Synthesis of Polycyclic Chromene Cores through Gold (I)-Catalyzed Intramolecular Hydroarylation Reaction (IMHA)

Article abstract of DOI:10.1002/ejoc.202100092

A regioselective gold (I)-catalyzed approach for the construction of polycyclic chromene cores has been developed. The reaction proceeds in good to excellent yields under mild condition with a broad range of substrates providing a simple and efficient too

Full text of DOI:10.1002/ejoc.202100092

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doi.org/10.1002/ejoc.202100092
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Synthesis of Polycyclic Chromene Cores through Gold (I)-
Catalyzed Intramolecular Hydroarylation Reaction (IMHA)
Antonio Arcadi,[a] Giancarlo Fabrizi,[b] Andrea Fochetti,[b] Roberta Franzini,[b]
Francesca Ghirga,[c] Antonella Goggiamani,*[b] Antonia Iazzetti,*[b] Federico Marrone,[b] and
Andrea Serraiocco[b]
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Dedicated to Prof. Franco Cozzi in occasion of his 70th birthday.
A regioselective gold (I)-catalyzed approach for the construction
of polycyclic chromene cores has been developed. The reaction
proceeds in good to excellent yields under mild condition with
a broad range of substrates providing a simple and efficient
tool for the synthesis of pyranochromene derivatives. Moreover,
the regiochemical control of the annulation of unsymmetrically
substituted propargylic ethers has been investigated focusing
on electronic/steric effects of the ligands of gold complexes as
well as on the electronic effects of the groups on the aromatic
rings.
Introduction
arylprop-2-yn-1-yl)oxy)benzene derivatives 4 to the corresponding
4,6-diaryl-2H,8H-pyrano[3,2-g]chromenes
5 and/or 4,10-diaryl-
The addition reaction of a broad range of nucleophiles with
alkynes catalyzed by gold(I) complexes has emerged as a
powerful tool in organic synthesis.[1] In the case of arenes as
nucleophiles, alkynes undergo gold(I)-catalyzed Friedel-Crafts-
type reactions to give hydroarylation products, which are
applied in the context of the synthesis of polycyclic and
polyheterocyclic derivatives.[2]
2H,8H-pyrano[2,3-f]chromenes 6 (Scheme 2) and of the 1,3,5-tris
((3-arylprop-2-yn-1-yl)oxy)benzene derivatives 7 to 4,8,12-triaryl-
2H,6H,10H-dipyrano[2,3-f:2’,3’-h]chromenes 8 (Scheme 2).
As 2H-chromene derivatives, these cyclization products
appeared to us very attractive for different remarkable features.
Indeed, the 2H-chromene ring system is the core structure of
numerous biologically active natural products,[4] and was
proved to code useful photochromic properties[5] opening new
perspectives on materials science. In this regard, for instance,
We previously described the regioselective access to the
angular pyranocumarine derivatives
2 through the gold-
catalyzed intramolecular hydroarylation of readily available 7-
(prop-2-yn-1-yloxy)-2H-chromen-2-ones 1a at their C-8 con-
gested position by tuning the electronic and steric properties of
the ligand on the gold complex.[3] On the other hand, the
combination of the JohnPhosAu(MeCN)SbF6 catalyzed intra-
molecular hydroarylation of 8-iodo-7-(prop-2-yn-1-yloxy)-2H-
chromen-2-one derivatives 1b followed by selective palladium/
formate CÀ I reduction allows for the exclusive formation of the
corresponding linear isomer 3 (Scheme 1).
Subsequently, we envisaged to investigate the intramolecular
gold-catalyzed hydroarylation of the readily available 1,3-bis((3-
Scheme 1. Our previous work: IMHA of 7-(prop-2-yn-1-yloxy)-2H-chromen-2-
one derivatives 1a or 1b.
[a] Prof. A. Arcadi
Università degli Studi di L’Aquila
Dipartimento di Scienze Fisiche e Chimiche,
Via Vetoio, 67100 Coppito (AQ), Italy
[b] Prof. G. Fabrizi, A. Fochetti, Dr. R. Franzini, Prof. A. Goggiamani,
Dr. A. Iazzetti, F. Marrone, A. Serraiocco
Dipartimento di Chimica e Tecnologie del Farmaco
Sapienza, Università di Roma
P.le A. Moro 5, 00185 Rome, Italy
E-mail: antonella.goggiamani@uniroma1.it
antonia.iazzetti@uniroma1.it
[c] Dr. F. Ghirga
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia
Viale Regina Elena 291, 00161 Rome, Italy
Part of the “Franco Cozzi’s 70th Birthday” Special Collection.Supporting in-
formation for this article is available on the WWW under https://doi.org/
10.1002/ejoc.202100092
Scheme 2. Work hypothesis.
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this heterocyclic motif has been linked to photochromic
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crystals[6] and to photochromic organogelators.[7] Due to its
importance, several studies in the field of gold catalysis have
been focused on providing access to this relevant heterocyclic
scaffold,[8] but to the best of our knowledge, there is a lack of
approaches to dipyranochromene derivatives, while only limited
synthetic methodologies of pyranochromenes are reported in
the literature.[9] This aspect may justify our efforts to develop a
new and efficient protocol for their preparation. Hereafter we
report the results of our investigation
Scheme 4. Au(I)-catalyzed IMHA of (((5-(((phenylethynyl)oxy)methyl)-1,3-
phenylene)bis(oxy))bis(prop-1-yne-3,1-diyl))dibenzene 7b.
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Results and Discussion
Table 1. Substrate Scope.
The 1,3-bis((3-arylprop-2-yn-1-yl)oxy)benzene derivatives 4b–h
and the 1,3,5-tris((3-arylprop-2-yn-1-yl)oxy)benzene building
blocks 7b–l were easily obtained from the corresponding cheap
phenols through a two- step procedure outlined in the
following Scheme 3.
We started our work performing the cyclization of the
compound 7b in the presence of the commercially available
gold catalyst JohnPhosAu(CH3CN)SbF6: pleasingly, using the
4 mol% of catalyst in CH2Cl2 at room temperature
(Scheme 4)[3,11] we observed the formation of compound 8b
rapidly and in excellent yield.
Entry[a]
(7)
R =
Time [h]
(8)
Yield [%][b]
1
2
(7c)
4-(Me)
(7d)
4-(OMe)
(7e)
3-(OMe)
(7f)
0.75
0.25
0.5
(8c)
95
(8d)
98
(8e)
91
Remarkably, this triple hydroarylation achieves the simulta-
neous formation of all three CÀ C bonds in
a one-pot
3
transformation.[12]
As an almost quantitative yield was obtained no further
screening experiments were carried out and we turned our
attention on the evaluation of the substrate scope (Table 1).
As expected, the introduction of an electron-donating
group in the para-position of the three aromatic rings attached
4
1.0
(8f)
4-(COMe)
(7g)
4-(CO2Me)
(7h)
4-(CN)
(7i)
3-(CF3)
(7j)
4-Cl
(7k)
4-Br
(7l)
90
(8g)
99
(8h)
99
(8i)
98
(8j)
98
(8k)
99
5
0.25
0.50
0.25
0.25
0.25
0.75
6
7
8
9
10
(8l)
3-Br
95
[a] Reactions were carried out on 0.3 mmol of 7c–l in 2 mL of CH2Cl2 at
room temperature in the presence of 0.04 equiv. of JohnPhosAu(CH3CN)
SbF6. [b] Yields are given for isolated products.
to the alkyne moiety of the starting ethers 7 efficiently
promoted the triple hydroarylation reaction (Table 1, entries 1
and 2). It is worth emphasizing that the reaction is also allowed
in almost quantitative yield even in the presence of strong
withdrawing substituents (Table 1, entries 4–7). Furthermore,
the reaction is totally compatible with aryl halides due to the
inertness of gold(I) catalysts towards oxidative addition reac-
tions under homogeneous conditions allowing further function-
alization of the halide substituted dipyranochromenes (Table 1,
entries 8–10).
Scheme 3. 3a) Synthesis of 1,3-bis((3-arylprop-2-yn-1-yl)oxy)benzene deriva-
tives 4b-h. Reagents and conditions: (i) K2CO3 (2.5 equiv.), propargyl bromide
(2.5 equiv.), DMF, rt; (ii) substituted iodobenzene (2.2 equiv.), Pd(PPh3)2Cl2
(0.02 equiv.), CuI (0.04 equiv.), DMF–Et3N, r.t. 3b) Synthesis of 1,3,5-tris((3-
arylprop-2-yn-1-yl)oxy)benzene derivatives 7b-l. Reagents and conditions: (i)
K2CO3 (3.5 equiv.), propargyl bromide (3.5 equiv.), DMF, rt; (ii) substituted
iodobenzene (3.3 equiv.), Pd(PPh3)2Cl2 (0.02 equiv.), CuI (0.04 equiv.), DMF–
Et3N, r.t.
Based on the above results and considering the relevance of
flavonoid derivatives in developing potent anticancer agents,[13]
we investigated the gold-catalyzed IMHA of the propargyl
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ethers of the 5,7-dihidroxyflavone (chrysin). The dipropargyl
ether 2-phenyl-5,7-bis((p-tolyl)prop-2-yn-1-yl)oxy)-4H-chro-
mene-4-one 9 lead to the formation of the 4,11-di-p-tolyl-
2H,8H,12H-dipyrano[2,3-f.2’,3’-h]chromen-8-one 10 in almost
quantitative yield (Scheme 5).
efficiency and atom economy in synthetic organic chemistry. In
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8
9
order to achieve the desired regioselective control of the gold
(I)-catalyzed IMHA of the substrates 4b–h, we explored the
annulation reaction with three different catalysts. Our results,
summarized in the Table 2, showed that the robust air stable
JohnPhosAu(CH3CN)SbF6 catalyst 1 (see Figure 1) is a suitable
catalyst to afford regioselectively the 4,5-diaryl-2H,8H-pyrano-
[3,2-g]chromenes 6b–h in high yields and a good tolerance for
both the functional groups and steric hindrance. A worsening
of the selectivity was observed in the presence of a strong
electron withdrawing at the 4-position of the aryl moiety
bonded to the alkyne moiety (Table 2, entries 10–15). The
catalyst 2 as well as the catalyst 3 (see Figure 1) resulted also
efficient catalysts but failed to achieve the regiocontrol of the
annulation reaction of 4b–h.
Switching to the 5-methoxy-2-phenyl-7-((3-(p-tolyl)prop-2-
yn-1-yl)oxy)-4H-chromen-4-one 11 the formation of two iso-
meric products was expected (12 and 13): in our hypothesis
Au(I)-catalyzed regiodivergent IMHA to the ortho- and para-
position of the -OMe group would have be established by
tuning the electronic and steric properties of the ligand on the
gold complex. Indeed, altering three-coordinate Au(I) com-
plexes was reported to play a key role in the adjacent
cyclization.[10]
Surprisingly, a regioselective cyclization at the para-position
leading the exclusive formation of 12 was observed both in the
presence of JohnPhosAu(CH3CN)SbF6 and with the electron-
deficient tris(2,4-di-tert-butylphenyl) phosphite ligand (L1). For-
mation of 13 was not observed (Scheme 6).
