Catalysis by β-Cyclodextrin Hydrate - Synthesis of 2,2-Disubstituted 2H-Chromenes in Aqueous Medium

Article abstract of DOI:10.1002/adsc.201500358

A cost-effective, operationally simple and eco-compatible protocol for the one-pot synthesis of photochromic pyrans by the reaction of propargyl alcohols as well as propargyl ethers with differently substituted phenols under ambient atmosphere in aqueous

Full text of DOI:10.1002/adsc.201500358

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DOI: 10.1002/adsc.201500358
Catalysis by b-Cyclodextrin Hydrate – Synthesis of
2,2-Disubstituted 2H-Chromenes in Aqueous Medium
Avishek Ghatak,a Sagar Khan,a and Sanjay Bhara,*
a
Department of Chemistry, Organic Chemistry Section, Jadavpur University, Kolkata – 700 032, India
Fax: (+91)-33-2413-7902; e-mail: sanjaybharin@yahoo.com or sanjay_bhar@chemistry.jdvu.ac.in
Received: April 10, 2015; Revised: October 15, 2015; Published online: January 18, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500358.
Abstract: A cost-effective, operationally simple and catalyst. This is the first report where b-cyclodextrin
eco-compatible protocol for the one-pot synthesis of hydrate acted as a catalyst for an organic transforma-
photochromic pyrans by the reaction of propargyl al- tion but b-cyclodextrin alone failed.
cohols as well as propargyl ethers with differently
substituted phenols under ambient atmosphere in Keywords: aqueous-phase catalysis; cyclodextrins;
aqueous medium has been developed using b-cyclo- green chemistry; organic catalysis; regioselectivity;
dextrin hydrate as an efficient, recyclable and stable synthetic methods
Introduction
thiazoles, quinoxalines, quinazolins, oxindoles, tryp-
tanthrin and azepins. But surprisingly b-cyclodextin
The development of novel methods and catalysts for hydrate, which is much cheaper than cyclodextrins,
important organic reactions always remains a formida- has not yet been used as a catalyst to date to the best
ble challenge to organic chemists due to the wide- of our knowledge.
spread applicability of the reaction products in the
2H-Chromenes (2H-benzopyran derivatives) consti-
pharmaceutical industry and academia. The art of per- tute an important class of compounds as they are
forming efficient chemical transformations by identi- present as a structural backbone in many natural
fying alternative reaction conditions utilizing less products,[3–5] biologically active pharmaceutical and
toxic and inexpensive metal-free catalysts and avoid- medicinal compounds such as anti-HIV,[6a] antitu-
ing the use of organic solvents as reaction medium mor,[6b] antibacterial/antimicrobial,[6c,d] fungicidal,[6e]
represents a fundamental target of modern organic and insecticidal agents,[6f] health-promoting phyto-
synthesis. Presently organic reactions in the aqueous chemicals such as antioxidants,[6g] and polyphenols.[6h]
phase[1] have attracted the attention of researchers In addition, they have also been extensively used as
due to specific advantages of water as an environmen- photochromic materials in diverse fields including
tally benign and economically affordable solvent. laser dyes, organic light emitting devices (OLEDs),
However, the fundamental problem to perform or- optical brighteners, organic scintillators, triplet sensi-
ganic reactions in aqueous medium is the poor misci- tizers and fluorescence probes.[7] Owing to the diverse
bility of many organic substrates with water. Cyclic range of interesting properties and important applica-
oligosaccharides possessing hydrophobic cavities are tions, the development of synthetic strategies for the
well known as supramolecular catalysts, which by re- construction of the 2H-benzopyran skeleton has re-
versible formation of host-guest complexes, activate ceived significant attention at all times. Along with
the organic molecules and thus efficiently catalyze the the classical methods,[4] many new methods have been
reactions under milder conditions as compared to developed[8,9] in recent times where tremendous em-
their homogeneous counterparts, often with improved phasis is put on metal-catalyzed annulations such as
selectivity. Cyclodextrins (CDs) and crown ethers are hydroarylation.[9] But there is still a demand for new
examples of those biomimetic catalysts used exten- metal-free, economically viable and eco-compatible
sively in many novel transformations with high yield protocols applicable to a wide range of substrates. We
and good selectivity. There are several reports[2] report herein for the first time an aqueous phase syn-
where CDs are used for the synthesis of important thesis of 2H-chromenes under metal-free conditions
classes of biologically active heterocycles like using b-cyclodextrin hydrate (to be cited as b-CD hy-
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Avishek Ghatak et al.
