Efficient Synthesis of Isoquinolines via Rh(III)-Catalyzed Oxidative Annulation of Picolinamides with Alkynes

Article abstract of DOI:10.1055/s-0033-1340870

An efficient synthesis of isoquinolines via Rh(III)-catalyzed oxidative annulation of picolinamides with alkynes using Cu(OAc)₂ as an oxidant has been developed. The scope of the reaction was studied with a selection of various picolinamides an

Full text of DOI:10.1055/s-0033-1340870

1036▌
LETTER
letter
Efficient Synthesis of Isoquinolines via Rh(III)-Catalyzed Oxidative Annu-
lation of Picolinamides with Alkynes
Synthesis of Isoquinolines via C–H Functionalization of Pyridines
Zhen-Chao Qian,a Jun Zhou,a Bo Li,a Bing-Feng Shi*a,b
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
b
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
Shanghai 200032, P. R. of China
Fax +86(571)87951895; E-mail: bfshi@zju.edu.cn
Received: 11.12.2013; Accepted after revision: 05.02.2014
ployed internal oxidants such as O-acetyl oximes and ox-
Abstract: An efficient synthesis of isoquinolines via Rh(III)-cata-
imes to synthesize isoquinolines under Rh(III)-catalyzed
lyzed oxidative annulation of picolinamides with alkynes using
systems.
Cu(OAc)2 as an oxidant has been developed. The scope of the reac-
tion was studied with a selection of various picolinamides and al-
kynes, and the desired isoquinolines were obtained in good to
Table 1 Optimization of Reaction Conditionsa
excellent yields.
Et2NOC
Ph
Ph
CONEt2
H
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
Ph
Ph
Key words: isoquinoline, rhodium(III), C–H activation, pyridine,
oxidative annulation
Ph
N
N
+
additive, solvent, 120 °C
Ph
H
1a
2a
(2.2 equiv)
3a
Isoquinolines are valuable and prevalent structural motifs
in natural products, pharmaceuticals, materials and agro-
chemicals.1 Consequently, a variety of methods have been
developed for the synthesis of these scaffolds. Although
traditional methods such as Pomeranz–Fritsch, Bischler–
Napieralski, and Pictet–Spengler reactions have been fre-
quently applied in the synthesis of isoquinolines, these
methods often employ intramolecular cyclization of high-
ly functionalized substrates with strong acids and elevated
temperatures.2 Therefore, various transition-metal-cata-
lyzed methods have been developed to address these
drawbacks. In this case, the intermolecular cyclization of
o-haloaldimines and alkynes catalyzed by Pd3 and Ni4 has
proved its success. Shortly afterwards, highly prefunc-
tionalized substrates, such as o-alkynylaryl aldimines,
aldoximes and azides, were employed in the intramolecu-
lar cyclization process.5 However, many of these methods
still suffer from limited substrate scope, require multistep
sequences to prepare the starting materials, encouraging
Entry
Additive
Solvent
Yield (%)
1
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
AgOAc (2 equiv)
DCE
DCE
DCE
92
0
2b
3c
4
31
22
0
1,4-dioxane
DMF
5
6
t-AmOH
toluene
DCE
16
trace
24
0
7
8
9
Ag2CO3 (1 equiv)
DCE
a Conditions: 1a (0.2 mmol), 2a (0.44 mmol), [Cp*RhCl2]2 (2.5
mol%), AgSbF6 (10 mol%), additive in solvent (2 mL), sealed tube
under nitrogen, 120 °C, 24 h, isolated yield.
the development of new methodology with high efficien- b The reaction was carried out without [Cp*RhCl2]2.
c The reaction was carried out without AgSbF6.
cy and economy.
Recently, Rh(III)-catalyzed C–H activation has become a
powerful tool in organic synthesis, partly owing to the
lower catalytic loading and high functional group toler-
ance.6–8 Especially, Rh(III)-catalyzed oxidative annula-
tion using alkynes has emerged as a valuable and versatile
tool for the synthesis of N-hetereocycles,7 such as isoquin-
olines.9 Fagnou9a and Miura9b have independently demon-
strated the Rh(III)-catalyzed oxidative coupling of
aromatic imines with alkynes towards isoquinolines.
