selective horner–wittig/nazarov vs. knoevenagel/nazarov...

113

D. Szczęsna et al. LetterSyn lett

SYNLETT0 9 3 6 - 5 2 1 4 1 4 3 7 - 2 0 9 6© Georg Thieme Verlag Stuttgart · New York2017, 28, 113–116letter

hted

mat

eria

l.

Selective Horner–Wittig/Nazarov vs. Knoevenagel/Nazarov Reac-tions in the Synthesis of Biologically Active 3-Aryl-Substituted 1-IndanonesDorota Szczęsnaa Marek Koprowskia Ewa Różycka-Sokołowskab Bernard Marciniakb Piotr Bałczewski*a,b

a Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, [email protected]

b Jan Długosz University in Częstochowa, Institute of Chemistry, Envi-ronmental Protection and Biotechnology, The Faculty of Mathemat-ics and Natural Sciences, Armii Krajowej 13/15, 42-201 Częstochowa, Poland

Ar1

Ar2

O

H

Knoevenagel reaction

Horner–Wittigreaction

O

P(OMe)2

O

Ar1

Ar2

O

Ar2

Ar1

Nazarovreaction

Ar1

O

P(OMe)2

O

Ar2

Ar1

O

Ar2

O

P(OMe)2

O

Dow

nloa

ded

by: S

hang

hai J

iaot

ong

Uni

vers

ity. C

opyr

ig

Received: 02.07.2016Accepted after revision: 29.08.2016Published online: 20.09.2016DOI: 10.1055/s-0036-1588599; Art ID: st-2016-b0428-l

Abstract 3-Aryl-1-indanones and a previously unknown group of 3-aryl-2-phosphoryl-1-indanones have been synthesized from β-keto-phosphonates and aromatic aldehydes via corresponding chalcones, ina selective Horner–Wittig or Knoevenagel olefination, followed by aNazarov cyclization. In preliminary tests, the final compounds and theintermediate chalcones revealed anticancer activity against HeLa andK562 at the μM level.

Key words Knoevenagel reaction, Horner–Wittig reaction, Nazarovreaction, β-ketophosphonates, 1-indanones

1-Indanones can be classified as cycloneolignanones, asubgroup of lignans that constitute a large family of chemi-cal compounds occurring in plants.1 1-Indanone derivativeshave found application in the synthesis of natural products,in medicine, and in agrochemistry.2–4

Our present research program envisaged developmentof the synthesis of 3-aryl-substituted 1-indanones 5 and 6of which those with a 2-phosphoryl group are an unknowngroup of indanones. Frontier, Eisenberg, et al. described thesynthesis of 3-vinyl-2-phosphoryl 1-indanones5 while Xuand Yu published the synthesis of 3-aryl-1-indanones.6 Thesecond aim of the program was to test the biological activi-ty of the new compounds (anticancer, anxiolytic, antide-pressant). The most effective way of synthesizing 1-in-danones is the Nazarov reaction of α,β-unsaturated ketones(chalcones).7,8 Using our approach, we synthesized the car-bonyl components of this reaction in the Knoevenagel orthe Horner–Wittig olefination reactions. We succeeded inelaborating suitable reaction conditions allowing the syn-thesis of chalcones 3 or 4 from the same substrates, that is,

β-aryl (Ar1) β-ketophosphonates 1 and aromatic (Ar2) alde-hydes 2 (Scheme 1). It is worth noting that the choice of abase (NaH or amine) was crucial for selective syntheses of 3or 4. β-Ketophosphonates 1 were obtained by condensationof aromatic (Ar1) aldehydes with lithium derivative of di-methyl methylphosphonate followed by oxidation of the re-sulting β-hydroxyalkylphosphonate by PCC.9

α-Phosphoryl-substituted chalcones of type 3 were syn-thesized by the Knoevenagel olefination using catalyticamounts of piperidine in refluxing toluene10 while chal-cones of type 4 were obtained in the Horner–Wittig olefina-tion with sodium hydride in freshly distilled tetrahydrofu-

Figure 1 2-Phosphoryl-substituted chalcones 3 obtained under the Knoevenagel reaction conditions

O

O

O

Ar2

P(O)(OMe)2

O

Ar2

P(O)(OMe)2S

3a(a) (Z) 33%

N

(b)

NO2

(c)

Br

(d)

COOMe

N

Br

3a 3b

3a(b) (Z) 55%

(a)

3a(c) (Z) 53%

3a(d) (Z) 53%

3b(d) (Z) 15%

3a(e) (Z) 83%

(e)

3a(f) (Z) 53%

3a(g) (Z) 28%

(f) (g)

© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, 113–116

114


Dow

nloa

ded

by: S

hang

hai J

iaot

ong

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.

