Cp?-Free Cobalt-Catalyzed C-H Activation/Annulations by Traceless N, O-Bidentate Directing Group: Access to Isoquinolines

Article abstract of DOI:10.1021/acs.orglett.9b00866

N,O-Bidentate directing-enabled, traceless heterocycle synthesis is described via Cp?-free cobalt-catalyzed C-H activation/annulation. The weakly coordinating nature of the carboxylic acid was employed for the preparation of isoquinolines. Meanwhile, the N-O bond of the α-imino-oxy acid can serve as an internal oxidant. Terminal as well as internal alkynes can be efficiently applied to the catalytic system. This operationally simple approach shows a broad substrate scope with the products obtained in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.9b00866

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cp*-Free Cobalt-Catalyzed C−H Activation/Annulations by Traceless
N,O‑Bidentate Directing Group: Access to Isoquinolines
Xiao-Cai Li, Cong Du, He Zhang, Jun-Long Niu,* and Mao-Ping Song*
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, P. R. China
S
* Supporting Information
ABSTRACT: N,O-Bidentate directing-enabled, traceless heterocycle synthesis is described via Cp*-free cobalt-catalyzed C−H
activation/annulation. The weakly coordinating nature of the carboxylic acid was employed for the preparation of isoquinolines.
Meanwhile, the N−O bond of the α-imino-oxy acid can serve as an internal oxidant. Terminal as well as internal alkynes can be
efficiently applied to the catalytic system. This operationally simple approach shows a broad substrate scope with the products
obtained in good to excellent yields.
ubstituted isoquinolines are one of the most important
reported by Yu,9 who has demonstrated the Pd-catalyzed β-
Sheterocycles, which are frequently found in natural C(sp3)-H iodination and arylation using the L,X-type α-imino-
oxy acid auxiliary. Then, a similar auxiliary was applied in the
visible-light-promoted C−H functionalization by Studer.10
Inspired by the aforementioned progress and guided by our
previous work,11 we attempted to explore an efficient method
for the preparation of isoquinolines using the cheaper and
readily available cobalt salt as the catalyst. Herein a new
protocol for Cp*-free cobalt-catalyzed C−H activation/
annulation based on a traceless directing group is reported.
In the reaction, external metal oxidant was absent due to the
fact that the N−O bond of the auxiliary can act as an internal
oxidant.12 Meanwhile, the weakly coordinating carboxyl motif
in the N,O-bidentate directing group is crucial for the system.
The directing group can be removed directly in situ along the
catalytic process, which has great potential for streamlining the
synthesis of isoquinolines.
products, pharmaceuticals, chiral ligands, as well as organic
materials.1 Unfortunately, conventional synthetic routes
usually suffer from poor functional group tolerance and
harsh reaction conditions such as strong acids or high
temperature.2 Hence, it is highly desirable to develop an
efficient strategy that exhibits mild conditions and good
functional group tolerance.3 Alternatively, transition-metal-
catalyzed C−H bond activation has emerged to be a practical
method for the construction of heterocycles in recent years,4
which provides a complementary approach to obtain isoquino-
lines. In this context, transition-metal-catalyzed C−H
functionalization to furnish isoquinolines has been reported
and proven to be an effective method. In general, the practical
utility of these transformations relies on precious metal
catalysts such as Rh, Pd, and Ru.5
We commenced our study by selecting α-imino-oxy acid
(1a), which was prepared by commercially available starting
materials, and diphenylacetylene (2a) as model substrates.
Optimization studies on the reaction are summarized in Table
1. Initially, the desired product 3aa was observed in 24% when
Co(acac)3 was used as the catalyst in 1,2-dichloroethane
(DCE) at 100 °C in air (entry 1). Among the solvents
examined, hexafluoroisopropanol (HFIP) exhibited the best
transformation, giving the product 3aa in 56% yield (entries
1−3). Subsequently, alternative cobalt salts including Cp*Co-
(III) species (entries 4−7) were found to be inferior compared
with Co(acac)3, and no product was obtained without the
cobalt salt (entry 8). Further investigations (entries 9−12)
revealed that 1-adamantane carboxylic acid might act as both a
From the viewpoint of sustainable development, focus has
shifted to the use of environmentally and less expensive
transition-metal catalysts for C−H activation.6 More recently,
considerable progress has been accomplished with first-row
transition metals to lead to isoquinolines. Among them, the
strategy was mainly achieved through monodentate directing
groups,7 whereas examples of utilizing bidentate directing
groups remain relatively rare. In 2016, Zhu reported on the
demonstration of 2-hydrazinylpyridine-directed (N,N-biden-
tate directing group), traceless synthesis of isoquinolines by
cobalt(II) catalyst.8a Then, picolinamide as a N,N-bidentate
directing group for the cobalt-catalyzed selective synthesis of
isoquinolines was proposed by Cui.8b
However, the above-mentioned strategies mainly employed
the L,L-type (i.e., neutral, neutral) bidentate directing groups;
the L,X-type (i.e., neutral, anionic) counterparts have not been
developed in the area. Notably, pioneering studies have been
Received: March 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00866
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
[Co] (20 mol %)
Co(acac)3
Co(acac)3
additive (1 equiv)
solvent
yield (%)
1
2
DCE
TFE
24
46
3
4
5
6
7
8
9
10
11
12
13
14
Co(acac)3
Co(acac)2
Co(OAc)2·4H2O
Cp*Co(CO)I2
[Cp*Co(MeCN)3][(SbF6)2]
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
52
35
N.R.
