Aryl hetaryl ketones and thioketones as efficient inhibitors of peptidyl-prolyl cis-trans isomerases

Article abstract of DOI:10.1002/cbdv.201200275

A series of 18 differently substituted new aryl hetaryl ketones and thioketones were synthesized in four to six steps from commercial starting materials. The new ketones were evaluated as inhibitors of the peptidyl-prolyl cis-trans isomerase hPin1 with K_i values ranging in the one-digit micromolar to sub-micromolar numbers. A crystal structure revealed the non-planar arrangement of the aryl residues at the carbonyl compound and supports the hypothesis that the new compounds might mimic the transition state of the enzymatic conversion.

Full text of DOI:10.1002/cbdv.201200275

2618
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Aryl Hetaryl Ketones and Thioketones as Efficient Inhibitors of Peptidyl-
Prolyl cis-trans Isomerases
by Thomas Hedigera), Walter Frankb), Michael Schumannc), Gunter Fischer*c), and Manfred Braun*a)
a) Institut fꢀr Organische und Makromolekulare Chemie, Universitꢁt Dꢀsseldorf, Universitꢁtsstrasse 1,
DE-40225 Dꢀsseldorf
(phone: þ492118114731; fax þ492118115079; e-mail: braunm@uni-duesseldorf.de)
b) Institut fꢀr Anorganische Chemie und Strukturchemie, Universitꢁt Dꢀsseldorf, Universitꢁtsstrasse 1,
DE-40225 Dꢀsseldorf
c) Max-Planck-Forschungsstelle fꢀr Enzymologie der Proteinfaltung, Weinbergweg 22, DE-06120 Halle
(phone: þ493455522800; fax: þ493455511972; e-mail: fischer@enzyme-halle.mpg.de)
Dedicated to Professor Dieter Seebach at the occasion of his 75th birthday
A series of 18 differently substituted new aryl hetaryl ketones and thioketones were synthesized in
four to six steps from commercial starting materials. The new ketones were evaluated as inhibitors of the
peptidyl-prolyl cis-trans isomerase hPin1 with Ki values ranging in the one-digit micromolar to sub-
micromolar numbers. A crystal structure revealed the non-planar arrangement of the aryl residues at the
carbonyl compound and supports the hypothesis that the new compounds might mimic the transition
state of the enzymatic conversion.
Introduction. – The structure of proteins distinctly depends on the rigidity of the
amide bond with only two energetically preferred conformational states, leading to cis
and trans peptide-bond isomers 1. The peptide bonds between 19 out of the 20 gene-
coded amino acids overwhelmingly adopt the trans-conformation. In contrast, the
imidic peptide bond preceding a proline residue realizes comparable thermodynamic
stability for both isomers in unfolded polypeptide chains and also, in many cases, in
native proteins. As a consequence, the presence of cis prolyl bonds can affect a variety
of isomer-specific signaling processes in the cell. The activation barrier encountered
with the rotation about this bond amounts to 75 to 100 kJ molꢀ1. It is required to
convert cis-1 (w¼08) to trans-1 (w¼1808) through the transition state 2 with a
perpendicular arrangement of the substituents at the amide bond (w¼908) [1]
(Scheme 1). The ubiquitously distributed peptidyl prolyl cis/trans isomerases
(PPIases), discovered in 1984, catalyze the interconversion of cis-1 and trans-1 by
substantially lowering the barrier to rotation [2]. Consequently, PPIases have been
found to play a key role in accelerating slow steps in the refolding as well as in structural
modifications in the native state of proteins. Three families of PPIases have been
characterized: i) the cyclophilins, ii) the FK-506 binding proteins, and iii) the parvulins,
the latter including human Pin1, a PPIase that is specific for phosphorylated serine and
threonine preceding proline [3]. The role Pin1 plays in cell cycle, cancer pathogenesis,
and Alzheimerꢂs disease has been studied intensively during the last decade [4], and
Pin1 emerged as an ꢃanticancer drug targetꢂ [5]. It is, therefore, not surprising that
ꢄ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2619
Scheme 1. cis-trans Isomerization of PeptidylꢀProlyl Bonds. Aryl indanyl ketones 3 and aryl hetaryl
ketones, and thioketones 4 as transition-state analogs of the ꢃtwisted amideꢂ 2.
various attempts have been made to develop peptidic and small-molecule inhibitors of
Pin1 [6][7]. Despite intense efforts and remarkable progress in this area, there seems to
be still a need for low-molecular-weight, cell-entering compounds with efficient Pin1
inhibition.
Guided by the idea to inhibit PPIases by mimicking the transition state 2 due to
compounds that intrinsically feature a ꢃtwistedꢂ arrangement of residues at a carbonyl
group, we developed (bi)aryl indanyl ketones 3 as PPIase inhibitors that turned out to
be not only potent inhibitors of Pin1 [8], but also of cyclophilins with a remarkable
selectivity towards the latterꢂs isoforms [9]. MC/FEP calculations have confirmed the
idea that aryl indanyl ketones also resemble the transition state of cyclophilin-A
catalysis preferably by favorable stabilization of the residues Arg55 and Asn102 of the
enzyme [10].
In the aryl-indanyl series, the individual enantiomers of 3 (R1 ¼Me, X¼F) were
found not only to exhibit distinctly different inhibitory activities but also substantial
differences in biochemical effects [8][9]. Racemic biaryl indanyl ketones 3 (R1 ¼H,
X¼Aryl) lacking a stereogenic quaternary center were, according to our studies, in
general more potent inhibitors than their (mono)aryl counterparts. Unfortunately,
enantiomerically pure biaryl indanyl ketones of that type [11] underwent racemization
through the corresponding enol under the conditions applied in the biochemical assay.
Therefore, we decided to develop ketones without stereogenic center that form easily
interconvertible atropisomers, assuming that the enzyme would incorporate preferably
the better-fitting axially chiral stereoisomer. This requirement seems to be fulfilled in
aryl or biaryl ketones and thioketones 4 (Y¼O, S) with an additional 1-benzofuran, 1-
benzothiophene, or 1H-indol moiety (X¼O, S, MeN). Therein, an alkyl substituent
C(2) was anticipated to prevent planarity of the aromatic rings, so that the concept of
twisted ketones as mimics of the ꢃtwisted amideꢂ transition state 2 would be maintained
in aryl hetaryl ketones and thioketones 4. Thus, the series of aryl hetaryl ketones 11,
biaryl hetaryl ketones 10, as well as thioketones 12 and 13 were synthesized, and the

2620
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
inhibitory activities were determined on Pin1 and, additionally for one compound, on
cyclophylin A.
Results and Discussion. – The heterocyclic starting materials 7 were either
purchased or prepared by known procedures [12]1). The FriedelꢀCrafts acylation of
heterocycles 7 with the acyl chlorides 6, obtained from commercially available
carboxylic acids 5, served for the preparation of the key intermediate ketones 8a–8h.
As expected, complete regiocontrol occurred in the acylation step, the heteroaromatic
compounds being attacked at C(3) exclusively. The yields given in Scheme 2 refer to
two steps, and the lower yields observed in some cases are partly caused by
demethylation occurring in the course of the FriedelꢀCrafts acylation. The correspond-
ing phenolic ketones are readily removed by column chromatography, but isolated in
the case of compound 11a (see Scheme 5, below).
Scheme 2. Synthesis of Key-Intermediate Ketones 8
i) SOCl2, reflux, 3 h, 258, 30 h. ii) AlCl3, CH2Cl2, 258, 30 h.
The substitution pattern of the aryl hetaryl ketones 8a–8f, with Br in para-position
to the MeO group, served as the key intermediates for the formation of a series of biaryl
indanyl ketones, a structural motif that had proved as fruitful in the development of aryl
indanyl ketones as PPIase inhibitors. Thus, Suzuki coupling reactions [13a]2) of
ketones 8a–8f with (5-fluoro-2-methoxy)phenylboronic acid, (3,5-dimethoxy)phenyl-
boronic acid, and (4-trifuoromethoxy)phenylboronic acid led to the formation of
ketones 9a–9f, 9g, and 9h, respectively. Complete cleavage of the phenolic ether groups
occurred upon treatment with BBr3, so that the ketones 10a–10h were readily obtained
(Scheme 3).
The Br-substituent in the ketone 8b also allowed metal-catalyzed exchange
reactions. Thus, a Pd-mediated reaction with potassium hexacyanoferrate(II) [14] led
1
)
)
2-Butyl-1-benzothiophene (7f) was prepared by metallation of 1-benzothiophene with BuLi and
subsequent treatment with 1-iodobutane.
A modified procedure was applied for the preparation of ketones 9c, 9g, and 9h [13b].
2

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2621
Scheme 3. Synthesis of Biaryl Hetaryl Ketones 9 by Suzuki Coupling and Deprotection to Phenols 10
i) [Pd(dppf)Cl2] (dppf¼1,1’-Bis(diphenylphosphino)ferrocene), CsCO3, MeO(CH2)2OMe/H2O 1:1,
reflux, 15 h. ii) BBr3, CH2Cl2, ꢀ788 to 258, 30 h. iii) Pd(OAc)2, PPh3, PrOH/H2O 5 :1, reflux, 2 h; then
258, 30 h.
to the formation of the nitrile 8i. A Br/I exchange occurred upon treatment with NaI in
the presence of CuI [15] to yield ketone 8j (Scheme 4).
3
)
Modified conditions: Pd(OAc)2, PPh3, PrOH/H2O 5:1, reflux, 2 h, then: 258, 30 h.

2622
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Scheme 4. Synthesis of Aryl Hetaryl Ketones 8j and 8k
i) [Pd(dppf)Cl2], Na2CO3, K4[Fe(CN)6], N-methylpyrrolidin-2-one (NMP), 1208, 20 h. ii) CuI, NaI,
MeNH(CH2)2NHMe, 1,4-dioxane, reflux, 20 h.
The synthesis of phenolic compounds 11a–11e featuring a monoaryl hetaryl ketone
skeleton was again easily accomplished by demethylation of methoxy derivatives 8b
and 8g–8j with BBr3 (Scheme 5)4).
Scheme 5. Synthesis of Monoaryl Hetaryl Ketones 11a–11e
i) BBr3, CH2Cl2, ꢀ788 to 258, 30 h.
As we were interested whether the replacement of a C¼O by a C¼S moiety might
be favorable for PPIase inhibition, selected ketones 9a and 9e were converted to
thioketones 12a and 12b, respectively, by treatment with Lawessonꢂs reagent [16]. Here
again, demethylation was performed with BBr3 to give phenolic thioketones 13a and
13b (Scheme 6).
In addition to the analytical and spectroscopic characterization, the crystal structure
of a representative biaryl indanyl ketone, 10b, was determined. The structure shown in
the Figure reveals a strong intramolecular H-bond of the chelated phenolic OH group
with the C¼O group. In addition, the OH substituent in para-position to the F-atom is
engaged in the formation of a H-bridged dimer with a cyclic H-bond pattern R22(18)
[17]. The crystal structure clearly reveals non-planarity of the 1-benzoforan ring and
the phenyl residue at the CO group. The planes of both residues are twisted by ca. 538, a
value that results from the addition of the dihedral angle O1ꢀC1ꢀC12ꢀC13 and
O1ꢀC1ꢀC2ꢀC9. Thus, the CO group is neither in plane with the phenyl nor with the
4
)
Obtained as a by-product in the FriedelꢀCratfs acylation according to Scheme 2.

