Highly efficient synthesis of chalcones from poly carbonyl aromatic compounds using bf3-et2o via a regioselective condensation reaction

Article abstract of DOI:10.1248/cpb.c15-00939

A new, simple, highly efficient method for the synthesis of different types of carbonyl chalcones through a regioselective condensation reaction of appropriate 5-acetyl-2-hydroxybenzaldehyde with various substituted acetophenones and 4-hydroxyisothalaldehyde with various substituted aldehydes using BF3-Et2O as a reagent is described.

Full text of DOI:10.1248/cpb.c15-00939

570
Chem. Pharm. Bull. 64, 570–576 (2016)
Vol. 64, No. 6
Regular Article
Highly Efficient Synthesis of Chalcones from Poly Carbonyl Aromatic
Compounds Using BF3–Et2O via a Regioselective Condensation Reaction
,a,b
Satyanarayana Reddy Julakanti,* Manimala Patel,a,b and Venkateswarlu Ponnerib
a Natural Products Chemistry Division, CSIR Indian Institute of Chemical Technology; Tarnaka, Hyderabad,
b
Telangana 500007, India: and Department of Chemistry, Sri Venkateswara University; Tirupathi, A.P. 517507, India.
Received November 25, 2015; accepted February 16, 2016
A new, simple, highly efficient method for the synthesis of different types of carbonyl chalcones through
a regioselective condensation reaction of appropriate 5-acetyl-2-hydroxybenzaldehyde with various substi-
tuted acetophenones and 4-hydroxyisothalaldehyde with various substituted aldehydes using BF3–Et2O as a
reagent is described.
Key wordsꢀ borontrifluoride-etherate;ꢀregioselectivity;ꢀcarbonylꢀchalcone;ꢀClaisen–Schmidtꢀreaction
Chalconesꢀ areꢀ consideredꢀ asꢀ theꢀ precursorsꢀ ofꢀ flavonoids/ methyldisilazideꢀ (LiHDMS)20) and calcined NaNO3/naturalꢀ
isoflavonoidsꢀ andꢀ areꢀ abundantꢀ inꢀ edibleꢀ plants.ꢀ Flavonoidsꢀ phosphates.21)ꢀBesideꢀbaseꢀcatalyzedꢀmethods,ꢀsomeꢀacidꢀcata-
representꢀ anꢀ outstandingꢀ classꢀ ofꢀ naturallyꢀ occurringꢀ com- lyzedꢀmethodologiesꢀhaveꢀalsoꢀbeenꢀreportedꢀforꢀtheꢀsynthesisꢀ
pounds.1)ꢀ Chalconesꢀ areꢀ openꢀ chainꢀ flavonoidsꢀ inꢀ whichꢀ twoꢀ ofꢀ chalconesꢀ whichꢀ includesꢀ theꢀ useꢀ ofꢀ AlCl3,22) dry Zn(bpy)
aromaticꢀringsꢀareꢀseparatedꢀbyꢀaꢀthreeꢀcarbonꢀα,β-unsaturatedꢀ (OAc)2,23)ꢀTiCl4,24)ꢀCp2ZrH2/NiCl2,25) Zeolites19)ꢀandꢀRuCl3.26)
carbonyl system, i.e.ꢀ 1,3-diphenyl-2-propen-1-oneꢀ derivative.ꢀ
Recently, BF3–Et2Oꢀ hasꢀ beenꢀ utilizedꢀ asꢀ aꢀ condensingꢀ
The equilibrium between the open chain chalcone form and agentꢀ inꢀ theꢀ synthesisꢀ ofꢀ chalcones,27) stilbenes,28)ꢀ regiose-
theꢀcyclicꢀflavanoneꢀisomerꢀisꢀtheꢀkeyꢀstepꢀforꢀtheꢀoriginꢀofꢀtheꢀ lectiveꢀ deacetylationꢀ regioselectiveꢀ cyclizationꢀ ofꢀ prenylatedꢀ
skeletalꢀ modificationsꢀ ofꢀ theꢀ biosyntheticꢀ pathway.ꢀ Chalconesꢀ chalcones29)ꢀ andꢀ inꢀ theꢀ synthesisꢀ ofꢀ chromano-chalconesꢀ via
areꢀknownꢀforꢀdiverseꢀbiologicalꢀactivities,ꢀamongꢀwhichꢀanti- regioselectiveꢀcyclizationꢀofꢀprenylatedꢀchalcones.30) However,
inflammatory,2) antimalarial,3) antitubercular,4) nitric oxide the use BF3–Et2O has not been yet explored for the synthesis
regulationꢀ modulatory,5) cardiovascular,6) anticancer7) and an- ofꢀ carbonylꢀ chalconesꢀ withꢀ freeꢀ aldehydeꢀ groupꢀ onꢀ benzeneꢀ
tileishmanial activities8) have been reported in the past decade. ring.
The structure–activity relationship (SAR) study of chal-
cones revealed that the presence of hydroxyl, allyl and prenyl
Results and Discussion
groupsꢀinꢀitsꢀskeletonꢀcommonlyꢀenhancesꢀitsꢀbiologicalꢀactiv-
Inꢀtheꢀpresentꢀstudy,ꢀchalconesꢀwereꢀpreparedꢀbyꢀusingꢀtheꢀ
ities.9,10) The reported synthetic chalcones I–IVꢀ(Fig.ꢀ1)ꢀexhibitꢀ keyꢀstartingꢀmaterial,ꢀi.e.ꢀ5-acetyl-2-hydroxybenzaldehydeꢀ(1).
