Transition Metal-Free Cross-Dehydrogenative Coupling Reaction of Coumarins with Acetonitrile or Acetone

Article abstract of DOI:10.1021/acs.joc.8b01508

A transition metal-free cross-dehydrogenative coupling of coumarins with acetonitrile or acetone has been established. A series of coumarins were subjected to reaction with acetonitrile or acetone in the presence of tert-butyl benzoperoxoate and potassium fluoride for direct synthesis of 3-cyanomethyl (or acetomethyl) coumarins. The method exhibits good functional group tolerance, and desired products were obtained in moderate to good yields. Meanwhile, a radical pathway was proposed to describe the cross-dehydrogenative coupling of coumarins with acetonitrile.

Full text of DOI:10.1021/acs.joc.8b01508

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Article
Transition Metal-Free Cross-Dehydrogenative Coupling
Reaction of Coumarins with Acetonitrile or Acetone
Rongxing Zhang, Shengzhou Jin, Qian Liu, Sen Lin, and Zhaohua Yan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01508 • Publication Date (Web): 08 Oct 2018
Downloaded from http://pubs.acs.org on October 8, 2018
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Transition Metal-Free Cross-Dehydrogenative Coupling Reaction of
Coumarins with Acetonitrile or Acetone
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‡
‡
Rongxing Zhang , Shengzhou Jin , Qian Liu, Sen Lin*, Zhaohua Yan*
Department of Chemistry, Nanchang University, No. 999, Xuefu Rd. Nanchang, 330031, P. R. China
Supporting Information
ABSTRACT: A transition metalꢀfree crossꢀdehydrogenative coupling of coumarins with acetonitrile or acetone has been esꢀ
tablished. A series of coumarins were subjected to reaction with acetonitrile or acetone in the presence of tertꢀbutyl benzoperꢀ
oxoate (TBPB) and potassium fluoride (KF) for direct synthesis 3ꢀcyanomethyl (or acetomethyl) coumarins. The method exꢀ
hibits good functional group tolerance and desired products were obtained in moderate to good yields. Meanwhile, a radical
pathway was proposed to describe the crossꢀdehydrogenative coupling of coumarins with acetonitrile.
INTRODUCTION
Direct crossꢀdehydrogenativeꢀcoupling reactions via transꢀ
formations of CꢀH bond into other bonds have established as
effective and robust methods for the preparation of valuable
fragments of pharmaceuticals and intermediates of natural
1
products. Among them, the oxidative CꢀH activation of aceꢀ
tonitrile and acetone has been received extensively attention
because these groups not only play an important role in bioacꢀ
2
3
4
tive molecules , pharmaceuticals , and specialty chemicals ,
but also it can be good approaches toward other valuable
5
synthons . As a consequence, the development of novel and
Figure 1. Representative bioactive coumarins.
effective strategies to realize CꢀH activation of acetonitrile and
acetone leading to useful structures usually remains to be exꢀ
tremely attractive and significant. Previously, various 2ꢀ
Coumarins and chalcones possessing α,βꢀunsaturated ketonꢀ
ic fragment in their structures have widely emerged as natural
6
1
0
11
products , fluorescent materials and bioactive molecules
(
cyanomethylation of olefins with acetonitrile were described
via metalꢀcatalyzed diꢀfunctionalization leading to organocyaꢀ
12
Figure 1). Therefore, it is greatly challengable and signifiꢀ
13
7
8
cant for molecular modification of coumarins and chalcones.
In recent years, various metalꢀcatalyzed crossꢀ
dehydrogenativeꢀcoupling reactions for coumarins and chalꢀ
nides. Very recently, Rao reported ironꢀcatalyzed crossꢀ
dehydrogenative coupling of acetonitrile with 2ꢀ
phenylimidazo[1,2ꢀa] pyridine, and ironꢀcatalyzed 2ꢀ
cyanomethylation of indoles and pyrroles were developed by
14ꢀ15
cones have been described , for example, Jafarpour and othꢀ
14
9
er research groups reported the metalꢀcatalyzed regioselecꢀ
Guo group.
15a
tive Cꢀ3 alkylation of coumarins and Prof. Huang has realꢀ
ized the copperꢀcatalyzed dehydrogenative coupling of
methylarylenes with α, βꢀunsaturated ketones. On the basis of
the fact that the 3ꢀcyanomethylation (or 3ꢀacetmethyl) of couꢀ
marins and chalcones have not yet been reported, herein, we
described
a
nonmetalꢀcatalyzed crossꢀdehydrogenativeꢀ
coupling reaction of coumarins with acetonitrile or acetone via
3
direct oxidative Csp ꢀH activation. (Scheme 1).
Scheme 1. MetalꢀTransitionꢀFree Catalyzed Crossꢀ
Dehydrogenative Coupling Reaction of Coumarins with
Acetonitrile or Acetone.