drate hereafter) as a reusable biomimetic catalyst (entry 5) in lesser time. With further increase of the
with a broad substrate scope. This is going to be the catalyst amount to 7 mol%, the yield of the reaction
first report of using b-cyclodextrin hydrate as a cata- remained more or less same (entry 6).The yield was
lyst for an organic transformation which is much su- not satisfactory when 18-crwon-6 was used as a cata-
perior to b-cyclodextrin.
lyst (entries 7 and 8). The aforesaid reaction did not
occur in absence of any catalyst. Thereby the impor-
tance of b-CD hydrate in terms of its catalytic activity
was firmly established. Owing to the poor solubility
of b-CD in water at 258C (1.84%, w/v),[10] the catalyst
Results and Discussion
When an equimolecular mixture of 2-phenylbut-3-yn- remained sparingly soluble at room temperature but
2-ol (1a) and p-cresol (2a) was heated in water at became soluble at the reaction temperature (608C) in
608C in the presence of b-CD hydrate, 2,6-dimethyl- aqueous medium. Therefore, when the reaction was
2-phenyl-2H-chromene (3a) was obtained (Scheme 1). complete, the reaction mixture was cooled to room
temperature to precipitate the catalyst and ethyl ace-
tate (20 mL) was added to dissolve the product where
the catalyst (b-CD hydrate) remained insoluble. So
the catalyst was separated simply by filtration. It was
washed thoroughly with EtOAc, dried at 1008C for
one hour and used for the next reaction. It was suc-
cessfully recycled with little variation of yield
(Figure 1). Due to its sparing solubility at room tem-
perature and complete miscibility with the reaction
medium at the elevated temperature, b-CD hydrate
seems to behave as a homogeneous catalyst during
the reaction but offers the advantage of a heterogene-
Scheme 1. Reaction of 2-phenylbut-3-yn-2-ol (1a) with p-
cresol (2a) using different catalysts.
This reaction was optimized using some analogous ous catalyst towards its separation and isolation from
catalysts in varying amounts and different time inter- the reaction mixture. The reactions took place in
vals. The results are summarized in Table 1.
aqueous condition and did neither require inert envi-
ronment nor any organic co-solvent as the reaction
medium. It needs an eco-friendly solvent, namely,
ethyl acetate, for the isolation of the product. More-
Table 1. Optimization of b-CD hydrate catalyzed heterodo-
mino reaction between 2-phenylbut-3-yn-2-ol (1a) and p- over, the reactions are of high atom-economy and
cresol (2a).
generate water as the sole and innocuous by-product.
Therefore, the present protocol also bodes for eco-
compatibility which bears immense relevance to the
improvement of environmental performance. The
Entry Catalyst
Mol% Time [h] Yield of 3a [%]
1
2
3
4
5
6
7
8
b-CD
g-CD
a-CD
b-CD hydrate
b-CD hydrate
b-CD hydrate
18-crown-6
18-crown-6
10
10
10
2
10
10
10
8
–
trace
30
65
85
87
56
57
4
6
7
6
4
7
10
10
It is important to note that there was no reaction
when an equimolecular mixture of 1a and 2a was
heated at 608C in water in the presence of 10 mol%
of b-CD (entry 1). The reaction was extremely slug-
gish in the presence of 10 mol% of g-CD (entry 2).