variousꢀ biologicalꢀ activities.11–14) Many methods are available SalicylaldehydeꢀwasꢀacetylatedꢀwithꢀAC2O in the presence of
forꢀ theꢀ synthesisꢀ ofꢀ chalcones.ꢀ Amongꢀ those,ꢀ baseꢀ catalyzedꢀ AlCl3ꢀinꢀdichloromethaneꢀ(DCM)ꢀsolvent31)ꢀtoꢀaffordꢀ5-acetyl-
Claisen–Schmidtꢀ reactionꢀ isꢀ theꢀ mostꢀ widelyꢀ used,ꢀ inꢀ whichꢀ 2-hydroxybenzaldehydeꢀ (1).ꢀ Anotherꢀ startingꢀ material,ꢀ i.e.,
ketone condenses with an aldehyde in the presence of aq. 4-hydroxy-5-methylisothalaldehydeꢀ (2) was prepared via the
NaOH,15) KOH,16,17) Ba(OH)2,18) hydrotalcites,19) lithium hexa- Duffꢀformylationꢀreactionꢀofꢀcommerciallyꢀavailableꢀ O-cresol
Chartꢀ 1
Chartꢀ 2
*ꢀToꢀwhomꢀcorrespondenceꢀshouldꢀbeꢀaddressed.ꢀ e-mail:ꢀsjsnreddy@gmail.com
© 2016 The Pharmaceutical Society of Japan

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Fig.ꢀ 1.ꢀ BiologicallyꢀActiveꢀSyntheticꢀChalcones
Fig.ꢀ 2.ꢀ PossibleꢀMechanismꢀforꢀtheꢀFormationꢀofꢀDesiredꢀChalconesꢀUsingꢀBF3–Et2O
in the presence of hexamethylenetetramine (HMTA) and tri- othersꢀacetophenonesꢀandꢀtheꢀresultsꢀareꢀsummarizedꢀinꢀTableꢀ
fluoroaceticꢀ acidꢀ (TFA)ꢀ atꢀ 120°C.32) In the previous reports 2.ꢀ Severalꢀ otherꢀ acetophenonesꢀ likeꢀ 3-methoxyacetophenone,ꢀ
onꢀtheꢀsynthesisꢀofꢀchalcones,ꢀweꢀobservedꢀthat,ꢀacetylꢀgroupꢀ 3,4-dimethoxyacetophenone,ꢀ 3-bromoacetophenone,ꢀ 2,4-di-
adjacentꢀ toꢀ theꢀ hydroxylꢀ groupꢀ mightꢀ beꢀ formingꢀ aꢀ complexꢀ chloroacetophenone,ꢀ 4-methoxyacetophenone,ꢀ 4-fluoroaceto-
with BF3–Et2O to prevent the condensation reaction27)ꢀ (Fig.ꢀ phenoneꢀ andꢀ thiophene-2-carboxaldehydeꢀ reactedꢀ smoothlyꢀ
2).ꢀ Therefore,ꢀ anꢀ attemptꢀ wasꢀ madeꢀ toꢀ investigateꢀ theꢀ aboveꢀ with 2ꢀ affordingꢀ theirꢀ respectiveꢀ chalconesꢀ 6b–hꢀ inꢀ goodꢀ
described property of BF3–Et2Oꢀtoꢀperformꢀtheꢀregioselectiveꢀ yields (entries 2–8, Table 2).
Claisen–Schmidtꢀcondensationꢀreactionꢀofꢀ1 and 2.
Inꢀ caseꢀ ofꢀ lowꢀ yieldingꢀ reactions,ꢀ theꢀ startingꢀ materialsꢀ
Initially,ꢀ weꢀ attemptedꢀ theꢀ reactionꢀ ofꢀ 5-acetyl-2-hydroxy- wereꢀ recoveredꢀ throughꢀ columnꢀ chromatographyꢀ andꢀ weꢀ didꢀ
benzaldehydeꢀ 1ꢀ withꢀ benzaldehydeꢀ 3aꢀ inꢀ 1,4-dioxaneꢀ usingꢀ notꢀobserveꢀtheꢀformationꢀofꢀtheirꢀregioisomers.ꢀAllꢀtheꢀprod-
2eq of BF3–Et2Oꢀ(Chartꢀ1).ꢀTheꢀreactionꢀproceededꢀsmoothlyꢀ uctsꢀwereꢀcharacterizedꢀbyꢀNMR,ꢀMassꢀandꢀIRꢀspectroscopy.ꢀ
at ambient temperature to afford the desired chalcone 4a Beside BF3–Et2O,ꢀtheꢀeffectꢀofꢀvariousꢀotherꢀLewisꢀacidsꢀsuchꢀ
in 81% yield. The scope of the reaction was explored with asꢀAlCl3,ꢀZnCl2,ꢀSnCl4ꢀandꢀTiCl4 was studied for this transfor-
differentꢀ aromaticꢀ aldehydesꢀ suchꢀ asꢀ 3-methoxybenzal- mation. In all those cases, formation of desired chalcone was
dehyde,ꢀ 4-isopropylbenzaldehyde,ꢀ 4-methoxybenzaldehyde,ꢀ notꢀ regioselective;ꢀ indeedꢀ thoseꢀ Lewisꢀ acidsꢀ gaveꢀ mixtureꢀ ofꢀ
3-methoxy-4-benzyloxybenzaldehyde,ꢀ 4-fluorobenzaldehyde,ꢀ cross condensation and self condensation products in variable
3-phenoxybenzaldehyde,ꢀ 4-methylbenzaldehydeꢀ andꢀ 3,4,5-tri- ratiosꢀalongꢀwithꢀunreactedꢀstaringꢀmaterialsꢀwhichꢀcouldꢀnotꢀ
methoxybenzaldehydeꢀ (entriesꢀ 2,ꢀ 4–10,ꢀ Tableꢀ 1).ꢀ Allꢀ theꢀ beꢀseparableꢀonꢀcolumnꢀchromatography.
above aldehydes reacted well with acetophenone 1ꢀ affordingꢀ
its desired chalcones 4b and d–j,ꢀrespectivelyꢀinꢀgoodꢀyields.ꢀ
Conclusion
Heteroaromaticꢀaldehydesꢀsuchꢀasꢀthiophene-2-carboxaldehydeꢀ
We have reported a simple protocol for the synthesis of car-
alsoꢀparticipatedꢀwellꢀinꢀthisꢀreactionꢀtoꢀgiveꢀrespectiveꢀprod- bonylꢀchalconesꢀwithꢀfreeꢀaldehydeꢀgroupꢀonꢀbenzeneꢀringꢀvia
uct 4c (entry 3, Table 1).
