Cobalt-Catalyzed Enantioselective Hydroarylation of 1,6-Enynes

Article abstract of DOI:10.1021/jacs.0c03246

An asymmetric hydroarylative cyclization of enynes involving a C-H bond cleavage is reported. The cobalt-catalyzed cascade generates three new bonds in an atom-economical fashion. The products were obtained in excellent yields and excellent enantioselectivities as single diastereo- and regioisomers. Preliminary mechanistic studies indicate that the reaction shows no intermolecular C-H crossover. This work highlights the potential of cobalt catalysis in C-H bond functionalization and enantioselective domino reactivity.

Full text of DOI:10.1021/jacs.0c03246

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Article
Cobalt-Catalyzed Enantioselective Hydroarylation of 1,6-Enynes
Andrew Whyte, Alexa Torelli, Bijan Mirabi, Liher Prieto, José F Rodríguez, and Mark Lautens
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03246 • Publication Date (Web): 25 Apr 2020
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Cobalt−Catalyzed Enantioselective Hydroarylation of 1,6-Enynes
Andrew Whyte,†,‡ Alexa Torelli,†,‡ Bijan Mirabi,† Liher Prieto,†, § José F. Rodríguez,† and Mark
Lautens†*
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†Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario
M5S 3H6, Canada
§Department of Organic Chemistry II, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain
catalysis, cobalt, enantioselective, C−H functionalization, enynes
ABSTRACT: An asymmetric hydroarylative cyclization of enynes involving a C–H bond cleavage is reported. The cobalt–
catalyzed cascade generates three new bonds in an atom-economical fashion. The products were obtained in excellent yields and
excellent enantioselectivities as single diastereo- and regioisomers. Preliminary mechanistic studies indicate the reaction shows no
intermolecular C–H crossover. This work highlights the potential of cobalt catalysis in C–H bond functionalization and enantiose-
lective domino reactivity.
synthesis, and use in domino processes.17 Considering the
INTRODUCTION
The functionalization of inert C–H bonds promoted by
variety of cobalt−catalyzed 1,6–enyne cyclization strategies
reported in the literature,18 methods that cleave C–H bonds
remain significantly underexplored.19
transition metals has unlocked a myriad of possibilities in
organic synthesis over the past decade.1 Its foremost impact in
Scheme 1. Enantioselective cobalt−catalyzed C–H bond
functionalization of indoles with alkenes and enynes
catalysis stems from greatly improving synthetic efficiency by
removing previously required prefunctionalization of
substrates. Precious metals have been the most widely
explored catalysts to functionalize C–H bonds, however, first-
row transition metals have recently emerged as cost-effective
alternatives that display unique reactivity patterns.2 In
particular, cobalt has proven to be a potent catalyst to break
otherwise inert C–H bonds.3
While numerous C–H functionalizations have been explored
including cyanation,4 amidation,5 halogenation,6,4a alkylation,7
and arylation,8 the hydroarylation of alkenes9 and alkynes10
comprise nearly half of all reports of cobalt-catalyzed C–H
functionalizations. Despite the volume of work, only a handful
of enantioselective methods have been reported,11 which
predominantly employ indoles bearing directing groups for C2
functionalization.12
In 2015, Yoshikai reported a low-valent cobalt-catalyzed
hydroarylation of indoles using chiral phosphoramidite ligands
to obtain moderate enantioselectivities (Scheme 1a).13 More
recently, Ackermann reported a Co(III) variant employing
chiral carboxylic acids for enantioinduction to functionalize N-
pyridyl indoles (Scheme 1b).14 Despite these advances,
enantioselective cobalt-catalyzed transformations via C–H
bond functionalization have posed a formidable challenge in
organic chemistry. Recently, Cramer reported an alternative
strategy by employing chiral Cp* ligands to perform ortho-C–
H functionalization of benzamide derivatives bearing internal
Scheme 1. Previous work on cobalt-catalyzed C–H bond func-
tionalization of indoles with alkenes and the design of a tandem
oxidants.15
In light of our work exploring domino reactivity and C–H
functionalizations, we sought to merge these concepts in an
asymmetric fashion.16 We considered 1,6-enynes as an ideal
scaffold for our initial investigations based on their ease of
enyne cyclization/C–H bond functionalization cascade
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Table 1. Cobalt−Catalyzed Asymmetric Hydroarylative Cyclization of Enynes: Optimization of Reaction Conditions
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2
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entry
variation of standard condition
none
yield [%]a
conv. [%]
2i remaining
erb
1
2
3
4
5
6
7
8
9
96 (90)
99
5
0.49 equiv
0.17 equiv
1.50 equiv
0.32 equiv
1.41 equiv
0.07 equiv
1.50 equiv
0.16 equiv
0.85 equiv
b
95.5:4.5
n.d.