But the same reaction produced 3a in 30% yield
when it was done with 10 mol% of a-CD (entry 3).
Surprisingly, the yield of the reaction was dramatically
increased to 65% (entry 4) when b-CD hydrate was
used as a catalyst in lesser amount (2 mol%). Further
increase of the amount of b-CD hydrate to 4 mol%
Figure 1. Recycling of b-CD hydrate using 1a (2 mmol), 2a
(2 mmol) and b-CD hydrate (4 mol%) as catalyst at 608C
brought about the increment of yield to 85% for 6 h in water; the yield is of the isolated product 3a.
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Catalysis by b-Cyclodextrin Hydrate
Scheme 2. Synthesis of 2,2-disubstituted 2H-chromenes (3)
through one-pot reaction between 1 and 2 in aqueous
medium using b-CD hydrate as catalyst.
Scheme 3. Construction of the 2,2-spirocyclic 2H-chromene
framework.
eco-compatibility of this protocol has been assessed in
terms of E-factor, mass intensity, atom economy and
atom efficiency (see the Supporting Information).
ly at the o-position with respect to the phenolic-OH
The remarkable recyclability and superior catalytic group in spite of the availability of the more accessi-
activity of b-CD hydrate prompted us to extend the ble p-positions in the substrates 2b and 2c. So we
applicability of this newly developed protocol. There- speculated that the aryl propargyl ether was initially
fore, we carried out systematic investigations on the formed in the first step followed by ring closure in
À
synthesis of 2H-chromenes 3 through the reactions of a 6-endo-dig fashion through C C bond formation via
various propargyl alcohols 1 with differently substitut- the intramolecular nucleophilic attack at the C C
ꢀ
ed phenols 2 using b-cyclodextrin hydrate (4 mol%) bond by the electron-rich proximal o-carbon of the ar-
as a catalyst under the optimized reaction conditions omatic ring. Indeed, when the reaction was run for
(Scheme 2). The results are shown in Table 2.
a limited duration, we were able to isolate the aryl
As shown in Table 2, a wide variety of the sub- propargyl ether 4a as the plausible intermediate.
strates underwent regioselective heterodomino reac- When 4a was further subjected to the optimized reac-
tion in the presence of b-CD hydrate in aqueous tion condition, 3a was obtained as the product. Thus
medium to afford the 2H-chromenes 3 in good yield. the intermediacy of 4a in the said reaction was clearly
p-Cresol (2a) reacted with substituted a-alkynols 1a established (Scheme 4).
and 1b to produce the corresponding gem-disubstitut-
ed 2H-chromenes in good yield (entries 1 and 2). Un-
substututed phenol 2b (entries 3 and 4) and the steri-
cally congested phenol 2c bearing an alkyl substituent
at the o-position (entries 5 and 6) also reacted
smoothly in this protocol. Interestingly, the bromo
substituent in 2d remained totally unaffected under
the present conditions (entries 7 and 8) and afforded
3g and 3h, respectively, with satisfactory yield. p-
Chlorophenol 2e was found to be problematic[6h] in
some reports, but it responded efficiently in the pres-
Scheme 4. Intermediacy of aryl propargyl ether.
