Cu(OAc)2 Mediated Synthesis of 3-Sulfonyl Chromen-4-ones

Article abstract of DOI:10.1021/acs.joc.8b00177

Copper acetate mediated (4 + 2) annulation of sulfonylacetylenes with salicylic acids provides sulfonyl chromen-4-ones in the presence of benzotriazol-1-yloxy tri(dimethylamino)phosphonium hexafluorophosphate (BOP, Castro's reagent) and 4-dimethylaminopyridine (DMAP) in MeNO₂ at reflux for 3 h. The uses of various metal complexes and activating reagents are investigated for facile and efficient transformation. A plausible mechanism is proposed.

Full text of DOI:10.1021/acs.joc.8b00177

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Article
Cu(OAc)2 Mediated Synthesis of 3-Sulfonyl Chromen-4-ones
Meng-Yang Chang, Yu-Hsin Chen, and Heui-Sin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00177 • Publication Date (Web): 02 Feb 2018
Downloaded from http://pubs.acs.org on February 4, 2018
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Cu(OAc)2 Mediated Synthesis of 3-Sulfonyl Chromen-4-ones
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Meng-Yang Chang,*a,b Yu-Hsin Chena and Heui-Sin Wanga
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aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan bDepartment of
Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
Supporting Information Placeholder
R
Cu(OAc) (1.1 equiv)
2
BOP (1.1 equiv)
DMAP (1.0 equiv)
O
O
O
O
S
O
Z
O
S
O
OH
OH
R
Ar
Ar
+
MeNO (3 mL), reflux, 3 h
2
Z
ABSTRACT: Copper acetate mediated (4+2) annulation of sulfonylacetylenes with salicyclic acids provides sulfonyl chromen-4-
ones in the presence of BOP and DMAP in MeNO2 at reflux for 3 h. The uses of various metal complexes and activating reagents
are investigated for facile and efficient transformation. A plausible mechanism has been proposed.
Introduction
represents a continuing need in the organic synthetic field.
Although developed synthetic protocols have been extensively
investigated for the functionalization of chromen-4-ones, most
of these substituents (Y and Z groups of pyran-4-one) of re-
ported molecules focused on alkyl and aryl groups (by a car-
bon-carbon bond linkage). Among the present scaffolds in the
family, a core structure having a heteroatom-conjugated group
Functionalized chromen-4-ones (benzopyran-4-ones) are the
key component of naturally occurring oxygen-containing het-
erocyclic compounds which possess various biological activi-
ties.1-2 A large number of synthetic routes have been reported
for this core structure along with their related derivatives, in-
cluding common and classic Claisen condensation,3a the
Baker-Venkatamaran rearrangement,3b-c the Kostanecki-
Robinson reaction,3d the Simonis reaction,3e and the Ruhe-
mann reaction3f under different metallic, basic, acidic, organo-
catalytic, solvent-free, or microwave-enchanced conditions.
Recently, other efforts involving intermolecular (4+2)4 or
(3+2+1)5 annulation and intramolecular annulation6 were also
demonstrated to provide more efficient synthetic pathways via
“a~e” bond formations of a pyran-4-one motif (Scheme 1).
(e.g., R2N,4a,6d I,6e F3CS,6f RSO2 ) is relatively rare, especially
7
those with a sulfonyl substituent (Y = RSO2). The traditional
route for the involvement of a sulfonyl group requires addi-
tional two-step steps, including nucleophilic addition of
chromen-4-ones with thiophenolate followed by oxidation of
the corresponding sulfides.7a-b However, the direct introduction
of a sulfonyl group into the chromen-4-ones skeleton had not
been reported until recently. As a result of the recent findings,
new methods for their preparation are needed.
Scheme 1. Annulation Routes of Chromen-4-ones
Results and Discussion
(4+2) annulation (a + c)
(3+2+1) annulation (a + c + d)
O
Y
Continuing our research on the synthesis of sulfonyl frame-
works,8 herein, we present various copper salts in a mediated
synthesis of sulfonyl chromen-4-ones 1 via one-pot efficient
(4+2) annulation of salicyclic acids 2 with sulfonylacetylenes
3 in the presence of activating reagents (Scheme 2).9 On the
basis of the facile preparation of 3,10 adopted by Zhang10b and
Waser,10c skeleton 3 was obtained from an AlCl3 mediated
coupling reaction of RSO2Cl and TMS-protected acetylenes.
Skeleton 2 was afforded from Pinnick oxidation of commer-
cially available 2-hydroxybenzaldehydes besides 2a (Ar = Ph).
Sn(IV), Chang4a
Al(III), Oh4b
Ru(II), Lee4d
Y
CO
I
Pd(II),
X
Alper,5a Capretta,5b Yang5c
+
+
Ar
Ar
OMe
X = Cl, H
OH
Z
Z
O
O
d
c
Y
Z
N
O
2
Y
Z
intramolecular annulation (a)
O
H
Ar
+
b
Ar
OH
X = O, K CO , Fu6a
Y
2
3
e O a
Rh(III), Yao4c
X = O, amine, Yang6b
Ar
Z
chromen-4-ones
X = H , Pd(0), Liu6c
O
2
X
(4+2) annulation (d + e)
O
O
N
O
O
TMS
Y
HO
+
Ar
Ar
Ar
Ar
Scheme 2.Our Synthetic Route of 1
Z
OTf
KF, Ma4e
Z
O
OMe
ICl, Larock6e
OH NMe
Ag(I), Yang6f
2
NHC, Liu6d
R
O S
O
O
S
O
Z
O
copper
salts
O
R
OH
However, intermolecular annulations are also popular ap-
proaches to such chromen-4-ones among existing methods.
Development of a new, single-vessel route for the simultane-
ous bond formation and ring-construction of diversified
chromen-4-ones from readily available starting materials still
Ar
Ar
+
activating
reagents
O
OH
Z
1
2
3
The initial study commenced with treatment of model sub-
strates 2a (Ar = Ph, 0.5 mmol) and 3a (R = Tol, Z = Me, 1.1
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equiv) with a 0.3 equivalent of Cu(OAc)2 in MeNO2 at rt or
100 C for 3 h. However, two conditions were unsuccessful.
trolling Cu(OAc)2 as the promoter, we found that other kinds
o
of activating reagents, HBTU and DCC, were ineffective in
the current reaction (entries 14-15). After elongating the reac-
tion time (3  6 h), isolated yield (71%) was decreased (entry
16). To avoid the production of poison HMPA, BOP was
changed to PyBOP. However, lower yield (70%) of 1a were
produced (entry 17). From these observations, we concluded
that Cu(OAc)2, BOP, and DMAP provided optimal conditions
(refluxing MeNO2 and 3 h) for one-pot (4+2) cyclization.
Following, a stoichiometric amount of Cu(OAc)2 was in-
creased to 1.1 equivalent, only an 18% yield of 1a was provid-
ed under the refluxing MeNO2 condition for 3 h. With the
addition of DMAP (1.0 equiv), the yield was enhanced to 35%.
The results prompted us to optimize the condition to improve
the yield of 1a. Gratifyingly, when BOP (1.1 equiv, benzotria-
zol-1-yloxy tri(dimethylamino)phosphonium hexafluorophos-
phate, Castro’s reagent), and DMAP (1.0 equiv) were added to
the reaction mixture, the yield of 1a was enhanced 80%. Com-
pared with 1.0 equivalent of DMAP, a catalytic amount of
DMAP (0.2 equiv) was treated to Cu(OAc)2 mediated reaction
of 2a and 3a in the presence of BOP (1.1 equiv), however, 1a
was isolated in lower yield (51%).
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Scheme 3. Plausible Mechanism
O
O
O
O
N
N
Cu(OAc) + DMAP
2
BOP
N
P
OH
O
O
PF
6
Cu
Cu
OH
2a
O
A
O
H
N
N
N
B
N
H
O
N
+ 2 OAc
3a
Table 1. Reaction Conditionsa
O
3a
Cu
O
No BOP
Tol
S
Tol
O
O
copper salts
additives
O
O
S
N
N
P
O
S
O
CuO
O
O
O
O
N
E
OH
O
O
S
Tol
Tol
PF
6
S
+
O
O
O
Tol
6
S
conditions
O
OH
2a
Tol
O
O
1a
O

O
O
Cu
O
3a
O

PF
Cu
O
CuO
+
HMPA
entry copper salts (eq) activators solvent time (h) 1a (%)b
1a
D
C
BTA-OAc
N
N
N
N
1
2
3
4
5
6
7
8
9
Cu(OAc)2 (1.1) BOP
Cu(OAc)2 (1.1) BOP
Cu(OAc)2 (1.1) BOP
Cu(OAc)2 (1.1) BOP
Cu(OAc)2 (1.1) BOP
Cu(OAc)2 (1.1) BOP
Cu(OAc)2 (1.1) BOP
Cu(OTf)2 (1.1) BOP
MeNO2
DMSO
DMF
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
6
3
80
N
OAc
N
c
─
On the basis of our experimental results, a plausible mecha-
nism for the formation of 1a is illustrated in Scheme 3. Initial-
ly, DMAP mediated complexation of Cu(OAc)2 with hydroxyl
and carboxylic acid groups of 2a yields A. By intermolecular
cross coupling of A and BOP, B should be afforded via the O-
P bond cleavage of BOP. Following the involvement of 3a, the
oxy-copper arm of in-situ generated C attacks the β-position
of 3a via the O-C bond formation. Subsequently, the corre-
sponding formed α-anion promotes the intramolecular C-C
bond formation and the release of HMPA to produce D. Final-
ly, the construction of 1a furnished via the acetate anion medi-
ated the removal of benzotriazoyl acetate (BTA-OAc) and
copper oxide (CuO). The by-product BTA-OAc was isolated
to confirm the mechanism pathway. On the other hand, when
the Cu(OAc)2 mediated reaction is not involved with BOP,
cross coupling of A and 3a provided E through a syn-addition.