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THF instead of DCM
0
MeCN instead of DCM
Toluene instead of DCM
CoCl2 instead of CoBr2
CoI2 instead of CoBr2
0
2
n.d.
89
89
15
80
6
94:6
7
91:9
70
95.5:4.5
n.d.
Co(acac)2 instead of CoBr2
1.2 equiv enyne instead of 1.5 equiv
20 mol% ZnI2 instead of NaBARF
0
93 (86)
36
97
39
95.5:4.5
94:6
aNMR yield determined by 1H-NMR with 1,3,5-trimethoxybenzene as standard, isolated yield in parenthesis. Determined by chiral HPLC
using IB column eluting with 50% IPA in hexanes.
however
we
observed
marginally
decreased
RESULTS AND DISCUSSION
enantioselectivities. We successfully scaled the reaction to 2
mmol, employing reduced catalyst, ligand, NaBARF, Zn, and
solvent amounts and obtained product 2a in 83% yield and
96:4 er.
We initiated our studies by employing N-pyridyl indoles and
found optimal conditions related to those reported by
RajanBabu (Table 1).20 We observed the desired product as a
single diastereomer and regioisomer in 90% yield and 95.5:4.5
er. Other chiral bisphosphine ligands failed in this reaction
(see SI for details). We examined the effect of solvation and
found that more polar solvents such as THF (Entry 2) and
acetonitrile (Entry 3) inhibited product formation. Toluene
(Entry 4) provided the product in 89% yield and 94:6 er. A
cobalt catalyst survey revealed that CoCl2 (Entry 5) and
Co(acac)2 (Entry 7) were ineffective. A 70% yield was
obtained when CoI2 was used (Entry 6), however, we did not
obtain full conversion and only trace amounts of enyne
remained. Although we could reduce the amount of enyne to
1.2 equivalents (Entry 8), we obtained the product in slightly
reduced yield (86% yield). Following reports by Hilt21 and
Cheng,19b,19c ZnI2 (Entry 9) was explored in place of NaBARF,
however the product was obtained in 36% yield and 94:6 er.
Scheme 2. Optimization of Directing Group on the Indole
After optimizing the parameters of the reaction, we
examined the effect of the directing group in the
hydroarylative cyclization. The 2-pyridyl directing group
provided product 3a in 99% yield and 97:3 er. The N-
pyrimidyl group furnished product 3b in 92% yield, however,
with lower enantioselectivity (92:8 er). Both acetyl (3c) and
Boc (3d) groups could be used in place of N-heterocyclic
directing groups in 79.5:20.5 er and 92:8 er respectively.
Sulfonamide-based directing groups were unsuccessful in this
process (3e) and free indole (3f) gave no product. We briefly
examined the effect of substituents on the 2-pyridyl group,
based on Ackermann’s findings.14 A methyl substituent at the
meta or para positions (3g, 3h) of the pyridine provided
products in good yield, (85% yield and 77% yield
respectively), and nearly identical enantioselectivity compared
to the unsubstituted pyridine. A bromide (3i) or chloride (3j)
at C5 of the pyridyl group also furnished the product with
results comparable to the unsubstituted pyridyl group,
Scheme 2. Reactions performed on a 0.20 mmol scale. All report-
ed yields are after isolation, er determined by chiral HPLC. Run
on 2 mmol scale using 2.5 mol% CoBr2, (R,R)-QuinoxP* (3
mol%), Zn (10 mol%), NaBARF (4 mol%), 2a (1.5 equiv), DCM
(0.4 M), 60 °C, 24 h.
1
The effect of various substituents on the indole (Scheme 3)
was also investigated. A proximal methyl on the indole moiety
showed little impact on the yield of 3k (94% yield), but a
noticeable decrease in enantioselectivity was observed. Both a
methyl (3m) and benzyl ether (3n) at C-4 of the indole
generated products with high yields (88% and 95%
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respectively) and enantioselectivities (95:5 and 95.5:4.5 er
(3z) was isolated in 61% yield and 60.5:39.5 er. Interstingly,
the nature of the C−H bond and directing group appear to have
a dramatic effect on the enantioselectivity. Based on these
results, a furan-based substrate was tested to obtain product
3aa, in 79% yield and 90.5:9.5 er. Notably, the er was higher
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respectively). The substrate bearing a bromide in the same
position (3o) generated the product in 99% yield and with
excellent enantioselectivity (97:3 er). Electron-donating
groups such as methyl (3o) and methoxy (3p) were tolerated
and gave the desired products in excellent yields (96% and
97% respectively) and high enantioselectivities. Furthermore,
halogens at C5 including fluoride (3q) and bromide (3r)
furnished products in near quantitative yields and high e.r.
