Synthesis of 3-substituted isocoumarin derivatives via CuI-catalyzed reaction of o-bromobenzamides with 1,3-diketones

Article abstract of DOI:10.1055/s-0031-1290949

An approach to a variety of 3-substituted isocoumarins has been developed. The reaction proceeded from o-bromobenzamide derivatives and 1,3-diketones via CuI-catalyzed reaction in DMF under the action of KOat 120°C without ligands or additives. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290949

1892▌
PAPER
paper
Synthesis of 3-Substituted Isocoumarin Derivatives via CuI-Catalyzed
Reaction of o-Bromobenzamides with 1,3-Diketones
Shangjun Cai, Fei Wang, Chanjuan Xi*
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
E-mail: cjxi@tsinghua.edu.cn
Received: 14.03.2012; Accepted after revision: 30.03.2012
versatile building blocks in a wide variety of plant
alkaloids10 and in pharmacological compounds.11 During
the course of our investigations, we obtained the 3-substi-
tuted isocoumarin rather than the expected isoquinoli-
nones. Herein, we would like to report CuI-catalyzed
reaction of o-bromobenzamide and 1,3-diketones to syn-
thesize 3-substituted isocoumarins.
Abstract: An approach to a variety of 3-substituted isocoumarins
has been developed. The reaction proceeded from o-bromobenz-
amide derivatives and 1,3-diketones via CuI-catalyzed reaction in
DMF under the action of K3PO4 at 120 °C without ligands or addi-
tives.
Key words: copper, domino reaction, isocoumarins, o-bromobenz-
amides, 1,3-diketones
Initially, o-bromobenzamide (1a) and pentane-2,4-dione
(2a) were used as the model substrates for the optimiza-
tion of the reaction conditions. The results are summa-
rized in Table 1. Substrates 1a and 2a were first subjected
to the following typical conditions: CuI, 10 mol%; sol-
vent, toluene; and base, Cs2CO3 at 120 °C to afford 3-
methyl-1H-isochromen-1-one (3a) in 20% yield after 24
hours (Table 1, entry 1). Other bases were also evaluated
in the reaction (entries 2–5). Among the bases screened,
K3PO4 proved to be superior. Then, different solvents
such as MeCN, N-methyl-2-pyrrolidone (NMP), DMF,
and DMSO were screened (entries 2, 6–9). To our delight,
DMF was found to be efficient and the yield of product in-
creased to 70% (entry 8). Prolonging the reaction time to
48 hours did not help to improve yield of 3a (entry 10).
Usually, ligands play an important role in the copper-
catalyzed coupling reactions, thus several ligands were
screened (entries 11–13). Surprisingly, all the ligands
screened did not help the reaction, in other words, the re-
action did not need ligand or additive. The reaction also
showed a strong dependence on temperature. Thus, the re-
action did not proceed at 80 °C (entry 14), but on heating
the reaction mixture to 110 °C, the desired product was
formed in 60% yield (entry 15). At a still higher tempera-
ture of 130 °C, the desired product was formed in 69%
yield (entry 16). On the other hand, the reaction did not
take place at all in the absence of CuI (entry 17). Based on
these results, the optimal conditions involved the follow-
ing ligand-free parameters: CuI as catalyst, K3PO4 as
base, and DMF as solvent, at 120 °C. Furthermore, since
the unexpected isocoumarin was obtained in the reaction,
we carefully authenticated product 3a by elemental anal-
yses, solution NMR, and melting point. All the data
showed that the isocoumarin had formed.
