N-Iminopyridinium ylide-directed, cobalt-catalysed coupling of sp2C-H bonds with alkynes

Article abstract of DOI:10.1039/d0cc05294a

N-Iminopyridinium ylides are competent monodentate directing groups for cobalt-catalysed annulation of sp²C-H bonds with internal alkynes. The pyridine moiety in the ylide serves as an internal oxidant and is cleaved during the reaction. The annulation reactions possess excellent compatibility with heterocyclic substrates, tolerating furan, thiophene, pyridine, pyrrole, pyrazole, and indole functionalities.

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N-Iminopyridinium ylide-directed,
cobalt-catalysed coupling of
Cite this:DOI: 10.1039/d0cc05294a
sp2 C–H bonds with alkynes†
Received 3rd August 2020,
Accepted 10th August 2020
Se Hun Kwak
and Olafs Daugulis
*
DOI: 10.1039/d0cc05294a
rsc.li/chemcomm
N-Iminopyridinium ylides are competent monodentate directing cobalt salt promoted transformations typically possess high
groups for cobalt-catalysed annulation of sp2 C–H bonds with internal regioselectivity for reactions with unsymmetrical alkynes and
alkynes. The pyridine moiety in the ylide serves as an internal oxidant require a bidentate directing group.5 Only on rare cases,
and is cleaved during the reaction. The annulation reactions possess monodentate directing groups can be used.5i Reactions that
excellent compatibility with heterocyclic substrates, tolerating furan, are catalysed by various cyclopentadienylcobalt(III) complexes
thiophene, pyridine, pyrrole, pyrazole, and indole functionalities.
can be performed by employing simpler, monodentate, direct-
ing groups, but the regioselectivity observed for unsymmetric
First-row transition-metal, and more specifically, cobalt-catalysed alkynes may be lower.6 Other metals and low-valent cobalt
carbon–hydrogen bond functionalization has received substantial catalysis have been employed as well.7 Among cobalt-
attention in recent years.1 Compared to their 4d and 5d analogues, catalysed transformations that result in the formation of iso-
non-noble transition metals are abundant and cheap. Additionally, quinolones, few papers report the use of monodentate directing
the reaction manifolds accessible by 3d transition metals some- groups.6e,m The compatibility of these methodologies with
times differ from those of their 4d and 5d counterparts.
heterocyclic substrates is underexplored. We report here N-
We have recently reported palladium-catalysed, N-imino- iminopyridinium ylide-directed, cobalt-catalysed coupling of
pyridinium ylide-directed sp3 C–H arylation and alkylation sp2 C–H bonds with alkynes that uses the N–N bond as an
reactions.2a Furthermore, copper-promoted sp2 C–H/N–H cou- internal oxidant forming isoquinolones. These transformations
plings were also disclosed.2b Monodentate N-iminopyridinium are highly compatible with heterocyclic substrates.
ylide directing groups appear to be nearly as efficient as the
The reaction optimization studies are presented in Table 1.
widely used bidentate auxiliaries in palladium-catalysed C–H The use of simple cobalt salts such as Co(OAc)2 and Co(acac)2
functionalization.2,3 Their performance in copper-promoted did not afford any product, and thus cyclopentadienylcobalt(III)
sp2 C–H amination is superior to those of other monodentate complexes were employed. After screening a number of sol-
directing groups.2b Thus, we were interested in exploring the vents, cobalt complexes, and additives, we found that the best
reactivity of N-iminopyridinium ylides in cobalt-catalysed C–H results were obtained by using
a [Cp*Co(MeCN)3][SbF6]2
functionalization. catalyst in HFIP solvent with added pivalic acid. Subsequently,
A pioneering report by Matsunaga and Kanai in 2014 modification of the ylide moiety was undertaken (entries 1–3).
described Cp*Co(III)-catalysed coupling of alkynes with aro- Relatively low yield was obtained by employing a ylide derived
matic C–H bonds.4a,b Our group reported a method for from commercially available 1-aminopyridinium iodide and p-
cobalt-catalysed, aminoquinoline- and picolinamide-directed toluoyl chloride (entry 1). Switching to 4-methoxypyridinium
coupling of alkynes with C(sp2)–H bonds. The reaction employs derivative 2 and 4-tert-butylpyridinium ylide 3, previously uti-
a simple Co(OAc)2 hydrate catalyst, and oxygen from the air as a lized for copper promoted C–H amination,2b allowed the yields
terminal oxidant.4c Subsequently, many similar high-valent to be increased to 81–82% (entries 2 and 3). Pivalic acid additive
cobalt catalysed transformations have been reported.5,6 Simple was found to be optimal for the reaction (entries 4 and 5).
