Ring-opening reactions of 2-aryl-3, 4-dihydropyrans with nucleophiles

Article abstract of DOI:10.1039/c1cc10355e

Ring-opening reactions of 2-aryl-3, 4-dihydropyrans with nucleophiles were reported for the first time. A possible mechanism was also proposed. Finally, this method was used in the synthesis of a novel tetrahydrocarbazole derivative that possesses a biolo

Full text of DOI:10.1039/c1cc10355e

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Ring-opening reactions of 2-aryl-3, 4-dihydropyrans with nucleophilesw
Minghao Li,a Conghui Tang,a Jie Yanga and Yanlong Gu*ab
Received 19th January 2011, Accepted 25th February 2011
DOI: 10.1039/c1cc10355e
Ring-opening reactions of 2-aryl-3, 4-dihydropyrans with
nucleophiles were reported for the first time. A possible mechanism
was also proposed. Finally, this method was used in the synthesis
of a novel tetrahydrocarbazole derivative that possesses a
biologically active skeleton.
no reaction occurred (entry 1). When some weak acids, such as
I2 and boric acid, were used, a product, 3a, was formed, but
the yields obtained are rather poor (entries 2 to 3). Therefore,
some commonly used strong acids, such as Sc(OTf)3, InCl3,
Bi(OTf)3 and TsOH were then examined in this reaction, and it
was found that substrate 1a was almost completely consumed,
however, 3a was obtained only in a small amount (entries 4 and 7).
In these cases, many by-products that are difficult to isolate
were observed by TLC detection. Solid acids, such as
montmorillonite K10 and Amberlyst-15, were also used, and
no significant improvement was observed (entries 8 and 9).
Many other catalysts were also examined, and no good result
was obtained (see ESIw). In order to improve the reaction
yield, we then sought the help of a catalyst that has been rarely
used in organic reactions, MnCl2Á4H2O. To our great delight,
the model reaction proceeded smoothly in this case, and 3a
was finally obtained in 95% of yield (entry 10). Anhydrous
MnCl2 also worked well, but the yield of 3a was inferior
(entry 11). Further investigation revealed that the solvent also
played a key role in controlling the catalytic activity of
Dihydropyran and their derivatives are widely present in
nature-occurring products.1 Some of dihydropyrans showed
important biological and pharmaceutical activities, and therefore,
their synthesis has attracted much attention.2 We have recently
reported a three-component reaction of olefins, formaldehyde
and b-dicarbonyl compounds, which generated a variety of 2,5,6-
trisubstituted 3,4-dihydropyran derivatives in high yields
(see electronic supporting information (ESI)w).3 In view of
the fact that this reaction opens, indeed, an easy access to the
dihydropyrans, use of these products in organic synthesis
becomes thus a downstream topic for us.
A literature survey stated that reactions of such substituted
3, 4-dihydropyrans have been rarely explored due perhaps to
the difficulty of preparation.4 Particularly, the 2-aryl-3, 4-di-
hydropyrans involve a benzyl ether fragment that is generally
unstable in the presence of a nucleophile under acidic
condition.5 Therefore, we decided to evaluate the reactivity
of these dihydropyrans towards nucleophiles with the aid of an
acid catalyst. In this paper, we also describe a highly selective
ring-opening reaction of 2-aryl-3, 4-dihydropyrans with
nucleophiles, which offers a versatile method to link a
b-dicarbonyl fragment together with the nucleophiles. To the
best of our knowledge, only a few examples of ring-opening
reactions of dihydropyrans have been performed so far,6 and
this type of ring-opening reaction has not been reported yet.
