Selective Synthesis of Indoles by Cobalt(III)-Catalyzed C-H/N-O Functionalization with Nitrones

Article abstract of DOI:10.1021/acscatal.5b02937

The redox-neutral annulation of alkynes by differently decorated nitrones set the stage for a step-economical access to indoles with ample substrate scope. The redox-neutral C-H/N-O functionalization process proceeded through kinetically relevant C-H activation by carboxylate assistance, and displayed an excellent site- and regio-selectivity with unsymmetrical nitrones and alkynes.

Full text of DOI:10.1021/acscatal.5b02937

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Letter
Selective Synthesis of Indoles by Cobalt(III)-
Catalyzed C-H/N-O Functionalization with Nitrones
Hui Wang, Marc Moselage, María González, and Lutz Ackermann
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02937 • Publication Date (Web): 29 Feb 2016
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Selective Synthesis of Indoles by Cobalt(III)ꢀCatalyzed
C−H/N−O Functionalization with Nitrones
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Hui Wang, Marc Moselage, María J. González, and Lutz Ackermann*
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität,
Tammannstraße 2, 37077 Göttingen, Germany
Supporting Information Placeholder
ABSTRACT: The redox-neutral annulation of alkynes by differently decorated nitrones set the stage for a step-economical access
to indoles with ample substrate scope. The redox-neutral C–H/N–O
functionalization process proceeded through kinetically relevant C–H
activation by carboxylate assistance, and displayed an excellent site-
and regio-selectivity with unsymmetrical nitrones and alkynes.
KEYWORDS: C–H activation, carboxylates, cobalt, indole, mecha-
nism
Substituted indoles are important structural motifs found in
compounds of relevance to medicinal chemistry, crop protec-
tion, and drug discovery, among others.1 As a consequence,
there is a continued strong demand for the development of
generally applicable de-novo syntheses of these heteroarenes.2
In this context, the recent years have witnessed the emergence
of C–H functionalizations as increasingly powerful tools for
the assembly of heteroarenes,3 thereby avoiding the use of
prefunctionalized substrates.4 Specifically, versatile transition
metal catalysts set the stage for the direct synthesis of indoles.5
Despite undisputable advances, these protocols largely re-
quired precious second-row transition metals.6 In the past few
years, naturally-abundant base metal catalysts proved instru-
mental for efficient C–H activation reactions,7 with major
advances being accomplished by high-valent cobalt catalysts8
as reported by Matsunaga/Kanai,9 Ackermann,10 Glorius,11
Daugulis,12 and Chang,13 among others.14 In spite of this sig-
nificant progress, a cobalt(III)-catalyzed de-novo synthesis of
indoles by C–H activation technology has thus far proven
elusive. Within our program on base metal-catalyzed C–H
functionalizations,15 we became attracted to devise protocols
for cobalt(III)-catalyzed indole syntheses, on which we report
herein.
Notable features of our findings include (i) unprecedented
robust cobalt(III)-catalyzed indole synthesis by C–H activation
(ii) isohypsic, i.e. redox-neutral, C–H/N–O functionalization
with easily-accessible nitrones 1 that avoid external oxidants,
and (iii) – in contrast to a very recently reported rhodium(III)-
catalyzed transformation16 – significantly improved selectivity
patterns in C–H functionalizations with unsymmetrical al-
kynes 2 (Figure 1).
At the outset of our studies, we tested various reaction con-
ditions for the envisioned C–H/N–O functionalization with
nitrone 1a and alkyne 2a (Table 1, and Tables S-1–S-3 in the
Supporting Information). Preliminary experiments highlighted
Cp*CoI2(CO) to be the catalyst of choice, and indicated that
HFIP and TFE were most suitable among a variety of sol-
vents.17,18 While K2CO3 and PivOH as additives gave rather
unsatisfactory results (entries 1, and 2), acetates proved to be
superior, with NaOAc being optimal (entries 3–5). The syn-
thesis of indole 3aa occurred in the absence of silver(I) salts
(entry 6), but was more effective when employing co-catalytic
amounts of AgSbF6 (entries 5–10). The isohypsic alkyne annu-
lation proceeded at lower reaction temperatures, yet best
yields were accomplished at 100 °C (entries 11–14). In recent
years, N-acyl amino acid ligands have been identified as pow-
erful ligands in metal-catalyzed C–H functionalizations, as
reported by Yu19 and our group.20 Thus, we conducted a com-
parative study with a series of amino acid ligands for the co-
balt-catalyzed C–H/N–O functionalization of nitrone 1a (en-
tries 16–27). Notably, Piv-Leu-OH emerged as a powerful
ligand, efficiently delivering the desired indole 3aa (entry 27).
