Cobalt-Catalyzed Carbonylative Cyclization of Pyridinyl Diazoacetates for the Synthesis of Pyridoisoquinolinones

Article abstract of DOI:10.1021/acs.orglett.5b03340

Dicobalt octacarbonyl-catalyzed carbonylative cyclization of pyridinyl diazoacetates is developed for the synthesis of pyridoisoquinolinones under mild conditions (room temperature) in a carbon monoxide atmosphere. Moreover, a synthetic method for various pyridoisoquinolinones from ethylpyridinyl aryl acetates is demonstrated through diazotization using TsN₃ and DBU followed by Co-catalyzed carbonylation to generate ketene intermediates, which can subsequently undergo intramolecular cyclization under mild conditions in a carbon monoxide atmosphere in a semi-one-pot fashion.

Full text of DOI:10.1021/acs.orglett.5b03340

Letter
pubs.acs.org/OrgLett
Cobalt-Catalyzed Carbonylative Cyclization of Pyridinyl
Diazoacetates for the Synthesis of Pyridoisoquinolinones
Yonghyeon Baek,† Sunghwa Kim,† Bongkeun Jeon, and Phil Ho Lee*
National Creative Research Initiative Center for Catalytic Organic Reactions, Department of Chemistry, Kangwon National
University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: Dicobalt octacarbonyl-catalyzed carbonylative
cyclization of pyridinyl diazoacetates is developed for the
synthesis of pyridoisoquinolinones under mild conditions
(room temperature) in a carbon monoxide atmosphere.
Moreover, a synthetic method for various pyridoisoquinoli-
nones from ethylpyridinyl aryl acetates is demonstrated
through diazotization using TsN3 and DBU followed by Co-catalyzed carbonylation to generate ketene intermediates, which
can subsequently undergo intramolecular cyclization under mild conditions in a carbon monoxide atmosphere in a semi-one-pot
fashion.
ransition-metal-catalyzed carbonylation using carbon
monoxide is one of the significant methods to prepare a
Scheme 1. Co-Catalyzed Carbonylative Cyclization for the
Synthesis of Pyridoisoquinolinones
T
variety of carbonyl compounds.1 In particular, Pd-catalyzed
carbonylative cross-coupling is an important method for the
synthesis of a large number of compounds having the carbonyl
functional group. However, the carbonylation of metal carbenes
is rarely reported due to the limitations of substrate scope and
harsh conditions, such as the high pressure of carbon
monoxide, high reaction temperature, and stoichiometric
processes. Moreover, because the carbonylation of metal
carbene furnishes ketenes, which are very important in organic
synthesis, the development of streamlined synthetic methods to
overcome these shortcomings is still highly attractive and
challenging.
Moreover, a useful synthetic method for a number of
pyridoisoquinolinones from pyridinyl aryl acetates is demon-
strated through diazotization using TsN3 and DBU followed by
Co-catalyzed carbonylation and the intramolecular cyclization
of ketene with a tethering pyridinyl moiety under mild
conditions in a carbon monoxide atmosphere in a semi-one-
pot fashion.7
Recently, Ungvar
́
y2 and Wang3 reported the transition-metal-
catalyzed carbonylation of metal carbenes derived from diazo
compounds with carbon monoxide for the preparation of
ketenes and the intermolecular addition of ketenes with
nucleophiles such as alcohols and amines, resulting in the
formation of a variety of carbonyl derivatives.4 However, we are
not aware of any reported examples of the transition-metal-
catalyzed carbonylation of diazo compounds and sequential
intramolecular cyclization. More recently, we demonstrated a
robust synthetic method for a wide range of pyridoisoindoles
from pyridinyl aryl diazoacetates under Cu-catalytic or metal-
free conditions.5 Inspired by our previous work, we envisioned
that treatment of diazoacetate possessing a nucleophilic
pyridinyl moiety with a transition-metal carbonyl catalyst,
under a CO atmosphere or not, would result in the
carbonylation of metal carbene to afford pyridinyl aryl-
substituted ketene, which can be applicable in intramolecular
cyclization reactions to provide pyridoisoquinolinones.6 Herein,
we report dicobalt octacarbonyl catalyzed carbonylative
cyclization of pyridinyl diazoacetates for the synthesis of
pyridoisoquinolinones under mild conditions (room temper-
ature) in a carbon monoxide atmosphere (Scheme 1).
