Copper-catalyzed selective synthesis of isoindolin-1-ones and isoquinolin-1-ones from the three-component coupling of 2-halobenzoic acid, alkynylcarboxylic acid and ammonium acetate

Article abstract of DOI:10.1002/adsc.201400451

Isoindolin-1-ones and isoquinolin-1-ones were selectively synthesized from the reaction of 2-halobenzoic acid, arylalkynylcarboxylic acid and ammonium acetate (NH₄OAc) in the presence of cesium carbonate (Cs₂CO₃) and a copper catalyst. Conducting the reaction under one-pot conditions provided isoindolin-1-ones in good yields. Changing the addition sequence of ammonium acetate after all reagents had reacted at 120 °C for 6 h selectively produced isoquinolin-1-ones. A variety of arylalkynylcarboxylic acids produced the corresponding isoindolin-1-ones and isoquinolin-1-ones in good yields.

Full text of DOI:10.1002/adsc.201400451

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DOI: 10.1002/adsc.201400451
Copper-Catalyzed Selective Synthesis of Isoindolin-1-ones and
Isoquinolin-1-ones from the Three-Component Coupling of
2-Halobenzoic Acid, Alkynylcarboxylic Acid and Ammonium
Acetate
Francis Mariaraj Irudayanathan,a Jieun Noh,a Jinseop Choi,a and Sunwoo Leea,*
a
Department of Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea
Fax : (+82)-62-530-3389; e-mail: sunwoo@chonnam.ac.kr
Received: May 5, 2014; Revised: June 30, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400451.
Abstract: Isoindolin-1-ones and isoquinolin-1-ones reagents had reacted at 1208C for 6 h selectively pro-
were selectively synthesized from the reaction of 2- duced isoquinolin-1-ones. A variety of arylalk-
halobenzoic acid, arylalkynylcarboxylic acid and am-
ACHTUNGTRENyNGNU nylcarboxylic acids produced the corresponding iso-
monium acetate (NH4OAc) in the presence of indolin-1-ones and isoquinolin-1-ones in good yields.
cesium carbonate (Cs2CO3) and a copper catalyst.
Conducting the reaction under one-pot conditions
provided isoindolin-1-ones in good yields. Changing Keywords: ammonium acetate; copper; decarboxyla-
the addition sequence of ammonium acetate after all tive coupling; isoindolin-1-ones; isoquinolin-1-ones
Introduction
a single or multistep preparation of the two starting
materials.
The development of an efficient synthetic method for
The isoquinolin-1-one moiety, which is the 6-mem-
the formation of heterocyclic rings is one of the most bered ring analogue of 3-methyleneisoindolin-1-one,
intensively studied research subjects in organic is found in a variety of bioactive compounds.[11]
chemistry.[1] The one-pot reaction has received more
3-Arylisoquinolin-1-ones exhibit antitumor activity
attention than multistep reactions.[2] Among the and serve as an important skeleton for the synthesis
hetero
cyclic ring compounds, isoindolin-1-one ring of bioactive heterocyclic compounds.[12] As shown in
ACHTUNGTRENNUNG
systems are regarded as one of the key scaffolds for Figure 1 (b), the isoquinolin-1-one motif occurs in
medicinal and material chemistry applications.[3] As bioactive compounds showing thymidylate synthase
shown in Figure 1 (a), many natural products and bio- or topoisomerase I inhibitory activity.[13] A number of
logically active compounds contain the 3-methylenei- synthetic methods serve for synthesis of isoquinolin-1-
soindolin-1-one motif.
one.[14] As shown in Scheme 1 (b), other work uses
Previous reports consider a number of reaction transition metal catalysts in the cyclization of ortho-
methods for the preparation of 3-methyleneisoindo- substituted arylalkynes[15] and the C H activation of
À
lin-1-ones, including Horner–Wadsworth–Emmons benzamides with alkynes.[16] Recently, Pal reported
type of condensation,[4] addition to benzonitriles,[5] using the Pd/Cu-catalyzed intramolecular acetylenic
cyclization of 2-alkynylbenzamides,[6] substitution of Schmidt reaction, using acyl azide, to synthesize iso-
phthalides[7] and addition/dehydration of phthali- quinolin-1-one.[17] Although these methods have often
mides.[8] Recently, transition metal-catalyzed coupling been used for the synthesis of isoquinolinones, they
reactions such as Heck, Suzuki, carbonylation and So- require preparation of the starting materials or the
nogashira reactions have been used to synthesize 3- use of expensive precious metal catalysts.
methyleneisoindolin-1-ones.[9] Although the one-pot
Recently, we developed a one-pot reaction method
sequential reaction of coupling and cyclization of 2- for the preparation of isocoumarins and phthalides
halobenzamide and terminal alkyne, shown in from the coupling reaction of 2-iodobenzoic acids and
Scheme 1 (a) seems to be attractive,[10] it requires terminal alkynes in the presence of a copper cata-
lyst.[18] We found that this method provided the 6-
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Francis Mariaraj Irudayanathan et al.
Scheme 1. Synthesis of isoindolin-1-one and isoquinolin-1-
one.
