Indium-catalyzed oxidative cross-dehydrogenative coupling of chromenes with 1,3-dicarbonyls and aryl rings

Article abstract of DOI:10.1039/c5ob00277j

An effective indium-catalyzed oxidative cross-dehydrogenative coupling of electronically varied chromenes with 1,3-dicarbonyl compounds and aryl rings has been established. Both the C-H alkylation and arylation proceed smoothly at room temperature to affo

Full text of DOI:10.1039/c5ob00277j

Organic &
Biomolecular Chemistry
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Indium-catalyzed oxidative cross-dehydrogenative
coupling of chromenes with 1,3-dicarbonyls and
aryl rings†
Cite this: DOI: 10.1039/c5ob00277j
a,b
a
c
b
a
a,c
Fanmei Li,‡ Zhilin Meng,‡ Jing Hua, Wei Li, Hongxiang Lou and Lei Liu*
An effective indium-catalyzed oxidative cross-dehydrogenative coupling of electronically varied chro-
menes with 1,3-dicarbonyl compounds and aryl rings has been established. Both the C–H alkylation and
arylation proceed smoothly at room temperature to afford diverse α-substituted chromene compounds in
up to 91% yields. Besides these two types of C–H components, simple ketones like cyclohexanones also
prove to be well tolerated.
Received 8th February 2015,
Accepted 12th April 2015
DOI: 10.1039/c5ob00277j
www.rsc.org/obc
Introduction
Alkyl and aryl substituted chromans are present in a number
of biologically active natural products and synthetic pharma-
ceuticals possessing antioxidative, antipsychotic, antibacterial,
1
antifungal, antiviral, and anticancer activities (Fig. 1). The
nucleophilic addition of carbon-centered reagents to chro-
mene-based oxocarbenium ions represents an efficient and
2
powerful approach to access the substructures. In these reac-
tions, oxocarbenium intermediates are typically generated
in situ through the acid-mediated collapse of the corres-
ponding acetals. However, the substrate preparation suffers
3
from extra and unproductive steps and reagents. On the other
hand, the direct oxidative cross-dehydrogenative coupling
(CDC) of chromenes with readily available C–H components
provides excellent opportunities to synthesize the target simply
Fig. 1 Representative α-substituted chromans.
by connecting two C–H bonds with a minimal amount of inter-
4
,5
mediary refunctionalizations and with high atom economy.
Over the past several years, the oxidative CDC reaction
involving the isochroman type substrate has received much
attention, with several reaction systems well developed.
a trityl ion-mediated oxidative C–H arylation of chromenes
6
employing nucleophilic potassium aryltrifluoroborate salts as
8
coupling components. Huang and coworkers disclosed a
However, the direct C–H functionalization of chromenes
remains relatively unexplored. The Floreancig group developed
an oxidative coupling of chromenes with diverse allylic silanes
proline-catalyzed oxidative CDC of the unsubstituted 2H-chro-
9
mene with aldehydes. Albeit the above three pioneer studies,
7
the C–H functionalization of electronically varied chromenes
with dicarbonyls and aryl rings has not been established to
date. Herein, we reported our recent efforts on the oxidative
CDC reaction of chromenes using 1,3-dicarbonyls and aryl
rings as coupling partners.
and enolsilanes in high efficiency. Very recently, we reported
a
Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical
Sciences, Jinan 250012, P. R. China. E-mail: leiliu@sdu.edu.cn
b
Department of Pharmaceutical Analysis, School of Pharmacy, Shandong University
of Traditional Chinese Medicine, Shandong 250355, China
c
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources
Results and discussion
(
†
Guangxi Normal University), Ministry of Education of China, Guilin 541004, China
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00277j
These authors contributed equally to this work.
Initially, the oxidative CDC of chromene 1a with diisopropyl
malonate 2a was selected as the model reaction for optimiz-
‡
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a
Table 1 Reaction condition optimization
b
Entry
Oxidant
Additive
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
PhI(OAc)
—
CuI
CuBr
CuCl
CuCl
Cu(OAc)
CuOTf
Cu(OTf)
Fe(OTf)
Zn(OTf)
In(OTf)
AgOTf
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
<5
35
22
31
16
43
55
65
50
46
79
<5
<5
<5
60
70
66
8
<5
<5
<5
<5
90
28
63
46
50
56
33
<5
2
2
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2
3
Bi(OTf)
Mg(OTf)
3
2
c
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
d
e
2
Scheme 1 The scope of CDC reactions of chromenes and 1,3-dicarbo-
nyl compounds.
