Catalytic Synthesis of Indolines by Hydrogen Atom Transfer to Cobalt(III)–Carbene Radicals

Article abstract of DOI:10.1002/chem.201704626

We report a new method for the synthesis of indolines from o-aminobenzylidine N-tosylhydrazones proceeding through a cobalt(III)–carbene radical intermediate. This methodology employs the use of inexpensive commercially available reagents and allows for the transformation of easily derivatized benzaldehyde-derived precursors to functionalized indoline products. This transformation takes advantage of the known propensity of radicals to undergo rapid intramolecular 1,5-hydrogen atom transfer (1,5-HAT) to form more stabilized radical intermediates. Computational investigations using density functional theory identify remarkably low barriers for 1,5-HAT and subsequent radical rebound displacement, providing support for the proposed mechanism. We explore the effect of a variety of nitrogen substituents, and highlight the importance of adequate resonance stabilization of radical intermediates to the success of the transformation. Furthermore, we evaluate the steric and electronic effects of substituents on the aniline ring. This transformation is the first reported example of the synthesis of nitrogen-containing heterocycles from cobalt(III)–carbene radical precursors.

Full text of DOI:10.1002/chem.201704626

A Journal of
Accepted Article
Title: Catalytic Synthesis of Indolines via Hydrogen Atom Transfer to
Cobalt(III)-Carbene Radicals
Authors: Alexander S. Karns, Monalisa Goswami, and Bas de Bruin
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201704626
Link to VoR: http://dx.doi.org/10.1002/chem.201704626
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10.1002/chem.201704626
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Catalytic Synthesis of Indolines via Hydrogen Atom Transfer to
Cobalt(III)–Carbene Radicals
Alexander S. Karns,ǂ,[b] Monalisa Goswami,ǂ,[a] and Bas de Bruin*,[a]
Abstract: We report a new method for the synthesis of indolines from
o–aminobenzylidine N–tosylhydrazones proceeding through
a
cobalt(III)-carbene radical intermediate. This methodology employs
the use of inexpensive commercially-available reagents and allows for
the transformation of easily derivatized benzaldehyde-derived
precursors to functionalized indoline products. This transformation
takes advantage of the known propensity of radicals to undergo rapid
intramolecular 1,5-hydrogen atom transfer (1,5-HAT) to form more
stabilized radical intermediates. Computational investigations using
density functional theory identify remarkably low barriers for 1,5-HAT
and subsequent radical rebound displacement, providing support for
the proposed mechanism. We explore the effect of a variety of
nitrogen substituents, and highlight the importance of adequate
resonance stabilization of radical intermediates to the success of the
transformation. Furthermore, we evaluate the steric and electronic
effects of substituents on the aniline ring. This transformation is the
first reported example of the synthesis of nitrogen-containing
heterocycles from cobalt(III)-carbene radical precursors.
Introduction
Identifying new reactivity of well-known functional groups
broadens their versatility in organic synthesis. Prior to recent
discoveries, the diazo functional group had generally been
considered a precursor to discrete carbenes or metallocarbenes.
These carbene intermediates have been shown to participate in a
variety of two-electron processes including cyclopropanations,
1,2-shifts, and bond insertions.[1] However, the discovery of
Co(II)-metalloradical catalysis, which unlocks radical-type
reactivity from carbene precursors, has invalidated the one-
dimensional stereotype of carbenes and has enabled carbene
precursors to perform a variety of single-electron processes
(Figure 1a). In spite of their importance, carbene radicals have
thus far not been utilized in the synthesis of nitrogen-containing
rings structures. Such reactions would expand the currently still
limited synthetic toolbox available for the synthesis of
N-heterocyclic motifs.
Figure 1. Radical Reactivity from Carbene Precursors.
Planar cobalt(II) complexes exhibit unique catalytic properties that
have found niche applications in organic synthesis. These stable
metalloradicals contain an open-shell doublet d7-electronic
configuration resulting in a singly-occupied electrophilic dz2 orbital.
