A simple access to N-(un)substituted isoquinolin-1(2H)-ones: Unusual formation of regioisomeric isoquinolin-1(4H)-ones

Article abstract of DOI:10.1039/c4cc01580k

A ligand/additive/Pd-free Cu-mediated coupling/cyclization strategy afforded the first practical, one-pot and general approach towards synthesis of N-(un)substituted isoquinolin-1(2H)-ones. Both the catalyst and the solvent used are recyclable. The use of the Cu reagent in excess led to the unusual formation of regioisomeric and uncommon isoquinolin-1(4H)-ones. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01580k

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A simple access to N-(un)substituted isoquinolin-
1(2H)-ones: unusual formation of regioisomeric
isoquinolin-1(4H)-ones†
Cite this: Chem. Commun., 2014,
50, 6797
Received 2nd March 2014,
Accepted 6th May 2014
R. Gangadhara Chary,ab G. Dhananjaya,a K. Vara Prasad,a S. Vaishaly,a
Y. S. S. Ganesh,a Balakrishna Dulla,c K. Shiva Kumarc and Manojit Pal*c
DOI: 10.1039/c4cc01580k
www.rsc.org/chemcomm
A ligand/additive/Pd-free Cu-mediated coupling/cyclization strategy cyclization include the use of a base,6 an electrophile,7 or a
afforded the first practical, one-pot and general approach towards transition-metal catalyst.6,8 However, the lack of regioselectivity
synthesis of N-(un)substituted isoquinolin-1(2H)-ones. Both the due to the 5-exo vs. 6-endo cyclization and chemoselectivity due
catalyst and the solvent used are recyclable. The use of the Cu to the nucleophilicity of both the O- and N-atoms of the amide
reagent in excess led to the unusual formation of regioisomeric moieties (involved in these cyclizations) often afforded a mix-
and uncommon isoquinolin-1(4H)-ones.
ture of products in several cases (Scheme 1). While a chemo-
selective synthesis of isoquinolin-1(2H)-ones has been achieved
While the transition metal-catalyzed addition of an N–H bond via Pd-catalyzed cyclization of N-alkoxy-o-alkynylbenzamides,9
across the C–C triple bond affords various N-heterocycles,1 the methodology involved the use of 20 mol% of an expensive
several of these methods suffer from limitations, e.g., the lack Pd-catalyst along with the large excess (500 mol%) of p-benzo-
of generality and regioselectivity, the use of expensive or toxic quinone. Additionally, this 2-step methodology is not suitable
catalysts, ligands/additives and solvents, complicated operational for the preparation of N-unsubstituted isoquinolin-1(2H)-ones.
procedures, etc. Thus, development of simple, green and sustainable Herein we report the first Cu-mediated single-step coupling/
methodologies is in high demand.
cyclization of 2-iodobenzamide derivatives (1) with terminal
In view of the widespread occurrences of isoquinolin-1(2H)- alkynes (2) leading to a green and general approach towards
one frameworks in natural products2,3 (Fig. 1) and many bioactive N-(un)substituted isoquinolin-1(2H)-ones (3) (Scheme 2)
compounds4 a range of synthetic methods5 have been reported with remarkable chemo- and regioselectivities.10 We also
including the transition metal-catalyzed reactions.5a–j Since the
intramolecular cyclization of 2-alkynylbenzamides (generally
obtained via an additional step, e.g., Sonogashira coupling)
appeared as a potential strategy for the direct synthesis of
isoquinolin-1(2H)-ones, hence considerable efforts have been
devoted in this direction. Various conditions employed for this
Scheme 1 Intramolecular cyclization of 2-alkynyl benzamide.
Fig. 1 Natural products containing the isoquinolin-1(2H)-one core.
a Custom Pharmaceutical Services, Dr Reddy’s Laboratories Limited, Bollaram Road
Miyapur, Hyderabad 500 049, India
b Chemistry Division, JNT University, Kukatpally, Hyderabad 500085,
Andhra Pradesh, India
c Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com;
Tel: +91 40 6657 1500
† Electronic supplementary information (ESI) available: Experimental procedures,
Scheme 2 Cu-mediated synthesis of isoquinolin-1(2H)-ones and isoquinolin-
1(4H)-ones.
spectral data for all new compounds, copies of spectra. See DOI: 10.1039/c4cc01580k
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Table 1 Effect of reaction conditions on the coupling of 1b with 2aa
To establish the optimized reaction conditions the coupling
of 2-iodo-N-(4-methoxyphenyl)benzamide (1b) with phenyl acetylene
(2a) was performed in the presence of a range of Cu catalysts and
Cs2CO3 in PEG-400. Due to its polar nature, nontoxic properties and
high boiling point the PEG has several advantages over the other
conventional organic solvents.