ran at 0 °C.11 Only one synthesis of 3, based on manga-nese(III)-mediated phosphonation of arylalkenes, had beenpreviously described.12 A series of seven 3-aryl-2-phos-phoryl chalcones 3 with Ar2 = phenyl, 4-pyridyl, 4-nitro-phenyl, 4-bromophenyl, 4-methoxycarbonylphenyl, 6-bro-mo-3-pyridyl, and pyrenyl, isolated as single isomers, isshown in Figure 1. Configurations Z of the products wereassigned based on vicinal coupling constants betweenphosphorus atom and the PC=CH vinyl hydrogen atom (3:3JHP = 24.70–26.18Hz).13

The second series of six chalcones 4 without an α-phos-phoryl group was synthesized using the Horner–Wittig re-action in good yields (Figure 2). Configuration of substitu-ents around double bond in 4 was confirmed as E based on1D and 2D (ROESY) 1H NMR experiments (see SupportingInformation). The typical, large coupling constants due tovinyl protons (>15 Hz) strongly supported formation of Eisomers.11

Figure 2 Chalcones 4 obtained under the Horner–Wittig reaction con-ditions

Finally, representatives of the two groups of chalcones 3and 4 were cyclized in the Nazarov reaction using variousLewis acids, including TfOH, TFA, Nafion®, AcOH, HBr, TiCl4,Sc(OTf)3, AlCl3, FeCl3, and InCl3. The best yields of 3-aryl-2-phosphoryl-1-indanones 5, the so far unknown group ofcompounds, and 3-aryl-1-indanones 6 were obtained withFeCl3

14 in refluxing dichloromethane and AlCl315 in toluene,

at room temperature (Table 1, Figure 3).

Figure 3 New 1-indanones 5 and 6 obtained in the Lewis acid cata-lyzed Nazarov reaction of chalcones 3 and 4

Crystallographic discussion on 5c and its matrix latticeas well as results of the Hirshfeld surface analysis are dis-cussed in the Supporting Information (see also Figure 4, A–C).

Scheme 1 The general plan for the synthesis of 1-indanones 5 and 6 from β-ketophosphonates 1 via reaction-conditions-driven olefination–Nazarov reaction sequences

Ar1

Ar2

O

H

Knoevenagel reaction

Horner–Wittigreaction

O

P(OMe)2

O

Ar1

Ar2

O

Ar2

Ar1

1 2

(Z)-3

(E)-4

Nazarov reaction

Ar1

O

P(OMe)2

O

Ar2

5

Ar1

O

Ar2

6

piperidine, toluenereflux

NaH, 0 °C, THF

FeCl3 or AlCl3

O

OAr1:

S MeO OMe

O

P(OMe)2

O

S

O

Ar2

O

O

O

Ar2

MeO

OMe

O

Ar2

4a (E) 4b (E) 4c (E)

Ar2 =

Br NO2 COOMe

4b(d): 60%4b(c): 58%4a(b): 20%4a(a): 70%4b(a): 69%4c(a): 33%

(a) (b) (c)

(d)

O

O

O

P(O)(OMe)2

Br

O

O

O

P(O)(OMe)2

O

O

O

P(O)(OMe)2

COOMeO

Br

SO

Br

OMe

MeO

5a 5b

5c

6a

6b


115


Dow

nloa

ded

by: S

hang

hai J

iaot

ong

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.

Table 1 1-Indanones 5a–c and 6a,b Obtained in the Lewis Acid Cata-lyzed Nazarov Reaction

Preliminary biological tests showed a good anticanceractivity of chalcones and 1-indanones against HeLa/K562cell lines at the μM level [IC50 after 48 h – 4a(a): 80/7 μM;6b: 60/10 μM] (Supporting Information). None of the testedcompounds was cytotoxic to normal cells (HUVEC) after 48h (>1 mM).

In summary, a combination of Knoevenagel or Horner–Wittig olefinations with the Nazarov reaction allowed se-lective syntheses of unknown 2-phosphoryl-1-indanones 5and 1-indanones 6. These indanones were synthesized viathe Nazarov cyclization of intermediate 2-phosphoryl chal-cones 3 and chalcones 4, respectively. Both groups of prod-ucts were obtained from the same substrates β-ketophos-phonates 1 and aromatic aldehydes 2 and showed antican-cer activity. Further biological tests and chemicalmodifications of the lead structures are under way.

Acknowledgment

Scientific work financed from the science resources in 2010-2013 (NN204131640).

Supporting Information

Supporting information for this article is available online athttp://dx.doi.org/10.1055/s-0036-1588599. Supporting InformationSupporting Information

References and Notes

(1) Moss, G. P. Pure Appl. Chem. 2000, 72, 1493.(2) Nagle, D. G.; Zhou, Y.; Park, P. U. J. Nat. Prod. 2000, 63, 1431.(3) Cossy, J.; Belotti, D.; Magur, A. Synlett 2003, 1515.(4) Yu, H.; Kim, I. J.; Folk, J. E. J. Med. Chem. 2004, 47, 2624.(5) Vaidya, T.; Atesin, A. C.; Herrick, I. R.; Frontier, A. J.; Eisenberg, R.

