Platinum(II)-catalyzed intramolecular cyclization of alkynylbenzonitriles: Synthesis of 1-alkoxyisoquinolines and isoquinolones

Article abstract of DOI:10.1016/j.tetlet.2010.09.136

A facile synthesis of a series of 1-alkoxyisoquinolines and (2H)-isoquinolones by an intramolecular 6-endo-dig cyclization of ortho-alkynylbenzonitriles in the presence of a catalytic amount of hydrido(dimethylphosphinous acid-κP)[hydrogen bis(dimethylphosphinito- κP)]platinum(II) in various alcohols at 65-90 °C is described for the first time.

Full text of DOI:10.1016/j.tetlet.2010.09.136

Tetrahedron Letters 51 (2010) 6422–6425
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Tetrahedron Letters
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Platinum(II)-catalyzed intramolecular cyclization of alkynylbenzonitriles:
synthesis of 1-alkoxyisoquinolines and isoquinolones
⇑
Jim Li , Lijing Chen, Elbert Chin, Alfred S. Lui, Hasim Zecic
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of a series of 1-alkoxyisoquinolines and (2H)-isoquinolones by an intramolecular 6-
endo-dig cyclization of ortho-alkynylbenzonitriles in the presence of a catalytic amount of hydrido(dim-
Received 6 August 2010
Revised 23 September 2010
Accepted 27 September 2010
Available online 7 October 2010
ethylphosphinous acid-
jP)[hydrogen bis(dimethylphosphinito-jP)]platinum(II) in various alcohols at
65–90 °C is described for the first time.
Ó 2010 Elsevier Ltd. All rights reserved.
Isoquinolines and isoquinolones are a unique class of heterocy-
clic frameworks which are frequently found in many natural prod-
ucts, biologically active compounds, and clinical candidates.1–4 In
particular, the 1-alkoxyisoquinoline moiety is an essential compo-
nent of a class of potent hepatitis C virus (HCV) protease inhibi-
tors.3,4 There are extensive methodologies regarding the
synthesis of isoquinolines and isoquinolones available in the liter-
ature.5,6 Although there have been reports utilizing transition met-
iles in a catalysis manner under mild neutral conditions that have
not been reported before. Herein, we describe the first application
of platinum(II)-catalyzed regioselective intramolecular 6-endo-dig
cyclization of ortho-alkynylbenzonitriles that lead to isoquinoline
and isoquinolone rings under simple and mild neutral reaction
conditions illustrated in Scheme 1.
Our initial successful attempt for this transformation was con-
ducted with hydrido(dimethylphosphinous acid-jP)[hydrogen
O
P
P
H
OH
OR
O
H
Pt
N
O P
A
N
NH
R1
R2
R2
R2
+
ROH, heating
R1
R1
1
2
3
Scheme 1. Synthesis of 1-alkoxyisoquinolines 2 and isoquinolones 3 from ortho-alkynylbenzonitriles 1.
als for the construction of isoquinolines and isoquinolones,7
applications of platinum metal complexes involved in such cycliza-
tion transformations have not received much attention until re-
cently.8 Numerous examples reported in the literature describe
the use of metal complexes, such as Au, Ag, Pd, and Cu, to catalyze
cyclizations of arylalkynes bearing nucleophilic ortho-substitu-
tions.9–12 Platinum complexes are well known for their ability to
coordinate to an alkyne moiety and have the potential to initiate
the subsequent transformations.13 We reasoned that this Pt–
alkyne coordination feature would regioselectively direct an intra-
molecular ring cyclization with ortho-substituted nucleophilic
functionalities, such as nitriles, amides, acids, esters, and hydroxyl
groups. Applying this new approach, we studied the constructions
of isoquinolones and isoquinolones from ortho-alkynylbenzonitr-
bis(dimethylphosphinito-jP)]platinum(II) (A), which is a catalyst
used for hydrolyzing nitriles to primary amides under neutral con-
ditions.14 A mixture of ortho-CN-diphenylacetylene15,16 (1a) and
5 mol % of this Pt(II) catalyst in refluxing MeOH for 16 h afforded
18% of 1-methoxyisoquinoline 2a, 32% of methyl benzoate 4a,
and 27% of primary benzamide 5 (Table 1, entry 1). To our dismay,
only a trace amount of the isoquinolone 3a was observed in the
product mixture although none of the 5-exo-dig products were ob-
served. Both the reaction time and the catalyst loading influenced
the product formation during the preliminary studies. Increasing
the Pt(II) catalyst loading to 10 mol % not only improved both
yields of 1-methoxyisoquinoline 2a and isoquinolone 3a (26%
and 6%, respectively), but also produced less methyl benzoate 4a
and benzamide 5 (entry 2). Prolonging the reaction time by heating
1a with 10 mol % Pt(II) catalyst in MeOH from 16 to 48 h further
enhanced the yields of 1-methoxyisoquinoline 2a and isoquino-
lone 3a to 35% and 10%, respectively (entry 3). We observed that
⇑
Corresponding author. Tel.: +1 650 855 6972; fax: +1 650 852 1875.
