Ball milling for the quantitative and specific solvent-free Knoevenagel condensation + Michael addition cascade in the synthesis of various 2-amino-4-aryl-3-cyano-4H-chromenes without heating

Article abstract of DOI:10.1039/c4ra06603k

Ball milling is used as a facile, efficient, cheap, and environmentally friendly procedure for the solvent-free three-component reaction of aromatic aldehydes with malononitrile and dimedone, or 1,3-cyclohexanedione, resorcinol, and α- and β-naphthol. The

Full text of DOI:10.1039/c4ra06603k

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Ball milling for the quantitative and specific solvent-
free Knoevenagel condensation + Michael addition
cascade in the synthesis of various 2-amino-4-aryl-3-
cyano-4H-chromenes without heating
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
a
a
a*
b
Omid Hosseinchi Qareaghaj , Sara Mashkouri , M. Reza NaimiꢀJamal , Gerd Kaupp
DOI: 10.1039/x0xx00000x
Ballꢀmilling is used as a facile, efficient, cheap, and environmentally friendly procedure for the
solventꢀfree threeꢀcomponent reaction of aromatic aldehydes with malononitrile and dimedone,
www.rsc.org/
or 1,3ꢀcyclohexanedione, resorcinol, and
α
ꢀand
βꢀnaphthol. The reactions proceed
quantitatively at room temperature by milling stoichiometric mixtures of the reagents in the
presence of 10 mol% Na CO . This method offers the advantages of short reaction times, low
2
3
cost, quantitative yields and simple workꢀup with no need of any organic solvent. It is thus
enviroꢀeconomic without producing dangerous wastes. The orientation selectivity with
β
ꢀ
naphthol and resorcinol is discussed. Existing structural misattributions are pointed out and
1
clarified by H NMR spin coupling analysis.
a
Research Laboratory of Green Organic Synthesis and Polymers, Department of Chemistry, Iran
University of Science and Technology, 16846 Tehran, Iran. Eꢀmail address: naimi@iust.ac.ir (M. R.
NaimiꢀJamal).
b
Faculty 5, Department of Chemistry, University of Oldenburg, 26188 Edewecht, Germany.
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0ꢀ37
Introduction
yield and chromatographic workup,
later tried multi component reactions (MCR) for the preparation
of 4 ꢀchromenes. The catalytic processes for the oneꢀpot
synthesis of 2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀsubstituted 4 ꢀchromenes
have been recently complemented by the application of
potassium phthalimidoꢀ ꢀhydroxylate in water as another base
This is also true for the
The versatile synthesis of 2ꢀaminoꢀ3ꢀcyanoꢀ4ꢀarylꢀ4Hꢀ
H
chromenes is presently one of the most studied vehicles for the
presentation of new catalysts with mostly weak acids and bases,
even though uncatalyzed reactions of aldehydes with
malononitrile and 1,3ꢀdiketones provide quantitative wasteless
yields in stoichiometric solventless meltꢀreactions at still
moderate temperatures (125–150°C). Clearly, the uncatalyzed
H
N
3
though by using 10% excess of the reagent malononitrile,
which however creates additional wastes when recycling the
catalyst.
Other
approaches
utilized
for
example
1
syntheses provide the best possible scaleꢀup possibilities, but
2
0
hexadecyltrimethyl ammonium bromide (HTMAB), sodium
4ꢀdodecylbenzenesulfonic acid (DBSA),
Al O , the rare earth perfluorooctanoate (Re(PFO) ),
the also enviroꢀeconomic catalysis by milling with soda at room
temperature is of interest for the reactions with less reactive
2
1
20
stearate,
KF–
(S)ꢀ
27,28
2
2
23
2
2
3
3
reagents. The general importance of chromene derivatives or
2
4
25
26
proline,
(NH ) HPO ,
NMe OH,
MgO,
30
3
4 2
4
4
aminoꢀ4
H
ꢀchromenes have been amply collected in Ref. and in
2
9
tetrabutylammonium fluoride (TBAF), CeCl .7H O, ZnOꢀ
betaꢀZeolite, 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO), silica
gel supported polyphosphoric acid (PPA–SiO ),
Caro’s acid silica gel, and amino functionalized ionic
liquids. Some of these methods applied organic solvent such
as ethanol, dimethylformamide (DMF) or acetic acid,
3
2
the numerous papers cited therein, but we focus here on the
importance of 2ꢀaminoꢀ3ꢀcyanoꢀ4ꢀarylꢀ4 ꢀchromenes. These
compounds have been identified with the capacity to prevent
3
1
32
H
3
3
34
γꢀFe O ,
2 3
2
3
5
4,5
6
various types of human diseases. This includes antiallergic,
3
6
7
ꢀ9
10
antitumor and antibacterial activity. Most recent interest
found these compounds with additional substitution for antiꢀ
microbial activities in pharmaceutical applications and
2
4, 37
3
8
others
hydrocalcite,
water with propylpiperazineꢀNꢀsulfonic acid, or
3
9
40
or 1ꢀdeoxyꢀ1ꢀmethylaminoꢀsorbitol.
Also
1
1,12
biological studies.
cyanoꢀsubstituted 4
blocks for the synthesis of human drugs for virtually all kinds
Furthermore, the 2ꢀaminoꢀ4ꢀarylꢀ3ꢀ
ꢀchromenes are being used as building
4
1
42
heating by microwave or ultrasonic irradiation was applied.
However, most of these procedures have drawbacks of
providing dangerous wastes or less than quantitative yield of
pure product. These qualities are as yet only achieved upon
stoichiometric heating of the components at 150°C and 100–
30°C without catalyst. Some catalysis protocols still require
H
1
3,14
of neurodegenerate and other serious diseases.
most 4 ꢀchromene derivatives with the particular present
substitution react antibacterial even against highly resistant
For example,
H
1
1
1
5
Staphylococcusaureus and others.