Best catalytic performance was observed for [Cp*Co(MeCN)3]
[SbF6]2, while in situ generated active species (entry 6) and
[CpCo(MeCN)3][SbF6]2 (entry 7) gave lower yields.
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, USA.
E-mail: olafs@uh.edu
After identification of the optimal reaction conditions, we
† Electronic supplementary information (ESI) available. CCDC 1991068 and
evaluated the generality of the directed C–H annulation of aryl
ylides with symmetric alkynes such as diphenylacethylene and
2014034. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/d0cc05294a
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Table 1 Optimization of the reaction conditionsa
somewhat lower yields (16 and 17). The annulation is not limited
to aromatic substrates. Acrylic acid derivatives are reactive as well
(18 and 19). In addition to diphenylacetylene, 3-hexyne can be
employed as a substrate for the annulation to generate the
corresponding products (20–22). Comparison of t-butyl pyridi-
nium ylides with the corresponding methoxy pyridinium deri-
vatives is instructive. In some cases, performance is nearly
identical (4). For most other substrates, the methoxy derivative
performs substantially better (14, 16, and 17) even with shorter
reaction times.
The annulation protocol was investigated with respect to
heteroaryl substrates (Scheme 2). Thiophene derivatives gave
the expected products in good yields, irrespective of the sub-
stitution pattern (23–25). The best results were obtained with
3-substituted thiophene which afforded the cyclized product 25
regioselectively and reacted faster than other substrates. Furan
derivatives are competent substrates (26–28) but if a ylide
derived from furan-2-carboxylic acid was employed, the product
was isolated in a low yield (26). Notably, a brominated furan
derivative is reactive (28). Furthermore, nitrogen-containing
heteroarene substrates participate in the transformation.
Pyridine (29 and 30), pyrrole (31), pyrazole (32), and indole
moieties (33) are all compatible with the reaction conditions,
irrespective of the potentially strong coordinating ability of the
heteroatom which may interfere with the C–H functionalization
Entry
Deviation from standard conditions
Yieldb (%)
1
2
3
4
5
6
R1 = H, 1
24
82
81
77
55
60
R1 = OMe, 2
R1 = tBu, 3
1-AdCO2H instead of PivOH
Without PivOH
Cp*CoI2(CO) (20 mol%)
AgSbF6 (40 mol%)
1-AdCO2H (50 mol%)
[CpCo(MeCN)3][SbF6]2
7
7
a
b
Reaction conditions: ylide (0.2 mmol), HFIP (1 mL). Isolated yields.
Abbreviations: HFIP = 1,1,1,3,3,3-hexafluoroisopropanol, 1-AdCO2H =
1-adamantanecarboxylic acid, PivOH = pivalic acid.
3-hexyne (Scheme 1). Various functional groups such as alkoxy
(5), halides (6, 7, 13, 14, and 17), esters (10 and 15), nitrile (12),
trifluoromethyl (9), and sulfone (11) on the aryl rings are well
tolerated furnishing good to excellent yields of isoquinolones
regardless of the substituent electronic properties and positions
on the arene. The annulation of substrates with substituents at
the meta position of an aryl group occurred regioselectively at the
less hindered site (13–15). Compared to meta and para substi-
tuted compounds, ortho substituted substrates gave products in
Scheme 2 Reaction scope with respect to heteroaryl ylides.a a Reaction
scale: 0.2 mmol, HFIP 1 mL. b Time: 48 h. c Time: 20 h. d Catalyst: [Cp*Co
(MeCN)3][SbF6]2 (20 mol%), PivOH additive (30 mol%), 48 h. e Catalyst:
[Cp*Co(MeCN)3][SbF6]2 (20 mol%), PivOH additive (30 mol%), 72 h. f Pro-
duct major isomer is shown (5.9 : 1). Isolated yields are reported. Please see
the ESI† for details.
Scheme 1 Reaction scope with respect to ylides. a Reaction scale: 0.2 mmol,
HFIP 1 mL. b Time: 20 h. c Time: 48 h. d Catalyst: [Cp*Co(MeCN)3][SbF6]2
(20 mol%), PivOH (30 mol%), 48 h. e Time: 72 h. f Catalyst: [Cp*Co(MeCN)3]
[SbF6]2 (20 mol%), PivOH (30 mol%), 72 h. Isolated yields reported. Please see
the ESI† for details.