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2623
Scheme 6. Synthesis of Thioketones 12 and 13
i) Lawessonꢂs reagent, toluene, reflux, 6 h. ii) BBr3, ꢀ788 to 258, 30 h.
furan ring. Although these ring skeletons are not arranged perpendicularly, their non-
planarity might be sufficient to fulfil the requirement of mimicking the twisted-amide
transition state 2.
The inhibition of human Pin1 by biaryl hetaryl ketones 10a–10h, monoaryl hetaryl
ketones 11a–11e, and thioketones 13a and 13b was determined in a protease-free
PPIase assay with Suc-Ala-Glu-Pro-Phe-p-nitroanilide as the substrate [18]. As
compiled in Table 1, all the compounds, except two, exhibit substantial inhibition of
Pin1, most of them with Ki or IC50 values in the mono-digit mm range. First, a
comparison of Entries 1, 4, and 5 reveals that the heteroatom in the heterocyclic part
only marginally influences the activity, in as far as that 1-benzofuran derivative 10a
(Entry 1) is as active as 1H-indole derivative 10d (Entry 4), both being only slightly
superior to the 1-benzothiophene derivative 10e (Entry 5). The series of 1-benzofurans
derivatives 10a–10c (Entries 1–3) indicates that a lipophilic group (Me) at C(5) of the
heterocyclic moiety seems to be more favorable than a polar one (NCCH2). As
indicated by the results of Entries 5 and 6, the size of the alkyl group at C(2) of the
heterocycle has no substantial influence on the activity. It seems, when considering the
crystal structure of compound 10b, that a Me substituent is large enough to provide the
Table 1. Inhibition Constants Ki [mm] or IC50 Values [mm] (in brackets) of Ketones 10–11 and Thioketones
12 and 13
Entry
Ki [mm] (IC50 [mm])
Entry
Ki [mm]
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
2.10ꢁ0.27
(1.67ꢁ0.38)
(4.5ꢁ0.3)
2.22ꢁ0.51
3.70ꢁ0.66
3.66ꢁ0.86
(> 10)
9
10
11
12
13
14
15
16
11a
11b
11c
11d
11e
12a
13a
13b
2.6ꢁ0.3
7.4ꢁ1.1
4.1ꢁ0.6
a
)
1.0 ꢁ0.1
2.90ꢁ0.31
1.80ꢁ0.21
0.60ꢁ0.17
7.2ꢁ0.8
a) Inactive.

2624
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Figure. Molecular structure of 10b in the crystal. Displacement ellipsoids are drawn at the 50%
probability level, radii of H-atoms are chosen arbitrarily, and labels of H-atom bonded to C-atoms are
omitted for clarity. Selected geometric parameters ([ꢅ] and [8]): F1ꢀC22, 1.369(3); O1ꢀC1, 1.248(2);
O2ꢀC8, 1.385(3); O2ꢀC9, 1.365(3); O3ꢀC13, 1.357(3); O4ꢀC19, 1.376(3); C1ꢀC2, 1.468(3); C1ꢀC12,
1.467(3); C2ꢀC3, 1.458(3); C2ꢀC9, 1.364(3); O1ꢀC1ꢀC2, 119.61(19); O1ꢀC1ꢀC12, 119.67(19);
C2ꢀC1ꢀC12, 120.70(17); C1ꢀC12ꢀC13, 119.81(18); O3ꢀC13ꢀC12, 122.2(2); O4ꢀC19ꢀC18,
123.09(19); C2ꢀC1ꢀC12ꢀC13, 154.52(19); O3ꢀC13ꢀC12ꢀC1, 3.3(3); O1ꢀC1ꢀC12ꢀC13, ꢀ23.6(3);
O1ꢀC1ꢀC2ꢀC9, ꢀ29.1(3); C1ꢀC2ꢀC9ꢀC10, ꢀ4.6(4); C15ꢀC16ꢀC18ꢀC19, 45.7(3); O3ꢀH1, 0.93(3);
H1· · ·O1, 1.79(3); O3· · ·O1, 2.610(3); O3ꢀH1ꢀO1, 145(3); O4ꢀH2, 0.91(3), H2· · ·O1, 1.98(4),
O4· · ·O1, 2.835(2); O4ꢀH2ꢀO1, 156(3) (symmetry code: 1ꢀx, 1ꢀy, 1ꢀz); dashed lines indicate the
directions of H-bonding.
twisted conformation of the ketones. Concerning the residues in the biaryl moiety, the
fluoro-phenolic pattern of ketones 10a–10f is obviously superior to the CF3O
substituent in compound 10h (Entry 8) and, in particular, to the accumulation of
three phenolic OH groups in compound 10g (Entry 7). As in the aryl indanyl ketone
series, the ring-substituted biaryl pattern was always favorable for Pin1 inhibition, we
were interested whether – in the aryl hetaryl ketones described here – the switch from
the biaryl to the monoaryl pattern would influence the inhibitory activitiy. Generally,
highly substituted ring systems were found to lead to potent non-peptidic Pin1
inhibitors [19].
It turned out that four out of the five monoaryl derivatives 11a–11e act as inhibitors
(Entries 9–11 and 13). The only exception is the benzonitrile 11d (Entry 12) that did

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2625
not show any activity. Surprisingly, the replacement of the ꢃpseudohalogenꢂ cyanide by
Br (Entry 9) or I (Entry 13) leads to a remarkable enhancement of inhibition. The
result of the latter compound, 11e, with a Ki value of 1.0 mm indicates that the biaryl
pattern is in this series of compounds not crucial for inhibitory activity.
Finally, the CO group was replaced by CS in compounds 12a, 13a, and 13b, all of
which were found to be inhibitors. A comparison of compounds 12a and 13a (Entries 14
and 15) clearly shows that the free phenolic group in the carboaromatic moiety is
favorable, but not crucial for activity. Thioketone 13b, finally, exhibits the highest
inhibitory of the whole series, with its Ki value amounting to 0.6 mm (Entry 16). As it
was considered the most promising compound, it was also tested for the inhibition of
the PPIase cyclophylin A. Here also, thioketone 13b provided inhibitory activity, the
IC50 value amounting to 3.21ꢁ0.38 mm. The finding that the large majority of the
compounds prepared and tested act as PPIase inhibitors might support the hypothesis
that the ketones are mimicking the ꢃtwisted amideꢂ transition state 2.
Conclusions. – Based on the concept that aryl hetaryl ketones and thioketones have
a non-planar arrangement of the aromatic moieties at the CO or CS group and,
therefore, might function as transition-state analogs, a series of new potent inhibitors of
human Pin1 have been synthesized. In view of their relatively simple structures, the
inhibitory potency of the aryl hetaryl ketones and thioketones is remarkable, and it
makes them suitable cell-penetrating agents for further biochemical studies, and
promising candidates not only for the inhibition of Pin1 but also of cyclophilins.
We gratefully acknowledge the support of this work by Deutsche Forschungsgemeinschaft (Br 604/
17-1,2)
Experimental Part
General. Toluene was freshly distilled from Na under N2. THF and Et2O were freshly distilled from
Na with benzophenone as indicator under N2. CH2Cl2 was freshly distilled from NaH under N2. Other
solvents were used as purchased. Column chromatography (CC): Fluka silica gel 60 (SiO2; 230–400
mesh). TLC: Merck TLC silica gel 60 F254 aluminium sheets. M.p. (not corrected): Bꢀchi 540 melting-
point apparatus. NMR Spectra (CDCl3): Bruker Avance DRX 200, DRX 300, and DRX 500
spectrometers. MS: Thermo Finnigan Trace DSQ apparatus (GC/MS), ion-trap API mass spectrometer
Finnigan LCQ Deca (ESI), triple-quadrupole-mass spectrometer Finnigan TSQ 7000 (EI), and sector
field mass spectrometer Finnigan MAT 8200 (EI, 70 eV), HR-MS: FT-ICR APEX III (7.0 T; MALDI),
Bruker UHR-QTOF maxis 4G (ESI).
General Procedure for the Preparation of Ketones 8a–8h. A mixture of the carboxylic acid 5
(4.33 mmol) and SOCl2 (10 ml) was refluxed for 3 h in a 25-ml flask equipped with a magnetic stirrer and
a reflux condenser with a drying tube. After stirring at r.t. overnight, the remaining SOCl2 was removed
by evaporation with an oil pump. The residual acid chloride 6 was used without further purification.
A 25-ml two-necked flask, equipped with a magnetic stirrer, a reflux condenser with a drying tube,
and a pressure-equalizing dropping-funnel with a stopper was charged with AlCl3 (0.659 g, 4.94 mmol)
and CH2Cl2 (3 ml). The mixture was cooled in an ice bath, and a soln. of the crude acid chloride 6
(4.33 mmol), prepared as described above, in CH2Cl2 (4 ml) was added under vigorous stirring. Finally, a
soln. of the heteroaromatic compound 7 (4.12 mmol) in CH2Cl2 (3 ml) was added dropwise at 08. After
stirring at r.t. for 25 h, the mixture was poured on to ice. In case of formation of a precipitate, it was
dissolved by careful addition of conc. HCl. The layers were separated, and the aq. phase was extracted
three times with CH2Cl2. The combined org. layers were washed with H2O, 2% aq. NaOH, and H2O, and