Na
CAN
MnO
2
S
2
O
8
2
TBHP/CuBr
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
2
DCE
CHCl
3
lent yields (3a–3h). β-Keto esters proved to be suitable coupling
partners for the reaction, with 3i and 3j bearing a quaternary
carbon accessed. 1,3-Diketone moieties were also tolerated, as
demonstrated by the formation of 3k. The substituent effect of
the chromene component was next explored. Chromenes
bearing electron-donating as well as -withdrawing substituents
were well compatible with the oxidative CDC reaction in good
employed. yields (3l–3n). Notably, bromine was well tolerated for further
diversifications and manipulations.
CH
Toluene
PhCF
3 2
NO
3
EtOAc
Hexane
CH CN
3
a
General conditions: 1a (0.2 mmol), 2a (0.3 mmol), DDQ (0.2 mmol),
additive (10 mol%), and solvent (3.0 mL) at room temperature for 5 h,
b
c
unless stated otherwise. Isolated yield. 5 mol% In(OTf)
3
d
e
15 mol% In(OTf)
3
employed. 20 mol% In(OTf)
3
employed.
The high efficiency of the CDC with 1,3-dicarbonyl com-
ponents prompted us to explore the possibility of employing
simple ketones as nucleophilic partners (Scheme 2). In the
presence of phenylalanine (20 mol%), TFA (20 mol%), LiClO4
ation (Table 1). No reaction was observed when 2,3-dichloro-
,6-dicyanobenzoquinone (DDQ) was employed as the oxidant
(
1.5 equiv.), and DDQ (1.0 equiv.), the oxidative CDC reaction
5
of 1a with cyclohexanone (4a) proceeded smoothly at room
temperature delivering 5a in 60% yield with a dr of 1 : 1.
without any additive (entry 1, Table 1). Therefore, a variety of
metal additives were applied to the CDC reaction in CH Cl .
2
2
α-Aryl substituted chromans are key building blocks in
numerous biologically active natural products and synthetic
pharmaceuticals. The existing approaches rely on the nucleo-
philic attack of organoboranes onto cyclic oxocarbenium
intermediates. While high efficiency was achieved, the prepa-
ration of these boronate nucleophiles requires extra steps.
Employing aryl rings instead of the corresponding aryl boro-
nates would be an attractive solution to the issue of atoms as
Delightedly, copper salts effected the coupling, with Cu(OTf)
affording the best yields (entries 2–8, Table 1). Next, an exten-
sive investigation on different metal sources bearing a triflate
2
counteranion revealed 10 mol% of In(OTf)
entries 9–17). Other oxidants that are effective in promoting
the oxidative CDC reaction of isochromans including PhI
OAc) , Na , CAN (cerium ammonium nitrate), MnO , and
tert-butyl hydroperoxide (TBHP)/CuBr failed to effect the
3
as the ideal choice
(
(
2
2
S
2
O
8
2
2
model reaction (entries 18–22). The reaction was found to be
highly dependent on the solvent choice, and 1,2-dichloro-
ethane was identified as the optimal candidate (entries 23–30).
With the optimized reaction conditions in hand, the scope
of 1,3-dicarbonyl components was investigated (Scheme 1).
Commonly encountered symmetric 1,3-diesters were found to
be well compatible with the oxidation system in good to excel- Scheme 2 Oxidative CDC reaction of chromene with cyclohexanone.
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tolerated. The mild conditions endowed good functional group
compatibility, with bromine and ester tolerated for further
manipulation.
Experimental
1
13
Proton ( H NMR) and carbon ( C NMR) nuclear magnetic
resonance spectra were recorded at 300, 400, or 600 MHz and
75, 100, or 151 MHz, respectively. The chemical shifts are
given in parts per million (ppm) on the delta (δ) scale. The
1
solvent peak was used as a reference value, for H NMR: CDCl
=
3
Scheme 3 The scope of CDC reactions of chromenes with aryl rings.
13
3
7.27 ppm, for C NMR: CDCl = 77.23 ppm. Analytical TLC
was performed on precoated silica gel GF254 plates. HRMS
were carried out using an Orbitrap analyzer.
General procedure for the oxidative CDC reaction of
chromenes
To the solution of 1a (26.4 mg, 0.2 mmol) and 2a (56.4 mg,
0
0
.3 mmol) in DCE (3.0 mL) was added DDQ (45.4 mg,
.2 mmol) followed by In(OTf)3 (11.2 mg, 0.02 mmol). The
reaction mixture was stirred at room temperature for 5 h. Then
it was quenched with sat. aqueous NaHCO solution in an ice-
bath and extracted twice with CH Cl . The combined organic
3
2
2
layers were washed with brine, dried over anhydrous MgSO4
3
Fig. 2 A proposed mechanism for the In(OTf) -catalyzed CDC reaction.
and concentrated in vacuo. The residue was purified by chrom-
atography on silica gel to yield the desired 3a in 90% yield
(
57.2 mg).
well as step economy. Therefore, we next examined the CDC
reaction of chromenes with aryl rings under the optimized Characterization data for the products in Scheme 1
reaction conditions (Scheme 3). Aryls bearing electron-donat-
ing substituents served as suitable nucleophilic partners deli-
1
Diisopropyl 2-(2H-chromen-2-yl)malonate (3a).