Claisen–Schmidtꢀ condensationꢀ usingꢀ BF3–Et2O. This method
Next,ꢀ weꢀ studiedꢀ theꢀ reactionꢀ ofꢀ 4-hydroxy-5-methyliso- hasꢀ severalꢀ advantagesꢀ suchꢀ asꢀ regioselectivity,ꢀ highꢀ yieldsꢀ
thalaldehyde 2 with acetophenone 5a under similar reaction andꢀsimpleꢀprocedure.ꢀFreeꢀaldehydeꢀgroupꢀinꢀproductsꢀcanꢀbeꢀ
conditionsꢀ(Chartꢀ2).ꢀInꢀthatꢀcase,ꢀtheꢀcorrespondingꢀchalconeꢀ usedꢀ inꢀ furtherꢀ modificationsꢀ toꢀ generateꢀ aꢀ largeꢀ numberꢀ ofꢀ
6a was obtained as a sole product in 82% yield. The scope hybridꢀmoleculesꢀofꢀbiologicalꢀimportance.
of the above reaction was examined with respect to various

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Tableꢀ 1.ꢀ SynthesisꢀofꢀAldehydeꢀChalconesꢀ(4a–j)ꢀUsingꢀBF3–Et2O
Entry
1
Ketone
Aldehyde
Chalcone
Yield (%)a)
81
mpꢀ(°C)
145
2
79
161
3
4
73
68
130
226
5
6
85
70
158
161
7
8
41
67
193
139
9
78
71
205
205
10
a) Isolated yield. b)ꢀAllꢀproductsꢀwereꢀcharacterizedꢀbyꢀ1H-NMR,ꢀ13C-NMRꢀandꢀMSꢀdata.

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Tableꢀ 2.ꢀ SynthesisꢀofꢀAldehydeꢀChalconesꢀ(6a–h)ꢀUsingꢀBF3–Et2O
Entry
1
Acetophenone
–Arꢀgroup
Chalcone
Yield (%)a)
82
mpꢀ(°C)
134
2
3
4
5
6
7
81
71
77
76
86
69
163
201
173
212
160
205
8
71
174
a) Isolated yield. b)ꢀAllꢀproductsꢀwereꢀcharacterizedꢀbyꢀ1H-NMR,ꢀ13C-NMRꢀandꢀMSꢀdata.
packedꢀ inꢀ glassꢀ columns.ꢀ Allꢀ theꢀ reactionsꢀ wereꢀ performedꢀ
Experimental
Allꢀ theꢀ reagentsꢀ andꢀ solventsꢀ wereꢀ ofꢀ reagentꢀ gradeꢀ andꢀ underꢀanꢀatmosphereꢀofꢀnitrogenꢀinꢀovenꢀdriedꢀglassware.ꢀFou-
usedꢀwithoutꢀpurificationꢀunlessꢀspecifiedꢀotherwise.ꢀTechnicalꢀ rierꢀtransformꢀ(FT)-IRꢀspectraꢀwereꢀrecordedꢀasꢀKBrꢀdiscsꢀorꢀ
1
gradeꢀ ethylꢀ acetateꢀ andꢀ hexaneꢀ wereꢀ usedꢀ forꢀ columnꢀ chro- neat. The H-ꢀ andꢀ 13C-NMRꢀ spectraꢀ wereꢀ recordedꢀ inꢀ CDCl3
matographyꢀ andꢀ wereꢀ distilledꢀ priorꢀ itsꢀ use.ꢀ 1,4-Dioxaneꢀ wasꢀ andꢀ DMSO-d6ꢀ usingꢀ 300,ꢀ 400ꢀ andꢀ 500ꢀMHzꢀ spectrometers.ꢀ
purchasedꢀfromꢀAldrichꢀChemicalsꢀCo.ꢀColumnꢀchromatogra- Massꢀ spectraꢀ wereꢀ recordedꢀ onꢀ Microꢀ massꢀ VG-7070Hꢀ forꢀ
phyꢀ wasꢀ carriedꢀ outꢀ usingꢀ silicaꢀ gelꢀ (60–120,ꢀ 100–200ꢀ mesh)ꢀ electronꢀionizationꢀ(EI)ꢀandꢀVGꢀAutospecꢀMꢀforꢀFAB-MS.

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General Experimental Procedure for the Synthesis J=15.8ꢀHz,ꢀ 1H),ꢀ 7.59ꢀ (d,ꢀ J=9.0ꢀHz,ꢀ 1H),ꢀ 7.37ꢀ (d,ꢀ J=15.1ꢀHz,ꢀ
of Aldehyde Chalcones (4a–j) To a stirred solution of 1H), 7.07 (d, J=8.3, 1H), 6.91 (d, J=9.0ꢀHz,ꢀ1H),ꢀ3.86ꢀ(s,ꢀ3H);ꢀ
5-acetyl-2-hydroxybenzaldehydeꢀ 1ꢀ (100ꢀmg,ꢀ 0.61ꢀmmol)ꢀ andꢀ 13C-NMRꢀ(75ꢀMHz,ꢀCDCl3) δ:ꢀ196.4,ꢀ187.2,ꢀ164.8,ꢀ161.7,ꢀ145.0,ꢀ
benzaldehydeꢀ 3ꢀ (0.61ꢀmmol)ꢀ inꢀ dryꢀ 1,4ꢀ dioxaneꢀ (5ꢀmL)ꢀ wasꢀ 136.7, 134.8, 130.6, 130.2, 127.3, 118.2, 117.9, 114.3, 120.0,
addedꢀ graduallyꢀ BF3–Et2O (1.22mmol) at room temperature. 55.3;ꢀESI-MS:ꢀm/z=283 [M+Na]+.