(96.5:3.5 and 97:3 respectively). A silyl-protected benzyl
alcohol (3s) furnished product in decreased yield (39% yield),
however high enantioselectivity was retained (95:5 er).
Unfortunately, both nitro and cyano motifs were not tolerated
in this reaction (see SI for details). Indoles bearing a variety of
halogens at C6: fluoride (3t), chloride (3u), and bromide (3v),
furnished products in consistently high yields and
enantioselectivities.
compared to 3y, further illustrating
a stereoselectivity
difference between heteroaryl and aryl C−H bond donors.
Scheme 4. Participating Enynes
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Scheme 3. Aryl C−H Bond Donors
Scheme 4. Reactions performed on a 0.20 mmol scale. All report-
1
Scheme 3. Reactions performed on a 0.20 mmol scale. All report-
ed yields are after isolation, er determined by chiral HPLC. Run
1
ed yields are after isolation, er determined by chiral HPLC. Used
at 80 °C
0.2 mmol of enyne and 0.3 mmol of Ar−H.
Varying the nature of the indole core structure was also
examined (Scheme 3). A pyrrole which contains two potential
reactive C–H bonds was studied to explore chemoselectivity.
Employing 1.5 equivalents of the pyrrole, to favor mono-
functionalization, gave product 3w in 83% yield. Next, we
employed a substrate bearing a methyl substituent at the 2-
position of the pyrrole to prevent di-functionalization. Product
3x was isolated in 86% yield and 97:3 er. We attempted to
employ other heterocycles such as benzimidazole however, no
product was formed (see SI for details). Finally, substrates
with aryl C–H bonds were reacted. We found that 2-
phenylpyridine could be employed to generate product 3y in
68% yield and 87.5:12.5 er. Following Cheng’s work,19c
acetophenone was a competent C–H bond donor and product
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Scheme 5. Deprotection and Mechanistic Studies
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Scheme 5. Reactions performed on 0.20 mmol scale unless indicated otherwise. All yields are after isolation unless indicated otherwise.
1Yields were determined by 1H-NMR analysis of the
crude using 1,3,5-trimethoxybenzene as an internal standard
Next, we surveyed various enynes to examine the effect of
different aryl groups on the alkyne (Scheme 4). A methyl
substituent at the para position furnished product 4b in similar
yield and enantioselectivity compared to 3a. However, an
isopropyl group (4c) required higher temperature to reach
analogy to product 4f, we obtained product 4n, containing a
methoxy substituent, in good yield and 97:3 er without
requiring an increase in temperature. Unfortunately, electron-
withdrawing substituents such as fluoride (4o), trifluoromethyl
(4p), and an ethyl ester (4q) required higher temperatures and
were obtained with lower enantioselectivities. Product 4r,
containing a bromide was furnished in 86% yield and 94.5:5.5
er. Notably, a 3,5-dimethoxy substitution pattern furnished
product 4s in excellent yield (94%) and enantioselectivity
(96:4 er). Both cyano- and nitro- containing aryl rings were
not tolerated (see SI for details). Substituents at the ortho
position had a dramatic impact on the reaction. Although
products 4t and 4u (containing a methoxy and fluoride
substituent respectively) could be obtained in reasonable
yields, we observed a significant decrease in er (vide infra).
Furthermore, heterocycles such as thiophene (4v) and alkyl
substituents (4w) could be tolerated in the reaction, however
we observed poor enantioselectivities.
°
good conversion. At 80 C product 4c was isolated in 77%
yield and comparable enantioselectivity to 4b. Phenyl (4d) and
thienyl (4e) substituted phenyl rings required higher
temperatures and gave products in good yields and high er.