Several of these
elevated temperatures, often hazardous organic solvents, and
organic bases. Furthermore, the catalysts are often expensive or
not commercially available, and tedious workup procedures are
the rule with many wastes, because of only moderate product
yields, requiring chromatographic workup and recrystallization.
Thus, quantitative yield of the target products at room
temperature omitting wasteful workup is highly desired. We
therefore applied the wealth of the solventless (solventꢀfree
when choosing aqueous workup) stoichiometric MCR
technique with the easily removable environmentally safe
compounds are thus already commercially available.
Importantly, also both the 2ꢀamino and the 3ꢀcyano substituents
have been multiply converted with standard transformations to
create a multitude of useful applications. But unfortunately
there is some confusion with the correct chemical structure of
these very important commercial compounds, because the
necessary corrections of unduly claimed orientation selectivities
in some of the multiple component reactions (MCRs) were
never performed, and the reasons for the selectivities were not
discussed.
2, 43ꢀ47
catalyst sodium carbonate in a ballꢀmill,
and remind the
The synthesis by Knoevenagel condensation + Michael addition
of the highly substituted 4Hꢀchromenes was varied by many
methods in recent years in an attempt to improve ease and
efficiency by catalysis. The towꢀstep approach by cyclization of
4
8ꢀ
possibility that ballꢀmilling is scalable to hundreds of grams
5
2
,
which contrasts to recent reviews on milling in organic
5
3
synthesis by complaining lack of scaleꢀup developments. But
4
8ꢀ50
the existence of the reviews
applications in Refs.
on such scaleꢀup (further
preformed
arylidenemalononitriles
with
βꢀdicarbonyl
4
8ꢀ52
54
has been pointed out. We have
compounds were accelerated by the presence of an organic base
already reported that by combining MCRs and ballꢀmilling
allows for synthesis of a wide variety of interesting organic
1
6
17
such
triethylamine.
as
piperidine,
morpholine,
pyridine,
and
1
8,19
Furthermore, despite our report of an early
4
3ꢀ52,55,56
building blocks.
We also reported that sodium
quantitative wasteless procedure by stoichiometric melt
4
4ꢀ47
carbonate can be a useful basic catalyst in kneading milling.
1
reactions without catalyst, further twoꢀstep procedures tried to
This technique benefits from both the economical and the
synthetic point of view by not only omitting the unnecessary
decrease the temperature by catalysis at the expense of lower
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use of organic solvents, but also enhancing the rate of many extraction of the catalyst from the insoluble product crystals
organic reactions. with water in a then “solventꢀfree” process. No extra purifying
The ongoing hype with multiple repetitions of the MCR workup was required in both techniques.
syntheses in question, providing highly melting products, bears Kneading in the presence of sodium carbonate can now be used
the risk that the characterization of the products rests solely on to provide the completion of both the Knoevenagel
1
melting point comparison rather than on interpretation of H condensations by addition of aldehydes
1
with malononitrile
and the Michael
(as their enols) or with the
in the 25–30°C range. Mechanistically
ꢀnaphthol or resorcinol was the the intermediates 10, which are in equilibrium with their enols
reagent for Michael additions followed by cyclization, and one 11, undergo intramolecular cyclization to give 12, the tautomers
2
NMR coupling schemes that must fit with the claimed (mp 32°C) followed by dehydration to give
orientation specificities in these reactions. Unfortunately, there addition with 1,3ꢀdiketones 3a
are never argued discrepancies in the claimed molecular reactive phenols 3c
structures when for example
9
,
b
–
e
,
β
1
must not invoke melting points of published unassigned or of the products
4–8. Apparently, the basicity of ballꢀmilled
merely claimed molecular structures without taking care of a Na CO and the acidity of NaHCO are improved by continued
2
3
3
safe structure elucidation.
creation of new surfaces of these solids (Scheme 1).
With the desire to understand the surprising orientation
specificities in these MCR syntheses we continued our
2
preliminary grinding and heating experiments by ball milling
with sodium carbonate catalysis in order to obtain quantitative
yield without heating and without producing dangerous wastes.
We assess the correctness of the product structures and report
on the selectivity of the weakly basic catalyst towards phenols.
These oneꢀpot solventꢀfree syntheses react various
benzaldehydes with malononitrile and dimedone, or 1,3ꢀ
cyclohexandione, or resorcinol, or
α
ꢀ
or
βꢀnaphthol.
Quantitative yields are indeed obtained by kneading ball
milling with sodium carbonate as an efficient, selective, cheap,
enviroꢀeconomic, and easily separated catalyst without external
heating.
Results
It was previously reported that the catalystꢀfree ballꢀmilling
reaction of 4ꢀchlorobenzaldehyde (
1, Ar = 4ꢀClC H ) with
6 4
malononitrile ( ) to give the Knoevenagel condensate could not
2
be completed in the solidꢀstate after 10 min at room
temperature but afforded only 7% of the corresponding
5
7
benzylidene malononitrile
9 (Scheme 1). However, the
Scheme 1. Possible mechanism for the preparation of 4–8.
uncatalyzed melt reactions occurred quantitatively at 150°C
with 4ꢀHꢀ, 4ꢀOHꢀ, 4ꢀClꢀ and 4ꢀNO ꢀbenzaldehyde and the
stoichiometric followꢀup Michael additions with dimedone (3a)
2
The corresponding results with dimedone
(3a), 1,3ꢀ
cyclohexanedione (3b), resorcinol (3c), and ꢀ (3d) and
α
βꢀ
occurred in melts at 100–130°C to quantitatively give the 7,7ꢀ
naphthol (3b) (Scheme 2) are reported in Table 1. The times for
quantitative reaction were detected by TLC tests. Table 1
reveals that electronꢀwithdrawing groups accelerate the
reaction. For example, all reactions of 4ꢀnitroꢀ and 4ꢀ
1
dimethylꢀ5ꢀoxoꢀ5,6,7,8ꢀtetrahydroꢀ4
pot MCR reaction of 4ꢀchlorobenzaldehyde
malononitrile ( ) and less reactive ꢀnaphthol (3e) was
H
ꢀchromenes 4a. The oneꢀ
(
1a) with
2
β
incomplete (78% 8a) at 150°C (4 h), but when 10 mol% of
cyanobenzaldehyde and
2 with 3a–3e were completed by 10
ground Na CO was admixed, the reaction temperature could
2
3
minutes milling, but 4ꢀmethoxyꢀ and 4ꢀhydroxybenzaldehyde
needed up to 40 minutes for completion. Also the ball milling
of 4ꢀchloroꢀ and 4ꢀbromobenzaldehydes proceeded rapidly and
be decreased to 125°C (1 h) and quantitative or near
quantitative yields were obtained also with a series of further
2
benzaldehydes (Scheme 1).