Heterocycles are ubiquitous in natural products, pharma-
ceuticals, organic materials, and numerous functional
molecules. As a consequence, the ongoing interest for de-
veloping new, versatile, and efficient syntheses of hetero-
cycles has always been an important task for the synthetic
community. Among a variety of new synthetic transfor-
mations, transition metal-catalyzed reactions are some of
the most attractive methodologies for synthesizing hetero-
cyclic compounds, since a transition metal-catalyzed re-
action can directly construct complicated molecules from
readily accessible starting materials under mild condi-
tions.1 A recent advance in copper-catalyzed reactions
provided the opportunity for the development of new
methodologies to assemble heterocycles.2 For example,
Ma et al. and Bao et al. had developed Cu-catalyzed dom-
ino process for elaboration of heterocycles such as in-
doles,2e,m isoquinolines,2p and quinoxalin-2(1H)-ones.2q
Our group has recently established some domino process-
es for elaboration of heterocycles via Cu-catalyzed addi-
tion/cyclization or coupling/cyclization reactions, which
included formation of 2-thioxo-2,3-dihydroquinazolin-
4(1H)-one,3 2-aminobenzimidazoles,4 thiophenes,5 and
pyrroles.6 As part of an ongoing program in our laboratory
to systematically synthesize a variety of heterocyclic
compounds action in a one-pot strategy, we found that Cu-
catalyzed reaction of o-halobenzoic acids with 1,3-dike-
tones afforded 3-substituted isocoumarins,7 which are
ubiquitous structural units in natural products with biolog-
ical interests.8 Fan and co-workers reported that Cu-cata-
lyzed tandem reaction of o-bromobenzoates with acyclic
1,3-diones also afforded 3-substituted isocoumarins.9 En-
couraged by these results, we envisioned that Cu-cata-
lyzed reaction of o-bromobenzamides with acyclic 1,3-
diones could afford isoquinolinone derivatives, which are
Under these optimized conditions, a study on the substrate
scope has been carried out, and the results are summarized
in Table 2. At first, o-bromobenzamide 1a was used to re-
act with various 1,3-diketones. Both pentane-2,4-dione
(2a) and heptane-3,5-dione (2b) showed good perfor-
mance (Table 2, entries 1, 2). The reaction of 1a with 1,3-
SYNTHESIS 2012, 44, 1892–1897
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DOI: 10.1055/s-0031-1290949; Art ID: SS-2012-C0267-ST
© Georg Thieme Verlag Stuttgart · New York

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CuI-Catalyzed Reaction of o-Bromobenzamides with 1,3-Diketones
1893
ture was fully characterized by X-ray diffraction analy-
sis.12 The structure of 3h is shown in Figure 1 with some
corresponding bond lengths and angles. It clearly shows
the formation of isocoumarin in the reaction. When 2-bro-
mo-4-fluorobenzamide (1e) was treated with 2a the prod-
uct 3i was obtained in lower yield (entry 10); most of the
starting materials remained, which may be attributed to
electron deficiency on the benzene ring of o-bromobenz-
amide. A substrate with two substituents situated para and
meta to the acylamino group also afforded an good yield
of the corresponding products (entries 11 and 12). When
N-substituted o-bromobenzamides were employed in the
reaction, isocoumarin 3a was obtained again (entries
13,14).
Table 1 Optimization of the Reaction between o-Bromobenzamide
and Pentane-2,4-dionea
O
O
catalyst, base
ligand
O
O
O
NH2
+
solvent
temp, time
Br
1a
2a
3a
Entry Base
Ligand
Solvent Temp Time Yield
(°C) (h) (%)b
1
2
Cs2CO3
K3PO4
–
–
toluene 120 24 20
toluene 120 24 54
toluene 120 24 n.r.
toluene 120 24 33
toluene 120 24 27
MeCN 120 24 31
3
t-BuONa –
4
DBU
–
5
DABCO
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
–
6
–
7
–
NMP
DMF
120 24 51
120 24 70
8
–
9
–
DMSO 120 24 65
10
11
12
13
14
15
16
17c
–
DMF
DMF
DMF
120 48 71
120 24 32
120 24 67
120 24 31
80 24 n.r.
110 24 60
130 24 69
120 24 n.r.
proline
DMEDA
1,10-phenanthroline DMF
–
–
–
–
DMF
DMF
DMF
DMF
Figure 1 Structure of 3h. Selected bond lengths (Å) and angles (°):
O3–C7, 1.382(3); O3–C8, 1.389(3); C7–O3–C8, 122.19(17); C9–
Cb–O3, 121.57(19); O3–C7–C4, 117.09(18).
Although there is little experimental evidence at present to
determine the exact reaction pathway for the cascade se-
quence process, the following three steps are believed to
play some part in the reaction (Scheme 1): (i) coupling re-
action,13 (ii) retro-Claisen deacylation to give intermedi-
ate 5,14 and (iii) an intramolecular lactonization with loss
of an amine.
a Unless otherwise noted, the reaction was performed with 1a (0.5
mmol), 2a (0.5 mmol), CuI (0.05 mmol), and base (1 mmol) in solvent
(1 mL) under N2.
b Isolated yield; n.r. = no reaction.
c Without CuI.
diphenylpropane-1,3-dione (2c) did not proceed even by
heating the reaction to 130 °C for 48 hours (entry 3).