Following coordination of a nucleophilic diazo functional group,
these complexes have been found to undergo an intramolecular
metal-to-carbon single electron transfer to form a radical carbene
intermediate, which is best described as a one-electron reduced
Fischer-type carbene (Figure 1b).[2] These intermediates retain
the reactive nature of radicals, but with a decreased susceptibility
toward carbene dimerization.[2]
[a]
Dr. M. Goswami and Prof. dr. B. de Bruin
This carbon-centered radical has been shown to participate in
various single-electron reactions including 1,2-addition[3] and
radical recombination (Figure 1c).[2b] In a recent example, our
group recently disclosed the formation of indene products from
radical carbene precursors which undergo a formal 1,2-addition
across a pendant olefin.[4] However, the only reported example in
this context of hydrogen atom transfer, a fundamental radical
transformation, utilized as a strategy in CC bond formation is
limited to the formation of highly specific sulfolane or sultone
derivatives.[5]
Van ’t Hoff Institute for Molecular Sciences (HIMS), Homogeneous
and Supramolecular Catalysis group.
University of Amsterdam, Science Park 904, 1098 XH Amsterdam,
The Netherlands. E-Mail: b.debruin@uva.nl
[b]
A. Karns
Department of Chemistry
University of California, Irvine, 1102 Natural Sciences II
Irvine, California 92697-2025, United States
ǂ
These authors provided equal contributions to this project.
Supporting information for this article is given via a link at the end of
the document.
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azide functional groups, have been shown to undergo C–H
abstraction in the formation of C–N bonds, but generally have
been limited in application to tailor-made starting materials.[23] To
date, the only disclosed method for indoline formation via
metalloradical catalysis was disclosed by the Che group, in which
they invoked a mechanism involving C–H abstraction by the
analogous iron(IV) nitrene radical to lead to formation of the key
CN bond (Figure 2a).[24]
We herein disclose a method for a complementary synthesis of
indolines by exploiting our observation that cobalt radical
intermediates undergo 1,5-hydrogen atom abstraction reactions
(Figure 2b). We identified [CoII(TPP)] as a cheap, commercially
available, air- and moisture-stable catalyst for this transformation,
and demonstrated the need for a planar cobalt(II) catalyst through
a series of control experiments. The scope of this methodology
was investigated through the installation of several functional
groups on the carbene precursor, and we examined our proposed
mechanism via computational studies. Overall, this method
represents the first synthesis of N-heterocycles via a cobalt(III)-
carbene radical mediated C–H activation and subsequent radical
rebound sequence.
Results and Discussion
Reaction Optimization – We began our investigation using the
N-benzyl substituted hydrazone 1a as a test substrate, designed
to facilitate 1,5-hydrogen atom abstraction through stabilization of
the intermediate benzylic radical (Table 1).
Figure 2. (a) Previous method for indoline synthesis by C-N bond formation. (b)
Our new method for indoline synthesis by C-C bond formation. (c) Catalysts
tested during reaction optimization in this study.
Table 1. Optimization of Conditions for Indoline Synthesis
The indoline N-heterocycle is commonly observed among both
natural products and pharmaceutical scaffolds, and the need to
access this important motif has led to a variety of methods by
which it can be obtained. Simple indolines can be efficiently
prepared from indole precursors in high yields, but this
transformation requires the use of strongly acidic, strongly
hydridic, or highly pressurized conditions.[6,7] Several dependable
and versatile methods have also been reported employing Pd,[8,9]
Cu,[10,11] Ni,[12] Ti,[13] and amines[14] as ring-closing catalysts.
Furthermore, a variety of methods to form indolines involving
radical ring-closing,[15] alkylation,[16] formal 1,2-addition across
Catalyst
Loading
Base
Equiv.
Yield
Entry
Catalyst
Time (h)
(%) [a]
1
2
--
--
1.7
1.7
1.7
1.7
1.7
1.7
1.7
1.7
1.2
3.0
1.7
1.7
18h
18h
18h
18h
18h
18h
18h
18h
18h
18h
6h
--
[Co(MeTAA)]
[Co(salen)]
[Co(TPP)]
[Co(TMP)]
[CoII(TPPF20)]
CoCl2
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
25 mol%
25 mol%
5 mol%
5 mol%
5 mol%
1 mol%
83%
76%
>99%
>99%
>99%
trace
--
3
olefins,[17–19]
benzyne
functionalization,[20]
and
[4+2]
4
cycloadditions[21] each present their own advantages. However,
several of these existing methods suffer from functional group
intolerance, the necessity of expensive noble transition metal
catalysts, harsh reaction conditions, and/or require the use of
protecting groups that require tedious conditions for their removal.