Indole has been frequently used as a nucleophile. In view of
the great importance of indole derivatives in organic synthesis
and pharmaceutical synthesis, we, thus investigated the
reaction of a 2-aryl-3, 4-dihydropyran, 1a, with indole, 2a
and the results are listed in Table 1. In the absence of catalyst,
Table 1 Ring-opening reaction of 1a with 2a in different conditionsa
Entry
Catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
—
I2
H3BO3
Bi(OTf)3
Sc(OTf)3
lnCl3
TsOH
Montmorillonite K10
Amberlyst-15
MnCl2Á4H2O
MnCl2
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
MnCl2Á4H2O
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
Toluene
1,4-Dioxane
CH3CN
0
4
5
12
31
20
28
Trace
13
95
a Institute of Physical Chemistry and Industrial Catalysis, Hubei Key
Laboratory of Material Chemistry and Service Failure, School of
Chemistry and Chemical Engineering, Huazhong University of
Science and Technology, 1037 Luoyu road, Hongshan District,
Wuhan 430074, China. E-mail: klgyl@hust.edu.cn;
9
10
11
12
13
14
15
16b
52
Trace
Trace
31
39
93
Fax: (+)(0)86-(0)27-87 54 45 32
b State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Lanzhou, 730000, China
w Electronic supplementary information (ESI) available: Experimental
details, Spectroscopic data of the products and 1H and 13C NMR
profiles. See DOI: 10.1039/c1cc10355e
DCE
CH3NO2
a
The reaction was performed in 0.25 mmol scale in 1.0 ml of solvent.
The reaction was performed in 20 mmol scale.
b
c
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MnCl2Á4H2O, and nitromethane proved to be an appropriate
solvent for this system (entries 12 to 15).
formation of benzylcarbenium are normally quite easy and
insusceptible to the choice of acid catalyst.8 However, in the
model reaction, catalyst showed a significant effect on the
performance. It might result from (i) the presence of keto-
carbonyl that is also reactive toward the nucleophile under
acidic conditions in the skeleton of the product; (ii) instability
of the ester group under acidic condition, which tended to
further convert the ring-opening product through a decarboxyl-
ation reaction pathway. Furthermore, when the electrophilic
alkylation of the benzylcarbenium (I) to indole is unsuccessful,
4a-type by-product might be generated as an alternative way
to consume (I), which is also an acid-labile species. Realizing
the ring-opening reaction, thus, is a challenge, and the key is
how to control the catalysis driving toward the ring-opening
product without disturbing the other coexistent organic
functionalities. Kobayashi has accomplished a classification
of many Lewis acids according to their activities in organic
reactions.9 In the ranking of Kobayashi, anhydrous MnCl2
was considered as an inactive one. Therefore, we believe that
acid strength of MnCl2 might be responsible for the high
selectivity. Furthermore, water might also play, to some
extent, a role in tuning the Lewis acidity of MnCl2 to be
suitable for the reaction.
With the optimized conditions in hand, we probed the scope
of the reaction with respect to both the dihydropyrans and
indoles. As shown in Fig. 1, a variety of dihydropyrans and
indoles could be applied in the ring-opening reaction, and the
corresponding products were obtained in good to excellent
yields. Particularly, indoles substituted by
a moderate
electron-withdrawing group, such as 2-phenylindole, can also
be used to react with a dihydropyran, 1b, under catalysis of
MnCl2Á4H2O. A reaction in preparative-scale (20 mmol) was
also investigated, and it was found that the reaction proceeded
uneventfully, indicating the effectiveness of this method for
practical synthesis (Table 1, entry 16). It should be noted that
because the formed product contains not only a fragment of
1,3-dicarbonyl compound, but also an indole ring, it would
not be unreasonable to expect that these products could be
useful for organic synthesis. To the best of our knowledge,
this is the first report for preparing this specific class of
compounds.
The mechanism of the ring-opening reaction most likely
involves
a manganese-assisted nucleophilic substitution.
Firstly, activation of the dihydropyran by a manganese(II)
species is achieved via a cleavage of C–O bond in the ring. This
is followed by nucleophilic attack of indole to the benzyl-
carbenium (I), which then leads to formation of the final
product.7 As a support of this mechanism, a dehydrogenation
product of (I), 4a, was also isolated in 22% by treating 1b in
the absence of nucleophile (Fig. 2). However, there was no
product generated during the treatment of 4a with indole.