When unsymmetrical 1,3-diketone 2d was engaged in the
system, the reaction regioselectively gave one product 3c
in 32% yield (entry 4). Other substituted o-bromobenz-
amide derivatives were then applied under the optimized
conditions. In most cases, the reaction with o-bromo-
benzamide derivatives could proceed smoothly and the
products were obtained in satisfactory yields. For exam-
ple, when 1b or 1c was treated with 2a under the opti-
mized conditions, the desired product was obtained in
62% or 71% yield, respectively (entries 5, 6). When 2-
bromo-5-methoxybenzamide (1d) was employed as the
substrate, the desired product was formed only in 24%
yield (entry 7). Reaction of 1c with 2b afforded the prod-
uct 3h in 64% yield (entry 9). To our delight, the product
3h was suitable for single crystal analysis, and its struc-
O
O
R1
R1
retro-Claisen
deacylation
COR4
NHR2
NHR2
COR4
coupling
+
Br
O
COR3
1
2
COR3
4
O
O
O
R1
R1
R1
NHR2
OH
NHR2
O
R4
3
R4
R4
5
6
Scheme 1 Possible reaction pathway for the formation of 3-substitut-
ed isocoumarins
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1892–1897

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S. Cai et al.
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Table 2 Reaction of o-Bromobenzamides with 1,3-Diketonesa
O
O
R1
R1
O
O
CuI (10 mol%)
NH2
O
+
R2
R3
R3
K3PO4, DMF
120 °C
Br
1
2
3
Entry
Substrate 1
Substrate 2
Time (h) Product
Yield (%)b
65
O
O
O
O
O
O
1
1a
2a
24
3a
NH2
O
O
O
Br
O
O
O
2
3
1a
1a
1a
1b
1c
1d
1b
1c
1e
1f
2b
24
48
24
24
24
48
24
24
48
24
3b
3c
3c
3d
3e
3f
57
Et
Et
Et
Ph
Ph
O
2c
2d
2a
2a
2a
2b
2b
2a
2a
n.r.
32
Ph
Ph
O
O
O
O
O
4
Ph
O
NH2
5
O
O
62
Br
O
O
O
NH2
6
71
MeO
MeO
MeO
MeO
Br
O
O
NH2
Br
7
24
O
O
O
8
3g
3h
3i
48
Et
O
9
64
MeO
Et
O
O
O
O
NH2
10
11
trace
66
F
Br
F
O
MeO
MeO
MeO
MeO
NH2
Br
O
3j
Synthesis 2012, 44, 1892–1897
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CuI-Catalyzed Reaction of o-Bromobenzamides with 1,3-Diketones
1895
Table 2 Reaction of o-Bromobenzamides with 1,3-Diketonesa (continued)
O
O
R1
R1
O
O
CuI (10 mol%)
NH2
O
+
R2
R3
R3
K3PO4, DMF
120 °C
Br
1
2
3
Entry
Substrate 1
Substrate 2
Time (h) Product
Yield (%)b
59
O
MeO
MeO
12
1f
2b
24
3k
O
Et
O
O
O
NHMe
O
O
13
14
1g
1h
2a
2a
24
24
3a
3a
55
52
Br
O
NHBu
Br
a Unless otherwise noted, the reaction was performed with 1 (0.5 mmol), 2 (0.5 mmol), CuI (0.05 mmol), and K3PO4 (1 mmol) in DMF (1 mL)
under N2 for 24 h.
b Isolated yield; n.r. = no reaction.
13C NMR (75 MHz, DMSO-d6): δ = 19.0, 103.2, 119.1, 125.2,
127.6, 128.6, 135.0, 137.3, 154.4, 161.9.
ESI-MS: m/z = 161.4 [M + H]+.