Moreover, it is less expensive and recyclable. Initially, the use of
CuCl and CuBr was found to be ineffective (entries 1 and 2, Table 1)
whereas CuI afforded the uncyclized intermediate 5 (entry 3, Table 1).
The use of anhydrous Cu(OAc)2 however afforded the expected
isoquinolin-1(2H)-one 3i (entry 4, Table 1) within 2 h. All these
reactions were carried out using 20 mol% of the catalyst. While the
reaction proceeded in the presence of 10 or 5 mol% of catalysts
(entries 5 and 6, Table 1), the product yield was decreased significantly
in these cases. The product yield was also decreased when Cu(OAc)2Á
2H2O or Cu(OAc)2ÁH2O was used (entries 7 and 8, Table 1). The use of
other bases such as Na2CO3 or K2CO3 (entries 9 and 10, Table 1) was
examined but found to be less effective. The use of other solvents, e.g.,
acetonitrile, 1,4-dioxane, DMF, DMSO and 1 : 1 PEG-H2O was also
found to be less effective. The recyclability of both Cu(OAc)2 and PEG-
400 was examined. The catalyst was recovered by filtration (after
diluting the reaction mixture with EtOAc) followed by drying and
Entry
Catalyst
Base
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
CuCl
CuBr
CuI
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2Á2H2O
Cu(OAc)2ÁH2O
Cu(OAc)2
Cu(OAc)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
72
65
70
2
0
0
80c
82 (79, 75, 73)d
4
72e
50 f
19
12
12
12
6
33
12
30
8
a
All the reactions were carried out by using 2-iodobenzamide 1b
(1.0 mmol), phenyl acetylene 2a (1.0 mmol), a base (2.0 mmol), and a catalyst
(0.2 mmol) in PEG-400 (5.0 mL) at 80–90 1C under nitrogen. b Isolated yields.
c Yield of compound 5. d Yields after recovery and reuse of the catalyst after
the 1st (2.2 h), 2nd (2.4 h) and 3rd (2.5 h) recycle, respectively. e 0.1 mmol of
the catalyst was used. f 0.05 mmol of the catalyst was used.
report the unusual formation of regioisomeric isoquinolin- then recycled three times (entry 4, Table 1) without affecting the
1(4H)-ones (4) in the presence of excess of the same Cu reagent product yield significantly. Similarly, the PEG-400 recovered (by dilut-
(Scheme 2).
ing the filtrate with cold water, collecting the aqueous layer and
Table 2 Cu-mediated synthesis of isoquinolin-1(2H)-ones (3)a
Entry
Iodoamide (1); R1 & R2
=
Alkyne (2); R3
–C6H5; 2a
–C6H4(C5H11-n)-p; 2b
–C6H13-n; 2c
–(CH2)2CH2Cl; 2d
–C6H4Br-p; 2e
–C6H4(OC5H11-n)-p; 2f
–C6H4CH3-p; 2g
=
Time (h)
Product (3)
Yieldb (%)
1
2
3
4
5
6
7
H & –C6H3Me2-m,m; 1a
3
3
3
4
4
4
4
3a
3b
3c
3d
3e
3f
81
76
68
71
83
79
75
1a
1a
1a
1a
1a
1a
3g
8
1a
4
3h
68
9
H & –C6H4OMe-p; 1b
1b
1b
1b
1b
1b
H & –C6H5; 1c
Cl & –C6H4OMe-p; 1d
OMe & –C6H4OMe-p; 1e
–C6H5; 2a
–C6H4(C5H11)-p; 2b
–C6H13-n; 2c
–C6H4Br-p; 2e
–C6H4(OC5H11-n)-p; 2f
–C6H4Me-p; 2g
–C6H4(C5H11-n)-p; 2b
–C6H4(C5H11-n)-p; 2b
–C6H4(C5H11-n)-p; 2b
3
3
3
3
4
4
3
3
3
3i
3j
82
77
75
82
79
73
56
63
73
10
11
12
13
14
15
16
17
3k
3l
3m
3n
3o
3p
3q
18
H & H; 1f
3
3r
93
19
20
21
1f
1f
1f
–C6H4Me-p; 2g
–C6H4(C5H11-n)-p; 2b
2e
3
3
3
3s
3t
3u
84
87
83
a
All the reactions were carried out by using 1 (1.0 mmol), terminal 2 (1.0 mmol), Cs2CO3 (2.0 mmol), and anhyd Cu(OAc)2 (0.2 mmol) in PEG-400
b
(5.0 mL) at 80–90 1C under nitrogen. Isolated yields.
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Scheme 3 Synthesis of isoquinolin-1(4H)-ones (4).