The reaction mixture was stirred at room temperature for
(E)-5-(3-(4-(Benzyloxy)-3-methoxyphenyl)acryloyl)-2-
24h. After completion, the reaction mixture was diluted with hydroxybenzaldehydeꢀ(4f)
ethylꢀ acetateꢀ (100ꢀmL)ꢀ andꢀ washedꢀ withꢀ waterꢀ (3×25ꢀmL)ꢀ toꢀ
Yieldꢀ 70%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 161°C;ꢀ 1H-NMRꢀ
decompose the BF3–Et2O complex. After extraction, the or- (500ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.41ꢀ (s,ꢀ 1H),ꢀ 10.00ꢀ (s,ꢀ 1H),ꢀ 8.31ꢀ (s,ꢀ
ganicꢀ phaseꢀ wasꢀ driedꢀ overꢀ anhydrousꢀ Na2SO4,ꢀ filteredꢀ andꢀ 1H), 8.23 (d, J=8.6,ꢀ Hz,ꢀ 1H),ꢀ 7.79ꢀ (d,ꢀ J=15.3ꢀHz,ꢀ 1H),ꢀ 7.44ꢀ
the solvent was evaporated under reduced pressure. The crude (d, J=7.6ꢀHz,ꢀ 2H),ꢀ 7.41–7.30ꢀ (m,ꢀ 4H),ꢀ 7.18ꢀ (s,ꢀ 2H),ꢀ 7.09ꢀ (d,ꢀ
productꢀ wasꢀ purifiedꢀ byꢀ silicaꢀ gelꢀ columnꢀ chromatographyꢀ J=8.6ꢀHz,ꢀ 1H),ꢀ 6.92ꢀ (d,ꢀ J=8.6ꢀHz,ꢀ 1H),ꢀ 5.21ꢀ (s,ꢀ 2H),ꢀ 3.96ꢀ (s,ꢀ
usingꢀhexane–ethylꢀacetateꢀasꢀaꢀmobileꢀphaseꢀtoꢀaffordꢀdesiredꢀ 3H); 13C-NMRꢀ(75ꢀMHz,ꢀCDCl3) δ:ꢀ196.4,ꢀ187.2,ꢀ164.8,ꢀ150.7,ꢀ
chalcones 4a–jꢀinꢀgoodꢀyields,ꢀwhichꢀwereꢀlightꢀyellowꢀsolids. 149.7, 145.2, 136.2, 136.3, 134.9, 130.6, 128.5, 128.0, 127.9,
5-Cinnamoyl-2-hydroxybenzaldehydeꢀ(4a)
127.1,ꢀ 122.9,ꢀ 122.0,ꢀ 118.7,ꢀ 117.9,ꢀ 113.4,ꢀ 110.8,ꢀ 70.8,ꢀ 56.0;ꢀ ESI-
Yieldꢀ 81%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 145°C;ꢀ IRꢀ νm1ax:ꢀ 2923,ꢀ MS:ꢀm/z=389 [M+Na]+.
2845, 1654, 1598, 1444, 1213, 1160, 1038, 848cm−1; H-NMRꢀ
(300ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.41ꢀ (s,ꢀ 1H),ꢀ 10.02ꢀ (s,ꢀ 1H),ꢀ 8.32ꢀ (d,ꢀ (4g)
J=1.5ꢀHz,ꢀ 1H),ꢀ 8.24ꢀ (dd,ꢀ J=2.2,ꢀ 9.0ꢀHz,ꢀ 1H),ꢀ 7.83ꢀ (d,ꢀ J=15.8,
(E)-5-(3-(4-Fluorophenyl)acryloyl)-2-hydroxybenzaldehydeꢀ
Yieldꢀ 41%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 193°C;ꢀ 1H-NMRꢀ
1H), 7.68–7.60 (m, 2H), 7.50 (d, J=15.1ꢀHz,ꢀ 1H),ꢀ 7.45–7.38ꢀ (400ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.46ꢀ (s,ꢀ 1H),ꢀ 10.02ꢀ (s,ꢀ 1H),ꢀ 8.34ꢀ
(m, 3H), 7.09 (d, J=9.0ꢀHz,ꢀ 1H);ꢀ 13C-NMRꢀ (75ꢀMHz,ꢀ CDCl3) (d, J=2.3ꢀHz,ꢀ 1H),ꢀ 8.25ꢀ (dd,ꢀ J=2.2,ꢀ 8.8ꢀHz,ꢀ 1H),ꢀ 7.84ꢀ (d,ꢀ
δ:ꢀ196.3,ꢀ187.1,ꢀ164.8,ꢀ145.0,ꢀ136.7,ꢀ134.9,ꢀ134.4,ꢀ130.6,ꢀ130.2,ꢀ J=15.5ꢀHz,ꢀ 1H),ꢀ 7.69–7.64ꢀ (m,ꢀ 2H),ꢀ 7.47ꢀ (d,ꢀ J=15.56ꢀHz,ꢀ 1H),ꢀ
129.5,ꢀ128.8,ꢀ128.3,ꢀ120.5,ꢀ117.9;ꢀelectrosprayꢀionizationꢀ(ESI)- 7.17–7.10 (m, 3H); 13C-NMRꢀ(75ꢀMHz,ꢀCDCl3) δ:ꢀ190.1,ꢀ184.9,ꢀ
MS:ꢀm/z=253 [M+Na]+.