H NMR
(
600 MHz, CDCl ) δ = 7.12 (td, J = 8.0, 1.4 Hz, 1H), 6.99 (dd, J =
3
vering 7a–7c. The heteroaryl moiety (6d) was also tolerated
with the C–H functionalization process. With respect to the
chromene partner, the electron-deficient moiety was tolerated
providing 7e in modest yield, though no reactivity was
observed for the electron-rich one (7f).
7
.4, 1.2 Hz, 1H), 6.88 (td, J = 7.4, 0.6 Hz, 1H), 6.75 (d, J = 8.1
Hz, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.90 (dd, J = 9.9, 4.0 Hz, 1H),
5
1
1
.48 (ddd, J = 9.3, 3.9, 0.7 Hz, 1H), 5.14 (dt, J = 12.5, 6.2 Hz,
H), 5.06 (dt, J = 12.5, 6.3 Hz, 1H), 3.80 (d, J = 9.3 Hz, 1H),
.30–1.26 (m, 6H), 1.23 (dd, J = 6.2, 0.7 Hz, 6H); C NMR
13
According to the pioneering study of Li, a plausible mech-
anism for the indium-catalyzed oxidative CDC of chromenes
(
75 MHz, CDCl ) δ = 166.4, 166.1, 152.4, 129.7, 126.8, 125.4,
3
1
2
1
22.7, 121.8, 121.5, 116.7, 72.9, 69.5, 69.4, 57.6, 21.9, 21.8,
6
c
3
was proposed in Fig. 2. In the presence of In(OTf) , DDQ pro-
1.8, 21.7; IR νmax 2986, 2920, 2845, 1740, 1480, 1456, 1358,
moted the C–H oxidation of chromene 1a to provide oxocarbe-
nium intermediate 8. In(OTf)3 activated the dicarbonyl
compound giving 9 for the subsequent nucleophilic addition
process to afford 3b. The arylation of 8 with 6a generated 7a.
−1
270, 1202, 1148, 1113, 1011, 773 cm ; HRMS (EI) m/z [M +
+
H] calculated for C18
H
23
O
5
: 319.1540, found 319.1541.
1
Dimethyl 2-(2H-chromen-2-yl)malonate (3b).
H
NMR
(
600 MHz, CDCl ) δ = 7.13 (t, J = 7.0 Hz, 1H), 7.00 (d, J = 6.7
3
Hz, 1H), 6.90 (d, J = 6.6 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.52
(
(
d, J = 9.6 Hz, 1H), 5.96–5.84 (m, 1H), 5.58–5.45 (m, 1H), 3.90
1
3
d, J = 9.1 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 3H); C NMR (75 MHz,
) δ = 167.2, 166.8, 152.1, 129.9, 126.9, 125.7, 122.3, 122.0,
Conclusions
CDCl
3
In summary, we have developed an indium-catalyzed oxidative 121.4, 116.7, 72.9, 56.7, 52.9, 52.8; IR νmax 2986, 2919, 2845,
−
1
C–H alkylation and arylation of chromenes promoted by DDQ 1738, 1433, 1459, 1270, 1202, 1145, 1111, 1011, 775, 694 cm
;
+
and a catalytic amount of In(OTf)
components for the CDC is broad, with a wide range of dicar- found 263.0917.
bonyl compounds and aryl rings well tolerated. The simple Diethyl 2-(2H-chromen-2-yl)malonate
ketone like cyclohexanone also serves as an effective coupling (600 MHz, CDCl ) δ = 7.13 (t, J = 6.7 Hz, 1H), 6.99 (d, J = 6.9
3 15 5
. The scope of nucleophilic HRMS (EI) m/z [M + H] calculated for C14H O : 263.0914,
1
(3c).
H
NMR
3
partner. The scope with respect to chromenes is also broad, Hz, 1H), 6.90 (d, J = 7.1 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.51
with electron-donating and -withdrawing substituents well (d, J = 9.6 Hz, 1H), 5.98–5.82 (m, 1H), 5.56–5.44 (m, 1H),
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1
4
3
1
1
2
6
2
.31–4.15 (m, 4H), 3.86 (d, J = 9.0 Hz, 1H), 1.30 (t, J = 5.4 Hz,
Bis(3-chlorobenzyl) 2-(2H-chromen-2-yl)malonate (3h).