Shortly after that, Chiba,9c Li,9d Rovis9e and Hua9f em-
The above mentioned synthetic methods employed pre-
functionalized arenes as substrates to construct heterocy-
cles. Inspired by our continuous studies of Rh(III)-
catalyzed C–H functionalization of pyridine derivatives,10
we envisioned that the use of pyridine derivatives as sub-
strates might be an efficient and straightforward strategy,
considering the widespread availability of these sub-
strates. Takahashi has developed a stoichiometric cou-
pling of zirconacyclopentadienes with dihalopyridines for
the preparation of quinolines and isoquinolines.11a Sato
demonstrated the Ni-catalyzed [2+2+2] cycloaddition of
diynes and 3,4-pyridynes for the synthesis of isoquino-
line.11b Miura reported one isolated example of synthesis
of isoquinoline from pyridin-4-ylboronate catalyzed by
SYNLETT 2014, 25, 1036–1040
Advanced online publication: 11.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340870; Art ID: ST-2013-W1130-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Isoquinolines via C–H Functionalization of Pyridines
1037
rhodium.11c Recently, Li realized the Rh(III)-catalyzed 4–7). Cu(OAc)2 is essential to the success of this transfor-
synthesis of quinolines using pyridines and alkynes.11d mation, while other additives such as AgOAc and Ag2CO3
We now report a Rh(III)-catalyzed synthesis of isoquino- led to reduced yields (entries 8 and 9).
lines via oxidative annulation of functionalized pyridines
with alkynes using Cu(OAc)2 as an oxidant.
With the optimized conditions in hand, we then examined
the scope of various alkynes and the reaction shows broad
Our work started with the oxidative annulation of N,N-di- substrate tolerance among internal alkynes (Table 2). The
ethylpicolinamide (1a) with diphenylacetylene (2a) under reactions of 1a with different diarylacetylenes 2b–d pro-
[Cp*RhCl2]2/AgSbF6 catalytic system (Table 1). We were ceeded efficiently to produce quinolines 3b–d in excellent
delighted to find that isoquinoline 3a was isolated in 92% yields (Table 2, entries 2–4). Symmetrical dialkyl alkyne,
yield when DCE was used as solvent and Cu(OAc)2 was 4-octyne (2e) also reacted with 1a to give 3e in moderate
used as oxidant (entry 1). We further confirmed that both yield (entry 5). When unsymmetrical alkyne, 1-phenyl-
[Cp*RhCl2]2 and AgSbF6 are crucial for the present reac- 1-butyne (2f) was employed, isoquinoline 3f was obtained
tion (entries 2 and 3). DCE was found to be the ideal sol- predominantly with phenyl group distal to the amide
vent, while other solvents resulted in low yields (entries group (entry 6).
Table 2 Reaction of N,N-Diethylpicolinamide 1a with Alkynes 2a
R1
Et2NOC
N
R2
R2
CONEt2
H
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
R1
N
+
R2
Cu(OAc)2 (2 equiv)
120 °C, DCE, 24 h
R1
H
1a
2
3
(2.2 equiv)
Entry
Alkyne 2
Product 3
Yield (%)
R
R
R
R
Et2NOC
N
R
R
1
2
3
4
2a, R = H
2b, R = Me
2c, R = Cl
2d, R = F
3a, R = H
3b, R = Me
3c, R = Cl
92
88
95
87
3d, R = F
Et2NOC
Pr
Pr
Pr
Pr
N
5
6
41
56
Pr
Pr
Et
2e
3e
Et2NOC
Ph
Ph
Et
N
Ph
Et
2f
3f
a Conditions: 1a (0.2 mmol), 2 (0.44 mmol), [Cp*RhCl2]2 (2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2 (0.4 mmol), DCE (2 mL), sealed tube
under nitrogen, 120 °C, 24 h, isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1036–1040

1038
Z.-C. Qian et al.