Figure 1. Bioactive compounds containing the isoindolin-1-
one or isoquinolin-1-one structure.
ylic acids ensures easy storage as they are very stable
and can be easily handled and prepared from by one-
step coupling reaction involving a simple work-up
endo-dig (isocoumarin) and 5-exo-dig species (phtha- procedure.[19] (iv) Employing a copper catalyst in the
lide) as major products at 100 and 258C, respectively. absence of a ligand for the construction of sp carbon
During this development we discovered that the five- and sp2 carbon bonds, instead of an expensive palladi-
membered ring product, 3-methyleneisoindolin-1-one, um catalysts, allows the process to be cost effective.
was formed as a major product when alkynylcarboxyl-
ic acid and 2-iodobenzoic acid reacted with ammoni-
um acetate (NH4OAc). Our previous report showed Results and Discussion
that the 5-exo-dig product was never obtained via the
decarboxylative coupling of alkynylcarboxylic acid, By screening a variety of parameters in the reaction
even when it was formed with low regioselectivity of 2-iodobenzoic acid, phenylpropiolic acid and am-
from a terminal alkyne. Therefore, this encouraged us monium acetate we optimized the synthesis of isoin-
to develop a one-pot highly selective synthesis of 3- dolin-1-one. Table 1 summarizes these results.
methyleneisoindolin-1-ones from the decarboxylative
We tested a number of bases at 3 equivalents (en-
coupling of alkynylcarboxylic acids with 2-iodobenzo- tries 1–5) while maintaining 10 mol% CuI in DMSO
ic acid and amines. It should be possible to expand at 1208C. Of these, Cs2CO3 showed the best yield of
this to the selective synthesis of isoquinolin-1-ones the 5-membered ring product, 3-benzylideneisoindo-
from isocoumarin.
lin-1-one (3aa) (entry 1). K2CO3 and Na2CO3 showed
We believe that this methodology affords several product yields of 60% and 26%, respectively (en-
advantages: (i) We selectively obtained 3-methylene- tries 2 and 3).
A
Organic bases, such as Et3N and 1,8-diazabicycloun-
starting materials by changing the sequence of dec-7-ene (DBU), showed poor yields (entries 4 and
NH4OAc addition to the reaction mixture. (ii) 2- 5). Using CuBr decreased the product yield to 40%
Bromo- and 2-iodobenzoic acids are economical and (entry 6) and using CuCl afforded the desired product
commercially available. (iii) Use of arylalkynylcarbox- with 5% yield, however the major product was 1,4-di-
2
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Copper-Catalyzed Selective Synthesis of Isoindolin-1-ones and Isoquinolin-1-one
Table 1. Optimization of the synthesis of isoindolin-1-one.[a]
Scheme 2. Reacting 2-iodobenzoic acid with a variety
of arylalkynylcarboxylic acids selectively afforded the
desired 5-membered ring products, 3-benzylidene-
AHCTUNGTREGiNNNU soindolin-1-ones, with good yield. Alkyl-substituted
arylalkynylcarboxylic acids provided 3ab, 3ac, 3ad,
3ae and 3af with good yields. Alkoxy-substituted aryl-
AHCTUNGTREGaNNUN lkynylcarboxylic acids 2g and 2h afforded the corre-
Entry
Catalyst
Base
Solvent
Yield [%][b]
sponding products 3ag and 3ah with 65 and 59%
yields, respectively. 3-(Naphthalen-2-yl)propiolic acid
and 3-(thiophen-2-yl)propiolic acid produced 3ai and
3aj with 54% and 68% yields, respectively. Fluoro-
and chloro-substituted arylalkynylcarboxylic acids
gave the desired products 3ak, 3al, and 3am with
good yields. The reaction with propiolic acid pro-
duced 3-methyleneisoindolin-1-one (3an) with 71%
yield. Using substituted 2-iodobenzoic acids, such as
2-iodo-6-methoxybenzoic acid and 2-iodo-4-methyl-
benzoic acid selectively provided the desired isoindo-
lin-1-ones 3ba, 3bh and 3ca in good yields. In addi-
tion, 2-iodo-5-fluorobenzoic acid and 2-iodo-4-chloro-
benzoic acid provided the corresponding isoindol-1-
ones 3da and 3ea with 47% and 53% yields, respec-
tively. However, when we employed aliphatic alkynyl-
carboxylic acids such as 1-octynoic, 1-butynoic and 1-
pentynoic acids as alkyne source, we failed to obtain
the desired isoindolin-1-ones.
To expand this methodology for the synthesis of
isoquinolin-1-one 4, we first carried out the reactions
of 2-iodobenzoic acid and arylalkynylcarboxylic acid
in the absence of NH4OAc at 1208C for 6 h, and then
added NH4OAc. We expected the first step to afford
isocoumarin and the next step to provide the amine-
substitution reaction. As expected, the sequential re-
action produced the desired isoquinolin-1-ones 4, as
shown in Scheme 3. Phenylpropiolic acid afforded the
desired product 4aa in 85% yield. Methyl-substituted
arylalkynylcarboxylic acids 2b and 2c gave the corre-
sponding products 4ab and 4ac with good yields.
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cs2CO3
K2CO3
Na2CO3
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
diglyme
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
81
60
26
27
49
40
5 (33)[c]
23
30
5
50
16
20
58
55
53
21
61
75
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3[e]
Cs2CO3
–
Cu
Cu(OTf)2
Cu(acac)2
ACHTUNGTRENNUNG(OAc)2
9
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
10
11
12
13
14
15[d]
16
17
18[f]
19[g]
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cs2CO3
Cs2CO3
[a]
Reaction conditions: 1a (1 mmol), 2a (1.1 mmol),
NH4OAc (1.5 mmol), Cu (0.1 mmol) and base (3.0 mmol)
were reacted.
Isolated yield.
Yield of 1,4-diphenylbutadiyne.
2 equivalents of phenylpropiolic acid were used.
2 equivalents of base were used.
2-Bromobenzoic acid was used instead of 2-iodobenzoic
acid.