For this reason, there remains a need for new, efficient, and
broadly-applicable catalytic routes to expand the currently
available methods for indoline synthesis from readily-available
starting materials.
5
6
7
8
Rh2(OAc)4
Co(TPP)
9
35%
65%
95%
90%
10
11
12
Co(TPP)
Although carbene or nitrene precursors have previously been
used in the synthesis of indolines,[22] each method has been
proposed to proceed via standard two-electron mechanisms
commonly observed from these complexes. Cobalt(III) nitrene
radicals, which are formed via an analogous decomposition of
Co(TPP)
Co(TPP)
18h
[a] NMR yields.
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Table 2. Investigation of Substituent Effects on Indoline Formation
We initially found that heating of the tosyl hydrazone in the
presence of lithium tert-butoxide as a base resulted exclusively in
carbene dimerization products when in the absence of a metal
catalyst (Table 1, entry 1). However, the addition of
[CoII(MeTAA)], a high-spin metalloradical catalyst with known
propensity to form radicals from carbene precursors (for
structures of the catalysts, see Figure 2),[4] resulted in conversion
to the desired indoline product in 83% yield (entry 2). [CoII(salen)]
complexes also facilitated ring-closure, but at reduced and
somewhat less producible yields (entry 3). After establishing
porphyrins as more reliable ligands, we determined commercially
available and air- and moisture-stable catalyst [CoII(TPP)] to be
superior in this context, leading to quantitative yield of the indoline
product (entry 4). More electron rich ([CoII(TMP)]) or electron
deficient ([CoII(TPPF20)]) cobalt porphyrins gave similar results,
and provide no specific advantages over the commercially
available [CoII(TPP)] catalyst (entry 4-6). Using CoCl2 as a
catalyst led to formation of only trace quantities of the indoline
product, suggesting that planar (porphyrin-like) ligands are
essential (entry 7). Additionally, introduction of rhodium(II) acetate
dimer to facilitate 1,2-carbene insertion[25] resulted in no indoline
product, probably because the lithium tert-butoxide base
necessary to accomplish in situ diazo formation from the
tosylhydrazone precursor resulted in catalyst decomposition
(entry 8).
Yield (%)
Entry
Substrate
Product
[a]
R = Ph
R' = H
1
1a
1b
2a
2b
98%
92%
R = (p-CF3)-Ph
2
3
R' = H
R = (p-OMe)-Ph
1c
1d
2c
2d
96%
97%
R' = H
R = (o-Me)-Ph
4
R' = H
R = 2-furanyl
R' = H
5
6
1e
1f
2e
2f
95%
95%
The molar ratio of lithium tert-butoxide has a significant effect on
the yield of this transformation. Decreasing the amount of base to
1.2 equivalents limits the yield to 35%, whereas the addition of
three equivalents of base decreases the yield to 65% (entries
9-10). We postulate that this need for superstoichiometric base is
related to the low solubility of lithium tert-butoxide in benzene. In
addition to reagent optimization, we also found that near-
quantitative yields could be acquired with shorter reaction times
of 6 hours (Entry 11), and the catalyst loading could be decreased
to 0.01 equivalents with only a slight loss of yield (Entry 12).
R = 2-pyridyl
R' = H
R = H
R' = H
7
8
9
1g
1h
1i
2g
2h
2i
0%
0%
R = CH3
R' = H
Scope – To test the versatility of this transformation, we designed
a series of substrates with substituents that might have steric or
electronic implications on the proposed reaction mechanism
(Table 2). We found that the electron density on the N-benzyl ring
(entries 1-3) has little effect on the yield of the reaction.
Additionally, the introduction of a sterically bulky ortho substituent
on the benzylic functionality (entry 4) does not prevent the ring-
closure. The formed radical is also sufficiently stabilized by both
electron-rich and electron-poor heterocycles (entries 5 and 6,
respectively). The surprisingly low impact of the electronic
environment of the N-substituent supports the proposed single-
electron mechanism. Electron donating and electron withdrawing
substituents at the aniline moiety are also well tolerated (entries
11 and 12).
A clear limitation of this methodology involves the need for
substituents at the nitrogen atom that provide sufficient
stabilization of the proposed radical intermediate. We found that
a 1,5-hydrogen atom abstraction to form primary (entry 7) and
secondary (entry 8) radicals was not possible, suggesting that the
carbene radical intermediate is not reactive enough to generate
the required N-CHR radical intermediates in absence of aromatic
R-substituents providing resonance stabilisation.
