Diversity-oriented synthesis of chromenes via metal-free domino reactions from ketones and phenols

Article abstract of DOI:10.1021/co3000506

Functionalized chromenes have been synthesized via highly selective metal-free domino reactions from ketones and phenols. 2H-Chromenes, 4H-chromenes, spiran and benzocyclopentane can be respectively prepared starting from the corresponding cyclic ketones,

Full text of DOI:10.1021/co3000506

Research Article
pubs.acs.org/acscombsci
Diversity-Oriented Synthesis of Chromenes via Metal-Free Domino
Reactions from Ketones and Phenols
Wei-Jian Xue, Qi Li, Fang-fang Gao, Yan-ping Zhu, Jun-gang Wang, Wei Zhang, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Hubei, Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: Functionalized chromenes have been synthe-
sized via highly selective metal-free domino reactions from
ketones and phenols. 2H-Chromenes, 4H-chromenes, spiran
and benzocyclopentane can be respectively prepared starting
from the corresponding cyclic ketones, aryl methyl ketones,
acetone, and 3-pentanone.
KEYWORDS: diversity-oriented synthesis, metal-free, domino reaction
INTRODUCTION
■
Chromenes and their derivatives are an important class of
structural motifs present in many natural products and
synthetic molecules.1 They have also been applied in medicine,2
health-promoting agents,3 and photochromic materials.4
Consequently, many synthetic methods have been developed
for the construction of chromenes, including: (1) transition
metal-catalyzed reactions;5 and (2) organocatalyst-promoted
reactions.6 Despite extensive studies into the synthesis of
chromenes, the development of a general strategy with high
selectivity, which uses readily available starting materials under
mild conditions, is still of great interest.
Diversity-oriented synthesis (DOS) as a tool for the
discovery of novel and biologically active small molecules has
drawn much attention from synthetic chemists.7 DOS has many
advantages including accessible complexity of molecules,
consecutive reaction patterns, high reaction rate and efficiency,
and minimal environmental impact.8 Thus, DOS has received
growing interest.
On the other hand, domino reactions are useful procedures
for self-organized synthesis of organic compounds.9 Compared
with stepwise reactions, domino reactions should be more
effective for the synthesis of complex organic compounds in
one pot without separation and purification of the inter-
mediates. Recently, we have developed a self-sorting domino
reaction,10 a focusing domino reaction11 and a self-labor
domino reaction.12 Herein, we reported a highly selective
synthesis of diverse chromenes via DOS-domino strategy from
ketones and phenols in the presence of TsOH·H2O without a
metal catalyst as shown in Figure 1.
Figure 1. (A) Divergent DOS strategy for the construction of novel
skeletons. (B) Chemical structures of the substances.
obtained when TsOH·H2O was used as the catalyst in benzene.
However, the yield slightly increased to 20% when n-hexane
was used as the solvent. Other popular solvents were found
unsuitable for the reaction (Table 1, entries 4−11). The catalyst
had an influence on the reaction. No product was obtained
RESULTS AND DISCUSSION
Initially, we screened the acidic catalysts in various solvents
(Table 1). A 15% yield of the chromene compound 6a was
Received: May 13, 2012
Revised: June 25, 2012
Published: June 28, 2012
■
© 2012 American Chemical Society
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Research Article
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Reaction Scope of Phenols 1 and Ketones 2
b
entry
catalyst
solvent
time (h)
T (°C)
yield (%)
1
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
InCl3
benzene
n-hexane
toluene
acetone
THF
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
25
40
80
100
110
100
15
20
17
0
2
3
4
5
0
6
DMSO
MeCN
0
7
0
8
DCE
0
9
dioxane
DMF
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
CH3OH
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
0
0
AlCl3
0
AuCl3
0
CF3SO3H
HCl
6
0
AcOH
0
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
0
0
30
37
37
52
a
Reaction was performed with phenols 1 (0.5 mmol), ketones 2 (1.5
mmol), and TsOH·H2O (0.5 mmol) in n-hexane (3 mL) at 100 °C for
4 h. Isolated yields are given.
a
Reaction conducted with 0.5 mmol of 1a, 1.5 mmol of 2a, and 0.5
b
mmol of TsOH·H2O in 3 mL n-hexane. Isolated yields.
alkylation reaction of phenol used electron rich aromatic
substrates as starting materials in this condition.