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With the optimized conditions in hand, cyanomethylation of
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various coumarins were explored and the result was summaꢀ
rized in Scheme 2. Cyanomethylation of coumarins bearing
various groups (e.g., Me, OMe, OEt, NEt ) were realized to
2
form 3ꢀcyanomethylcoumarins in moderate to good yields
(3aaꢀ3ag, 78ꢀ58 %). Then, two benzoꢀcoumarins and a fuꢀ
rocoumarin as substrates were used to conduct cyanomethylaꢀ
tion reaction leading to desired products in moderate good
yields (3ahꢀ3aj, 83ꢀ56 %). Surprisingly, the desired product
was obtained in good yield for cyanomethylation of 4ꢀmethylꢀ
2
H,5Hꢀpyrano[3,2ꢀc] chromeneꢀ2,5ꢀdione with structure of
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dilactone (3ak, 65 %).
RESULTS AND DISCUSSION
a
Scheme 2. 3ꢀCyanomethylation of Various Coumarins
Initially, our research began with the cyanomethylation for
synthesis of 3aa using coumarin (0.20 mmol) 1a and acetoniꢀ
trile (5 mL) 2a to conduct model reaction in the presence of
various oxidants (2.5 equiv.) and nitrogen (N ) at 110 ℃ for 16
2
h (Table 1, entries 1ꢀ4). The desired product 3aa was obtained
in 36 % yield when tertꢀbutyl benzoperoxoate (TBPB) was
employed as radical initiator and in these cases either low
yields were gain or no reaction occurred for other radical initiꢀ
ators such as TBHP, DTBP, DCP. To improve the yield of
3
aa, different bases were employed as additives and inorganic
bases (Na CO , KF NaHCO ) exhibiting more health effect
2
3
3
than organic bases (NEt , DBU) for synthesis of 3aa (Table 1,
3
5
ꢀ9). Among them the yield of 3aa was increased to 67 %
when KF (1.0 equiv.) was selected as an additive, but no deꢀ
sired product was obtained when NaOH was selected as an
additive (Table 1, entry 10). To our delight, the yield of 3aa
was improved to 78 % when the amount of acetonitrile was
increased to 10 mL (Table 1, entry 11). However, cyanomethꢀ
ylation of coumarin 1a was conducted when 10 % mol FeCl2
was added in the reaction system showed a downtrend in yield
of 3aa (Table 1, entry 12), and the desired product 3aa was not
a
Reaction conditions: 1a (0.20 mmol), 2a (10 mL), KF (1.0
equiv.), TBPB (2.5 equiv.) under N , 16 h, isolated yields.
2
detected with employment of 10 % mol Cu(OAc) as catalyst
Next, the 3ꢀacetmethylation of coumarins was investigated,
and a series of desired products were isolated in moderated to
good yields, as shown in Scheme 3. Among them, the target
products were obtained in moderated yields for 3ꢀ
acetmethylation of coumarins with methyl, methoxy, ethoxy,
cyclohexyl groups on the benzene (3baꢀ3be, 54ꢀ48 %). Simiꢀ
larly, the 3ꢀcyanomethylation, 3ꢀacetmethylation of benzoꢀ
coumarin and 4ꢀmethylꢀ2H,5Hꢀpyrano[3,2ꢀc] chromeneꢀ2,5ꢀ
dione also work well and the corresponding products were
obtained in good yields (3bfꢀ3bh, 74ꢀ72 %).
2
(Table 1, entry 13). Likewise, the use of 1.5 equiv. or 3.5 equiv.
of TBPB showed an obvious downtrend in yield of 3aa (Table 1,
entries 12ꢀ15).
a
Table 1. Optimization of the Reaction Conditions
b
entry
Oxidants
equiv.)
Base
(equiv.)
Catalyst (%
Yield
(%)
N.R.
trace
21
(
mol)
a
Scheme 3. 3ꢀAcetmethylation of Various Coumarins
1
2
3
4
5
TBHP(2.5)
DTBP(2.5)
DCP (2.5)
TBPB (2.5)
TBPB (2.5)
TBPB (2.5)
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
37
23
NEt3
DBU
6
trace
61
7
TBPB (2.5) Na CO
2 3
8
TBPB (2.5) NaHCO3
43
67
9
10
11
TBPB (2.5)
TBPB (2.5)
TBPB (2.5)
TBPB (2.5)
TBPB (2.5)
TBPB (1.5)
TBPB (3.5)
KF
NaOH
KF
KF
KF
trace
c
78
1
1
1
1
2
3
4
5
FeCl (10)
Cu(OAc) (10)
72
trace
52
2
2
KF
KF
ꢀ
ꢀ
71
a
Reaction conditions: 1a (0.20 mmol), 2a (5 mL), base (1.0
c
equiv.), under N , 110 ℃ , 16 h, isolated yields. 2a (10 mL).