E-mail address: jli@calithera.com (J. Li).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.136

J. Li et al. / Tetrahedron Letters 51 (2010) 6422–6425
6423
the formation of both isoquinolines 2a–2d and isoquinolone 3a
was inversely proportional to that of benzoate esters 4a–4d and
benzamide 5 in the product mixture.
were heated at reflux temperature in EtOH for 36 h. We believed
steric hindrance from the ortho-substitutions disfavored the re-
quired Pt–alkyne coordination step and hence prevented the sub-
Next, we investigated solvents other than MeOH for this reac-
tion. Results from the reactions with ortho-CN-diphenylacetylene
(1a) are summarized in Table 1. We initially found that polar sol-
vents such as MeOH worked well with 5–10 mol % Pt(II) catalyst
under reflux to afford 2a in 18–35% yield, accompanied by 2–10%
of 3a and 20–32% of 4a (entries 1–3). Elevating the reaction tem-
perature further enhanced this intramolecular cyclization. We ob-
served an increase in the overall yields of isoquinolines and
isoquinolones while the yield of benzamide diminished as the sol-
vent went from MeOH to cyclopentanol. Heating 1a with 10 mol %
of Pt(II) catalyst in EtOH for 16 h gave 48% of 1-ethoxyisoquinoline
2b, 15% of isoquinolone 3a and 20% of ethyl benzoate 4b (entry 4).
In addition, only a very small amount of benzamide 5 was observed
in the product mixture. Increasing the Pt(II) catalyst loading from
10 to 20 mol % only slightly improved the yields of 2b from 48%
to 52% and 3a from 15% to 20%, respectively (entry 5). Employing
bulkier i-PrOH was able to give the corresponding 1-isopropoxy-
isoquinoline 2c and isoquinolone 3a (45% and 17% yields, respec-
tively) after heating at reflux temperature for 16 h (entry 6).
Heating 1a in cyclopentanol at 90 °C for 16 h afforded 2-cyclopent-
oxyisoquinoline 2d and isoquinolone 3a in 41% and 20% yields,
respectively (entry 7).
sequent
intramolecular
cyclization.
The
intramolecular
cyclization of substrates with heteroaromatic rings, such as 3-pyr-
idyl (1i) and 3-thenyl (1j), also provided 1-ethoxyisoquinolines 2i
and 2j in 30% and 49% yields, and isoquinolones 3i and 3j in 12%
and 14% yields, respectively (entries 6 and 7). Substrate 1k bearing
a distal cyclohexyl group also gave the corresponding 1-ethoxyiso-
quinoline 2k and isoquinolone 3k in 43% and 19% yields,
respectively.
Next we examined the electronic effect of substitutions on the
backbone benzonitrile ring system (entries 9–15). Substrates with
an electron-poor system seemed to be more favorable toward this
intramolecular cyclization. Both benzonitriles 1l and 1m bearing
fluorine moieties afforded 1-ethoxyisoquinolines 2l and 2m (42%
and 37% yields, respectively) and isoquinolones 3l and 3m (ꢀ5%
and 11% yields, respectively) upon refluxing for 16 h in EtOH (en-
tries 9 and 10). In contrast, the intramolecular cyclizations of elec-
tron-rich benzonitriles 1n and 1o required longer reaction times of
48 and 24 h in refluxing EtOH to provide 1-ethoxyisoquinolines
(16% of 2n and 40% of 2o, respectively) and isoquinolones (<5%
of 3n and 16% of 3o, respectively). We also studied this intramolec-
ular cyclization of substrates with backbone heteroaromatic ring
(entries 13–14). Cyclization of 3-cyano-pyridine 1p occurred upon
refluxing in EtOH for 16 h to afford 32% of 1-ethoxyisoquinoline 2p
and 46% of isoquinolone 3p. Under the same conditions, 4-cyano-
pyridine 1q provided 24% of 1-ethoxyisoquinoline 2q and 13% iso-
quinolone 3q. In the case of 3p, the nitrogen atom in the pyridine
ring of 1p was either likely involved in coordination with the Pt–
alkyne complex or its electron-withdrawing nature made the car-
bon–carbon triple bond more electrophilic for the subsequent
nucleophilic addition of the amide group.