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Scheme 5 Competition reaction.
completely replaced with hydrogens in the absence of alkyne
(45 to 45-d3). The reaction of deuterated ylide with 3-hexyne
gave the isoquinoline product with 52% hydrogen incorpora-
tion (45 to 46-h). When the reaction was stopped before
completion, H/D scrambling in both the recovered ylide start-
ing material and product was observed (45 to 45-h and 46-h,
eqn (3)). These results suggest that the C–H bond cleavage step
is not the rate determining step.
In a competitive annulation using a 1 : 1 molar mixture
of tert-butyl pyridinium ylide 3 and methoxy pyridinium ylide
47, a 1 : 1.35 mixture of 6-methyl-isoquinoline 4 and 6-ethyl-
isoquinoline 48 was obtained (Scheme 5). Somewhat higher
reaction rate for the methoxy pyridinium ylide may reflect the
higher coordinating ability of a more electron-rich ylide.
We attempted to prepare the cyclometalated complex via
C–H activation of the pyridinium ylide with a stoichiometric
amount of [Cp*Co(MeCN)3][SbF6]2, but the desired cobaltacycle
could not be isolated. Reversible C–H cobaltation may have
contributed to the failure to isolate the complex. However, the
Cp*Co(III)-pyridinium ylide complex 50 was prepared by
chelation-assisted oxidative addition of the pyridinium ylide
Ar–I bond to Cp*Co(CO)2, generated in situ from cobalt carbonyl
(Scheme 6, eqn (1)).9 Complex 50 was characterized by single
crystal X-ray diffraction and NMR spectroscopy. Iodide abstraction
by treatment of AgSbF6 in acetonitrile afforded cationic cobalt
complex 51, which is a competent annulation catalyst, affording
isoquinolone 4 in 68% yield (Scheme 6, eqn (2)).
Scheme 3 Reactions with unsymmetrical alkynes.a a Reaction scale: 0.2 mmol,
HFIP 1 mL. b [Cp*Co(MeCN)3][SbF6]2 (20 mol%), PivOH (30 mol%), 48 h.
c [Cp*Co(MeCN)3][SbF6]2 (15 mol%), PivOH (20 mol%), 48 h.
step of the annulation reaction.8 In all cases except that for the 6-
methoxypyridinium substrate (30), formation of only one product
isomer was observed. For 30, two isomers (C2 : C4 = 5.9 : 1) were
obtained. Next, the annulation of heterocycles with 3-hexyne was
investigated. Thiophenes and benzo[b]thiophene gave products in
good yields (34–37). However, the furan-containing substrate
afforded 38 in a modest yield. In most cases the methoxy-
substituted pyridine ylide derivative performs substantially better
compared with the ylide derived from t-butylpyridine.
Regioselectivity of the reactions with unsymmetrical alkynes
was investigated next (Scheme 3). The annulation with ethyl
hept-2-ynoate exhibited good selectivity (39 and 40). The use of
ethyl 3-phenylpropiolate resulted in about 2 : 1 ratio of isomeric
products 41 and 42. Poor selectivity was observed in the reaction
with 4-phenylbut-3-yn-2-one (43 and 44). The selectivities are
consistent with those observed for cyclopentadienylcobalt(III)-
catalysed annulation reactions with alkynes.6
We carried out preliminary mechanistic experiments to
delineate the annulation mechanism. The C–H bond cleavage
step is reversible as determined by D/H scrambling (Scheme 4).
Two deuterium atoms at the ortho positions of the ylide were
Based on the mechanistic studies and the reported mecha-
nism for high valent cobalt catalysed annulations with alkynes in
Scheme 4 Scrambling experiments.
Scheme 6 Cp*Co(III)-pyridinium ylide complex.
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3 (a) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem. Soc.,
2005, 127, 13154–13155; (b) O. Daugulis, J. Roane and L. D. Tran,
Acc. Chem. Res., 2015, 48, 1053–1064; (c) S. Rej, Y. Ano and
N. Chatani, Chem. Rev., 2020, 120, 1788–1887.
4 (a) H. Ikemoto, T. Yoshino, K. Sakata, S. Matsunaga and M. Kanai, J. Am.