With the ring-contraction of E having an eight-membered ring
and the elimination of CuO, 1a is afforded. From the possible
mechanism, we found that the stoichiometric amounts of
Cu(OAc)2, BOP, and DMAP required at least one equivalent,
such that a one-pot reaction provided better yield (80%) of 1a.
55
d
CH2Cl2
MeCN
THF
─
<5
28
d
toluene
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
─
68
32
14
CuSO4 (1.1)
BOP
BOP
BOP
10 CuF2 (1.1)
11 CuI (1.1)
d
─
12 Cu(OAc)2 (1.5) BOP
13 Cu(OAc)2 (2.0) BOP
14 Cu(OAc)2 (1.5) HBTU
15 Cu(Oac)2 (2.0) DCC
16 Cu(OAc)2 (1.1) BOP
17 Cu(OAc)2 (1.1) PyBOP
78
80
30
11
71
70
aThe reactions were run on a 0.5 mmol scale with 2a, 3a (1.1
equiv), DMAP (1.0 equiv), activators (1.1 equiv), solvent (3
mL), reflux. bIsolated yields. cComplex results. dNo reaction.
To study the scope and limitations of this approach, 2 and 3
were reacted with the combination of Cu(OAc)2, BOP, and
DMAP to afford diversified 1, as shown in Table 2. With op-
timal conditions established (Table 1, entry 1) and a plausible
mechanism proposed (Scheme 3), we found that this route
allowed a direct (4+2) annulation under mild conditions in
moderate to good yields (54%-86%). Among entries 1-38,
efficient formation of 1a-1al showed that the substituents (Ar,
R, and Z) did not affect the yield. The structures of 1a, 1f, 1h,
and 1al were determined by single-crystal X-ray crystallog-
raphy.11 For the electronic nature of aryl substituents (Ar) of 2,
not only electron-neutral but electron-withdrawing and elec-
tron-donating groups were appropriate. For the sulfonyl sub-
stituents (R) of 3, both aliphatic and aromatic groups were
well-tolerated. However, for the Z substituents of 3, only ali-
phatic groups (Me, Et, CF3, and CH2Ar) could be well-applied.
Controlling DMAP as the base, we surveyed the effect of
the additives on the reaction, revealing that activating reagents
were indispensable for constructing a core structure of
chromen-4-one, as shown in Table 1, entry 1. Furthermore,
solvent screening was performed. It was obvious that the reac-
tion was highly solvent-dependent with poor (28%; <5%) and
moderate (58%) yields obtained in THF, MeCN, and DMF,
respectively (entries 3, 5, 6), while no desired products were
detected in DMSO, CH2Cl2, or toluene (Table 1, entries 2, 4,
7). Subsequently, some copper(II) complexes were studied,
such as Cu(OTf)2, CuSO4, and CuF2. However, none of them
obtained higher yields of 1a than Cu(OAc)2 (entries 8-10).
After changing Cu(OAc)2 to CuI, no desired products were
produced (entry 11). Next, other catalytic amounts (1.5 and
2.0 equiv) of Cu(OAc)2 were examined; however, the isolated
yields were similar (78% and 80%) (entries 12-13). By con-
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Table 2. Synthesis of 1a
Especially, 3k-3m having both electron-withdrawing groups,
sulfonyl and CF3, could produce only one regioisomer (for 1o-
1t, entries 15-20). The possible reason should be sulfonyl
group with bulkier steric hindrance inhibited oxy-copper arm
of C to attack the α-position of 3 such that β-carbon position
(conjugated a CF3 group) with less-hindrance face could be
installed regioselectively. Attempts to afford flavonoid 1am
(for 3ab, Z = Ph) failed because the phenyl group could make
the electron density of π-system more likely to inhibit the first
step of (4+2) annulation (entry 38). However, for the
Cu(OAc)2/BOP mediated reactions of 2a with 3ac and 3ad,
complex results were observed and no desired 1an and 1ao
was observed (entries 40-41). The results showed that β-aceto
(Ac) and ditosylamino (NTs2) could cause the electrophilic
instability of the β-position of 3a. In comparison with sulfonyl
alkyne 3a, Cu(OAc)2 mediated reaction of 2a with sulfoxide-
substitutetd alkyne 3a’ (R = Tol, Z = Me)12 was examined. In
particular, complex mixture were observed and no 3a’ was
recovered due to sulfoxide group was activated by BOP.12b
R
S
Cu(OAc) (1.1 equiv)
2
BOP (1.1 equiv)
DMAP (1.0 equiv)
O
O
O
O
S
O
Z
O
O
5
4
OH
R
Ar
Ar
+
4
5
OH
MeNO (3 mL), reflux, 3 h
2
3
Z
2
3
1
6
7
8
9
entry 2, Ar =
3, R =, Z =
1, (%)b
1a, 80
1b, 84
1c, 86
1d, 78
1e, 74
1f, 82
1g, 68
1h, 80
1i, 80
1j, 73
1k, 74
1l, 66
1m,84
1n, 68
1o, 74
1p, 73
1q, 64
1r, 60
1s, 66
1t, 54
1u, 73
1v, 78
1w, 72
1x, 78
1y, 78
1
2
3
4
5
6
7
8
9
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
3a, Tol, Me
3b, Ph, Me
3c, Me, Me
10
11
12
13
14
15
16
17
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3d, 4-FC6H4, Me
3e, 4-MeOC6H4, Me
3a, Tol, Me
2b, 5-FC6H3
2c, 4-MeOC6H3 3a, Tol, Me
2a, Ph
2a, Ph
3f, Tol, Et
3g, Ph, Et
10 2a, Ph
3h, Me, Et
11 2a, Ph
3i, 4-FC6H4, Et
3j, 4-MeOC6H4, Et
3f, Tol, Et
Scheme 4. One-step Synthesis of 4a-4d
12 2a, Ph
O
S
O
S
Tol
Tol
13 2b, 5-FC6H3
1H
O
O
S
O
N
O
NH
80% N H (2 mL)
2
4
N
H
N
(1)
(2)
14 2c, 4-MeOC6H3 3f, Tol, Et
Tol
O
2H
dioxane (3 mL)
reflux, 3 h
OH
O
OH
15 2a, Ph
3k, Tol, CF3
3l, Ph, CF3
4a' (not detected)
1a
4a (90%)
16 2a, Ph
NH
(2.0 equiv)
O
O
S
17 2a, Ph
3m, Me, CF3
3n, 4-FC6H4, CF3
3k, Tol, CF3
O
N
HCl H N
Ph
2
Tol
O
18 2a, Ph
N
Ph
DMSO (3 mL)
reflux, 3 h
O
1a
4b (85%)
19 2b, 5-FC6H3
O
S
1 equiv
O
H N
2
Ph
NH
20 2c, 4-MeOC6H3 3k, Tol, CF3
HO
Tol
Tol
O
O
O
O
O
S
O
S
Tol
HO
21 2a, Ph
3o, Tol, CH2Ph
H
S
N
N
Tol
O
NH
22 2a, Ph
3p, Tol, CH2-4-MeC6H4
3q, Tol, CH2-2-thienyl
3r, Tol, CH2-4-FC6H4
3s, Tol, CH2-4-MeOC6H4
N
Ph
O
N
Ph
O
I
N
H
Ph
23 2a, Ph
V
IV
O
O
S
O
S
Tol
Ph
Tol
24 2a, Ph
O
O
N
NH
25 2a, Ph
HO
HO
III
HN
HN
Ph
II
26 2a, Ph
3t, Tol, CH2-3,4-(MeO)2C6H4 1z, 72
27 2a, Ph
3u, Tol, CH2-1-naphthyl
3v, 3-MeC6H4, Me
3w, 4-EtC6H4, Me
3x, 4-iPrC6H4, Me
3y, 4-nBuC6H4, Me
3z, 4-tBuC6H4, Me
3aa, nBu, Me
1aa,70
1ab, 80
1ac, 82
1ad, 84
1ae, 80
1af, 83
1ag, 76
1ah, 70
1ai, 71
1aj, 73
1ak, 73
1al, 63
1am, ─c
1an, ─d
1ao, ─d
H N
2
N
28 2a, Ph
O
O
HN
H N
2
S
(2.0 equiv)
Tol
N
(3)
N
29 2a, Ph
+
O
DMSO (3 mL)
reflux, 3 h
O
OH
OH
4d (38%)
30 2a, Ph
1a
4c (48%)
H N
O
S
2
31 2a, Ph
1 equiv
O
O
S
Tol
H N
2
O
O
S
32 2a, Ph
HO
Tol
Tol
NH
2
33 2a, Ph
O
N
N
O
S
O
NH
HN
Tol
34 2d, 5-BrC6H3
35 2e, 5-ClC6H3
36 2f, naphthyl
3a, Tol, Me
O
H N
2
O
O
S
O
O
OH
H N
3a, Tol, Me
VI
IX
S
Tol
Tol
O
O
2
3a, Tol, Me
N
OH
VIII
HO
H N
2
H N
2
VII
37 2g, 5-Br-naphthyl 3a, Tol, Me
1 equiv
38 2h, 3,5-F2C6H2
39 2a, Ph
3a, Tol, Me
As an extension of one-pot annulations, the synthetic appli-
cations of 1a with 1,2-, 1,3-, and 1,4-diamino synthons were
investigated next (Scheme 4, equations 1-3). Treatment of 1a
with N2H4 provided only sole 4a with a 1H-skeleton in a 90%
yield via (3+2) annulation (equation 1). However, the reported
2H-skeleton of 4a’ was not observed on the framework having
a sulfonyl substituent.13 As shown in equation 2), changing
hydrazine (1,2-N2) to benzamidine (1,3-N2),6f 4b was pro-
3ab, Tol, Ph
3ac, Tol, Ac
3ad, Tol, NMs2
40 2a, Ph
41 2a, Ph
aReactions were run on a 0.5 mmol scale with 2, 3 (1.1 equiv),
Cu(OAc)2 (1.1 equiv), BOP (1.1 equiv), DMAP (1.0 equiv),
MeNO2 (3 mL), 3 h, reflux. bIsolated yields. cNo reaction.