In conclusion, we have demonstrated a new method based
on CuI-catalyzed domino process for the construction of
3-substituted isocoumarins from o-bromobenzamides and
1,3-diketones. The reaction of o-bromobenzamides with
Anal. Calcd for C10H8O2: C, 74.99; H, 5.03. Found: C, 74.89; H,
1,3-diketones was performed well without addition of any 5.06.
ligand or additive. Considering the relatively inexpensive
3-Ethyl-1H-isochromen-1-one (3b)15
catalytic system and the commercial availability of the
starting materials, it should be of great benefit in organic
synthesis.
Yield: 49 mg (57%); white solid; mp 70–72 °C.
1H NMR (300 MHz, CDCl3): δ = 1.28 (t, JH,H = 7.6 Hz, 3 H), 2.57
(q, JH,H = 14.4 Hz, 2 H), 6.25 (s, 1 H), 7.36 (d, JH,H = 7.9 Hz, 1 H),
7.45 (t, JH,H = 7.2 Hz, 1 H), 7.67 (t, JH,H = 7.6 Hz, 1 H), 8.25 (d,
JH,H = 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 11.4, 26.8, 102.1, 120.3, 125.2,
127.7, 129.7, 134.8, 137.8, 159.7, 163.2.
All the reactions were carried out in a predried screw-capped tube
with a Teflon-lined septum under N2 atmosphere. Unless otherwise
indicated, all materials were obtained from commercial sources and
used as received. DMF, toluene, MeCN, and DMSO were freshly
distilled. Column chromatography was performed on silica gel (par-
ticle size 10–40 μm). 1H NMR and 13C NMR spectra were recorded
on 300 MHz and 600 MHz spectrometer at r.t. with DMSO-d6 and
CDCl3 as the solvent.
ESI-MS: m/z = 175.3 [M + H]+.
3-Phenyl-1H-isochromen-1-one (3c)15
Yield: 35 mg (32%); white solid; mp 85–87 °C.
1H NMR (300 MHz, DMSO-d6): δ = 7.45–7.59 (m, 5 H), 7.66–7.68
(m, 1 H), 7.80–7.92 (m, 3 H), 8.12–8.15 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 102.1, 119.8, 124.9, 126.6,
128.6, 128.9, 129.0, 130.0, 131.6, 135.4, 137.3, 152.4, 161.3.
ESI-MS: m/z = 223.2 [M + H]+.
3-Substituted Isocoumarins 3; General Procedure
A sealed tube was charged with a mixture of o-bromobenzamide 1
(0.5 mmol), 1,3-diketone 2 (0.5 mmol), CuI (0.05 mmol, 10 mg),
and K3PO4 (1.0 mmol, 212 mg) in DMF (1 mL) and the reaction
mixture was stirred at r.t. under N2 atmosphere. Half an hour later,
the tube was sealed and the mixture was allowed to stir at 120 °C for
the indicated time (Table 2). After completion, the mixture was
cooled to r.t., then H2O (5 mL) was added, and the mixture was ex-
tracted with EtOAc (3 × 5 mL), and the combined organic layers
were dried (Na2SO4). Evaporation of the solvent followed by puri-
fication of the residue on silica gel [petroleum ether (bp 60–90 °C)–
EtOAc, 5:1] provided the desired product (Table 2).
3,6-Dimethyl-1H-isochromen-1-one (3d)7
Yield: 53 mg (62%); white solid; mp 68–70 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.22 (s, 3 H), 2.41 (s, 3 H), 6.46
(s, 1 H), 7.32 (d, JH,H = 11.7 Hz, 2 H), 7.96 (d, JH,H = 8.3 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 19.1, 21.4, 103.1, 116.7, 125.1,
128.7, 129.0, 137.5, 145.8, 154.5, 161.9.
ESI-MS: m/z = 175.3 [M + H]+.
3-Methyl-1H-isochromen-1-one (3a)15
Yield: 51 mg (65%); white solid; mp 68–70 °C.
6-Methoxy-3-methyl-1H-isochromen-1-one (3e)16
Yield: 67 mg (71%); white solid; mp 93–95 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.16 (s, 3 H), 6.40 (s, 1 H), 7.42
(q, JH,H = 14.4 Hz, 2 H), 7.70 (t, JH,H = 7.2 Hz, 1 H), 8.02 (d, JH,H
=
7.6 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1892–1897

1896
S. Cai et al.
PAPER
1H NMR (300 MHz, DMSO-d6): δ = 2.20 (s, 3 H), 3.86 (s, 3 H), 6.45
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of spectra of compound 3a–h, 3j–k and CIF (X-ray data)
(s, 1 H), 6.98 (s, 1 H), 7.04 (d, JH,H = 8.6 Hz, 1 H), 7.98 (d, JH,H
=
8.6 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 19.2, 55.8, 103.3, 107.5, 112.2,
of 3h.SnuIpofoprimntgirSatnuIfiogp
mooiratn
r
t
116.2, 131.0, 140.0, 155.1, 161.7, 164.5.