quantitatively without external heating. Only in the case of 8c
,
We now found that a quantitative yield of the product 8a (Table
the subsequent heating of the reaction mixture to 125°C for 1 h
was necessary to afford the product quantitatively, probably
due to the presence of the electronꢀreleasing phenolic OH group
1
) was obtained at room temperature when the above mixture
was milled for 10 min. 100% conversion was achieved because
the product becomes an insoluble powder. After sublimation in
a vacuum at 180°C the product was completely separated from
the so recycled catalyst and this process was thus “solventless”.
But such high workup temperature could be avoided by simple
and the least reactivity of
βꢀnaphthol among the other reagents
3
. Conversely, all uncatalyzed quantitative corresponding
2
reactions required heating to 125°C for 1 h. Solid Na CO has
2
3
58
a clear advantage over K CO . A similar work of Zhou et al
2
3
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reported lower yields of 67–74% when grinding with naphthol), as we do and so many other research groups in the
stoichiometric amounts of K CO3 and could not avoid the field. The same discrepancy exists when cyanoaceticethylester
2
formation of deeply colored byꢀproducts. A major difference is used instead of malononitrile for providing the corresponding
appears to be the different qualities of the continuously products with 3ꢀethoxycarbonyl substitution. Furthermore, the
hydrated catalysts when the water of reaction is liberated. It is CAS Registry Database also interprets the poorly defined
6
2
63
well known that sodium carbonate takes up 10 H O to form a products with βꢀnaphthol in the papers of Pasha and Jin with
2
stable solid hydrate, whereas the stable solid hydrate of the straight ring condensation. A clear discussion of the correct
potassium carbonate contains only 1.5 H O. Also structure in these MCRs is of utmost importance, as several of
2
stoichiometric grinding with the weaker basic NaHCO was these products are commercially available. For example the
3
inferior by giving 74–93% yield upon similar grinding for 90 product from benzaldehyde, malononitrile and
β
ꢀnaphthol is
5
8
min, here without coloration.
still sold and advertised (December 2013 according to CAS
The surprising orientation specificities giving only one product Registry Database) by 4 companies (American Custom
in all cases were detected by purity checks with sharp melting Chemical Corp.; ChemPur GmbH; Fluorochem Ltd; Gencore
points, thin layer chromatography and the physical data that Bio PharmaPvT Ltd) as straight “ꢀ4
Hꢀnaphtho[2,3ꢀb]pyran” (a
also correspond to the available published ones. The NMR synonym for “ꢀ4 ꢀbenzo[ ]chromene”) (CAS registry number
H
g
spectroscopic data reveal only one series of resonance signals.
924708ꢀ55ꢀ4). Similar advertisements continue to exist with
substituted products with claimed straight ring condensation.
Ar
Conversely, 23 Suppliers sell these products as angular “ꢀ4ꢀ
naphtho[2,1ꢀb]ꢀpyran” (a synonym for ꢀ4 ꢀbenzo[ ]chromene)
CAS registry number 111861ꢀ46ꢀ2 for Ar = C H ). As the
Hꢀ
CN
H
f
O
NH2
(
6
5
8
(a-c)
research groups that published the angular structure (reaction at
Cꢀ1 of ꢀnaphthol) also used various catalysts (e. g. TiCl or
ß
4
3
e
bases or phaseꢀtransfer catalysis) at room temperature or with
heating (including microwave), it appears clear that one of
these orientation claims must be wrong. Clearly, highꢀ
resolution H NMR provides a clear decision. Unfortunately,
the claims of the straight structure were never substantiated by
Ar
Ar
O
CN HO
CN
CN
3
d
3
c
Ar
1
H
CN
1
O
NH2
HO
O
NH2
1
2
3
6
(a,b)
7(a,b)
0 mol% Na2CO3, Ball-milling
a crystal structure determination or by an analysis or discussion
1
3
b
3
a
of the aromatic proton resonance coupling schemes by
H
5
9ꢀ63
NMR. Thus these papers
do not take care of the ArꢀHꢀ
O
Ar
O
Ar
resonances that are only published as multiplet containing 10 or
CN
CN
1
2
1
1 ArꢀH. However, our H NMR spectra exhibit the ArꢀH
O
NH2
O
NH2
signal at highest field for all substituted derivatives of the
β
ꢀ
4
(a-k)
5(a-g)
naphthol products with large splitting (7–9 Hz range of an AB
spin system) evidently by the coupling with the vicinal ArꢀH,
and so do our here studied products (see the examples 8b and
OH
O
O
O
O
OH
8c in Fig. 1 with the analysis in the Experimental).
HO
OH
3
a
3b
3c
3d
3e
Scheme 2. Preparation of different 2ꢀaminoꢀ4Hꢀpyran
derivatives.