dComplex mixture.
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duced in an 85% yield. The plausible mechanism could be that
CH2Cl2 (3 x 20 mL). The combined organic layers were
I was formed by the Michael addition of 1a with benzamidine.
Then, the ring-opening of I provided imine II. After tauto-
meization, the intramolecular ring-closure of III with enamino
motif produced IV. Next, the SNAr reaction of IV generated
4b by removal of TolSO2H. Furthermore, one-pot annulation
of 1a with o-diaminobenzene (1,4-N2) was examined (equa-
tion 3). Unexpectedly, 4c and 4d were isolated in 48% and
38% yields, respectively. The initial event could be that VI
was formed by the Michael addition of 1a with one o-
diaminobenzene (1 equiv). After removing the 2-methyl-1H-
benzimidazole, VII was transformed to VIII. 2-Methyl-1H-
benzimidazole could be isolated to confirm the reaction pro-
cess. Next, condensation of VIII with another o-
diaminobenzene (1 equiv) provided 4c and 4d by removal of
the TolSO2H or TolSO2Me of IX, respectively. To the best of
our knowledge, the transformations of equations 1-3 have not
been explored to date. By the use of chromen-4-one as the
model substrate, four kinds of pyrazole, pyrimidine, quinoxa-
line and benzimidazole were generated by a one-pot synthetic
route. The structures of 4a-4d were determined by single-
crystal X-ray crystallography.11
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Purification on silica
gel (hexanes/EtOAc = 8/1~4/1) afforded 1.
2-Methyl-3-(toluene-4-sulfonyl)chromen-4-one (1a). Yield
= 80% (126 mg); Colorless solid; mp = 153-155 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C17H15O4S 315.0691, found 315.0698; H NMR
9
(400 MHz, CDCl3): δ 8.06-8.04 (m, 1H), 8.00 (d, J = 8.4 Hz,
2H), 7.68-7.64 (m, 1H), 7.43-7.40 (m, 1H), 7.38-7.34 (m, 1H),
7.30 (d, J = 8.4 Hz, 2H), 3.03 (s, 3H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 172.5, 171.6, 154.9, 144.3, 138.8, 134.5,
129.2 (2x), 128.3 (2x), 126.11, 126.05, 124.2, 123.5, 117.7,
21.6, 20.9. Single-crystal X-Ray diagram: crystal of com-
pound 1a was grown by slow diffusion of EtOAc into a solu-
tion of compound 1a in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the triclinic crystal system, space
group P - 1, a = 7.1482(5) Å , b = 10.6504(7) Å , c = 11.8975(8)
Å , V = 825.16(10) Å 3, Z = 2, dcalcd = 1.265 g/cm3, F(000) =
328, 2θ range 1.870~26.403o, R indices (all data) R1 = 0.0347,
wR2 = 0.0808.
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3-Benzenesulfonyl-2-methylchromen-4-one (1b). Yield =
In summary, we have developed a Cu(OAc)2 promoted one-
pot (4+2) annulation of sulfonylacetylene 2 with salicyclic
acid 3 in the presence of BOP and DMAP in MeNO2 at reflux
for 3 h in moderate to good yields. The one-pot process pro-
vides a series of sulfonyl chromen-4-ones 1 via a cascade
pathway of C-O and then C-C bond formations. The related
plausible mechanisms have been proposed. The structures of
the key products were confirmed by X-ray crystallography.
Further investigations regarding the synthetic application of
copper salts will be conducted and published in due course.
o
84% (126 mg); Colorless solid; mp = 91-93 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H13O4S 301.0535, found 301.0533; 1H NMR (400
MHz, CDCl3): δ 8.09-8.06 (m, 2H), 7.95 (dd, J = 1.6, 8.0 Hz,
1H), 7.62-7.57 (m, 1H), 7.54-7.50 (m, 1H), 7.47-7.43 (m, 2H),
7.36 (d, J = 8.4 Hz, 1H), 7.30-7.264 (m, 1H), 2.98 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 172.2, 171.8, 154.6, 141.4, 134.4,
133.2, 128.4 (2x), 128.0 (2x), 126.0, 125.6, 123.7, 123.2,
117.6, 20.7.
3-Methanesulfonyl-2-methylchromen-4-one (1c). Yield =
Experimental Section
o
86% (102 mg); Colorless solid; mp = 132-134 C (recrystal-
General. All reagents and solvents were obtained from
commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of
dry nitrogen with magnetic stirring. Products in organic sol-
vents were dried with anhydrous magnesium sulfate before
concentration in vacuo. Melting points were determined with a
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C11H11O4S 239.0378, found 239.0377; H NMR
(400 MHz, CDCl3): δ 8.19 (dd, J = 2.0, 8.0 Hz, 1H), 7.76-7.71
(m, 1H), 7.48-7.44 (m, 2H), 3.40 (s, 3H), 2.90 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 173.5, 171.6, 155.0, 134.9, 126.4,
126.1, 123.7, 123.4, 117.8, 44.6, 20.5.
1
SMP3 melting apparatus. H and 13C NMR spectra were rec-
3-(4-Fluorobenzenesulfonyl)-2-methylchromen-4-one (1d).
orded on a Varian INOVA-400 spectrometer operating at 400
and at 100 MHz, respectively. Chemical shifts (δ) are reported
in parts per million (ppm) and the coupling constants (J) are
given in Hertz. High resolution mass spectra (HRMS) were
measured with a mass spectrometer Finnigan/Thermo Quest
MAT 95XL. X-ray crystal structures were obtained with an
Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD).
o
Yield = 78% (124 mg); Colorless solid; mp = 149-151 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C16H12FO4S 319.0440, found
1
319.0442; H NMR (400 MHz, CDCl3): δ 8.18-8.13 (m, 2H),
8.05 (dd, J = 1.6, 8.0 Hz, 1H), 7.70-7.66 (m, 1H), 7.43 (dd, J =
0.4, 8.4 Hz, 1H), 7.40-7.36 (m, 1H), 7.21-7.15 (m, 2H), 3.03 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 172.5, 171.9, 165.6 (d, J
= 254.0 Hz), 154.9, 137.6 (d, J = 3.0 Hz), 134.7, 131.4 (d, J =
9.1 Hz, 2x), 126.3, 126.0, 124.0, 123.4, 117.7, 115.8 (d, J =
22.0 Hz, 2x), 21.0.
Representative synthetic procedure of skeleton 1 is as fol-
lows: BOP (245 mg, 0.55 mmol, benzotriazo-1-
yloxytri(dimethylamino)phosphonium hexafluorophosphate)
was added to a solution of 2 (0.5 mmol) and Cu(OAc)2 (100
mg, 0.55 mmol) in MeNO2 (2 mL) at rt. The reaction mixture
was stirred at rt for 5 min. DMAP (60 mg, 0.5 mmol, p-
dimethylaminopyridine) was added to the reaction mixture.
The reaction mixture was stirred at reflux for 2 h and then
cooled to rt. Then, 3 (0.55 mmol) in MeNO2 (1 mL) was added
to the reaction mixture at rt. The reaction mixture was stirred
at reflux for an additional 1 h. The reaction mixture was
cooled to rt and the solvent was concentrated. The residue was
diluted with water (10 mL) and the mixture was extracted with
3-(4-Methoxybenzenesulfonyl)-2-methylchromen-4-one (1e).
o
Yield = 74% (122 mg); Colorless solid; mp = 118-120 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H15O5S 331.0640, found 331.0645;
1H NMR (400 MHz, CDCl3): δ 8.09-8.06 (m, 3H), 7.69-7.64
(m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.39-7.35 (m, 1H), 6.98 (d,
J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.03 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 172.6, 171.4, 163.5, 154.9, 134.5, 133.8,
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The Journal of Organic Chemistry
130.8 (2x), 126.11, 126.09, 123.6, 117.7, 115.1, 113.8 (2x),
2-Ethyl-3-methanesulfonylchromen-4-one (1j). Yield = 73%
2
3
o
55.6, 21.0.