Subsequently, we went on further study to achieve a
regiodivergent annulation reaction and explore the site control
of the gold-catalyzed IMHA. To this purpose we selected the
IMHA of the aryl propargyl ethers 4b–h as suitable substrates
to evaluate the possibility to selectively prepare the corre-
sponding regioisomeric linear products 5b–h and/ or angular
6b–h regioisomers by appropriately choosing the catalyst or by
modifying the reaction conditions. Regiodivergent method-
ologies are included as the key factor in the concept of
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Table 2. Au(I)-catalyzed IMHA of aryl propargyl ethers 4b–h.[a]
Entry
(4)
R=
Catalyst
Time
[h]
Overall yield
[%][b]
5/6
Ratio[c]
1
2
3
4
5
6
7
8
Cat. 1
Cat. 2
Cat. 3
Cat. 1
Cat. 2
Cat. 3
Cat. 1
Cat. 2
Cat. 3
Cat. 1
Cat. 2
Cat. 3
Cat. 1
Cat. 2
Cat. 3
Cat. 1
Cat. 2
Cat. 3
Cat. 1
Cat. 2
Cat. 3
0.5
0.5
0.5
1
1
1
4.5
3
1.75
2.5
1.5
3
95
90
96
98
98
98
98
99
98
99
97
97
92
98
96
89
89
96
93
95
92
2/98
(4b)
H
40/60
46/54
0/100
39/61
42/58
0/100
7/93
28/72
39/61
40/60
42/58
13/87
41/59
43/57
5/95
(4c)
4-Me
(4d)
4-OMe
9
10
11
12
13
14
15
16
17
18
19
20
21
(4e)
4-COMe
1
(4f)
4-CO2Me
0.5
0.5
0.5
0.5
0.5
1
(4g)
4-Cl
28/72
39/61
4/96
29/71
30/70
Scheme 5. Au(I)-catalyzed IMHA of 2-phenyl-5,7-bis((p-tolyl)prop-2-yn-1-yl)
oxy)-4H-chromene-4-one 9.
(4h)
2-Br
0.5
0.5
[a] Reactions were carried out on 0.3 mmol of 4 in 2 ml of CH2Cl2 at room
temperature under the presence of 0.04 equiv. of catalyst 1 or catalyst 2 or
catalyst 3. [b] Overall yield refers to the mixture of regiosomers 5+6. [c]
1
Isomeric ratios were calculated from the H NMR analyses.
Figure 1. Catalysts used to explore the regiochemical outcome of the Au(I)-
catalyzed IMHA: catalyst 1: (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]
gold(I) hexafluoroantimonate; catalyst 2: chloro(methyldiphenylphosphine)
gold(I) and AgSbF6; catalyst 3: [Tris(2,4-di-tert-butylphenyl)phosphite]gold(I)
chloride and AgSbF6
Scheme 6. Regioselective Au(I)-catalyzed IMHA of 5-methoxy-2-phenyl-7-((3-
(p-tolyl)prop-2-yn-1-yl)oxy)-4H-chromen-4-one one 11 to 12: reactions were
carried out on 0.3 mmol of 11 in 2 mL of CH2Cl2 at room temperature under
the presence of 0.04 equiv. of the catalyst.
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Conversely, these latter catalysts accomplished the highly
ylphenyl)-phosphine and tri(furan-2-yl)phosphine (Table 3, en-
tries 1, 4–6, 8). Likely, the reaction completely failed with the
tris-(pentafluorophenyl)phosphine gold(I)chloride/AgSbF6 be-
cause of the rapid decomposition of the catalytic system under
the reaction conditions (Table 3, entry 7). A worsening of the
effectiveness and of the regioselectivity occurred in the
presence of the gold(I) catalyst bearing the tricyclohexyl
phosphine moiety (Table 3, entry 9). Control experiments with
either the gold catalyst alone or the silver salt showed no
conversions (Table 3, entries 2–3). Excellent results were ob-
served with the electron-deficient phosphite ligands (Table 3,
entries 10–12) and best results in terms of the regioselective
outcome were observed using the electron-deficient tris(2,4-di-
tert-butylphenyl) phosphite ligand (catalyst 3) (Table 3, en-
try 10). Conversely, disappointing results were observed with
Au(I) complexes coordinated with the rigid, bulky electron-rich
ligands (Table 3, entries 13–19).
1
2
3
4
5
6
7
8
9
regioselective IMHA of the propargyl ether 14a to afford the 1-
(4-(5-acetyl-2H-chromen-4-yl)phenyl)ethan-1-one 15a in about
quantitative yield (Table 3, entries 1, 10).
Indeed, in order to determine the pivotal role of the
structural features of the propargylic ethers derivatives and of
the catalytic system on the regioselective outcome of the IMHA,
we screened a variety of Au(I)complexes generating in situ the
active catalysts by the combined use of LAuCl complexes and
AgSbF6.[14] Accordingly to the remarkable applicability of the
Ph3PAuCl/AgSbF6 catalytic system for the regioselective forma-
tion of complex coumarins useful as neuroimaging[11] and the
better results provided by triphenylphosphine-gold(I) catalysis
results in terms of yield and selectivity compared to the
platinum-catalyzed IMHA of functionalised propargyl ethers
agents,[15] we observed the regioselective formation of 15a in
high yield and with good regioselectivity in the presence of the
gold(I) catalyst bearing methyldiphenylphosphine, triphenyl-
phosphine, tris-(4-chlorophenyl)-phosphine, tris-(4-trifluormeth-
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11
12
13
14
15
16
17
18
19
20
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22
23
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25
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27
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However, the IMHA reaction of a variety propargylic ethers
14 in the presence of the catalyst 3 showed the relevance of
Table 3. Au(I)-catalyzed IMHA of the (4-(3-(3-acetylphenoxy)prop-1-yn-1-yl)phenyl)ethan-1-one 14a.[a]
Entry
Catalyst
Time
[h]
Overall
Ratio
yield [%][b]
15a/16a[c]
1
2
3
4
5
6
7
Me(Ph)2PAuCl/AgSbF6
Me(Ph)2PAuCl
AgSbF6
Ph3PAuCl/AgSbF6
(p-Cl-C6H4)3PAuCl/AgSbF6
(p-CF3-C6H4)3PAuCl/AgSbF6
(C6F5)3PAuCl/AgSbF6
3
3
3
5
8
3
99
90/10
–
-
94/6
90/10
92/8
–
[d]
–
–
[d]
99
99
99
–
[e]
–
8
9
1
99
95/5
24
75[f]
75/25
10
3
99
98/2
11
12
1
2
99
99
95/5
94/6
13
14
15
16
17
18
19
JPAuCl/AgSbF6
CyJPAuCl/AgSbF6
XPhosAuCl/AgSbF6
t-BuXPhosAuCl/AgSbF6
RuPhosAuCl/AgSbF6
DavePhosAuCl/AgSbF6
SPhosAuCl/AgSbF6
1
1.5
4
3
7
8.5
3
99
99
99
99
99
99
99
41/59
53/47
63/37
43/57
43/57
84/16
63/37
[a] Reactions were carried out on 0.3 mmol of 14a in 2 ml of CH2Cl2 at room temperature under the presence of 0.04 equiv. of the catalyst. [b] Overall yield is
referred to the mixture of regiosomers 15a+16a. [c] Isomeric ratios were calculated from the 1H NMR analyses [d] The starting 14a was quantitatively
recovered. [e] Instantaneous precipitation of the catalyst. [f] The starting 14a was recovered in 11% yield.
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the features of the starting alkyne to address
a
regiochemical control of the cyclization reaction (see Table 4).
The high regioselective formation of the regioisomers 15
was observed by reacting starting alkynes, bearing withdrawing
substituents in both the aromatic rings (Table 4 entries 1 and 2),
while the reversing of the regioselectivity occurred with the
same catalyst in the presence of electron donating substituents
(Table 4, entries 4, 5, and 7).
high Experimental Section
1
2
3
4
5
6
7
8
9
General information
All the commercially available reagents, catalysts, bases and
solvents were used as purchased, without further purification.
Reaction products 5b/6b–5h/6h and 15a/16a–15g/16g were
obtained as isomeric mixtures by filtration on a pad of SiO2 to
eliminate the catalysts before calculating the isomeric ratio from 1H
NMR analyses. When possible, to obtain suitable NMR spectra of
each compound, the isomeric mixtures were further purified by
semi-preparative HPLC under normal phase condition using a
Nucleodur 100–5 column (762007.100) and eluting with n-hexane/
AcOEt mixtures. Isomeric mixture 15d+16d, 15f+16f, 15g+16g
revealed to be inseparable and were characterized without further
purification. 1H NMR (400.13 MHz), 13C NMR (100.6 MHz), and 19F
spectra (376.5 MHz) were recorded with a Bruker Avance 400
spectrometer, equipped with Nanobay console and Cryoprobe
Prodigy probe. Splitting patterns are designed as s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), or bs (broad singlet).
IR spectra were recorded with a PerkinElmer SpectrumOne FT-ATR
spectrophotometer. HRMS were recorded with an Orbitrap Exactive
Mass spectrometer with ESI source. Melting points were determined
with a Büchi B-545 apparatus and are uncorrected.
On the other hand, employing a substrate with opposite
electronic effect on the two aromatic moieties, the ring closing
reaction is mainly driven by the group on the phenol ring (R1).
Indeed, when an electron-withdrawing substituent is linked to
the phenol ring, reaction gives compound 15 as the main
component of the isomeric mixtures in spite of the presence of
a strong electron-donating group on the other ring (Table 4,
entry 2). Using a starting alkyne bearing a mild electron-
donating group R1 and a strong electron -withdrawing group R2
the site control of the cyclization results to be poorer even with
a slight prevalence of the isomer 15 (Table 4, entry 6). In all the
examined cases about a quantitative yield of the IMHA products
was observed.
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15
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Synthetic procedures
Conclusion
Starting materials has been prepared according to the literature
through a two-step procedure.[16]
In conclusion, we developed an efficient protocol for the
synthesis of pyranochromene derivatives through a gold (I)-
catalyzed intramolecular hydroarylation reaction (IMHA) that
proceeds in good to excellent yields under mild conditions,
being compatible with different functional groups such as
ether, bromo, trifluoromethyl, acetyl, cyano, and carbomethoxy.
The cyclization of unsymmetrically substituted propargylic
ethers allows the formation of two isomeric derivatives: both
electronic/steric effects of the ligands of gold complexes and
electronic effects of the substituents on the aromatic rings of
the of the starting alkyne prove to be crucial for the selectivity.
The typical procedures for the preparation of compounds 4b, 7b,
14a and for the synthesis of 5b/6b are reported below. Com-
pounds 8 and 15/16 were synthetized according to the same
procedure outlined for compounds 5b/6b.
Typical procedure for the preparation of 4b
A flask equipped with a magnetic stirring bar was charged with
PdCl2(PPh3)2 (42 mg, 0.06 mmol, 0.02 equiv.) and CuI (22.8 mg,
0.12 mmol, 0.04 equiv.) dissolved in diisopropylamine (6 mL) and
N,N-dimethylformamide (3 mL). The resultant solution was stirred
under nitrogen at room temperature for 10 minutes before adding
Table 4. Au(I)-catalyzed IMHA of phenyl propargyl ethers 14a–g in the presence of catalyst 3.[a]
Entry
14
R1
R2
Time
[h]
Overall yield
[%][b]
Ratio
15/16[c]
1
2
3
4
5
6
7
14a
14b
14c
14d
14e
14f
COMe
COMe
COMe
OMe
OMe
Me
COMe
OMe
Cl
COMe
Cl
COMe
OMe
3
0.5
2
1.5
0.5
1.5
0.5
99
99
98
99
99
99
97
98/2
74/26
94/6
34/66
36/64
60/40
23/77
14g
Me
[a] Reactions were carried out on a 0.4 mmol of 14 in 2 ml of CH2Cl2 at room temperature under the presence of 0.04 equiv. of the Catalyst 3. [b] Overall yield
is referred to the mixture of regiosomers 15+16. [c] Isomeric ratios were calculated from the H NMR analyses.