The structures of all products were secured on the basis of their
spectral data. The typical NH and C≡N FTꢀIR bands are of
2
1
course present in all of the corresponding derivatives. The Hꢀ
NMR spectra of all described products show one characteristic
singlet signal in the range of 4.1–5.6 ppm for the 4ꢀH and the
1
3
C NMR spectra exhibit one specific signal in the range of 54–
0 ppm for the carbon at position 4. The reaction orientation of
6
the products
papers, Kumar
6
and
8
is still controversial. Thus, in a series of
5
9ꢀ61
published the reactions of ꢀnaphthol with
β
aromatic aldehydes and malononitrile using various catalysts
and heating devices including microwaves as straight “2ꢀ
aminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ4
reaction at Cꢀ3 of ꢀnaphthol), rather than the angular 2ꢀaminoꢀ
ꢀbenzo[ ]chromenes (reaction at Cꢀ1 of
Hꢀbenzo[g]chromenes” (from claimed
β
4
ꢀarylꢀ3ꢀcyanoꢀ4
H
f
β
ꢀ
4
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DOI: 10.1039/C4RA066 K
1
OH structure by 0.015 kcal/mol more stable. The H NMR
spectra of 6a provide a clear structural decision. They
,b,c
exhibit the highꢀfield ArꢀH (the 8ꢀH that is next to the
heterocyclic oxygen atom) as slightly broadened singlet signal
4
5
(
with not resolved J or J longꢀrange couplings below 1.8 Hz
or smaller), and a 6ꢀH/5ꢀH AB system (the 6ꢀH signal with
more longꢀrange broadening), in addition to the deeper field Arꢀ
H signals of the 4ꢀsubstituent (AA’BB’ for 6b
,c). Thus, the
6
7
structure (reaction at Cꢀ4 of resorcinol as proposed in Ref. )
6
6
8
is confirmed, and the suggestion in Ref. (that claimed reaction
1
at Cꢀ2 of resorcinol) is unsupported. Importantly, our H NMR
spectra of 6a, 6b and 6c concur with the ones of Ref. also
1
3
with the singlet signal from 8ꢀH without vicinal coupling
partner. These products were synthesized in solution with a
“
tungstic
Furthermore, the melting points of the corresponding products
from refluxing water with potassium phthalimidoꢀ
acid
functionalized
mesoporous
catalyst”.
Nꢀ
3
76
77
hydroxylate and those in the Refs. and correspond with
ours. Thus, the structure
6
is found independent of the reaction
conditions.
1
The remaining 7ꢀOHꢀgroup of 6a–c was not able to undergo the
Figure 1. 500ꢀMHz HꢀNMR spectra of 8b and 8c in DMSOꢀ
Michael addition with excessive arylidenemalononitriles under
our reaction conditions. The electronic conditions would allow
d6 for the aromatic proton resonances.
1
for it, but the acidity of 7ꢀOH in the compounds 6 is apparently
Also when checking the corresponding HꢀNMRꢀdata of others,
not high enough. Stronger conditions should be helpful for the
corresponding second Michael addition.
who disclosed the spectra (though without discussion), one
finds the same coupling scheme. There cannot be any doubt
that the ArꢀHꢀsignal at highest field belongs to the hydrogen
that is next to the heterocyclic oxygen. Furthermore, two
slightly broadened singlet signals would have to be expected
from the ArꢀHs of the central ring in the straight structure. But
such singlets cannot be found in any of these spectra. This now
The advance of the present enviroꢀeconomic methodology may
for example be demonstrated by comparison of the efficiencies
for the syntheses of compound 4e in various previous
publications in Table 2. The reported results clearly show that
the present protocol at room temperature and with short
reaction times is the only one giving quantitative yields and not
requiring the use of organic solvents etc for workup. The
previous catalytic techniques sometimes at elevated
temperatures and long reaction times exhibit lower and never
quantitative yields. They require costly purification workup
with serious waste formation by removal/recovery of catalysts
and organic nonꢀproduct materials in organic solvents. It is also
noteworthy that our easily separated catalyst Na CO is the
safely validates the angular ꢀ4
the products from the reactions with
the reaction conditions and arylic substitution. Also published
H
ꢀbenzo[
f]chromene structures of
β
ꢀnaphthol, independent of
6
4
Xꢀray diffraction analyses of related compounds (8a with H,
6
5
66
CH3, or Br instead of Cl, the latter in the (S)ꢀconfiguration)
support the angular structure. Clearly, all chemical, biological,
and medicinal results that were based on the still commercially
advertised and sold products with the unsupported nominal
2
3
cheapest and greenest one among the others. Our workꢀup
procedure is extremely simple. The obtained solid product
powder is quantitatively flushed out with water from the
milling vessel, filtered and dried for quantitatively isolated pure
product yields and a soda solution. No purification workup was
necessary. These solventꢀfree syntheses are thus enviroꢀ
economic. When desired, the powders can also be directly
sublimed off from the catalyst.
straight ꢀ4
reinterpreted.
Hꢀbenzo[g]chromene structure” must be urgently
Another structural question to be settled is the surprising
orientation specificity of the reactions with resorcinol. While a
reaction at its Cꢀ2 would be electronically more suitable the so
experienced more crowding of the arylꢀgroup with the
remaining OHꢀgroup would disfavor that possibility. Thus,
reaction at Cꢀ4 of resorcinol comes to the fore. Experimentally,
one obtains the 7ꢀhydroxyꢀ4
Hꢀchromene structures 6 but not
Discussion
the 5ꢀOHꢀ4 ꢀchromene isomers, not even as detectable sideꢀ
H
products. Unfortunately, we cannot argue with product
stabilities because quantum chemical calculations predict the
actually obtained 6a and the not obtained isomeric structure
energetically very close. The semiꢀempirical PM3 method
calculates the obtained 7ꢀOH structure by 0.28 kcal/mol more
stable, but DFT B3LYP 6ꢀ31G* calculates the not obtained 5ꢀ
The selectivity of the milled solid catalyst Na CO between
2
3
different phenols is remarkable. The reactions go to completion
despite the increasing amounts of crystal water from the
Knoevenagel condensation. Since the solid decaꢀhydrate of
soda (mp 34°C) might have easily melted in its environment it
is almost certain that this hydration state was not reached and
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that at least part of the water of reaction was also included in Also the exclusive Michael addition of βꢀnaphthol at Cꢀ1 is
the solid products with many functional groups. While highly remarkable, because reaction at Cꢀ3 would be facilitated
resorcinol and the naphthols react smoothly, phenol and the by less steric crowding. It appears however that the much
phenolic groups in 4j or 6a
,b,c do not react with the higher electron density of the naphthol and of the naphtholate at
Knoevenagel reagents . This may be roughly related to the Cꢀ1 is the prevailing factor. Density functional calculations at
9
wellꢀknown pK ꢀvalues for aqueous solution even though the the B3LYP 6ꢀ31G* level calculate the electrostatic charges at
a
acidities in the present medium would be different. Thus, the Cꢀ1 as –0.505 and at Cꢀ3 as –0.224 for βꢀnaphthol or as –0.605
reactive phenols such as resorcinol (pK = 9.15), αꢀnaphthol at Cꢀ1 and as –0.326 at Cꢀ3 for the βꢀnaphtholate anion. The
a1
(
pK = 9.3), and βꢀnaphthol (pK = 9.57) are considerably large electrostatic differences substantiate the experimentally
a a
stronger acids than the weaker alkylꢀ and alkoxyꢀphenols. We found orientation specificities to Cꢀ1 but not to Cꢀ3 of βꢀ
may refer here to phenol (pK = 9.99) and reference compounds naphthol in its reactions with the Knoevenagel intermediate
9
.