This result implies that (i) the benzylcarbenium (I) might be,
indeed, formed, which can then generate both the desired
product and 4a depending on the reaction condition, and
(ii) 4a was not involved in the catalytic cycle. It is well known
that organic reactions with a mechanism of an acid-catalyzed
Other carbon-based nucleophiles, such as 2-naphthol and
4-hydroxy-6-methyl-2-pyrone, can also react with 2-aryl-3,
4-dihydropyrans in the presence of an appropriate catalyst
(Scheme 1). These results imply that many other nucleophiles
may also be applicable in this type ring-opening reaction, and
the investigation is underway in our group.
High efficiency of these reactions led us to further explore
their application in the synthesis of a complex molecule. It is
known that 2-(3-arylpropyl)-b-diketones can undergo a radical
cyclization to form a skeleton of tetrahydronaphthalene.10 It
occurred to us that cyclization of 3a-type product might also
be possible. Thus, we started a three-step synthesis involving:
(i)
a domino Knoevenagel/oxo Diels–Alder reaction of
4-methoxystyrene (6a), acetylacetone (5a) and aqueous
formaldehyde that generated a dihydropyran 1c in 93% of
yield; (ii) MnCl2Á4H2O-catalyzed ring-opening of 1c with
indole that generated the corresponding product, 3o, in 91%
of yield, and (iii) Mn(OAc)3-promoted radical cyclization of
3o in acetic acid. In the last step, both phenyl and indole rings
are theoretically reactive toward the radical cyclization.
Interestingly, only one product, 7a, was obtained in 72% of
yield, indicating that the indole ring is much more reactive
than the phenyl ring under the present condition. It should be
noted that skeleton of 7a was known to possess biological
activity.11 Although method of accessing this skeleton is
available, it only works for the synthesis of few molecules,12
and how to modify the skeleton with substituent groups is still
a challenge. The method in Scheme 2 not only offers an
alterative way for the synthesis of this skeleton, but also is
capable of modifying the structure in some specific positions,
thus is valuable for organic synthesis.
In conclusion, ring-opening reactions of 2-aryl 3, 4-dihydro-
pyrans with nucleophiles were described. Indoles, 2-naphthol
and 4-hydroxy-6-methyl-2-pyrone could be used to react with
an appropriate dihydropyran to form the corresponding ring-
opening products. Skeletons of the obtained products contain
Fig.
1
Substrate scope of MnCl2Á4H2O-catalyzed ring-opening
reactions of 2-aryl-3, 4-dihydropyrans with thiophenols and thiols.
Unless otherwise specified, all the reactions were conducted under the
optimized condition in Table 1.
c
4530 Chem. Commun., 2011, 47, 4529–4531
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Liang and all the other stuff members in the Analytical and
Testing Center of HUST, for their contributions to our works.
Notes and references
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Fig. 2 Plausible mechanism of the ring-opening reaction of dihydro-
pyran 1b with a nucleophile.
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Scheme 1 Ring-opening reaction of 2-aryl-3, 4-dihydropyran with
other nucleophiles.
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P. B. Brondani, D. C. Flores, H. G. Bonacorso, A. F. C. Flores
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Scheme 2 Synthesis of 2, 3, 4, 9-tetrahydro-1H-carbazole 7a.
not only a core structure of the nucleophile, but also a moiety of
b-dicarbonyl compound. Particularly, because of the presence of
1,3-diketone moiety, the ring-opening product could be further
cyclised through a radical pathway initiated by Mn(OAc)3.
Finally, a complex and valuable 2, 3, 4, 9-tetrahydro-1H-carba-
zole, 7a, was prepared in an overall yield of 61% through a three-
step synthesis starting from very simple substrates.
Financial support from National Natural Science Founda-
tion of China (20903042), the Program for new Century
Excellent Talents in the University of China (NCET-10-
0383). This work was also supported by Specialized Research
Fund for the Doctoral Program of Higher Education
(20090142120081). The authors are also grateful for Ms. Ping
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V. A. Doughty, P. J. Oakley, A. Quddus, M. R. Teall and
J. D. Wrigley, Patent, WO 2005013985, C. A. 142 : 240606.
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G. Zhao, Chem. Eur. J., 2010, 16, 5853–5857; (b) N. T. Jui, E. C. Y.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4529–4531 4531