1
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°
iodobenzene (1387 mg, 760 μl, 6.8 mmol, 2.2 equiv.) and 1,3-bis
(prop-2-yn-1-yloxy)benzene (576 mg, 3.1 mmol, 1.0 equiv.) and
stirred for 4 hours at room temperature. After this time, the reaction
mixture was diluted with Et2O and washed with a saturated NH4Cl
solution, HCl 2 N and with brine. The organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by chromatography on SiO2 (25–40 μm),
eluting with a 95/5 (v/v) n-hexane/AcOEt mixture (Rf =0.24) to
obtain 813 mg (77% yield) of 1,3-bis((3-phenylprop-2-yn-1-yl)oxy)
benzene 4b.
Mp: 73–74; C; IR (neat): 2920, 2227, 1683, 1592, 1448, 1361, 1258,
1
2
3
4
5
6
7
8
1026 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.90 (d, J=8.4 Hz, 2
H), 7.65 (s, 1 H), 7.61 (d, J=7.6 Hz, 1 H) 7.53 (d, J=8.4 Hz, 2 H), 7.43
(t, J=8.0 Hz, 1 H), 7.26–7.23 (m, 1 H), 5.0 (s, 2H), 2.62 (s, 3 H), 2.60 (s,
3 H); 13C NMR (100.6 MHz) (CDCl3): δ=197.7, 197.2, 157.8, 138.5,
136.7, 132.0, 129.7, 128.2, 126.9, 122.0, 120.4, 113.7, 86.7, 86.6, 56.7,
26.7, 26.6; HRMS: m/z [M+Na]+ calcd for C19H16O3 Na: 315.0992,
found: 315.0992.
Typical procedure for the preparation of 5b/6b:
9
A flask equipped with a magnetic stirring bar was charged with 1,3-
Compound 4b: Yield: 77% (813 mg); n-hexane/AcOEt mixture 95/5
(v/v) Rf =0.24; pale yellow solid.
bis((3-phenylprop-2-yn-1-yl)oxy)benzene
(101.5 mg,
0.3 mmol,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1 equiv) and CH2Cl2 (2 mL) before adding catalyst 1 or 2 or 3
(catalyst 1: JohnPhosAu(MeCN)SbF6, 9.2 mg, 0.012 mmol, 0.04 equiv;
catalyst 2: MePh2PAuCl, 5.2 mg, 0.012 mmol, 0.04 equiv. and
AgSbF6, 4.1 mg, 0.012 mmol, 0.04 equiv; catalyst 3: [Tris(2,4-di-tert-
À 1
°
Mp=61–62 C; IR (neat): 2907, 2223, 1587, 1488, 1365, 1257 cm
;
1H NMR (400.13 MHz) (CDCl3): δ=7.48–7.46 (m, 4 H), 7.35–7.25 (m, 7
H), 6.76 (t, J=2.3 Hz, 1 H), 6.72 (dd, J1 =8.2 Hz, J2 =2.3 Hz, 2 H), 4.93
(s, 4 H); 13C NMR (100.6 MHz) (CDCl3): δ=159.2, 132.0, 130.1, 128.8,
128.4, 122.4, 108.1, 102.7, 87.3, 83.9, 56.9; HRMS: m/z [M+H]+ calcd
for C24H19O2: 339.1380; found: 339.1379.
butylphenyl)phosphite]gold
chloride,
10.5 mg,
0.012 mmol,
0.04 equiv. and AgSbF6, 4.1 mg, 0.012 mmol, 0.04 equiv).The result-
ing mixture was stirred for 30 minutes, then it was concentrated
under reduced pressure and the residue was filtered on a pad of
SiO2 to afford 96.2 mg of isomeric mixture 5b+6b (95% overall
yield) using catalyst 1 or 91.5 mg of isomeric mixture 5b+6b (90%
overall yield) using catalyst 2 or 97.3 mg of isomeric mixture 5b+
6b (96% overall yield) using catalyst 3. Regioisomeric ratio was
calculated by 1H NMR analyses on the residue obtained after
filtration. Afterwards, the two isomers were separated by semi-
preparative HPLC to obtain suitable NMR spectra of each com-
pound.
Typical procedure for the preparation of 7b
A flask equipped with a magnetic stirring bar was charged with
PdCl2(PPh3)2 (29.2 mg, 0.042 mmol, 0.02 equiv.) and CuI (15.8 mg,
0.083 mmol, 0.04 equiv.) dissolved in diisopropylamine (10 mL) and
N,N-dimethylformamide (5 mL). The resultant solution was stirred
under nitrogen at room temperature for 10 minutes before adding
iodobenzene (1401 mg, 768 μl, 6.87 mmol, 3.3 equiv.) and 1,3,5-tris
(prop-2-yn-1-yloxy)benzene (500 mg, 2.08 mmol, 1.0 equiv.) and
stirred for 24 hours at room temperature. After this time, the
reaction mixture was diluted with Et2O and washed with a
saturated NH4Cl solution, HCl 2 N and with brine. The organic layer
was dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by chromatography on SiO2 (25-
40 μm), eluting with a 85/15 (v/v) n-hexane/AcOEt mixture (Rf =
0.24) to obtain 584 mg (60% yield) of 1,3,5-tris((3-phenylprop-2-yn-
1-yl)oxy)benzene 7b.
HPLC eluent=n-hexane/AcOEt mixture 95/5 (v/v); Rf =0.22
Overall yield (catalyst 1): 95% (96.2 mg); 5b/6b=2/98.
Overall yield (catalyst 2): 90% (91.5 mg); 5b/6b=40/60;
Overall yield (catalyst 3): 96% (97.3 mg); 5b/6b=46/54;
°
Compound 5b: yellow solid; mp: 139–140 C; IR (neat): 2919, 2838,
1676, 1599, 1575, 1489 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=
7.32–7.21 (m, 10 H), 6.81 (d, J=8.4 Hz, 1 H), 6.47 (d, J=8.4 Hz, 1 H),
5.78 (t, J=4.5 Hz, 1 H), 5.50 (t, J=3.9 Hz, 1 H), 4.59 (d, J=4.5 Hz, 2
H), 4.27 (d, J=3.9 Hz, 2 H); 13C NMR (100.6 MHz) (CDCl3): δ=157.0,
151.2, 141.3, 138.7, 137.2, 136.3, 128.8, 128.5, 127.8, 127.7, 127.1,
127.0, 126.7, 121.0, 118.9, 117.4, 113.2, 109.1, 65.0, 64.4; HRMS: m/z
[M+H]+ calcd for C24H19O2: 339.1380; found: 339.1376.
Compound 7b: Yield: 60% (584 mg); n-hexane/AcOEt mixture
85/15 (v/v) Rf =0.24; white solid.
À 1
°
Mp=76-77 C; IR (neat): 2921, 2233, 1716, 1601, 1508, 1350 cm
;
1H NMR (400.13 MHz) (CDCl3): δ=7.48–7.46 (m, 6 H), 7.36–7.28 (m, 9
H), 6.41 (s, 3 H), 4.91 (s, 6 H); 13C NMR (100.6 MHz) (CDCl3): δ=159.8,
132.0, 128.8, 128.4, 123.4, 95.7, 87.4, 83.7, 57.1; HRMS: m/z [M+
Na]+ calcd for C33H24O3Na: 491.1618; found: 491.1629.
°
Compound 6b: white solid; mp: 176–177 C; IR (neat): 2962, 2826,
1599, 1487, 1252, 1158 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=
7.33–7.26 (m, 10 H), 6.79 (s, 1 H), 6.54 (s, 1 H), 5.69 (t, J=4.0 Hz, 2
H), 4.85 (d, J=4.0 Hz, 4 H); 13C NMR (100.6 MHz) (CDCl3): δ=156.2,
138.2, 137.0, 128.5, 128.3, 127.9, 123.7, 117.2, 117.1, 104.4, 65.7;
HRMS: m/z [M+H]+ calcd for C24H19O2: 339.1380; found: 339.1376.
Typical procedure for the preparation of 14a:
A flask equipped with a magnetic stirring bar was charged with
PdCl2(PPh3)2 (56.0 mg, 0.08 mmol, 0.02 equiv.) and CuI (30.0 mg,
0.16 mmol, 0.04 equiv.) dissolved in diisopropylamine (5 mL) and
N,N-dimethylformamide (4 mL). The resultant solution was stirred
under nitrogen at room temperature for 10 minutes before adding
1-(4-iodophenyl)ethan-1-one (1180 mg, 4.8 mmol, 1.2 equiv.) in
diisopropylamine (3 mL) and 1-(3-(prop-2-yn-1-yloxy)phenyl)ethan-
1-one (700 mg, 4.0 mmol, 1.0 equiv.) and stirred for 1 hour at room
temperature. After this time, the reaction mixture was diluted with
Et2O and washed with a saturated NH4Cl solution, HCl 2 N and with
brine. The organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
chromatography on SiO2 (25–40 μm), eluting with a 75/25 (v/v) n-
hexane/AcOEt mixture (Rf =0.23) to obtain 1063 mg (91% yield) of
1-(4-(3-(3-acetylphenoxy)prop-1-yn-1-yl)phenyl)ethan-1-one 14a.
Characterization data of 4c–h, 7c–l, 9, 11, 14b–g
Compound 4c: Yield: 82% (901.5 mg); n-hexane/AcOEt mixture
97/3 (v/v); Rf =0.24; known Compound;[16] white solid;
°
Mp=120-121 C; IR (neat): 2914, 2229, 1587, 1488, 1366, 1153,
1039 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.34 (d, J=8.0 Hz, 4
H), 7.23 (t, J=8.2 Hz, 1 H), 7.10 (d, J=8.0 Hz, 4 H), 6.73 (t, J=2.3 Hz,
1 H), 6.68 (dd, J1 =8.2 Hz, J2 =2.3 Hz, 2 H), 4.89 (s, 4 H), 2.34 (s, 6 H);
13C NMR (100.6 MHz) (CDCl3): δ=159.2, 139.0, 131.9, 130.0, 129.2,
119.3, 108.0, 102.7, 87.5, 83.3, 57.0, 21.6; HRMS: m/z [M+H]+ calcd
for C26H23O2: 367.1693; found: 367.1688.
Compound 4d: Yield: 49% (625.0 mg); n-hexane/AcOEt mixture
90/10 (v/v); Rf =0.24; known Compound;[16] white solid.
Compound 14a: Yield: 91% (1063 mg); n-hexane/AcOEt mixture
75/25 (v/v); Rf =0.23; pale yellow solid.
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°
Mp=123-124 C ; IR (neat): 2964, 2228, 1603, 1487, 1247, 1142,
87.4, 82.4, 57.1, 55.4; HRMS: m/z [M+H]+ calcd for C36H31O6:
559.2115; found: 559.2130.
1
2
3
4
5
6
7
8
9
1036 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.38 (d, J=8.9 Hz, 4
H), 7.23 (t, J=8.2 Hz, 1 H), 6.82 (d, J=8.9 Hz, 4 H), 6.73 (t, J=2.4 Hz,
1 H), 6.67 (dd, J1 =8.2 Hz, J2 =2.4 Hz, 2 H), 4.88 (s, 4 H), 3.80 (s, 6 H);
13C NMR (100.6 MHz) (CDCl3): δ= 160.0, 159.2, 133.5, 130.0, 114.5,
114.0, 108.0, 102.7, 87.3, 82.6, 57.0, 55.4; HRMS: m/z [M+H]+ calcd
for C26H23O4: 399.1591; found: 399.1588.
Compound 7e: Yield: 65% (726.69 mg); n-hexane/AcOEt mixture
85/15 (v/v); Rf =0.24; orange oil.