Fig. 2 Appearance of olefinic protons of 3c, 3d and 3k in 1H NMR.
were prepared by reacting 1f with 2 in the presence of 2.0 equiv.
of Cu(OAc)2 (Scheme 3). Notably, as a class these compounds
are not common in the literature.12b
distilling off the contaminated water under vacuum) was recycled
three times affording product 3i in 80, 78 and 76% yields, respectively.
Overall, the combination of 20 mol% of anhydrous Cu(OAc)2 and
2 equiv. of Cs2CO3 in PEG-400 was found to be optimum and used to
expand the generality and scope of this methodology further.
The proposed reaction mechanism (Scheme 4) leading to 3
involved the generation of an active catalyst A [via the interaction of
Cu(OAc)2 with PEG] that facilitated the formation of C via B with the
regeneration of A (the coupling step).13 The intramolecular cyclization
of C14 was then facilitated by A to afford 3 with the regeneration of A
(the cyclization step). The 5-exo-dig cyclization10 was not favored
perhaps due to the possible steric crowding between the bulky Cu
species and R3 in the corresponding 5-membered ring intermediate.
Though not clearly understood, the formation of 4 could be due to the
intramolecular addition of an amide anion to the alkyne during the
coupling reaction (Scheme 5). In a separate study, the 2-iodo-N,N-
dimethylbenzamide (1g) was coupled with alkyne 2c (Scheme 6) under
the conditions given in Scheme 3 when the product was trapped as a
normal Sonogashira product 6 indicating that the reaction might be
A variety of isoquinolin-1(2H)-ones (3) were synthesized by using
this Pd-free Cu-mediated method (Table 2). Both N-substituted
(3a–q) and unsubstituted derivatives (3r–u) were obtained in a single
step without involving any N-deprotection step5i,9 for compounds
3r–u. All the synthesized isoquinolin-1(2H)-ones (3) were character-
ized by using NMR, IR, and HRMS spectra.11 For example, com-
pounds 3c, 3d and 3k contain a –CH2– group next to the double
bond of the heterocyclyl ring (Fig. 2). In the case of the endocyclic
double bond (6-membered ring), the olefinic proton does not couple
with the protons of the –CH2– group and therefore appears as a
singlet near d 6.0. However, in the case of the exocyclic double bond
(5-membered ring), the vinylic hydrogen being next to the –CH2–
group is known to couple with these protons to give a triplet near d
5.2, as observed by Kundu et al.6 This was not observed in the case of
3c, 3d and 3k. Additionally, the gHMBC (gradient heteronuclear
multiple bond coherence) NMR study11 of 3i (Fig. 3) shows that
its olefinic proton has a cross peak with an aromatic C–H
(appearing near 130 ppm) in addition to two other cross peaks
with aromatic quaternary carbons. This is not possible in the
case of the corresponding regioisomeric isoindolin-1-one derivative
as its olefinic proton would show three cross peaks with three
aromatic quaternary carbons. Nevertheless, compound 3u was
further functionalized via a Suzuki coupling with naphthalen-2-
ylboronic acid to give 3-(4-(naphthalen-2-yl)phenyl)isoquinolin-
1(2H)-one (6) in 80% yield (see ESI†).
During our studies on the coupling of 2-iodobenzamide (1f)
with a terminal alkyne we observed formation of a different
product exclusively when the reaction was performed in the
presence of excess of Cu(OAc)2. This new product characterized
as a regioisomeric isoquinolin-1(4H)-one derivative prompted
us to examine this reaction further. Thus, six derivatives12a (4)
Scheme 4 Proposed reaction mechanism leading to compound 3.
Fig. 3 Cross peaks shown by the olefinic proton of 3i in the gHMBC NMR
study (see ESI†).
Scheme 5 Proposed reaction mechanism leading to compound 4.
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3 G. R. Pettit, Y. H. Meng, D. L. Herald, K. A. N. Graham, R. K. Pettit
and D. L. Doubek, J. Nat. Prod., 2003, 66, 1065.
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Scheme 6 Coupling of amide 1g with alkyne 2c.
´
´
5 (a) A. V. Fernandez, J. A. Varela and C. Saa, Synthesis, 2012, 3285;
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C. Li, J. Org. Chem., 2007, 72, 8555; (g) C. C. Liu, K. Parthasarathy and
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metal mediated method, see: D. Y. Li, X. S. Shang, G. R. Chen and
P. N. Liu, Org. Lett., 2013, 15, 3848.
Scheme 7 Coupling of amide 1c with alkyne 2b under the conditions
given in Scheme 3.