ent method and afforded the corresponding pyrans 3i
and 3j with good yield (entries 9 and 10). p-Methoxy-
phenol 2f also produced the methoxypyrans 3k and 3l
It is extremely important to note that although
with high yield (entries 11 and 12) where the methoxy commercially available b-CD hydrate (Aldrich) came
group remained unaffected and the course of the re- out as an efficient catalyst for the aforesaid reaction
action was totally guided by the o-directing effect of in aqueous medium, b-CD failed miserably (entry 1
the phenolic-OH moiety. The present method was ex- versus entries 4–6 in Table 1). According to an early
tended to naphthols 2g and 2h, where the correspond- report,[11a] b-CD hydrate contains exchangeable hy-
ing photochromic naphthopyrans (3m–3o) were pro- drogen atoms associated with a proton conductivity
duced in quite good yield (entries 13–15). The unique- similar to that of hydrated proteins. Some water mole-
ness of the present method is also associated with the cules are present inside the hydrophobic cavity of b-
efficient preparation of bis-benzopyran derivative 3p CD hydrate along with some outside forming an ex-
from quinol 2i (entry 16). This protocol was success- tended hydrogen bonding network. This provides an
fully utilized for the construction of a novel and un- efficient path for the long range movement of protons
precedented 2,2-spirocyclic 2H-chromene skeleton which is responsible for the protonic conductivity via
(Scheme 3) from an appropriate propargyl alcohol 1c. a concerted and co-operative translocation of protons
In course of the aforesaid investigation, it was through the so-called flip-flop hydrogen bond.[11b] The
À
found that C C bond formation took place exclusive- acidity of the residual water molecules inside the hy-
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Avishek Ghatak et al.
Table 2. Reaction of different phenols with propargyl alcohols under the optimized reaction conditions using b-
CD hydrate as catalyst.
[a]
Yield of the isolated pure products, fully characterized spectroscopically.
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Catalysis by b-Cyclodextrin Hydrate
Table 3. Acidity measurements.
note that the reactions took place smoothly in the
presence of b-CD hydrate but not in the presence of
b-CD. In search for the answer of this puzzle we first
measured the pH of the aqueous media at room tem-
perature (308C) and at the reaction temperature
(608C) containing b-CD and b-CD hydrate separately
in the same concentration of the reaction mixture
Substance
pH at 308C
pH at 608C
b-CD
b-CD hydrate
6.12
6.36
5.98
5.34
drophobic cavity of b-CD hydrate is consequently en- (Table 3). The pH of the solution containing b-CD hy-
hanced. The reactions did neither occur in the ab- drate at the reaction temperature was found to be
sence of b-CD hydrate nor under the non-aqueous lower indicating higher acidity of the reaction
solid phase condition with catalytic as well as stoichio- medium. From this observation it appeared that the
metric amounts of b-CD hydrate. Moreover, not acidity of the medium might be crucial. But the reac-
a trace of 3a was obtained when 4a was heated alone tions between 1a and 2a totally failed in media of
in water at 608C in the absence of b-CD hydrate. these pH values in the absence of b-CD hydrate.
Therefore, the essentiality of b-CD hydrate in aque- Therefore, apart from imparting acidity, a more cru-
ous medium for promoting both the steps was firmly cial role of b-CD hydrate was anticipated.
substantiated. It was indeed a matter of surprise to
Then we speculated that p-cresol (1a) might form
an inclusion complex with b-CD hydrate. The FT-IR
spectra of b-CD hydrate and the inclusion complex of
1a in b-CD hydrate (Figure 2) looked similar, analo-
gous to the observations made by Li et al.[12] A broad
band centered at 3363 cmÀ1 appeared due to nstrO H
À
of b-CD hydrate, which was found to be narrowed in
the FT-IR spectrum of the inclusion complex and ap-
peared at a lower frequency (3352 cmÀ1). These obser-
vations provided a good indication of the formation
of the inclusion complex, which was a common phe-
nomenon observed by many researchers during the
syntheses of the inclusion complexes of different
guest molecules with b-cyclodextrin as host.[12–15]
The TGA curve (Figure 3a) of b-CD hydrate
showed a sharp weight loss of about 15% around
1108C due to the loss of water molecules, but no fur-
ther weight loss was observed up to 3008C. But in the
case of the 1:1 inclusion complex of 1a with b-CD hy-
drate (Figure 3b), because of the hydrogen bonding
interaction between phenol molecules and water mol-
ecules present in the cavity of b-CD hydrate, the
TGA curve depicted a sharp weight loss of about
Figure 2. Comparison between FT-IR spectra of b-CD hy-
drate (CDH) and inclusion complex of 1a with b-CD hy-
drate (CDHI).