IR (neat): 2935, 2230, 1716, 1598, 1466, 1143 cmÀ 1 1H NMR
;
(400.13 MHz) (CDCl3): δ=7.20 (t, J=8.0 Hz, 3 H), 7.04 (d, J=7.6 Hz,
3 H), 6.98 (m, 3 H), 6.88 (dd, J1 =8.0 Hz, J2 =2.0 Hz, 3 H), 6.38 (s, 3
H), 4.88 (s, 6 H), 3.78 (s, 9 H); 13C NMR (100.6 MHz) (CDCl3): δ=159.8,
159.4,129.5, 124.5, 123.3, 116.7, 115.5, 95.7, 87.4, 83.6, 57.0, 55.4;
HRMS: m/z [M+Na]+ calcd for C36H30O6Na: 581.1935; found:
581.1946.
Compound 4e: Yield: 50% (612.3 mg); n-hexane/AcOEt mixture
80/20 (v/v); Rf =0.25; pale yellow solid.
°
Mp=127-129 C ; IR (neat): 2957, 2167, 1682, 1489, 1261, 1141,
841 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.87 (d, J=8.6 Hz, 4 H),
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
7.50 (d, J=8.6 Hz, 4 H), 7.26 (t, J=8.3 Hz, 1 H), 6.72-6.71 (m, 1 H),
6.69 (dd, J1 =8.3 Hz, J2 =2.2 Hz, 2 H), 4.92 (s, 4 H), 2.58 (s, 6 H); 13C
NMR (100.6 MHz) (CDCl3): δ = 197.4, 159.1, 136.8, 132.1, 130.2,
128.3, 127.1, 108.1, 102.7, 87.2, 86.5, 56.8, 26.7; HRMS: m/z [M+
Na]+ calcd for C28H22O4Na: 445.1410; found: 445.1405.
Compound 7f: Yield: 60% (713.0 mg); n-hexane/AcOEt mixture
80/20 (v/v); Rf =0.22; pink solid.
1
Mp=118–120 C; IR (neat): 2916, 2857, 2223, 1681, 1599, cmÀ 1; H
°
NMR (400.13 MHz) (CDCl3): δ=7.86 (d, J=8.4 Hz, 6 H), 7.50 (d, J=
8.4 Hz, 6 H), 6.38 (s, 3 H), 4.91 (s, 6 H), 2.58 (s, 9 H); 13C NMR
(100.6 MHz) (CDCl3): δ=197.3, 159.6, 136.7, 131.9, 128.2, 126.9, 95.6,
86.8, 86.5, 56.8, 26.6; HRMS: m/z [M+Na]+ calcd for C39H30O6Na:
617.1935; found: 617.1943.
Compound 4f: Yield: 47% (641.1 mg); n-hexane/AcOEt mixture
90/10 (v/v); Rf =0.24; yellow solid.
°
Mp=111-112 C ; IR (neat): 2904, 2234, 1709, 1588, 1489, 1153,
765 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.96 (d, J=8.5 Hz, 4 H),
1
Compound 7g: Yield: 65% (835.8 mg); n-hexane/AcOEt mixture
85/15 (v/v); Rf =0.25; white solid.
7.48 (d, J=8.5 Hz, 4 H), 7.25 (t, J=8.2 Hz, 1 H), 6.72-6.71 (m, 1 H),
6.69 (dd, J1 =8.2 Hz, J2 =2.2 Hz, 2 H), 4.92 (s, 4 H), 3.91 (s, 6 H); 13C
NMR (100.6 MHz) (CDCl3): δ=166.5, 159.1, 131.9, 130.2, 130.1, 129.6,
127.0, 108.1, 102.7, 86.8, 86.5, 56.8, 52.4; HRMS: m/z [M+H]+ calcd
for C28H23O6: 455.1489; found: 455.1482.
°
Mp=148–149 C; IR (neat): 2923, 2235, 1601, 1469, 1434,
1329 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.94 (d, J=8.5 Hz, 6
H), 7.47 (d, J=8.5 Hz, 6 H), 6.38 (s, 3 H), 4.90 (s, 6 H), 3.91 (s, 9 H); 13
C
NMR (100.6 MHz) (CDCl3): δ=166.5, 159.7, 131.9, 130.1, 129.6, 126.9,
95.7, 86.7, 86.6, 56.9, 52.4; HRMS: m/z [M+Na]+ calcd for
C39H30O9Na: 665.1782; found: 665.1791.
Compound 4g: Yield: 79% (965.8 mg); n-hexane/AcOEt mixture
93/7 (v/v); Rf =0.24; known Compound;[16] white solid.
°
Mp=120-121 C ; IR (neat): 2932, 2228, 1610, 1585, 1488, 1142,
Compound 7h: Yield: 93% (960.5 mg); n-hexane/AcOEt mixture
70/30 (v/v); Rf =0.27; yellow solid.
750 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.38 (d, J=8.6 Hz, 4 H),
1
7.29 (d, J=8.6 Hz, 4 H), 7.27-7.25 (m, 1 H) 6.74-6.72 (m, 1 H), 6.70
(dd, J1 =8.2 Hz, J2 =2.3 Hz, 2 H), 4.91 (s, 4 H); 13C NMR (100.6 MHz)
(CDCl3): δ=159.1, 134.9, 133.2, 130.1, 128.8, 120.8, 108.1, 102.7,
86.2, 84.9, 56.8; HRMS: m/z [M+H]+ calcd for C24H17Cl2O2: 407.0600;
found: 407.0604.
°
Mp=173–174 C; IR (neat): 2910, 2226, 1599, 1508, 1364,
1141 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.59 (d, J=8.2 Hz, 6
H), 7.51 (d, J=8.2 Hz, 6 H), 6.34 (s, 3 H), 4.90 (s, 6 H); 13C NMR
(100.6 MHz) (CDCl3): δ=159.6, 132.4, 132.1, 127.0, 118.3, 112.3, 95.5,
87.9, 85.7, 56.7; HRMS: m/z [M+Na]+ calcd for C36H21N3O3Na:
566.1475; found: 566.1476.
Compound 4h: Yield: 66% (1015.4 mg); n-hexane/AcOEt mixture
95/5 (v/v) Rf =0.24; White solid.
Compound 7i: Yield: 94% (1138 mg); n-hexane/AcOEt mixture
85/15 (v/v); Rf =0.25; orange solid.
°
Mp=94-95 C ; IR (neat): 2926, 2234, 1610, 1585, 1467, 1141,
847 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.56 (dd, J1 =7.9 Hz,
À 1
J2 =1.2 Hz, 2 H), 7.46 (dd, J1 =7.6 Hz, J2 =1.7 Hz, 2 H), 7.25-7.21 (m, 3
H), 7.16 (dt, J1 =7.9 Hz, J2 =1.8 Hz, 2 H), 6.80 (t, J=2.4 Hz, 1 H), 6.72
(dd, J1 =8.2 Hz, J2 =2.4 Hz, 2 H), 4.96 (s, 4 H); 13C NMR (100.6 MHz)
(CDCl3): δ=159.1, 133.9, 132.5, 130.04, 129.97, 127.1, 125.8, 124.6,
108.4, 103.0, 88.6, 85.8, 56.9; HRMS: m/z [M+H]+ calcd for
C24H17Br2O2: 496.9569; found: 496.9563.
°
Mp=64–66 C; IR (neat): 2925, 2238, 1602, 1471, 1433, 1328 cm
;
1H NMR (400.13 MHz) (CDCl3): δ=7.69 (bs, 3 H), 7.60–7.55 (m, 6 H),
7.41 (t, J=7.8 Hz, 3 H), 6.38 (s, 3 H), 4.90 (s, 6 H); 13C NMR
(100.6 MHz) (CDCl3): δ=159.8, 135.0, 131.1 (q, JCF =32.5 Hz), 129.0,
128.8 (q, JCF =3.7 Hz), 125.5 (q, JCF =4.1 Hz), 123.7 (q, JCF =270.6 Hz),
123.2, 95.7, 85.9, 85.3, 56.8; 19F NMR (376.5 MHz) (CDCl3): δ=-63.0;
HRMS: m/z [M+Na]+ calcd for C36H21F9O3Na: 695.1239; found:
695.1240.
Compound 7c: Yield: 46% (470.1 mg); n-hexane/AcOEt mixture
90/10 (v/v); Rf =0.25; pale brown solid.
Compound 7j: Yield: 73% (835.0 mg); n-hexane/AcOEt mixture
90/10 (v/v); Rf =0.26; white solid.
°
Mp=101–102 C; IR (neat): 2924, 2236, 1601, 1434, 1329,
1240 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.33 (d, J=8.0 Hz, 6
H), 7.09 (d, J=8.0 Hz, 6 H), 6.37 (s, 3 H), 4.87 (s, 6 H), 2.33 (s, 9 H); 13
C
°
Mp=131–132 C; IR (neat): 2916, 2224, 1599, 1470, 1362,
1247 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.27 (d, J=8.6 Hz, 6H),
7.18 (d, J=8.6 Hz, 6H), 6.28 (s, 3H), 4.79 (s, 6H); 13C NMR (100.6 MHz)
(CDCl3): δ=159.8, 135.0, 133.2, 128.8, 120.8, 95.7, 86.3, 84.7, 56.9;
HRMS: m/z [M+H]+ calcd for C33H22Cl3O3: 571.0629; found:
571.0641.
NMR (100.6 MHz) (CDCl3): δ=159.8, 139.0, 131.9, 129.2, 119.3, 95.7,
87.6, 83.1, 57.1, 21.6; HRMS: m/z [M+H]+ calcd for C36H31O3:
511.2268; found: 511.2274.
Compound 7d: Yield: 40% (469 mg); n-hexane/AcOEt mixture
90/10 (v/v) Rf =0.23; white solid.
Compound 7k: Yield: 402% (621.9 mg); n-hexane/AcOEt mixture
90/10 (v/v); Rf =0.25; pale brown solid.
°
Mp=109–111 C; IR (neat): 2922, 2241, 1602, 1471, 1433,
1328 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.38 (d, J=8.9 Hz, 6
H), 6.81 (d, J=8.9 Hz, 6 H), 6.37 (s, 3 H), 4.86 (s, 6 H), 3.79 (s, 9 H); 13
C
°
Mp=142–143 C; IR (neat): 2913, 2224, 1682, 1597, 1468,
1361 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.41 (d, J=8.6 Hz, 6
NMR (100.6 MHz) (CDCl3): δ=160.0, 159.8, 133.5, 114.4, 114.0, 95.6,
H), 7.27 (d, J=8.6 Hz, 6 H), 6.35 (s, 3 H), 4.86 (s, 6 H); 13C NMR
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(100.6 MHz) (CDCl3): δ=159.7, 133.4, 131.7, 123.2, 121.2, 95.7, 86.4,
(100.6 MHz) (CDCl3): δ=197.2, 160.8, 158.9, 136.6, 131.9, 129.9,
128.2, 127.1, 107.2, 106.9, 101.6, 87.2, 86.3, 56.6, 55.3, 26.6; HRMS:
m/z [M+Na]+ calcd for C18H16O3Na: 303.0992, found: 303.0990 m/z.
1
2
84.9, 56.9; HRMS: m/z [M+Na]+ calcd for C33H21Br3O3Na: 726.8913;
found: 726.8912.
3
4
5
6
7
8
9
Compound 7l: Yield: 85% (1198.3 mg); n-hexane/AcOEt mixture
90/10 (v/v); Rf =0.24; yellow oil.
Compound 14e: Yield: 90% (1010 mg); n-hexane/AcOEt mixture
80/20 (v/v); Rf =0.26; pale yellow solid.