R = -CH=CH2
R' = H
80%
R = Ph
R' = 3-Me
10
1j
2j
80%
81%
96%
R = Ph
R' = 4-OMe
11 1k
2k
2l
R = Ph
R' = 4-CF3
12
1l
[a] Isolated Yields
However, we found the allylic radical to be sufficiently stabilised
to provide 89% yield of the desired vinyl indoline product (entry 9).
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Functionalization of the aniline ring also provided substituted
indoline products in high yields. Introduction of a 5-methyl
substituent (entry 10) did not significantly affect reactivity and
provided an 80% yield of product. Additionally, we found that
electron-rich (entry 11) and electron-poor (entry 12) aniline
precursors successfully provided ring-closed products.
Substitution on the aniline ring has a more significant effect on
product yield as compared to substitution on the benzyl ring
(entries 2 and 3). We postulate that the electronics mainly
influence the presumed rate-limiting step of converting the tosyl
hydrazone substrate into the diazo compound. Substituents on
the aniline ring should have a significant influence on this polar
two-electron step, as opposed to radical-type steps.
with similar systems that have previously been studied
extensively, we considered a radical-type pathway involving
activation of the in situ formed diazo compound by the [CoII(Por)]
catalyst. The computations were performed at the BP86 and def2-
TZVP level using the non-functionalised [CoII(Por)] system. The
choice for this computational method is based on previous
realistic mechanistic pathways calculated by us for such systems
active as catalysts in related reactions. We further incorporated
Grimme’s dispersion corrections (DFT-D3) for these systems. For
the substrate, we included a full model for the diazo compound
formed from substrate S1. Based on the energies obtained from
these calculations we propose the mechanistic cycle depicted in
Figure 3.
Coordination of the diazo substrate on the catalyst to form a
substrate-bound adduct B[27] is exergonic by 4.9 kcal mol1. From
this adduct B, elimination of dinitrogen via TS1 (barrier: ΔG‡= +8.8
kcal mol1) leads to the formation of carbene-radical intermediate
C (ΔG°= 13.8 kcal mol1). From this intermediate C the key
1,5-HAT step proceeds readily via the low barrier transition state
TS2 (barrier: ΔG‡= +2.1 kcal mol1) to give intermediate D (ΔG°=
12.6 kcal mol1). Ring-closure by radical rebound and homolysis
of the CoC bond proceeds through the low, albeit slightly higher
barrier transition state TS3 (ΔG‡= +11.5 kcal mol1).
The computed barriers of all steps of the catalytic cycle depicted
in Figure 3 are surprisingly low. This suggests that formation of
the diazo compound from the tosyl hydrazone precursors, which
requires heating, is the rate limiting step of the reaction. Once the
diazo compound is generated, the next highest electronic barrier
in the catalytic reaction is the ring-closing step from species D to
liberate the product and regenerate catalyst A. Release of product
E with regeneration of catalyst A is strongly exergonic.
We also calculated the spin density distribution of the
intermediates C and D (Figure 3b and 3c). Maximum spin-density
in intermediate C is indeed located on the “carbene carbon” with
some further delocalisation in the neighbouring phenyl ring
(Figure 3b). The unpaired electron of intermediate D formed after
the 1,5-HAT step is delocalised over the benzylic carbon with
considerable delocalisation also on the adjacent phenyl ring
(Figure 3c).
Conclusions
In this work, we report a novel route for the synthesis of several
substituted indolines which have relevance to both natural
product and pharmaceutical scaffolds. The reaction initiates
efficiently via a [CoII(Por)]-catalysed pathway via activation of an
in-situ formed diazo compound to form a carbene radical. The
ensuing 1,5-hydrogen atom transfer step transforms the reactive
carbene radical into a more stabilized conjugated radical, which
then liberates the desired N-heterocylic product with regeneration
of the catalyst via a ring-closing radical displacement step. This
reaction uses inexpensive, commercially-available reagents and
allows for the use of tosyl hydrazones as safe, stabile precursors
to diazo compounds.[26]
Figure 3. Calculated Mechanism for Indoline Formation. (a) DFT-D3 calculated
(Turbomole BP86, def2-TZVP) free energies (ΔG298K° in kcal mol1) for the
proposed reaction pathway. Energies of all intermediates are reported with
respect to species A as the reference point (barriers for the transition states are
reported in between brackets). (b) Spin density plot of intermediate C showing
maximum spin density at the carbene carbon. (c) Spin density plot of
intermediate D after the 1,5-HAT step showing maximum spin density on the
benzylic carbon and some delocalisation over the adjacent phenyl ring.