[b]
[c]
[d]
[e]
[f]
[g]
Phenylacetylene was used instead of 2a.
phenylbutadiyne formed by the homocoupling of phe- Halo-substituted arylalkynylcarboxylic acids 2p, 2q
nylpropiolic acid (entry 7). All copper(II) species af- and 2r provided the corresponding products 4ap, 4aq,
forded lower product yields than when using cop- and 4ar with 65%, 68% and 74% yields, respectively.
per(I) species (entries 8–10). Using solvents other
We previously reported a convenient method to
than dimethyl sulfoxide (DMSO) did not give satis- obtain arylalkynylcarboxylic acids from the Sonoga-
factory results (entries 11–13) and decreased the shira coupling reaction of aryl iodide and propiolic
product yield to 58% at 1008C (entry 14). Either in- acid.[19a] These reaction conditions, using Cs2CO3 and
creasing the amount of phenylpropiolic acid or de- DMSO, suggested the possibility of synthesizing isoin-
creasing the amount of base reduced the product dolin-1-ones and isoquinolin-1-ones from the reaction
yields (entries 15 and 16). Although the desired prod- of aryl iodide and propiolic acid.
uct was formed in the absence of base, it was obtained
As shown in Scheme 4, aryl iodide and propiolic
in a low yield (entry 17). Using 2-bromobenzoic acid acid were first reacted in the presence of Cs2CO3
in place of 2-iodobenzoic acid also provided the de- using a palladium catalyst. The reaction with 2-iodo-
sired product with 61% yield, (entry 18). We found benzoic acid and NH4OAc was carried out without
that formation of a six-membered ring product was any isolation process of the intermediates. Thus we
not observed under the mentioned conditions.
obtained the desired isoindolin-1-ones 3aa and 3ab
We used a variety of arylalkynylcarboxylic acids to from iodobenzene and 4-iodotoluene in 65% and
evaluate the optimized conditions for the synthesis of 55% yields, respectively and isoquinolin-1-ones 4aa
the isoindolin-1-one. The results are summarized in and 4ab in 68% and 61% yields, respectively.
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Scheme 2. Synthesis of isoindolin-1-one from a variety of arylalkynylcarboxylic acids. Reaction conditions: 1 (3.0 mmol), 2
(3.3 mmol), NH4OAc (4.5 mmol), CuI (0.3 mmol) and Cs2CO3 (9.0 mmol) in DMSO at 1208C for 6 h.
To study the reaction pathway, we investigated the ed with an amine source.[20] To clearly understand the
reaction conditions for the formation of isoindolin-1- reaction pathway in our optimized conditions, we in-
one (Scheme 5). When 1a and 2a were allowed to dependently reacted phthalide 6 and isocoumarin 7
react at 258C without NH4OAc, phthalide 6 was ob- with NH4OAc under the optimized conditions. As
served. Upon adding NH4OAc and heating the reac- shown in Scheme 6, phthalide 6 and isocoumarin 7
tion mixture at 1208C the expected isoindolin-1-one were converted to the corresponding isoindolin-1-one
3aa was formed with 52% yield. However, when the 3aa and isoquinolin-1-one 4aa, respectively, and we
same reaction was conducted at 258C with NH4OAc, found no interconverted products at high temperature
neither 6 nor 3aa was observed. Upon further heating in either case. These results support that such inter-
the reaction mixture at 1208C the isoindolin-1-one conversions are ruled out in the reaction pathway.
3aa was formed with 72% yield. From these results,
we can infer that phthalide is not the intermediate for isoquinolin-1-one in detail, we further investigated
the formation of isoindolin-1-one. the reactions with two possible intermediates: 2-iodo-
It is known that the amine-substitution reaction benzamide and 2-phenylethynylbenzoic acid.
transforms phthalide and isocoumarin into isoindolin- Reacting 2-alkynyl-substituted benzoic acid 8 under
1-one and isoquinolin-1-one, respectively, when treat- these optimized conditions afforded 3-phenylisoqui-
To study the reaction pathway for the formation of
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Copper-Catalyzed Selective Synthesis of Isoindolin-1-ones and Isoquinolin-1-one
Scheme 6. Amine substitution reactions.
nolin-1-one (4aa) as a major product with 60% yield,
and a five-membered ring compound 3aa was formed
as a minor product with 12% yield [Scheme 7 (a)].
This result suggests that the decarboxylative coupling
reaction of alkynylcarboxylic acid and 2-halobenzoic
acid might not be the first step in this reaction. The
reaction of 2-iodobenzamide (9) and phenylpropiolic
acid (2a) with 10% CuI and Cs2CO3 provided only
the five-membered ring product 3aa with a 65% yield
[Scheme 7 (b)]. However, the possible intermediate,
Scheme 3. Synthesis of isoquinolin-1-ones by sequential re-
action. Reaction conditions: 1 (3.0 mmol), 2 (3.3 mmol), CuI
(0.3 mmol) and Cs2CO3 (9.0 mmol) in DMSO at 1208C for
6 h, then NH4OAc (4.5 mmol) was added and reacted at
1208C for 6 h.
Scheme 4. Sequential synthesis of isoindolin-1-one and isoquinolin-1-one.
Scheme 5. Studies for the formation of 3aa.
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Francis Mariaraj Irudayanathan et al.
Conclusions
We have developed an efficient one-pot method for
the synthesis of isoindolin-1-ones as well as a sequen-
tial method for the synthesis of isoquinolin-1-ones.
With CuI (10 mol%) and Cs2CO3 (3 equivalents), re-
action of 2-halobenzoic acid and arylalkynylcarboxylic
acid at 1208C in the presence of NH4OAc selectively
produced the isoindolin-1-one with good yields. Con-
ducting the same reaction in the absence of NH4OAc
and then adding NH4OAc to the reaction mixture af-
forded the corresponding isoquinolin-1-one with good
yields. We suggest that isoindolin-1-one was formed
through amide bond formation first or concerted cou-
pling pathway. This method afforded the direct syn-
thesis of the 5-exo-dig product with high regioselectiv-
ity, using arylalkynylcarboxylic acids, which are easily
prepared from the coupling of propiolic acid and aryl
halides. In addition, isoquinolin-1-one was selectively
obtained via the formation of isocoumarin.