2
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Based on the above experimental results and the previous
8, 9, 13d
literature studies
, a plausible mechanism for cyanomethꢀ
ylation of coumarins has been proposed in Scheme 6. Initially,
the benzoate radical and tertꢀbutoxy radical were produced by
the thermal hemolytic cleavage of TBPB. Next, cyanomethyl
radical B emerged by singleꢀelectronꢀtransfer of acetonitrile A
with benzoate radical or tertꢀbutoxy radical releasing benzoic
acid or tertꢀbutanol. The cyanomethyl radical attacks the carꢀ
bonꢀcarbon double bond of coumarin C leading to intermediꢀ
ate D, which is suggested that direct oxidation by benzoate
radical or tertꢀbutoxy radical and deprotonation to produce
desired product E.
a
Reaction conditions: 1 (0.20 mmol), 2b (10 mL), KF (1.0 equiv.),
TBPB (2.5 equiv.) under N , 110 ℃ , 16 h, isolated yields.
2
To further extend substrates scope, cyanomethylation of α,
βꢀunsaturated ketones were carried out (Scheme 4). (E)ꢀ4ꢀ
phenylbutꢀ3ꢀenꢀ2ꢀone derivatives were also tested as subꢀ
strates and the desired products were obtained in moderate
yields (5abꢀ5ac, 31ꢀ58%) for substrates 4b and 4c with elecꢀ
Scheme 6. Plausible Mechanism
tronꢀdonating groups (OMe, and NEt ) on the benzene ring,
2
however, no desired product was obtained for 4a without elecꢀ
tronꢀdonating group on the benzene ring.
Scheme 4. 3ꢀCyanomethylation of α, βꢀUnsaturated Keꢀ
tones
a
Reaction conditions: 4aꢀ4c (0.20 mmol), MeCN (10 mL), KF
(
1.0 equiv.), TBPB (2.5 equiv.) under N , 110 ℃ , 6 h, isolated
2
yields.
CONCLUSION
Some control experiments were carried out to investigate
the reaction mechanism (Scheme 5). Two different radical
scavenger, 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) and
,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) were introduced into
cyanomethylation of coumarin under optimized conditions for
h and the result shown that the 3ꢀcyanomethylation was inꢀ
hibited ((a)ꢀ(b)) and compound 6aa was detected by GCꢀMS.
Therefore, a singleꢀelectronꢀtransfer (SET) pathway was conꢀ
sidered and cyanomethyl radical might act as intermediate.
Meanwhile, a kinetic isotope effect (KIE) was described via an
In summary, we have descried a novel dehydrogenative
coupling reaction of coumarins with acetonitrile via direct
C(sp )ꢀH activation of acetonitrile toward 3ꢀcyanomethylꢀ
3
2
coumarins. The method exhibits good functional group tolerꢀ
ance and 3ꢀcyanomethylꢀcoumarins were obtained in moderate
to good yields. Meanwhile, 3ꢀacetomethyl coumarins were
obtained in moderate yields when acetonitrile was replaced by
acetone. Thus, we provided an efficient and novel method for
synthesis of cyanomethyl (or acetomethyl)ꢀsubstituted coumaꢀ
rins and a radical pathway was put forward to describe the
oxidative CꢀH activation of acetonitrile.
3
intermolecular competition experiment between CH CN and
3
CD CN and the K /K radio was 12.5 ((c)), the KIE experiꢀ
3
H
D
3
ment suggested that the cleavage of C(sp )ꢀH might be the
radioꢀdominant step for this reaction system.
EXPERIMENTAL SECTION
General Information. The NMR spectra were recorded 400 MHz
Scheme 5. Control Experiments and Kinetic Isotope Effect
KIE) Study.
1
1
13
1
(
H) or 600 MHz ( H) and 100 MHz ( C{ H} NMR) or 150 MHz
13
1
(
( C{ H} NMR) in CDCl
3
using tetramethylsilane as an internal referꢀ
ence. NMR multiplicities are abbreviated as follows: s = singlet, d =
doublet, m = multiplet, br = broad signal. Chemical shifts (δ) and
coupling constants (J) were expressed in ppm and Hz, respectively.
Coumarins 1d, 1g, 1h, 1i, 1g, 1k, and α, βꢀunsaturated ketones 4a, 4b,
16
4c were prepared according to the literature procedure . The rest of
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chemicals were purchased from the Sinopharm Chemical Reagent
J = 2.5 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.72 (s, 2H), 2.49 (s, 3H),
13 1
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Co., Adamas, Aladdin and TCI used as received. QꢀTOF were used
for the HRMS and GCꢀMS measurement. HRMS (ESI) data were
obtained using electron spray ionization and GCꢀMS data were obꢀ
tained using electron impact ionization.
1.43 (t, J = 7.0 Hz, 3H). C{ H} NMR (100 MHz, Chloroformꢀd) δ
(ppm) 162.4, 160.7, 154.2, 150.7, 126.0, 116.6, 113.3, 113.0, 112.2,
+
101.2, 64.3, 15.6, 15.5, 14.5. HRMS (ESIꢀTOF) m/z: [M+H] Calcd
for C14
-(7-(diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)-acetonitrile
(3af): Purified by using a flash column chromatography (43.2 mg,
3
H14NO 244.0968; Found: 244.0969.