Once the desired reaction conditions17 [10 mol % of the Pt(II)
catalyst in refluxing EtOH] were established, we proceeded to
investigate the scope of this transformation for
a series of
ortho-alkynylbenzonitriles. This Pt(II)-catalyzed intramolecular
cyclization seemed to be generally applicable for various
substrates (Table 2). We first investigated the electronic and steric
effects of substituents on the distal group of the b-position on the
alkyne (entries 1–8). We found that electronic factors played a
small role for this ring cyclization process. Substrates (1e and 1f)
bearing both of electron-donating and electron-withdrawing sub-
stituents at the para-position gave the cyclized products in similar
yields (entries 2 and 3). However, both substrates (1g and 1h)
bearing an ortho-substituent with an electron-donating or a with-
drawing moiety (Me and Cl) provided nearly no cyclization reac-
The newly formed 1-alkoxyisoquinolines (2a–2q) can be fur-
ther converted into the corresponding isoquinolones (3a–3q) un-
der the acidic deprotection conditions illustrated in Scheme 2.
We demonstrated this transformation with 1-methoxyisoquino-
line (2a) and 1-ethoxyisoquinoline (2b) to the corresponding iso-
quinolone 3a in 97% and 92% yields respectively, upon heating
with 4 equiv of 48% HBr in acetic acid at 50 °C for 2 and 5 h,
respectively.18
tion at all (entries
4 and 5). The corresponding primary
benzamides were isolated as the major products after the reactions
Table 1
Effects of Pt(II) catalyst loading and solventsa
OR
O
O
O
Pt catalyst A
CN
ROH,heating
N
NH
OR
NH2
+
+
+
1a
2a - 2d
3a
4a - 4d
5a
Product yieldb (%)
Entry
1
Pt(II) catalyst (mol %)
Solvent
Temp (°C)
Time (h)
2
3
4
5
1
2
3
4
5
6
7
1a
1a
1a
1b
1b
1c
1d
5
10
10
10
20
10
10
MeOH
MeOH
MeOH
EtOH
EtOH
i-PrOH
Cyclopentanol
65
65
65
78
78
82
90
16
16
48
16
16
16
16
18
26
35
48
52
45
41
2
6
32
27
20
20
17
18
14
27
16
5c
10
15
20
17
20
<5c
<5c
<5c
0
a
b
c
All reactions were performed with benzonitrile substrates (100 mg) and Pt(II) catalyst in various alcohols (4 mL) at the indicated temperature and reaction time.
Isolation yields.
Based on the analysis of the crude product mixture.

6424
J. Li et al. / Tetrahedron Letters 51 (2010) 6422–6425
Table 2
1-Ethoxyisoquinolines and isoquinolones from Pt(II)-catalyzed intramolecular cyclizationa
O
P
P
H
OH
H
Pt
OEt
O
O P
CN
A
N
NH
R1
+
R2
R2
R2
X
X
X
EtOH, reflux
Y
Y
R1
Y
R1
1b - 1q
2b - 2q
3b - 3q
Entry
Alkyne
R1
R2
X
Y
Time (h)
Yieldb (%)
2
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1b
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
Ph
H
H
H
H
H
H
H
H
C
C
C
C
C
C
C
C
C
C
C
C
C
N
C
C
C
C
C
C
C
C
C
C
C
C
N
C
16
16
16
36
36
16
16
16
16
16
48
24
16
16
48
31
40
0c
15
6
p-MeO-C6H4–
p-F-C6H4–
o-CH3–C6H4–
o-Cl-C6H4–
3-Pyridyl
3-Thiophene
Cyclohexyl
Ph
Ph
Ph
Ph
Ph
5
0c
0d
5d
12
14
19
ꢀ5e
11
<5e
16
46
13
30
49
43
42
37
16
40
32
24
3-F
5-CF3
5-MeO
4-Me
H
Ph
H
a
b
c
All reactions were performed with benzonitrile substrates (100 mg) and Pt(II) catalyst (10 mol %) in refluxing EtOH (4 mL) for the indicated reaction time.