Scheme 7. Study of the reaction pathway.
Experimental Section
General Procedure for Synthesis of (Z)-3-
Benzylideneisoindolin-1-ones
2-Iodobenzoic acid derivative (3.0 mmol), Cs2CO3 (2.9 g,
9.0 mmol), ammonium acetate (347 mg, 4.5 mmol), copper
iodide (57 mg, 0.3 mmol) were added into a vial containing
anhydrous DMSO (5 mL), followed by addition of the ap-
propriate alkynylcarboxylic acid derivative (3.3 mmol). The
suspension was stirred for 6 h at 1208C. After completion of
the reaction, the mixture was poured into the ethyl acetate
(50 mL) and washed with water (2ꢁ25 mL), brine (2ꢁ
25 mL), then dried over Na2SO4. Evaporation of the solvent
under reduced pressure provided the crude product, which
was purified by column chromatography (hexane:EtOAc=
9:1) or re-crystallization to afford the final product.
(Z)-3-Benzylideneisoindolin-1-one (3aa):[9c] 2-Iodobenzoic
acid (744 mg, 3.0 mmol) and phenylpropiolic acid (482 mg,
3.3 mmol) afforded 3aa as an off-white solid; yield: 537 mg
(2.4 mmol, 81%); mp 182–1858C; 1H NMR (300 MHz,
CDCl3): d=8.59 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.77 (d,
J=7.7 Hz, 1H), 7.61 (m, 1H), 7.54- 7.38 (m, 5H), 7.30 (m,
1H), 6.53 (s, 1H); 13C NMR (75 MHz, CDCl3): d=168.8,
138.1, 135.0, 133.1, 132.3, 129.3, 129.2, 128.6, 128.4, 127.7,
123.6, 119.8, 105.8.
Scheme 8. Proposed reaction pathways.
2-iodobenzamide (10), was not observed when 2-iodo-
benzoic acid (1a) and NH4OAc were allowed to react
in the absence of phenylpropiolic acid [Scheme 7 (c)].
Based on these results, we propose the reaction
pathways as shown in Scheme 8.
In the absence of NH4OAc, the path A is a major
pathway to produce isocoumarin 7. And isoquinolin-
1-one 4 was formed through an amine substitution re-
action after adding NH4OAc. In the presence of
NH4OAc, path B, which is a concerted three-compo-
nent reaction pathway, might be a major pathway to
give isoindolin-1-one 4. However, we do not rule out
(Z)-3-(4-Methylbenzylidene)isoindolin-1-one (3ab):[9c] 2-
Iodobenzoic acid (744 mg, 3.0 mmol) and 3-para-tolylpro-
piolic acid (529 mg, 3.3 mmol) afforded 3ab as an off-white
solid; yield: 529 mg (2.2 mmol, 75%); mp 206–2088C;
1H NMR (300 MHz, CDCl3): d=8.38 (s, 1H), 7.87 (d, J=
7.5 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.62 (t, J=7.5 Hz,
1H), 7.50 (t, J=7.4 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.24
(d, J=8.1 Hz, 2H), 6.53 (s, 1H), 2.39 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=169.4, 138.7, 138.2, 132.8, 132.6, 132.4,
130.3, 129.4, 129.0, 128.8, 123.9, 120.1, 106.5, 21.7.
(Z)-3-(3-Methylbenzylidene) isoindolin-1-one (3ac): 2-Io-
path C in which the amide formation is the first step. dobenzoic acid (744 mg, 3.0 mmol) and 3-meta-tolylpropiolic
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Copper-Catalyzed Selective Synthesis of Isoindolin-1-ones and Isoquinolin-1-one
acid (529 mg, 3.3 mmol) afforded 3ac as an off-white solid;
yield: 494 mg (2.1 mmol, 70%); mp: 201–2048C; 1H NMR
(300 MHz, CDCl3): d=8.34 (s, 1H), 7.90 (m, 1H), 7.79 (m,
1H), 7.64 (m, 1H), 7.52 (m, 1H), 7.35–7.30 (m, 2H), 7.13 (d,
J=7.5 Hz, 1H), 6.54 (s, 1H), 2.42 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=168.9, 139.0, 138.2, 134.9, 132.9, 132.5,
132.2, 129.1, 128.9, 128.7, 128.5, 125.7, 123.5, 119.7, 106.1,
21.5; HR-MS (APCI): m/z=236.1072, calcd. for C16H14NO
[M+H]+: 236.1075.
132.2, 131.7, 129.8, 128.9, 128.5, 127.4, 123.6, 119.6, 114.8,
105.9, 55.4.
(Z)-3-(Naphthalen-2-ylmethylene)isoindolin-1-one
(3ai):[9c] 2-Iodobenzoic acid (744 mg, 3.0 mmol) and 3-(naph-
thalen-2-yl)propiolic acid (647 mg, 3.3 mmol) afforded 3ai as
an off-white solid; yield: 472 mg (1.7 mmol, 58%); mp 223–
1
2258C; H NMR (300 MHz, CDCl3): d=8.11–8.05 (m, 1H),
7.97–7.82 (m, 5H), 7.70 (m, 1H), 7.61–7.52 (m, 5H), 7.09 (s,
1H); 13C NMR (75 MHz, CDCl3): d=168.4, 137.6, 134.7,
133.9, 132.3, 131.8, 131.6, 129.4, 129.2, 128.8, 128.6, 126.6,
126.4, 125.6, 124.4, 123.6, 120.0, 103.4.