2
General procedure for the 3ꢀcyanomethylation of coumarins with
acetonitrile. Coumarins 1 (0.2 mmol), KF (0.2 mmol, 11.6 mg),
TBPB (0.5 mmol), and acetonitrile 2a (10 mL) were mixed and stirred
at 110 ℃ in a sealed tube under N for 16 h. After completion of the
2
reaction, the reaction mixture was cooled to room temperature, and
diluted with dichloromethane (5 × 3 mL), the organic layers were
1
8
0 %); yellow solid; mp: 83ꢀ84 ℃ . H NMR (400 MHz, Chloroformꢀd)
δ (ppm) 7.41 (d, J = 9.1 Hz, 1H), 6.59 (dd, J = 9.1, 2.6 Hz, 1H), 6.45
(
1
d, J = 2.6 Hz, 1H), 3.69 (s, 2H), 3.40 (q, J = 7.1 Hz, 4H), 2.43 (s, 3H),
.19 (t, J = 7.1 Hz, 6H). C{ H} NMR (100 MHz, Chloroformꢀd) δ
13
1
(ppm)161.5, 155.0, 151.0, 150.9, 126.0, 117.1, 109.0, 108.6, 108.4,
2 3 2 4
combined, washed with sat. aq. Na CO (10 mL), dried (Na SO ), and
+
9
7.3, 44.7, 15.5, 15.2, 12.4. HRMS (ESIꢀTOF) m/z: [M+H] Calcd
for C16 271.1441; Found: 271.1443.
-(4-methyl-2-oxo-6,7,8,9-tetrahydro-2H-benzo[g]chromen-3-yl)-
0
1
2
3
4
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concentrated in vacuo. The residue was purified by column chromaꢀ
tography using 10ꢀ 20 % ethyl acetate in petroleum as an eluent to get
target compounds.
General procedure for the 3ꢀacetomethylation of coumarins with
acetone. Coumarins 1 (0.2 mmol), KF (0.2 mmol, 11.6 mg), TBPB
19 2 2
H N O
2
acetonitrile (3ag): Purified by using a flash column chromatography
1
(29.4 mg, 58 %); white solid; mp: 161ꢀ162 ℃ . H NMR (400 MHz,
Chloroformꢀd) δ (ppm) 7.32 (s, 1H), 7.02 (s, 1H), 3.76 (s, 2H), 2.88 –
(
0.5 mmol), and acetone 2b (10 mL) were mixed and stirred at 110 ℃
1
3
1
2
(
1
.80 (m, 4H), 2.51 (s, 3H), 1.82 (p, J = 3.3 Hz, 4H). C{ H} NMR
100 MHz, Chloroformꢀd) δ (ppm) 160.6, 150.5, 150.3, 143.1, 134.0,
24.7, 117.3, 116.6, 116.5, 114.5, 29.6, 29.0, 22.9, 22.5, 15.8, 15.5.
in a sealed tube under N for 16 h. After completion of the reaction,
2
the reaction mixture was cooled to room temperature, and diluted with
dichloromethane (5 × 3 mL), the organic layers were combined,
washed with sat. aq. Na CO (10 mL), dried (Na SO ), and concenꢀ
2 3 2 4
trated in vacuo. The residue was purified by column chromatography
using 20 % ethyl acetate in petroleum as an eluent to get target comꢀ
pounds.
General procedure for the 3ꢀcyanomethylation of α, βꢀ
unsaturated ketones with acetonitrile. α, βꢀunsaturated ketones 4aꢀ
+
HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C16
Found: 254.1180.
H
16NO
2
254.1176;
2
-(4-methyl-2-oxo-2H-benzo[h]chromen-3-yl)-acetonitrile
(3ah):
Purified by using a flash column chromatography (41.4 mg, 83 %);
1
white solid; mp: 194ꢀ195 ℃ . H NMR (400 MHz, Chloroformꢀd) δ
(
ppm) 8.55 – 8.41 (m, 1H), 7.85 (dd, J = 6.8, 2.5 Hz, 1H), 7.72 – 7.53
13 1
(m, 4H), 3.80 (s, 2H), 2.59 (s, 3H). C{ H} NMR (100 MHz, Chloroꢀ
formꢀd) δ (ppm) 160.2, 151.4, 149.6, 134.8, 129.0, 127.7, 127.4,
4
c (0.2 mmol), KF (0.2 mmol, 11.6 mg), TBPB (0.5 mmol), and aceꢀ
tonitrile 2a (10 mL) were mixed and stirred at 110 ℃ in sealed tube
under N for 6 h. After completion of the reaction, the reaction mixꢀ
1
24.6, 122.8, 122.5, 120.3, 116.4, 115.0, 114.8, 16.1, 15.8. HRMS
2
+
(
2
ESIꢀTOF) m/z: [M+H] Calcd for C16H12NO 250.0863; Found:
ture was cooled to room temperature, and diluted with dichloroꢀ
methane (5 × 3 mL), the organic layers were combined, washed with
sat. aq. Na CO (10 mL), dried (Na SO ), and concentrated in vacuo.
