOK (24 mg, 0.2 mmol) at room temperature
under a nitrogen atmosphere. After stirring for 5 min, compound
1a (50 mg, 0.2 mmol) was added and the resulting dark red
solution was irradiated for 10 min at 130 ◦C (monitored by TLC).
The mixture was extracted with ethyl acetate (10 mL ¥ 3). The
combined organic layers were washed with brine (10 mL), dried
over anhydrous Na2SO4, filtered and concentrated to give the crude
product, which was further purified by column chromatography
(petroleum ether/ethyl acetate 6 : 1) to afford compound 3aa as a
white solid; m.p. 235–236 ◦C; IR (KBr) nmax 3429, 3053, 2212, 1651,
1620, 1570, 1464, 1400, 1365, 1217, 1167, 764, 710 cm-1; 1H NMR
(300 MHz, CDCl3) d: 8.27 (dd, J = 1.8, 7.9 Hz, 1H), 7.91 (dd, J =
1.4, 7.4 Hz, 1H), 7.70–7.79 (m, 2H), 7.44–7.67 (m, 5H), 7.12–7.21
(m, 3H), 6.70–6.77 (m, 2H), 5.51 (s, 1H). 13C NMR (100 MHz,
CDCl3) d: 175.8, 166.0, 155.9, 136.2, 135.8, 134.3, 133.9, 131.2,
131.1, 128.9, 128.6, 128.3, 127.6, 126.4, 126.3, 126.1, 122.6, 118.8,
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4 CCDC 755402† (3aa) contains the supplementary crystallographic
data for this paper. These data can be obtained free of
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charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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7 Removal of TMS-alkynes under basic conditions, see: T. W. Greene and
P. G. M Wuts In Protective Groups in Organic Chemistry, 3rd ed., Wiley-
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8 CCDC 792937† (3ka) contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2684 | Org. Biomol. Chem., 2011, 9, 2680–2684
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