162.8, 140.7, 134.3, 129.6, 129.5, 129.1, 129.0, 127.6, 119.9,
(E)-2-Hydroxy-5-(3-(3-methoxyphenyl)acryloyl)benzaldehydeꢀ 115.9,ꢀ114.1,ꢀ113.9;ꢀESI-MS:ꢀm/z=293 [M+Na]+.
(4b) (E )-2-Hydroxy-5-(3-(3-phenoxyphenyl)acryloyl)-
Yieldꢀ 79%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 161°C;ꢀ 1H-NMRꢀ benzaldehydeꢀ(4h)
(400ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.39ꢀ (s,ꢀ 1H),ꢀ 10.00ꢀ (s,ꢀ 1H),ꢀ 8.30ꢀ
Yieldꢀ 67%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 139°C;ꢀ 1H-NMRꢀ
(d, J=2.3ꢀHz,ꢀ 1H),ꢀ 8.21ꢀ (dd,ꢀ J=2.3,ꢀ 8.5ꢀHz,ꢀ 1H),ꢀ 7.76ꢀ (d,ꢀ (300ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.40ꢀ (s,ꢀ 1H),ꢀ 10.00ꢀ (s,ꢀ 1H),ꢀ 8.30ꢀ (d,ꢀ
J=15.5ꢀHz,ꢀ 1H),ꢀ 7.45ꢀ (d,ꢀ J=15.5ꢀHz,ꢀ 1H),ꢀ 7.30ꢀ (t,ꢀ J=7.7ꢀHz,ꢀ J=1.5ꢀHz,ꢀ1H),ꢀ8.21ꢀ(dd,ꢀJ=2.2,ꢀ9.0ꢀHz,ꢀ1H),ꢀ7.77ꢀ(d,ꢀJ=15.1ꢀHz,ꢀ
1H), 7.21 (d, J=7.01, 1H), 7.11 (s, 1H), 7.07 (d, J=8.5ꢀHz,ꢀ1H),ꢀ 1H), 7.45 (d, J=15.1ꢀHz,ꢀ1H),ꢀ7.39–7.37ꢀ(m,ꢀ5H),ꢀ7.15–6.95ꢀ(m,ꢀ
6.92 (dd, J=2.3,ꢀ8.5ꢀHz,ꢀ1H),ꢀ3.85ꢀ(s,ꢀ3H);ꢀ13C-NMRꢀ(75ꢀMHz,ꢀ 5H); 13C-NMRꢀ(100ꢀMHz,ꢀCDCl3) δ:ꢀ196.3,ꢀ187.0,ꢀ164.9,ꢀ157.7,ꢀ
CDCl3) δ:ꢀ196.4,ꢀ187.2,ꢀ164.9,ꢀ159.8,ꢀ145.0,ꢀ136.8,ꢀ135.9,ꢀ135.0,ꢀ 156.6, 144.2, 136.7, 136.4, 135.0, 130.2, 129.8, 123.6, 123.5,
130.3,ꢀ129.9,ꢀ121.0,ꢀ120.9,ꢀ120.0,ꢀ118.0,ꢀ116.2,ꢀ113.5,ꢀ55.3;ꢀESI- 121.3,ꢀ120.8,ꢀ119.9,ꢀ118.9,ꢀ118.0;ꢀESI-MS:ꢀm/z=345 [M+Na]+.
MS:ꢀm/z=283 [M+Na]+.
(E)-2-Hydroxy-5-(3-(thiophen-2-yl)acryloyl)benzaldehydeꢀ
(4c)
(E)-2-Hydroxy-5-(3-p-tolylacryloyl)benzaldehydeꢀ(4i)
Yieldꢀ 78%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 205°C;ꢀ 1H-NMRꢀ
(300ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.40ꢀ (s,ꢀ 1H),ꢀ 10.01ꢀ (s,ꢀ 1H),ꢀ 8.32ꢀ
Yieldꢀ 73%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 130°C;ꢀ 1H-NMRꢀ (d, J=1.5ꢀHz,ꢀ 1H),ꢀ 8.23ꢀ (dd,ꢀ J=2.2,ꢀ 9.0ꢀHz,ꢀ 1H),ꢀ 7.82ꢀ (d,ꢀ
(400ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.40ꢀ (s,ꢀ 1H),ꢀ 10.02ꢀ (s,ꢀ 1H),ꢀ 8.30ꢀ J=15.1ꢀHz,ꢀ 1H),ꢀ 7.54ꢀ (d,ꢀ J=8.3ꢀHz,ꢀ 2H),ꢀ 7.47ꢀ (d,ꢀ J=15.8ꢀHz,ꢀ
(d, J=2.6ꢀHz,ꢀ 1H),ꢀ 8.21ꢀ (dd,ꢀ J=2.6,ꢀ 8.9ꢀHz,ꢀ 1H),ꢀ 7.96ꢀ (d,ꢀ 1H), 7.22 (d, J=8.3ꢀHz,ꢀ 1H),ꢀ 7.08ꢀ (d,ꢀ J=9.0ꢀHz,ꢀ 1H),ꢀ 2.41ꢀ (s,ꢀ
J=15.1ꢀHz,ꢀ 1H),ꢀ 7.42ꢀ (d,ꢀ J=5.3ꢀHz,ꢀ 1H),ꢀ 7.37ꢀ (d,ꢀ J=3.5ꢀHz,ꢀ 3H); 13C-NMRꢀ(75ꢀMHz,ꢀCDCl3) δ:ꢀ196.4,ꢀ187.3,ꢀ164.9,ꢀ145.3,ꢀ
1H), 7.29 (d, J=15.1ꢀHz,ꢀ 1H),ꢀ 7.10ꢀ (d,ꢀ J=5.3ꢀHz,ꢀ 1H),ꢀ 7.07ꢀ (d,ꢀ 141.3, 136.8, 134.9, 131.8, 130.6, 129.7, 128.5, 120.0 119.7,
J=5.3ꢀHz,ꢀ 1H);ꢀ 13C-NMRꢀ (100ꢀMHz,ꢀ CDCl3) δ:ꢀ 196.4,ꢀ 186.6,ꢀ 118.0,ꢀ21.5;ꢀESI-MS:ꢀm/z=267 [M+Na]+.