a
such as 4ꢀmethylphenol (pK = 10.26) and 2ꢀmethoxyphenol Kumars group unduly claimed the latter choice without analysis
a
5
9ꢀ61
(
pK = 9.98). It thus appears that our solid catalyst cannot of their 1H NMR data.
a
deprotonate the weaker phenols 4j and 6a,b,c and this would
explain its selection between phenols.
Table 2 Comparison of the present method with some reported methods in the preparation of 4e.
Catalyst
loading
Catalyst
Temp.
Time
Yield (%)
This work (Na CO )
rt
60°C
rt
10 min
4h
0.5ꢀ2h
0.5ꢀ2h
1 h
50 min
2 h
8min
10 mol%
5 mol%
10 mol%
10 mol%
10 mol%
100 mg
10 mol%
100 mg
16 mol%
20 mol%
100
90
78
80
93
87
94
85
93
92
2
3
2
3
Re(PFO)3
Diammonium hydrogen phosphate
2
5
2
6
NMe OH
rt
4
3
0
CeCl3
ZnOꢀbeta Zeolite
reflux
reflux
reflux
reflux
reflux
rt
3
1
3
2
DABCO
Silica gelꢀsupported polyphosphoric acid
33
3
5
Caro's Acid–Silica Gel
15 min
>30 min
2
4
D,LꢀProline
Table 1 Synthesis of 2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ4Hꢀchromenes under solventꢀfree kneading ballꢀmilling conditions catalyzed by 10 mol%
sodium carbonate.
Entry
Aldehyde (1)
Enolꢀ Naphthol
Product
Time
Yield
Mp (Obsd.)
Mp (Lit)
a
o
(%)
( C)
o
(min)
( C)
1
7
1
4ꢀClꢀC H CHO
3a
10
>99
213ꢀ214
(208ꢀ210)
6
4
4
a
1
2
0
5
2
3
PhCHO
3a
3a
25
15
>99
>99
219ꢀ221
196ꢀ197
(226ꢀ228)
(191ꢀ192)
4
b
2ꢀClꢀC H CHO
6
4
4
c
4
ꢀMeꢀ
2
3
4
3a
35
>99
211ꢀ213
(210ꢀ213)
O
C H CHO
6
4
CN
NH2
O
4d
6
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4
ꢀNO2ꢀ
23
5
6
3a
10
20
>99
>99
177ꢀ178
206ꢀ209
(177ꢀ179)
(204ꢀ205)
C H CHO
6
4
4
e
3
ꢀNO2ꢀ
23
C H CHO
6
4
3
a
4
f
CN
4
ꢀCNꢀ
2
3
7
8
3a
3a
10
35
>99
>99
221ꢀ224
196ꢀ198
(225ꢀ228)
(196ꢀ198)
O
C H CHO
6
4
CN
O
NH2
4g
6
9
4ꢀBrꢀC H CHO
6
4
4
h
4
ꢀMeOꢀ
2
5
9
3a
35
>99
197ꢀ199
(201ꢀ202)
C H CHO
6
4
4
i
4
ꢀHOꢀ
2
5
1
0
1
3a
3a
40
15
>99
>99
205ꢀ206
220ꢀ221
(204ꢀ205)
(233ꢀ234)
C H CHO
6
4
4
j
2
ꢀNO2ꢀ
25
1
1
1
1
C H CHO
6
4
4
k
7
0
2
3
4
4ꢀClꢀC H CHO
3b
3b
3b
20
20
10
>99
>99
>99
241ꢀ244
229ꢀ230
223ꢀ225
(241ꢀ243)
(221ꢀ223)
(234ꢀ236)
6
4
5
a
3
ꢀNO2ꢀ
71
72
C H CHO
6
4
5
b
4
ꢀNO2ꢀ
C H CHO
6
4
5
c
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7
3
1
5
4ꢀBrꢀC H CHO
3b
35
>99
238ꢀ240
(241ꢀ242)
6
4
5
d
4
ꢀHOꢀ
7
2
1
1
1
6
7
8
3b
3b
3b
40
15
35
>99
>99
>99
244ꢀ246
205ꢀ208
199ꢀ202
(234ꢀ236)
(208ꢀ210)
(198ꢀ200)
C H CHO
6
4
5
e
7
4
2
ꢀClꢀC H CHO
6 4
5
f
4
ꢀMeOꢀ
7
5
C H CHO
6
4
5
g
3
1
2
9
0
PhCHO
3c
3c
10
5
>99
>99
230ꢀ231
228ꢀ230
(230ꢀ232)
6
a
7
6
(230ꢀ231)
(240ꢀ241)
4
4
ꢀClꢀC H CHO
6
4
6
b
c
7
7
2
1
3c
5
>99
240ꢀ241
ꢀBrꢀC H CHO
6
4
6
NH2
CN
O
3
2
2
2
3
3d
3d
10
10
>99
>99
233ꢀ235
232ꢀ234
(233ꢀ235)
(234ꢀ236)
4
4
ꢀClꢀC H CHO
6 4
Cl
7
7
a
3
3
ꢀBrꢀC H CHO
6
4
b
2
4
3e
12
>99
207ꢀ209
(207ꢀ208)
4
ꢀClꢀC H CHO
6 4
8
a
8
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3
ꢀNO2ꢀ
2
2
2
5
6
3e
3e
12
>99
>99
237ꢀ239
260ꢀ262
(232ꢀ235)
(260ꢀ262)
C H CHO
6
4
8
b
4
ꢀHOꢀ
2
b
C H CHO
6
4
8
c
a
Isolated yields after extraction of Na CO from the insoluble crystals with water and drying.