2 3 2 4
The residue was purified by column chromatography using 5ꢀ10 %
ethyl acetate in petroleum as an eluent to get target compounds.
2-(2-oxo-2H-chromen-3-yl)-acetonitrile (3aa): Purified by using a
2
2
50.0864.
-(1-methyl-3-oxo-3H-benzo[f]chromen-2-yl)-acetonitrile (3ai): Puriꢀ
fied by using a flash column chromatography (37.4 mg, 75 %); white
1
solid; mp: 180ꢀ181 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm)
(
(
ppm) 8.43 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.94 – 7.89
m, 1H), 7.65 (ddd, J = 8.6, 6.7, 1.6 Hz, 1H), 7.60 – 7.54 (m, 1H),
flash column chromatography (28.9 mg, 78 %); white solid; mp: 155ꢀ
13
1
1
7.41 (d, J = 8.9 Hz, 1H), 3.88 (s, 2H), 2.96 (s, 3H). C{ H} NMR
(100 MHz, Chloroformꢀd) δ (ppm) 159.88, 153.1, 152.5, 134.3, 131.6,
1
56 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm)7.94 (s, 1H), 7.57
(
td, J = 8.2, 7.7, 2.7 Hz, 2H), 7.39 – 7.31 (m, 2H), 3.70 (s, 2H).
13
1
129.8, 129.6, 127.9, 125.77, 125.2, 117.2, 116.3, 116.3, 114.8, 22.2,
C{ H} NMR (100 MHz, Chloroformꢀd) δ (ppm) 160.1, 153.3, 140.6,
132.3, 128.0, 125.0, 118.7, 118.4, 116.7, 116.1, 19.6. HRMS (ESIꢀ
TOF) m/z: [M+H] Calcd for C11
+
1
6.3. HRMS (ESIꢀTOF) m/z: [M+H]
250.0863; Found 250.0859.
-(5-methyl-7-oxo-3-phenyl-7H-furo[3,2-g]-chromen-6-yl)-
Calcd for C16H12NO
2
+
8 2
H NO 186.0550; Found 186.0547.
2
2
-(6-methyl-2-oxo-2H-chromen-3-yl)-acetonitrile (3ab): Purified by
acetonitrile (3aj): Purified by using a flash column chromatography
using a flash column chromatography (24.7 mg, 62 %); white solid;
1
1
(35.3 mg, 56 %); white solid; dry distillation: 230 ℃ . H NMR (400
mp: 123ꢀ124 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm) 7.87 (d,
MHz, Chloroformꢀd) δ (ppm) 7.72 (s, 1H), 7.58 (t, J = 7.5 Hz, 2H),
J = 1.7 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.27 – 7.22 (m, 1H), 3.68 (s,
13
1
1
3
1
7.52 – 7.45 (m, 4H), 6.26 (s, 1H), 3.96 (s, 2H), 2.45 (s, 3H). C{ H}
NMR (100 MHz, Chloroformꢀd) δ (ppm) 160.7, 155.6, 152.5, 152.2,
143.1, 129.7, 129.6, 128.8, 128.8, 125.1, 120.6, 117.2, 115.7, 114.7,
2H), 2.42 (s, 3H). C{ H} NMR (100 MHz, Chloroformꢀd) δ (ppm)
1
2
2
2
60.3, 151.5, 140.5, 134.8, 133.3, 127.8, 118.5, 118.1, 116.4, 116.1,
+
0.8, 19.6. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C12
00.0706; Found 200.0705.
H10NO
2
+
113.8, 100.0, 19.2, 16.6. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for
C
2
20
H
14NO
3
316.0968; Found 316.0968.
-(4-methyl-2,5-dioxo-2H,5H-pyrano[3,2-c]-chromen-3-yl)-
acetonitrile (3ak): Purified by using a flash column chromatography
-(7-methoxy-2-oxo-2H-chromen-3-yl)-acetonitrile (3ac): Purified by
using a flash column chromatography (31.8 mg, 74 %); white solid;
1
mp: 159ꢀ160 ℃ . HNMR (400 MHz, Chloroformꢀd) δ (ppm) 7.84 (s,
1
(
34.7 mg, 65 %); white solid; dry distillation: 246 ℃ . H NMR (600
1
=
H), 7.42 (d, J = 8.7 Hz, 1H), 6.88 (dd, J = 8.7, 2.5 Hz, 1H), 6.82 (d, J
2.5 Hz, 1H), 3.87 (s, 3H), 3.64 (s, 2H). C{ H} NMR (100 MHz,
13 1
MHz, Chloroformꢀd) δ (ppm) 8.01 (dd, J = 8.0, 1.6 Hz, 1H), 7.65 –
7.60 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3.67
Chloroformꢀd) δ (ppm) δ 163.1, 160.4, 155.2, 140.7, 128.9, 116.3,
1
3
1
(
s, 2H), 2.70 (s, 3H). C{ H} NMR (150 MHz, Chloroformꢀd) δ
(ppm) 161.2, 157.9, 157.9, 154.2, 153.2, 135.1, 125.3, 124.0, 116.9,
15.52, 115.50, 112.6, 103.7, 18.8, 15.7. HRMS (ESIꢀTOF) m/z:
114.8, 113.2, 112.0, 100.7, 55.9, 19.3. HRMS (ESIꢀTOF) m/z: [M+H]
+
Calcd for C12
3
H10NO 216.0655, Found 216.0656.