First, we investigated the scope and limitation of transition-
metal carbonyl catalyzed carbonylative cyclization of pyridiny-
laryl diazoacetate 1a as the substrate under a CO atmosphere
(Table 1). A variety of pyridinylaryl diazoacetates were easily
prepared from Rh-catalyzed alkylation8 of 2-arylpyridines with
Meldrum’s acid and the diazotization reaction9 of the
corresponding pyridinyl aryl acetates (see the Supporting
Information). Although Cr(CO)6, Mo(CO)6, W(CO)6, and
Fe3(CO)12 (2.0 mol % each) were completely ineffective
(entries 1−4), Co2(CO)8 (2.0 mol %) successfully produced
pyridoisoquinolinone in 95% isolated yield in toluene at 25 °C
under a CO atmosphere after CO bubbling for 2 min (entry 5).
When Co2(CO)8-catalyzed carbonylative cyclization was
carried out under a CO atmosphere without CO bubbling or
under a N2 atmosphere without CO bubbling, the cyclization
reaction did not go to completion, and the desired product 2a
was obtained in 61% and 19% yields, respectively, along with
Received: November 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03340
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Scheme 2. Scope of Aryl Groups
b
entry
cat. (mol %)
solvent
time (h)
yield (%)
1
2
3
4
5
Cr(CO)6 (2.0)
Mo(CO)6 (2.0)
W(CO)6 (2.0)
Fe3(CO)12 (2.0)
Co2(CO)8 (2.0)
Co2(CO)8 (2.0)
Co2(CO)8 (2.0)
Co2(CO)8 (1.0)
Co2(CO)8 (2.0)
Co2(CO)8 (2.0)
Co2(CO)8 (2.0)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
12
12
12
12
5
0
0
0
0
c
97 (95)
d
e
6
5
61 (35)
f
e
7
5
19 (70)
8
24
12
12
5
56
57
30
88
9
10
11
CH3CN
THF
a
Reactions were carried out with 1a (0.2 mmol) and metal carbonyl
(1.0−2.0 mol %) in solvent (1.25 mL) at 25 °C. After CO bubbling for
b
2 min, the reaction mixture was stirred under CO atmosphere. NMR
c
yield using dibromomethane as an internal standard. Isolated yield.
d
e
Under CO atmosphere without CO bubbling. Recovery yield of 1a.
f
Under N2 atmosphere without CO bubbling.
recovery of 1a (entries 6 and 7). These results indicate that the
CO bubbling and atmosphere are essential for the carbonylative
cyclization. The use of 1.0 mol % of Co2(CO)8 gave inferior
results compared to 2.0 mol % (Table 1, entries 5 and 8).
Toluene gave the best result among the solvents (DCE,
CH3CN, and THF; entries 9−11). Screening of a series of Pd
and Rh catalysts did not give satisfactory results (see the
Supporting Information).
Next, the scope of substrates in this carbonylative cyclization
reaction was examined with pyridinyl aryl diazoacetates (1)
possessing a wide range of substituents on the aryl groups
under the optimal conditions (Scheme 2). Electronic
modification of the substituents at the aryl moiety of 1 had
little effect on the reaction efficiency. The substrates possessing
both electron-donating groups (R = Me and MeO) and
electron-withdrawing groups (R = F, Cl, CF3, CN, CH3CO,
and EtO2C) on the aryl moiety were well tolerated under the
reaction conditions and provided the corresponding products
2b−l in good to excellent yields ranging from 70% to 94%.
When 2,3-naphthyl-substituted pyridinyl diazoacetate (1n)
underwent the Co-catalyzed carbonylative cyclization, the
desired benzopyridoisoquinolinone 2n was produced in 76%
yield. However, 1,2-naphthyl-substituted pyridinyl diazoacetate
(1o) was cyclized to 2o in 45% yield. This decreased efficiency
was attributed to the steric congestion of the bent polycyclic
aromatic compound. When pyridinyl diazoacetate (1p)
possessing an estrone moiety was employed as the substrate,
the carbonylative cyclization product 2p was satisfactorily
obtained in 84% yield. Moreover, the arene is not limited to a
benzene skeleton. Heteroaromatic diazoacetate 1q obtained
from (thiophene-2-yl)pyridine was applied to the present Co-
catalyzed carbonylative cyclization, affording 2q in 54% yield.