Isolation yields.
The corresponding primary benzamide 5g was isolated in 93% yield.
The corresponding primary benzamide 5h was isolated in 89% yield.
Based on analysis of the crude product mixture.
d
e
York, 1985; (c) Bentley, K. W.; Marrview, T.; Midmar, A. Nat. Prod. Rep. 2006, 23,
444.
OR
O
2. For recent examples, see: (a) Lee, S.-H.; Van, H. T. M.; Yang, S. H.; Lee, K.-T.;
Kwon, Y.; Cho, W.-J. Bioog. Med. Chem. Lett. 2009, 19, 2444; (b) Cinelli, M. A.;
Cordero, B.; Dexheimer, T. S.; Pommier, Y.; Cushman, M. Bioorg. Med. Chem.
2009, 17, 7145.
3. Gonzalez-Diaz, H.; Cruz-Monteagudo, M.; Vina, D.; Santana, L.; Uriarte, E.; De
Clercq, E. Bioorg. Med. Chem. Lett. 2005, 15, 1651.
4. Oertqvist, P.; Peterson, S. D.; Aakerblom, E.; Gossas, T.; Sabnis, Y. A.; Fransson,
R.; Lindeberg, G.; Danielson, U. H.; Karlen, A.; Sandstroem, A. Bioorg. Med. Chem.
2007, 15, 1448.
48% HBr, AcOH, 50 oC
N
NH
R1
R2
R2
X
X
Y
R1
Y
2
3
R = Me, Et, R1 = Ph, R2 = H, X = Y = C
Scheme 2. Synthesis of isoquinolones 3 from 1-alkoxyisoquinolines 2.
5. For recent reviews on synthesis, see: (a) Joule, J. A.; Mills, K. In Heterocyclic
Chemistry, 4th ed.; Blackwell Science Ltd: Oxford, 2000; (b) Alvarez, M.; Joule, J.
A. Isoquinolines In Science of Synthesis; Black, D., Ed.; Thieme: Germany, 2005;
Vol. 15, p 661; (c) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341.
In summary, we describe a facile route to regioselectively syn-
thesize both 1-alkoxyisoquinoline and isoquinolone skeletons from
various readily accessible ortho-alkynylbenzonitriles via hydri-
6. (a) Fisher, L. E.; Muchowski, J. M.; Clark, R. D. J. Org. Chem. 1992, 57, 2700; (b)
Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
do(dimethylphosphinous acid-
jP)[hydrogen bis(dimethylphosphi-
7. (a) Sakamoto, T.; Annaka, M.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1986,
34, 2754; (b) Nagarajan, A.; Balasubramanian, T. R. Indian J. Chem., Sect. B: Org.
Chem. 1989, 28, 67; (c) Batchu, V. R.; Barange, D. K.; Kumar, D.; Sreekanth, B. R.;
Vyas, K.; Reddy, E. A.; Pal, M. Chem. Commun. 2007, 19, 1966; (d) Niu, Y.-N.; Yan,
Z.-Y.; Gao, G.-L.; Wang, H.-L.; Shu, X.-Z.; Ji, K.-G.; Liang, Y.-M. J. Org. Chem. 2009,
74, 2893; (e) Gao, H.; Zhang, J. Adv. Synth. Catal. 2009, 351, 85.
8. For recent examples, see: (a) Nakamura, I.; Sato, Y.; Terada, M. J. Am. Chem. Soc.
2009, 131, 4198; (b) Liu, X.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2009, 48, 2367;
(c) Yang, S.; Li, Z.; Jian, X.; He, C. Angew. Chem., Int. Ed. 2009, 48, 3999; (d) Gruit,
M.; Michalik, D.; Tillack, A.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 7212; (e)
Shu, X.-Z.; Zhao, S.-C.; Ji, K.-G.; Zheng, Z.-J.; Liu, X.-Y.; Liang, Y.-M. Angew. Chem.,
Int. Ed. 2009, 48, 117; (f) Guo, Z.; Cai, M.; Jiang, J.; Yang, L.; Hu, W. Org. Lett.