1
[
2
-(4,6-dimethyl-2-oxo-2H-chromen-3-yl)-acetonitrile (3ad): Purified
+
4
M+H] Calcd for C15H10NO 268.0604; Found 268.0604.
by using a flash column chromatography (27.7 mg, 65 %); white solid;
1
3-(2-oxopropyl)-2H-chromen-2-one (3ba): Purified by using a flash
mp: 157ꢀ158 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm) 7.45 –
column chromatography (21.8 mg, 54 %); white solid; mp: 88ꢀ
7.41 (m, 1H), 7.36 (dd, J = 8.4, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H),
1
1
3
1
89 ℃ . H NMR (600 MHz, Chloroformꢀd) δ (ppm) 7.50 (s, 1H), 7.39
3.77 (s, 2H), 2.53 (s, 3H), 2.43 (s, 3H). C{ H} NMR (100 MHz,
Chloroformꢀd) δ (ppm) 160.4, 150.5, 150.5, 134.4, 133.4, 124.8,
(
ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.35 (dd, J = 7.8, 1.6 Hz, 1H), 7.20 (d,
J = 8.3 Hz, 1H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 3.58 (s, 2H), 2.21 (s,
1
19.3, 116.8, 116.3, 115.6, 21.1, 15.8, 15.6. HRMS (ESIꢀTOF) m/z:
13
1
+
3H). C{ H} NMR (150 MHz, Chloroformꢀd) δ (ppm) 204.2, 161.5,
53.5, 141.9, 131.3, 127.6, 124.5, 122.9, 119.2, 116.5, 44.5, 30.3.
[
M+H] Calcd for C13
H12NO
2
214.0863; Found 214.0864.
1
2
-(7-ethoxy-4-methyl-2-oxo-2H-chromen-3-yl)-acetonitrile
(3ae):
+
HRMS (ESIꢀTOF) m/z: [M+H]
Found 203.0707.
11 3
Calcd for C12H O 203.0703;
Purified by using a flash column chromatography (38.43 mg, 79 %);
1
white solid; mp: 144ꢀ145 ℃ . H NMR (400 MHz, Chloroformꢀd) δ
7
-methoxy-3-(2-oxopropyl)-2H-chromen-2-one (3bb): Purified by
(
ppm) 7.53 (d, J = 8.9 Hz, 1H), 6.86 (dd, J = 8.9, 2.5 Hz, 1H), 6.76 (d,
using a flash column chromatography (27.8 mg, 60 %); white solid;
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The Journal of Organic Chemistry
1
13
1
mp: 97ꢀ98 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm) 7.52 (s,
1H), 7.35 – 7.30 (m, 1H), 6.85 – 6.77 (m, 2H), 3.85 (d, J = 2.4 Hz,
3
4H), 2.45 (s, 3H), 1.20 (t, J = 7.1 Hz, 6H). C{ H} NMR (100 MHz,
Chloroformꢀd) δ (ppm) 196.8, 149.3, 145.0, 132.5, 125.2, 120.1,
1
2
3
4
5
6
7
8
9
1
3
1
+
H), 3.62 (s, 2H), 2.28 (s, 3H). C{ H} NMR (100 MHz, Chloroꢀ
formꢀd) δ (ppm) 204.6, 162.4, 161.8, 155.2, 142.0, 128.5, 119.1,
12.8, 112.6, 100.6, 55.7, 44.3, 30.2. HRMS (ESIꢀTOF) m/z: [M+H]
118.1, 111.4, 44.5, 25.0, 15.3, 12.5. HRMS (ESIꢀTOF) m/z: [M+H]
Calcd for C16H N O 257.1648; Found: 257.1654.
21 2
1
+
Calcd for C13
H
13
O
4
233.0808; Found 233.0805.
ASSOCIATED CONTENT
Supporting Information
4,6-dimethyl-3-(2-oxopropyl)-2H-chromen-2-one (3bc): Purified by
using a flash column chromatography (23.9 mg, 52 %); white solid;
1
mp: 94ꢀ95 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm) 7.38 (s,
The Supporting Information is available free of charge on the ACS
Publications website.
H and C NMR spectra for the products (PDF)
1
2
H), 7.29 (dd, J = 8.4, 2.1 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.81 (s,
H), 2.40 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H). C{ H} NMR (100 MHz,
Chloroformꢀd) δ (ppm) 204.3, 161.7, 150.4, 149.0, 133.8, 132.1,
24.6, 119.9, 119.8, 116.6, 42.2, 29.9, 21.0, 15.4. HRMS (ESIꢀTOF)
m/z: [M+H] Calcd for C14
13 1
1
13
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
AUTHOR INFORMATION
15 3
H O 231.1016; Found 231.1021.