DFT studies – To provide insight into the mechanism, we
explored the reaction computationally using DFT methods. In line
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Semproni, S. DeBeer, P. J. Chirik, Chem. Sci. 2014, 5, 1168–1174; g) C.
C. Comanescu, M. Vyushkova, V. M. Iluc, Chem. Sci., 2015, 6, 4570–
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To the best of our knowledge, this is the first example of a
cobalt(III)-carbene radical mediated CH activation/rebound
mechanism for the synthesis of N-heterocyclic organic products.
The metallo-radical catalysed indoline synthesis in this work
represents an example of a formal intramolecular carbene
insertion reaction into a benzylic CH bond, but proceeds via a
radical mechanism and displays highly controlled reactivity of the
key CoIII-carbene radical intermediates involved.
[3]
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Experimental Section
[4]
[5]
B. G. Das, A. Chirila, M. Tromp, J. N. H. Reek, B. de Bruin, J. Am. Chem.
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General Procedure for Indoline Formation: To a flame dried
schlenk tube was added substrate (0.300 mmol) followed by the
[Co(TPP)] (10 mg, 0.015 mmol, 5.0 mol%). The schlenk tube was
evacuated and back-filled with nitrogen three times, and
evacuated prior to transfer to a glove box. Once inside a glove
box, the reaction flask was slowly filled with nitrogen, and lithium
tert-butoxide (40.8 mg, 0.510 mmol, 1.7 equiv.) was added. The
solids were dissolved in 6 mL of benzene and the reaction flask
was removed from the glove box and transferred to an oil bath
preheated to 60 °C. After 18 hours, the reaction mixture was
cooled to room temperature, opened to air, and 6 mL of water was
added in a single portion. The water layer was extracted 3 times
with hexanes (3  6 mL). The organic portions were dried over
MgSO4, filtered through cotton, and concentrated in vacuo. The
crude residue was then purified via silica gel chromatography to
provide the pure indoline product.
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[6]
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[7]
[8]
[9]
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See supporting Information for further procedures and
characerisation data.
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Acknowledgements
A.S.K. would like to thank the NSF GROW fellowship (DGE-
1321846) for financial support, as well as Prof. Chris Vanderwal
for supporting his request to gain experience abroad. M.G and
BdB thank the Netherlands Organization for Scientific Research
(NWO-CW VICI grant 016.122.613, BdB) and the University of
Amsterdam (RPA Sustainable Chemistry) for financial support.
For palladium–catalyzed aryl–carbon couplings, see: T. Watanabe, S.
Oishi, N. Fujii, H. Ohno, Org. Lett. 2008, 10, 1759–1762.
[10] For copper–catalyzed aryl–nitrogen couplings: a) A. Klapars, X. Huang,
S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 7421–7428; b) K. Yamada,
T. Kubo, H. Tokuyama, T. Fukuyama, Synlett. 2002, 2, 231–234.
[11] For an aryl–N/C–N coupling cascade, see: A. Minatti, S. L. Buchwald,
Org. Lett. 2008, 10, 2721–2724.
[12] R. Omar–Amrani, A. Thomas, E. Brenner, R. Schneider, Y. Fort, Org.
Lett. 2003, 5, 2311–2314.
Keywords: Cobalt • Metalloradical • 1,5-HAT • Carbene Radical
• Indolines
[13] (a) P. Wipf, J. P. Maciejewski, Org. Lett., 2008, 10, 4383–4386. (b) A.
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Entry for the Table of Contents
FULL PAPER
A radical new method for indoline
synthesis exploits the propensity of
cobalt(III)-carbene radicals to facilitate
1,5-hydrogen atom transfer. This
article discusses reaction optimization,
highlights scope and limitations, and
provides computational support for the
proposed mechanism.
Alexander S. Karns, Monalisa Goswami,
and Bas de Bruin*
Page No. – Page No.
Catalytic Synthesis of Indolines via
Hydrogen Atom Transfer to
Cobalt(III)–Carbene Radicals
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