2010, 12, 652.
nito- P)]platinum(II)-catalyzed
j
intramolecular 6-endo-dig
cyclization for the first time. The advantage of this versatile meth-
od is able to provide easy access to a variety of 3-substituted 1-alk-
oxyisoquinolines and isoquinolones under simple catalytic and
favorable neutral conditions. Further work to study the scope of
this reaction and its mechanism are ongoing and the results will
be reported in due course.
Acknowledgments
9. For recent examples using Pd, see: Roy, S.; Roy, S.; Neuenswander, B.; Hill,
D.; Larock, R. C. J. Comb. Chem. 2009, 11, 1061. and references cited
therein.
10. For recent examples using Ag, see: (a) Su, S.; Porco, J. A., Jr. J. Am. Chem. Soc.
2007, 129, 7744; (b) Yao, Y.-S.; Yao, Z.-J. J. Org. Chem. 2008, 73, 5221.
11. For recent examples using Au, see: (a) Das, A.; Chang, H.-K.; Yang, C.-H.; Liu, R.-
S. Org. Lett. 2008, 10, 4061; (b) Aikawa, H.; Tago, S.; Umetsu, K.; Haginiwa, N.;
Asao, N. Tetrahedron 2009, 65, 1774.
The authors thank Hans Maag and Joseph M. Muchowski for
their helpful discussions and revision of this manuscript.
References and notes
1. (a) Bentley, K. W. In The Isoquinoline Alkaloids; Hardwood Academic:
Amsterdam, 1998; Vol. 1; (b)The Chemistry and Biology of Isoquinoline
Alkaloids; Philipson, J. D., Roberts, M. F., Zenk, M. H., Eds.; Springer: New
12. For recent examples using Cu, see: Malkov, A. V.; Westwater, M.-M.; Gutnov,
A.; Ramirez-Lopez, P.; Friscourt, F.; Kadlcikova, A.; Hodacova, J.; Rankovic, Z.;
Kotora, M.; Kocovsky, P. Tetrahedron 2008, 64, 11335.

J. Li et al. / Tetrahedron Letters 51 (2010) 6422–6425
13. (a) Bennett, M. A.; Yoshida, T. J. Am. Chem. Soc. 1978, 100, 1750; (b) Cucciolito, (dimethylphosphinito-
6425
j
P)]platinum(II) (21 mg, 0.05 mmol) in EtOH (4 mL)
M. E.; de Renzi, A.; Roviello, G.; Ruffo, F. Organometallics 2008, 27, 1351.
14. (a) Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657; (b) Ghaffar, T.;
Parkins, A. W. J. Mol. Catal. A: Chem. 2000, 160, 249; (c) Jiang, X.-B.; Minnaard, A.
J.; Feringa, B. L.; de Vries, J. G. J. Org. Chem. 2004, 69, 2327.
was heated to refluxed for 16 h. The reaction was cooled to room temperature
and concentrated. The crude product mixture was purified to afford 2-
ethoxyisoquinoline 2b (59 mg, 48% yield) as a viscous oil and isoquinolone 3a
(16 mg, 15% yield) as a solid upon standing at room temperature.
15. All ortho-alkynylbenzonitriles were readily prepared via Sonogashira-coupling
reaction from commercially available aryl halides and alkynes.
18. Representative experimental procedure:
A
mixture of isoquinoline 2a
L) in AcOH (0.5 mL) in a
(0.30 mmol, 70 mg) and 48% HBr (1.19 mmol, 200
l
16. A base-prompted cyclization of 2-alkynylbenzonitriles was reported earlier,
see: Lu, W.-D.; Lin, C.-F.; Wang, C.-J.; Wang, S.-J.; Wu, M.-J. Tetrahedron 2002,
58, 7315. and references cited therein.
sealed tube was heated at 50 °C for 2 h. The reaction was cooled to room
temperature and poured into a mixture of ice and saturated aq NaHCO3
solution. The reaction was extracted with EtOAc. The extract was washed with
brine, dried (MgSO4) and concentrated to provided analytical pure
isoquinolone 3 (64 mg, 97% yield) as a creamy-colored solid.
17. Representative experimental procedure: A mixture of benzonitrile 1a (100 mg,
0.49 mmol) and hydrido(dimethylphosphinous acid-jP)[hydrogen bis