Chem. Soc., 2014, 136, 5424–5431; (b) T. Yoshino and S. Matsunaga, Adv.
Synth. Catal., 2017, 359, 1245–1262; (c) L. Grigorjeva and O. Daugulis,
Angew. Chem., Int. Ed., 2014, 53, 10209–10212.
5 (a) D. Kalsi and B. Sundararaju, Org. Lett., 2015, 17, 6118–6121;
(b) V. G. Landge, G. Jaiswal and E. Balarman, Org. Lett., 2016, 18,
812–815; (c) C. Kuai, L. Wang, B. Li, Z. Yang and X. Cui, Org. Lett.,
2017, 19, 2102–2105; (d) R. Mei, W. Ma, Y. Zhang, X. Guo and
L. Ackermann, Org. Lett., 2019, 21, 6534–6538; (e) T. T. Nguyen,
L. Grigorjeva and O. Daugulis, ACS Catal., 2016, 6, 551–554;
( f ) S. Zhai, S. Qiu, X. Chen, J. Wu, H. Zhao, C. Tao, Y. Li,
B. Cheng, H. Wang and H. Zhai, Chem. Commun., 2018, 54,
98–101; (g) R. Mei, N. Sauermann, J. C. A. Oliveira and
Scheme 7 Proposed catalytic cycle.
´
L. Ackermann, J. Am. Chem. Soc., 2018, 140, 7913–7921; (h) A. M.
´
´
´
´
Martınez, N. Rodrıguez, R. Gomez-Arrayas and J. C. Carretero, Chem.
– Eur. J., 2017, 23, 11669–11676; (i) T. T. Nguyen, L. Grigorjeva and
O. Daugulis, Angew. Chem., Int. Ed., 2018, 57, 1688–1691; ( j) L.-
B. Zhang, X.-Q. Hao, Z.-J. Liu, X.-X. Zheng, S.-K. Zhang, J.-L. Niu and
M.-P. Song, Angew. Chem., Int. Ed., 2015, 54, 10012–10015.
the literature, we propose the catalytic cycle in Scheme 7.6e,i,k,m,10
The reaction starts with ligand exchange followed by subse-
quent chelation assisted C–H activation to give the cobaltacycle
A. Ligand exchange between the alkyne and nitrile, followed by
migratory insertion forms the seven-membered cobaltacycle B.
Next, intramolecular C–N bond formation furnishes the iso-
quinoline and releases the pyridine and Co(III) catalyst closing
the catalytic cycle.
6 (a) S. S. Bera, S. Debbarma, A. K. Ghosh, S. Chand and M. S. Maji,
J. Org. Chem., 2017, 82, 420–430; (b) L. Kong, S. Yu, X. Zhou and
X. Li, Org. Lett., 2016, 18, 588–591; (c) Z.-Z. Zhang, B. Liu, J.-W. Xu,
S.-Y. Yan and B.-F. Shi, Org. Lett., 2016, 18, 1776–1779; (d) R. Tanaka,
H. Ikemoto, M. Kanai, T. Yoshino and S. Matsunaga, Org. Lett., 2016,
18, 5732–5735; (e) X. Yu, K. Chen, S. Guo, P. Shi, C. Song and J. Zhu,
Org. Lett., 2017, 19, 5348–5351; ( f ) X. Xu, Y. Yang, X. Zhang and
W. Yi, Org. Lett., 2018, 20, 566–569; (g) H. Wang, M. Moselage,
In conclusion, we have shown that N-iminopyridinium
ylides act as competent monodentate directing groups for
cobalt-catalysed annulation of sp2 C–H bonds with internal
alkynes. Coupling reactions proceed in hexafluoroisopropanol
solvent at increased temperatures and are catalysed by the
[Cp*Co(MeCN)3][SbF6]2 complex. The pyridine moiety in the
ylide is cleaved during the reaction, serving as an internal oxidant.
The annulation reactions possess excellent compatibility with
heterocyclic substrates, tolerating furan, thiophene, pyridine,
pyrrole, pyrazole, and indole functionalities.
´
M. J. Gonzalez and L. Ackermann, ACS Catal., 2016, 6, 2705–2709;
(h) N. Barsu, M. Sen, J. R. Premkumar and B. Sundararaju, Chem.