LETTER
N
N
O
N
O
[Cp*RhCl2]2
Ph
Ph
Ph
Ph
H
H
N
CuOAc
1a
3a
Cp*Rh(OAc)2
AcOH
Rh(I)
C–H
activation
N
N
O
Ph
Ph
N
N
O
Cu(OAc)2
Rh(OAc)Cp*
RhCp*
Ph
E
Ph
A
Ph
Ph
Ph
Ph
O
Rh(OAc)Cp*
Ph
N
N
N
O
Ph
N
Ph
Ph
Rh
N
N
O
Cp*
D
B
Ph
Ph
Rh(OAc)Cp*
AcOH
C
Scheme 1 Plausible mechanism for the reaction of 1a with alkyne
The scope of picolinamides was also investigated, as giv- In summary, we have demonstrated that isoquinolines can
en in Table 3. Picolinamides bearing substitutions at be synthesized efficiently by the oxidative annulations of
the 6-position were generally more reactive and afforded picolinamides with internal alkynes in the presence of a
higher yields than those carrying substitutions at the 5-po- rhodium catalyst and Cu(OAc)2.12 Further investigations
sition, because of the steric congestion (Table 3, entries 1– to study the mechanism of this reaction are under way.
6). Halogenated picolinamides, such as chloride and fluo-
ride, were also tolerated, giving moderate to high yields
(entries 2 and 3). Electron-withdrawing group, such as
Acknowledgment
Financial support from the National Science Foundation of China
(21002087, 21272206, J1210042), the Fundamental Research
Funds for the Central Universities (2010QNA3033), Zhejiang Pro-
vincial NSFC (Z12B02000), Qianjiang Project (2013R10033) and
Specialized Research Fund for the Doctoral Program of Higher
Education (20110101110005) is gratefully acknowledged.
carboxylic ester, survived under the standard conditions,
affording isoquinoline 1g in excellent yield (entry 6). Oth-
er N,N-dialkyl-substituted picolinamides reacted with di-
phenylacetylene (2a) under current conditions to afford
the desired products in good yields (entries 7 and 8).
A plausible mechanism for the reaction of 1a with diphe-
nylacetylene (2a) is illustrated in Scheme 1, according to
previous studies.7d,e The active catalyst Cp*Rh(OAc)2 is
coordinated by 1a via the Lewis basic amide oxygen and
subsequent ortho C–H activation leads to the five-mem-
bered rhodacyclic intermediate A. Alkyne then coordi-
nates A, followed by regioselective insertion of the alkyne
to yield the seven-membered intermediate B. Dissociation
of rhodium from the oxygen, followed by a second ortho
C–H activation, gives rhodacyclic intermediate D. A sec-
ond coordination of alkyne and regioselective insertion
affords intermediate E. Subsequently, isoquinoline 3a and
Rh(I) species are generated by reductive elimination. This
Rh(I) species is then reoxidized to Rh(III) by Cu(OAc)2 to
accomplish the catalytic cycle.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) Bentley, K. W. In The Isoquinoline Alkaloids; Vol. 1;
Hardwood Academic: Amsterdam, 1998.
(2) Organic Reactions; Vol. 6; Adams, R., Ed.; Wiley: New
York, 1951, 74–206.
(3) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63,
5306. (b) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1,
553.
(4) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179.
(5) (a) Huang, Q.; Larock, R. C. Tetrahedron Lett. 2002, 43,
3557. (b) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org.
Synlett 2014, 25, 1036–1040
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Isoquinolines via C–H Functionalization of Pyridines
1039
Table 3 Reaction of Picolinamides 1 with Diphenylacetylene 2aa
Chem. Soc. 2010, 132, 18326. (e) Hyster, T. K.; Rovis, T.
J. Am. Chem. Soc. 2010, 132, 10565. (f) Rakshit, S.;
Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
9585. (g) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F.
J. Am. Chem. Soc. 2011, 133, 2154. (h) Muralirajan, K.;
Parthasarathy, K.; Cheng, C.-H. Angew. Chem. Int. Ed.