Notably, a methoxy substituent in the para position did not
require higher temperatures, and furnished product in 81%
yield and 97:3 er. Halogens, including fluoride (4g), chloride
(4h), and bromide (4i) were tolerated in the para position. The
products (4g-4i) were obtained in good yields (79%, 99% and
80% respectively) and all achieved 95.5:4.5 er. Single crystal
X-ray diffraction was performed on 4h and all products are
assigned stereochemistry by analogy. An electron-
withdrawing trifluoromethyl group (4j) produced the
corresponding product in 70% yield and a slightly lower
enantioselectivity (93.5:6.5 er). Other functionalities were
tested such as an alkyl ester-tethered phenol (4k) which gave
the product in moderate yield (51%) and good
enantioselectivity (94:6 er). Building on the results from
product 3s, we hypothesized a more stable TIPS group would
perform better than a TBS group. At 80 °C product 4l,
containing a TIPS protected benzyl alcohol, was obtained in
73% yield and 95:5 er. A methyl substituent in the meta
position also required a higher temperature (80 °C) and we
obtained the product (4m) in 92% yield and 96:4 er. In
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Scheme 6. Potential Reaction Pathways
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Scheme 6. Proposed reaction pathways via oxidation cyclization or oxidation addition. Ligands omitted for clarity.
We examined other types of enyne scaffolds to expand the
scope beyond the synthesis of pyrrolidines. The analogous
tetrahydrofuran product (4x) was formed in comparable yield
(87% yield) and 94:6 er. Product 4y, bearing a geminal diester,
was formed in 71% yield and 97:3 er. Unfortunately, nosyl-
protected pyrrolidines were unsuccessful (see SI for details).
However, thienyl-based sulfonamides (4z) gave the product in
97% yield and 96:4 er. Finally, substrates bearing alkene
substitutents failed to react. Removal of the pyridine-based
directing group was possible, generating the free indole (5a) in
66% yield (Scheme 5).22
To gain insight into the reaction mechanism we synthesized
deuterated substrate d-1a (80% D) and subjected it to the
standard conditions. Product d-3a was obtained in quantitative
yield with 78% deuterium incorporation supporting that the
heterocycle remains bound following C−H bond cleavage. We
performed a crossover experiment with substrate 1d and d-1a,
and observed the deuterium label exclusively in d-3a derived
from the deuterated substrate. No deuterium incorporation was
seen in 3d indicating a lack of crossover between substrates
during the reaction. The absence of crossover rules out
mechansims involving a ligand-to-ligand hydrogen transfer
which has been previously reported in cobalt (III)-catalyzed
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C−H bond cleavages.23 A KIE experiment was undertaken by
Additional mechanistic studies and applications are currently
underway in our laboratory.
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employing a 1:1 mixture of the proto- and deuterium labelled
substrates. The measured KIE (1.4) contrasts to Cheng’s report
of 2.8 when using acetophenone as a C−H bond donor.19c The
distinction between aryl and heteroaryl motifs is further
exemplified by differences in enantioselectivity. Products 3y
and 3z, arising from insertion into aryl C−H bonds, were
obtained in lower enantioselectivities compared with 3a
containing heteroaryl C−H bonds. This observation further
illustrates a potential mechansitic deviation between this
work, using heteroaryl C−H bonds, and Cheng’s report, using
aryl C−H bonds. Finally, we probed the chelating effect
between the enyne and catalyst by constructing enynes
resembling the substrate lacking either the alkyne (2ab) or
alkene (2ac). In both instances we failed to observe products
resulting from a hydrometallation process and only observed
unreacted starting material. The lack of reactivity suggests that
chelation of the enyne to the cobalt-catalyst is critical for
product formation.18b
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: Crystallographic data for 4h
(CIF), CCDC 1983369.
Experimental procedures, characterization data, 1H/13C NMR
spectra, X-ray structures of 4h, and HPLC spectra for new com-
pounds
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AUTHOR INFORMATION
Corresponding Author
*mark.lautens@utoronto.ca
Author Contributions
‡A.W. and A.T. contributed equally to this work.
Based on these studies we propose the reaction proceeds
through via an oxidative cyclization or oxidative addition
pathway (Scheme 6). The abundance of previous reports on
cobalt-catalyzed enyne cyclizations under similar conditions
points toward an oxidative cyclization pathway (Scheme
6a).18,20 However, we do not observe any byproducts resulting
from the enyne dimerizing in a [2+2+2] reaction. The
oxidative cyclization mechanism would begin with initial
generation of the bisphosphine-ligated cationic cobalt (I)
catalyst (6a) in the presence of zinc and NaBARF, which has
been well precedented.20,24 The active catalyst, 6a, would then
undergo pre-coordination with the enyne (2a) to obtain
intermediate 6b. An enantioselective oxidation cyclization
would yield cobaltacycle 6c, which could then undergo
coordination to 1a, assisted by the pyridine directing group.