IR (neat): 2915, 2242, 1712, 1591, 1405, 1278 cmÀ 1
;
1H NMR
Mp=35–36 C; IR (neat): 2928, 2221, 1682, 1591, 1484, 1437, 1357,
°
1
(400.13 MHz) (CDCl3): δ=7.58–7.57 (m, 3 H), 7.46–7.43 (m, 3 H),
7.36–7.34 (m, 3 H), 7.15 (t, J=7.9 Hz, 3 H), 6.36 (s, 3 H), 4.88 (s, 6 H);
13C NMR (100.6 MHz) (CDCl3): δ=159.7, 134.7, 132.0, 130.5, 129.9,
124.3, 122.2, 95.7, 85.9, 85.1, 56.9; HRMS: m/z [M+Na]+ calcd for
C33H21Br3O3Na: 726.8913; found: 726.8914.
1258, 1014, 825 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.29 (d, J=
8.4 Hz, 2 H), 7.20 (d, J=8.4 Hz, 2 H), 7.14 (t, J=8.0 Hz, 1 H), 6.52 (m,
3 H), 4.80 (s, 2 H), 3.72 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=
160.8, 159.9, 134.8, 133.1, 129.9, 128.7, 120.8, 107.1, 106.9, 101.5,
86.0, 84.9, 56.6, 55.3; HRMS: m/z [M+H]+ calcd for C16H14O2Cl:
273.0677, found: 273.0674
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Compound 9: Yield: 92% (1407 mg); n-hexane/AcOEt mixture 90/10
(v/v); Rf =0.26; yellow solid.
Compound 14f: Yield: 89% (940 mg); n-hexane/AcOEt mixture
75/25 (v/v); Rf =0.24; pale yellow solid; known compound.[11]
°
Mp=162–163 C; IR (neat): 2926, 2220, 1638, 1598, 1483, 1365,
1
1161, 1100, 814 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.88–7.86
Mp=78–80 C; IR (neat): 2910, 2210, 1673, 1598, 1492, 1403, 1357,
°
1
(m, 2 H), 7.50–7.48 (m, 3 H), 7.35–7.31 (m, 4 H), 7.10 (d, J = 7.9 Hz, 2
H), 7.07 (d, J = 7.9 Hz, 2 H), 6.79 (d, J=2.3 Hz, 1 H), 6.77 (d, J=
2.3 Hz, 1 H), 6.68 (s, 1 H), 5.10 (s, 2 H), 5.00 (s, 2 H), 2.33 (s, 3 H), 2.31
(s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=177.4, 161.9, 160.8, 159.6,
158.9, 139.2, 138.9, 131.8 (overlapping, 2 C), 131.5, 131.2, 129.1,
129.0, 128.9, 126.0, 119.1, 118.7, 110.3, 109.1, 99.3, 95.1, 88.4, 88.3,
82.5, 81.9, 58.1, 57.3, 21.5, 21.4; HRMS: m/z [M+Na]+ calcd for
C35H26O4Na : 533.1723, found: 533.1727.
1257, 1026, 825 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.92 (d, J=
8.5 Hz, 2 H), 7.54 (d, J=8.5 Hz, 2 H), 7.25–7.21 (m, 1 H), 6.86–6.84
(m, 3 H), 4.93 (s, 2 H), 2.62 (s, 3 H), 2.38 (s, 3 H); 13C NMR (100.6 MHz)
(CDCl3): δ=197.3, 157.7, 139.6, 136.6, 131.9, 129.2, 128.2, 127.2,
122.4, 115.9, 111.7, 87.4, 86.2, 56.5, 26.6, 21.6; HRMS: m/z [M+Na]+
calcd for C18H16O2Na: 287.1043, found: 287.1040.
Compound 14g: Yield: 95% (940 mg); n-hexane/AcOEt mixture
80/20 (v/v); Rf =0.27; yellow oil; known compound.[11]
Compound 11: Yield: 95% (1126 mg); n-hexane/AcOEt mixture
90/10 (v/v); Rf =0.25; yellow solid.
IR (neat): 2916, 2224, 1604, 1584, 1508, 1488, 1244, 1150, 1031,
1
830 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.27 (d, J=8.8 Hz, 2 H),
°
Mp=172–173 C; IR (neat): 2922, 2224, 1639, 1614, 1493, 1376,
7.08 (t, J=7.2 Hz, 1 H), 6.74–6.64 (m, 5 H), 4.75 (s, 2 H), 3.66 (s, 3 H),
2.23 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): δ=159.9, 158.0, 139.6,
133.4, 129.2, 122.2, 115.9, 114.5, 114.0, 111.8, 87.1, 82.8, 56.7, 55.3,
21.6; HRMS: m/z [M+Na]+ calcd for C17H16O2Na: 275.1043, found:
275.1039.
1
1260, 1024, 820 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.81–7.78
(m, 2H), 7.43–7.40 (m, 3 H), 7.27 (d, J=8.1 Hz, 2 H), 7.04 (d, J=
8.1 Hz, 2 H), 6.65 (d, J=2.3 Hz, 1 H), 6.61 (s, 1 H), 6.42 (d, J=2.3 Hz,
1 H), 4.93 (s, 2 H), 3.89 (s, 3 H), 2.26 (s, 3 H); 13C NMR (100.6 MHz)
(CDCl3): δ=177.6, 162.1, 161.0, 160.8, 159.7, 139.3, 131.7, 131.5,
131.2, 129.2, 128.9, 126.0, 118.7, 109.7, 109.1, 96.7, 94.1, 88.4, 81.9,
57.2, 56.5, 21.6; HRMS: m/z [M+Na]+ calcd for C26H20O4Na:
419.1254, found: 419.1247.
Characterization data of 5c–h, 6c–h, 8b–l, 10a, 12a, 15a–g, 16a–g
Isomeric mixture 5c+6c
Compound 14b: Yield: 93% (1039 mg); n-hexane/AcOEt mixture
75/25 (v/v) Rf =0.24; pale yellow solid.
HPLC eluent=n-hexane/AcOEt mixture 95/5 (v/v); Rf =0.21
Overall yield (catalyst 1): 98% (107.9 mg); 5c/6c=0/100
Overall yield (catalyst 2): 98% (108.3 mg); 5c/6c=39/61
Overall yield (catalyst 3): 98% (107.5 mg); 5c/6c=42/58
°
Mp=49–50 C; IR (neat): 2934, 2227, 1682, 1581, 1508, 1246, 1026,
832 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.73–7.69 (m, 2 H),
7.41–7.37 (m, 3 H), 7.25 (dd, J1 =8.4 Hz, J2 =2.4 Hz, 1 H), 6.85 (d, J=
8.4 Hz, 2 H), 4.97 (s, 2 H), 3.94 (s, 3 H), 3.82 (s, 3 H); 13C NMR
(100.6 MHz) (CDCl3): δ=166.9, 159.9, 157.7, 133.4, 131.5, 129.4,
122.6, 120.3, 115.4, 114.2, 113.9, 87.6, 82.1, 56.9, 55.3, 52.2; HRMS:
m/z [M+Na]+ calcd for C18H16O3Na: 303.0992, found: 303.0991.
°
Compound 5c: white solid; mp=168–170 C; IR (neat): 2919, 2846,
1678, 1602, 1489, 1259 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=
7.19–7.06 (m, 8 H), 6.82 (d, J=8.4 Hz, 1 H), 6.46 (d, J=8.4 Hz, 1 H),
5.76 (t, J=4.4 Hz, 1 H), 5.48 (t, J=3.7 Hz, 1 H), 4.57 (d, J=4.4 Hz, 2
H), 4.29 (d, J=3.7 Hz, 2 H), 2.31 (s, 3 H), 2.30 (s, 3 H); 13C NMR
(100.6 MHz) (CDCl3): δ=157.0, 151.3, 138.3, 137.6, 137.1, 136.6,
136.2, 135.8, 129.1, 128.7, 128.4, 127.0, 126.7, 120.6, 119.0, 116.9,
113.2, 109.0, 64.9, 64.4, 21.4, 21.3; HRMS: m/z [M+H]+ calcd for
C26H23O2: 367.1693; found: 367.1691.
Compound 14c: Yield: 93% (1055 mg); n-hexane/AcOEt mixture
75/25 (v/v) Rf =0.25; pale yellow solid.
°
Mp=58–60 C; IR (neat): 2920, 2227, 1683, 1591, 1484, 1437, 1265,
1013, 825 cmÀ 1;1H NMR (400.13 MHz) (CDCl3): δ=7.56–7.55 (m, 1 H),
7.52 (d, J = 7.6 Hz, 1 H), 7.33 (t, J=7.9 Hz, 1 H), 7.29 (d, J=8.5 Hz, 2
H), 7.20 (d, J=8.5 Hz, 2 H), 7.15 (dd, J1 =7.9 Hz, J2 =2.4 Hz, 1 H),
4.88 (s, 2 H), 2.53 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=197.7,
157.9, 138.5, 134.9, 133.1, 129.7, 128.7, 121.9, 120.6, 120.4, 113.7,
86.5, 84.3, 56.7, 26.8; HRMS: m/z [M+Na]+ calcd for C17H13O2ClNa:
307.0496, found: 307.0497.
°
Compound 6c: yellow solid; mp=184–185 C; IR (neat): 2922, 2838,
1676, 1489, 1257, 1117 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.18
(d, J=8.0 Hz, 4 H), 7.12 (d, J=8.0 Hz, 4 H), 6.84 (s, 1 H), 6.52 (s, 1 H),
5.66 (t, J=4.0 Hz, 2 H), 4.81 (d, J=4.0 Hz, 4 H), 2.35 (s, 6 H); 13C NMR
(100.6 MHz) (CDCl3): δ=156.2, 137.5, 136.9, 135.3, 129.0, 128.3,
123.8, 117.2, 116.8, 104.3, 65.6, 21.3; HRMS: m/z [M+H]+ calcd for
C26H23O2: 367.1693; found: 367.1689.
Compound 14d: Yield: 90% (1010 mg); n-hexane/AcOEt mixture
75/25 (v/v) Rf =0.25; brown solid.
°
Mp=64–65 C; IR (neat): 2919, 2220, 1678, 1592, 1483, 1448, 1360,
1
1257, 1026, 835 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.81 (d, J=
Isomeric mixture 5d+6d
8.4 Hz, 2 H), 7.44 (d, J=8.4 Hz, 2 H), 7.14 (t, J=8.4 Hz, 1 H), 6.57–
6.48 (m, 3 H), 4.84 (s, 2 H), 3.72 (s, 3 H), 2.51 (s, 3 H); 13C NMR
HPLC eluent=n-hexane/AcOEt mixture 90/10 (v/v); Rf =0.21
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Overall yield (catalyst 1): 98% (116.9 mg); 5d/6d=0/100
Overall yield (catalyst 2): 99% (118.4 mg); 5d/6d=7/93
Overall yield (catalyst 3): 98% (117.3 mg); 5d/6d=28/72
64.3, 52.3, 52.2; HRMS: m/z [M+H]+ calcd for C28H23O6: 455.1489;
found: 455.1484.
1
2
3
4
5
6
7
8
9
°
Compound 6f: white solid; mp=216–217 C; IR (neat): 3070, 2866,
1713, 1653, 1575, 1161 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.95
(d, J=8.2 Hz, 4 H), 7.31 (d, J=8.2 Hz, 4 H), 6.60 (s, 1 H), 6.52 (s, 1 H),
5.72 (t, J=4.0 Hz, 2 H), 4.83 (d, J=4.0 Hz, 4 H), 3.91 (s, 6 H); 13C NMR
(100.6 MHz) (CDCl3): δ=166.9, 156.4, 142.9, 136.3, 129.74, 129.70,
128.4, 123.1, 118.6, 116.8, 104.7, 65.5, 52.3; HRMS: m/z [M+Na]+
calcd for C28H22O6Na: 477.1309; found: 477.1299.