H
1
3
H), 1.24 (t, J = 5.4 Hz, 3H); C NMR (101 MHz, CDCl ) δ = NMR (400 MHz, CDCl ) δ = 7.34–7.26 (m, 6H), 7.21 (d, J = 7.2
3
3
66.8, 166.5, 152.2, 129.8, 126.9, 125.6, 122.5, 121.9, 121.4, Hz, 1H), 7.17–7.07 (m, 2H), 6.99 (d, J = 7.3 Hz, 1H), 6.90 (t, J =
16.6, 72.9, 61.9, 61.9, 57.1, 14.3, 14.2; IR νmax 2986, 2921, 7.4 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.51 (d, J = 9.8 Hz, 1H),
843, 1737, 1423, 1459, 1277, 1229, 1145, 1112, 1011, 775, 5.85 (dd, J = 9.8, 4.0 Hz, 1H), 5.55 (dd, J = 9.1, 3.9 Hz, 1H),
94 cm− ; HRMS (EI) m/z [M + H] calculated for C16
1
+
5.24–5.05 (m, 4H), 4.01 (d, J = 9.1 Hz, 1H); C NMR (101 MHz,
CDCl ) δ = 166.3, 166.0, 152.0, 137.4, 137.1, 134.7, 134.6, 130.1,
NMR 130.1, 130.0, 128.8, 128.8, 128.4, 128.3, 127.0, 126.4, 126.3,
13
19 5
H O :
91.1227, found 291.1225.
3
1
Dibenzyl 2-(2H-chromen-2-yl)malonate (3d).
600 MHz, CDCl
H
(
3
) δ = 7.37–7.33 (m, 8H), 7.30–7.26 (m, 2H), 125.9, 122.1, 122.0, 121.3, 116.7, 72.8, 66.6, 66.6, 57.0; IR νmax
.08 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 6.9 Hz, 1H), 6.88 (t, J = 7.3 2954, 2922, 2848, 1736, 1489, 1457, 1386, 1270, 1204, 1137,
7
Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 9.9 Hz, 1H), 5.85 1111, 1071, 801, 760 cm− ; HRMS (EI) m/z [M + H] calculated
1
+
(
5
dd, J = 9.8, 4.0 Hz, 1H), 5.56 (dd, J = 9.2, 3.9 Hz, 1H), for C26
H
21Cl
2
O
5
: 483.0761, found 483.0766.
1
3
1
.26–5.10 (m, 4H), 4.00 (d, J = 9.2 Hz, 1H); C NMR (75 MHz,
Ethyl 2-(2H-chromen-2-yl)-3-oxobutanoate (3i). H NMR
CDCl ) δ = 166.5, 166.2, 152.1, 135.5, 135.2, 129.8, 128.8, 128.7, (400 MHz, CDCl ) δ = 7.13 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 6.0 Hz,
3
3
1
1
1
28.6, 128.6, 128.5, 128.3, 126.9, 125.7, 122.3, 122.0, 121.4, 1H), 6.95–6.86 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.49 (t, J =
16.7, 72.9, 67.5, 57.1; IR νmax 2952, 2924, 2851, 1737, 1519, 10.1 Hz, 1H), 5.88–5.80 (m, 1H), 5.62–5.45 (m, 1H), 4.27 (q, J =
−
1
488, 1457, 1384, 1292, 1226, 1208, 1113, 962, 806, 748 cm
;
7.1 Hz, 1H), 4.21–4.16 (m, 1H), 4.04 (d, J = 9.4 Hz, 1H), 2.33 (s,
+
13
HRMS (EI) m/z [M + H] calculated for C26
H
23
O
5
: 415.1540, 2H), 2.23 (s, 1H), 1.32–1.23 (m, 3H); C NMR (101 MHz,
CDCl ) δ = 201.0, 200.5, 166.9, 166.5, 152.3, 152.0, 129.9, 129.8,
(3e). 127.0, 126.9, 125.6, 125.4, 122.9, 122.7, 122.1, 121.9, 121.5,
) δ = 7.22 (d, J = 8.0 Hz, 2H), 121.5, 116.6, 116.5, 73.3, 73.0, 64.8, 63.5, 62.0, 61.8, 30.6, 30.5,
.19–7.11 (m, 6H), 7.10–7.04 (m, 1H), 6.97 (dd, J = 7.4, 1.4 Hz, 14.3, 14.2; IR νmax 2987, 2918, 2845, 1742, 1717, 1487, 1456,
found 415.1542.