In addition, modification of a wide range of substituents (R =
Me, MeO, F, and CH3CO) on the pyridine moiety was
tolerated without notably affecting the catalytic effectiveness
(Scheme 3, 4a−d). Diazoacetate (3e) possessing an isoquino-
line moiety showed moderate reactivity in this transformation
due to the steric congestion arising from the intramolecular
cyclization. Pyrimidine-substituted diazoacetate (3f) is appli-
a
Reactions were carried out with 1 (0.2 mmol, 1.0 equiv) and
Co2(CO)8 (2.0 mol %) in toluene (1.25 mL) at 25 °C under CO
b
atmosphere after CO bubbling. Co2(CO)8 (5.0 mol %) was used.
c
Co2(CO)8 (15.0 mol %) was used.
a
Scheme 3. Scope of Pyridyl Groups
a
Reactions were carried out with 3 (0.2 mmol) and Co2(CO)8 (2.0
mol %) in toluene (1.25 mL) at 25 °C under CO atmosphere after CO
bubbling. Co2(CO)8 (15.0 mol %) was used. Co2(CO)8 (5.0 mol %)
was used.
b
c
B
DOI: 10.1021/acs.orglett.5b03340
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cable to the present transformation, providing the correspond-
ing cyclic product (4f) in 87% yield.
Scheme 5. Proposed Mechanism
Subsequently, because pyridinyl aryl diazoacetates (1 and 3)
were easily obtained from the diazotization reaction of the
corresponding pyridinyl aryl acetates,9 we envisioned that this
carbonylative cyclization for the synthesis of pyridoisoquinoli-
nones could be achieved directly through diazotization followed
by the Co-catalyzed carbonylative cyclization from pyridinyl
aryl acetates in a one-pot fashion (Scheme 4). First, after
Scheme 4. Synthesis of Pyridoisoquinolinones from
a
Pyridinyl Aryl Esters in a Semi-One-Pot Fashion
molecular cyclization of the ketene group with the pyridinyl
moiety in IV provides pyridinium enolate V, which is in
resonance with pyridoisoquinolinone 2 and 4. The elucidation
of the detailed reaction mechanism must wait further study.
In conclusion, we have successfully developed a dicobalt
octacarbonyl catalyzed carbonylative cyclization of pyridinyl
diazoacetates for the synthesis of pyridoisoquinolinones under a
carbon monoxide atmosphere. Moreover, a useful synthetic
method for a wide range of pyridoisoquinolinones from
pyridinyl aryl acetates has been demonstrated through
diazotization using TsN3 and DBU followed by Co-catalyzed
carbonylation and intramolecular cyclization of ketene with a
tethering pyridinyl moiety under a carbon monoxide
atmosphere in a semi-one-pot procedure. These transforma-
tions are attractive due to the use of an inexpensive and
commercially available Co catalyst and an easily accessible
starting material and the release of harmless N2 under mild
conditions (room temperature).
a
Reactions were carried out with 5 (0.2 mmol, 1.0 equiv), TsN3 (0.4
mmol), and DBU (0.4 mmol) in THF at 25 °C for 12 h. After the
reaction mixture was filtered through a short pad of silica, Co2(CO)8
(50.0 mol %) in THF was added to filtrate at 25 °C for 6 h under CO
atmosphere.
pyridinyl aryl diazoacetate 5a was treated with TsN3 and DBU
in THF at 25 °C for 12 h, Co2(CO)8 catalyst (2.0 mol %) was
added to the reaction mixture for carbonylative cyclization.
However, because the remaining DBU in the reaction mixture
deactivated the Co catalyst, the corresponding cyclic product 2a
was not produced. Accordingly, we attempted the synthesis of
the pyridoisoquinolinone (2 and 4) in a two-step, semi-one-pot
procedure.7 After pyridinyl aryl diazoacetate 5a was treated
with TsN3 and DBU in THF for 12 h, the reaction mixture was
filtered through a short pad of silica, and the filtrate was used as
the starting material in the following Co-catalyzed carbonylative
cyclization at 25 °C under a CO atmosphere, leading to the
formation of 2a in 51% yield. Likewise, pyridinyl aryl
diazoacetates (5) possessing a variety of substituents (R1 =
Me and EtO2C, R2 = MeO) on the aryl and pyridinyl groups
are applicable in this modified method, providing the
corresponding pyridoisoquinolinones (2d, 2l, and 4b) in
good yields ranging from 60% to 63%.