N.R.
N.R.
N.R.
23
44
71
59
84
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
NaOPiv·H2O
PivOH
1-AdOH
dipivaloylmethane
1-AdOH
1-AdOH
c
d
91
a
Reaction conditions: substrate 1a (0.2 mmol), 2a (1.5 equiv), Co(acac)3 (20 mol %), HFIP (1.0 mL), 1-AdOH (50 mol %), dipivaloylmethane (1
b
c
d
equiv), air atmosphere, 12 h. Isolated yield. 1-AdOH (50 mol %), dipivaloylmethane (50 mol %). 1-AdOH (1 equiv), dipivaloylmethane (50
mol %). N.R. = no reaction. 1-AdOH = 1-adamantane carboxylic acid.
proton donor and a ligand, whereas dipivaloylmethane might
serve as a ligand in the catalytic process, which is beneficial to
the system.13 Therefore, we attempted to adjust the amounts
of additives. The product was detected in 91% yield when 1-
adamantane carboxylic acid (1 equiv) in conjunction with
dipivaloylmethane (0.5 equiv) was added to the reaction
(entries 13 and 14). Either elevated or lower temperature was a
disadvantage for the reaction activity (see the Supporting
Information).
Scheme 1. Co(III)-Catalyzed Synthesis of Isoquinoline
Derivative
a b
,
Different directing groups are discussed as follows (see
Figure 1). The results indicate that substrate 1a exhibits a
Figure 1. Screening of directing groups for the reaction.
preferable reactivity for the reaction under identical conditions.
A series of monodentate directing groups (A−D) failed to
promote the reaction. In contrast, the bidentate coordinating
groups E and F could give 3aa in moderate yield. Moreover, it
seems that increasing the steric bulk of α-imino-oxy acid
auxiliary carbon center could facilitate the reaction; however,
when the directing group G bearing the ethyl ester displaced
the auxiliary E, the product 3aa was not detected, further
highlighting the unique property of the weakly coordinating
carboxyl-directing motif.
a
Reaction conditions: substrate 1a (0.2 mmol), 2a (1.5 equiv),
Co(acac)3 (20 mol %), 1-AdOH (1 equiv), dipivaloylmethane (50
mol %), HFIP (1.0 mL), air atmosphere, 12 h. Isolated yield. Yield
of 1 mmol scale.
b
c
With the optimal conditions in hand, we first investigated
the substrate scope of this reaction between various substrate
1 derivatives and diphenylacetylene 2a. As shown in Scheme 1,
a wide variety of functionalized α-imino-oxy acids were
tolerated by the cobalt catalyst to give the desired product 3.
The yield of product decreased (3aa−3da) when methyl was
replaced by hydrogen, n-propyl, or phenyl. The para-
substituted α-imino-oxy acids bearing both electron-donating
and electron-withdrawing groups were compatible with the
B
DOI: 10.1021/acs.orglett.9b00866
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Organic Letters
Letter
optimized reaction conditions, thus affording the correspond-
ing products in 70−97% yields (3ea−3ja). Substitution on the
meta position allowed C−H activation to take place exclusively
on the less hindered position (3ma−3oa); in particular, 3ma
was generated in an excellent yield of 94%. When a sterically
hindered ortho-fluoro-substituted α-imino-oxy acid was
employed, the corresponding product 3pa was obtained in
77% yield. Meanwhile, the 1q derived from a bicyclic system
was smoothly converted to the corresponding benzo[h]-
isoquinoline 3qa. In addition, the heteroarene α-imino-oxy
acid was compatible in this transformation of 3ra with 61%
yield.