2
3
b
o
For the quantitative yield for this case, subsequent heating of the reaction mixture at 125 C was necessary.
To exclude the possibility that their experimental technique 35 Hz. The temperature within the milling beaker was close to
would have drastically changed the orientation specificity of βꢀ the room temperature of about 25°C It did never reach or
6
0ꢀ62
naphthol the reported melting points in Refs.
are invoked. exceed 30°C by the milling, but malononitrile (mp 32°C) melts
“2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ4 in the presence of the other reactants, so this is actually
g]chromenes” are reported with melting points of 274, kneading. Melting points were determined with a Barnstead
The
now
challenged
Hꢀ
benzo[
1
87, 191, and 260°C for Ar = 4ꢀH, 4ꢀNO , 4ꢀCH O, and 2ꢀClꢀ electrothermal melting point apparatus and are uncorrected.
2 3
5
9ꢀ61
1
phenyl.
spectroscopically
benzo[ ]chromenes. Furthermore the mps correspond with all NMR spectra were recorded on a DRXꢀ500 Avance Bruker
other published ꢀ4 ꢀbenzo[ ]chromenes that consistently spectrometer and 250 MHz on a Bruker ADVANCE DPXꢀ250.
These values concur with those of the HꢀNMRꢀ Infrared (IR) spectra were recorded with a Shimadzu 8400s FTꢀ
1
validated
2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ4
H
ꢀ
IR spectrometer using potassium bromide pellets. 500 MHz H
f
H
f
1
exhibit the splitting of the highest field ArꢀH signal in the Hꢀ The chemical shifts are reported in ppm (δꢀscale) relative to
NMR spectrum from the cited authors in Table 1 and also in internal TMS and coupling constants are reported in DMSOꢀd6.
Table 2 of Ref. 2. Thus βꢀnaphthol reacts at Cꢀ1 but not at Cꢀ3 The density function calculations were performed with the
independent of the experimental conditions, because the program TITAN of Wave function Inc., Irvine USA and
electron density is almost twice as high at the experimentally Schrödinger Inc., Portland USA. All solid reagents were
chosen position.
purchased from commercial sources and used without further
purification when uniform by TLC (silica gel with ethyl acetate
and hexane in a 1:5 ratio). The liquid aldehydes were distilled
Conclusions and Outlook
We have demonstrated a “green” atomꢀeconomic and enviroꢀ prior to use. All products are previously described compounds
economic method for the solidꢀstate preparation of several 2ꢀ and they were identified and structurally characterized. Their
aminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ4Hꢀchromenes and clarified still existing physical and spectral data corresponded with the cited literature
detrimental controversies with the product structures. The data. Product purity was checked by melting point, by thin layer
solventꢀfree technique with the ecoꢀefficient catalyst is superior chromatography (TLC) on silica gel with ethyl acetate and
1
to the less productive solution techniques that use expensive hexane in a 1:5 ratio, and by highꢀresolution H NMR spectra.
and harmful catalysts, solid supports, ultrasound or microwave,
which requires purifying workup by using organic solvents for Typical Procedure for the Synthesis of 4
removal of the support of unreacted reagents and of side In a typical experiment, a stoichiometric mixture of an aromatic
products. The here reported milling protocol without heating aldehyde (
) (1.0 mmol), malononitrile ( ) (66 mg, 1.0 mmol),
H-chromenes
1
2
has the advantages of operational simplicity, mild reaction dimedone (3a) (140 mg, 1.0 mmol) or 3b-e (112 mg, 110 mg,
conditions, quantitative product yields, and no need of organic 144 mg, and 144 mg, respectively, 1.0 mmol each) and
solvents for workup and purification. The soda catalyst is cheap anhydrous sodium carbonate (11 mg, 0.1 mmol) were ballꢀ
and nonꢀtoxic. These benefits make our methodology a valid milled for the appropriate time (Table 1). When the reaction
contribution to the existing processes in the field of the 2ꢀ was completed, as indicated by FTIR spectrum of the solid in
aminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ4
H
ꢀchromene derivatives’ synthesis.
KBr pellets and TLC to detect uniformity, the reaction product
from repetitive runs without taking material for IR and TLC)
(
Experimental section
Material and methods
was scraped out on a filter and the holdup flushed out with cold
washing water (3 times, 5 mL each) that was shaken in the mill
for about 1 min prior to the pouring on the solid product for
extracting the inorganic catalyst. After drying the product from
the filter in a vacuum the pure product was directly obtained
with no need for extra purification. The products could also be
quantitatively obtained in pure form by complete collection
The ball mill was a Retsch MM 400 swing mill. A 10 mL
stainless steel vessel was applied. Two stainless steel balls with
7
mm diameter were used, and the milling frequency was at 30–
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Journal Name
from the ballꢀmilling vessel (using the holdup from a previous (DMSOꢀd
, 125 MHz), 39.84, 56.62, 118.18, 120.95, 121.24,
6
1
1
21.58, 123.59, 124.89, 126.94, 127.62, 127.75, 128.57, 130.82(2C),
32.48(2C), 133.62, 143.61, 145.95, 161.02.
run) and sublimation in a good vacuum in the temperature
range of 150–190°C. FTIRꢀspectra of the washed or
recrystallized or sublimed products corresponded to the raw
spectra still containing the catalyst.