°
Compound 5d: yellow solid; mp=90–91 C; IR (neat): 2922, 2846,
1677, 1601, 1489, 1247 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=
7.26–7.23 (m, 4 H), 6.92–6.86 (m, 5 H), 6.53 (d, J=8.4 Hz, 1 H), 5.81
(t, J=4.6 Hz, 1 H), 5.54 (t, J=3.9 Hz, 1 H), 4.64 (d, J=4.6 Hz, 2 H),
4.37 (d, J=3.9 Hz, 2 H), 3.84 (s, 6H); 13C NMR (100.6 MHz) (CDCl3):
δ=159.4, 158.8, 157.1, 151.4, 136.8, 135.9, 133.7, 131.1, 129.9, 128.2,
126.7, 120.2, 119.1, 116.6, 113.9, 113.2, 113.1, 109.0, 64.9, 64.5, 55.5,
55.4; HRMS: m/z [M+Na]+ calcd for C26H22O4Na: 421.1410; found:
421.1405.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Isomeric mixture 5g+6g
HPLC Eluent=n-hexane/AcOEt mixture 95/5 (v/v); Rf =0.21
Overall yield (catalyst 1): 89% (108.9 mg); 5g/6g=5/95
Overall yield (catalyst 2): 89% (109.1 mg); 5g/6g=28/72
Overall yield (catalyst 3): 96% (117.2 mg); 5g/6g=39/61
°
Compound 6d: white solid; mp=185–186 C; IR (neat): 2916, 2839,
1677, 1610, 1489, 1257 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.20
(d, J=8.8 Hz, 4 H), 6.83 (d, J=8.8 Hz, 4 H), 6.80 (s, 1 H), 6.50 (s, 1 H),
5.62 (t, J=4.0 Hz, 2 H), 4.80 (d, J=4.0 Hz, 4 H), 3.80 (s, 6 H); 13C NMR
(100.6 MHz) (CDCl3): δ=159.3, 156.2, 136.6, 130.7, 129.6, 123.7,
117.3, 116.4, 113.7, 104.4, 65.7, 55.4; HRMS: m/z [M+Na]+ calcd for
C26H22O4Na: 421.1410; found: 421.1405.
°
Compound 5g: yellow solid; mp=132–133 C; IR (neat): 2960, 2840,
1587, 1486, 1401, 1088 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.27
(d, J=8.4 Hz, 2 H), 7.22 (d, J=8.4 Hz, 2 H), 7.19–7.15 (m, 4 H), 6.76
(d, J=8.4 Hz, 1 H), 6.46 (d, J=8.4 Hz, 1 H), 5.76 (t, J=4.6 Hz, 1 H),
5.50 (t, J=4.0 Hz, 1 H), 4.58 (d, J=4.6 Hz, 2 H), 4.29 (d, J=4.0 Hz, 2
H); 13C NMR (100.6 MHz) (CDCl3): δ=157.1, 151.1, 140.0, 137.0,
136.3, 135.2, 133.8, 132.7, 130.1, 128.7, 128.5, 128.0, 126.7, 121.5,
118.5, 117.6, 112.8, 109.3, 64.9, 64.3; HRMS: m/z [M+H]+ calcd for
C24H17Cl2O2: 407.0600; found: 407.0598.
Isomeric mixture 5e+6e
HPLC eluent=n-hexane/AcOEt mixture 80/20 (v/v); Rf =0.22
Overall yield (catalyst 1): 99% (131.0 mg); 5e/6e=39/61
Overall yield (catalyst 2): 97% (128.8 mg); 5e/6e=40/60
Overall yield (catalyst 3): 97% (128.6 mg); 5e/6e=42/58
°
Compound 6g: white solid; mp=179–180 C; IR (neat): 2962, 2836,
1615, 1484, 1398, 1155 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.27
(d, J=8.5 Hz, 4 H), 7.18 (d, J=8.5 Hz, 4 H), 6.62 (s, 1 H), 6.51 (s, 1 H),
5.66 (t, J=4.0 Hz, 2 H), 4.81 (d, J=4.0 Hz, 4 H); 13C NMR (100.6 MHz)
(CDCl3): δ=156.4, 136.7, 136.0, 133.9, 130.0, 128.6, 123.1, 117.8,
116.9, 104.6, 65.6; HRMS: m/z [M+H]+ calcd for C24H17Cl2O2:
407.0600; found: 407.0606.
°
Compound 5e: yellow solid; mp=157–158 C; IR (neat): 2922, 2838,
1674, 1601, 1489, 1258 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.98
(d, J=8.4 Hz, 2 H), 7.95 (d, J=8.4 Hz, 2 H), 7.42–7.39 (m, 4 H), 6.85
(d, J=8.4 Hz, 1 H), 6.56 (d, J=8.4 Hz, 1 H), 5.92 (t, J=4.6 Hz, 1 H),
5.64 (t, J=4.0 Hz, 1 H), 4.69 (d, J=4.6 Hz, 2 H), 4.35 (d, J=4.0 Hz, 2
H), 2.64 (s, 3 H), 2.63 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=198.0,
197.8, 157.1, 151.0, 146.2, 136.6, 136.5, 135.8, 135.4, 128.9, 128.6,
128.0, 127.3, 126.8, 122.5, 120.6, 118.4, 118.3, 112.7, 109.4, 64.9,
64.3, 26.82, 26.79; HRMS: m/z [M+Na]+ calcd for C26H22O4Na:
445.1410; found: 445.1402.
Isomeric mixture 5h+6h
HPLC eluent=n-hexane/AcOEt mixture 95/5 (v/v); Rf =0.22
Overall yield (catalyst 1): 93% (138.2 mg); 5h/6h=4/96
Overall yield (catalyst 2): 95% (141.4 mg); 5h/6h=29/71
Overall yield (catalyst 3): 92% (137.2 mg); 5h/6h=30/70
Compound 5h: yellow oil; IR (neat): 2930, 2835, 1676, 1575, 1490,
°
Compound 6e: yellow solid; mp=190–191 C; IR (neat): 2959, 2814,
1676, 1576, 1488, 1257 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.88
(d, J=8.2 Hz, 4 H), 7.34 (d, J=8.2 Hz, 4 H), 6.57 (s, 1 H), 6.53 (s, 1 H),
5.74 (t, J=4.0 Hz, 2 H), 4.85 (d, J=4.0 Hz, 4 H), 2.58 (s, 6 H); 13C NMR
(100.6 MHz) (CDCl3): δ=197.7, 156.4, 143.1, 136.6, 136.2, 128.7,
128.5, 123.2, 118.6, 116.8, 104.7, 65.6, 26.7; HRMS: m/z [M+Na]+
calcd for C26H22O4Na: 445.1410; found: 445.1402.
1427 cmÀ 1 1H NMR (400.13 MHz) (CDCl3): δ=7.55-7.47 (m, 2 H),
;
7.27-6.98 (m, 6 H), 6.36 (s, 2 H), 5.65 (bs, 1 H), 5.39 (bs, 1 H), 4.76–
4.61 (m, 2 H), 4.42–4.33 (m, 1 H), 4.22–4.14 (m, 1 H); 13C NMR
(100.6 MHz) (CDCl3): δ=155.7, 150.6, 142.6, 139.4, 136.5, 135.3,
133.0, 132.0, 131.4, 130.0, 129.3, 128.3, 127.5, 127.0, 126.3, 123.8,
122.6, 122.2, 118.9, 117.8, 112.4, 109.3, 65.0, 64.9; HRMS: m/z [M+
H]+ calcd for C24H17Br2O2: 496.9569; found: 496.9565.
Isomeric mixture 5f+6f
HPLC Eluent=n-hexane/AcOEt mixture 90/10 (v/v); Rf =0.20
Overall yield (catalyst 1): 92% (125.4 mg); 5f/6f=13/87;
Overall yield (catalyst 2): 98% (133.4 mg); 5f/6f=41/59;
Overall yield (catalyst 3): 96% (130.9 mg); 5f/6f=43/57;
°
Compound 6h: white solid; mp=159–161 C; IR (neat): 2925, 2837,
1676, 1576, 1488, 1427 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=7.45
(m, 2 H), 7.19–7.16 (m, 3 H), 7.06 (dt, J1 =7.6 Hz, J2 =1.8 Hz, 3 H),
6.42 (s, 1 H), 5.80–5.74 (m, 1 H), 5.55 (s, 2 H), 4.95–4.88 (m, 4 H); 13C
NMR (100.6 MHz) (CDCl3): δ=155.4, 138.7, 136.0, 132.6, 131.2, 129.1,
127.2, 123.7, 123.2, 118.5, 116.4, 104.0, 65.7; HRMS: m/z [M+H]+
calcd for C24H17Br2O2: 496.9569; found: 496.9565.
°
Compound 5f: white solid; mp=176–177 C; IR (neat): 2924, 2848,
1678, 1601, 1259, 1157 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=8.05
(d, J=8.4 Hz, 2 H), 8.02 (d, J=8.4 Hz, 2 H), 7.38 (dd, J1 =8.4 Hz, J2 =
2.8 Hz, 4 H), 6.84 (d, J=8.4 Hz, 1 H), 6.55 (d, J=8.4 Hz, 1 H), 5.91 (t,
J=4.5 Hz, 1 H), 5.63 (t, J=4.0 Hz, 1 H), 4.69 (d, J=4.5 Hz, 2 H), 4.34
(d, J=4.0 Hz, 2 H), 3.94 (s, 6 H); 13C NMR (100.6 MHz) (CDCl3): δ=
167.2, 167.0, 157.1, 151.0, 146.0, 143.3, 136.5, 135.5, 129.8, 129.6,
129.2, 128.7, 127.1, 126.8, 122.3, 118.34, 118.30, 112.8, 109.4, 64.9,
Compound 8b: yield (catalyst 1): 98% (137.8 mg); white solid.
°
Mp=222–223 C; IR (neat): 2831, 1623, 1571, 1490, 1425,
1
1320 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.36–7.28 (m, 15 H),
5.67 (t, J=4.6 Hz, 3 H), 4.25 (d, J=4.6 Hz, 6 H); 13C NMR (100.6 MHz)
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(CDCl3): δ=153.8, 141.4, 136.1, 127.7, 127.1, 126.9, 118.9, 107.9,
H), 7.19 (d, J=8.5 Hz, 6 H), 5.64 (t, J=4.6 Hz, 3 H), 4.24 (d, J=4.6 Hz,
6 H); 13C NMR (100.6 MHz) (CDCl3): δ=153.6, 139.7, 135.1, 132.7,
128.5, 127.9, 119.3, 107.7, 64.1; HRMS: m/z [M+H]+ calcd for
C33H22Cl3O3: 571.0629; found: 571.0638.
1
2
3
4
5
6
7
8
9
64.2; HRMS: m/z [M+Na]+ calcd for C33H24O3Na: 491.1618; found:
491.1624.
Compound 8c: yield (catalyst 1): 95% (145.7 mg); white solid.
Compound 8k: yield (catalyst 1): 99% (209.5 mg); pale brown solid.
°
Mp=214–216 C; IR (neat): 2984, 2831, 1624, 1571, 1425,
1120 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.17 (d, J=8.0 Hz, 6
Mp=244–245 C; IR (neat): 3023, 2830, 1624, 1571, 1490,
°
H), 7.12 (d, J=8.0 Hz, 6 H), 5.63 (t, J=4.6 Hz, 3 H), 4.23 (d, J=4.6 Hz,
6 H), 2.36 (s, 9 H); 13C NMR (100.6 MHz) (CDCl3): δ=153.9, 138.4,
136.4, 136.0, 128.4, 127.0, 118.4, 108.0, 64.2, 21.3; HRMS: m/z [M+
H]+ calcd for C36H31O3: 511.2268; found: 511.2276.