2626
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
dried (Na2SO4). The crude products 8 obtained after evaporation of the solvent were purified by CC
(yields refer to compounds 7).
(5-Bromo-2-methoxyphenyl)(2-methyl-1-benzofuran-3-yl)methanone (8a). From 6a (1.08 g,
4.33 mmol), 7a (544.5 mg, 4.12 mmol), AlCl3 (659 mg, 4.94 mmol), and CH2Cl2 (10 ml). Yield: 885 mg
1
(62%). Yellow solid. Rf (CHCl3) 0.63. M.p. 98–1018. H-NMR (500 MHz, CDCl3): 2.5 (s, 3 H); 3.69 (s,
3 H); 6.80 (d, J¼8.8, 1 H); 7.19–7.22 (m, 1 H); 7.27–7.29 (m, 1 H); 7.43–7.46 (m, 1 H); 7.49 (d, J¼2.5,
1 H), 7.58 (dd, J¼2.5, J¼8.8, 1 H). 13C-NMR (125 MHz, CDCl3): 14.8; 56.0; 110.8; 113.1; 113.3; 117.6;
121.2; 124.0; 124.5; 126.2; 131.3; 132.5; 134.5; 153.5; 156.0; 163.9; 189.4. GC/EI-MS (70 eV): 346, 344 (75,
Mþ ), 315, 313 (20), 265 (35), 234 (70), 215, 213 (40), 159 (100), 131 (25). Anal. calc. for C17H13BrO3
(345.19): C 59.15, H 3.80; found: C 59.16, H 3.86.
(5-Bromo-2-methoxyphenyl)(2,5-dimethyl-1-benzofuran-3-yl)methanone (8b) From 6a (3.23 g,
12.93 mmol), 7b (1.8 g, 12.31 mmol), AlCl3 (1.97 g, 14.77 mmol), and CH2Cl2 (30 ml). Yield: 2.89 g
(65%). Yellow solid. Rf (CHCl3) 0.54 . M.p. 110–1138. 1H-NMR (500 MHz, CDCl3): 2.39 (s, 3 H); 2.41 (s,
3 H); 3.7 (s, 3 H); 6.89 (d, J¼8.8, 1 H); 7.08 (dd, J¼1.4, 8.4, 1 H); 7.31 (d, J¼8.4, 1 H); 7.4 (s, 1 H); 7.47
(d, J¼2.5, 1 H); 7.6 (dd, J¼2.5, 8.8, 1 H). 13C-NMR (125 MHz, CDCl3): 14.8; 21.4; 56.0; 110.2; 113.0;
113.3; 117.5; 121.3; 125.6; 126.2; 131.3; 132.6; 133.6; 134.4; 152.0; 155.9; 164.0; 189.5. GC/EI-MS (70 eV):
360, 358 (40, Mþ ), 329, 327 (14), 279 (24), 264 (18), 248 (62), 215, 213 (42), 173 (100), 145 (32). Anal.
calc. for C18H15BrO3 (359.21): C 60.18, H 4.21; found: C 59.94, H 4.37.
[3-(5-Bromo-2-methoxybenzoyl)-2-methyl-1-benzofuran-5-yl]acetonitrile (8c) From 6a (793 mg,
3.18 mmol), 7c (519 mg, 3.03 mmol), AlCl3 (485 mg, 3.64 mmol), and CH2Cl2 (12 ml). Yield: 765 mg
(66%). Colorless solid. Rf (CHCl3) 0.54. M.p. 143–1468. 1H-NMR (500 MHz, CDCl3): 2.46 (s, 3 H); 3.71
(s, 3 H); 3.77 (s, 2 H); 6.91 (d, J¼8.3, 1 H); 7.24–7.25 (m, 1 H); 7.44 (d, J¼8.4, 1 H); 7.49 (d, J¼2.3, 1 H);
7.53 (s, 1 H); 7.60 (dd, J¼2.4, 8.8, 1 H). 13C-NMR (125 MHz, CDCl3): 14.8; 23.6; 56.0; 111.4; 113.0; 113.2;
113.3; 117.5; 118.1; 121.0; 124.3; 125.8; 127.0; 131.3; 132.1; 134.8; 153.0; 156.9; 164.9; 189.2. GC/EI-MS
(70 eV): 385, 383 (84, Mþ ), 354, 352 (18), 304 (40), 273 (40), 215, 213 (58), 198 (100), 185 (36), 170 (34),
115 (30). Anal. calc. for C19H14BrNO3 (384.22): C 59.39, H 3.67, N 3.65; found: C 59.33, H 3.82, N 3.40.
(5-Bromo-2-methoxyphenyl)(1,2-dimethyl-1H-indol-3-yl)methanone (8d) From 6a (1.08 g,
4.33 mmol), 7d (598 mg, 4.12 mmol), AlCl3 (659 mg, 4.94 mmol), and CH2Cl2 (10 ml). Yield: 509 mg
(35%). Colorless solid. Rf (hexane/AcOEt 1:1) 0.35. M.p. 174–1778. 1H-NMR (500 MHz, CDCl3): 2.62
(s, 3 H); 3.71 (s, 3 H); 3.73 (s, 3 H); 6.89 (d, J¼8.8, 1 H); 7.07–7.10 (m, 1 H); 7.20–7.24 (m, 1 H); 7.30–
7.32 (m, 1 H); 7.41 (d, J¼2.5, 1 H); 7.54 (dd, J¼2.5, 8.8, 1 H). 13C-NMR (125 MHz, CDCl3): 12.5; 29.7;
56.0; 109.2; 113.0; 113.4; 113.8; 120.6; 122.2; 122.3; 126.8; 131.0; 133.2; 134.6; 146.4; 155.6; 189.2. EI-MS
(70 eV): 359, 357 (34, Mþ ), 328, 326 (23), 247 (46), 172 (100), 144 (35). Anal. calc. for C18H16BrO2
(358.23): C 60.35, H 4.50, N 3.91; found: C 60.29, H 4.51, N 3.90.
(5-Bromo-2-methoxyphenyl)(2-methyl-1-benzothiophen-3-yl)methanone (8e). From 6a (1.08 g,
4.33 mmol), 7e (611 mg, 4.12 mmol), AlCl3 (659 mg, 4.94 mmol), CH2Cl2 (10 ml). Yield: 931 mg
1
(63%). Yellow solid. Rf (CHCl3) 0.5. M.p. 86–918. H-NMR (500 MHz, CDCl3): 2.49 (s, 3 H); 3.62 (s,
3 H); 6.85 (d, J¼9.5, 1 H); 7.29–7.31 (m, 2 H); 7.57–7.75 (m, 4 H). 13C-NMR (125 MHz, CDCl3): 16.1;
56.1; 113.1; 113.7; 121.6; 123.3; 124.4; 125.0; 128.4; 129.2; 132.4; 135.4; 137.1; 138.7; 150.0; 156.8; 189.8.
GC/EI-MS (70 eV): 362, 360 (45, Mþ ), 331, 329 (15), 281 (50), 266 (30), 250 (75), 215, 213 (25), 175
(100), 147 (85). Anal. calc. for C17H13BrO2S (361.25): C 56.52, H 3.63; found: C 56.38, H 3.62.
(5-Bromo-2-methoxyphenyl)(2-butyl-1-benzothiophen-3-yl)methanone (8f). From 6a (1.62 g,
6.49 mmol), 7f (1.18 g, 6.18 mmol), AlCl3 (988 mg, 7.41 mmol), and CH2Cl2 (15 ml). Yield: 1.84 g
(74%). Yellow oil. Rf (CHCl3) 0.61. 1H-NMR (500 MHz, CDCl3): 0.86 (t, J¼7.3, 3 H); 1.30 (sext., J¼7.4,
2 H); 1.66 (quint., J¼7.6, 2 H); 2.87 (t, J¼7.7, 2 H); 3.60 (s, 3 H); 6.84 (d, J¼8.6, 1 H); 7.22–7.30 (m,
2 H); 7.57–7.60 (m, 3 H); 7.75–7.77 (m, 1 H). 13C-NMR (125 MHz, CDCl3): 13.7; 22.4; 29.6; 33.9; 56.02;
113.0; 113.7; 121.7; 123.0; 124.2; 124.8; 132.1; 132.3; 132.7; 135.5; 137.3; 138.6; 155.2; 157.1; 190.0. EI-MS
(70 eV): 404, 402 (40, Mþ ), 373, 371 (35), 323 (17), 292 (22), 280 (34), 215, 213 (100), 147 (68), 133 (37).
Anal. calc. for C20H19BrO2S (403.33): C 59.56, H 4.75; found: C 59.34, H 5.01.
(2,5-Dimethyl-1-benzofuran-3-yl)(2-methoxy-5-methylphenyl)methanone (8g). From 6b (530 mg,
2.87 mmol), 7b (400 mg, 2.74 mmol), AlCl3 (438 mg, 3.28 mmol), and CH2Cl2 (10 ml). Yield: 603 mg
(75%). Yellow solid. Rf (CHCl3) 0.46. M.p. 111–1128. 1H-NMR (500 MHz, CDCl3): 2.33 (s, 3 H); 2.37 (s,
3 H); 2.38 (s, 3 H); 3.68 (s, 3 H); 6.88 (d, J¼8.4, 1 H); 7.06 (d, J¼8.3, 1 H); 7.17 (d, J¼1.8, 1 H); 7.26–7.28