(92 mg); Colorless solid; mp = 71-73 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C12H13O4S 253.0535, found 253.0532; 1H NMR (400 MHz,
CDCl3): δ 8.08 (dd, J = 1.6, 8.0 Hz, 1H), 7.70-7.66 (m, 1H),
7.43 (d, J = 8.0 Hz, 1H), 7.41-7.37 (m, 1H), 3.32 (s, 3H), 3.26
(q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 175.7, 173.6, 154.8, 134.7, 126.1, 125.7,
123.0, 122.8, 117.6, 44.4, 26.3, 12.3.
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5
6
7
6-Fluoro-2-methyl-3-(toluene-4-sulfonyl)chromen-4-one
(1f). Yield = 82% (136 mg); Colorless solid; mp = 134-136 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H14FO4S 333.0597, found
1
333.0602; H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.4 Hz,
8
2H), 7.54 (dd, J = 3.2, 8.0 Hz, 1H), 7.39 (dd, J = 4.0, 9.2 Hz,
1H), 7.32-7.27 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.95 (s, 3H),
2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.7, 171.4 (d,
J = 2.2 Hz), 159.5 (d, J = 247.2 Hz), 150.8 (d, J = 1.6 Hz),
144.2, 138.2, 128.9 (2x), 128.0 (2x), 124.4 (d, J = 7.6 Hz),
123.3, 122.4 (d, J = 25.0 Hz), 120.0 (d, J = 8.3 Hz), 110.4 (d, J
= 24.3 Hz), 21.2, 20.6. Single-crystal X-Ray diagram: crystal
of compound 1f was grown by slow diffusion of EtOAc into a
solution of compound 1f in CH2Cl2 to yield colorless prisms.
The compound crystallizes in the monoclinic crystal system,
space group P 21/n, a = 9.1290(8) Å , b = 18.4090(16) Å , c =
9.3444(8) Å , V = 1470.8(2) Å 3, Z = 4, dcalcd = 1.501 g/cm3,
F(000) = 688, 2θ range 2.213~26.389o, R indices (all data) R1
= 0.0459, wR2 = 0.0872.
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2-Ethyl-3-(4-fluorobenzenesulfonyl)chromen-4-one
(1k).
Yield = 74% (123 mg); Colorless solid; mp = 100-102 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C17H14FO4S 333.0597, found 333.0598; H
1
NMR (400 MHz, CDCl3): δ 8.15-8.10 (m, 2H), 8.00 (dd, J =
2.0, 8.4 Hz, 1H), 7.68-7.64 (m, 1H), 7.42 (dd, J = 0.8, 8.4 Hz,
1H), 7.37-7.33 (m, 1H), 7.18-7.12 (m, 2H), 3.45 (q, J = 7.6 Hz,
2H), 1.48 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
176.1, 172.6, 165.4 (d, J = 253.9 Hz), 154.9, 137.6 (d, J = 2.3
Hz), 134.6, 131.3 (d, J = 9.9 Hz, 2x), 126.1, 125.8, 123.23,
123.15, 117.6, 115.6 (d, J = 22.7 Hz, 2x), 26.0, 12.6.
2-Ethyl-3-(4-methoxybenzenesulfonyl)chromen-4-one (1l).
o
7-Methoxy-2-methyl-3-(toluene-4-sulfonyl)chromen-4-one
(1g). Yield = 68% (117 mg); Colorless solid; mp = 92-94 C
Yield = 66% (114 mg); Colorless solid; mp = 75-77 C (re-
o
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H17O5S 345.0797, found 345.0798;
1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 2H), 7.96
(d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.92 (dd, J = 2.4,
8.8 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 3.00 (s,
3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.9,
171.2, 164.7, 156.7, 144.2, 139.0, 129.2 (2x), 128.4 (2x),
127.5, 124.1, 117.3, 115.2, 100.1, 55.9, 21.6, 20.8.
[M + H]+ calcd for C18H17O5S 345.0797, found 345.0796; H
NMR (400 MHz, CDCl3): δ 8.08-8.04 (m, 1H), 8.06 (d, J =
9.2 Hz, 2H), 7.68-7.63 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.37-
7.33 (m, 1H), 6.96 (d, J = 9.2 Hz, 2H), 3.83 (s, 3H), 3.47 (q, J
= 7.6 Hz, 2H), 1.49 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 175.6, 172.8, 163.4, 155.0, 140.0, 134.4, 130.7 (2x),
126.0 (2x), 123.5, 117.6, 113.7 (2x), 67.0, 55.5, 26.9, 12.6.
2-Ethyl-6-fluoro-3-(toluene-4-sulfonyl)chromen-4-one (1m).
Yield = 84% (145 mg); Colorless solid; mp = 130-132 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
2-Ethyl-3-(toluene-4-sulfonyl)chromen-4-one (1h). Yield =
80% (131 mg); Colorless solid; mp = 93-95 oC (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C18H17O4S 329.0848, found 329.0851; 1H NMR (400
MHz, CDCl3): δ 7.92 (d, J = 8.0 Hz, 2H), 7.88 (dd, J = 1.6, 8.0
Hz, 1H), 7.56-7.52 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.22 (d,
J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 3.38 (q, J = 7.6 Hz,
2H), 2.26 (s, 3H), 1.40 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 175.5, 172.2, 154.5, 143.8, 138.4, 134.2,
128.7 (2x), 127.9 (2x), 125.6, 125.3, 123.0, 122.9, 117.3, 26.4,
21.1, 12.3. Single-crystal X-Ray diagram: crystal of com-
pound 1h was grown by slow diffusion of EtOAc into a solu-
tion of compound 1h in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the triclinic crystal system, space
group P -1, a = 8.922(2) Å , b = 10.140(2) Å , c = 10.581(2) Å ,
V = 768.7(3) Å 3, Z = 2, dcalcd = 1.419 g/cm3, F(000) = 344, 2θ
range 2.204~26.563o, R indices (all data) R1 = 0.0457, wR2 =
0.0984.
[M + H]+ calcd for C18H16FO4S 347.0753, found 347.0761; H
1
NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.4 Hz, 2H), 7.62 (dd,
J = 2.8, 8.0 Hz, 1H), 7.44 (dd, J = 4.0, 9.2 Hz, 1H), 7.37-7.32
(m, 1H), 7.27 (d, J = 8.8 Hz, 2H), 3.45 (q, J = 7.6 Hz, 2H),
2.36 (s, 3H), 1.47 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 173.9, 171.9, 159.7 (d, J = 247.1 Hz), 151.1 (d, J =
1.5 Hz), 144.3, 138.4, 129.1 (2x), 128.2 (2x), 124.5 (d, J = 7.5
Hz), 123.0, 122.6 (d, J = 25.8 Hz), 120.0 (d, J = 8.4 Hz), 110.7
(d, J = 24.3 Hz), 26.7, 21.4, 12.5.
2-Ethyl-7-methoxy-3-(toluene-4-sulfonyl)chromen-4-one
(1n). Yield = 68% (122 mg); Colorless gum; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C19H19O5S 359.0953, found
1
359.0955; H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz,
2H), 7.86 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 6.84
(dd, J = 2.4, 9.2 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H),
3.40 (q, J = 7.6 Hz, 2H), 2.33 (s, 3H), 1.44 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 175.3, 171.8, 164.5, 156.5,
143.9, 138.8, 128.9 (2x), 128.0 (2x), 127.0, 123.1, 116.8,
115.0, 99.8, 55.8, 26.5, 21.3, 12.5.
3-Benzenesulfonyl-2-ethylchromen-4-one (1i). Yield = 80%
o
(126 mg); Colorless solid; mp = 178-180 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H15O4S 315.0691, found 315.0699; 1H NMR (400
MHz, CDCl3): δ 8.14-8.11 (m, 2H), 8.04 (dd, J = 1.2, 8.0 Hz,
1H), 7.69-7.65 (m, 1H), 7.60-7.56 (m, 1H), 7.53-7.49 (m, 2H),
7.43 (d, J = 8.4 Hz, 1H), 7.38-7.34 (m, 1H), 3.49 (q, J = 7.6
Hz, 2H), 1.51 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 176.1, 172.7, 155.0, 141.7, 134.5, 133.3, 128.5 (2x),
128.2 (2x), 126.1, 126.0, 123.4, 123.3, 117.7, 26.9, 12.7.
3-(Toluene-4-sulfonyl)-2-trifluoromethylchromen-4-one
(1o). Yield = 74% (136 mg); Colorless solid; mp = 137-139 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H12F3O4S 369.0408, found
1
369.0412; H NMR (400 MHz, CDCl3): δ 8.09-8.07 (m, 3H),
7.81-7.77 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.51-7.47 (m, 1H),
7.33 (d, J = 8.4 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz,
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CDCl3): δ 172.5, 154.6 (q, J = 40.9 Hz), 153.8, 145.3, 137.2,
135.8, 129.4 (2x), 129.3 (2x), 128.4, 127.6, 126.2, 123.7,
118.4, 118.2 (q, J = 277.4 Hz), 21.6.