Because pyridoisoquinolinones (2 and 4) are fluorescent,
their optical properties in CH2Cl2 solution were examined (see
the Supporting Information). The pyridoisoquinolinone
fluorophores displayed Stokes shifts ranging from 41 to 75
units. The extinction coefficients were variable from 67264 to
245677 M−1·cm−1. The pyridoisoquinolinone (2q) affords high
quantum yields and extinction coefficients, which are an
attractive property for biological probes.6
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03340.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Author Contributions
†Y.B. and S.K. contributed equally to this work.
Notes
Although the mechanism of the present reaction has not
been completely established, a feasible reaction pathway is
illustrated in Scheme 5. Coordination of the cobalt catalyst to
the nitrogen atom in pyridinyl diazoacetate 1 and 3 results in
the formation of the intermediate I, which is converted to a
cobalt ethoxycarbonyl carbene complex II through dinitrogen
extrusion. Migration of a CO from the Co carbene II affords
the metal-complexed ketene intermediate III, which is followed
by decomplexation to furnish ethoxycarbonyl ketene IV with
regeneration of the cobalt catalyst.2a,b,j−l Subsequent intra-
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIP)
(2011-0018355) and 2015H1CA1035955.
C
DOI: 10.1021/acs.orglett.5b03340
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) (a) Huang, C.; Gevorgyan, V. Org. Lett. 2010, 12, 2442. (b) Li,
H.; He, K.-H.; Liu, J.; Wang, B.-Q.; Zhao, K.-Q.; Hu, P.; Shi, Z.-J.
Chem. Commun. 2012, 48, 7028.
(8) Yu, X.; Yu, S.; Xiao, J.; Wan, B.; Li, X. J. Org. Chem. 2013, 78,
5444.
DEDICATION
■
This paper is dedicated to Professor Barry M. Trost (Stanford
University) on the occasion of his 75th birthday.
(9) (a) Regitz, M. Tetrahedron Lett. 1964, 5, 1403. (b) Lee, S. L.;
Kang, B. C.; Hwang, G.-S.; Ryu, D. H. Org. Lett. 2013, 15, 1428.
REFERENCES
■
(1) (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988, 110,
1557. (b) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V.
Carbonylation, Direct Synthesis of Carbonyl Compounds; Plenum Press:
New York, 1991. (c) Hatanaka, O. Y.; Fukushima, S.; Hiyama, T.
Tetrahedron 1992, 48, 2113. (d) Ishiyama, T.; Kizaki, H.; Hayashi, T.;
Suzuki, A.; Miyaura, N. J. Org. Chem. 1998, 63, 4726. (e) In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley: New York, 2002; Chapter VI, pp 2505−2714. (f) Lee, P. H.;
Lee, S. W.; Lee, K. Org. Lett. 2003, 5, 1103. (g) Lee, S. W.; Lee, K.;
Seomoon, D.; Kim, S.; Kim, H.; Kim, H.; Shim, E.; Lee, M.; Lee, S.;
Lee, P. H. J. Org. Chem. 2004, 69, 4852. (h) Barnard, C. F. J.
Organometallics 2008, 27, 5402. (i) Brennfuhrer, A.; Neumann, H.;
̈
Beller, M. ChemCatChem 2009, 1, 28. (j) Brennfuhrer, A.; Neumann,
̈
H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114. (k) Grigg, R.;
Mutton, S. P. Tetrahedron 2010, 66, 5515. (l) Wu, X.-F.; Neumann,
H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986. (m) Jafarpour, F.;
Rashidi-Ranjbar, P.; Kashani, A. Eur. J. Org. Chem. 2011, 2011, 2128.
(2) (a) Tuba, R.; Ungvar
(b) Ungvari, N.; Kegl, T.; Ungvar
219, 7. (c) Tuba, R.; Fordos, E.; Ungvar
2005, 236, 113. (d) Tuba, R.; Fordos, E.; Ungvar
s, E.; Ungvari, N.; Keg
Eur. J. Inorg. Chem. 2006, 2006, 1875. (f) Kegl, T.; Ungvar
Organomet. Chem. 2007, 692, 1825. (g) Ungvari, N.; Ungvar
Modern Carbonylation Methods; VCH: Weinheim, 2008; pp 199−221.