Angew. Chem. Int. Ed. 2010, 49, 3363.(6) Yu, Y.-N.; Xu, M.-H. J. Org. Chem. 2013, 78, 2736.(7) Pellissier, H. Tetrahedron 2005, 61, 6479.(8) Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3,

1531.(9) Koprowski, M.; Szymańska, D.; Bodzioch, A.; Marciniak, B.;

Różycka-Sokołowska, E.; Bałczewski, P. Tetrahedron 2009, 65,4017.

(10) General Procedure for the Synthesis of 3To a stirred solution of β-ketophosphonate 1 (1.757 mmol) andthe corresponding aldehyde 2 (1.933 mmol) in dry toluene,piperidine (2.531 mmol) was added, and the resulting solutionwas refluxed for 30 h using a Dean–Stark apparatus. The reac-tion mixture was concentrated under reduced pressure. Thecrude product was purified by column chromatography(hexane–EtOAc = 2:1, v/v) to afford desired compounds 3a (f):yellow crystals, mp 116–117 °C. Rf = 0.30 (hexane–EtOAc = 2:1v/v), 0.64 (hexane–EtOAc = 1:2, v/v); yield 53%. 1H NMR (200

Substrate Conditions Product Yield (%)

3a(d) AlCl3 (2 equiv), toluene, 20 °C 5a 30

3a(e) FeCl3 (2 equiv), CH2Cl2, 40 °C 5b 80

3a(f) FeCl3 (1.5 equiv), CH2Cl2, 40 °C 5c 62

4a(a) AlCl3 (2 equiv), toluene, 20 °C 6a 50

4c(a) FeCl3 (2 equiv), CH2Cl2, 40 °C 6b 90

Figure 4 (A) A view of the molecule 5c with the atom-numbering scheme and displacement ellipsoids drawn at the 30% probability level. (B) Part of the crystal structure of 5c, showing three C-H···O hydrogen bonds (red-, green-, and blue-dashed lines) linking the molecules into a two-dimensional framework build up from the R22(10), R22(14) and R65(33) rings; all H atoms not involved in these interactions are omitted for clarity. (C) Hirshfeld surface of molecule 5c mapped with dnorm dis-tance, showing the most dominant interactions in crystal. Symmetry codes (i) 1/2+x, 3/2–y, –1/2+z; (ii) –x, –y, –z; (iii) –x, 1–y, –z.


116


Dow

nloa

ded

by: S

hang

hai J

iaot

ong

Uni

vers

ity. C

opyr

ight

ed m

ater

ial.

MHz, CDCl3): δ = 3.73 (s, 3 H, C(O)OCH3), 3.77 (d, J3PH =10.1 Hz, 6

H, P(O)(OCH3)2), 5.93 (s, 2 H, OCH2O), 6.64 (d, J3HH =8.1 Hz, 1 H,

ArH), 7.27–7.34 (m, 3 H, ArH), 7.40 (d, J3PH =9.6 Hz, 1 H,

HC=CP(O)), 7.77–7.80 (m, 3 H, ArH), 7.82 (s, 1 H, ArH). 31P NMR(81 MHz, CDCl3): δ = 16.28. 13C NMR (50 MHz, CDCl3): δ = 51.99(s, C(O)CH3)), 52.04 (d, J2

PC = 6.0, P(O)OCH3)2), 100.80 (s,OCH2O), 106.82 (s, ArH), 107.05 (s, ArH), 125.88 (s, ArH), 128.25(s, 2 × o-PhH), 128.47 (d, J1

PC = 145.7 Hz, =C-P(O)), 128.55 (s, 2 ×m-PhH), 136.60 (s), 136.13 (s), 136.56 (s), 143.77 (s, COCH2O),143.89 (s, COCH2O), 151.6 (s, HC=CP), 164.9 (s, C(O)OCH3), 186.4(s, C=O). MS (CI, isobutane): m/z = 419.1 (42) [M+ + 1], 361 (100)[M+ + 1 – C(O)OCH3], 344.1 (40) [M+ + 1 – C(O)OCH3; –OH].HRMS-EI (70 eV): m/z calcd for C20H19PO8: 418.08110; found:418.08089; Δ: 0.55 (<5).

(11) Irgolic, K. J. In Houben-Weyl; Klamann, D., Ed.; Thieme: Stutt-gart, 1990, 4th ed., Vol. E12b 150.

(12) Pan, X.-Q.; Zou, J.-P.; Zhang, G.-L.; Zhang, W. Chem. Commun.2010, 46, 1721.