In addition, aryl methyl ketones were employed to probe the
scope of the reaction. As shown in Scheme 2, 4H-chromenes
could be obtained when aryl methyl ketones were used as the
substrates. Generally, good yields were obtained starting from
the p-halogenated aryl methyl ketones (Scheme 2, 7b, 7c, and
7d). The corresponding products were also in good yields with
4-methoxyacetophenone as substrate (Scheme 2, 7f). No
corresponding product was obtained with 4-nitroacetophenone
as substrate (Scheme 2, 7e), which indicated that the electronic
effect of aromatic ketones influenced the reaction. This may be
because the aldol reaction of electron withdrawing aromatic
substrates as starting materials cannot occur in this condition.
Corresponding products were obtained in good yields when
aryl methyl ketones with an aromatic substituent were
employed (Scheme 2, 7g and 7h).
When acetone was used as the substrate, a spiro compound 8
was obtained in 25% yield. We found a similar spiro compound
was reported in the literature from the reaction of catechol and
acetone.13 However, benzocyclopentane 9 was obtained
starting from 3-pentanone in 31% yield, which indicated that
the steric effect of the alkyl ketone influenced the reaction. The
mixture was too difficult to be purified when the 4-heptanone
was used. Furthermore, the structures of 6a, 6cm, 7c, 8, and 9
were also confirmed by X-ray crystallography (Figure 2).14
To investigate the detailed reaction process, we used GC-MS
to detect the proposed intermediates for this reaction. It was
verified that the corresponding intermediates 6am, 7am, 8m,
and 9m were present in the reaction mixture.15 The
corresponding intermediates are listed in Scheme 4.
when TsOH·H2O replaced by other protic or lewis acid (Table
1, entries 12−17). The reaction temperature was then
optimized to increase the product yield, and 100 °C was
found to be the optimal temperature (Table 1, entries 18−22).
The effect of reaction time on the yield of 6a was subsequently
examined. Higher yields were observed when the reaction was
carried out for 4 h (Table 1, entries 23). Ultimately, optimal
conditions were identified as 1 equiv of phenol (1a), 3 equiv of
ketone (2), and 0.5 equiv of TsOH·H2O in n-hexane at 100 °C
(Table 1, entry 23).
On the basis of the successful synthesis of the 2H-chromene
6a, the optimized conditions were applied to the range of other
phenols and cyclic ketones, the results are listed in Scheme 1.
Generally, moderate yields were obtained using substituted
cyclohexanones (Scheme 1, 6b, 6c, and 6d). No product was
obtained when cyclopentanone was used (Scheme 1, 6e),
which indicated that the steric effect and the strain of cyclic
ketone influenced the reaction. Encouraged by the results
obtained with cyclohexanones, we focused our attention on
phenols. The corresponding products were also obtained in
moderate yields with naphthols as the substrates (Scheme 1, 6g
and 6h). When 4-methoxyphenol was employed as the
substrate, the corresponding product was isolated in moderate
yield (Scheme 1, 6f). No product was obtained when phenol,
m-cresol, 4-(tert-butyl) phenol, and 4-nitrophenol were used
(Scheme 1, 6i, 6j, 6k, and 6l), which indicated that electron
rich aromatic substrates were necessary for the domino
cyclization reaction. This may be because the Friedel-crafts
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ACS Combinatorial Science
Research Article
generate target compound 8 (Scheme 5c).13 The intermediate
9m is formed by the Friedel−Crafts alkylation reaction of 1a
with 5. Consequently, the target compound 9 is generated by
9m reacting with 5 (Scheme 5d). To verify the possible
reaction mechanism, the reactions of 2c with 6cm and 1a with
7am were used to synthesize the corresponding target
compounds. Fortunately, final products were obtained from
the above reactions in 85% and 90% yields.
a
Scheme 2. Reaction Scope of Aromatic Ketones 3
CONCLUSION
■
In conclusion, in this study, we have developed a novel method
for the synthesis of functionalized chromenes from ketones and
phenols based on metal-free domino reactions, which could be
useful for generation of related compound library. The mild
reaction conditions, simple operation and absence of metal
catalyst make the described reactions an appropriate protocol
for the synthesis of potentially bioactive compounds. Further
studies on the applications of this reaction will be reported in
due course.