2011, 50, 4169. (i) Song, G.; Chen, D.; Pan, C.-L.; Crabtree,
R. H.; Li, X. J. Org. Chem. 2010, 75, 7487. (j) Chen, J.;
Song, G.; Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426.
(k) Chuang, S.-C.; Gandeepan, P.; Cheng, C.-H. Org. Lett.
2013, 15, 5750. (l) Shi, Z.; Tang, C.; Jiao, N. Adv. Synth.
Catal. 2012, 354, 2695. (m) Zhang, G.; Yang, L.; Wang, Y.;
Xie, Y.; Huang, H. J. Am. Chem. Soc. 2013, 135, 8850.
(8) For selected examples, see: (a) Ueura, K.; Satoh, T.; Miura,
M. Org. Lett. 2007, 9, 1407. (b) Patureau, F. W.; Glorius, F.
J. Am. Chem. Soc. 2010, 132, 9982. (c) Tsai, A. S.; Brasse,
M.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2011, 13, 540.
(d) Tan, X.; Liu, B.; Li, X.; Li, B.; Xu, S.; Song, H.; Wang,
B. J. Am. Chem. Soc. 2012, 134, 16163. (e) Gong, T.-J.;
Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F.; Fu, Y.; Liu,
L. Org. Lett. 2011, 13, 3235. (f) Park, S. H.; Kim, J. Y.;
Chang, S. Org. Lett. 2011, 13, 2372. (g) Li, B.-J.; Wang,
H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem. Int. Ed. 2012, 51,
3948. (h) Qin, X.; Liu, H.; Qin, D.; Wu, Q.; You, J.; Zhao,
D.; Guo, Q.; Huang, X.; Lan, J. Chem. Sci. 2013, 4, 1964.
(i) Zhou, B.; Du, J.; Yang, Y.; Li, Y. Org. Lett. 2013, 15,
2934. (j) Dong, J.; Long, Z.; Song, F.; Wu, N.; Guo, Q.; Lan,
J.; You, J. Angew. Chem. Int. Ed. 2013, 52, 580. (k) Shang,
Y.; Jie, X.; Zhao, H.; Hu, P.; Su, W. Org. Lett. 2014, 16, 416;
and references therein.
R12NOC
Ph
CONR1
2
Ph
Ph
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
N
H
N
+
Ph
Cu(OAc)2 (2 equiv)
120 °C, DCE, 24 h
Ph
R2
H
R2
Ph
1
2a
2.2 equiv
3
Entry
Picolinamide 1
Product 3
Yield (%)
Et2NOC
Ph
CONEt2
N
Ph
Ph
N
R
R
Ph
1
2
3
4
1b, R = Me
1c, R = F
1d, R = Cl
1e, R = OAc
3g, R = Me
3h, R = F
3i, R = Cl
48
88
67
40
3j, R = OAc
Ph
Et2NOC
CONEt2
N
Ph
Ph
N
R
5
6
7
8
90
98
94
71
R
Ph
(9) (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
1f, R = Me
3k, R = Me
(b) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura,
M. Chem. Commun. 2009, 5141. (c) Too, P. C.; Wang,
Y.-F.; Chiba, S. Org. Lett. 2010, 12, 5688. (d) Zhang, X.;
Chen, D.; Zhao, M.; Zhao, J.; Jia, A.; Li, X. Adv. Synth.
Catal. 2011, 353, 719. (e) Hyster, T. K.; Rovis, T. Chem.
Commun. 2011, 47, 11846. (f) Zheng, L.; Ju, J.; Bin, Y.;
Hua, R. J. Org. Chem. 2012, 77, 5794.
1g, R = CO2Me
3l, R = CO2Me
R2NOC
Ph
CONR2
N
Ph
Ph
N
Ph
(10) Zhou, J.; Li, B.; Hu, F.; Shi, B.-F. Org. Lett. 2013, 15, 3460.
(11) (a) Takahashi, T.; Li, Y.; Stepnicka, P.; Kitamura, M.; Liu,
Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,
576. (b) Iwayama, T.; Sato, Y. Chem. Commun. 2009, 5245.