2
ꢀAminoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ4Hꢀbenzo[f]chromeneꢀ3ꢀcarbonitrile
–1
1
(
8a): IR (KBr), ν(cm ): 3452, 3334, 2190, 1666, 1590, 1409; H
NMR (DMSOꢀd , 500 MHz), δ (ppm): 4.95(s, 1H, CH), 7.09 (AB,
6
Representative spectral data
1H, J=8.5 Hz ArH), 7.19 (s, 2H, NH
Hz, ArH), 7.36 (BB’AA’, 2H, “J”=8.35 Hz, ArH), 7.57–7.66 (m,
Hꢀchromeneꢀ3ꢀcarbonitrile (4e): IR (KBr), ν (cm ): 3406, 3325, 3H, ArH), 7.89 (br. d, 1H, J=8.0 Hz, ArH), 8.24 (BA, 1H, J=8.5 Hz,
182, 3080, 2964, 2190, 1681, 1519, 1367; H NMR (DMSOꢀd 500 ArH).
), 7.27 (AA’BB’, 2H, “J”=8.35
2
2
4
3
ꢀAminoꢀ7,7ꢀdimethylꢀ4ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxoꢀ5,6,7,8ꢀtetrahydroꢀ
–
1
1
6,
MHz), δ (ppm): 0.96 (s, 3H) 1.04 (s, 3H), 2.11 (AB, J=16.0 Hz, 1H),
2
.25 (BA, J=16.0 Hz, 1H), 2.50 (s, 2H), 4.36 (s, 1H), 7.17 (s, 2H, 2ꢀAminoꢀ4ꢀ(3ꢀnitrophenyl)ꢀ4Hꢀbenzo[f]chromeneꢀ3ꢀcarbonitrile
–1
NH ), 7.45 (AA’BB’, “J”=8.2 Hz, 2H), 8.17 (BB’AA’, “J”=8.2 Hz, (8b): IR (KBr), ν(cm ): 3462, 3357, 3206, 2190, 1658, 1589, 1410;
2
13
1
2
5
1
H); C NMR (125 MHz, DMSOꢀd ) 27.79, 29.11, 32.66, 36.56,
H NMR (DMSOꢀd
0.74, 56.91, 57.91, 112.63, 120.17 (2C), 124.51, 129.49(2C), 2H, NH ), 7.41 (AB, 1H, “J”=8.9 Hz, ArH), 7.42ꢀ7.48 (m, 2H,
ArH), 7.57–7.60 (m, 1H, ArH), 7.67 (d, 1H, “J”=7.7 Hz, ArH), 7.87
d, 1H, “J”=8.2 Hz, ArH), 7.94 (d, 1H, “J”=7.6 Hz, ArH), 7.99 (d,
1H, “J”=7.9 Hz, ArH), 8.04 (d, 1H, “J”=8.1 Hz, ArH), ), 8.08 (s, 1H,
6
, 500 MHz), δ (ppm): 5.63(s, 1H, CH), 7.17 (s,
6
2
47.14, 153.15, 159.48, 163.96, 196.53.
(
2
ꢀAminoꢀ7,7ꢀdimethylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀoxoꢀ5,6,7,8ꢀ
–
1
13
tetrahydroꢀ4Hꢀchromeneꢀ3ꢀcarbonitrile (4i): IR (KBr), ν (cm ): ArH), C NMR (DMSOꢀd
, 125 MHz), 39.87, 57.82 (=CꢀCN),
6
1
3
(
375, 3321, 3186, 2962, 2192, 1683, 1654, 1510, 1369; H NMR 115.47, 117.74, 121.04, 122.18, 122.72, 124.36, 128.28, 129.48,
DMSOꢀd 500 MHz), δ (ppm) 0.95 (s, 3H); 1.04 (s, 3H), 2.09 (AB, 130.78, 130.95, 131.33 (2C), 131.73 (2C), 134.59, 148.61, 148.86,
6,
J=16 Hz, 1H), 2.23 (BA, J=16. Hz, 1H), 2.50(s, 2H), 3.72 (s, 3H), 160.84(=CꢀO,ꢀN).
4
7
.12 (s, 1H), 6.84 (AA’BB’, “J”=8.05 Hz, 2H), 6.94 (s, 2H, NH ),
2
1
3
.05 (BB’AA’, “J”=8.05 Hz, 2H); C NMR (125 MHz, DMSOꢀd6) 2ꢀAminoꢀ4ꢀ(4ꢀhydroxyphenyl)ꢀ4Hꢀbenzo[f]chromeneꢀ3ꢀcarbonitrile
–1
δ (ppm) 27.65, 29.28, 32.64, 35.63, 50.70, 50.89, 55.87, 59.46, (8c): IR (KBr), ν(cm ): 3452, 3308, 3175, 2195, 1653, 1589, 1510,
1
1
1
13.87, 114.55(2C), 120.65, 129.31(2C), 137.72, 158.79, 159.29, 1412; H NMR (DMSOꢀd
62.99, 196.51.
6.63 (d, 2H, J=7.8 Hz, AA’BB’), 6.89 (s, 2H, NH
J=7.8 Hz, BB’AA’), 7.32 (d, 1H, “J”=8.8 Hz, ArH), 7.40ꢀ7.46 (m,
ꢀAminoꢀ7ꢀhydroxyꢀ4ꢀphenylꢀ4Hꢀchromeneꢀ3ꢀcarbonitrile (6a): IR 2H, ArH), 7.85 (br. d, “J”= 7.7 Hz, 1H, ArH), 7.905ꢀ7.92 (br.d, 2H,
6
, 500 MHz), δ (ppm): 5.17 (s, 1H, CH),
), 6.98 (d, 2H,
2
2
(
–1
13
KBr), ν(cm ): 3495, 3425, 3337, 2189, 1649, 1589, 1504, 1456, ArH), 9.26 (s, 1H, OH), C NMR (DMSOꢀd , 125 MHz), 40.89,
6
1
1
6
404, 1153; H NMR (DMSOꢀd , 250 MHz), δ (ppm): 4.64 (s, 4ꢀH), 59.28 (=CꢀCN), 116.21 (2C), 117.04, 117.65, 121.51, 124.59,
6
.43 (s, 8ꢀH), 6.49 (AB, J=8.25 Hz, 6ꢀH), 6.83 (BA, J=8.25 Hz, 5ꢀ 125.71, 127.81, 128.88 (2C), 129.28, 130.10, 131.09, 131.68,
H), 6.91 (s, 2NH), 7.17–7.25 (m, 3ArH), 7.30–7.36 (m, 2ArH), 9.74 137.11, 147.54, 156.82, 160.38 (=CꢀO,ꢀN).