Figure 3. a) TGA curve of b-CD hydrate and b) 1:1 inclusion complex of 1a with b-CD hydrate.
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Avishek Ghatak et al.
Figure 4. The most stable complex of p-cresol 1a docked into the cavity of b-CD hydrate in different modes.
10% due to the loss of non-hydrogen bonded water
Due to the presence of water molecules within the
molecules. Thereafter a slow weight loss was observed cavity of b- CD hydrate, it was speculated that the hy-
due to the loss of hydrogen bonded molecules. Also drogen bonding interaction between the water and
the TGA curve of b-CD[16] was distinctly different guest molecules might facilitate the inclusion of the
from that of the b-CD hydrate as there was no ques- guest within the host cavity. From the molecular
tion of any initial water loss in the case of b-CD. It is docking experiments (PDB ID: ARUXOA), it was
extremely important to note that when b-CD hydrate, observed that 1a and 2a had a different affinity to b-
pre-heated at 1308C for 4 h (where the initial loss of CD hydrate with a preferred orientation of the li-
water was supposed to be complete), was used in the gands inside its cavity: 1a was more included than 2a
present aqueous reaction medium in place of com- within the cavity. Also 1a formed one hydrogen bond
mercially available b-CD hydrate, the reaction be- (2.362 Š) with the water molecules present within the
tween 1a and 2a did not occur at all. Therefore, the cavity of b- CD hydrate (Figure 4) whereas 2a formed
presence of water molecules inside the cavity of b-CD two hydrogen bonds (2.418 and 2.328 Š) with the
hydrate was proved to be essential for the proposed -CH2OH group located near the wider side (secon-
reaction.
dary hydroxy rim) (Figure 5).
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Catalysis by b-Cyclodextrin Hydrate
Figure 5. The most stable complex of propargyl alcohol 2a docked into the secondary hydroxy rim of b-CD hydrate in differ-
ent modes.
Hydrogen bonding of the phenolic-OH group of 1a Table 4. Synthesis of 2,2-disubstituted 2H-chromenes from
propargyl ethers.
with the water molecules inside the cavity of b-CD
hydrate as a consequence of inclusion might increase
its nucleophilic property. As a consequence, nucleo-
En- R1 R2
try
X
R3
Prod- Time [h]/
uct
Yield [%][a]
1
philic attack by 1a on 2a is facilitated. H NMR titra-
1
2
3
4
5
6
7
8
9
10
Ph Me Me
Ph Me Et
Ph Ph Et
Ph Me TBDMS
Ph Ph TBDMS
Ph Me CH(Me)2
Ph Me (CH2)4-CH3
Ph Me (CH2)4-CH3
Ph Ph CH2-CH=CH2 4-OMe 3l
Ph Ph CH2-CH=CH2 4-Br 3h
4-Me
H
2-Me
4-Br
4-Cl
4-OMe 3k
2-Me
4-Cl
3a
3c
3f
3g
3j
10/78
10/74
9/72
9/76
10/67
9/74
tion experiments were also performed using 1a as
guest and b-CD hydrate as host. We observed very
small changes in the chemical shift values of the hy-
drogen atoms of both the guest and host molecules
(see the Supporting Information). On the basis of the
aforesaid experimental findings, the essential presence
of b-CD hydrate for the aforesaid chemical transfor-
mation is quite evident. But the phenomenon of “in-
clusion” in this reaction is only a hypothesis because
no direct and full evidence could be given. Although
the exact reaction pathway and mode of catalysis still
remain unclear to us, the synthetic importance of this
b-CD hydrate-mediated protocol has been well-estab-
lished and its widespread applicability is further sub-
stantiated with the following observations.
3e
3i
9/76
11/69
10/72
10/70
[a]
Yield of the isolated pure products, fully characterized
spectroscopically.