(c) Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2011, 76, 2867. (d) Song, G.; Gong, X.; Li, X. J. Org.
Chem. 2011, 76, 7583.
1h, R = Cy
1i, R = Bn
3m, R = Cy
3n, R = Bn
a Conditions: 1 (0.2 mmol), 2a (0.44 mmol), [Cp*RhCl2]2(2.5 mol%),
AgSbF6 (10 mol%), Cu(OAc)2 (0.4 mmol), DCE (2 mL), sealed tube
under nitrogen, 120 °C, 24 h, isolated yield.
(12) General Procedure for the Synthesis of Isoquinolines 3
via Oxidative Annulation of Picolinamides 1 with 2:
N,N-Diethylpicolinamide (1; 0.2 mmol, 1.0 equiv),
Chem. 2002, 67, 3437. (c) Su, S.; Porco, J. A. Jr. J. Am.
Chem. Soc. 2007, 129, 7744. (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.
[Cp*RhCl2]2 (0.005 mmol, 2.5 mol%), AgSbF6 (0.02 mmol,
10 mol%), Cu(OAc)2 (0.4 mmol, 2.0 equiv), alkyne 2 (0.44
mmol, 2.2 equiv) and DCE (2 mL) were added to a 20-mL
Schlenk tube. After being purged with nitrogen, the mixture
was stirred at 120 °C for 24 h. Then concd aq NH3 (2 mL)
was added and stirred for 5 min. The resulting mixture was
extracted with EtOAc. The organic layer was dried over
Na2SO4, concentrated under reduced pressure and purified
by chromatography on silica gel to afford isoquinoline 3.
5,6,7,8-Tetraphenylisoquinoline-1-carboxylic Acid
Diethylamide (3a): Compound 3a was prepared in 92%
yield according to the general procedure as a white solid. 1H
NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H), 1.21
(t, J = 6.8 Hz, 3 H), 2.60–2.69 (m, 1 H), 2.72–2.81 (m, 1 H),
2.95–3.04 (m, 1 H), 3.36–3.44 (m, 1 H), 6.59 (d, J = 6.8 Hz,
1 H), 6.75–6.86 (m, 9 H), 7.04–7.13 (m, 5 H), 7.20–7.27 (m,
(6) For selected reviews on Rh(III)-catalyzed C–H
functionalization, see: (a) Satoh, T.; Miura, M. Chem. Eur. J.
2010, 16, 11212. (b) Colby, D. A.; Tsai, A. S.; Bergman, R.
G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (c) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
(d) Patureau, F. W.; Wencel-Delord, J.; Glorius, F.
Aldrichimica Acta 2012, 45, 31. (e) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(7) For selected examples of Rh(III)-catalyzed coupling
between arenes and alkynes, see: (a) Umeda, N.; Tsurugi,
H.; Satoh, T.; Miura, M. Angew. Chem. Int. Ed. 2008, 47,
4019. (b) Yamashita, M.; Horiguchi, H.; Hirano, K.; Satoh,
T.; Miura, M. J. Org. Chem. 2009, 74, 7481. (c) Guimond,
N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050.
(d) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am.
5 H), 7.43 (d, J = 5.6 Hz, 1 H), 8.40 (d, J = 5.6 Hz, 1 H). 13
NMR (100 MHz, CDCl3): δ = 168.9, 156.5, 143.3, 142.5,
C
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1036–1040

1040
Z.-C. Qian et al.
LETTER
141.4, 139.7, 139.6, 138.3, 138.2, 138.1, 136.5, 133.5,
131.4, 131.3, 130.9, 130.8, 130.7, 130.6 (2 × C), 127.9,
127.2 (2 × C), 127.0, 126.9, 126.7, 126.5, 125.9, 125.7,
125.6, 124.0, 120.1, 77.5, 77.2, 76.8, 45.3, 40.1, 13.8, 13.7.
HRMS (EI–TOF): m/z [M+] calcd for C38H32N2O: 532.2515;
found: 532.2511.
Synlett 2014, 25, 1036–1040
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.