EXPERIMENTAL PROCEDURES
■
General Procedure for the Synthesis of 2H-Chro-
menes (6a−6h). TsOH·H2O (0.5 mmol) was added to a
stirred solution of 3-methoxybenzene-1,2-diol (70 mg, 0.5
mmol) and cyclohexanone (147 mg, 1.5 mmol) in n-hexane (3
mL). The reaction mixture was stirred at 100 °C in a sealed
tube for 4 h. The mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography to
give 3-methoxy-7,8,9,10-tetrahydrospiro[benzo[c]chromene-
6,1′-cyclohexan]-4-ol (6a) (78 mg, 52% yield). mp = 115.4−
119.5 °C; IR (KBr cm−1) 3488, 2929, 2834, 1617, 1513, 1461,
a
Reaction was performed with phenol 1a (0.5 mmol), ketones 2 (1.5
mmol), and TsOH·H2O (0.5 mmol) in n-hexane (3 mL) at 100 °C for
4 h. Isolated yields are given.
1
1354, 1218, 1084; H NMR (400 MHz, CDCl3) δ (ppm) 6.62
(d, J = 8.4 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H) 3.88
(s, 3H), 2.32 (d, J = 6 Hz, 2H), 2.07 (d, J = 6 Hz, 2H), 1.88 (d,
J = 8.4 Hz, 2H), 1.75- 1.68 (m, 8H), 1.58- 1.49 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 146.6, 138.5, 133.9, 132.9,
123.7, 119.2, 112.2, 103.5, 79.2, 55.9, 31.8 (×2), 25.2, 24.8,
24.4, 22.7, 22.0, 21.6( × 2); HRMS (APCI) m/z [M + H]+
calcd for C19H25O3 301.1798; found 301.1799.
a
Scheme 3. Reaction Scope of Ketones 4 and 5
General Procedure for the Synthesis of 4H-Chro-
menes (7a−7h). TsOH·H2O (0.5 mmol) was added to a
stirred solution of 3-methoxybenzene-1,2-diol (70 mg, 0.5
mmol) and acetophenone (180 mg, 1.5 mmol) in n-hexane (3
mL). The reaction mixture was stirred at 100 °Cin a sealed tube
for 4 h. The mixture was concentrated under reduced pressure.
The residue was purified by flash chromatography to give 7-
methoxy-4-methyl-2,4-diphenyl-4H-chromen-8-ol (7a) (129
mg, 75% yield). mp = 116.4−120.2 °C; IR (KBr cm−1) 3491,
3055, 2969, 2928, 1666, 1626, 1589, 1499, 1446, 1345, 1289,
1231, 1203, 1091, 1030; 1H NMR (400 MHz, CDCl3) δ (ppm)
7.73 (t, J = 4 Hz, 2H), 7.40−7.26 (m, 6H), 7.19−7.14 (m, 2H),
6.53 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 5.59 (s, 1H),
5.45 (s, 1H), 3.02 (s, 3H), 1.84 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 149.8, 145.7, 145.2, 138.5, 133.9, 133.2, 128.4
(×2), 128.3 (×2), 128.1, 127.2 (×2), 125.9, 124.6 (×2), 122.7,
118.1, 107.3, 106.4, 56.1, 39.4, 30.3; HRMS (APCI) m/z [M +
H]+ calcd for C23H21O3 345.1485; found 345.1486.
a
Reaction was performed with phenol 1a (0.5 mmol), ketones 4 (2.0
mmol), or 5 (1.5 mmol) and TsOH·H2O (0.5 mmol) in n-hexane (3
mL) at 100 °C for 4 h.