H]+ calcd for C23H19O4S 391.1004, found 391.1002; H NMR
(400 MHz, CDCl3): δ 7.96 (dd, J = 1.6, 8.4 Hz, 1H), 7.61-7.56
(m, 1H), 7.41-7.31 (m, 7H), 7.21 (d, J = 8.0 Hz, 2H), 7.04-
7.01 (m, 2H), 4.62 (s, 2H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 160.3, 152.9, 145.3, 138.4, 136.1, 132.7, 132.0,
131.9, 129.9 (2x), 129.6, 128.6 (2x), 128.5 (2x), 128.1 (2x),
127.1, 124.3, 118.5, 116.8, 56.5, 21.6.
3-Benzenesulfonyl-2-trifluoromethylchromen-4-one
(1p).
Yield = 74% (131 mg); Colorless solid; mp = 196-198 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C16H10F3O4S 355.0252, found 355.0254;
1H NMR (400 MHz, CDCl3): δ 8.23-8.20 (m, 2H), 8.09 (dd, J
= 1.6, 8.0 Hz, 1H), 7.82-7.78 (m, 1H), 7.66-7.62 (m, 1H),
7.58-7.48 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 172.4,
154.9 (q, J = 40.9 Hz), 153.9, 140.2, 135.8, 134.1, 129.2 (2x),
128.8 (2x), 127.7, 126.9, 126.3, 123.8, 118.4, 118.2 (q, J =
277.4 Hz).
2-(4-Methylbenzyl)-3-(toluene-4-sulfonyl)chromen-4-one
(1v). Yield = 78% (158 mg); Colorless solid; mp = 199-201 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C24H21O4S 405.1161, found 405.1161;
1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 1.2, 8.0 Hz, 1H),
7.60-7.56 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.40-7.33 (m, 2H),
7.22 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.89 (d, J =
8.0 Hz, 2H), 4.64 (s, 2H), 2.45 (s, 3H), 2.38 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 160.4, 152.8, 145.3, 138.5, 138.3, 136.1,
132.0, 131.9, 129.9 (2x), 129.7, 129.5 (2x), 129.2 (2x), 128.2
(2x), 127.0, 124.3, 118.6, 116.8, 56.6, 21.6, 21.3.
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3-Methanesulfonyl-2-trifluoromethylchromen-4-one (1q).
o
Yield = 64% (93 mg); Colorless solid; mp = 158-160 C (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C11H8F3O4S 293.0095, found 293.0094; H
NMR (400 MHz, CDCl3): δ 8.22 (dd, J = 1.6, 8.0 Hz, 1H),
7.89-7.84 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.61-7.57 (m, 1H),
3.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 173.5, 154.9 (d,
J = 41.7 Hz), 154.0, 136.1, 127.9, 126.3, 126.2, 123.6, 118.5,
118.0 (q, J = 277.4 Hz), 44.8.
2-Thiophen-2-ylmethyl-3-(toluene-4-sulfonyl)chromen-4-
one (1w). Yield = 72% (143 mg); Colorless solid; mp = 191-
193 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C21H17O4S2 397.0568, found
1
397.0566; H NMR (400 MHz, CDCl3): δ 7.91 (dd, J = 1.2,
3-(4-Fluorobenzenesulfonyl)-2-trifluoromethylchromen-4-
one (1r). Yield = 60% (112 mg); Colorless solid; mp = 193-
195 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C16H9F4O4S 373.0158, found
8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.44
(dd, J = 1.2, 4.8 Hz, 1H), 7.39-7.32 (m, 2H), 7.263 (d, J = 8.4
Hz, 2H), 7.05-7.00 (m, 2H), 4.78 (s, 2H), 2.44 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 159.8, 152.8, 145.5, 140.2, 136.1,
132.6, 132.4, 130.4, 130.0 (2x), 128.3, 128.1 (2x), 127.3,
126.9, 125.2, 124.5, 118.4, 116.9, 56.8, 21.6.
1
373.0155; H NMR (400 MHz, CDCl3): δ 8.27-8.22 (m, 2H),
8.10 (dd, J = 1.6, 8.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.59 (d, J =
8.4 Hz, 1H), 7.54-7.50 (m, 1H), 7.24-7.19 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 172.4, 166.1 (d, J = 255.5 Hz), 154.9 (q,
J = 41.0 Hz), 153.9, 136.1 (d, J = 3.0 Hz), 135.9, 132.5 (d, J =
9.9 Hz, 2x), 127.8, 126.8, 126.2, 123.7, 118.5, 118.2 (q, J =
277.5 Hz), 116.2 (d, J = 22.7 Hz, 2x).
2-(4-Fluorobenzyl)-3-(toluene-4-sulfonyl)chromen-4-one
(1x). Yield = 78% (159 mg); Colorless solid; mp = 183-185 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C23H18FO4S 409.0910, found
1
409.0912; H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 1.2,
6-Fluoro-3-(toluene-4-sulfonyl)-2-trifluoromethylchromen-
4-one (1s). Yield = 66% (127 mg); Colorless solid; mp = 179-
181 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H11F4O4S 387.0314, found
8.4 Hz, 1H), 7.63-7.58 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.40
(d, J = 8.8 Hz, 1H), 7.39-7.35 (m, 1H), 7.262 (d, J = 8.0 Hz,
2H), 7.05 (br s, 2H), 7.03 (br s, 2H), 4.59 (s, 2H), 2.46 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 162.7 (d, J = 247.1 Hz), 160.3,
152.9, 145.6, 138.8, 136.2, 132.3, 131.7 (d, J = 7.5 Hz, 2x),
131.0, 130.1 (2x), 128.6 (d, J = 3.7 Hz), 128.1 (2x), 127.1,
124.5, 118.4, 117.0, 115.7 (d, J = 21.3 Hz, 2x), 56.6, 21.7.
1
387.0312; H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.0 Hz,
2H), 7.73 (dd, J = 3.2, 7.6 Hz, 1H), 7.61 (dd, J = 4.0, 9.2 Hz,
1H), 7.54-7.49 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 171.9 (d, J = 22.0 Hz), 161.9,
159.4, 154.7 (q, J = 40.9 Hz), 150.1, 145.5, 137.0, 129.5 (2x),
129.4 (2x), 125.2 (d, J = 7.6 Hz), 124.1 (d, J = 25.7 Hz), 120.9
(d, J = 8.3 Hz), 118.2 (q, J = 277.4 Hz), 111.4 (d, J = 24.3 Hz),
21.7.
2-(4-Methoxybenzyl)-3-(toluene-4-sulfonyl)chromen-4-one
(1y). Yield = 78% (164 mg); Colorless solid; mp = 188-190 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C24H21O5S 421.1110, found 421.1112;
1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 1.6, 8.4 Hz, 1H),
7.59-7.55 (m, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8
Hz, 1H), 7.34-7.32 (m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.94 (d,
J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.65 (s, 2H), 3.84 (s,
3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.6,
159.7, 152.7, 145.3, 138.2, 136.1, 131.8, 131.7, 131.0, 129.9
(2x), 128.1 (2x), 127.0 (2x), 124.8, 124.3, 118.6, 116.8, 113.9
(2x), 56.5, 55.3, 21.6.
7-Methoxy-3-(toluene-4-sulfonyl)-2-
trifluoromethylchromen-4-one (1t). Yield = 54% (107 mg);
Colorless solid; mp = 140-142 oC (recrystallized from hexanes
and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C18H14F3O5S 399.0514, found 399.0511; H NMR (400 MHz,
CDCl3): δ 8.08 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 9.2 Hz, 1H),
7.34 (d, J = 8.4 Hz, 2H), 7.03 (dd, J = 2.4, 9.2 Hz, 1H), 6.92 (d,
J = 2.4 Hz, 1H), 3.92 (s, 3H), 2.42 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 171.6, 165.6 (2x), 155.5 (d, J = 42.0 Hz),
145.3, 137.3, 129.4 (2x), 129.3 (2x), 127.7, 119.7, 118.3 (q, J
= 276.7 Hz), 117.5, 117.1, 100.3, 56.2, 21.7.
2-(3,4-Dimethoxybenzyl)-3-(toluene-4-sulfonyl)chromen-4-
one (1z). Yield = 72% (162 mg); Colorless solid; mp = 137-
139 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C25H23O6S 451.1215, found
451.1218; H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 1.2,
8.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.36
2-Benzyl-3-(toluene-4-sulfonyl)chromen-4-one (1u). Yield =
1
o
73% (142 mg); Colorless solid; mp = 180-182 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
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(d, J = 8.0 Hz, 1H), 7.33-7.29 (m, 1H), 7.23 (d, J = 8.0 Hz,
128.6 (2x), 128.4 (2x), 126.13, 126.11, 124.3, 123.6, 117.7,
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6
7
8
9
2H), 6.84 (d, J = 8.0 Hz, 1H), 6.72 (br s, 1H), 6.66 (dd, J = 2.0,
8.4 Hz, 1H), 4.66 (br s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 2.42 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 160.5, 152.7, 149.3,
148.8, 145.3, 138.4, 136.4, 131.84, 131.78, 129.9 (2x), 127.9
(2x), 126.9, 125.1, 124.2, 122.1, 118.5, 116.8, 113.2, 111.0,
56.6, 55.91, 55.86, 21.6.