(13) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.(b) Kelly, S. E. Comprehensive Organic Synthesis; Vol. 1; Trost, B.M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 729.(c) Magoulas, G. E.; Bariamis, S. E.; Athanassopoulos, C. M.;Haskopoulos, A.; Dedes, P. G.; Krokidis, M. G.; Karamanos, N. K.;Kletsas, D.; Papaioannou, D.; Maroulis, G. Eur. J. Med. Chem.2011, 46, 721.

(14) Nazarov Cyclization for the Synthesis of 5b with FeCl3To chalcone 3a(e) (0.100 g, 0.278 mmol) in dry CH2Cl2 (100 mL),FeCl3 (0.090 g, 0.555 mmol) was added, and the solution wasrefluxed by 5 h. The reaction mixture was washed with water (3× 30 mL), dried (MgSO4), filtered, and the solvent was removedin vacuo. The crude product was purified by column chroma-tography (acetone–PE = 1:1, v/v) to afford 5b (0.080 g, 80%).Compound 5b: beige solid; mp 131–133 °C; Rf = 0.35 (acetone–PE = 1:1, v/v). 1H NMR (200 MHz, CDCl3): δ = 3.22 (dd, J3

HH = 3.4

Hz, J2PH = 26.1 Hz, 1 H, HCP(O)), 3.75 (d, J3

PH = 10.6 Hz, 3 H,P(O)OCH3), 3.80 (d, J3

PH = 10.3 Hz, 3 H, P(O)OCH3), 4.78 (dd,J3

HH = 3.4 Hz, J3PH = 12.40 Hz, 1 H, HCHCP(O)), 6.06 (s, 2 H,

OCH2O), 6.59 (s, 1 H, ArH) 7.04–7.33 (m, 6 H, ArH). 31P NMR (81MHz, CDCl3): δ = 24.45. 13C NMR (50 MHz, CDCl3): δ = 46.71 (s,CHPh), 53.91 (d, 1JPC = 146.5 Hz, CHP(O)), 53.43 (d, 2JPC = 4.9 Hz,P(O)(OCH3)2), 102.43 (s, OCH2O), 105.4 (s, ArH), 105.8 (s, ArH),127.5 (s), 127.65 (s), 130.9 (s), 142.2 (s), 149.1 (s), 154.2 (s,OCH2OC), 155.0 (s, OCH2OC), 196.5 (s, C=O). MS (CI, 70 eV): m/z= 361.0 (100) [M+ + 1]. HRMS (EI, 70 eV): m/z calcd for C18H17-PO6: 360.07679; found: 360.07689; Δ 1.42 (<5). IR (KBr): 3400,3064, 3027, 2956, 2915, 1696, 1604, 1474, 1452, 1305, 1255,1041, 867, 833 cm–1.

(15) The Nazarov Cyclization for the Synthesis of 6a with AlCl3To chalcone 4a(a) (0.110 g, 0.377 mmol) in dry toluene (100mL), AlCl3 (0.101 g, 0.754 mmol) was added, and the solutionwas stirred for 18 h. The reaction mixture was washed withwater (3 × 30 mL), dried (MgSO4), and evaporated The crudeproduct was purified by column chromatography (hexane–EtOAc = 1:3, v/v) to afford 6a (0.099 g, 50%).Compound 6a: beige solid; mp 103–105 °C; Rf = 0.09 (hexane–acetone = 1:9, v/v); yield 90%. 1H NMR (200 MHz, CDCl3): δ =3.63 (dd, J3

HH = 5.6 Hz, J2HH = 9.1 Hz, 1 H, CH2C(O)), 4.63 (dd,

J2HH = 9.1 Hz, J3

HH = 5.1 Hz, 1 H, CH2C(O)), 4.73 (dd, J3HH = 5.6 Hz,

J3HH = 5.0 Hz, 1 H, CHCH2C(O)), 6.99–7.14 (m, 4 H, ArH), 7.55 (d,

J3HH = 5.1 Hz, 1 H, CH=CH-C(S)), 7.72 (d, J3

HH = 5.1 Hz, 1 H,CH=CHS). 13C NMR (50 MHz, CDCl3): δ = 37.72 (s, CH2), 48.12 (s,CH2), 123.35 (s, =CBr), 125.91 (s, 2 × o-Ar), 126.32 (s, ArH),126.74 (s, 2 × m-ArH), 127.13 (s, ArH), 127.95 (s), 130.46 (s),132.31 (s), 195.84 (s, C=O). MS (CI, isobutane): m/z = 294 (100)[M+ + H (80Br)], 292 (100) [M+ + H (79Br)], 214 (52) [M+ – Br].HRMS (EI, 70 eV): m/z calcd for C13H9SBrO: 291.95614; found:291.95647; Δ 1.3 (<5).


selective horner–wittig/nazarov vs. knoevenagel/nazarov...

Documents