165.0, 140.1, 137.5, 136.7, 134.9, 132.4, 130.3, 129.0,128.4,
120.0,ꢀ119.3,ꢀ118.9;ꢀESI-MS:ꢀm/z=259 [M+Na]+.
(E)-2-Hydroxy-5-(3-(4-isopropylphenyl)acryloyl)-
benzaldehydeꢀ(4d)
(E)-2-Hydroxy-5-(3-(3,4,5-trimethoxyphenyl)acryloyl)-
benzaldehydeꢀ(4j)
Yieldꢀ 71%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 146°C;ꢀ 1H-NMRꢀ
(500ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.38ꢀ (s,ꢀ 1H),ꢀ 10.02ꢀ (s,ꢀ 1H),ꢀ 8.30ꢀ
Yieldꢀ 68%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 226°C;ꢀ 1H-NMRꢀ (d, J=2.9ꢀHz,ꢀ 1H),ꢀ 8.21ꢀ (dd,ꢀ J=2.9,ꢀ 8.8ꢀHz,ꢀ 1H),ꢀ 7.71ꢀ (d,ꢀ
(500ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.38ꢀ (s,ꢀ 1H),ꢀ 10.01ꢀ (s,ꢀ 1H),ꢀ 8.30ꢀ J=15.8ꢀHz,ꢀ 1H),ꢀ 7.33ꢀ (d,ꢀ J=14.8ꢀHz,ꢀ 1H),ꢀ 7.08ꢀ (d,ꢀ J=9.8ꢀHz,ꢀ
(d, J=2.0ꢀHz,ꢀ 1H),ꢀ 8.22ꢀ (dd,ꢀ J=2.0,ꢀ 9.0ꢀHz,ꢀ 1H),ꢀ 7.80ꢀ (d,ꢀ 1H), 6.82 (s, 2H), 3.91 (s, 6H), 3.87 (s, 3H); 13C-NMRꢀ
J=16.0ꢀHz,ꢀ 1H),ꢀ 7.56ꢀ (d,ꢀ J=8.0ꢀHz,ꢀ 2H),ꢀ 7.44ꢀ (d,ꢀ J=16.0ꢀHz,ꢀ (75ꢀMHz,ꢀ CDCl3) δ:ꢀ 196.4,ꢀ 187.3,ꢀ 164.9,ꢀ 153.4,ꢀ 145.4,ꢀ 136.8,ꢀ
1H), 7.25 (d, J=8.0, 2H), 7.07 (d, J=8.0ꢀHz,ꢀ 1H),ꢀ 2.99–2.90ꢀ 135.0,ꢀ 130.4,ꢀ 130.0,ꢀ 129.6,ꢀ 120.0,ꢀ 118.0ꢀ 105.7,ꢀ 60.9,ꢀ 56.1;ꢀ ESI-
(m, 1H), 1.28 (d, J=7.0, 6H); 13C-NMRꢀ (75ꢀMHz,ꢀ CDCl3) δ:ꢀ MS:ꢀm/z=343 [M+Na]+.
196.4, 187.3, 164.8, 152.1, 145.2, 136.7, 134.9, 132.1, 130.5,
128.5,ꢀ 127.0,ꢀ 119.9,ꢀ 119.7,ꢀ 117.9,ꢀ 34.0,ꢀ 23.6;ꢀ ESI-MS:ꢀ m/z=259 of Aldehyde Chalcones (6a–h) To a stirred solution of
[M+Na]+.
4-hydroxy-5-methylisophthalaldehydeꢀ (0.61mmol) and
(E)-2-Hydroxy-5-(3-(4-methoxyphenyl)acryloyl)- acetophenone 5ꢀ (0.61ꢀmmol)ꢀ inꢀ dryꢀ 1,4ꢀ dioxaneꢀ (5ꢀmL)ꢀ wasꢀ
General Experimental Procedure for the Synthesis
2
benzaldehydeꢀ(4e)
addedꢀ graduallyꢀ BF3–Et2O (1.22mmol) at room temperature.
Yieldꢀ 85%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 158°C;ꢀ 1H-NMRꢀ The reaction mixture was stirred at room temperature (r.t.)
(300ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.38ꢀ (s,ꢀ 1H),ꢀ 10.01ꢀ (s,ꢀ 1H),ꢀ 8.30ꢀ for 24h. After completion, the reaction mixture was diluted
(d, J=2.2ꢀHz,ꢀ 1H),ꢀ 8.22ꢀ (dd,ꢀ J=2.2,ꢀ 9.0ꢀHz,ꢀ 1H),ꢀ 7.79ꢀ (d,ꢀ withꢀethylꢀacetateꢀ(100ꢀmL)ꢀandꢀwashedꢀwithꢀwaterꢀ(3×25ꢀmL)ꢀ

Vol. 64, No. 6 (2016)
Chem. Pharm. Bull.