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2627
(m, 1 H); 7.29 (d, J¼8.3, 1 H); 7.43 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.6; 20.4; 21.4; 55.8; 110.0;
111.4; 117.9; 121.5; 125.4; 126.6; 129.1; 130.2; 130.7; 132.2; 133.3; 151.9; 154.8; 163.5; 191.6. GC/EI-MS
(70 eV): 294 (88, Mþ ), 279 (74), 263 (58), 248 (22), 173 (38), 160 (18), 149 (100), 145 (20), 135 (22), 91
(40). Anal. calc. for C19H13O3 (294.34): C 77.53, H 6.16; found: C 77.40, H 6.25.
(2,5-Dimethyl-1-benzofuran-3-yl)[2-methoxy-5-(trifluoromethyl)phenyl]methanone (8h). From 6c
(857 mg, 3.59 mmol), 7b (500 mg, 3.42 mmol), AlCl3 (547 mg, 4.10 mmol), and CH2Cl2 (15 ml). Yield:
140 mg (12%). Yellow oil. Rf (CHCl3) 0.75 . 1H-NMR (500 MHz, CDCl3): 2.37 (s, 3 H); 2.40 (s, 3 H); 3.79
(s, 3 H); 7.08 (d, J¼8.6, 2 H); 7.32 (d, J¼8.4, 1 H); 7.34 (s, 1 H); 7.64 (d, J¼2.1, 1 H); 7.76 (dd, J¼2.1, 8.7,
1 H). 13C-NMR (125 MHz, CDCl3): 14.8; 21.4; 56.1; 109.1; 110.2; 111.4; 117.5; 121.3; 125.7; 126.2; 128.6;
129.0; 131.1; 131.2; 133.7; 152.0; 164.1; 168.9; 197.7. GC/EI-MS (70 eV): 348 (100, Mþ ), 317 (60), 305 (6),
279 (6), 248 (4), 203 (84), 173 (56), 160 (28), 145 (38), 115 (20). Anal. calc. for C19H15F3O3 (348.32): C
65.52, H 4.34; found: C 65.25, H 4.17.
General Procedure for the Preparation of Ketones 9a and 9b, and 9d–9f. A 100-ml two-necked flask,
equipped with a magnetic stirrer, a reflux condenser, and a connection to the combined N2/vacuum line,
was charged with ketone 8 (1.45 mmol), (5-fluoro-2-methoxyphenyl)boronic acid, CsCO3 (1.18 g,
3.6 mmol), and [Pd(dppf)Cl2] (dppf¼1,1’-bis(diphenylphosphio)ferrocene) (58.25 mg, 0.0725 mmol).
The flask was closed with a septum, and the air in the flask was replaced by N2. A 3 :1 mixture of 1,2-
dimethoxyethane and H2O (62.5 ml) was injected through the septum, and the mixture was refluxed
under vigorous stirring for 15 h. After cooling to r.t., H2O was added, and the mixture was extracted three
times with CHCl3. The combined org. layers were dried (Na2SO4), and the solvent was removed in a
rotary evaporator. The crude products 9a and 9b and 9d–9g thus obtained were purified by CC.
(5’-Fluoro-2’,4-dimethoxy-1,1’-biphenyl-3-yl)(2-methyl-1-benzofuran-3-yl)methanone (9a). From 8a
(500 mg,1.45 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (246.4 mg, 1.45 mmol), Cs2CO3 (1.18 g,
3.63 mmol), [Pd(dppf)Cl2] (58.25 mg, 0.0725 mmol), and 1,2-dimethoxyethane/H2O 3 :1 (62.5 ml).
1
Yield: 558 mg (98%). Yellow oil. Rf (hexane/AcOEt 1:1) 0.58. H-NMR (500 MHz, CDCl3): 2.52 (s,
3 H); 3.71 (s, 3 H); 3.77 (s, 3 H); 6.86 (dd, J(H,F)¼4.5, J(H,H)¼8.9, 1 H); 6.96 (td, J(H,H)¼3.1,
J(H,F)¼8.3, 1 H); 7.02–7.06 (m, 3 H); 7.19–7.28 (m, 2 H); 7.43 (d, J¼8.2, 1 H); 7.57 (d, J¼1.7, 1 H); 7.62
(dd, J¼1.7, J¼8.6, 1 H). 13C-NMR (125 MHz, CDCl3): 14.7; 55.8; 56.1; 110.6; 111.3; 112.3 (d, J(C,F)¼
8.6); 114.2 (d, J(C,F)¼22.7); 117.0 (d, J(C,F)¼23.2); 118.0; 121.5; 123.8; 124.3; 126.5; 130.0; 130.3; 132.7;
152.6; 153.5; 156.2; 163.7; 191.0. EI-MS (70 eV): 390 (100, Mþ ), 359 (32), 265 (58), 159 (92). Anal. calc.
for C24H19FO4 (390.40): C 73.84, H 4.91; found: C 73.67, H 5.01.
(2,5-Dimethyl-1-benzofuran-3-yl)(5’-fluoro-2’,4-dimethoxy-1,1’biphenyl-3-yl)methanone (9b). From
8b (2.0 g,5.57 mmol), (5-fluoro-2-methoxy-1,1’-phenyl)boronic acid (946.2 mg, 5.57 mmol), Cs2CO3
(4.53 g, 13.93 mmol), [Pd(dppf)Cl2] (223.8 mg, 0.278 mmol), and 1,2-dimethoxyethane/H2O 3 :1
(240 ml). Yield: 1.08 g (48%). Yellow solid. Rf (hexane/AcOEt 3 :1) 0.5. M.p. 159–1618. 1H-NMR
(500 MHz, CDCl3): 2.38 (s, 3 H); 2.43 (s, 3 H); 3.72 (s, 3 H); 3.79 (s, 3 H); 6.85–6.88 (m, 1 H); 6.96 (td,
J(H,H)¼3.0, J(H,F)¼8.6, 1 H); 7.02–7.08 (m, 3 H); 7.30 (d, J¼8.3, 1 H); 7.45 (s, 1 H); 7.55 (d, J¼2.0,
1 H); 7.63 (dd, J¼2.0, J¼8.7, 1 H). 13C-NMR (125 MHz, CDCl3): 14.7; 21.4; 55.9; 56.1; 110.0; 111.3; 112.4
(d, J(C,F)¼8.4); 114.2 (d, J(C,F)¼22.7); 117.0 (d, J(C,F)¼23.5); 117.8; 121.7; 125.5; 126.6; 129.9; 130.1;
130.4; 130.7; 132.6; 133.4; 152.0; 152.6; 156.1; 163.9; 191.1. EI-MS (70 eV): 404 (46, Mþ ), 389 (12), 373
(17), 279 (27), 259 (17), 173 (37), 145 (13), 135 (100). Anal. calc. for C25H21FO4 (404.43): C 74.24, H 5.23;
found: C 74.06, H 5.35.
(1,2-Dimethyl-1H-indol-3-yl)(5’-fluoro-2’,4-dimethoxy-1,1’-biphenyl-3-yl)methanone (9d). From 8d
(400 mg,1.12 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (190 mg, 1.12 mmol), Cs2CO3 (910 mg,
2.8 mmol), [Pd(dppf)Cl2] (45.0 mg, 0.056 mmol), and 1,2-dimethoxyethane/H2O 3 :1 (48 ml). Yield:
356 mg (79%). White solid. Rf (hexane/AcOEt 1:1) 0.25. M.p. 170–1718. 1H-NMR (500 MHz, CDCl3):
2.64 (s, 3 H); 3.68 (s, 3 H); 3.73 (s, 3 H); 3.79 (s, 3 H); 6.84 (dd, J(H,F)¼4.5, J(H,H)¼8.9, 1 H); 6.91–
6.95 (m, 1 H); 7.01 (dd, J¼3.1, J(H,F)¼9.1, 1 H); 7.05–7.09 (m, 2 H); 7.18–7.21 (m, H); 7.29–7.34 (m,
H); 7.48 (d, J¼2.1, 1 H); 7.60 (dd, J¼2.1, J¼8.5, 1 H). 13C-NMR (125 MHz, CDCl3): 12.5; 29.6; 55.9;
56.2; 109.0; 111.3; 112.4 (d, J(C,F)¼8.6); 113.9 (d, J(C,F)¼22.5); 117.0; 121.0; 122.0 (d, J(C,F)¼20.8);
127.0; 129.7; 129.9; 131.2; 136.7; 139.9; 141.7; 157.0 (d, (C,F)¼268.4); 164.6; 173.7; 191.0. EI-MS (70 eV):
403 (62, Mþ ), 372 (90), 357 (15), 278 (50), 172 (100), 145 (56). HR-EI-MS: 403.1573 (Mþ, C25H22FNOþ3 ;
calc. 403.1584).

2628
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
(5’-Fluoro-2’,4-dimethoxy-1,1’-biphenyl-3-yl)(2-methyl-1-benzothiophen-3-yl)methanone (9e). From
8e (500 mg,1.38 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (235.2 mg, 1.38 mmol), Cs2CO3 (1.13 g,
3.46 mmol), [Pd(dppf)Cl2] (55.6 mg, 0.069 mmol), and 1,2-dimethoxyethane/H2O 3 :1 (60 ml). Yield:
474 mg (84%). Yellow oil. Rf (hexane/AcOEt 1:1) 0.61. 1H-NMR (500 MHz, CDCl3): 2.51 (s, 3 H); 3.68
(s, 3 H); 3.74 (s, 3 H); 6.84–7.82 (m, 10 H). 13C-NMR (125 MHz, CDCl3): 16.0; 55.8; 56.0; 111.7; 112.2 (d,
J(C,F)¼8.4); 114.2 (d, J(C,F)¼22.7); 117.0 (d, J(C,F)¼23.6); 121.5; 123.6; 124.2; 124.9; 129.9; 130.0;
130.4 (d, J(C,F)¼7.6); 131.4; 133.0; 133.7; 137.2; 139.0; 149.1; 152.5 (d, J(C,F)¼1.7); 157.1 (d, J(C,F)¼
238.7); 157.2; 191.3. GC/EI-MS (70 eV): 406 (100, Mþ ), 391 (25), 375 (25), 281 (45), 175 (80), 147 (85).
Anal. calc. for C24H19FO3S (406.47): C 70.92, H 4.71; found: C 70.55, H 4.69.
(2-Butyl-1-benzothiophen-3-yl)(5’-fluoro-2’,4-dimethoxy-1,1’-biphenyl-3-yl)methanone (9f). From
8f (920 mg, 2.28 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (387.5 mg, 2.28 mmol), Cs2CO3
(1.85 g, 5.7 mmol), [Pd(dppf)]Cl2] (91.6 mg, 0.114 mmol), and 1,2-dimethoxyethane/H2O 3 :1 (98 ml).
Yield: 366 mg (36%). Yellow oil. Rf (hexane/AcOEt 3 :1) 0.42. 1H-NMR (500 MHz, CDCl3): 0.84 (t, J¼
7.3, 3 H); 1.25–1.34 (m, 2 H); 1.66 (quint., J¼7.6, 2 H); 2.90 (t, J¼7.8, 2 H); 3.66 (s, 3 H); 3.71 (s, 3 H);
6.83–6.86 (m, 1 H); 6.93–7.03 (m, 3 H); 7.27–7.29 (m, 2 H); 7.64–7.67 (m, 3 H); 7.75–7.77 (m, 1 H).
13C-NMR (125 MHz, CDCl3): 13.7; 22.4; 29.6; 33.9; 55.9; 56.0; 11.6; 12.2 (d, J(C,F)¼8.7); 114.2 (d,
J(C,F)¼22.6); 117.0 (d, J(H,F)¼23.6); 121.6; 123.4; 124.0; 124.7; 129.7; 129.9; 131.7; 133.0; 134.0; 137.3;
138.9; 152.0; 154.3; 156.1; 157.5; 158.0; 191.6. EI-MS (70 eV): 448 (34, Mþ ), 417 (16), 405 (36), 281 (25),
259 (53), 161 (50), 135 (100). Anal. calc. for C27H25FO3S (448.55): C 72.30, H 5.62; found: C 72.23, H 5.62.
General Procedure for the Preparation of Ketones 9c, 9g, and 9h. A 25-ml two-necked, flask,
equipped with a magnetic stirrer and a connection to the combined N2/vacuum line, was charged with
ketone 8 (0.26 mmol), arylboronic acid (0.274 mmol), and PrOH (5 ml). After the flask has been flushed
with N2, a mixture of Pd(OAc)2 (0.18 mg, 0.78 mmol), PPh3 (0.615 mg, 2.34 mmol), Na2CO3 (0.033 g,
0.312 mmol), and H2O (1 ml) was added. The soln. was refluxed for 2 h and then stirred at r.t. overnight.
After the addition of H2O, the mixture was extracted three times with AcOEt. The combined org. layers
were dried (Na2SO4), and the solvent was removed in vacuo to give crude product 9 that was submitted to
CC.
{3-[(5’-Fluoro-2’,4-dimethoxy-1,1’-biphenyl-3-yl)carbonyl]-2-methyl-1-benzofuran-5-yl}acetonitrile
(9c). From 8c (100 mg, 0.26 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (46.6 mg, 0.27 mmol),
Na2CO3 (33 mg, 0.31 mmol), Pd(OAc)2 (0.18 mg, 0.78 mmol), PPh3 (0.62 mg, 2.34 mmol), and PrOH/H2O
1
5 :1 (6 ml). Yield: 111 mg (99%). Yellow solid. Rf (CHCl3) 0.26. M.p. 164–1668. H-NMR (500 MHz,
CDCl3): 2.47 (s, 3 H); 3.73 (s, 3 H); 3.77 (s, 2 H); 3.78 (s, 3 H); 6.86–6.88 (m, 1 H); 6.97 (td, J(H,H)¼3.1,
J(H,F)¼8.9, 1 H); 7.04–7.05 (m, 1 H); 7.07 (d, J¼8.7, 1 H); 7.24–7.26 (m, 1 H); 7.44 (d, J¼8.5, 1 H); 7.57
(d, J¼2.3, 1 H); 7.60 (s, 1 H); 7.65 (dd, J¼2.3, J¼8.6, 1 H). 13C-NMR (125 MHz, CDCl3): 14.7; 23.6; 55.8;
56.1; 111.3; 112.3 (d, J(C,F)¼8.3); 114.3 (d, J(C,F)¼22.7); 117.1 (d, J(C,F)¼23.1); 118.1; 121.4; 124.1;
125.6; 127.4; 129.8; 129.9; 130.2; 130.5; 133.0; 152.6; 153.1; 157.1 (d, J(C,F)¼246.4); 158.1; 164.7; 190.8.
EI-MS (70 eV): 429 (1, Mþ ), 304 (14), 277 (100), 259 (18), 201 (24), 173 (32), 149 (26), 133 (25). HR-
ESI-MS: 430.1451 ([MþH]þ , C26H21FNO4þ ; calc. 430.1449).
(2,5-Dimethyl-1-benzofuran-3-yl)(3’,4,5’-trimethoxy-1,1’-biphenyl-3-yl)methanone (9g). From 8b
(500 mg, 1.39 mmol), (3,5-dimethoxyphenyl)boronic acid (266 mg, 1.46 mmol), Na2CO3 (176 mg,
1.67 mmol), Pd(OAc)2 (1.0 mg, 4.17 mmol), PPh3 (3.3 mg, 12.51 mmol), PrOH/H2O 5 :1 (24 ml). Yield:
615 mg (quant.). Yellow solid. Rf (CHCl3) 0.36. M.p. 144–1468. 1H-NMR (500 MHz, CDCl3): 2.38; 2.42
(s, 3 H); 3.78 (s, 3 H); 3.82 (s, 6 H); 6.44 (t, J¼2.2, 1 H); 6.69 (d, J¼2.2, 2 H); 7.06 (d, J¼8.6, 1 H); 7.07
(dd, J¼1.8, 8.3, 1 H); 7.31 (d, J¼8.3, 1 H); 7.45 (s, 1 H); 7.60 (d, J¼2.4, 1 H); 7.70 (d, J¼2.4, 8.6, 1 H).
13C-NMR (125 MHz, CDCl3): 14.8; 21.5; 55.4; 55.9; 99.2; 99.3; 104.9; 105.4; 105.6; 110.1; 111.8; 117.8;
121.5; 125.5; 126.5; 127.4; 130.3; 142.0; 152.0; 156.5; 161.1; 163.9; 191.2. EI-MS (70 eV): 416 (100, Mþ ),
401 (14), 385 (50), 360 (21), 279 (37), 257 (36), 173 (31), 159 (11), 145 (11). HR-ESI-MS: 417.1696
([MþH]þ , C26H25Oþ5 ; calc. 417.1697).
(2,5-Dimethyl-1-benzofuran-3-yl)[4-methoxy-4’-(trifluoromethoxy)-1,1’-biphenyl-3-yl]methanone
(9h). From 8b (500 mg, 1.39 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (300.7 mg, 1.46 mmol),
Na2CO3 (176 mg, 1.67 mmol), Pd(OAc)2 (1.0 mg, 4.17 mmol), PPh3 (3.3 mg, 12.51 mmol), and PrOH/H2O
1
5 :1 (24 ml). Yield: 478 mg (78%). Yellow solid. Rf (CHCl3) 0.58. M.p. 116–1178. H-NMR (500 MHz,
CDCl3): 2.37 (s, 3 H), 2.43 (s, 3 H), 3.78 (s, 3 H), 7.08 (d, J¼8.3, 1 H); 7.08 (d, J¼8.7, 1 H); 7.25–7.27 (m,