35.6, 33.0, 22.3, 21.0, 13.8.
3-(4-t-Butylbenzenesulfonyl)-2-methylchromen-4-one (1af).
Yield = 83% (148 mg); Colorless solid; mp > 220 C (recrys-
o
tallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C20H21O4S 357.1161, found 357.1163; 1H
NMR (400 MHz, CDCl3): δ 8.09-8.04 (m, 3H), 7.66 (dt, J =
1.6, 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.42 (dt, J = 1.2, 8.0
Hz, 1H), 7.37 (dt, J = 1.2, 8.0 Hz, 1H), 3.04 (s, 3H), 1.31 (s,
9H); 13C NMR (100 MHz, CDCl3): δ 172.6, 171.6, 157.2,
155.0, 138.7, 134.5, 128.2 (2x), 126.14, 126.10, 125.6 (2x),
124.3, 123.7, 117.7, 35.2, 31.0 (3x), 21.0.
2-Naphthalen-1-ylmethyl-3-(toluene-4-sulfonyl)chromen-4-
one (1aa). Yield = 70% (154 mg); Colorless solid; mp = 167-
169 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C27H21O4S 441.1161, found
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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
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58
59
60
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441.1166; H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 1.6,
8.0 Hz, 1H), 7.91-7.88 (m, 2H), 7.67-7.63 (m, 1H), 7.50-7.37
(m, 6H), 7.30 (d, J = 8.0 Hz, 2H), 7.17-7.12 (m, 3H), 4.64 (d,
J = 14.0 Hz, 1H), 4.19 (d, J = 13.6 Hz, 1H), 2.39 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 160.1, 153.3, 145.3, 140.6, 136.4,
133.5, 132.3, 131.0, 130.3, 129.9 (2x), 129.4, 128.8, 128.7,
128.0, 127.9 (2x), 127.3, 127.0, 126.2, 125.3, 124.5, 124.2,
118.5, 117.0, 57.3, 21.6.
3-(n-Butane-1-sulfonyl)-2-methylchromen-4-one
(1ag).
Yield = 76% (106 mg); Colorless gum; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C14H17O4S 281.0848, found 281.0843; H
1
NMR (400 MHz, CDCl3): δ 8.01 (dd, J = 1.6, 8.0 Hz, 1H),
7.65-7.60 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4
Hz, 1H), 3.45-3.41 (m, 2H), 2.76 (s, 3H), 1.65-1.57 (m, 2H),
1.36-1.27 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 173.2, 172.0, 154.5, 134.6, 126.0, 125.5,
122.8, 121.5, 117.5, 54.9, 23.9, 21.09, 20.06, 13.2.
2-Methyl-3-(toluene-3-sulfonyl)chromen-4-one (1ab). Yield
= 80% (126 mg); Colorless solid; mp = 123-125 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
6-Bromo-2-methyl-3-(toluene-4-sulfonyl)chromen-4-one
(1ah). Yield = 70% (137 mg); Colorless solid; mp = 121-123
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H14BrO4S 392.9796, found
1
H]+ calcd for C17H15O4S 315.0691, found 315.0693; H NMR
(400 MHz, CDCl3): δ 8.06 (dt, J = 1.2, 8.0 Hz, 1H), 7.93-7.90
(m, 2H), 7.67 (dt, J = 1.6, 8.8 Hz, 1H), 7.43-7.35 (m, 4H),
3.04 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
172.5, 171.8, 155.0, 141.6, 138.7, 134.5, 134.2, 128.4, 128.3,
126.2, 126.1, 125.4, 124.1, 123.6, 117.7, 21.3, 20.9.
1
392.9795; H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 2.4 Hz,
1H), 7.97 (d, J = 8.4 Hz, 2H), 7.73 (dd, J = 2.4, 8.8 Hz, 1H),
7.33-7.29 (m, 3H), 3.03 (s, 3H), 2.40 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 171.8, 171.3, 153.7, 144.6, 138.4, 137.5,
129.2 (2x), 128.7, 128.4 (2x), 124.8, 124.5, 119.6, 31.5, 21.6,
21.0.
3-(4-Ethylbenzenesulfonyl)-2-methylchromen-4-one (1ac).
Yield = 82% (134 mg); Colorless solid; mp = 155-157 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C18H17O4S 329.0848, found 329.0852; H
6-Chloro-2-methyl-3-(toluene-4-sulfonyl)-chromen-4-one
(1ai). Yield = 71% (124 mg); Colorless solid; mp = 204-206
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H14ClO4S 349.0301, found
NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.4 Hz, 1H), 8.03 (d,
J = 8.8 Hz, 2H), 7.68-7.64 (m, 1H), 7.41 (d, J = 8.8 Hz, 1H),
7.38-7.35 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 3.04 (s, 3H), 2.69
(q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 172.5, 171.6, 154.9, 150.4, 139.0, 134.5,
128.4 (2x), 128.1 (2x), 126.11, 126.06, 124.3, 123.6, 117.7,
28.8, 20.9, 14.9.
1
349.0308; H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 2.4 Hz,
1H), 7.99 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 2.8, 8.8 Hz, 1H),
7.38 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 3.03 (s, 3H),
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.8, 171.4,
153.3, 144.6, 138.5, 134.7, 132.2, 129.2 (2x), 128.5 (2x),
125.5, 124.5, 124.4, 119.5, 21.6, 20.9.
3-(4-Isopropylbenzenesulfonyl)-2-methylchromen-4-one
(1ad). Yield = 84% (144 mg); Colorless solid; mp = 157-159
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C19H19O4S 343.1004, found
2-Methyl-3-(toluene-4-sulfonyl)benzo[h]chromen-4-one
(1aj). Yield = 73% (133 mg); Colorless solid; mp > 245 C
o
1
343.1002; H NMR (400 MHz, CDCl3): δ 8.08-8.06 (m, 1H),
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C21H17O4S 365.0848, found 365.0849;
1H NMR (400 MHz, CDCl3): δ 8.44 (d, J = 7.2 Hz, 1H), 8.05
(d, J = 7.6 Hz, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 7.2
Hz, 1H), 7.74-7.68 (m, 3H), 7.33 (d, J = 7.6 Hz, 2H), 3.19 (s,
3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.5,
152.5, 144.4, 138.7, 136.1, 131.0, 129.8, 129.3 (2x), 128.6,
128.5 (2x), 128.0, 127.6, 126.3, 124.0, 122.3, 122.0, 120.5,
21.7, 20.8.
8.05 (d, J = 8.4 Hz, 2H), 7.68-7.64 (m, 1H), 7.43-7.39 (m, 2H),
7.36 (d, J = 8.4 Hz, 2H), 3.04 (s, 3H), 2.99-2.92 (m, 1H), 1.24
(d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 172.6,
171.6, 154.9 (2x), 139.0 134.5, 128.5 (2x), 126.7 (2x), 126.14,
126.07, 124.2, 123.6, 117.7, 34.2, 23.5 (2x), 21.0.
3-(4-n-Butylbenzenesulfonyl)-2-methylchromen-4-one (1ae).
Yield = 80% (142 mg); Colorless solid; mp = 112-114 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
1
[M + H]+ calcd for C20H21O4S 357.1161, found 357.1163; H
6-Bromo-2-methyl-3-(toluene-4-sulfonyl)-
NMR (400 MHz, CDCl3): δ 8.07 (dd, J = 1.6, 8.0 Hz, 1H),
8.03 (d, J = 8.4 Hz, 2H), 7.66 (dt, J = 1.6, 8.4 Hz, 1H), 7.42 (d,
J = 8.4 Hz, 1H), 7.37 (dt, J = 1.2, 8.0 Hz, 1H), 7.31 (d, J = 8.4
Hz, 2H), 3.04 (s, 3H), 2.65 (t, J = 7.6 Hz, 2H), 1.63-1.55 (m,
2H), 1.38-1.29 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 172.5, 171.6, 155.0, 149.2, 138.9, 134.5,
benzo[h]chromen-4-one (1ak). Yield = 73% (161 mg); Color-
o
less solid; mp = 225-227 C (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C21H16BrO4S 442.9953, found 442.9956; H NMR (400 MHz,
CDCl3): δ 8.44 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H),
8.25 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.83-7.73 (m, 2H), 7.33
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(d, J = 8.0 Hz, 2H), 3.18 (s, 3H), 2.41 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 171.1, 170.6, 151.7, 144.7, 138.4, 134.2,
131.0, 129.3 (2x), 128.6 (2x), 128.5, 128.4, 127.9, 124.1,
124.0, 122.3, 120.7, 120.5, 21.7, 20.8.
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C17H13N2O 261.1028, found 261.1030; 1H NMR (400 MHz,
CDCl3): δ 8.57-8.54 (m, 2H), 8.25 (dd, J = 0.8, 8.0 Hz, 1H),
7.63-7.40 (m, 6H), 2.81 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 159.6, 157.8, 149.9, 149.4, 145.6, 138.1, 131.1, 129.8, 128.4
(2x), 128.1 (2x), 123.7, 122.4, 122.1, 112.5, 18.6. Single-
crystal X-Ray diagram: crystal of compound 4b was grown by
slow diffusion of EtOAc into a solution of compound 4b in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the orthorhombic crystal system, space group P b c a, a =
13.4110(6) Å , b = 10.1144(4) Å , c = 18.3473(10) Å , V =
2488.7(2) Å 3, Z = 8, dcalcd = 1.389 g/cm3, F(000) = 1088, 2θ
range 2.220~26.392o, R indices (all data) R1 = 0.1095, wR2 =
0.2093.