575
to decompose the BF3–Et2O complex. After extraction, the J=8.8ꢀHz,ꢀ 2H),ꢀ 7.76ꢀ (d,ꢀ J=15.5ꢀHz,ꢀ 1H),ꢀ 7.72ꢀ (s,ꢀ 1H),ꢀ 7.66ꢀ (d,ꢀ
organicꢀphaseꢀwasꢀdriedꢀoverꢀanhydrousꢀNa2SO4,ꢀfilteredꢀandꢀ J=2.1, 1H), 7.47 (d, J=15.5ꢀHz,ꢀ 1H),ꢀ 6.99ꢀ (d,ꢀ J=8.8ꢀHz,ꢀ 2H),ꢀ
the solvent was evaporated under reduced pressure. The crude 3.90 (s, 3H), 2.33, (s, 3H); 13C-NMRꢀ (75ꢀMHz,ꢀ CDCl3) δ:ꢀ
productꢀ wasꢀ purifiedꢀ byꢀ silicaꢀ gelꢀ columnꢀ chromatographyꢀ 196.4, 188.1, 163.4, 161.6, 142.2, 136.3, 132.3, 130.9, 130.6,
usingꢀhexane–ethylꢀacetateꢀasꢀaꢀmobileꢀphaseꢀtoꢀaffordꢀdesiredꢀ 127.8,ꢀ126.6,ꢀ120.2,ꢀ119.8,ꢀ113.7,ꢀ55.4,ꢀ15.0;ꢀESI-MS:ꢀm/z=297
chalcones 6a–hꢀinꢀgoodꢀtoꢀmoderateꢀyields,ꢀwhichꢀwereꢀlightꢀ [M+Na]+.
yellow solids.
(E)-5-(3-(4-Fluorophenyl)-3-oxoprop-1-enyl)-2-hydroxy-3-
(E)-2-Hydroxy-3-methyl-5-(3-oxo-3-phenylprop-1-enyl)- methylbenzaldehydeꢀ(6g)
benzaldehydeꢀ(6a)
Yieldꢀ 69%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 205°C;ꢀ 1H-NMRꢀ
Yieldꢀ 82%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 134°C;ꢀ IRꢀ (neat)ꢀ νmax (500ꢀMHz,ꢀCDCl3) δ:ꢀ11.54ꢀ(s,ꢀ1H),ꢀ9.94ꢀ(s,ꢀ1H),ꢀ8.10–8.05ꢀ(m,ꢀ
1
2925, 2874, 1658, 1589, 1208, 1160, 984, 815cm−1; H-NMRꢀ 2H), 7.78 (d, J=15.5ꢀHz,ꢀ 1H),ꢀ 7.73ꢀ (s,ꢀ 1H),ꢀ 7.67ꢀ (d,ꢀ J=1.9ꢀHz,ꢀ
(300ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.53ꢀ (s,ꢀ 1H),ꢀ 9.93ꢀ (s,ꢀ 1H),ꢀ 8.04ꢀ (d,ꢀ 1H), 7.43 (d, J=15.5ꢀHz,ꢀ1H),ꢀ7.19ꢀ(t,ꢀJ=8.5,ꢀ8ꢀHz,ꢀ2H),ꢀ2.30ꢀ(s,ꢀ
J=1.5ꢀHz,ꢀ1H),ꢀ8.01ꢀ(d,ꢀJ=1.5ꢀHz,ꢀ1H),ꢀ7.76ꢀ(d,ꢀJ=15.1ꢀHz,ꢀ1H),ꢀ 3H); 13C-NMRꢀ(100ꢀMHz,ꢀCDCl3) δ:ꢀ196.4,ꢀ188.3,ꢀ164.3,ꢀ161.9,ꢀ
7.72 (s, 1H), 7.66 (d, J=2.2ꢀHz,ꢀ1H),ꢀ7.53ꢀ(s,ꢀ1H),ꢀ7.51ꢀ(s,1H),ꢀ 143.3, 136.3, 132.4, 131.0, 130.9, 128.1, 126.4, 120.0, 115.8,
7.46 (d, J=15.8ꢀHz,ꢀ 2H),ꢀ 2.32ꢀ (s,ꢀ 3H);ꢀ 13C-NMRꢀ (75ꢀMHz,ꢀ 115.6,ꢀ15.1;ꢀESI-MS:ꢀm/z=285 [M+Na]+.
CDCl3) δ:ꢀ 196.4,ꢀ 190.0,ꢀ 161.8,ꢀ 143.1,ꢀ 138.1,ꢀ 136.4,ꢀ 132.7,ꢀ
(E)-2-Hydroxy-3-methyl-5-(3-oxo-3-(thiophen-2-yl)prop-1-
132.3,ꢀ 128.6,ꢀ 128.4,ꢀ 128.0,ꢀ 126.5,ꢀ 120.6,ꢀ 119.9,ꢀ 15.1;ꢀ ESI-MS:ꢀ enyl)benzaldehydeꢀ(6h)
m/z=267 [M+Na]+.