Interestingly, the rhodium(III) complex [Cp*RhCl2]2 failed to
provide the desired product 3aa in comparable yields (entry
28–30). Moreover, the key importance of the cobalt catalyst
and the carboxylate additive for the C–H activation process
was verified (entries 31 and 32).
Figure 1. Cobalt-Catalyzed Indole Synthesis
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Table 1. Optimization of Alkyne Annulation a
With optimized reaction conditions being identified, we
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2
3
4
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8
probed the scope of the cobalt(III) catalysis in the C–H/N–O
functionalization with various nitrones 1 (Scheme 2). The
most user-friendly cobalt catalyst showed a considerable
chemo-selectivity, by fully tolerating important electrophilic
functional groups, such as fluoro, chloro, bromo, ester or
thiophene substituents. The intramolecular competition exper-
iments with meta-substituted nitrones 1h and 1j bearing two
inequivalent ortho-C–H bonds site-selectively delivered in-
doles 3ha and 3ja,9a,10b,g respectively, as the sole products.
entry
1
additive 1
AgSbF6
additive 2
K2CO3
T (°C)
3aa (%)
120
10
2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
---
HOPiv
120
120
120
120
120
120
120
120
120
23
66
86
88
90
62
82
80
82
86
9
9
3
KOAc
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4
CsOAc
Cp*CoI2(CO) (5.0 mol %)
AgSbF6 (20 mol %)
additive (20 mol %)
Ph
Ph
H
N
5
NaOAc
R
Ph
+
R
O
6
NaOAc
N
HFIP, 100 °C, 16 h
Ph
H
under air
7
AgPF6
NaOAc
PMP
8
AgBF4
NaOAc
1
2
3
9
AgOTf
AgOTs
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
NaOAc
Ph
Ph
Ph
Ph
F
Me
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31
NaOAc
Ph
Ph
NaOAc
N
N
H
N
H
H
NaOAc
50
46
77
92
67b
73
83
80
77
78
80
6
3ea
NaOAc:
3aa
NaOAc:
3da
NaOAc:
NaOAc
80
70%
92%
76%
Piv-Leu-OH: 67%
gram-scale: 82%
Piv-Leu-OH: 88%
Piv-Leu-OH: 68%
NaOAc
100
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100
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100
100
100
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100
120
120
NaOAc
Ph
Ph
Ph
Cl
Br
Piv-Ile-ONa
Ac-Ile-ONa
Ac-Leu-ONa
Ac-IIe-OH
Piv-IIe-OH
Piv-IIe-ONa
Fmoc-Met-OH
Piv-Pro-OH
Piv-Ala-OH
Piv-Asn-OH
Piv-Phe-OH
Piv-Leu-OH
NaOAc
Ph
Ph
Ph
N
N
N
Me
H
H
H
H
3ha
NaOAc:
3fa
NaOAc:
3ga
NaOAc:
78%
70%
91%
Piv-Leu-OH: 89%
Piv-Leu-OH: 76%
Piv-Leu-OH: 80%
O
Ph
Ph
S
EtO
Ph
Ph
N
N
74
72
73
71
88
13c
31c
40c
--- d
7
H
H
H
3ja
NaOAc:
Piv-Leu-OH: 77%
3ia
NaOAc:
Piv-Leu-OH: 61%
82%
67%
Scheme 2. C–H/N–O Functionalization with Nitrones 1
HOPiv
The versatile cobalt(III) catalysts also enabled the annula-
tion of substituted tolane derivatives 2b–2f by the C–H/N–O
functionalization process (Scheme 3). Thereby, a variety of
2,3-diaryl indoles 3 was accessed in a step-economical fash-
ion.
CsOAc
NaOAc
32
---
a
Reaction conditions: 1a (0.50 mmol), 2a (0.75 equiv), Cp*CoI2(CO) (5.0 mol %),
additive 1 (10 mol %), additive 2 (20 mol %), HFIP (2.0 mL), T, 16 h. b 3 h. c Using
[Cp*RhCl2]2 (2.5 mol %). d Without Cp*CoI2(CO). PMP = para-methoxyphenyl.