3
Bis(4-methylbenzyl)
2-(2H-chromen-2-yl)malonate
1
H NMR (400 MHz, CDCl
3
7
1
−
1
H), 6.87 (td, J = 7.4, 0.7 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.47 1356, 1272, 1222, 1149, 1113, 1019, 773 cm ; HRMS (EI) m/z
+
(
d, J = 9.9 Hz, 1H), 5.84 (dd, J = 9.8, 4.0 Hz, 1H), 5.52 (ddd, J = [M + H] calculated for C15
.3, 4.0, 0.7 Hz, 1H), 5.23–5.04 (m, 4H), 3.95 (d, J = 9.3 Hz, 1H),
H
17
O
4
: 261.1121, found 261.1122.
1-(2H-chromen-2-yl)-2-oxocyclopentanecarboxylate
.37 (s, 3H), 2.36 (s, 3H); C NMR (101 MHz, CDCl ) δ = 166.6, (3j). H NMR (600 MHz, CDCl ) δ = 7.07 (t, J = 7.7 Hz, 1H),
9
2
1
1
5
1
Ethyl
1
3
1
3
3
66.2, 152.1, 138.5, 138.4, 132.5, 132.3, 129.8, 129.4, 129.4, 6.95–6.90 (m, 1H), 6.83 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.9 Hz,
28.6, 128.5, 126.8, 125.7, 122.4, 121.9, 121.4, 116.7, 72.9, 67.5, 1H), 6.51–6.43 (m, 1H), 5.81 (s, 1H), 5.65 (dd, J = 10.0, 2.6 Hz,
7.1, 21.4; IR νmax 2953, 2924, 2852, 1736, 1519, 1488, 1457, 1H), 4.28–4.15 (m, 2H), 2.58–2.41 (m, 3H), 2.40–2.31 (m, 1H),
−1
13
385, 1293, 1228, 1205, 1113, 960, 805, 748 cm ; HRMS (EI) 2.06–1.95 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); C NMR (75 MHz,
+
m/z [M + H] calculated for C28
43.1853.
Bis(4-methoxybenzyl) 2-(2H-chromen-2-yl)malonate (3f).
NMR (400 MHz, CDCl
27 5 3
H O : 443.1853, found CDCl ) δ = 212.5, 168.7, 153.5, 129.7, 126.9, 126.2, 121.9, 121.5,
4
120.6, 115.5, 77.9, 65.5, 61.9, 39.3, 28.3, 20.3, 14.2;
1
H
IR νmax 2988, 2919, 2845, 1744, 1716, 1480, 1446, 1358,
−1
3
) δ = 7.25 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 1277, 1204, 1148, 1113, 1011, 773, 754, 695 cm ; HRMS (EI)
+
8
6
1
5
3
1
1
5
1
.6 Hz, 2H), 7.10–7.03 (m, 1H), 6.96 (dd, J = 7.2, 1.2 Hz, 1H), m/z [M + H] calculated for C H O : 287.1278, found
17 19 4
.90–6.81 (m, 5H), 6.57 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 9.9 Hz, 287.1278.
H), 5.81 (dd, J = 9.8, 4.0 Hz, 1H), 5.50 (dd, J = 9.2, 3.9 Hz, 1H), 3-(2H-Chromen-2-yl)pentane-2,4-dione
.19–5.02 (m, 4H), 3.92 (d, J = 9.3 Hz, 1H), 3.82 (s, 3H), 3.81 (s, (600 MHz, CDCl ) δ = 7.14 (t, J = 7.0 Hz, 1H), 7.00 (d, J = 7.3
1
(3k).
H
NMR
3
13
H); C NMR (101 MHz, CDCl
3
) δ = 166.6, 166.3, 160.0, 159.9, Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.48
52.1, 130.4, 130.3, 129.8, 127.7, 127.4, 126.8, 125.7, 122.4, (d, J = 9.7 Hz, 1H), 5.74 (dd, J = 9.8, 3.9 Hz, 1H), 5.61–5.55 (m,
1
3
21.9, 121.4, 116.7, 114.1, 114.1, 72.9, 67.4, 67.4, 57.1, 55.5, 1H), 4.28 (d, J = 9.7 Hz, 1H), 2.33 (s, 3H), 2.19 (s, 3H); C NMR
5.5; IR νmax 2955, 2924, 2852, 1737, 1520, 1488, 1450, 1364, (75 MHz, CDCl ) δ = 201.6, 201.2, 152.1, 130.0, 127.1, 125.7,
293, 1228, 1202, 1113, 963, 805, 748, 695 cm ; HRMS (EI) m/z 122.5, 122.2, 121.5, 116.6, 73.7, 73.1, 31.2, 29.6; IR νmax 2937,
3
−1
+
[M + H] calculated for C H O : 475.1751, found 475.1755.
2859, 1707, 1483, 1457, 1385, 1230, 1205, 1128, 1113, 1013,
2
8
27 7
1
−1
+
Bis(4-bromobenzyl) 2-(2H-chromen-2-yl)malonate (3g).