Yieldꢀ 71%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 174°C;ꢀ 1H-NMRꢀ
(E)-2-Hydroxy-5-(3-(3-methoxyphenyl)-3-oxoprop-1- (400ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.54ꢀ (s,ꢀ 1H),ꢀ 9.95ꢀ (s,ꢀ 1H),ꢀ 7.89ꢀ (dd,ꢀ
enyl)-3-methylbenzaldehydeꢀ(6b)
J=1.1,ꢀ 3.7ꢀHz,ꢀ 1H),ꢀ 7.81ꢀ (d,ꢀ J=15.5ꢀHz,ꢀ 1H),ꢀ 7.73ꢀ (brꢀs,ꢀ 1H),ꢀ
Yieldꢀ 81%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 163°C;ꢀ 1H-NMRꢀ 7.70 (dd, J=1.1,ꢀ 4.8ꢀHz,ꢀ 1H),ꢀ 7.67ꢀ (d,ꢀ J=2.0ꢀHz,ꢀ 1H),ꢀ 7.34ꢀ (d,ꢀ
(300ꢀMHz,ꢀ CDCl3) δ:ꢀ 11.54ꢀ (s,ꢀ 1H),ꢀ δ 9.94 (s, 1H), 7.77 (d, J=15.52ꢀHz,ꢀ 1H),ꢀ 7.20ꢀ (dd,ꢀ J=3.7,ꢀ 4.8ꢀHz,ꢀ 1H),ꢀ 2.34ꢀ (s,ꢀ 3H);ꢀ
J=15.8, 1H), 7.73 (s, 1H), 7.67 (d, J=1.5ꢀHz,ꢀ 1H)ꢀ 7.62ꢀ (d,ꢀ 13C-NMRꢀ (100ꢀMHz,ꢀ CDCl3) δ:ꢀ 196.4,ꢀ 181.6,ꢀ 161.8,ꢀ 145.4,ꢀ
J=7.5ꢀHz,ꢀ 1H),ꢀ 7.56ꢀ (t,ꢀ J=1.5, 1H), 7.48–7.39 (m, 2H), 7.14 142.3, 136.4, 133.8, 132.4, 131.6, 128.2, 128.0, 126.3, 120.1,
(dd, J=3.0,ꢀ 8.3ꢀHz,ꢀ 1H),ꢀ 3.90ꢀ (s,ꢀ 3H),ꢀ 2.33ꢀ (s,ꢀ 3H);ꢀ 13C-NMRꢀ 119.9,ꢀ15.1;ꢀESI-MS:ꢀm/z=273 [M+H]+.
(125ꢀMHz,ꢀ CDCl3) δ:ꢀ 196.4,ꢀ 189.7,ꢀ 161.8,ꢀ 159.8,ꢀ 143.1,ꢀ 139.5,ꢀ
136.6, 132.4, 129.5, 128.0, 126.5, 120.9, 120.6, 119.9, 119.1,
Acknowledgments Theꢀ authorꢀ J.ꢀ S.ꢀ R.ꢀ thanksꢀ toꢀ UGC,ꢀ
Newꢀ Delhi,ꢀ Indiaꢀ forꢀ providingꢀ UGC-JRFꢀ andꢀ SRFꢀ fellow-
112.9,ꢀ55.4,ꢀ15.1;ꢀESI-MS:ꢀm/z=297 [M+Na]+.
(E)-5-(3-(3,4-Dimethoxyphenyl)-3-oxoprop-1-enyl)-2- shipsꢀ andꢀ alsoꢀ gratefullyꢀ thankꢀ toꢀ Dr.ꢀ J.ꢀ S.ꢀ Yadav,ꢀ Naturalꢀ
hydroxy-3-methylbenzaldehydeꢀ(6c)
ProductsꢀChemistryꢀdivisionꢀforꢀhisꢀconstantꢀsupport.
Yieldꢀ 71%,ꢀ lightꢀ yellowꢀ solid,ꢀ mpꢀ 201°C;ꢀ 1H-NMRꢀ
(300ꢀMHz,ꢀ CDCl3,) δ:ꢀ 11.52ꢀ (s,ꢀ 1H),ꢀ 9.94ꢀ (s,ꢀ 1H),ꢀ 7.77ꢀ (d,ꢀ
Conflict of Interest Theꢀ authorsꢀ declareꢀ noꢀ conflictꢀ ofꢀ
J=15.8ꢀHz,ꢀ 1H),ꢀ 7.74ꢀ (s,ꢀ 1H),ꢀ 7.70ꢀ (dd,ꢀ J=2.2,ꢀ 8.3ꢀHz,ꢀ 1H),ꢀ interest.
7.67 (d, J=2.2ꢀHz,ꢀ 1H),ꢀ 7.64ꢀ (d,ꢀ J=2.2ꢀHz,ꢀ 1H)ꢀ 7.49ꢀ (d,ꢀ
J=15.1ꢀHz,ꢀ 1H),ꢀ 6.94ꢀ (d,ꢀ J=9.0ꢀHz,ꢀ 1H)ꢀ 3.98ꢀ (s,ꢀ 6H),ꢀ 2.34ꢀ (s,ꢀ
3H); 13C-NMRꢀ(100ꢀMHz,ꢀCDCl3) δ:ꢀ196.4,ꢀ188.1,ꢀ161.6,ꢀ153.3,ꢀ
149.2, 142.2, 136.3, 132.2, 131.2, 127.9, 126.7, 122.9, 120.2,
119.9,ꢀ110.7,ꢀ109.9,ꢀ29.6,ꢀ15.1;ꢀESI-MS:ꢀm/z=327 [M+Na]+.
(E)-5-(3-(3-Bromophenyl)-3-oxoprop-1-enyl)-2-hydroxy-3-
methylbenzaldehydeꢀ(6d)
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(300ꢀMHz,ꢀCDCl3) δ:ꢀ11.56ꢀ(s,ꢀ1H),ꢀ9.95ꢀ(s,ꢀ1H),ꢀ8.15ꢀ(s,ꢀ1H),ꢀ
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(d, J=6.0ꢀHz,ꢀ 1H),ꢀ 7.41ꢀ (s,ꢀ 1H),ꢀ 7.38–7.35ꢀ (m,ꢀ 2H),ꢀ 7.00ꢀ (d,ꢀ
J=15.8ꢀHz,ꢀ 1H),ꢀ 2.31ꢀ (s,ꢀ 3H);ꢀ 13C-NMRꢀ (75ꢀMHz,ꢀ CDCl3) δ:ꢀ
196.3, 192.1, 162.2, 144.7, 144.1, 136.5, 132.6, 131.7, 130.7,
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