Commun., 2016, 52, 1338–1341; (i) L. Kong, X. Yang, X. Zhou, S. Yu
and X. Li, Org. Chem. Front., 2016, 3, 813–816; ( j) P. K. Dutta and
S. Sen, Eur. J. Org. Chem., 2018, 5512–5519; (k) Y. Liang and N. Jiao,
Angew. Chem., Int. Ed., 2016, 55, 4035–4039; (l) S. Prakash,
K. Muralirajan and C.-H. Cheng, Angew. Chem., Int. Ed., 2016, 55,
1844–1848; (m) G. Sivakumar, A. Vijeta and M. Jeganmohan, Chem. –
Eur. J., 2016, 22, 5899–5903; (n) R. Mandal and B. Sundararaju, Org.
Lett., 2017, 19, 2544–2547.
7 (a) X.-X. Zheng, C. Du, X.-M. Zhao, X. Zhu, J.-F. Suo, X.-Q. Hao,
J.-L. Niu and M.-P. Song, J. Org. Chem., 2016, 81, 4002–4011;
(b) G. Cera, T. Haven and L. Ackermann, Chem. Commun., 2017,
53, 6460–6463; (c) L. C. Misal Castro, A. Obata, Y. Aihara and
N. Chatani, Chem. – Eur. J., 2016, 22, 1362–1367; (d) T. Matsubara,
L. Ilies and E. Nakamura, Chem. – Asian J., 2016, 11, 380–384;
(e) J. Yang and N. Yoshikai, Angew. Chem., Int. Ed., 2016, 55,
2870–2874; ( f ) B. J. Fallon, E. Derat, M. Amatore, C. Aubert,
F. Chemla, F. Ferreira, A. Perez-Luna and M. Petit, J. Am. Chem.
Soc., 2015, 137, 2448–2451. A metal-free approach: (g) Y. Zhao,
C. Shi, X. Su and W. Xia, Chem. Commun., 2020, 56, 5259–5262.
8 (a) L. V. Desai, K. J. Stowers and M. S. Sanford, J. Am. Chem. Soc.,
2008, 130, 13285–13293; (b) T. Cernak, K. D. Dykstra, S. Tyagarajan,
P. Vachal and S. W. Krska, Chem. Soc. Rev., 2016, 45, 546–576;
(c) M. Shang, S.-Z. Sun, H.-X. Dai and J.-Q. Yu, J. Am. Chem. Soc.,
2014, 136, 3354–3357; (d) M. Shang, M.-M. Wang, T. G. Saint-Denis,
M.-H. Li, H.-X. Dai and J.-Q. Yu, Angew. Chem., Int. Ed., 2017, 56,
5317–5321; (e) Y.-J. Liu, H. Xu, W.-J. Kong, M. Shang, H.-X. Dai and
J.-Q. Yu, Nature, 2014, 515, 389–393.
We are grateful to the Welch Foundation (Chair E-0044) and
NIGMS (Grant No. R01GM077635) for supporting this work. We
thank Dr Xiqu Wang for collecting diffraction data and solving
the X-ray structures of 41 and 50.
Conflicts of interest
The authors declare no conflict of interest.
Notes and references
1 (a) P. Gandeepan, T. Mu¨ller, D. Zell, G. Cera, S. Warratz and
L. Ackermann, Chem. Rev., 2019, 119, 2192–2452; (b) A. A. Kulkarni
and O. Daugulis, Synthesis, 2009, 4087–4109; (c) M. Moselage, J. Li and
L. Ackermann, ACS Catal., 2016, 6, 498–525; (d) A. Baccalini, S. Vergura,
P. Dolui, G. Zanoni and D. Maiti, Org. Biomol. Chem., 2019, 17,
10119–10141.
´
9 (a) J. Sanjose-Orduna, D. Gallego, A. Garcia-Roca, E. Martin, J. Benet-
´
Buchholz and M. H. Perez-Temprano, Angew. Chem., Int. Ed., 2017,
56, 12137–12141; (b) S. Martınez de Salinas, J. Sanjose-Orduna,
C. Odena, S. Barranco, J. Benet-Buchholz and M. H. Perez-
´
´
´
2 (a) K. K. A. Le, H. Nguyen and O. Daugulis, J. Am. Chem. Soc., 2019,
Temprano, Angew. Chem., Int. Ed., 2020, 59, 6239–6243.
141, 14728–14735; (b) S. H. Kwak and O. Daugulis, J. Org. Chem., 10 H. Huang, X. Ji, W. Wu and H. Jiang, Chem. Soc. Rev., 2015, 44,
2019, 84, 13022–13032.
1155–1171.
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