Scheme 3. Mechanistic Studies
Subsequently, the scope of the reaction with respect to
alkynes was examined, and experimental results are illustrated
in Scheme 2. In general, both terminal and internal alkynes
a b
,
Scheme 2. Substrate Scope for Alkynes
more reactive cobalt catalytic center during the catalytic
process8a (see the SI). Furthermore, significant H/D exchanges
could be detected in the reactions of both isotopically labeled
substrates [D5]-1a and 1a/D2O under standard reaction
conditions without 2a (Scheme 3, eqs 1 and 2). Additionally,
we also conducted the reaction of [D5]-1a with 2a for 2 h
under standard reaction conditions; the existence of 11% H/D
exchange in product [D4]-3aa (Scheme 3, eq 3) was observed.
The previously described experiments of H/D exchange
indicate that the C−H cleavage process might be reversible.
A kinetic isotope effect (KIE) value of 3.0 was observed
between 1a or [D5]-1a and 2a in the parallel experiments
(Scheme 3, eq 4), which indicates that Co-catalyzed C−H
bond cleavage might be involved in the rate-limiting step.
Then, a KIE (1.4) was observed in the competitive reaction of
1a and [D5]-1a with 2a (see the SI).
On the basis of the above mechanistic studies and related
reports,8,9,14 a plausible Co(III)/Co(I) catalytic cycle is
illustrated in Scheme 4. Initially, Co(acac)3 undergoes ligand
a
Reaction conditions: substrate 1a (0.2 mmol), 2a (1.5 equiv),
Scheme 4. Plausible Reaction Mechanism
Co(acac)3 (20 mol %), 1-AdOH (1 equiv), dipivaloylmethane (50
mol %), HFIP (1.0 mL), air atmosphere, 12 h. Isolated yield.
b
were compatible with the reaction. The diphenylacetylene
derivative 2b could also smoothly perform and gave the
product 3ab in moderate yield. For the unsymmetrical internal
alkyne, it could afford 84% of 3ac with exclusive
regioselectivity. Similarly, dialkyl (2d and 2e) alkynes reacted
smoothly to give corresponding isoquinolines in 85 and 74%
yields. When terminal alkynes were employed, the correspond-
ing cyclization products were furnished with moderate to good
yields, yet with relatively high regioselectivities (3af−3ag).
Meanwhile, chain alkynes were also compatible with the
reaction conditions and gave the corresponding products (3ah,
3ai). Moreover, we observed that triisopropylsilylacetylene was
a suitable alkyne, yielding an isoquinoline that can be
subsequently functionalized (3ak).
Additional experiments were performed to probe the
mechanism of the reaction (Scheme 3). The competition
experiment between 1e/1f and 2a was performed and revealed
the preferred reaction for electron-rich 1e (1e/1f = 1.43; see
the SI). Meanwhile, under an atmosphere of Ar, the yield of
product decreased significantly; even the cobalt salt loading
increased to 1 equiv, suggesting that oxygen most likely
changes the coordination environment for the generation of a
exchange to generate a catalytically active species. Then,
coordination of the substrate 1a to the catalytically active
species and subsequent cyclometalation by C−H bond
cleavage provide intermediate A. Alkyne 2a is then coordinated
to the Co(III) center of intermediate A to provide
intermediate B. Then, coordinative insertion of the carbon−
carbon triple bond into the C−Co bond of intermediate B
results in the seven-membered cobaltacyclic intermediate C.
Finally, intermediate C might undergo intramolecular sub-
C
DOI: 10.1021/acs.orglett.9b00866
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Organic Letters
Letter
Ed. 2009, 48, 5094. (j) Girard, S. A.; Knauber, T.; Li, C.-J. Angew.
Chem., Int. Ed. 2014, 53, 74.
(5) For a comprehensive review on the synthesis of isoquinoline via
C−H bond functionalization, see: He, R.; Huang, Z.-T.; Zheng, Q.-Y.;
Wang, C.-Y. Tetrahedron Lett. 2014, 55, 5705.
stitution, leading to product 3aa and side product 2-
hydroxyisobutyric acid (or the release of side product CO2
and acetone)15 along with the regeneration of the catalytically
active species for a new catalytic cycle.
In summary, we described an efficient cobalt-catalyzed C−H
activation/annulation of α-imino-oxy acids with terminal as
well as internal alkynes. Meanwhile, a strategy based on a
traceless oxidizing directing group was successfully utilized for
the process. The weakly coordinating nature of the carboxylic
acid plays a crucial role in the synthesis of isoquinolines. The
reaction exhibits a broad substrate scope, with the products
obtained in good yields. Further applications of the directing
group strategy in other related types of C−H functionalization
and detailed mechanistic studies are actively ongoing in our
laboratory.