(Z)-3-(3,5-Dimethylbenzylidene)isoindolin-1-one (3ad): 2-
Iodobenzoic acid (744 mg, 3.0 mmol) and 3-(3,5-dimethyl-
phenyl) propiolic acid (575 mg, 3.3 mmol) afforded 3ad as
a pale yellow solid; yield: 523 mg (2.1 mmol, 70%); mp 237–
(Z)-3-(Thiophen-2-ylmethylene)isoindolin-1-one (3aj):[6b]
2-Iodobenzoic acid (744 mg, 3.0 mmol) and 3-(thiophen-2-
yl)propiolic acid (502 mg, 3.3 mmol) afforded 3aj as an off-
white solid; yield: 464 mg (2.0 mmol, 68%); mp 144–1488C;
1H NMR (300 MHz, CDCl3): d=8.03 (s, 1H), 7.90 (m, 1H),
7.75 (m, 1H), 7.63 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H),
7.15 (m, 1H), 7.11 (m, 1H), 6.72 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=168.3, 138.0, 138.1, 132.3, 131.5, 129.1,
128.5, 128.1, 127.9, 126.2, 123.8, 119.6, 99.3.
1
2408C; H NMR (300 MHz, CDCl3): d=7.96 (s, 1H), 7.90
(m, 1H), 7.81 (m, 1H), 7.64 (m, 1H), 7.51 (m, 1H), 7.31 (d,
J=8.4 Hz, 1H), 7.07 (d, J=6.6 Hz, 2H), 6.58 (s, 1H), 2.35
(s, 6H); 13C NMR (75 MHz, CDCl3): d=168.6, 137.9, 137.8,
136.8, 133.0, 132.1, 131.6, 130.7, 129.0, 129.9, 128.1, 127.2,
123.5, 119.8, 104.6, 21.2, 19.9; HR-MS (APCI): m/z=
250.1230, calcd. for C17H16NO [M+H]+: 250.1232.
(Z)-3-(4-Fluorobenzylidene) isoindolin-1-one (3ak):[8d] 2-
Iodobenzoic acid (744 mg, 3.0 mmol) and 3-(4-fluorophe-
nyl)propiolic acid (532 mg, 3.3 mmol) afforded 3ak as an
off-white solid; yield: 474 mg (2.0 mmol, 66%); mp 242–
(Z)-3-(4-tert-Butylbenzylidene)isoindolin-1-one (3ae): 2-
Iobenzoic acid (744 mg, 3.0 mmol) and 3-(4-tert-butylphe-
nyl)propiolic acid (667 mg, 3.3 mmol) afforded 3ae as an
off-white solid; yield: 507 mg (1.8 mmol, 61%); mp 245–
1
2458C; H NMR (300 MHz, CDCl3): d=8.05 (s, 1H), 7.89
1
2488C; H NMR (300 MHz, CDCl3): d=8.07 (s, 1H), 7.85
(d, J=7.5 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.66 (m, 1H),
7.55 (m, 1H), 7.47 (m, 1H), 7.30 (m, 1H), 7.20–7.15 (m,
2H), 6.56 (s, 1H); 13C NMR (75 MHz, CDCl3): d=168.6,
(m, 1H), 7.77 (m, 1H), 7.61 (m, 1H), 7.50 (m, 1H), 7.47–
7.42 (m, 2H), 7.39–7.33 (m, 2H), 6.53 (s, 1H), 1.33 (s, 9H);
13C NMR (75 MHz, CDCl3): d=168.8, 151.0, 138.2, 132.6,
132.2, 132.1, 129.1, 128.6, 128.2, 126.2, 123.5, 119.7, 105.9,
34.7, 31.2; HR-MS (APCI): m/z=278.1545, calcd. for
C19H20NO [M+H]+: 278.1545.
(Z)-3-(4-Butylbenzylidene)isoindolin-1-one (3af): 2-Iodo-
benzoic acid (744 mg, 3.0 mmol) and 3-(4-butylphenyl)pro-
piolic acid (667 mg, 3.3 mmol) afforded 3af as an off-white
solid; yield: 448 mg (1.6 mmol, 54%); mp 126–1288C;
1H NMR (300 MHz, CDCl3): d=8.34 (s, 1H), 7.91–7.85 (m,
1H), 7.78 (m, 1H), 7.63 (m, 1H), 7.50 (m, 1H), 7.37 (d, J=
8.0 Hz, 2H), 7.23 (s, 1H), 6.54 (s, 1H), 2.64 (m, 2H), 1.62
(m, 2H), 1.37 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=168.9, 142.8, 138.3, 132.4, 132.3, 132.1,
129.3, 128.9, 128.6, 128.4, 123.5, 119.7, 106.1, 35.4, 33.5, 22.3,
13.9; HR-MS (APCI): m/z=278.1545, calcd. for C19H20NO
[M+H]+: 278.1545.
159.8 (d, JC,F =246.8 Hz), 138.0, 134.2, 132.4, 129.8 (d, JC,F
=
24.2 Hz), 129.7 (d, JC,F =26.1 Hz), 129.4, 128.8, 124.8 (d,
J
J
C,F =3.5 Hz), 123.6, 122.7 (d, JC,F =14.2 Hz), 120.0, 116.2 (d,
C,F =22.2 Hz), 98.6 (d, JC,F =3.1 Hz).