1425 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.43 (d, J=8.4 Hz, 6
H), 7.13 (d, J=8.4 Hz, 6 H), 5.64 (t, J=4.6 Hz, 3 H), 4.24 (d, J=4.6 Hz,
6 H); 13C NMR (100.6 MHz) (CDCl3): δ=153.6, 140.2, 135.1, 130.9,
128.8, 120.8, 119.3, 107.6, 64.1; HRMS: m/z [M+Na]+ calcd for
C33H21Br3O3Na: 726.8913; found: 726.8912.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Compound 8d: yield (catalyst 1): 98% (164.1 mg); white solid.
Compound 8l: yield (catalyst 1): 95% (201.3 mg); brown solid.
°
Mp=260–261 C; IR (neat): 2941, 2832, 1722, 1574, 1482,
1287 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.20 (d, J=8.7 Hz, 6
Mp=201–204 C; IR (neat): 2958, 2832, 1723, 1572, 1423,
°
H), 6.85 (d, J=8.7 Hz, 6 H), 5.61 (t, J=4.6 Hz, 3 H), 4.24 (d, J=4.6 Hz,
6 H), 3.83 (s, 9H); 13C NMR (100.6 MHz) (CDCl3): δ=158.7, 153.9,
135.7, 133.9, 128.2, 117.9, 113.1, 107.9, 64.2, 55.4; HRMS: m/z [M+
H]+ calcd for C36H31O6: 559.2115; found: 559.2128.
1287 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.43–7.37 (m, 6 H),
7.21–7.16 (m, 6 H), 5.68 (t, J=4.6 Hz, 3 H), 4.27 (d, J=4.6 Hz, 6 H);
13C NMR (100.6 MHz) (CDCl3): δ=153.5, 143.3, 134.7, 130.2, 129.9,
129.3, 125.8, 121.7, 119.8, 107.6, 64.1; HRMS: m/z [M+Na]+ calcd
for C33H21Br3O3Na: 726.8913; found: 726.8914.
Compound 8e: yield (catalyst 1): 91% (152.7 mg); white solid.
Compound 10: yield (catalyst 1): 98% (150.0 mg); pale yellow solid.
°
Mp=162–164 C; IR (neat): 3023, 2831, 1624, 1570, 1424,
1118 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.28–7.22 (m, 3 H),
Mp=171–173 C; IR (neat): 2919, 1643, 1558, 1446, 1357, 1261,
°
1
6.90–6.83 (m, 9 H), 5.69 (t, J=4.6 Hz, 3 H), 4.26 (d, J=4.6 Hz, 6 H),
3.82 (s, 9 H); 13C NMR (100.6 MHz) (CDCl3): δ=159.3, 153.7, 142.9,
136.0, 128.7, 119.8, 118.9, 112.7, 112.5, 108.0, 64.2, 55.4; HRMS: m/z
[M+Na]+ calcd for C36H30O6Na: 581.1935; found: 581.1947.
1118, 832 cmÀ 1; H NMR (400.13 MHz) (CDCl3): δ=7.32 (t, J=7.4 Hz,
1 H), 7.21 (d, J=8.1 Hz, 2 H), 7.15–7.11 (m, 8 H), 6.72 (d, J=7.4 Hz, 2
H), 6.65 (s, 1 H), 5.87 (t, J=4.7 Hz, 1 H), 5.79 (t, J=4.7 Hz, 1 H), 4.89
(d, J=4.7 Hz, 2 H), 4.29 (d, J=4.7 Hz, 2 H), 2.37 (s, 3 H), 2.29 (s, 3 H);
13C NMR (100.6 MHz) (CDCl3): δ=176.5, 159.8, 157.3, 155.8, 153.2,
136.8, 136.7, 136.3, 135.8, 134.2, 134.0, 129.9, 129.7, 128.2, 127.6,
127.3, 126.2, 125.7, 124.9, 118.6, 118.3, 110.0, 109.3, 107.2, 105.9,
64.8, 63.3, 20.3, 20.2; HRMS: m/z [M+Na]+ calcd for C35H26O4Na :
533.1723, found: 533.1727.
Compound 8f: yield (catalyst 1): 90% (161.0 mg); white solid.
°
Mp=234–235 C; IR (neat): 3023, 2831, 1682, 1624, 1571,
1426 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.93 (d, J=8.3 Hz, 6
H), 7.36 (d, J=8.3 Hz, 6 H), 5.71 (t, J=4.6 Hz, 3 H), 4.24 (d, J=4.6 Hz,
6 H), 2.62 (s, 9 H); 13C NMR (100.6 MHz) (CDCl3): δ=198.0, 153.6,
146.2, 135.8, 135.2, 128.0, 127.3, 120.3, 107.6, 64.1, 26.8; HRMS: m/z
[M+Na]+ calcd for C39H30O6Na: 617.1935; found: 617.1942.
Compound 12: yield (catalyst 1): 97% (115.1 mg); 12/13: 100/0.
Yield (catalyst 3): 99% (117.9 mg); 12/13: 100/0; pale yellow solid.
°
Compound 8g: yield (catalyst 1): 99% (190.2 mg); white solid.
Mp=195–196 C; IR (neat): 2922, 1642, 1566, 1475, 1450, 1384,
1
1260, 1111, 861 cmÀ 1; H NMR (400.13 MHz) (DMSOd6): δ=7.38 (t,
°
Mp=240–242 C; IR (neat): 2957, 1716, 1597, 1467, 1286,
J=7.4 Hz, 1 H), 7.21–7.12 (m, 6 H), 6.78 (d, J=7.4 Hz, 2 H), 6.72 (d,
J=6.0 Hz, 2 H), 5.94 ( t, J=4.7 Hz, 1 H), 4.76 (d, J=4.7 Hz, 2 H), 3.89
(s, 3 H), 2.25 (s, 3 H); 13C NMR (100.6 MHz) (DMSOd6): δ=176.2,
161.4, 161.0, 159.7, 154.6, 137.6, 137.2, 134.2, 130.5, 129.5, 128.7,
125.9, 120.6, 110.1, 108.2, 105.5, 97.5, 65.4, 56.8, 21.1; HRMS: m/z [M
+Na]+ calcd for C26H20O4Na: 419.1254, found: 419.1249.
1143 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.99 (d, J=8.4 Hz, 6
H), 7.33 (d, J=8.4 Hz, 6 H), 5.69 (t, J=4.6 Hz, 3 H), 4.23 (d, J=4.6 Hz,
6 H), 3.92 (s, 9 H); 13C NMR (100.6 MHz) (CDCl3): δ=167.2, 153.5,
146.0, 135.3, 129.2, 128.7, 127.1, 120.1, 107.6, 64.1, 52.2; HRMS: m/z
[M+Na]+ calcd for C39H30O9Na: 665.1782; found: 665.1787.
Compound 8h: yield (catalyst 1): 99% (161.3 mg); pale yellow solid.
°
Mp=187–188 C; IR (neat): 2941, 2228, 1723, 1573, 1424,
Isomeric mixture 15a+16a
1286 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.62 (d, J=8.1 Hz, 6
HPLC eluent=n-hexane/AcOEt mixture 80/20 (v/v); Rf =0.21
Overall yield (catalyst 3): 99% (116.0 mg); 15a/16a: 98/2.
H), 7.35 (d, J=8.1 Hz, 6 H), 5.71 (t, J=4.5 Hz, 3 H), 4.25 (d, J=4.5 Hz,
6 H); 13C NMR (100.6 MHz) (CDCl3): δ=153.4, 145.8, 134.6, 131.7,
127.8, 120.8, 119.2, 110.7, 107.3, 64.1; HRMS: m/z [M+Na]+ calcd
for C36H21N3O3Na: 566.1475; found: 566.1475.
°
Compound 15a: pale yellow solid; mp=147–148 C; IR (neat): 2922,
1674, 1603, 1569, 1490, 1254, 1080, 829 cmÀ 1; 1H NMR (400.13 MHz)
(CDCl3): δ=7.92 (d, J=8.3 Hz, 2 H), 7.31–7.28 (m, 3 H), 7.19–7.15 (m,
2 H), 6.09 (t, J=4.8 Hz, 1 H), 4.74 (d, J=4.8 Hz, 2 H), 2.62 (s, 3 H),
2.10 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=201.8, 197.5, 157.0,
145.4, 139.4, 136.7, 136.1, 129.2, 128.8, 127.2, 123.2, 122.2, 121.5,
119.6, 64.4, 29.2, 26.6; HRMS: m/z [M+Na]+ calcd for C19H16O3Na:
315.0992, found: 315.0991.
Compound 8i: yield (catalyst 1): 98% (197.4 mg); orange solid.
°
Mp=154–156 C; IR (neat): 2831, 1624, 1571, 1488, 1426,
1120 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.55–7.51 (m, 6 H),
7.48–7.42 (m, 6 H), 5.70 (t, J=4.6 Hz, 3 H), 4.24 (d, J=4.6 Hz, 6 H);
13C NMR (100.6 MHz) (CDCl3): δ=153.6, 141.9, 134.9, 130.5, 130.1 (q,
J
CF =31.7 Hz), 128.3, 124.4 (q, JCF =270.6 Hz), 124.1 (q, JCF =3.7 Hz),
123.7 (q, JCF =3.7 Hz), 120.1, 107.5, 64.0; 19F NMR (376.5 MHz)
(CDCl3): δ=m, (-62.3)–(-62.9); HRMS: m/z [M+Na]+ calcd for
C36H21F9O3Na: 695.1239; found: 695.1242.
°
Compound 16a: pale yellow solid; mp=109–110 C; IR (neat): 2923,
1675, 1606, 1569, 1490, 1255, 1080, 830 cmÀ 1; 1H NMR (400.13 MHz)
(CDCl3): δ=8.02 (d, J=8.3 Hz, 2 H), 7.49–7.43 (m, 4 H), 7.04 (d, J=
7.9 Hz, 1 H), 6.01 (t, J=3.9 Hz, 1 H), 4.9 (d, J=3.9 Hz, 2 H), 2.7 (s, 3
H), 2.6 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=197.6, 197.2, 154.7,
142.4, 138.0, 136.7, 135.9, 128.7, 128.6, 127.2, 125.6, 123.7, 121.4,
Compound 8j: yield (catalyst 1): 98% (168.0 mg); white solid.
°
Mp=231–233 C; IR (neat): 2958, 1723, 1572, 1454, 1422,
1287 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.28 (d, J=8.5 Hz, 6
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116.1, 65.3, 26.7, 26.6; HRMS: m/z [M+Na]+ calcd for C19H16O3Na:
315.0992, found: 315.0991.
4.6 Hz, 2 H, 15d), 3.41 (s, 3 H, 15d), 2.63 (s, 3 H, 16d), 2.62 (s, 3 H,
15d); 13C NMR (100.6 MHz) (CDCl3): δ=197.9, 197.7, 160.9, 157.0,
156.3, 156.1, 146.1, 143.4, 136.4, 136.3, 135.7, 135.5, 130.0, 128.8,
128.6, 128.5, 127.8, 127.1, 126.5, 121.8, 118.1, 116.3, 112.9, 109.5,
107.1, 105.3, 102.1, 65.4, 64.5, 55.4, 55.2, 26.7, 26.6. HRMS: m/z [M+
Na]+ calcd for C18H16O3Na: 303.0992, found: 303.0990 m/z.
1
2
3
4
5
Isomeric mixture 15b+16b
HPLC eluent=n-hexane/AcOEt mixture 80/20 (v/v); Rf =0.22
6
7
8
9
Isomeric mixture 15e+16e
Overall yield (catalyst 3): 99% (111.6mg); 15b/16b: 74/26
Overall yield (catalyst 3): 99% (107.3 mg); 15e/16e: 36/64.