ESI-MS: m/z = 191.3 [M + H]+.
References
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Yield: 23 mg (24%); white solid; mp 99–101 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.21 (s, 3 H), 3.84 (s, 3 H), 6.49
(s, 1 H), 7.36–7.40 (m, 1 H), 7.45 (s, 1 H), 7.48 (s, 1 H).
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124.1, 127.1, 131.1, 152.2, 158.7, 162.0.
ESI-MS: m/z = 191.3 [M + Na]+.
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3-Ethyl-6-methyl-1H-isochromen-1-one (3g)7
Yield: 45 mg (48%); white solid; mp 60–62 °C.
1H NMR (300 MHz, DMSO-d6): δ = 1.12 (t, JH,H = 7.5 Hz, 3 H),
2.36 (s, 3 H), 2.43–2.50 (m, 2 H), 6.41 (s, 1 H), 7.28 (d, JH,H = 4.1
Hz, 2 H), 7.91 (d, JH,H = 8.6 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 11.0, 21.4, 25.8, 101.6, 116.9,
125.3, 128.7, 129.1, 137.4, 145.8, 159.1, 161.8.
ESI-MS: m/z = 189.1 [M + H]+.
3-Ethyl-6-methoxy-1H-isochromen-1-one (3h)16
Yield: 65 mg (64%); white solid; mp 94–95 °C.
1H NMR (600 MHz, DMSO-d6): δ = 1.19 (t, JH,H =7.6 Hz, 3 H),
2.50–2.54 (m, 2 H), 3.88 (s, 3 H), 6.47 (s, 1 H), 7.04–7.08 (m, 2 H),
8.00 (d, JH,H = 8.2 Hz, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 10.9, 25.9, 55.7, 101.7, 107.7,
112.3, 116.2, 130.9, 139.8, 159.6, 161.5, 164.4.
ESI-MS: m/z = 205.4 [M + H]+.
Anal. Calcd for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.67; H,
5.98.
6,7-Dimethoxy-3-methyl-1H-isochromen-1-one (3j)17
Yield: 72 mg (66%); white solid; mp 135–137 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.21 (s, 3 H), 3.84 (s, 3 H), 3.88
(s, 3 H), 6.42 (s, 1 H), 7.02 (s, 1 H), 7.40 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 19.1, 55.6, 56.0, 103.0, 106.5,
108.6, 111.8, 133.1, 148.9, 153.1, 155.0, 161.7.
ESI-MS: m/z = 221.2 [M + H]+.
3-Ethyl-6,7-dimethoxy-1H-isochromen-1-one (3k)
Yield: 69 mg (59%); white solid; mp 168–170 °C.
1H NMR (300 MHz, DMSO-d6): δ = 1.17 (t, JH,H =7.6 Hz, 3 H), 2.51
(q, JH,H =14.4 Hz, 2 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 6.43 (s, 1 H),
7.07 (s, 1 H), 7.42 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 11.0, 25.8, 55.7, 56.0, 101.5,
106.7, 108.6, 112.0, 133.1, 148.9, 155.0, 157.7, 161.7.
ESI-MS: m/z = 235.3 [M + H]+.
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Bioorg.
Med. Chem. 2005, 13, 6529. (f) Engelmeier, D.; Hadacek,
F.; Hofer, O.; Lutz-Kutschera, G.; Nagl, M.; Wurz, G.;
Greger, H. J. Nat. Prod. 2004, 67, 19.
HRMS: m/z calcd for C13H14O4: 234.0892; found: 234.0891.
Acknowledgment
(9) Fan, X.; He, Y.; Cui, L.; Guo, S.; Wang, J.; Zhang, X. Eur.
J. Org. Chem. 2012, 673.
This work was supported by the National Natural Science Founda-
tion of China (20972085 and 21032004) and national basic research
program of China (2012CB933402).
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1892–1897