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2629
2 H); 7.31 (d, J¼8.4, 1 H); 7.42 (s, 1 H); 7.55–7.58 (m, 2 H); 7.28 (d, J¼2.4, 1 H); 7.68 (dd, J¼2.4, J¼8.6,
1 H). 13C-NMR (125 MHz, CDCl3): 14.8; 21.4; 55.0; 110.2; 112.0; 117.8; 118.8; 121.4; 121.4; 125.6; 126.4;
127.3; 128.0; 130.2; 131.3; 132.5; 133.5; 138.6; 148.5; 152.0; 156.6; 163.9; 191.0. EI-MS (70 eV): 440 (100,
Mþ ), 425 (16), 409 (75), 370 (16), 351 (13), 314 (36), 297 (41), 295 (70), 252 (20), 225 (15), 189 (31), 173
(68), 159 (36). HR-ESI-MS: 441.1309 ([MþH]þ , C25H20F3O4þ ; calc. 441.1308).
3-[(2,5-Dimethyl-1-benzofuran-3-yl)carbonyl]-4-methoxybenzonitrile (8i). A 50-ml two-necked
flask, equipped with a magnetic stirrer and a connection to the combined N2/vacuum line, was charged
with 8b (0.637 g, 1.77 mmol), Na2CO3 (0.188 g, 1,77 mmol), [Pd(dppf)Cl2] (0.013 g, 0.0177 mmol), and
pre-dried K4[Fe(CN)6] (0.162 g, 0.44 mmol). The flask was closed with a septum, and the air in the flask
was replaced by N2. After the addition of N-methylpyrrolidin-2-one (20 ml), the soln. was refluxed to
1208 for 20 h, cooled to r.t. and diluted with H2O, brine, and CH2Cl2. The layers were separated. The org.
phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by CC to give (300 mg,
56%). Yellow solid. 8i. Rf (CHCl3) 0.33. M.p. 151–1538. 1H-NMR (500 MHz, CDCl3): 2.37 (s, 3 H); 2.43
(s, 3 H); 3.8 (s, 3 H); 7.08 (d, J¼8.7, 1 H); 7.08–7.10 (m, 1 H); 7.26 (s, 1 H); 7.32 (d, J¼8.4, 1 H); 7.66 (d,
J¼2.1, 1 H); 7.80 (dd, J¼2.1, 8.7, 1 H). 13C-NMR (125 MHz, CDCl3): 14.9; 21.5; 56.2; 105.5; 110.4; 112.1;
117.3 (CN); 118.3; 121.0; 125.9; 125.9; 132.0; 132.5; 133.8; 136.0; 152.0; 159.9; 164.3; 188.6. GC/EI-MS
(70 eV): 305 (100, Mþ ), 274 (60), 173 (50), 160 (75), 145 (40), 117 (35), 102 (20). Anal. calc. for
C19H15NO3 (305.33): C 74.74, H 4.95, N 4.59; found: C 74.55, H 5.23, N 4.41.
(2,5-Dimethyl-1-benzofuran-3-yl)(5-iodo-2-methoxyphenyl)methanone (8j). A 50-ml two-necked
flask, equipped with a magnetic stirrer, a reflux condenser, and a connection to the combined N2/vacuum
line, was charged with 8b (1.00 g, 2.78 mmol), CuI (0.0265 g, 0.139 mmol), and NaI (0.828 g, 5.56 mmol).
The flask was closed with a septum, and the air in the flask was replaced by N2. Dry 1,4-dioxane (15 ml)
and N,N’-dimethylethylenediamine (0.03 ml, 0.278 mmol) were injected by syringes, and the mixture was
refluxed for 20 h. After cooling to r.t., a concentrated soln. of NH4OH (10 ml) was added, and the
mixture was poured into H2O and extracted three times (CH2Cl2). The combined org. layers were dried
with (Na2SO4) and the solvent was removed in a rotary evaporator. The residue was submitted to CC to
give 8j (1.07 g, 95%). Yellow solid. Rf (CHCl3) 0.66. M.p. 112–1168. 1H-NMR (500 MHz, CDCl3): 2.39 (s,
3 H); 2.40 (s, 3 H); 3.70 (s, 3 H); 6.78 (d, J¼8.7, 1 H); 7.08 (dd, J¼1.4, 8.4, 1 H); 7.30 (d, J¼8.4, 1 H); 7.40
(s, 1 H); 7.63 (d, J¼2.3, 1 H); 7.75 (dd, J¼2.3, 8.7, 1 H). 13C-NMR (125 MHz, CDCl3): 14.8; 21.4; 55.9;
82.6; 110.1; 113.8; 117.5; 121.3; 125.6; 126.2; 133.1; 133.6; 137.0; 140.4; 151.9; 156.6; 164.0; 189.4. GC/EI-
MS (70 eV): 406 (100, Mþ ), 375 (20), 279 (22), 261 (50), 248 (46), 173 (66), 159 (22). Anal. calc. for
C18H15IO3 (406.21): C 53.22, H 3.72; found: C 53.06, H 3.66.
General Procedure for Preparation of Thioketones 12. A soln. of ketone 8a or 8e (0.68 mmol) and 2,4-
bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan 2,4-disulfide (Lawessonꢂs reagent; 0.138 g, 0.34 mmol)
in dry toluene (10 ml) was refluxed for 6 h. The solvent was removed in a rotary evaporator, and the
residue was purified by CC.
(5’-Fluoro-2’,4-dimethoxybiphenyl-3-yl)(2-methyl-1-benzofuran-3-yl)methanethione (12a). From 9a
(1.1 g, 2.8 mmol), Lawessonꢂs reagent (566.3 mg, 1.4 mmol), and toluene (40 ml). Yield: 1.01 g (89%).
Blue solid. Rf (CHCl3) 0.77. M.p. 153–1568. 1H-NMR (500 MHz, CDCl3): 2.37 (s, 3 H); 3.66 (s, 3 H); 3.75
(s, 3 H); 6.88 (dd, J(H,F)¼4.5, J(H,H)¼ 8.9, 1 H); 6.95–6.99 (m, 2 H); 7.07 (dd, J¼3.0, 9.0, 1 H); 7.22–
7.30 (m, 2 H); 7.43 (d, J¼8.0, 1 H); 7.56 (d, J¼2.1, 1 H); 7.58 (dd, J¼2.2, 8.5, 1 H), 7.88–7.89 (m, 1 H).
13C-NMR (125 MHz, CDCl3): 15.8; 56.0; 56.2; 110.5; 111.2; 112.4 (d, J(C,F)¼8.4); 114.2 (d, J(C,F)¼
22.6); 117.1 (d, J(C,F)¼23.7); 122.1; 124.2; 124.8; 128.3; 130.3; 130.4; 131.9; 139.1; 152.7; 153.5; 153.8;
156.2; 161.8; 215.7. EI-MS (70 eV): 406 (31, Mþ ), 373 (56), 342 (33), 249 (13), 213 (19), 149 (100), 131
(15). HR-EI-MS: 406.1037 (Mþ, C24H19FO3Sþ ; calc. 406.1039).
(5’-Fluoro-2’,4-dimethoxybiphenyl-3-yl)(2-methyl-1-benzothiophen-3-yl)methanethione (12b). From
9e (277 mg, 0.68 mmol), Lawessonꢂs reagent (138 mg, 0.34 mmol), and toluene (10 ml). Yield: 210 mg
(73%). Green oil. Rf (CHCl3) 0.66. 1H-NMR (500 MHz, CDCl3): 2.47 (s, 3 H); 3.47 (s, 3 H); 3.77 (s, 3 H);
6.85–6.91 (m, 3 H); 7.08–7.11 (m, 1 H); 7.22–7.28 (m, 2 H); 7.61–7.64 (m, 2 H); 7.71–7.73 (m, 1 H) 7.88
(d, J¼2.3, 1 H). 13C-NMR (125 MHz, CDCl3): 16.1; 56.1; 56.2; 111.7; 112.4 (d, J(C,F)¼9.1); 114.2 (d,
J(C,F)¼22.4); 117.0 (d, J(C,F)¼23.5); 121.4; 123.2; 123.6; 124.2; 124.6; 124.9; 126.5; 131.5; 132.4; 133.7;
136.7; 153.4; 155.2; 157.6; 169.1. EI-MS (70 eV): 422 (44, Mþ ), 406 (40), 391 (53), 389 (100), 358 (89),
281 (20), 147 (71). HR-ESI-MS: 423.0881 ([MþH]þ , C24H20FO2S2þ ; calc. 423.0883).