HPLC eluent=n-hexane/AcOEt mixture 90/10 (v/v); Rf =0.22
°
Compound 15b: pale yellow solid; mp=137–138 C; IR (neat): 2920,
1680, 1602, 1578, 1480, 1265, 1060, 856 cmÀ 1; 1H NMR (400.13 MHz)
(CDCl3): δ=7.27 (t, J=7.9 Hz, 1 H), 7.15–7.07 (m, 4 H), 6.84 (d, J=
8.7 Hz, 2 H), 5.96 (t, J=4.8 Hz, 1 H), 4.70 (d, J=4.8 Hz, 2 H), 3.81 (s, 3
H), 2.04 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=202.7, 159.4,
157.0, 140.2, 136.8, 132.9, 129.0, 128.8, 123.0, 121.2, 120.5, 119.1,
114.0, 64.6, 55.3, 29.8; HRMS: m/z [M+Na]+ calcd for C18H16O3Na:
303.0992, found: 303.0991.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
°
Compound 15e: pale yellow solid; mp=101–102 C; IR (neat): 2925,
1
1608, 1488, 1248, 1034, 837; H NMR (400.13 MHz) (CDCl3): δ=7.33
(d, J=8.2 Hz, 2 H), 7.24–7.20 (m, 3 H), 6.72 (d, J=7.6 Hz, 1 H), 6.56
(d, J=7.6 Hz, 1 H), 5.87 (t, J=4.6 Hz, 1 H), 4.68 (d, J=4.6 Hz, 2 H),
3.52 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=157.2, 156.5, 139.6,
135.6, 132.4, 129.9, 128.4, 127.7, 121.0, 113.2,109.6, 105.4, 64.6, 55.4;
HRMS: m/z [M+H]+ calcd for C16H14O2Cl: 273.0677, found: 273.0674.
°
Compound 16b: pale yellow solid; mp=111–112 C; IR (neat): 2932,
1675, 1605, 1575, 1491, 1255, 1080, 860 cmÀ 1; 1H NMR (400.13 MHz)
(CDCl3): δ=7.38–7.36 (m, 2 H), 7.18 (d, J=8.6 Hz, 2 H), 7.03 (d, J=
8.5 Hz, 1 H), 6.87 (d, J=8.6 Hz, 2 H) 5.81 (t, J=4.0 Hz, 1 H), 4.82 (d,
J=4.0 Hz, 2 H), 3.78 (s, 3 H), 2.49 (s, 3 H); 13C NMR (100.6 MHz)
(CDCl3): δ=197.5, 159.6, 154.9, 137.8, 136.3, 130.0, 129.8, 128.4,
126.0, 122.0, 121.4, 116.1, 114.1, 65.6, 55.5, 26.8; HRMS: m/z [M+
Na]+ calcd for C18H16O3Na: 303.0992, found: 303.0989.
°
Compound 16e: pale yellow solid; mp=88–90 C; IR (neat): 2927,
1605, 1490, 1255, 1030, 830 cmÀ 1; 1H NMR (400.13 MHz) (CDCl3): δ=
7.38–7.36 (m, 3 H), 7.32 (d, J=8.4 Hz, 2 H), 7.28 (d, J=8.4 Hz, 2 H),
6.95 (d, J=8.2 Hz, 1 H) 5.84 (t, J=3.9 Hz, 1 H), 4.83 (d, J=3.9 Hz, 2
H), 2.49 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=197.4, 154.8,
138.1, 136.1, 135.8, 134.2, 130.0, 129.0, 127.7, 125.7, 123.1, 121.5,
116.2, 64.5, 26.8; HRMS: m/z [M+H]+ calcd for C16H14O2Cl: 273.0677,
found: 273.0675.
Isomeric mixture 15c+16c
HPLC eluent=n-hexane/AcOEt mixture 85/15 (v/v); Rf =0.21
Overall yield (catalyst 3): 98% (111.5 mg); 15c/16c: 94/6.
Isomeric mixture 15f+16f
Overall yield (catalyst 3): 99% (104.4 mg); 15f/16f: 60/40
°
Compound 15c: pale yellow solid; mp=130–132 C; IR (neat): 2922,
Pale yellow oil; IR (neat): 2932, 1684, 1604, 1565, 1463, 1262, 1016,
841 cmÀ 1; HRMS: m/z [M+H]+ calcd for C18H17O2: 265.1223, found:
265.1219.
1680, 1593, 1485, 1232, 1020, 830 cmÀ 1
;
1H NMR (400.13 MHz)
(CDCl3): δ=7.22–7.18 (m, 4 H), 7.07–7.04 (m, 3 H), 5.91 (t, J=4.8 Hz,
1 H), 4.62 (d, J=4.8 Hz, 2 H), 2.01 (s, 3 H); 13C NMR (100.6 MHz)
(CDCl3): δ=202.1, 157.1, 140.2, 139.8, 139.1, 136.5, 133.7, 129.3,
128.9, 128.7, 122.5, 122.2, 121.4, 119.5, 64.5, 29.5; HRMS: m/z [M+
Na]+ calcd for C17H13O2ClNa: 307.0496 m/z, found: 307.0497.
Reported NMR spectra refer to an isomeric mixtures 15f+16f in
the ratio 60/40; 1H NMR signals have been assigned to each specific
isomer while 13C NMR signals have not been assigned.
1H NMR (400.13 MHz) (CDCl3): δ= 8.01 (d, J=8.3 Hz, 2 H, 16f), 7.96
(d, J=8.0 Hz, 2 H, 15f), 7.47 (d, J=8.3 Hz, 2 H, 16f), 7.36 (d, J=
8.0 Hz, 2 H, 15f), 7.15 (t, J=7.8 Hz, 1 H, 15f), 6.90 (d, J=7.8 Hz, 1 H,
15f), 6.87 (d, J=7.8 Hz, 1 H, 16f ), 6.78 (d, J=7.8 Hz, 1 H, 15f), 6.77
(s, 1 H, 16f), 6.70 (bd, J=7.8 Hz, 1 H, 16f ), 6.00 (t, J=4.7 Hz, 1 H,
15f), 5.83 (t, J=4.0 Hz, 1 H, 16f), 4.86 (d, J=4.0 Hz, 2 H, 16f), 4.62
(d, J=4.7 Hz, 2 H, 15f), 2.66 (s, 3 H, 16f), 2.64 (s, 3 H, 15f), 2.33 (s, 3
H, 16f), 1.77 (s, 3 H, 15f); 13C NMR (100.6 MHz) (CDCl3): δ=197.69,
197.67, 156.5, 154.6, 146.1, 143.4, 143.3, 140.1, 137.7, 136.5, 136.4,
136.0, 135.6, 129.1, 128.8, 128.6, 128.5, 127.6, 125.4, 125.0, 123.9,
123.1, 122.1, 120.4, 119.9, 116.9, 114.1, 65.2, 64.2, 29.7, 26.7, 26.6,
22.7, 21.4.
°
Compound 16c: pale yellow solid; mp=107–108 C; IR (neat): 2930,
1676, 1569, 1492, 1255, 1020, 830 cmÀ 1
;
1H NMR (400.13 MHz)
(CDCl3): δ=7.38–7.36 (m, 2 H), 7.32 (d, J=8.4 Hz, 2 H), 7.28 (d, J=
8.4 Hz, 2 H), 6.95 (d, J=8.2 Hz, 1 H) 5.84 (t, J=3.9 Hz, 1 H), 4.83 (d,
J=3.9 Hz, 2 H), 2.49 (s, 3 H); 13C NMR (100.6 MHz) (CDCl3): δ=197.4,
154.8, 138.1, 136.1, 135.8, 134.2, 130.0, 129.0, 127.7, 125.7, 123.1,
121.5, 116.2, 64.5, 26.8; HRMS: m/z [M+Na]+ calcd for C17H13O2ClNa:
307.0496, found: 307.0495 m/z.
Isomeric mixture 15d+16d
Overall yield (catalyst 3): 99% (111.0 mg); 15d/16d: 34/66
16f: Known Compound.[11]
Pale yellow oil; IR (neat): 2922, 1676, 1601, 1512, 1250, 1030,
837 cmÀ 1
;
Isomeric mixture 15g+16g
Reported NMR spectra refer to an isomeric mixtures 15d+16d in
the ratio 34/66; 1H NMR signals have been assigned to each specific
isomer while 13C NMR signals have not been assigned.
Overall yield (catalyst 3): 97% (97.6 mg); 15 g/16 g: 23/77
Pale yellow oil; IR (neat): 2924, 1615, 1450, 1260, 1024, 874 cmÀ 1
;
1H NMR (400.13 MHz) (CDCl3): δ=7.98 (d, J=8.6 Hz, 2 H, 16d), 7.90
(d, J=8.6 Hz, 2 H, 15d), 7.44 (d, J=8.6 Hz, 2 H 16d), 7.31 (d, J=
8.6 Hz, 2 H, 15d), 7.18 (t, J=8.2 Hz, 1 H, 15d), 6.87 (d, J=8.2 Hz, 1
H, 16d), 6.87 (d, J=8.2 Hz, 1 H 15d), 6.50 (m, 2H, 15d+16d), 6.42
(dd, J1 =8.4 Hz, J2 =2.5, 1 H, 16d), 5.88 (t, J=4.6 Hz, 1 H, 15d), 5.72
(t, J=3.9 Hz, 1 H 16d), 4.84 (d, J=3.9 Hz, 2 H, 16d), 4.65 (d, J=
HRMS: m/z [M+Na]+ calcd for C17H16O2Na: 275.1043, found:
275.1039.
Reported NMR spectra refer to an isomeric mixtures 15g+16g in
the ratio 23/77; 1H NMR signals have been assigned to each specific
isomer while 13C NMR signals have not been assigned.
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1H NMR (400.13 MHz) (CDCl3): δ 7.19 (d, J=8.9 Hz, 2 H, 16g ), 7.07
(d, J=8.7 Hz, 2 H, 15g ), 7.01 (t, J=7.8 Hz, 1 H, 15 g), 6.97 (d, J=
7.8 Hz, 1 H, 15g), 6.85–6.83 (m, 3 H, 16g), 6.80–6.74 (m, 3 H, 15g),
6.64 (bs, 1 H, 16g), 6.60 (bd, J=7.8 Hz, 1 H, 16g), 5.79 (t, J=4.7 Hz,
1 H, 15g), 5.62 (t, J=3.9 Hz, 1 H, 16g), 4.72 (d, J=3.9 Hz, 2 H, 16g),
4.48 (t, J=4.7 Hz, 2 H, 16g), 3.76 (s, 3 H, 16g), 3.75 (s, 3 H, 15g),
2.22 (s, 3 H, 16g), 1.70 (s, 3 H, 15g); 13C NMR (100.6 MHz) (CDCl3):
δ=159.3, 159.0, 156.5, 154.8, 139.5, 137.9, 136.7, 136.0, 133.7, 130.8,
130.3, 129.7, 129.5, 128.6, 125.7, 125.0, 121.9, 121.6, 121.31, 121.38,
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Acknowledgements
We gratefully acknowledge the PRIN project 2017 “Targeting
Hedgehog pathway: virtual screening identification and sustain-
able synthesis of novel Smo and Gli inhibitors and their
pharmacological drug delivery strategies for improved therapeutic
effects in tumors.” (20175XBSX4) and Sapienza, University of
Rome, for financial support.
Conflict of Interest
[10] D. Ding, T. Mou, M. Feng, X. Jiang, J. Am. Chem. Soc. 2016, 138, 5218–
5221.
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The authors declare no conflict of interest.
Keywords: Annulation · Gold catalysis · Hydroarylation
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Manuscript received: January 26, 2021
Revised manuscript received: February 22, 2021
Accepted manuscript online: February 24, 2021
Eur. J. Org. Chem. 2021, 1676–1687
www.eurjoc.org
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