(6) Recent reviews on the use of first-row transition-metal catalysts
for C−H bond functionalization, see: (a) Hirano, K.; Miura, M. Chem.
Lett. 2015, 44, 868. (b) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org.
Chem. 2013, 19. (c) Yoshikai, N. Synlett 2011, 1047. (d) Nakao, Y.
Chem. Rec. 2011, 11, 242. (e) Nakamura, E.; Yoshikai, N. J. Org.
Chem. 2010, 75, 6061. (f) Wei, D.-H.; Zhu, X.-J.; Niu, J.-L.; Song, M.-
P. ChemCatChem 2016, 8, 1242.
(7) First-row transition-metal-catalyzed C−H functionalization to
yield isoquinolines, see: (a) Shih, W. C.; Teng, C. C.; Parthasarathy,
K.; Cheng, C.-H. Chem. - Asian J. 2012, 7, 306. (b) He, R.-Y.; Huang,
Z.-T.; Zheng, Q.-Y.; Wang, C.-Y. Angew. Chem., Int. Ed. 2014, 53,
4950. (c) Lu, Q.-Q.; Greßies, S.; Cembellin, S.; Klauck, F.; Daniliuc,
C. G.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 12778. (d) Jia, T.;
Zhao, C.-Y.; He, R.-Y.; Chen, H.; Wang, C.-Y. Angew. Chem., Int. Ed.
2016, 55, 5268. (e) Wang, H.; Koeller, J.; Liu, W.; Ackermann, L.
Chem. - Eur. J. 2015, 21, 15525. (f) Sun, B.; Yoshino, T.; Kanai, M.;
Matsunaga, S. Angew. Chem., Int. Ed. 2015, 54, 12968. (g) Muralirajan,
K.; Kuppusamy, R.; Prakash, S.; Cheng, C.-H. Adv. Synth. Catal. 2016,
358, 774. (h) Sen, M.; Kalsi, D.; Sundararaju, B. Chem. - Eur. J. 2015,
21, 15529. (i) Wang, J.; Zha, S.; Chen, K.; Zhu, J. Org. Chem. Front.
2016, 3, 1281.
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.9b00866.
Experimental procedures and spectral data for new
compounds (PDF)
(8) (a) Zhou, S.-G.; Wang, M.-Y.; Wang, L.-L.; Chen, K.-H.; Wang,
J.-H.; Song, C.; Zhu, J. Org. Lett. 2016, 18, 5632. (b) Kuai, C.-S.;
Wang, L.-H.; Li, B.-B.; Yang, Z.-H.; Cui, X.-L. Org. Lett. 2017, 19,
2102.
AUTHOR INFORMATION
Corresponding Authors
■
(9) (a) Zhu, R.-Y.; Liu, L.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2017, 139,
12394. (b) Zhu, R.-Y.; Liu, L.-Y.; Park, H. S.; Hong, K.; Wu, Y.-W.;
Senanayake, C. H.; Yu, J.-Q. J. Am. Chem. Soc. 2017, 139, 16080.
(10) (a) Jiang, H.; Studer, A. Angew. Chem., Int. Ed. 2017, 56, 12273.
(b) Jiang, H.; Studer, A. Angew. Chem., Int. Ed. 2018, 57, 1692.
(11) (a) Zhang, L.-B.; Hao, X.-Q.; Liu, Z.-J.; Zheng, X.-X.; Zhang,
S.-K.; Niu, J.-L.; Song, M.-P. Angew. Chem., Int. Ed. 2015, 54, 10012.
(b) Wang, Y.; Du, C.; Wang, Y.-Y.; Guo, X.-K.; Fang, L.; Song, M.-P.;
Niu, J.-L.; Wei, D.-H. Adv. Synth. Catal. 2018, 360, 2668. (c) Guo, X.-
K.; Zhang, L.-B.; Wei, D.-H.; Niu, J.-L. Chem. Sci. 2015, 6, 7059.
(d) Du, C.; Li, P.-X.; Zhu, X.-J.; Suo, J.-F.; Niu, J.-L.; Song, M.-P. ;
Song, M.-P. Angew. Chem., Int. Ed. 2016, 55, 13571. (e) Du, C.; Li, P.-
X.; Zhu, X.-J.; Han, J.-N.; Niu, J.-L.; Song, M.-P. ACS Catal. 2017, 7,
2810. (f) Zhang, L.-B.; Hao, X.-Q.; Zhang, S.-K.; Liu, Z.-J.; Zheng, X.-
X.; Gong, J.-F.; Niu, J.-L.; Song, M.-P. Angew. Chem., Int. Ed. 2015, 54,
272.