2630
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
General Procedure for the Preparation of Phenolic Ketones 10 and 11, and Thioketones 13. A 100-ml
two-necked flask, equipped with a magnetic stirrer and a connection to the combined N2/vacuum line,
was charged with ketone 8b, 8g–8j, 9a–9h, or thioketone 12. The air in the flask was replaced by N2, and
the flask was closed with a septum. CHCl2 (40 ml) was injected, the soln. was cooled to ꢀ788, and BBr3
was added dropwise by syringe. Stirring was continued overnight, while the mixture was allowed to reach
r.t. H2O and dil. HCl were added, the layers were separated, and the aq. phase was extracted three times
with CH2Cl2. The combined org. layers were concentrated under reduced pressure, and the residue was
purified by CC.
(5’-Fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)(2-methyl-1-benzofuran-3-yl)methanone (10a). From 9a
(903 mg, 2.31 mmol), BBr3 (0.84 ml), and CH2Cl2 (50 ml). Yield: 463 mg (55%). Yellow solid. Rf
(hexane/AcOEt 3 :1) 0.37. 1H-NMR (500 MHz, CDCl3): 2.61 (s, 3 H); 6.78–6.90 (m, 3 H); 7.20 (d, J¼8.6,
1 H); 7.25–7.33 (m, 2 H); 7.48–7.49 (m, 2 H); 7.65 (dd, J¼2.0, 8.6. 1 H); 7.79 (d, J¼2.0, 1 H); 12.10 (s,
1 H). 13C-NMR (125 MHz, CDCl3): 14.4; 111.1; 115.3 (d, J(C,F)¼23.0), 116.4 (d, J(C,F)¼23.5); 116.8
(d, J(C,F)¼8.3); 119.1; 120.6; 120.7; 123.8; 124.9; 126.6; 127.0; 127.8 (d, J(C,F)¼7.6); 133.2; 137.1; 148.4;
153.7; 157.0 (d, J(C,F)¼239.1); 160.4; 162.3; 195.8. EI-MS (70 eV): 362 (41, Mþ ), 347 (13), 345 (11), 230
(60), 132 (100). Anal. calc. for C22H15FO4 (362.35): C 72.92, H 4.17; found: C 72.74, H 4.10.
(2,5-Dimethyl-1-benzofuran-3-yl)(5’-fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)methanone; 10b).
From 9b (500 mg,1.24 mmol), BBr3 (0.45 ml), and CH2Cl2 (30 ml). Yield: 465 mg (quant.). Yellow
1
solid. Rf (hexane/AcOEt 1:1) 0.64. M.p. 151–1528. H-NMR (500 MHz, CDCl3): 2.41 (s, 3 H); 2.59 (s,
3 H); 6.79–6.89 (m, 3 H); 7.12 (d, J¼8.2, 1 H); 7.19 (d, J¼8.6, 1 H); 7.28 (s, 1 H); 7.35 (d, J¼8.4, 1 H);
7.66 (dd, J¼2.2, J¼8.6. 1 H); 7.80 (d, J¼2.2, 1 H); 12.11 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.5;
21.3; 110.7; 115.2 (d, J(C,F)¼23.0); 116.2; 116.4 (d, J(C,F)¼23.5); 116.8 (d, J(C,F)¼8.2); 119.0; 120.5;
120.6; 126.0; 126.6; 127.0; 127.8 (d, J(C,F)¼8.1); 133.3; 133.5; 137.1; 152.1; 157.0 (d, J(C,F)¼238.7);
160.7; 162.3; 171.2; 195.9. EI-MS (70 eV): 376 (31, Mþ ), 359 (10), 230 (19), 173 (9), 146 (100). Anal. calc.
for C23H17FO4 (376.38): C 73.40, H 4.55; found: C 73.53, H 4.64.
{3-[(5’-Fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)carbonyl]-2-methyl-1-benzofuran-5-yl}acetonitrile
(10c). From 9c (111 mg, 0.26 mmol), BBr3 (0.1 ml), and CH2Cl2 (5 ml). Yield: 66 mg (63%). Yellow oil.
1
Rf (hexane/AcOEt 1:1) 0.52. H-NMR (500 MHz, CDCl3): 2.62 (s, 3 H); 3.78 (s, 2 H); 6.78–6.81 (m,
1 H); 6.84–6.89 (m, 2 H); 7.20 (d, J¼8.6, 1 H); 7.24 (dd, J¼1.6, 8.5, 1 H); 7.48 (d, J¼8.6, 2 H); 7.66 (dd,
J¼2.2, 8.6, 1 H); 7.77 (d, J¼2.2, 1 H); 12.0 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.4; 23.5; 111.8; 115.2
(d, J(C,F)¼22.9); 116.3; 116.5 (d, J(C,F)¼23.4); 117.2 (d, J(C,F)¼8.3); 118.5; 119.1; 120.3; 120.4; 124.6;
125.4; 127.4; 127.6; 128.2; 133.1; 137.5; 148.5; 153.2; 157.0 (d, J(C,F)¼239.0); 161.6; 162.3; 195.5. EI-MS
(70 eV): 401 (49, Mþ ), 384 (9), 371 (8), 291 (15), 274 (9), 230 (100), 191 (24), 171 (59), 149 (29), 115
(11). HR-ESI-MS: 402.1130 ([MþH]þ , C24H17FNO4þ ; calc. 402.1136).
(1,2-Dimethyl-1H-indol-3-yl)(5’-fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)methanone; 10d). From 9d
(250 mg, 0.62 mmol), BBr3 (0.22 ml), and CH2Cl2 (15 ml). Yield: 176 mg (76%). Yellow solid. Rf
(hexane/AcOEt 1:1) 0.44. M.p. 137–1398. 1H-NMR (500 MHz, CDCl3): 2.61 (s, 3 H); 3.76 (s, 3 H);
6.77–6.86 (m, 3 H); 7.15–7.20 (m, 2 H); 7.24–7.35 (m, 2 H); 7.49 (d, J¼7.9, 1 H); 7.56 (dd, J¼2.2, 8.5,
1 H); 7.78 (d, J¼2.2, 1 H); 12.24 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 12.4; 29.9; 109.5; 113.0; 115.1 (d,
J(C,F)¼22.8); 116.4 (d, J(C,F)¼23.5); 116.7 (d, J(C,F)¼8.2); 119.0; 120.2; 121.8; 121.8; 122.5; 126.3;
128.0 (d, (C,F)¼7.7); 133.6; 135.8; 136.6; 143.6; 148.5; 156.7 (d, J(C,F)¼238.4); 161.9; 196.1. EI-MS
(70 eV): 375 (5, Mþ ), 145 (100), 129 (8). Anal. calc. for C23H18FNO3 (375.39): C 73.59, H 4.83, N 3.73;
found: C 73.55, H 5.06, 3.64.
(5’-Fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)(2-methyl-1-benzothiophen-3-yl)methanone (10e).
From 9e (1.13 g, 2.77 mmol), BBr3 (1.0 ml), CH2Cl2 (40 ml). Yield: 871 mg (83%). Yellow solid. Rf
(hexane/AcOEt 1:1) 0.62. 1H-NMR (500 MHz, CDCl3): 2.58 (s, 3 H); 6.75–6.87 (m, 3 H); 7.21 (d, J¼8.6,
1 H); 7.32–7.34 (m, 2 H); 7.52–7.54 (m, 1 H); 7.56 (d, J¼1.9, 1 H); 7.64 (dd, J¼1.9, 8.6, 1 H); 7.78–7.80
(m, 1 H); 12.3 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 15.5; 115.3 (d, J(C,F)¼23.0); 116.4 (d, J(C,F)¼
23.0); 116.8 (d, J(C,F)¼8.2); 119.3; 120.6; 122.1; 122.6; 124.7; 127.3; 127.6 (d, J(C,F)¼7.8); 128.0; 131.0;
133.6; 137.6; 138.1; 138.6; 144;7; 148.4; 157.0 (d, J(C,F) ¼239.3); 162.7; 198.5. GC/EI-MS (70 eV): 378
(40, Mþ ), 345 (15), 230 (65), 148 (100). Anal. calc. for C22H15FO3S (378.42): C 69.83, H 4.00; found: C
68.56, H 4.14.