NMR (400 MHz, CDCl ) δ = 7.52–7.42 (m, 4H), 7.18 (d, J = 8.3
Hz, 2H), 7.15–7.06 (m, 3H), 6.98 (dd, J = 7.4, 1.4 Hz, 1H), 6.89
t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.48 (d, J = 9.9 Hz, (3l). H NMR (600 MHz, CDCl
H), 5.83 (dd, J = 9.8, 4.0 Hz, 1H), 5.57–5.47 (m, 1H), 5.17–5.01 6.46 (d, J = 9.7 Hz, 1H), 5.99–5.89 (m, 1H), 5.46–5.37 (m, 1H),
H
779, 754, 571 cm ; HRMS (EI) m/z [M + H] calculated for
: 231.1016, found 231.1013.
Diisopropyl 2-(6-methoxy-2H-chromen-2-yl)malonate
) δ = 6.69 (s, 2H), 6.56 (s, 1H),
3
14 15 3
C H O
1
(
1
3
1
3
(m, 4H), 3.97 (d, J = 9.1 Hz, 1H); C NMR (101 MHz, CDCl3) 5.17–5.10 (m, 1H), 5.07–5.01 (m, 1H), 3.82–3.76 (m, 4H),
1
3
δ = 166.3, 166.0, 152.0, 134.4, 134.1, 132.0, 131.9, 130.1, 130.0, 1.29–1.26 (m, 6H), 1.24–1.21 (m, 6H); C NMR (75 MHz,
1
7
1
29.9, 126.9, 125.8, 122.8, 122.7, 122.1, 122.0, 121.2, 116.6, CDCl
3
) δ = 166.4, 166.1, 154.6, 146.1, 125.5, 123.8, 122.2, 117.3,
2.8, 66.7, 66.7, 57.0; IR νmax 2951, 2921, 2848, 1736, 1488, 115.0, 111.9, 72.8, 69.4, 69.4, 57.2, 56.0, 21.9, 21.8, 21.7; IR
−
1
456, 1389, 1271, 1202, 1147, 1113, 1071, 800, 759 cm
;
νmax 2987, 2920, 2845, 1740, 1480, 1456, 1358, 1270, 1202,
+
−1
+
HRMS (EI) m/z [M + H] calculated for C26
H
21Br
2
O
5
: 570.9750, 1148, 1111, 1011, 773 cm ; HRMS (EI) m/z [M + H] calculated
found 570.9751.
for C H O : 349.1646, found 349.1648.
1
9
25 6
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1
13
Diisopropyl 2-(6-methyl-2H-chromen-2-yl)malonate (3m).
H
1H), 3.81 (s, 3H); C NMR (151 MHz, CDCl
3
) δ = 160.0, 153.3,
NMR (600 MHz, CDCl ) δ = 6.92 (d, J = 8.1 Hz, 1H), 6.80 (s, 133.1, 129.6, 128.9, 126.7, 125.1, 124.2, 121.6, 121.3, 116.3,
3
1
H), 6.65 (d, J = 8.1 Hz, 1H), 6.46 (d, J = 9.8 Hz, 1H), 5.90 (dd, 114.2, 77.0, 55.5; IR νmax 2930, 2837, 1610, 1586, 1513, 1485,
J = 9.8, 4.0 Hz, 1H), 5.43 (dd, J = 9.1, 3.6 Hz, 1H), 5.14 (dt, J = 1457, 1304, 1268, 1250, 1227, 1205, 1175, 1111, 1037, 955, 932,
2.5, 6.3 Hz, 1H), 5.05 (dt, J = 12.5, 6.3 Hz, 1H), 3.79 (d, J = 9.5 802, 756 cm− ; HRMS (EI) m/z calcd for C H O : [M + H]
1
+
1
16 15 2
Hz, 1H), 2.25 (s, 3H), 1.28 (t, J = 6.7 Hz, 6H), 1.22 (d, J = 6.2 Hz, 239.1067, found 239.1068.
1
3
1
6
1
2
1
H); C NMR (75 MHz, CDCl
3
) δ = 166.4, 166.1, 150.1, 131.1,
2-(2,4-Dimethoxyphenyl)-2H-chromene
(7b).
H
NMR
30.2, 127.3, 125.6, 122.8, 121.4, 116.4, 72.8, 69.4, 69.4, 57.4, (400 MHz, CDCl ) δ = 7.38 (d, J = 8.4 Hz, 1H), 7.13–7.07 (m,
1.9, 21.8, 21.7, 20.7; IR νmax 2957, 2928, 2845, 1743, 1480, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 6.78 (d, J =
3
−
1
459, 1358, 1270, 1138, 1113, 1011, 773 cm ; HRMS (EI) m/z 8.1 Hz, 1H), 6.53–6.43 (m, 3H), 6.29 (dd, J = 3.2, 1.7 Hz, 1H),
+
13
[
M + H] calculated for C H O : 333.1697, found 333.1694.