(12) For examples of the N−O bond of the directing group acting as
an internal oxidant for C−H functionalization, see: (a) Ye, B.;
Cramer, N. Science 2012, 338, 504. (b) Guimond, N.; Gouliaras, C.;
Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (c) Yang, X.-F.; Liu, S.;
Yu, S.-J.; Kong, L.-H.; Lan, Y.; Li, X.-W. Org. Lett. 2018, 20, 2698.
(d) Huang, X.-L.; Huang, J.-S.; Du, C.-L.; Zhang, X.-Y.; Song, F.-J.;
You, J.-S. Angew. Chem., Int. Ed. 2013, 52, 12970.
(13) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. (b) Tan, G.-Y.; He, S.; Huang, X.-L.; Liao, X.-R.; Cheng, Y.-Y.;
You, J.-S. Angew. Chem., Int. Ed. 2016, 55, 10414. (c) Nguyen, T. T.;
Grigorjeva, L.; Daugulis, O. ACS Catal. 2016, 6, 551.
(14) (a) Gong, W.; Zhang, G.-F.; Liu, T.; Giri, R.; Yu, J.-Q. J. Am.
Chem. Soc. 2014, 136, 16940. (b) Zhang, Z.-Z.; Han, Y.-Q.; Zhan, B.-
B.; Wang, S.; Shi, B.-F. Angew. Chem., Int. Ed. 2017, 56, 13145. (c) Lv,
N.; Chen, Z.-K.; Liu, Y.; Liu, Z.-X.; Zhang, Y.-H. Org. Lett. 2018, 20,
5845−5848. (d) Moselage, M.; Li, J.; Ackermann, L. ACS Catal.
2016, 6, 498. (e) Hao, X.-Q.; Du, C.; Zhu, X.-J.; Li, P.-X.; Zhang, J.-
H.; Niu, J.-L.; Song, M.-P. Org. Lett. 2016, 18, 3610.
*E-mail: niujunlong@zzu.edu.cn.
*E-mail: mpsong@zzu.edu.cn.
ORCID
Jun-Long Niu: 0000-0001-8012-4676
Mao-Ping Song: 0000-0003-3883-2622
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work described in this paper was supported by the
National Natural Science Foundation of China (nos. 21772179
and 21672192) and the Program for Science & Technology
Innovation Talents in Universities of Henan Province (no.
19HASTIT038).
REFERENCES
■
(1) (a) Bhadra, K.; Kumar, G. S. Med. Res. Rev. 2011, 31, 821.
(b) Kartsev, V. G. Med. Chem. Res. 2004, 13, 325. (c) Lim, C. W.;
Tissot, O.; Mattison, A.; Hooper, M. W.; Brown, J. M.; Cowley, A. R.;
Hulmes, D. I.; Blacker, A. J. Org. Process Res. Dev. 2003, 7, 379.
(d) Tsuboyama, A.; Iwawaki, H.; Furugori, M.; Mukaide, T.;
Kamatani, J.; Igawa, S.; Moriyama, T.; Miura, S.; Takiguchi, T.;
Okada, S.; Hoshino, M.; Ueno, K. J. Am. Chem. Soc. 2003, 125, 12971.
(2) Bentley, K. W. Nat. Prod. Rep. 2005, 22, 249.
(3) (a) Si, C.; Myers, A. G. Angew. Chem., Int. Ed. 2011, 50, 10409.
(b) Sha, F.; Huang, X. Angew. Chem., Int. Ed. 2009, 48, 3458.
(4) For reviews of C−H functionalization, see: (a) Ackermann, L.
Org. Process Res. Dev. 2015, 19, 260. (b) Collins, K. D.; Glorius, F.
Nat. Chem. 2013, 5, 597. (c) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012,
41, 5588. (d) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei,
A. Chem. Rev. 2015, 115, 12138. (e) Shin, K.; Kim, H.; Chang, S. Acc.
Chem. Res. 2015, 48, 1040. (f) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624. (g) Engle, K. M.; Mei, T. S.; Wasa,
M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (h) Giri, R.; Shi, B.-F.;
Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242.
(i) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int.
(15) Davies, J.; Sheikh, N. S.; Leonori, D. Angew. Chem., Int. Ed.
2017, 56, 13361.
D
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