Selective Horner-Wittig/Nazarov vsKnoevenagel/Nazarov Reactions in the Synthesis of Biologically Active 3-Aryl-Substituted 1-Indanones

Article abstract of DOI:10.1055/s-0036-1588599

3-Aryl-1-indanones and a previously unknown group of 3-aryl-2-phosphoryl-1-indanones have been synthesized from β-ketophosphonates and aromatic aldehydes via corresponding chalcones, in a selective Horner-Wittig or Knoevenagel olefination, followed by a Nazarov cyclization. In preliminary tests, the final compounds and the intermediate chalcones revealed anticancer activity against HeLa and K562 at the μM level.

Full text of DOI:10.1055/s-0036-1588599

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
D. Szczęsna et al.
Letter
Synlett
Selective Horner–Wittig/Nazarov vs. Knoevenagel/Nazarov Reac-
tions in the Synthesis of Biologically Active 3-Aryl-Substituted
1-Indanones
Dorota Szczęsnaa
Marek Koprowskia
O
O
O
O
Knoevenagel
reaction
P(OMe)2
P(OMe)2
Ewa Różycka-Sokołowskab
Bernard Marciniakb
Piotr Bałczewski*a,b
Ar1
Ar1
O
O
Ar2
Ar2
P(OMe)2
Ar1
O
Nazarov
reaction
O
O
a Department of Heteroorganic Chemistry, Centre of Molecular and
Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza
112, 90-363 Łódź, Poland
Ar2
H
Ar1
Ar1
Ar2
Horner–Wittig
reaction
Ar2
pbalczew@cbmm.lodz.pl
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
Received: 02.07.2016
Accepted after revision: 29.08.2016
Published online: 20.09.2016
β-aryl (Ar1) β-ketophosphonates 1 and aromatic (Ar2) alde-
hydes 2 (Scheme 1). It is worth noting that the choice of a
base (NaH or amine) was crucial for selective syntheses of 3
or 4. β-Ketophosphonates 1 were obtained by condensation
of 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 catalytic
amounts 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-
DOI: 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, in
a selective Horner–Wittig or Knoevenagel olefination, followed by a
Nazarov cyclization. In preliminary tests, the final compounds and the
intermediate chalcones revealed anticancer activity against HeLa and
K562 at the μM level.
Key words Knoevenagel reaction, Horner–Wittig reaction, Nazarov
reaction, β-ketophosphonates, 1-indanones
O
O
1-Indanones can be classified as cycloneolignanones, a
subgroup of lignans that constitute a large family of chemi-
cal compounds occurring in plants.1 1-Indanone derivatives
have found application in the synthesis of natural products,
in medicine, and in agrochemistry.2–4
P(O)(OMe)2
P(O)(OMe)2
O
O
S
Ar2
Ar2
3a
3b
(a)
(b)
(c)
Our present research program envisaged development
of the synthesis of 3-aryl-substituted 1-indanones 5 and 6
of which those with a 2-phosphoryl group are an unknown
group of indanones. Frontier, Eisenberg, et al. described the
synthesis of 3-vinyl-2-phosphoryl 1-indanones5 while Xu
and Yu published the synthesis of 3-aryl-1-indanones.6 The
second 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 or
the Horner–Wittig olefination reactions. We succeeded in
elaborating suitable reaction conditions allowing the syn-
thesis of chalcones 3 or 4 from the same substrates, that is,
N
NO2
3a(a) (Z)
33%
3a(b) (Z)
55%
3a(c) (Z)
53%
(d)
(e)
(f)
(g)
N
Br
COOMe
3a(f) (Z)
Br
3a(d) (Z)
53%
3a(e) (Z)
3a(g) (Z)
28%
83%
53%
3b(d) (Z)
15%
Figure 1 2-Phosphoryl-substituted chalcones 3 obtained under the
Knoevenagel reaction conditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
D. Szczęsna et al.
Letter
Synlett
O
O
O
O
Knoevenagel
reaction
P(OMe)2
P(OMe)2
Ar1
Ar1
piperidine, toluene
reflux
O
Ar2
O
Ar2
O
5
Ar2
(Z)-3
P(OMe)2
Nazarov reaction
FeCl3 or AlCl3
H
Ar1
O
O
2
1
Horner–Wittig
reaction
Ar1
Ar1
Ar2
NaH, 0 °C, THF
Ar2
6
(E)-4
O
O
Ar1:
MeO
OMe
S
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
ran at 0 °C.11 Only one synthesis of 3, based on manga-
nese(III)-mediated phosphonation of arylalkenes, had been
previously 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, is
shown in Figure 1. Configurations Z of the products were
assigned based on vicinal coupling constants between
phosphorus atom and the PC=CH vinyl hydrogen atom (3:
3JHP = 24.70–26.18Hz).13
Finally, representatives of the two groups of chalcones 3
and 4 were cyclized in the Nazarov reaction using various
Lewis 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 of
compounds, and 3-aryl-1-indanones 6 were obtained with
FeCl314 in refluxing dichloromethane and AlCl315 in toluene,
at room temperature (Table 1, Figure 3).
O
O
P(O)(OMe)2
P(O)(OMe)2
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 on
O
O
O
O
5a
5b
Br
1
1D and 2D (ROESY) H NMR experiments (see Supporting
O