6 N. G. Kundu and M. W. Khan, Tetrahedron, 2000, 56, 4777.
7 T. Yao and R. C. Larock, J. Org. Chem., 2005, 70, 1432.
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104, 2285; (b) A. Nagarajan and T. R. Balasubramanian, Indian
J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 1989, 28, 67;
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9 M. Jithunsa, M. Ueda, N. Aoi, S. Sugita, T. Miyoshi and O. Miyata,
Synlett, 2013, 475.
10 Notably, 5-membered ring products (isoindolin-1-ones) were
obtained from microwave assisted coupling/cyclization of 2-bromo-
benzamides with arylacetylene, e.g. for Cu-free Pd-mediated
method, see: (a) M. Hellal and G. D. Cuny, Tetrahedron Lett., 2011,
52, 5508; For Pd-free Cu-mediated method, see: (b) L. Zhang,
Y. Zhang, X. Wang and J. Shen, Molecules, 2013, 18, 654; For
microwave and the Pd-free Cu-mediated method, see: (c) J. Pan,
Z. Xu, R. Zeng and J. Zou, Chin. J. Chem., 2013, 31, 1022, DOI:
10.1002/cjoc.201300346. See also ; (d) H. Cao, L. McNamee and
H. Alper, Org. Lett., 2008, 10, 5281; (e) L. Li, M. Wang, X. Zhang,
Y. Jiang and D. Ma, Org. Lett., 2009, 11, 1309 and ref. 6.
following the pathway shown in Scheme 5.15 Moreover, coupling of 1c
with 2b under the same conditions afforded 3o (Scheme 7) confirm-
ing the need for the –CONH2 (with no substituent on NH2) group to
afford a product that belongs to the isoquinolin-1(4H)-one class 4.15
The observation that compound 3s did not provide the corresponding
isoquinolin-1(4H)-one derivative when treated with 2 equiv. of
Cu(OAc)2 (under the conditions given in Scheme 3) ruled out the
possibility of formation of 4 via isomerization of 3.15
In conclusion, Cu-mediated coupling/cyclization of 2-iodobenz-
amides with terminal alkynes in PEG afforded N-(un)substituted
isoquinolin-1(2H)-ones instead of isoindolin-1-ones. The methodology
is Pd-free and does not require the use of any expensive reactants,
reagents or catalysts. Both the Cu-catalyst and the solvent are recycl-
able. We also report the unprecedented formation of regioisomeric
isoquinolin-1(4H)-ones in the presence of excess of the Cu reagent.
RGC thanks the management of DRL for encouragement and
the analytical group of DRL for spectral data. Authors thank Mr
Perla Ganesh of Aurigene Discovery Technologies, Hyderabad and
Shivashankar Sripelly and N. Sunil K. Reddy of DRILS, Hyderabad
for NMR studies. Authors also thank Dr Sarbani Pal, MNR degree &
PG College, Hyderabad for her valuable inputs and discussion.
11 For COSY, HSQC and HMBC spectra of 3i and HSQC and HMBC
spectra of 3a see the ESI†.
12 (a) The appearance of a peak near 4.0–4.5 d in the 1H NMR spectra
and 43.0–43.5 ppm in 13C NMR spectra indicated the presence of a
benzylic–CH2– moiety in compound 4 (see ESI†). For HSQC and
HMBC spectra of 4a see the ESI†; (b) see: CSID: 10551086, http://
www.chemspider.com/Chemical-Structure.10551086.html (accessed
13:54, Mar 1, 2014).
13 We propose a Cu(II)/Cu(IV) pathway for the conversion of 1 to C instead
of the Cu(I)/Cu(III) mechanism (that though can not be ruled out
completely, for a review, see: E. Perotto, G. P. M. van Klink, G. van
Koten and J. G. de Vries, Dalton Trans., 2010, 39, 10338) as the second
pathway is unable to explain the recovery and recyclability of the catalyst.
Notes and references
1 For selected and scholarly reviews, see: (a) I. Nakamura and 14 The intermediacy of C was further supported by the fact that alkyne
Y. Yamamoto, Chem. Rev., 2004, 104, 2127; (b) F. Alonso,
I. P. Beletskaya and M. Yus, Chem. Rev., 2004, 104, 3079;
(c) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873.
5 (1 mmol) upon treatment with Cu(OAc)2 (20 mol%) and Cs2CO3
(2 mmol) in PEG-400 (5 mL) at 80–90 1C for 2 h afforded the cyclized
product 3i in 45% yield.
2 V. A. Glushkov and Y. V. Shklyaev, Chem. Heterocycl. Compd., 2001, 15 We thank one of the reviewers for his suggestion to perform this
37, 663, and references cited therein.
experiment.
6800 | Chem. Commun., 2014, 50, 6797--6800
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