7
-ethoxy-4-methyl-3-(2-oxopropyl)-2H-chromen-2-one (3bd): Purified
Corresponding Authors
by using a flash column chromatography (32.8 mg, 63 %); white
solid; mp: 124ꢀ125 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm)
7.50 (d, J = 8.9 Hz, 1H), 6.84 (dd, J = 8.9, 2.5 Hz, 1H), 6.78 (d, J =
1
*Email: senlin@ncu.edu.cn
*Email: yanzh@ncu.edu.cn
2
.5 Hz, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 2.30 (s, 3H), 2.27
Author Contributions
13
1
(
s, 3H), 1.44 (t, J = 7.0 Hz, 3H). C{ H} NMR (100 MHz, Chloroꢀ
formꢀd) δ (ppm) 204.7, 162.0, 161.6, 154.0, 149.4, 125.7, 116.5,
13.7, 112.8, 101.1, 64.1, 42.0, 29.9, 15.4, 14.5. HRMS (ESIꢀTOF)
‡
R.Z. and S.J. contributed equally to this work.
Notes
1
+
The authors declare no competing financial interest.
m/z: [M+H] Calcd for C15
4
2
mg, 48 %); white solid; mp: 117ꢀ118 ℃ . H NMR (400 MHz, Chloroꢀ
formꢀd) δ (ppm) 7.26 (s, 1H), 6.98 (s, 1H), 3.79 (s, 2H), 2.87 – 2.76
(m, 4H), 2.30 (s, 3H), 2.26 (s, 3H), 1.80 (p, J = 3.2 Hz, 4H). C{ H}
NMR (100 MHz, Chloroformꢀd) δ (ppm) 204.5, 161.9, 150.3, 149.1,
1
2
2
4
H
17
O
4
261.1121; Found 261.1124.
-methyl-3-(2-oxopropyl)-6,7,8,9-tetrahydro-2H-benzo[g]chrome n-
-one (3be): Purified by using a flash column chromatography (25.9
ACKNOWLEDGMENT
1
We thank the National Natural Science Foundation of China (No.
21362022) for financial support.
13
1
REFERENCES
41.7, 133.4, 124.6, 118.7, 118.0, 116.3, 42.2, 29.8, 29.5, 29.0, 23.0,
+
(1) (a) Yuan, K.; Wang, X.; Wang, S.ꢀN. Cascade Dehydrogenaꢀ
tive Hydroboration for the Synthesis of Azaborabenzofulꢀ
venes. Org. lett., 2018, 20, 1617ꢀ1620. (b) Zhang, C.; Santiaꢀ
go, C. B.; Crawford, J. M.; Sigman, M. S. Enantioselective
Dehydrogenative Heck Arylations of Trisubstituted Alkenes
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Ji, H.; Tian, J.ꢀD.; Zhang, Y.ꢀH. Synthesis and Biological
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prostate Cancer Agents. J. Med. Chem., 2015, 58, 4506–4520.
2.7, 15.3. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C17
71.1329; Found: 271.1326.
19 3
H O
-methyl-3-(2-oxopropyl)-2H-benzo[h]chromen-2-one (3bf): Purified
by using a flash column chromatography (39.4 mg, 74 %); white solid;
mp: 165ꢀ166 ℃ . H NMR (400 MHz, Chloroformꢀd) δ (ppm) 8.51 (dt,
J = 7.1, 3.6 Hz, 1H), 7.87 – 7.78 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H),
1
7
.59 (tq, J = 7.7, 3.9 Hz, 3H), 3.86 (s, 2H), 2.40 (s, 3H), 2.31 (s, 3H).
13
1
C{ H} NMR (100 MHz, Chloroformꢀd) δ (ppm) 204.4, 161.6, 150.1,
149.2, 134.4, 128.4, 127.5, 127.0, 124.1, 123.0, 122.4, 120.6, 119.3,
+
1
15.4, 42.2, 30.0, 16.0. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for
267.1016; Found 267.1019.
-methyl-2-(2-oxopropyl)-3H-benzo[f]chromen-3-one (3bg): Purified
17 15 3
C H O
1
(
2) (a) McGovernꢀGooch, K. R.; Mahajani, N. S.; Garagozzo, A.;
Schramm, A. J.; Hannah, L. G.; Sieburg, M. A.; Chisholm, J.