On the basis of the above experiments, the possible
mechanisms for the reactions are listed in Scheme 5. The
intermediate 6am is formed by the Friedel−Crafts alkylation
reaction of 1a with 2a. Then 6am reacts with 2a to generate
target the compound 6a (Scheme 5a). The acetophenone 3a
reacts with itself to form intermediate 7am, then 1a undergoes
intermolecular Michael addition reaction and dehydration
reaction with 7am to generate target compound 7a (Scheme
5b).6 1a reacts with 4 to form the intermediate 8m by Friedel−
Crafts alkylation reaction. Subsequently, 8m reacts with 4 by
double intermolecular alkylation, and double intramolecular
Friedel−Crafts alkylation reaction and dehydration reaction to
Procedure for the Synthesis of 6,6′-Dimethoxy-
3,3,3′,3′-tetramethyl-2,2′,3,3′-tetrahydro-1,1′-spirobi-
[indene]-4,4′,5,5′-tetraol (8). TsOH·H2O (0.5 mmol) was
added to a stirred solution of 3-methoxybenzene-1,2-diol (70
mg, 0.5 mmol) and acetone (232 mg, 2 mmol) in n-hexane (3
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Research Article
Figure 2. Crystal structures. (A) ORTEP drawing of 6a (ORTEP drawing with 30% ellipsoids). (B) ORTEP drawing of 7c (ORTEP drawing with
30% ellipsoids). (C) ORTEP drawing of 8 (ORTEP drawing with 30% ellipsoids). (D) ORTEP drawing of 9 (ORTEP drawing with 30% ellipsoids).
(E) ORTEP drawing of 6cm (ORTEP drawing with 30% ellipsoids).
a
Scheme 4. Intermediates of the Reactions
Scheme 6. Intermediates Reactions
Scheme 5. Proposed Reaction Pathway
a
Reaction was performed with 6cm (0.5 mmol) and 2c (0.5 mmol),
1a (0.5 mmol) and 7am (0.5 mmol), and TsOH·H2O (0.5 mmol) in
n-hexane (3 mL) at 100 °C for 4 h.
mL). The reaction mixture was stirred at 100 °Cin a sealed tube
for 4 h. The mixture was concentrated under reduced pressure.
The residue was purified by flash chromatography to give 6,6′-
dimethoxy-3,3,3′,3′-tetramethyl-2,2′,3,3′-tetrahydro-1,1′-spirobi
[indene]-4,4′,5,5′-tetraol (8) (100 mg, 25% yield). mp =
160.2−165.1 °C; IR (KBr cm−1) 3514, 3482, 2965, 2929, 2852,
1627, 1493, 1448, 1339, 1311, 1225, 1198, 1144, 1107, 832; 1H
NMR (400 MHz, CDCl3) δ (ppm) 5.96 (s, 2H), 5.28 (s, 2H),
5.26 (s, 2H), 3.74 (s, 6H), 2.26 (d, J = 13.2 Hz, 2H), 2.14 (d, J
= 12.8 Hz, 2H), 1.58 (s, 4H), 1.51 (s, 6H), 1.43 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 148.4 (×2), 141.9 (×2),
141.4 (×2), 132.3 (×2), 129.6 (×2), 97.7 (×2), 60.7 (×2), 58.4
(×2), 55.9, 43.2 (×2), 29.4 (×2), 28.8 (×2); HRMS (APCI)
m/z [M + H]+ calcd for C23H29O6 401.1959; found 401.1959.
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Research Article
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2929, 1629, 1486, 1456, 1377, 1285, 1241, 1153, 1117, 792; 1H
NMR (400 MHz, CDCl3) δ (ppm) 6.34 (s, 1H), 5.31 (s, 1H),
5.25 (s, 1H), 3.88 (s, 3H), 2.68−2.62 (m, 2H), 1.71 (s, 3H),
1.67−1.59 (m, 2H), 1.23−1.08 (m, 6H), 0.31−0.24 (m, 6H);
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Experimental procedures and compound characterization data
including GC/MS analysis and X-ray crystal data for 6a, 6am,
7c, 8, and 9. This information is available free of charge via the
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chwuax@mail.ccnu.edu.cn.
Present Address
Author Contributions
A.-X.W. conceived and designed the experiments, W.-J.X., Q.L.,
and F.-F.G. performed the experiments, W.-J.X., Y.-P.Z., and J.-
G.W. cowrote the manuscript and Supporting Information.
Funding
We appreciate the support of National Natural Science
Foundation of China (Grant 21032001) and PCSIRT (No.
IRT0953).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Xianggao Meng for X-ray crystal data analysis.
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