(br s, 1OH).
Acknowledgements
2
(
1
4
5
ꢀAminoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ7ꢀhydroxyꢀ4Hꢀchromeneꢀ3ꢀcarbonitrile
–1
6b): IR (KBr), ν(cm ): 3470, 3340, 3250, 2191, 1641, 1587, 1502, The financial support from The Research Council of Iran University
460, 1406, 1155; H NMR (DMSOꢀd , 250 MHz), δ (ppm): 4.67 (s, of Science and Technology (IUST), Tehran, Iran is gratefully
ꢀH), 6.41 (s, 8ꢀH), 6.48 (AB, J=7.5 Hz, 6ꢀH), 6.78 (BA, J=7.5 Hz, acknowledged.
ꢀH), 6.94 (s, 2NH), 7.19 (AA’BB’, “J”=7.0 Hz, 2ArH), 7.37
1
6
(BB’AA’, “J”=7.0 Hz, 2ArH), 9.89 (br.s, 1OH).
Notes and references
2
ꢀAminoꢀ4ꢀ(4ꢀbromophenyl)ꢀ7ꢀhydroxyꢀ4Hꢀchromeneꢀ3ꢀcarbonitrile
–
1
1.
2.
G. Kaupp, M. R. NaimiꢀJamal and J. Schmeyers, Tetrahedron, 2003,
9, 3753ꢀ3760.
M. R. NaimiꢀJamal, S. Mashkouri and A. Sharifi, Mol. Divers., 2010,
4, 473ꢀ477.
(
6c): IR (KBr), ν(cm ): 3472, 3340, 3259, 2189, 1641, 1585, 1502,
5
1
1
4
460, 1404, 1155; H NMR (DMSOꢀd , 250 MHz), δ (ppm): 4.66 (s,
6
ꢀH), 6.41 (s, 8ꢀH), 6.49 (AB, J=8.25 Hz, 6ꢀH), 6.79 (BA, J=8.25
1
Hz, 5ꢀH), 6.95 (s, 2NH), 7.13 (AA’BB’, “J”=8.2 Hz, 2ArH), 7.51 3.
BB’AA’, J=8.2 Hz, 2ArH), 9.76 (br s, 1OH).
M. G. Dekamin, M. Eslami and A. Maleki, Tetrahedron, 2013, 69,
1074ꢀ1085.
L. Bonsignore, G. Loy, D. Secci and A. Calignano, Eur. J. Med.
Chem., 1993, 28, 517ꢀ520.
(
4
.
2
ꢀAminoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ4Hꢀbenzo[h]chromeneꢀ3ꢀcarbonitrile
–
1
1
5.
Y. Gao, W. Yang and D.ꢀM. Du, TetrahedronꢀAsymmetr., 2012, 23,
(
7a): IR (KBr), ν(cm ): 3452, 3334, 2190, 1666, 1590, 1409; H
3
39ꢀ344.
NMR (DMSOꢀd , 500 MHz), δ (ppm): 4.96(s, 1H, CH), 7.10 (AB,
6
6
7
.
.
R. Ling, M. Yoshida and P. S. Mariano, J. Org. Chem., 1996, 61,
4439ꢀ4449.
L. R. Morgan, B. S. Jursic, C. L. Hooper, D. M. Neumann, K.
Thangaraj and B. LeBlanc, Bioorg. Med. Chem. Lett., 2002, 12, 3407ꢀ
3411.
A. Bolognese, G. Correale, M. Manfra, A. Lavecchia, O. Mazzoni, E.
Novellino, P. La Colla, G. Sanna and R. Loddo, J. Med. Chem., 2004,
47, 849ꢀ858.
H. Gourdeau, L. Leblond, B. Hamelin, C. Desputeau, K. Dong, I.
Kianicka, D. Custeau, C. Boudreau, L. Geerts, S.ꢀX. Cai, J. Drewe, D.
Labrecque, S. Kasibhatla and B. Tseng, Mol. Cancer Ther., 2004, 3,
1
H, “J”=8.5 Hz ArH), 7.20 (s, 2H, NH ), 7.28 (AA’BB’, 2H,
2
“
J”=8.4 Hz, ArH), 7.38 (BB’AA’, 2H, “J”=8.4 Hz, ArH), 7.57–7.66
m, 3H, ArH), 7.90 (d, 1H, J=8.0 Hz, ArH), 8.24 (BA, 1H, “J”=8.5
Hz, ArH).
(
8
.
2
ꢀAminoꢀ4ꢀ(4ꢀbromophenyl)ꢀ4Hꢀbenzo[h]chromeneꢀ3ꢀcarbonitrile
–1
(
7b): IR (KBr), ν(cm ): 3452, 3337, 2189, 1664, 1600, 1570, 1408;
1
9.
H NMR (DMSOꢀd , 500 MHz), δ (ppm): 4.94(s, 1H, CH), 7.10
6
(AB, 1H,
J=7.9 Hz, ArH), 7.2ꢀ7.23 (m, 4H, NH + ArH), 7.52
2
(
1
AA’BB’, 2H, “J”=7.3 Hz, ArH), 7.59–7.65 (m, 3H, ArH), 7.90 (d,
H, “J”=7.7 Hz, ArH), 8.24 (BA, 1H, J=7.9 Hz, ArH), C NMR
1
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