(Z)-3-(3-Chlorobenzylidene)isoindolin-1-one (3al):[6b] 2-
Iodobenzoic acid (744 mg, 3.0 mmol) and 3-(3-chlorophe-
nyl)propiolic acid (596 mg, 3.3 mmol) afforded 3al as an off-
white solid; yield: 598 mg (2.3 mmol, 78%); mp 202–2058C;
1H NMR (300 MHz, CDCl3): d=8.47 (s, 1H), 7.90 (d, J=
7.5 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.66 (m, 1H), 7.55 (m,
1H), 7.47 (s, 1H), 7.39–7.32 (m, 2H), 7.30 (m, 1H), 6.48 (s,
1H); 13C NMR (75 MHz, CDCl3): d=169.1, 137.9, 136.7,
135.2, 134.0, 132.4, 130.4, 129.6, 128.7, 128.3, 127.7, 126.6,
123.7, 119.8, 104.3.
(Z)-3-(4-Chlorobenzylidene)isoindolin-1-one (3am):[9c] 2-
Iodobenzoic acid (744 mg, 3.0 mmol) and 3-(4-chlorophenyl)
propiolic acid (596 mg, 3.3 mmol). afforded 3am as an off-
white solid; yield: (29 mg (2.1 mmol, 69%); mp 228–2318C;
1H NMR (300 MHz, CDCl3): d=8.03 (s, 1H), 7.90 (m, 1H),
7.75 (m, 1H), 7.63 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H),
7.18 (m, 1H), 7.11 (m, 1H), 6.72 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=168.9, 138.0, 134.3, 133.5, 133.4, 132.4,
129.6, 129.4, 128.6, 123.7, 123.6, 119.8, 104.5.
(Z)-3-(3-Methoxybenzylidene)isoindolin-1-one (3ag):[9c] 2-
Iodobenzoic acid (744 mg, 3.0 mmol) and (581 mg,
3.3 mmol) 3-(2-methoxyphenyl)propiolic acid afforded 3ag
as a pale yellow solid; yield: 490 mg (2.0 mmol, 65%); mp
141–1448C; 1H NMR (300 MHz, CDCl3): d=8.07 (s, 1H),
7.90 (m, 1H), 7.79 (m, 1H), 7.65 (m, 1H), 7.53 (m, 1H),
7.35 (m, 1H), 7.05 (m, 1H), 6.95 (m, 1H), 6.85 (m, 1H),
6.53 (s, 1H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
169.2, 160.6, 138.5, 136.7, 133.7, 132.7, 130.7, 129.7, 129.1
124.0, 121.1, 120.2, 114.5, 113.6, 106.2, 55.8.
3-Methyleneisoindolin-1-one (3an):[6b] 2-Iodobenzoic acid
(744 mg, 3.0 mmol) and acetylenedicarboxylic acid (429 mg,
3.3 mmol) afforded 3an as a colorless oil; yield: 309 mg
(2.1 mmol, 71%); 1H NMR (300 MHz, CDCl3): d=9.28 (s,
1H), 7.90 (m, 1H), 7.7 (m, 1H), 7.61 (m, 1H), 7.52 (m, 1H),
5.22 (d, J=1.9 Hz, 1H), 5.05 (d, J=2.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=169.5, 139.9, 137.1, 132.1, 130.1, 129.4,
123.2, 120.2, 90, 39.3.
(Z)-3-(4-Methoxybenzylidene)isoindolin-1-one (3ah):[9c] 2-
Iodobenzoic acid (744 mg, 3.0 mmol) and 3-(4-methoxyphe-
nyl)propiolic acid (582 mg, 3.3 mmol) afforded 3ah as a pale
yellow solid; yield: 445 mg (1.8 mmol, 59%); mp 197–
1
2008C; H NMR (300 MHz, CDCl3): d=8.07 (s, 1H), 7.87
(m, 1H), 7.77 (m, 1H), 7.63 (m, 1H), 7.50 (m, 1H), 7.35–
7.31 (m, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.52 (s, 1H), 3.86 (s,
3H); 13C NMR (75 MHz, CDCl3): d=168.9, 159.2, 138.3,
(Z)-3-Benzylidene-7-methoxy)isoindolin-1-one (3ba): 2-
Iodo-6-methoxybenzoic acid (834 mg, 3.0 mmol) and 3-phe-
nylpropiolic acid (482 mg, 3.3 mmol) afforded 3ba as an off-
Adv. Synth. Catal. 0000, 000, 0 – 0
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Francis Mariaraj Irudayanathan et al.
white solid; yield: 550 mg (2.2 mmol, 73%); mp 153–1568C;
General Procedure for Synthesis of 3-
1H NMR (300 MHz, CDCl3): d=8.08 (s, 1H), 7.68 (d, J=
8.5 Hz, 1H), 7.43 (d, J=4.5 Hz, 4H), 7.30–7.27 (m, 2H),
7.19 (m, 1H), 6.44 (s, 1H), 3.90 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=168.8, 161.0, 135.2, 132.9, 130.8, 130.2, 129.2,
128.3, 127.5, 121.1, 120.9, 105.8, 104.8, 55.8; HR-MS (APCI):
m/z=252.1027, calcd. for C16H14NO2 [M+H]+: 252.1025.
(Z)-7-Methoxy-3-(thiophen-2-ylmethylene)isoindolin-1-
one (3bj): 2-Iodo-6-methoxybenzoic acid (834 mg, 3.0 mmol)
and 3-(thiophen-2-yl)propiolic acid (502 mg, 3.3 mmol) af-
forded 3bj as an off-white solid; yield: 479 mg (1.9 mmol,
Phenylisoquinolin-1(2H)-ones
2-Iodobenzoic acid derivative (3.0 mmol), Cs2CO3 (2.9 g,
9.0 mmol), and copper iodide (57 mg, 0.3 mmol) were added
into a vial containing anhydrous DMSO (5 mL), followed by
addition of the appropriate alkynylcarboxylic acid derivative
(3.3 mmol). The suspension was stirred for 6 h at 1208C.