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2631
(2-Butyl-1-benzothiophen-3-yl)(5’-fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)methanone (10f). From
9f (351 mg, 0.78 mmol), BBr3 (0.28 ml), and CH2Cl2 (20 ml). Yield: 320 mg (97%). Yellow solid. Rf
(hexane/AcOEt 1:1) 0.63. M.p. 119–1208. 1H-NMR (500 MHz, CDCl3): 0.84 (t, J¼7.3, 3 H); 1.26 (t, J¼
7.1, 2 H); 1.30–1.37 (m, 2 H); 2.92 (t, J¼7.7, 2 H); 6.74–6.77 (m, 2 H); 6.85 (td, J¼3.0, 8.4, 1 H); 7.21 (d,
J¼8.6, 1 H); 7.30–7.34 (m, 2 H); 7.48–7.50 (m, 1 H); 7.53 (d, J¼2.2, 1 H); 7.64 (dd, J¼2.2, 8.6, 1 H);
7.80–7.82 (m, 1 H); 12.32 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 13.7; 22.3; 29.4; 33.8; 115.2 (d, J(C,F)¼
23.2); 116.3 (d, J(C,F)¼23.5); 116.8 (d, J(C,F)¼8.2); 119.2; 120.6; 122.2; 122.5; 124.6; 124.9; 127.3; 127.6;
133.5; 137.7; 138.0; 138.4; 139.7; 148.4; 150.7; 156.0; 162.7; 198.9. EI-MS (70 eV): 420 (30, Mþ ), 363 (100),
230 (37), 190 (54), 148 (91). Anal. calc. for C25H21FO3S (420.50): C 71.41, H 5.03; found: C 71.23, H 5.05.
(2,5-Dimethyl-1-benzofuran-3-yl)(3’,4,5’-trihydroxy-1,1’-biphenyl-3-yl)methanone (10g). From 9g
(300 mg, 0.72 mmol), BBr3 (0.5 ml), and CH2Cl2 (16 ml). Yield: 261 mg (97%). Yellow solid. Rf (hexane/
AcOEt 1:2) 0.56. M.p. 97–1018. 1H-NMR (500 MHz, CDCl3): 2.41 (s, 3 H); 2.59 (s, 3 H); 6.26 (t, J¼2.2,
1 H); 6.46 (d, J¼2.2, 2 H); 7.14 (dd, J¼1.5, 8.3, 1 H); 7.14 (d, J¼8.7, 1 H); 7.33 (s, 1 H); 7.38 (d, J¼8.4,
1 H); 7.71 (dd, J¼2.3, 8.7, 1 H); 7.88 (d, J¼2.3, 1 H); 12.06 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.6;
21.4; 101.6; 106.3; 110.7; 116.3; 118.7; 120.3; 120.7; 125.9; 126.8; 131.0; 131.1; 133.4; 135.0; 142.4; 152.2;
157.1; 160.6; 162.2; 196.0. EI-MS (70 eV): 374 (93, Mþ ), 359 (22), 357 (19), 228 (74), 186 (58), 146 (100).
HR-ESI-MS: 375.1226 ([MþH]þ , C23H19Oþ5 ; calc. 375.1227).
(2,5-Dimethyl-1-benzofuran-3-yl)[4-hydroxy-4’-(trifluoromethoxy)-1,1’-biphenyl-3-yl]methanone
(10h). From 9h (150 mg, 0.34 mmol), BBr3 (0.12 ml), and CH2Cl2 (10 ml). Yield: 130 mg (90%). Yellow
1
solid. Rf (hexane/AcOEt 1:1) 0.82. M.p. 111–1128. H-NMR (500 MHz, CDCl3): 2.40 (s, 3 H); 2.60 (s,
3 H); 7.14 (dd, J¼1.3, J¼8.4, 1 H); 7.17–7.21 (m, 3 H); 7.32 (s, 1 H); 7.39 (d, J¼8.4, 1 H); 7.40–7.43 (m,
2 H); 7.74 (dd, J¼2.4, 8.6, 1 H); 7.91 (d, J¼2.4, 1 H); 12.08 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.5;
21.3; 110.7; 116.3; 119.0; 120.4; 120.6; 121.4; 126.0; 126.7; 127.7; 130.5; 131.2; 133.3; 135.0; 138.5; 147.6;
152.2; 155.1; 160.8; 162.2; 207.4. EI-MS (70 eV): 426 (34, Mþ ), 409 (12), 300 (18), 281 (28), 189 (6), 146
(100), 115 (8). HR-ESI-MS: 427.1156 ([MþH]þ , C24H18F3O4þ ; calc. 427.1152).
(5-Bromo-2-hydroxyphenyl)(2,5-dimethyl-1-benzofuran-3-yl)methanone (11a). From 8b. Yield:
1
1.4 g (21%). Yellow solid. Rf (CHCl3) 0.66. M.p. 108–1128. H-NMR (500 MHz, CDCl3): 2.42 (s, 3 H);
2.57 (s, 3 H); 6.99 (d, J¼8.8, 1 H); 7.13 (d, J¼8.5, 1 H); 7.28 (s, 1 H); 7.37 (d, J¼8.4, 1 H); 7.60 (dd, J¼
2.4, 8.9, 1 H); 7.81 (d, J¼2.4, 1 H); 11.95 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.7; 21.4; 110.3; 110.6;
120.3; 120.5; 126.1; 126.5; 132.2; 133.7; 134.8; 138.3; 139.0; 152.2; 160.8; 161.4; 195.0. GC/EI-MS (70 eV):
346, 344 (40, Mþ ), 331, 329 (35), 248 (10), 201, 199 (5), 173 (15), 146 (100). HR-ESI-MS: 345.0200 ([Mþ
H]þ , C17H14BrOþ3 ; calc. 345.0121).
(2,5-Dimethyl-1-benzofuran-3-yl)(2-hydroxy-5-methylphenyl)methanone (11b). From 8g (230 mg,
0.78 mmol), BBr3 (0.28 ml), and CH2Cl2 (17 ml). Yield: 184 mg (84%). Yellow solid. Rf (hexane/AcOEt
3 :1) 0.6. M.p. 99–1008. 1H-NMR (500 MHz, CDCl3): 2.23 (s, 3 H); 2.40 (s, 3 H); 2.55 (s, 3 H); 6.99 (d, J¼
8.5, 1 H); 7.11 (dd, J¼1.3, 8.4, 1 H); 7.28 (s, 1 H); 7.33–7.35 (m, 1 H); 7.36 (d, J¼8.4, 1 H); 7.47 (d, J¼1.7,
1 H); 11.87 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.5; 20.3; 21.4; 110.4; 116.5; 118.0; 120.1; 120.6; 125.7;
127.0; 128.0; 132.5; 133.3; 137.5; 152.1; 159.9; 160.5; 196.1. GC/EI-MS (70 eV): 280 (52, Mþ ), 265 (30),
263 (32), 248 (4), 173 (6), 146 (100), 135 (18). Anal. calc. for C18H16O3 (280.32): C 77.12, H 5.75; found: C
76.94, H 5.84.
(2,5-Dimethyl-1-benzofuran-3-yl)[2-hydroxy-5-(trifluoromethyl)phenyl]methanone (11c). From 8h
(140 mg, 0.40 mmol), BBr3 (0.14 ml), and CH2Cl2 (10 ml). Yield: 103 mg (77%). Orange solid. Rf
(hexane/AcOEt 1:1) 0.69. M.p. 87–898. 1H-NMR (500 MHz, CDCl3): 2.39 (s, 3 H); 2.58 (s, 3 H); 7.14 (d,
J¼8.4, 2 H); 7.18 (d, J¼8.8, 1 H); 7.25 (s, 1 H); 7.38 (d, J¼8.4, 1 H); 7.75 (dd, J¼1.9, 8.7, 1 H); 8.02 (s,
1 H); 12.36 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.7; 21.3; 110.7; 115.9; 119.1; 119.7; 120.5; 121.0;
121.3; 126.2; 126.3; 130.4 (q, J(C,F)¼3.8); 132.6 (q, J(C,F)¼3.4); 133.7; 152.2; 161.4; 164.8; 195.2. GC/
EI-MS (70 eV): 334 (100, Mþ ), 319 (85), 317 (80), 302 (5), 189 (30), 173 (20), 161 (20), 146 (100), 115
(25). HR-ESI-MS: 335.0890 ([MþH]þ , C18H14F3O3þ ; calc. 335.0890).
3-[(2,5-Dimethyl-1-benzofuran-3-yl)carbonyl]-4-hydroxybenzonitrile (11d). From 8i (738 mg,
2.42 mmol), BBr3 (0.88 ml), and CH2Cl2 (50 ml). Yield: 468 mg (66%). Yellow solid. Rf (hexane/
AcOEt 1:1) 0.63. M.p. 159–1608. 1H-NMR (500 MHz, CDCl3): 2.41 (s, 3 H); 2.60 (s, 3 H); 7.14–7.19 (m,
1 H); 7.39 (d, J¼8.4, 1 H); 7.76 (dd, J¼2.1, 8.7, 1 H); 8.05 (d, J¼2.1, 1 H); 12.53 (s, 1 H). 13C-NMR
(125 MHz, CDCl3): 14.6; 21.4; 102.5; 110.9; 115.6; 118.1; 120.0; 120.1; 126.1; 126.4; 134.0; 137.5; 138.8;

2632
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
152.2; 165.7; 166.9; 194.9. GC/EI-MS (70 eV): 291 (74, Mþ ), 276 (46), 274 (44), 173 (10), 146 (100).
Anal. calc. for C18H13NO3 (291.30): C 74.22, H 4.50, N 4.81; found: C 74.17, H 4.68, N 4.30.
(2,5-Dimethyl-1-benzofuran-3-yl)(2-hydroxy-5-iodophenyl)methanone (11e). From 8j (942 mg,
2.32 mmol), BBr3 (0.84 ml), and CH2Cl2 (50 ml). Yield: 728 mg (80%). Yellow solid. Rf (hexane/
1
AcOEt 3 :1) 0.62. M.p. 125–1278. H-NMR (500 MHz, CDCl3): 2.43 (s, 3 H); 2.57 (s, 3 H); 6.88 (d, J¼
8.8, 1 H); 7.13 (dd, J¼1.3, 8.4, 1 H); 7.28 (s, 1 H); 7.37 (d, J¼8.4, 1 H); 7.76 (dd, J¼2.2, J¼8.8, 1 H); 7.99
(d, J¼2.2, 1 H); 11.97 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.7; 21.4; 79.4; 110.1; 110.6; 116.0; 120.6;
120.7; 122.4; 126.1; 126.5; 133.7; 141.0; 144.6; 152.2; 161.0; 162.1; 194.8. GC/EI-MS (70 eV): 392 (45, Mþ ),
377 (15), 247 (10), 219 (5), 195 (10), 173 (10), 146 (100). Anal. calc. for C17H13IO3 (392.19): C 52.06, H
3.34; found: C 52.31, H 3.15.
(5’-Fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)(2-methyl-1-benzofuran-3-yl)methanethione (13a).
From 12a (500 mg, 1.23 mmol), BBr3 (0.44 ml), and CH2Cl2 (26 ml). Yield: 300 mg (64%). Brown
1
solid. Rf (hexane/AcOEt 1:1) 0.64. M.p. 82–848. H-NMR (500 MHz, CDCl3): 2.47 (s, 3 H); 6.87–6.89
(m, 1 H); 6.94 (td, J¼3.0, 8.5, 1 H); 7.03 (d, J¼8.5, 1 H); 7.08 (dd, J¼2.9, 9.7, 1 H); 7.26–7.29 (m, 1 H);
7.31–7.35 (m, 1 H); 7.57–7.61 (m, 2 H), 7.63 (d, J¼2.2, 1 H); 7.67 (dd, J¼2.2, 8.5, 1 H); 9.54 (s, 1 H);
10.40 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.4; 111.2; 115.2 (d, J(C,F)¼22.9); 116.3; 114.4 (d,
J(C,F)¼23.7); 116.8 (d, J(C,F)¼8.2); 119.0; 120.6; 123.8; 124.8; 126.6; 127.2; 127.8 (d, J(C,F)¼7.5 ) ;
133.2; 137.2; 148.5; 153.7; 157.0 (d, J(C,F)¼239.0); 160.4; 162.2; 174.9; 195.9. EI-MS (70 eV): 378 (2, Mþ ),
362 (48), 345 (36), 230 (68), 159 (17), 132 (100). HR-EI-MS: 378.0743 (Mþ, C22H15FO3Sþ ; calc.
378.0726).
(5’-Fluoro-2’,4-dihydroxy-1,1’-biphenyl-3-yl)(2-methyl-1-benzothiophen-3-yl)methanethione (13b).
From 12b (150 mg, 0.36 mmol), BBr3 (0.13ml), and CH2Cl2 (10 ml). Yield: 121 mg (86%). Red oil. Rf
(hexane/AcOEt 1:1) 0.63. 1H-NMR (500 MHz, CDCl3): 2.46 (s, 3 H); 6.69–6.74 (m, 2 H); 6.83 (td, J¼
3.0, 8.3, 1 H); 7.28–7.37 (m, 4 H); 7.44 (d, 1 J¼2.2, 1 H); 7.61 (dd, J¼2.2, 8.6, 1 H); 7.77 (d, J¼7.2, 1 H);
13.44 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 14.2; 115.3 (d, J(C,F)¼22.9); 116.2 (d, J(C,F)¼23.4); 116.9
(d, J(C,F)¼8.4); 119.2; 121.0; 122.0; 122.2; 124.5; 124.6; 125.0; 125.1; 128.7; 131.1; 133.7; 137.8; 148.2;
157.9; 162.8; 171.2. EI-MS (70 eV): 394 (1, Mþ ), 361 (100), 345 (3), 147 (10). HR-ESI-MS: 395.05703
([MþH]þ , C22H16FO2Sþ2 ; calc. 395.0570).
Crystal-Structure Determination of 10b. A well-shaped crystal of 10b was selected by means of an
optical microscope and investigated at r.t. on an Oxford Diffraction Xcalibur (EOS) diffractometer,
using graphite monochromatized MoKa radiation. Unit cell parameters were determined by least-
squares refinement on the positions of 13,715 reflections, distributed equally in reciprocal space in the
Table 2. Crystal Data, X-Ray Measurement and Structure Determination Summary for Compound 10b
Empirical Formula
Formular weight
Crystal color; habit
Crystal size [mm3]
Crystal system
Space group
Unit cell dimensions a [ꢅ] 8.5156(12)
b [ꢅ] 11.1887(13)
C23H17FO4
376.37
Absorbtion coefficient [mmꢀ1
F(000)
q Range [8]
]
0.101
392
colorless, plate
0.30ꢃ0.28ꢃ0.18
triclinic
2.76ꢂqꢂ25.00
ꢀ10ꢂhꢂ10
ꢀ13ꢂkꢂ13
ꢀ12ꢂlꢂ13
6276/263
0.043
Index ranges
¯
P1
Reflections collected/unique
Rint
c [ꢅ] 11.2418(15)
Observed reflections [I 2s(I)]
Data/parameters
2563
3057/263
1.173
R1 ¼0.057
wR2 ¼0.107
R1 ¼0.072
wR2 ¼0.112
0.158/ꢀ0.106
a [8]
b [8]
g [8]
102.879(10)
108.594(11)
107.431(10)
906.5(2)
Goodness-of-fit on F2
Final R indices [I>2s(I)]
Volume [ꢅ3]
Z
Density (calc.; [g cmꢀ3])
Temp. [K]
2
R indices (all data)
1.379
291(2)
MoKa, l¼0.71073
Largest diff. peak/hole [e ꢅꢀ3
]
Wavelength [ꢅ]