(h) Fordos, E.; Tuba, R.; Parkanyi, L.; Kegl, T.; Ungvary, F. Eur. J. Org.
Chem. 2009, 2009, 1994. (i) Balogh, J.; Kegl, T.; Ungvary, F.; Skoda-
Foldes, R. Tetrahedron Lett. 2009, 50, 4727. (j) Ungvari, N.; Fordos,
y, F. Inorg. Chim. Acta 2009, 362, 1333.
i, N.; Fordos, E.; Kegl, T.; Ungvary, F. Inorg. Chim. Acta
2010, 363, 2016. (l) Ungvari, N.; Balogh, J.; Kegl, T.; Parkanyi, L.;
Ungvary, F. Organometallics 2010, 29, 3837. (m) For a review, see:
Kegl, T.; Ungvary, F. Lett. Org. Chem. 2010, 7, 634. (n) Balogh, J.;
Csok, Z.; Parkanyi, L.; Ungvary, F.; Kollar, L.; Skoda-Foldes, R. J.
Organomet. Chem. 2012, 718, 131.
́
y, F. J. Mol. Catal. A: Chem. 2003, 203, 59.
y, F. J. Mol. Catal. A: Chem. 2004,
y, F. J. Mol. Catal. A: Chem.
y, F. Inorg. Chim. Acta
l, T.; Ungvary, F.
y, F. J.
y, F.
́
́
́
̋
́
̈
̋
́
̈
2005, 358, 4081. (e) Fordo
̋
́
́
́
̈
́
́
́
́
̋
́
́
́
́
̈
́
́
́
̋
̈
̈
E.; Keg
́ ́
l, T.; Ungvar
(k) Ungvar
́
̋
́
́
̈
́
́
́
́
́
́
́
́
́
́
́
́
̈
(3) (a) Peng, C.; Cheng, J.; Wang, J. J. Am. Chem. Soc. 2007, 129,
8708. (b) Zhang, Z.; Liu, Y.; Gong, M.; Zhao, X.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2010, 49, 1139. (c) Zhang, Z.; Liu, Y.; Ling, L.;
Li, Y.; Dong, Y.; Gong, M.; Zhao, X.; Zhang, Y.; Wang, J. J. Am. Chem.
Soc. 2011, 133, 4330. (d) Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2011,
2011, 1015. (e) Zhang, Z.; Zhang, Y.; Wang, J. ACS Catal. 2011, 1,
1621. (f) Xia, Y.; Zhang, Y.; Wang, J. ACS Catal. 2013, 3, 2586.
(g) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236.
(4) (a) Barluenga, J.; Valdes
́
, C. Angew. Chem., Int. Ed. 2011, 50,
7486. (b) Barcs, B.; Kollar, L.; Keg
́
́
l, T. Organometallics 2012, 31, 8082.
(c) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560. (d) Shu, D.; Li,
X.; Zhang, M.; Robichaux, P. J.; Guzei, I. A.; Tang, W. J. Org. Chem.
2012, 77, 6463. (e) Zhou, P.-X.; Zhou, Z.-Z.; Chen, Z.-S.; Ye, Y.-Y.;
Zhao, L.-B.; Yang, Y.-F.; Xia, X.-F.; Luo, J.-Y.; Liang, Y.-M. Chem.
Commun. 2013, 49, 561. (f) Wu, X.-F.; Fang, X.; Wu, L.; Jackstell, R.;
Neumann, H.; Beller, M. Acc. Chem. Res. 2014, 47, 1041. (g) Chen, J.-
R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Rev. 2015, 115, 5301.
(h) Tang, Z.; Mandal, S.; Paul, N. D.; Lutz, M.; Li, P.; van der Vlugt, J.
I.; de Bruin, B. Org. Chem. Front. 2015, 2, 1561.
(5) Kim, C.-E.; Baek, Y.; Kim, S. H.; Lee, P. H. Adv. Synth. Catal.
2015, 357, 2903.
(6) Recently, pyridoisoquinolinones were prepared through C−H
bond functionalization. (a) Zhao, D.; Kim, J. H.; Stegemann, L.;
Strassert, C. A.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 4508.
(b) Kim, J. H.; Gensch, T.; Zhao, D.; Stegemann, L.; Strassert, C. A.;
Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 10975.
D
DOI: 10.1021/acs.orglett.5b03340
Org. Lett. XXXX, XXX, XXX−XXX