5.76 (dd, J = 9.9, 3.6 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H);
NMR (101 MHz, CDCl ) δ = 161.1, 157.5, 153.7, 129.4, 129.3,
) δ = 7.21 (d, J = 7.3 Hz, 1H), 7.11 (s, 126.6, 125.3, 123.7, 121.8, 121.6, 121.1, 116.2, 104.5, 98.9, 71.2,
H), 6.63 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 9.5 Hz, 1H), 6.02–5.93 55.8, 55.6; IR νmax 2956, 2921, 2850, 1611, 1588, 1505, 1485,
C
1
9
25 5
1
Diisopropyl 2-(6-bromo-2H-chromen-2-yl)malonate (3n).
NMR (600 MHz, CDCl
H
3
3
1
−
1
(
5
m, 1H), 5.48 (dd, J = 4.8, 3.8 Hz, 1H), 5.18–5.10 (m, 1H), 1356, 1227, 1208, 1157, 1120, 1110, 1035, 955, 766 cm ;
+
.10–5.02 (m, 1H), 3.76 (d, J = 8.7 Hz, 1H), 1.27 (s, 6H), 1.23 (d, HRMS (EI) m/z [M + H] calculated for C17
H
17
O
3
: 269.1172,
1
3
J = 5.5 Hz, 6H); C NMR (75 MHz, CDCl ) δ = 166.2, 165.9, found 269.1169.
3
1
1
6
1
51.5, 132.3, 129.3, 124.4, 124.1, 123.3, 118.4, 113.9, 73.1, 69.6,
2-(4,5-Dimethoxy-2-methylphenyl)-2H-chromene
(7c).
H
3
9.6, 57.5, 21.9, 21.8, 21.8, 21.7; IR νmax 2988, 2920, 2845, NMR (400 MHz, CDCl ) δ = 7.15–7.10 (m, 1H), 7.06–7.01
−
1
742, 1480, 1456, 1348, 1202, 1148, 1112, 1011, 779 cm
;
(m, 2H), 6.88 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.73 (s,
+
HRMS (EI) m/z [M + H] calculated for C18
H
22BrO
5
: 397.0645, 1H), 6.58 (dd, J = 9.9, 1.7 Hz, 1H), 6.15–6.07 (m, 1H), 5.75 (dd,
1
3
found 397.0644.
J = 9.8, 2.9 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 2.41 (s, 3H);
C
1
2
-(2H-Chromen-2-yl)cyclohexanone (5a). H NMR (600 MHz, NMR (101 MHz, CDCl ) δ = 153.8, 148.9, 147.3, 130.6, 129.6,
3
CDCl
3
) δ = 7.13–7.06 (m, 1H), 6.97–6.91 (m, 1H), 6.88–6.81 (m, 128.6, 126.8, 125.2, 124.9, 121.7, 121.4, 116.2, 114.1, 111.5,
1
6
5
2
1
1
1
2
1
5
2
H), 6.78 (d, J = 8.1 Hz, 0.5H), 6.72 (d, J = 8.1 Hz, 0.5H), 74.7, 56.2, 56.1, 18.8; IR νmax 2957, 2927, 2850, 1611, 1589,
.46–6.36 (m, 1H), 5.88–5.67 (m, 1H), 5.52–5.45 (m, 0.5H), 1505, 1485, 1356, 1227, 1208, 1157, 1120, 1111, 1035, 959,
.21–5.12 (m, 0.5H), 2.92–2.69 (m, 1H), 2.49–2.40 (m, 1.5H), 756 cm− ; HRMS (EI) m/z [M + H] calculated for C18
1
+
19 3
H O :
.38–2.21 (m, 1.5H), 2.11–1.98 (m, 1.5H), 1.94–1.91 (m, 0.5H), 283.1329, found 283.1330.