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2633
¯
range 2.048<q<29.828. An anorthic lattice was found consistent with space group types P1 and P1. In
accordance with E-statistics, significantly better results were observed in the centrosymmetric space
group type in the course of structure refinement. Crystal data as well as details of data collection and
structure refinement are collected in Table 2. Lorentz-polarization corrections were applied to the
collected data, and the structure was solved by direct methods [20] and subsequent difference Fourier
syntheses. Approximate positions of all H-atoms were found. Refinement by full-matrix least-squares
calculations on F2 [21] converged (max. shift/esd: 0.000) giving the final quality indicators listed in
Table 2. Refined parameters include positional parameters as well as anisotropic displacement
parameters for all the atoms heavier than H. For H-atoms bonded to O-atoms, positional and isotropic
displacement parameters were refined. With idealized bond lengths and angles assumed for all the CH
and Me groups, the riding model was applied for the corresponding H-atoms, and their isotropic
displacement parameters were constrained to 120 and 150% of the equivalent isotropic displacement
parameters of the parent C-atoms, respectively. In addition, the H-atoms of the Me groups were allowed
to rotate around the neighboring CꢀC bonds. CCDC-890359 contains the supplementary crystallographic
data (excluding structure factors) for this article. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
REFERENCES
[1] G. Fischer, Chem. Soc. Rev. 2000, 29, 119; G. Fischer, Angew. Chem. 1994, 106, 1479; G. Fischer,
Angew. Chem., Int. Ed. 1994, 33, 1415.
[2] G. Fischer, H. Bang, C. Mech, Biomed. Biochim. Acta 1984, 43, 1101.
[3] J. Fanghꢁnel, Angew. Chem. 2003, 115, 506; J. Fanghꢁnel, Angew. Chem., Int. Ed. 2003, 42, 490; Y.
Zhang, Mini-Rev. Org. Chem. 2004, 1, 359; K. P. Lu, X. Z. Zhou, Nat. Rev. Mol. Cell Biol. 2007, 8, 904.
[4] A. Ryo, Y.-C. Liou, K. P. Lu, G. Wulf, J. Cell Sci. 2003, 116, 773; G. M. Wulf, A. Ryo, G. G. Wulf,
S. W. Lee, T. Niu, V. Petkova, K. P. Lu, EMBO J. 2001, 20, 3459; Y.-C. Liou, A. Sun, A. Ryo, X. Z.
Zhou, Z.-X. Yu, H.-K. Huang, T. Uchida, R. Bronson, G. Bing, X. Li, T. Hunter, K. P. Lu, Nature
2003, 424, 556; P.-J. Lu, G. Wulf, X. Z. Zhou, P. Davies, K. P. Lu, Nature 1999, 399, 784.
[5] G. G. Xu, F. A. Etzkorn, Drug News Perspect. 2009, 22, 399.
[6] L. Henning, C. Christner, M. Kipping, B. Schelbert, K. P. Rꢀcknagel, S. Grabley, G. Kꢀllertz, G.
Fischer, Biochemistry 1998, 37, 5953; T. Uchida, M. Takamiya, M. Takahashi, H. Miyashita, H.
Ikeda, T. Terada, Y. Matsuo, M. Shirouzu, S. Yokoyama, F. Fujimori, T. Hunter, Chem. Biol. 2003,
10, 15; H. C. Wang, K. Kim, R. Bakhtiar, J. P. Germanas, J. Med. Chem. 2001, 44, 2593; E. Bayer, M.
Thutewohl, C. Christner, T. Tradler, F. Osterkamp, H. Waldmann, P. Bayer, Chem. Commun. 2005,
516; D. Wildemann, F. Erdmann, B. Hernandez Alvarez, G. Stoller, X. Z. Zhou, J. Fanghꢁnel, M.
Schutkowski, K. P. Lu, G. Fischer, J. Med. Chem. 2006, 49, 2147; S. Zhao, F. A. Etzkorn, Bioorg.
´
Med. Chem. Lett. 2007, 17, 6615; M. Braun, A. Hessamian-Alinejad, B. Feaux De Lacroix, B.
Hernandez Alvarez, G. Fischer, Molecules 2008, 13, 995; B. Wu, M. F. Rega, J. Wei, H. Yuan, R.
Dahl, Z. Zhang, M. Pellecchia, Chem. Biol. Drug Des. 2009, 73, 369; Y. Tatara, Y.-C. Lin, Y. Bamba,
T. Mori, T. Uchida, Biochem. Biophys. Res. Commun. 2009, 384, 394; C. Guo, X. Hou, L. Dong, E.
Dagostino, S. Greaseley, R. Ferre, J. Marakovits, M. C. Johnson, D. Matthews, B. Mroczkowski, H.
Parge, T. Van Asdale, I. Popoff, J. Piraino, S. Margosiak, J. Thomson, G. Los, B. W. Murray, Bioorg.
Med. Chem. Lett. 2009, 19, 5613; L. Dong, J. Marakovits, X. Hou, C. Guo, S. Greasley, E. Dagostino,
R. Ferre, M. C. Johnson, E. Kraynov, J. Thomson, V. Pathak, B. W. Murray, Bioorg. Med. Chem.
Lett. 2010, 20, 2210; T. Liu, Y. Liu, H.-Y. Kao, D. Pei, J. Med. Chem. 2010, 53, 2494; A. J. Potter, S.
Ray, L. Gueritz, C. L. Nunns, C. J. Bryant, S. F. Scrace, N. Matassova, L. Baker, P. Dokurno, D. A.
Robinson, A. E. Surgenor, B. Davis, J. B. Murray, C. M. Richardson, J. D. Moore, Bioorg. Med.
Chem Lett. 2010, 20, 586; A. Potter, V. Oldfield, C. Nunns, C. Fromont, S. Ray, C. J. Northfield, C. J.
Bryant, S. F. Scrace, D. Robinson, N. Matossova, L. Baker, P. Dokurno, A. E. Surgenor, B. Davis,
C. M. Richardson, J. B. Murray, J. D. Moore, Bioorg. Med. Chem. Lett. 2010, 20, 6483; K. E. Duncan,
B. R. Dempsey, L. E. Killip, J. Adams, M. L. Bailey, G. A. Lajoie, D. W. Litchfield, C. J. Brandl, G. S.

2634
CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Shaw, B. H. Shilton, J. Med. Chem. 2011, 54, 3854; C. Liu, J. Jin, L. Chen, J. Zhou, X. Chen, D. Fu, H.
Song, B. Xu, Bioorg. Med. Chem. 2012, 20, 2992.
[7] P. T. Flaherty, P. Jain, Ann. Rep. Med. Chem. 2011, 46, 337.
´
[8] S. Daum, F. Erdmann, G. Fischer, B. Feaux de Lacroix, A. Hessamian-Alinejad, S. Houben, W.
´
Frank, M. Braun, Angew. Chem. 2006, 118, 7615; S. Daum, F. Erdmann, G. Fischer, B. Feaux de Lacroix,
A. Hessamian-Alinejad, S. Houben, W. Frank, M. Braun, Angew. Chem., Int. Ed. 2006, 45, 7454.
´
[9] S. Daum, M. Schumann, S. Mathea, T. Aumꢀller, M. A. Balsley, S. L. Constant, B. Feaux de Lacroix,
F. Kruska, M. Braun, C. Schiene-Fischer, Biochemistry 2009, 48, 6268.
[10] S. V. Sambasivarao, O. Acevedo, J. Chem. Inf. Model. 2011, 51, 475.
[11] J. Pietruszka, R. C. Simon, F. Kruska, M. Braun, Eur. J. Org. Chem. 2009, 6217.
[12] H. W. Gschwend, H. R. Rodriguez, Org. React. 1979, 26, 1; P. Barker, P. Finke, K. Thompson, Synth.
Commun. 1989, 19, 257; H. Sekizaki, K. Itoh, E. Toyota, K. Tanizawa, Heterocycles 2003, 59, 237.
[13] a) A. Suzuki, M. Miyaura, J. Chem. Soc., Chem. Commun. 1979, 866; b) B. E. Huff, T. M. Koenig, D.
Mitchell, M. A. Staszak, Org. Synth. 2004, Coll. Vol. 10, 102.
[14] T. Schareina, A. Zapf, M. Beller, Chem. Commun. 2004, 1388.
[15] A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 14844.
[16] I. Thomsen, K. Clausen, S. Scheibye, S.-O. Lawesson, Org. Synth. 1990, Coll. Vol. 7, 372.
[17] M. C. Etter, J. C. MacDonald, J. Bernstein, Acta Crystallogr., Sect. B 1990, 46, 256.
[18] B. Janowski, S. Wçllner, M. Schutkowski, G. Fischer, Anal. Biochem. 1997, 252, 299.
[19] R. Siegrist, M. Zꢀrcher, C. Baumgartner, P. Seiler, F. Diederich, S. Daum, G. Fischer, C. Klein, M.
Dangl, M. Schwaiger, Helv. Chim. Acta 2007, 90, 217.
[20] G. M. Sheldrick, SHELXS86, Program for the Solution of Crystal Structures, University of
Gçttingen, Germany, 1985.
[21] G. M. Sheldrick, SHELXL97, Program for the Refinement of Crystal Structures, University of
Gçttingen, Germany, 1997.
Received July 17, 2012