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Human Ghrelin OꢀAcyltransferase: The Involvement of a
Functionally Required Cysteine Provides Mechanistic Insight
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Das, P.; and Gary, B. Schuster OneꢀElectron Oxidation of
Condensed DNA Toroids: InjectionꢀSite Dependent Charge
(Radical Cation) Mobility. Bioconjugate. Chem., 2008, 19,
by using a flash column chromatography (35.7 mg, 67 %); white
solid; mp: 165ꢀ166 ℃ . H NMR (600 MHz, Chloroformꢀd) δ (ppm)
8.32 (d, J = 8.6 Hz, 1H), 7.81 – 7.74 (m, 2H), 7.50 – 7.46 (m, 1H),
7
1
.42 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 3.83 (s, 2H), 2.62
13 1
(
(
s, 3H), 2.23 (s, 3H). C{ H} NMR (150 MHz, Chloroformꢀd) δ
ppm) 204.3, 161.2, 152.6, 151.1, 133.0, 131.5, 129.7, 129.5, 127.3,
1
25.5, 125.3, 120.6, 117.2, 115.3, 42.7, 30.0, 22.0. HRMS (ESIꢀTOF)
+
m/z: [M+H] Calcd for C17
-methyl-3-(2-oxopropyl)-2H,5H-pyrano[3,2-c]-chromene-2,5-dione
3bh): Purified by using a flash column chromatography (40.9 mg, 72
15 3
H O 267.1016; Found 267.1017.
1
235–1240.
4
(
%
(
3) (a) Honda, T.; Yoshizawa, H.; Sundararajan, C.; David, E.;
Lajoie, M. J.; Favaloro, F. G.; Janosik, T.; Su, X. B.; Honda,
Y.; Roebuck, B. D.; and Gribble G. W. Tricyclic Compounds
Containing Nonenolizable Cyano Enones. A Novel Class of
Highly Potent AntiꢀInflammatory and Cytoprotective Agents.
J. Med. Chem., 2011, 54, 1762–1778. (b) Ohtawa, M.; Ichikaꢀ
wa, S.; Teishikata, Y.; Fujimuro, M.; Yokosawa, H.; and
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furanosyl)guanine, a Potential Antitumor Agent against Bꢀ
Lymphoma Infected with Kaposi's SarcomaꢀAssociated Herꢀ
pesvirus. J. Med. Chem., 2007, 50, 2007–2010.
1
); white solid; dry distillation: 250 ℃ . H NMR (400 MHz, Chloroꢀ
formꢀd) δ (ppm) 8.06 (dd, J = 8.1, 1.8 Hz, 1H), 7.64 (t, J = 7.9 Hz,
1H), 7.36 (q, J = 7.9 Hz, 2H), 3.82 (s, 2H), 2.54 (s, 3H), 2.30 (s, 3H).
13
1
C{ H} NMR (100 MHz, Chloroformꢀd) δ (ppm) δ 203.2, 160.2,
1
1
C
59.1, 158.3, 152.9, 152.4, 134.3, 125.0, 123.8, 120.0, 116.7, 113.0,
+
04.1, 41.8, 29.9, 18.6. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for
16
H
13
O
5
285.0757; Found 285.0757.
(E)-3-(4-methoxybenzylidene)-4-oxopentanenitrile (5ab): Purified by
using a flash column chromatography (13.3 mg, 31 %); clear liqꢀ
uid. H NMR (400 MHz, Chloroformꢀd) δ (ppm) 7.70 (s, 1H), 7.48 –
7
3
1
1
(
4) (a) Wang， Y.ꢀS.; Jester, E. E.; El Said, K. R.; Abraham, A.;
Jennifer H.ꢀR.; and Plakas S. M. Cyano Metabolite as a Biꢀ
omarker of Nitrofurazone in Channel Catfish. J. Agric. Food
Chem., 2010, 58, 313–316. (b) Hao, X.ꢀL.; Kuang, H.; Li, L.ꢀY.;
Yuan, Y.; Peng, C.ꢀF.; Chen, W.; Wang L.ꢀB.; and Xu, C.ꢀ L.
Development of an EnzymeꢀLinked Immunosorbent Assay for
the αꢀCyano Pyrethroids Multiresidue in Tai Lake Water. J.
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.38 (m, 2H), 7.04 – 6.96 (m, 2H), 3.86 (s, 3H), 3.53 (s, 2H), 2.49 (s,
13 1
H). C{ H} NMR (100 MHz, Chloroformꢀd) δ (ppm) 196.9, 161.1,
44.1, 131.5, 129.3, 126.1, 117.6, 114.6, 55.4, 25.2, 15.3. HRMS
+
(ESIꢀTOF) m/z: [M+H] Calcd for C13
2
H14NO
2
216.1019; Found
16.1011.
(E)-4-(4-(diethylamino)-phenyl)-but-3-en-2-one (5ac): Purified by
using a flash column chromatography (33.3 mg, 65 %); yellow liqꢀ
uid. H NMR (400 MHz, Chloroformꢀd) δ (ppm) 7.61 (s, 1H), 7.42 –
1
7.37 (m, 2H), 6.74 – 6.68 (m, 2H), 3.61 (s, 2H), 3.42 (q, J = 7.1 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 6
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ano Ene Reactions. Applications in a Formal [2 + 2 + 2] Cyꢀ
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11489–11495.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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