6,8-Difluoro-2-methyl-3-(toluene-4-sulfonyl)chromen-4-one
(1al). Yield = 63% (110 mg); Colorless solid; mp = 179-181
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H13F2O4S 351.0503, found
9
1
351.0509; H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz,
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
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39
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42
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44
45
46
47
48
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2H), 7.49-7.46 (m, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.24-7.19 (m,
1H), 3.06 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 171.6, 170.7 (d, J = 6.1 Hz), 160.0 (d, J = 9.1 Hz), 157.5 (d,
J = 9.8 Hz), 152.1 (d, J = 11.4 Hz), 149.6 (d, J = 12.1 Hz),
144.7 (2x), 140.5 (d, J = 11.3 Hz), 138.2 (2x), 110.0 (d, J =
20.5 Hz), 109.7 (d, J = 19.7 Hz), 106.4 (d, J = 23.5 Hz), 106.4
(d, J = 24.2 Hz), 21.6, 20.8. Single-crystal X-Ray diagram:
crystal of compound 1al was grown by slow diffusion of
EtOAc into a solution of compound 1al in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the triclinic
crystal system, space group P -1, a = 10.374(3) Å , b =
2-Quinoxalin-2-ylphenol (4c) and 2-(1H-Benzoimidazol-2-
yl)phenol (4d). 1,2-Diaminobenzene (65 mg, 0.6 mmol) was
added to a solution of 1a (95 mg, 0.3 mmol) in DMSO (3 mL)
at rt. The reaction mixture was stirred at reflux for 3 h. The
reaction mixture was cooled to rt and the solvent was concen-
trated. The residue was diluted with water (10 mL) and the
mixture was extracted with CH2Cl2 (3 x 20 mL). The com-
bined organic layers were washed with brine, dried, filtered
and evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexanes/EtOAc = 4/1~1/2) afforded
4c and 4d. For 4c: Yield = 48% (32 mg); Colorless solid; mp
= 190-192 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H11N2O
11.581(3) Å , c = 19.365(5) Å , V = 2261.4(9) Å 3, Z = 6, dcalcd
=
1.543 g/cm3, F(000) = 1080, 2θ range 1.071~26.549o, R indi-
ces (all data) R1 = 0.0759, wR2 = 0.1405.
2-[5-Methyl-4-(toluene-4-sulfonyl)-2H-pyrazol-3-yl]-phenol
(4a). 80% N2H4(aq) (2 mL) was added to a solution of 1a (95
mg, 0.3 mmol) in dioxane (3 mL) at rt. The reaction mixture
was stirred at reflux for 3 h. The reaction mixture was cooled
to rt and the solvent was concentrated. The residue was diluted
with water (10 mL) and the mixture was extracted with
CH2Cl2 (3 x 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Purification on silica
gel (hexanes/EtOAc = 8/1~4/1) afforded 4a. Yield = 90% (89
1
223.0871, found 223.0877; H NMR (400 MHz, CDCl3): δ
9.54 (s, 1H), 8.19 (dd, J = 1.2, 8.0 Hz, 1H), 8.09-8.05 (m, 2H),
7.86-7.78 (m, 2H), 7.44 (dt, J = 1.2, 8.4 Hz, 1H), 7.13 (dd, J =
1.2, 8.4 Hz, 1H), 7.04 (dt, J = 1.2, 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 160.9, 152.1, 141.8, 139.7, 138.7, 133.2,
131.5, 130.1, 128.7, 127.6, 126.8, 119.6, 118.9, 117.1. Single-
crystal X-Ray diagram: crystal of compound 4c was grown by
slow diffusion of EtOAc into a solution of compound 4c in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the monoclinic crystal system, space group P 21/n, a =
5.9308(11) Å , b = 15.169(3) Å , c = 17.477(3) Å , V = 1564.7(5)
Å 3, Z = 2, dcalcd = 1.415 g/cm3, F(000) = 696, 2θ range
1.781~26.429o, R indices (all data) R1 = 0.0741, wR2 =
0.1118. For 4d: Yield = 38% (24 mg); Colorless solid; mp =
o
mg); Colorless solid; mp = 144-146 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
1
for C17H17N2O3S 329.0960, found 329.0962; H NMR (400
MHz, CDCl3): δ 9.19 (br s, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.30
(dd, J = 1.6, 7.6 Hz, 1H), 7.14-7.09 (m, 3H), 6.79 (d, J = 8.0
Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 2.29 (s, 6H); 13C NMR (100
MHz, CDCl3): δ 154.5, 147.3, 145.9, 144.0, 139.1, 131.0,
130.8, 129.4 (2x), 126.5 (2x), 119.6, 117.5, 116.6, 116.5, 21.3,
11.4. Single-crystal X-Ray diagram: crystal of compound 4a
was grown by slow diffusion of EtOAc into a solution of
compound 4a in CH2Cl2 to yield colorless prisms. The com-
pound crystallizes in the monoclinic crystal system, space
group P 21/c, a = 29.6762(12) Å , b = 13.3274(5) Å , c =
8.2384(3) Å , V = 3232.7(2) Å 3, Z = 8, dcalcd = 1.349 g/cm3,
F(000) = 1376, 2θ range 0.692~26.425o, R indices (all data)
R1 = 0.0637, wR2 = 0.1233.
o
226-228 C (recrystallized from hexanes and EtOAc); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C13H11N2O 211.0871,
1
found 211.0872; H NMR (400 MHz, DMSO-d6): δ 13.20 (br
s, 2H), 8.02 (dd, J = 1.2, 8.0 Hz, 1H), 7.66-7.64 (m, 2H), 7.37
(dt, J = 1.6, 8.4 Hz, 1H), 7.28 (t, J = 6.8 Hz, 1H), 7.27 (t, J =
7.2 Hz, 1H), 7.03 (dd, J = 0.8, 6.8 Hz, 1H), 7.00 (dd, J = 1.2,
8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 158.2 (2x),
151.9, 132.1 (2x), 126.5 (2x), 123.2, 119.6 (2x), 117.5 (2x),
112.9. Single-crystal X-Ray diagram: crystal of compound 4d
was grown by slow diffusion of EtOAc into a solution of
compound 4d in CH2Cl2 to yield colorless prisms. The com-
pound crystallizes in the monoclinic crystal system, space
group P 21, a = 3.7669(4) Å , b = 22.031(2) Å , c = 5.8049(6) Å ,
V = 480.22(8) Å 3, Z = 2, dcalcd = 1.454 g/cm3, F(000) = 220, 2θ
range 1.849~26.366o, R indices (all data) R1 = 0.0338, wR2 =
0.0929.
4-Methyl-2-phenylbenzo[4,5]furo[3,2-d]pyrimidine
(4b).
Benzamidine-HCl (93 mg, 0.6 mmol) was added to a solution
of 1a (95 mg, 0.3 mmol) in DMSO (3 mL) at rt. The reaction
mixture was stirred at reflux for 3 h. The reaction mixture was
cooled to rt and the solvent was concentrated. The residue was
diluted with water (10 mL) and the mixture was extracted with
CH2Cl2 (3 x 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Purification on silica
gel (hexanes/EtOAc = 4/1~1/1) afforded 4b. Yield = 85% (66
ASSOCIATED CONTENT
Supporting Information
o
mg); Colorless solid; mp = 124-126 C (recrystallized from
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6609. For KF, see: (e) Chai, G.; Qiu, Y.; Fu, C.; Ma, S. Org. Lett.
2011, 13, 5196-5199. For Wittig reaction, see: (f) Kumar, P.;
Bodas, M. S. Org. Lett. 2000, 2, 3821-3823.
Scanned photocopies of NMR spectral data for all compounds
2
3
4
5
and X-ray analysis data of 1a, 1f, 1h, 1al and 4a-4d. This infor-
mation is available free of charge via the Internet at http:
//pubs.acs.org.
(5) For Pd(II), see: (a) Yang, Q.; Alper, H. J. Org. Chem. 2010, 75,
948-950. (b) Awuah, E.; Capretta, A. Org. Lett. 2009, 11, 3210-
3213. (c) Liang, B.; Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fa-
thi, R.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 6097-6100.
(6) For K2CO3, see: (a) Zhao, J.; Zhao, Y.; Fu, H. Org. Lett. 2012,
14, 2710-2713. For organoamine, see: (b) Wen, S.-S.; Wang, J.;
Luo, Y.-M.; Yang, H. Tetrahedron 2014, 70, 9314-9320. For
Pd(0), see: (c) Zhao, X.; Zhou, J.; Lin, S.; Jin, X.; Liu, R. Org.
Lett. 2017, 19, 976-979. For NHC, see: (d) Vedachalam, S.;
Zeng, J.; Gorityala, B. K.; Antonio, M.; Liu, X.-W. Org. Lett.