Information). The typical, large coupling constants due to
vinyl protons (>15 Hz) strongly supported formation of E
isomers.11
P(O)(OMe)2
O
O
5c
O
O
O
COOMe
MeO
MeO
O
O
O
S
S
Ar2
Ar2
O
Ar2
OMe
4c (E)
4a (E)
4b (E)
(d)
OMe
6a
(a)
(b)
(c)
6b
Br
Ar2
=
Br
Figure 3 New 1-indanones 5 and 6 obtained in the Lewis acid cata-
lyzed Nazarov reaction of chalcones 3 and 4
COOMe
NO2
Br
4a(a): 70%
4b(a): 69%
4c(a): 33%
4a(b): 20%
4b(c): 58%
4b(d): 60%
Crystallographic discussion on 5c and its matrix lattice
as well as results of the Hirshfeld surface analysis are dis-
cussed in the Supporting Information (see also Figure 4, A–C).
Figure 2 Chalcones 4 obtained under the Horner–Wittig reaction con-
ditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
D. Szczęsna et al.
Letter
Synlett
Table 1 1-Indanones 5a–c and 6a,b Obtained in the Lewis Acid Cata-
lyzed Nazarov Reaction
Substrate
Conditions
Product
Yield (%)
3a(d)
3a(e)
3a(f)
4a(a)
4c(a)
AlCl3 (2 equiv), toluene, 20 °C
FeCl3 (2 equiv), CH2Cl2, 40 °C
FeCl3 (1.5 equiv), CH2Cl2, 40 °C
AlCl3 (2 equiv), toluene, 20 °C
FeCl3 (2 equiv), CH2Cl2, 40 °C
5a
5b
5c
6a
6b
30
80
62
50
90
Preliminary biological tests showed a good anticancer
activity of chalcones and 1-indanones against HeLa/K562
cell lines at the μM level [IC50 after 48 h – 4a(a): 80/7 μM;
6b: 60/10 μM] (Supporting Information). None of the tested
compounds was cytotoxic to normal cells (HUVEC) after 48
h (>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 5
and 1-indanones 6. These indanones were synthesized via
the 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 chemical
modifications of the lead structures are under way.
Acknowledgment
Scientific work financed from the science resources in 2010-2013 (N
N204131640).
Supporting Information
Supporting information for this article is available online at
Figure 4 (A) A view of the molecule 5c with the atom-numbering
http://dx.doi.org/10.1055/s-0036-1588599.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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.
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.
(10) General Procedure for the Synthesis of 3
To a stirred solution of β-ketophosphonate 1 (1.757 mmol) and
the corresponding aldehyde 2 (1.933 mmol) in dry toluene,
piperidine (2.531 mmol) was added, and the resulting solution
was refluxed for 30 h using a Dean–Stark apparatus. The reac-
tion mixture was concentrated under reduced pressure. The
crude 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 = 2:1
v/v), 0.64 (hexane–EtOAc = 1:2, v/v); yield 53%. 1H NMR (200
(9) Koprowski, M.; Szymańska, D.; Bodzioch, A.; Marciniak, B.;
Różycka-Sokołowska, E.; Bałczewski, P. Tetrahedron 2009, 65,
4017.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
D. Szczęsna et al.
Letter
Synlett
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,
Hz, J2 = 26.1 Hz, 1 H, HCP(O)), 3.75 (d, J3 = 10.6 Hz, 3 H,
PH
PH
P(O)OCH3), 3.80 (d, J3 = 10.3 Hz, 3 H, P(O)OCH3), 4.78 (dd,
PH
ArH), 7.27–7.34 (m, 3 H, ArH), 7.40 (d, J3 =9.6 Hz, 1 H,
J3HH = 3.4 Hz, J3 = 12.40 Hz, 1 H, HCHCP(O)), 6.06 (s, 2 H,
PH
PH
HC=CP(O)), 7.77–7.80 (m, 3 H, ArH), 7.82 (s, 1 H, ArH). 31P NMR
OCH2O), 6.59 (s, 1 H, ArH) 7.04–7.33 (m, 6 H, ArH). 31P NMR (81
MHz, 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
(81 MHz, CDCl3): δ = 16.28. 13C NMR (50 MHz, CDCl3): δ = 51.99
(s, C(O)CH3)), 52.04 (d, J2 = 6.0, P(O)OCH3)2), 100.80 (s,
PC
OCH2O), 106.82 (s, ArH), 107.05 (s, ArH), 125.88 (s, ArH), 128.25
(s, 2 × o-PhH), 128.47 (d, J1PC = 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).
= 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 AlCl3
To chalcone 4a(a) (0.110 g, 0.377 mmol) in dry toluene (100
mL), AlCl3 (0.101 g, 0.754 mmol) was added, and the solution
was stirred for 18 h. The reaction mixture was washed with
water (3 × 30 mL), dried (MgSO4), and evaporated The crude
product was purified by column chromatography (hexane–
EtOAc = 1:3, v/v) to afford 6a (0.099 g, 50%).
(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 FeCl3
To 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 was
refluxed by 5 h. The reaction mixture was washed with water (3
× 30 mL), dried (MgSO4), filtered, and the solvent was removed
in 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, J3HH = 3.4
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 = 5.6 Hz, J2 = 9.1 Hz, 1 H, CH2C(O)), 4.63 (dd,
HH
HH
J2HH = 9.1 Hz, J3HH = 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,
J3 = 5.1 Hz, 1 H, CH=CH-C(S)), 7.72 (d, J3 = 5.1 Hz, 1 H,
HH
HH
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).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D