It was evident from Table 4 that the aforesaid reac-
tion took place efficiently with differently substituted
In a recent report[17] we noted that an ether group propargyl ethers although it took a longer time than
acted as a leaving group during Ni-catalyzed cross- with the respective alcohols. The reactions did not
coupling of aryl and benzyl methyl ethers with orga- depend much on the electronic nature and steric bulk
noboron reagents. Therefore, we intended to extend of the substituent X. With the substrate 1d bearing
this protocol to propargyl ethers 5 as substrates both 38-propargylic OH and 18-propargylic OMe moi-
(Scheme 5). The results are presented in Table 4.
eties, initial etherification took place exclusively by
the displacement of the 38-OH group leaving behind
the 18-OMe unaffected (Scheme 6) in the product 3r.
This study also proved that the same protocol was ap-
plicable to the propargyl alcohols with internally sub-
stituted acetylenic linkage also.
The propensity of the 38-center towards this reac-
tion was elegantly demonstrated in the reaction of the
substrate 6 where the 38-propargyl methyl ether par-
ticipated regioselectively leaving behind the 18-prop-
argyl methyl ether intact (Scheme 7).
Scheme 5. Synthesis of 2,2-disubstituted 2H-chromenes from
propargyl ethers.
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Avishek Ghatak et al.
(2”10 mL). The aqueous reaction mixture was repeatedly
extracted with ethyl acetate (3”5 mL). The combined or-
ganic extracts were washed with water (3”10 mL) and dried
over anhydrous Na2SO4. The crude product was obtained by
removal of the solvent under reduced pressure and was then
further purified by filtration chromatography on a short
column of silica gel using 1–2% ethyl acetate-hexane as
eluent.
Scheme 6. Reactivity of 38-OH group of propargyl alcohol.
Acknowledgements
A. G. thanks CSIR, New Delhi, Government of India and S.
K. thanks UGC, New Delhi, Government of India for senior
research fellowships. The aforesaid investigation has enjoyed
financial support from DST-PURSE-program (II) at Jadav-
pur University. The authors also acknowledge the instrumen-
tal assistance received from the DST-FIST program and
DST-special assistance program at Jadavpur University.
Thanks to Mr. J. Poddar of Jadavpur University and Mr. N.
Dutta of IACS for necessary assistance. The authors express
profound gratitude to Professor S. Koner and Dr. S. Haldar
of Jadavpur University for helpful discussions and generous
instrumental support during this study.
Scheme 7. Regioselectivity of the reaction.
Conclusions
References
A cost-effective, operationally simple and eco-com-
patible protocol for the one-pot synthesis of photo-
chromic pyrans by reaction of propargyl alcohols as
well as propargyl ethers with differently substituted
phenols under ambient atmosphere in aqueous
medium has been developed using b-cyclodextrin hy-
drate as an efficient, recyclable and stable catalyst
used for the first time to date. The method permits
a convenient access to a wide range of structurally
novel and functionally important 2,2-disubstituted-
2H-chromene skeletons with great potential for future
applications. Moreover, this is the first report of the
application of b-cyclodextrin hydrate (in contrast to
b-cyclodextrin) as an efficient catalyst for an organic
transformation.
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Experimental Section
General Procedure for Synthesis of 2,2-Disubstituted
2H-Chromenes
To a stirred suspension of the appropriate propargyl alcohol
1 or propargyl ether 5 (2.0 mmol) and phenol 2 (2.0 mmol)
in 4 mL water, b-cyclodextrin hydrate (0.090 gm, 4 mol%)
was added and the reaction mixture was stirred for the re-
quired period of time at 608C until the reaction was com-
plete (monitored with TLC). Then the reaction mixture was
cooled to 58C, ethyl acetate (20 mL) was added to dissolve
the product and the catalyst was separated simply by filtra-
tion for reuse. The residue (recovered catalyst) was thor-
oughly washed with EtOAc (4”5 mL) followed by water
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