2010, 12, 352-355. For ICl, see: (e) Xhou, C.; Dubrovsky, A. V.;
Larock, R. C. J. Org. Chem. 2006, 71, 1626-1632. For Ag(I), see:
(f) Xiang, H.; Yang, C. Org. Lett. 2014, 16, 5686-5689. For
DMAP, see: (g) Zhai, D.; Chen, L.; Jia, M.; Ma, S. Adv. Synth.
Catal. 2018, 360, 153-160.
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AUTHOR INFORMATION
Corresponding Author
*Email: mychang@kmu.edu.tw
ORCID
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Meng-Yang Chang: 0000-0002-1983-8570
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors would like to thank the Ministry of Science and
Technology of the Republic of China for financial support
(MOST 106-2628-M-037-001-MY3).
(7) For synthesis of 2- or 3-sulfonyl chromen-4-ones, see: (a) Lee, G.
H.; Ha, C. J.; Pak, C. S. Synth. Commun. 1999, 29, 3155-3164.
(b) Patonay, T.; Patonay-Pei, E.; Litkei, G. Tetrehedron 1987, 43,
1827-1834. (c) Jadhav, K. P.; Ingle, D. B. Indian J. Chem. B
1983, 22, 150-153. (d) Zhao, W.; Xie, P.; Bian, Z.; Zhou, A.; Ge,
H.; Zhang, M.; Ding, Y.; Zheng, L. J. Org. Chem. 2015, 80,
9167-9175. (e) Wan, J.-P.; Zhong, S.; Guo, Y.; Wei, L. Eur. J.
Org. Chem. 2017, 30, 4401-4404.
(8) For synthesis of sulfonyl skeletons by authors, see: (a) Chang,
M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2014, 16, 6252-6255.
(b) Chang, M.-Y.; Lu, Y.-J.; Cheng, Y.-C. Tetrahedron 2015, 71,
1192-1201. (c) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2016, 18,
608-611 and references cited therein.
(9) For reviews on copper-mediated or catalyzed reactions, see: (a)
Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem. Int.
Ed. 2011, 50, 11062-11087. (b) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2010, 1, 13-31. (c) Zhang, M. Appl. Organometal.
Chem. 2010, 24, 269-284. (d) Evano, G.; Blanchard, N.; Toumi,
M. Chem. Rev. 2008, 108, 3054-3131. (e) Ma, D.; Cai, Q. Acc.
Chem. Res. 2008, 41, 1450-1460.
REFERENCES
(1) For reviews on synthesis of chromenones, see: (a) Kosmider, B.;
Osiecka, R. Drug Dev. Res. 2004, 63, 200-211. (b) Teillet, F.;
Boumendjel, A.; Boutonnat, J.; Ronot, X. Med. Res. Rev. 2008,
28, 715-745. (c) Talhi, O.; Silva, A. M. S. Curr. Org. Chem.
2012, 16, 859-896. (d) Kumazawa, Y.; Takimoto, H.; Matsumo-
to, T.; Kawaguchi, K. Curr. Pharm. Res. 2014, 20, 857-863. (e)
Ibrahim, M. A.; Ali, T. E.; Alnamer, Y. A.; Gabr, Y. A.
ARKIVOC 2010, i, 98-135. (f) Gaspar, A.; Matos, M. J.; Garrido,
J.; Uriarte, E.; Borges, F. Chem. Rev. 2014, 114, 4960-4992. (g)
Plaskon, A. S.; Grygorenko, O. O.; Ryabukhin, S. V. Tetrahe-
dron 2012, 68, 2743-2757. (h) Li, N.-G.; Shi, Z.-H.; Tang, Y.-P.;
Ma, H.-Y.; Yang, J.-P.; Li, B.-Q.; Wang, Z.-J.; Song, S.-L.;
Duan, J. A. J. Heterocycl. Chem. 2010, 47, 785-799. (i) Snatos,
C. M. M.; Silva, A. M. S. Eur. J. Org. Chem. 2017, 2017, 3115-
3133.
(10) Recent examples on synthesis of sulfonyl acetylenes, see: (a)
Meesin, J.; Katrun, P.; Pareseecharoen, C.; Pohmakotr, M.;
Reutrakul, V.; Soorukram, D.; Kuhakarn, C. J. Org. Chem. 2016,
81, 2744-2752. (b) Chen, H.; Zhang, L. Angew. Chem., Int. Ed.
2015, 54, 11775-11779. (c) Chen, C. C.; Waser, J. Org. Lett.
2015, 17, 736-739. (d) Singh, R.; Allam, B. K.; Singh, N.; Ku-
mari, K.; Singh, S. K.; Singh, K. N. Org. Lett. 2015, 17, 2656-
2659. (e) He, L.; Yang, X.; Tsui, G. C. J. Org. Chem. 2017, 82,
6192-6201. (f) Chen, P.; Zhu, C.; Zhu, R.; Wu, W.; Jiang, H.
Chem. Asian J. 2017, 1875-1878. (g) Wang, L.; Wei, W.; Yang,
D.; Cui, H.; Yue, H.; Wang, H. Tetrahedron Lett. 2017, 58,
4799-4802. For reviews, see: (h) Back, T. G. Tetrahedron 2001,
57, 5263-5301. (i) Back, T. G.; Clary, K. N.; Gao, D. Chem. Rev.
2010, 110, 4498-4553.
(11) CCDC 1545998 (1a), 1545997 (1f), 1545999 (1h), 1548936
(1al), 1546003 (4a), 1546002 (4b), 1546001 (4c) and 1546000
(4d) contain the supplementary crystallographic data for this pa-
per. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033;
e-mail: deposit@ccdc.cam.ac.uk).
(2) For biological activities of chromenones, see: (a) Valdameri, G.;
Genoux-Bastide, E.; Peres, B.; Gauthier, C.; Guitton, J.; Terreux,
R.; Winnischofer, S. M.; Rocha, M. E.; Boumendjel, A.; Di
Pietro, A. J. Med. Chem. 2012, 55, 966-970. (b) Keri, R. S.; Bu-
dagumpi, S.; Pai, R. K.; Balakrishna, R. G. Eur. J. Med. Chem.
2014, 78, 340-374. (c) Chen, Y.; Liu, H.-R.; Liu, H.-S.; Cheng,
M.; Xia, P.; Qian, K.; Wu, P.-C.; Lai, C.-Y.; Xia, Y.; Yang, Z.-
Y.; Morris-Natschke, S. L.; Lee, K.-H. Eur. J. Med. Chem. 2012,
49, 74-85. For a recent review, see: (d) Reis, J.; Gaspar, A.; Mi-
lhazes, N.; Borges, F. J. Med. Chem. 2017, 60, 7941–7957.
(3) Selected examples, for Claisen condensation, see: (a) Irgashev,
R. A.; Sosnovskikh, V. Y.; Kalinovich, N.; Kazakova, O.;
Roschenthaler, G.-V. Tetrahedron Lett. 2009, 50, 4903-4905.
For Baker-Venkatamaran rearrangement, see: (b) Riva, C.; De
Toma, C.; Donadel, L.; Boi, C.; Pennini, R.; Motta, G.; Leonardi,
A. Synthesis 1997, 195-201. (c) Castaneda, I. C. H.; Ulic, S. E.;
Vedova, C. O. D.; Metzler-Nolte, N.; Jios, J. L. Tetrahedron Lett.
2011, 52, 1436-1440. For Kostanecki-Robinson reaction, see: (d)
Frasinyuk, M.; Khilya, V. Chem. Heterocycl. Compd. 2008, 44,
666-670. For Simonis reaction, see: (e) Costantino, L.; Rastelli,
G.; Gamberini, M. C.; Vinson, J. A.; Bose, P.; Iannone, A.;
Staffieri, M.; Antolini, L.; Del Corso, A.; Mura, U.; Albasini, A.
J. Med. Chem. 1999, 42, 1881-1893. For Ruhemann reaction,
see: (f) Obrecht, D. Helv. Chim. Acta 1989, 72, 447-456.
(12) Synthesis of 3a’, see: (a) Kosugi, H.; Kitaoka, M.; Tagami, K.;
Takahashi, A.; Uda, H. J. Org. Chem. 1987, 52, 1078-1082. (b)
Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.; Suzuki, T.;
Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003, 68,
5550-5558. (c) Maezaki, N.; Yoshigami, R.; Maeda, J.; Tanaka,
T. Org. Lett. 2001, 3, 3627-3629.
(4) For Sn(IV), see: (a) Liu, H.; Yang, Y.; Wang, S.; Wu, J.; Wang,
X.-N.; Chang, J. Org. Lett. 2015, 17, 4472-4475. For Al(III), see:
(b) Kim, H. Y.; Song, E.; Oh, K. Org. Lett. 2017, 19, 312-315.
For Rh(III), see: (c) Sun, P.; Gao, S.; Yang, C.; Guo, S.; Lin, A.;
Yao, H. Org. Lett. 2016, 18, 6464-6467. For Ru(II), see: (d) Raja,
G. C. E.; Ryu, J. Y.; Lee, J.; Lee, S. Org. Lett. 2018, 20, 6606-
(13) Sapegin, A. V.; Kalinin, S. A.; Smirnov, A. V.; Dorogov, M. V.;
Krasavin, M. Tetrahedron 2014, 70, 1077-1083.
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