Ammonium acetate (347 mg, 4.5 mmol) was added to the re-
action mixture and reacted at 1208C for 6 h. After comple-
tion of the reaction, the mixture was poured into the ethyl
acetate (50 mL) and washed with water (2ꢁ25 mL), brine
(2ꢁ25 mL), then dried over Na2SO4. Evaporation of the sol-
vent under reduced pressure provided the crude product,
which was purified by column chromatography (hexane:E-
tOAc=9:1) or re-crystallization to afford the final product.
3-Phenylisoquinolin-1(2H)-one (4aa):[15c] 2-Iodobenzoic
acid (744 mg, 3.0 mmol) and phenylpropiolic acid (482 mg,
3.3 mmol) afforded 4aa as an off-white solid; yield: 497 mg
(2.24 mmol, 75%); mp 197–2008C; 1H NMR (300 MHz,
CDCl3): d=10.04 (s, 1H), 8.45 (m, 1H), 7.77 (m, 1H), 7.74
(m, 1H), 7.70 (m, 1H), 7.62 (d, J=7.0 Hz, 1H), 7.57–7.46
(m, 4H), 6.81 (s, 1H); 13C NMR (75 MHz, CDCl3): d=
163.8, 139.4, 138.3, 134.3, 132.9, 129.6, 129.2, 127.5, 126.7,
126.5, 126.1, 124.9, 104.3.
1
62%); mp 212–2158C; H NMR (300 MHz, CDCl3): d=8.00
(s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.42–7.31 (m, 2H), 7.17 (m,
1H), 7.13–7.02 (m, 2H), 6.59 (s, 1H), 3.90 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=168.5, 161.2, 138.5, 131.5, 131.1, 130.4,
128.3, 127.6, 125.9, 121.4, 121.2, 106.3, 98.6, 56.0; HR-MS
(APCI): m/z=259.0667, calcd. for C14H13NO2S [M+H]+:
259.0667.
(Z)-3-Benzylidene-6-methylisoindolin-1-one (3ca): 2-Iodo-
5-methylbenzoic acid (786 mg, 3.0 mmol) and 3-phenylpro-
piolic acid (482 mg, 3.3 mmol) afforded 3ca as an off-white
solid; yield: 459 mg (2.0 mmol, 65%); mp 207–2098C;
1H NMR (300 MHz, CDCl3): d=8.08 (s, 1H), 7.71–7.62 (m,
2H), 7.45 (m, 5H), 7.30 (m, 1H), 6.50 (s, 1H), 2.49 (s, 3H);
13C NMR (75 MHz, CDCl3): d=168.9, 139.7, 135.7, 135.2,
133.4, 133.2, 129.2, 128.9, 128.3, 127.5, 123.7, 119.6, 105.1,
21.6; HR-MS (APCI): m/z=236.1071, calcd. for C16H14NO
[M+H]+: 236.1075.
3-para-Tolylisoquinolin-1(2H)-one (4ab):[15c] 2-Iodobenzo-
ic acid (744 mg, 3.0 mmol) and 3-p-tolylpropiolic acid
(529 mg, 3.3 mmol) afforded 4ab as an off-white solid; yield:
550 mg (2.3 mmol, 78%); mp 215–2188C; 1H NMR
(300 MHz, CDCl3): d=10.35 (s, 1H), 8.40 (dd, J=8.0,
0.6 Hz, 1H), 7.67 (m, 3H), 7.58 (d, J=7.2 Hz, 1H), 7.47 (m,
1H), 7.32 (d, J=7.9 Hz, 2H), 6.76 (s, 1H), 2.43 (s, 3H);
13C NMR (75 MHz, CDCl3): d=163.9, 139.7, 139.6, 138.4,
132.7, 131.4, 129.9, 127.4, 126.4, 126.4, 125.9, 124.8, 103.7,
21.3.
(Z)-3-(2-Methoxybenzylidene)-6-methylisoindolin-1-one
(3co): 2-Iodo-5-methylbenzoic acid (786 mg, 3.0 mmol) and
3-(2-methoxyphenyl)propiolic acid 582 mg, 3.3 mmol) af-
forded 3cm as an off-white solid; yield: 517 mg (2.0 mmol,
1
65%); mp 223–2268C; H NMR (300 MHz, CDCl3): d=8.19
(s, 1H), 7.80–7.60 (m, 2H), 7.50–7.35 (m, 2H), 7.30 (m, 1H),
7.05–6.95 (m, 2H), 6.57 (s, 1H), 3.93 (s, 3H), 2.48 (s, 3H);
13C NMR (75 MHz, CDCl3): d=168.5, 156.4, 139.3, 135.9,
133.1, 133.1, 130.2, 129.1, 124.0, 123.6, 122.8, 121.3, 119.7,
111.6 (s), 101.5, 55.8, 21.6; HR-MS (APCI): m/z=266.1180,
calcd. for C17H16NO2 [M+H]+: 266.1181.
3-meta-Tolylisoquinolin-1(2H)-one (4ac):[15c] 2-Iodobenzo-
ic acid (744 mg, 3.0 mmol) and 3 m-tolylpropiolic acid
(529 mg, 3.3 mmol) afforded 4ac as an off-white solid; yield:
459 mg (1.94 mmol, 65%); mp: 209–2158C; 1H NMR
(300 MHz, CDCl3): d=9.19 (s, 1H), 8.40 (d, J=8.0 Hz, 1H),
7.66 (m, 1H), 7.57–7.60 (m, 3H), 7.52 (m, 1H), 7.32 (d, J=
8.0 Hz, 2H), 6.74 (s, 1H), 2.43 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=168.9, 139.0, 138.2, 134.9, 132.9, 132.5, 132.2,
129.1, 128.9, 128.7, 128.5, 125.7, 123.5, 119.7, 106.1, 21.5.