The C−H bond would be cleaved through a σ-bond metathesis
to generate 6e or 6f. Regardless of the selectivity, the product
would be formed through reductive elimination to yield
product 3a and regenerate the active catalyst 6a. An oxidative
cyclization mechanism should be more sensitive to the nature
of the alkyne substitutent and could greatly affect the
stereoselectivity of the oxidative cyclization. This pathway
would explain why ortho-substituted aryl rings (4t and 4u)
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the University of Toronto, the Natural Science and En-
gineering Research Council (NSERC), Alphora/Eurofins, and
Kennarshore Inc. for financial support. A.W. thanks the Walter C.
Sumner Memorial Fellowship and the Province of Ontario (QEII)
for funding. A.T. and B.M. thank the Province of Ontario (OGS)
for funding. L.P. acknowledges the Basque Government (Grupos
IT908-16) and UPV/EHU for financial support. J.R. thanks the
Government of Canada (NSERC-PGS) for support. We thank
Alan Lough (University of Toronto) for X-ray crystallography of
4h. We thank Dr. Darcy Burns and Dr. Jack Sheng (University of
Toronto) for their assistance in NMR experiments.
REFERENCES
(1) For selected reviews on C−H functionalization see: (a) Chu, J.
C. K.; Rovis, T. Complementary Strategies for Directed C(Sp3)−H
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A Comparison of Transition-Metal−Catalyzed
Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer.
Angew. Chem. Int. Ed. 2018, 57, 62–101. (b) He, J.; Wasa, M.; Chan,
K. S. L.; Shao, Q.; Yu, J.-Q. Palladium−Catalyzed Transformations of
Alkyl C–H Bonds. Chem. Rev. 2017, 117 , 8754–8786. (c) Zheng, Q.-
Z.; Jiao, N. Ag−Catalyzed C–H/C–C Bond Functionalization. Chem.
Soc. Rev. 2016, 45, 4590–4627. (d) Wencel-Delord, J.; Glorius, F. C–
H Bond Activation Enables the Rapid Construction and Late-Stage
Diversification of Functional Molecules. Nat. Chem. 2013, 5, 369–
375. (e) Davies, H. M. L.; Manning, J. R. Catalytic C–H Functionali-
zation by Metal Carbenoid and Nitrenoid Insertion. Nature. 2008,
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C–H Bond Activation. Chem. Rev. 2017, 117, 9086–9139. (g) Hart-
wig, J. F. Evolution of C–H Bond Functionalization from Methane to
Methodology. J. Am. Chem. Soc. 2016, 138, 2–24. (h) Alberico, D.;
Scott, M. E.; Lautens, M. Aryl−Aryl Bond Formation by Transition-
Metal−Catalyzed Direct Arylation. Chem. Rev. 2007, 107, 174–238.
(i) Abrams, D. J.; Provencher, P. A.; Sorensen, E. J. Recent Applica-
tions of C–H Functionalization in Complex Natural Product Synthe-
sis. Chem. Soc. Rev. 2018, 47, 8925–8967. (j) McMurray, L.; O’Hara,
F.; Gaunt, M. J. Recent Developments in Natural Product Synthesis
Using Metal−Catalysed C–H Bond Functionalisation. Chem. Soc.
Rev. 2011, 40, 1885. (k) Lyons, T. W.; Sanford, M. S. Palladi-
um−Catalyzed Ligand−Directed C−H Functionalization Reactions.
Chem. Rev. 2010, 110, 1147–1169. (l) Tsui, G. C.; Lautens, M. C−H
Activation Reactions in Domino Processes. In Domino Reactions;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2013;
Vol. 1, pp 67–104. (m) Baudoin, O. Transition Metal−Catalyzed Ary-
and alkyl substituents
enantioselectivities.
(4w) resulted in lower
Although the lack of reactivity of 2ab and 2ac (Scheme 5e)
suggests C−H bond oxidative addition is unlikely, it cannot be
ruled out as the catalyst might require 1,6-enyne coordination
(Scheme 6b). A C−H oxidation addition and subsequent enyne
coordination would yield intermediate 6h. The cobalt (III)
intermediate could then proceed via a carbometallation or
hydrometallation pathway (6i or 6j respectively), followed by
a second migratory insertion to yield intermediates 6e or 6f.
The pathways converge at this point to furnish product 3a.
CONCLUSIONS
In conclusion, we have developed a highly enantioselective
cobalt−catalyzed C–H functionalization of pyridyl-indoles
using 1,6-enynes. The reaction generates two new carbon-
carbon bonds and one carbon-hydrogen bond in
a
stereocontrolled fashion in excellent yields. The reaction
highlights potential of cobalt catalysis in C–H
functionalization and enantioselective transformations.
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lation of Unactivated C(Sp3)–H Bonds. Chem. Soc. Rev. 2011, 40,
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