1
3
1
.73–1.61 (m, 3H); C NMR (75 MHz, CDCl ) δ = 211.0, 210.8,
3-(2H-Chromen-2-yl)-1H-indole (7d). H NMR (400 MHz,
) δ = 8.06 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.36 (d, J =
3
54.2, 153.3, 129.4, 126.8, 126.7, 125.7, 125.0, 124.1, 123.3, CDCl
3
21.4, 121.2, 116.2, 115.7, 74.2, 73.6, 56.1, 55.7, 42.9, 42.5, 8.0 Hz, 1H), 7.25–7.14 (m, 3H), 7.07 (d, J = 7.5 Hz, 2H), 6.88 (t,
9.9, 28.2, 27.9, 27.7, 24.9, 24.7; IR νmax 3042, 2938, 2859, J = 7.4 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 9.8 Hz, 1H),
1
3
706, 1485, 1455, 1375, 1222, 1202, 1128, 1112, 1014, 754, 6.26 (d, J = 1.7 Hz, 1H), 5.98 (dd, J = 9.8, 3.6 Hz, 1H); C NMR
71 cm− ; HRMS (EI) m/z [M + H] calculated for C15
1
+
H
O
:
(101 MHz, CDCl
124.5, 124.0, 122.6, 122.0, 121.0, 120.1, 119.9, 116.4, 115.7,
17
2
3
) δ = 153.51, 136.7, 129.2, 126.5, 126.1, 124.6,
29.1223, found 229.1224.
1
1
11.3, 70.5; IR νmax 3409, 2947, 2918, 2846, 1603, 1544, 1484,
Characterization data for the products in Scheme 2
456, 1421, 1339, 1223, 1200, 1111, 1033, 1010, 938, 797,
1
−1
+
2
-(2H-Chromen-2-yl)cyclohexanone (5a). H NMR (600 MHz, 744 cm ; HRMS (EI) m/z [M + H] calculated for C H NO:
1
7
14
CDCl
3
) δ = 7.13–7.06 (m, 1H), 6.97–6.91 (m, 1H), 6.88–6.81 (m, 248.1070, found 248.1074.
1
1
6
5
2
1
1
1
2
1
5
2
H), 6.78 (d, J = 8.1 Hz, 0.5H), 6.72 (d, J = 8.1 Hz, 0.5H), 6-Bromo-2-(4-methoxyphenyl)-2H-chromene (7e). H NMR
.46–6.36 (m, 1H), 5.88–5.67 (m, 1H), 5.52–5.45 (m, 0.5H), (600 MHz, CDCl ) δ = 7.37 (t, J = 8.9 Hz, 2H), 7.15–6.86 (m,
.21–5.12 (m, 0.5H), 2.92–2.69 (m, 1H), 2.49–2.40 (m, 1.5H), 5H), 6.72 (d, J = 8.1 Hz, 0.5H), 6.53 (d, J = 9.8 Hz, 0.5H), 5.91
.38–2.21 (m, 1.5H), 2.11–1.98 (m, 1.5H), 1.94–1.91 (m, 0.5H), (dd, J = 10.0, 3.4 Hz, 0.5H), 5.86 (d, J = 7.0 Hz, 1H), 5.83 (dd,
.73–1.61 (m, 3H); C NMR (75 MHz, CDCl ) δ = 211.0, 210.8, J = 10.0, 3.4 Hz, 0.5H), 3.82 (s, 3H); C NMR (151 MHz, CDCl3)
3
1
3
13
3
54.2, 153.3, 129.4, 126.8, 126.7, 125.7, 125.0, 124.1, 123.3, δ 160.0, 154.3, 132.3, 130.0, 129.0, 127.6, 125.3, 124.3, 123.4,
21.4, 121.2, 116.2, 115.7, 74.2, 73.6, 56.1, 55.7, 42.9, 42.5, 119.6, 115.8, 114.2, 76.9, 55.5; IR νmax 2923, 2835, 1610, 1594,
9.9, 28.2, 27.9, 27.7, 24.9, 24.7; IR νmax 3042, 2938, 2859, 1558, 1513, 1481, 1445, 1304, 1247, 1208, 1174, 1035, 963, 820,
706, 1485, 1455, 1375, 1222, 1202, 1128, 1112, 1014, 754, 766 cm− ; HRMS (EI) m/z calcd for C16
1
H14BrO [M + H]
+
2
71 cm− ; HRMS (EI) m/z [M + H] calculated for C15
1
+
317.0172, found 317.0173.
17 2
H O :
29.1223, found 229.1224.
Characterization data for the substrates in Scheme 3
Acknowledgements
1
2
-(4-Methoxyphenyl)-2H-chromene (7a). H NMR (600 MHz,
3
CDCl ) δ = 7.39 (d, J = 7.9 Hz, 2H), 7.10 (t, J = 7.8 Hz, 1H), 7.02 This work was supported by the National Science Foundation
(d, J = 7.4 Hz, 1H), 6.93–6.85 (m, 3H), 6.76 (d, J = 8.1 Hz, 1H), of China (no. 21202093 and 21472112), the Program for New
6
.55 (d, J = 9.8 Hz, 1H), 5.88 (s, 1H), 5.79 (dd, J = 9.8, 3.0 Hz, Century Excellent Talents in University (no. NCET-13-0346),
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the Shandong Science Fund for Distinguished Young Scholars
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(
Org. Biomol. Chem.
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