3-(2-Fluorophenyl)isoquinolin-1(2H)-one (4ap): 2-Ioben-
zoic acid (744 mg, 3.0 mmol) and 3-(2-fluorophenyl) propiol-
ic acid (532 mg, 3.3 mmol) afforded 4ap as an off-white
solid; yield: 467 mg (1.95 mmol, 65%); mp 215–2178C;
1H NMR (300 MHz, CDCl3): d=8.07 (s, 1H), 7.85 (m, 1H),
7.77 (m, 1H), 7.61 (m, 1H), 7.50 (m, 1H), 7.47–7.42 (m,
2H), 7.39–7.33 (m, 2H), 6.53 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=162.9, 159.6 (d, JC,F =248.4 Hz), 137.8, 134.3,
132.9, 131.3 (d, JC,F =8.7 Hz), 129.2 (d, JC,F =2.7 Hz), 127.5,
(Z)-3-Benzylidene-6-fluoroisoindolin-1-one
(3da):
5-
Fluoro-2-iodobenzoic acid (798 mg, 3.0 mmol) and phenyl-
propiolic acid (482 mg, 3.3 mmol) afforded 3da as an off-
white solid; yield: 337 mg (1.4 mmol, 47%); mp: 201–2048C;
1H NMR (300 MHz, CDCl3): d=8.48 (s, 1H), 7.76 (m, 1H),
7.54 (s, 1H), 7.45 (d, J=4.5 Hz, 4H), 7.31–7.35 (m, 2H),
6.51 (s, 1H); 13C NMR (75 MHz, CDCl3): d=167.8, 165.0 (d,
J
C,F =248.5 Hz), 134.7, 134.0, 132.2, 130.7, 129.2, 128.4, 127.8,
121.7 (d, JC,F =8.7 Hz), 120.1 (d, JC,F =24.4 Hz), 110.1 (d,
J
C,F =23.7 Hz), 106.2; HR-MS (APCI): m/z=240.0825,
calcd. for C15H11FNO [M+H]+: 240.0825.
(Z)-3-Benzylidene-5-chloroisoindolin-1-one
(3ea):
4-
chloro-2-iodobenzoic acid (847 mg, 3.0 mmol) and phenyl-
propiolic acid (482 mg, 3.3 mmol) 3ea as an off-white solid;
yield: 405 mg (1.6 mmol, 53%); mp 148–1518C; 1H NMR
(300 MHz, CDCl3): d=10.27 (s, 1H), 8.32 (d, J=8.4 Hz,
1H), 7.71–7.74 (m, 2H), 7.49–7.59 (m, 4H), 7.41 (m, 1H),
6.69 (s, 1H); 13C NMR (75 MHz, CDCl3): d=163.2, 141.0,
140.8, 139.6, 139.3, 133.9, 129.9, 129.7, 129.3, 127.1, 126.2,
125.7 103.2; HR-MS (APCI): m/z=256.0529, calcd. for
C15H11ClNO [M+H]+: 256.0529.
127.2, 126.7, 125.2, 125.1 (d, JC,F =3.6 Hz), 122.0 (d, JC,F
=
11.6 Hz), 116.8 (d, JC,F =22.2 Hz), 106.8 (d, JC,F =3.4 Hz);
HR-MS (APCI): m/z=240.0822, calcd. for C15H11FNO [M+
H]+: 240.0825.
3-(4-Bromophenyl)isoquinolin-1-one (4aq):[15c] 2-Iodoben-
zoic acid (744 mg, 3.0 mmol) and 3-(4-bromophenyl)propiol-
ic acid (746 mg, 3.3 mmol) afforded 4aq as a pale yellow
solid; yield: 612 mg (2.03 mmol, 68%); mp 258–2628C;
1H NMR (300 MHz, CDCl3): d=10.63 (s, 1H), 8.40 (d, J=
8
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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FULL PAPERS
Copper-Catalyzed Selective Synthesis of Isoindolin-1-ones and Isoquinolin-1-one
7.9 Hz, 1H), 7.69 (m, 1H), 7.59–7.62 (m, 4H), 7.50–7.47 (m,
2H), 6.82 (s, 1H), 7.59–7.62 (m, 4H), 7.50–7.47 (m, 2H),
6.82 (s, 1H);13C NMR (75 MHz, CDCl3): d=165.3, 138.4,
138.2, 133.4, 132.7, 132.4, 131.8, 127.8, 127.4, 127.2, 126.6,
123.9, 105.7.
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3-(4-Chlorophenyl)isoquinolin-1(2H)-one (4ar):[15c] 2-Io-
dobenzoic acid (744 mg, 3.0 mmol) and (581 mg, 3.3 mmol)
3-(4-chlorophenyl)propiolic acid afforded 4ar as an off-
white solid; yield: 567 mg (2.2 mmol, 74%); mp 241–2438C;
1H NMR (300 MHz, DMSO-d6): d=11.57 (s, 1H), 8.21 (m,
1H), 7.83–7.79 (m, 2H), 7.73–7.71 (m, 2H), 7.60–7.55 (m,
2H), 7.50 (m, 1H), 6.95 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=162.7, 138.8, 137.7, 133.9, 132.7, 132.6, 128.7,
128.5, 126.8, 126.6, 126.4, 124.9, 103.6.
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Acknowledgements
This research was supported by Basic Science Research Pro-
gram through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (NRF-2012R1A1B3000871). Spectral data were
obtained from the Korea Basic Science Institute, Gwangju
branch.
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Copper-Catalyzed Selective Synthesis of Isoindolin-1-ones
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Coupling of 2-Halobenzoic Acid, Alkynylcarboxylic Acid
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Francis Mariaraj Irudayanathan, Jieun Noh, Jinseop Choi,
Sunwoo Lee*
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