Next, we explored the dependence of the catalytic efficacy
on the C-substitution pattern of the nitrones 1 (Scheme 1). In
stark contrast to a recently reported rhodium-catalyzed trans-
formation,16 the PMP substituent proved to be superior to the
bulky, and less atom-economical mesityl substitution pattern
that proved to be mandatory for the rhodium(III) catalysis.16
Scheme 1. Influence of the C-Substitution Pattern
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Interestingly, the dialkyl-substituted alkyne 2l delivered 3,3-
1
2
3
4
disubstituted 3H-indole 4al (Scheme 5), which contrasts
Chang’s22a report on rhodium(III)-catalyzed syntheses of in-
dolines,16,22a while being in agreement with a more recent
finding.22b
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Scheme 5. Formation of 3H-Indole 4al
The user-friendly nature of the C–H activation strategy was
reflected by the use of a cationic single-component catalyst,
thus avoiding the use of any additional silver salts (Scheme 6).
Scheme 3. Cobalt(III)-Catalyzed Annulation of Tolanes 2
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In contrast to a recent rhodium-catalyzed indole synthesis,16
the expedient cobalt catalysis proved particularly effective for
the challenging annulation of unsymmetrically substituted
alkynes 2 in a regio-selective fashion (Scheme 4).21 Hence, the
C–H/N–O functionalization process furnished products 3ag–
3hj, generally placing the aryl moiety proximal to the nitrogen
heteroatom. It is particularly noteworthy that the unsymmet-
rical diaryl-substituted alkyne 2k delivered indole 3ak with
excellent levels of regio control, while a rhodium(III) catalyst
previously furnished the two regioisomers without a signifi-
cant element of selectivity.16
Scheme 6. Single-Component Catalyst
In consideration of the unique selectivity features of the co-
balt(III)-catalyzed C–H/N–O functionalization, we became
intrigued by unravelling the catalysts mode of action.17 To this
end, intermolecular competition experiments revealed elec-
tron-rich nitrones 1 to be inherently more reactive. This find-
ing can be rationalized in terms of a base (acetate)-assisted
intramolecular electrophilic substitution-type (BIES)10a,23
mechanism being operative within the C–H cobaltation via
carboxylate24 assistance (Scheme 7a). Electron-rich alkynes 2
were found to be preferentially converted (Scheme 7b), which
is suggestive of a kinetically relevant alkyne coordination. In
contrast to a rhodium-catalyzed alkyne annulation,16 we did
not observe any H/D scrambling when using isotopically la-
beled co-solvents (Scheme 7c),17 while independent reactions
with substrates 1a and [D]5-1a revealed a kinetic isotope effect
(KIE) of kH/kD ≈ 2.7 (Scheme 7d). These observations provide
strong support for a rate-determining C–H activation.
Scheme 4. Annulation of Unsymmetrical Alkynes 2
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Scheme 8. Plausible Catalytic Cycle
In summary, we have described the first cobalt-catalyzed
de-novo indole synthesis by C–H activation. The versatile
cationic cobalt(III) catalyst proved to be broadly applicable in
the alkyne annulation by easily accessible nitrones via C–
H/N–O functionalization. The robust cobalt-catalyzed indole
synthesis was characterized by an excellent functional group
tolerance and a unique regio-selectivity in the annulation of
unsymmetrical alkynes. Mechanistic studies provided strong
support for a kinetically relevant C–H cobaltation through
carboxylate assistance.
Scheme 7. Key Mechanistic Findings
Based on these mechanistic studies we propose the catalytic
cycle for the C–H/N–O functionalization to commence by a
rate-determining C–H cobaltation of cationic co-
balt(III)carboxylate complex 5 that generates metallacyle 6
(Scheme 8). The subsequent insertion of alkyne 2 delivers the
intermediate 7, which thereafter undergoes N–O cleavage,
along with C–O formation. The thus-formed cobalt(III) eno-
late 8 regenerates the catalytically active cationic complex 5
by proto-demetalation with HOAc. Thereby, protected ortho-
amino ketone 9 is formed, which upon hydrolysis and subse-
quent intramolecular condensation furnishes the desired indole
3.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data, and H and 13C
NMR spectra for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Author
* Lutz.Ackermann@chemie.uni-goettingen.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Support by the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007–
2013)/ERC Grant agreement no. 307535, the CSC (fellowship to
H.W.), and the DAAD (fellowship to M.J.G.) is gratefully
acknowledged.
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