CoIII-Carbene Radical Approach to Substituted 1H-Indenes

Article abstract of DOI:10.1021/jacs.6b05434

A new strategy for the catalytic synthesis of substituted 1H-indenes via metalloradical activation of o-cinnamyl N-tosyl hydrazones is presented, taking advantage of the intrinsic reactivity of a Co^III carbene radical intermediate. The reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of functionalized 1H-indene derivatives. The cheap and easy to prepare low spin cobalt(II) complex [Co^II(MeTAA)] (MeTAA = tetramethyltetraaza[14]annulene) proved to be the most active catalyst among those investigated, which demonstrates catalytic carbene radical reactivity for a nonporphyrin cobalt(II) complex, and for the first time catalytic activity of [Co^II(MeTAA)] in general. The methodology has been successfully applied to a broad range of substrates, producing 1H-indenes in good to excellent yields. The metallo-radical catalyzed indene synthesis in this paper represents a unique example of a net (formal) intramolecular carbene insertion reaction into a vinylic C(sp²)-H bond, made possible by a controlled radical ring-closure process of the carbene radical intermediate involved. The mechanism was investigated computationally, and the results were confirmed by a series of supporting experimental reactions. Density functional theory calculations reveal a stepwise process involving activation of the diazo compound leading to formation of a Co^III-carbene radical, followed by radical ring-closure to produce an indanyl/benzyl radical intermediate. Subsequent indene product elimination involving a 1,2-hydrogen transfer step regenerates the catalyst. Trapping experiments using 2,2,6,6-tetra-methylpiperidine-1-oxyl (TEMPO) radical or dibenzoylperoxide (DBPO) confirm the involvement of cobalt(III) carbene radical intermediates. Electron paramagnetic resonance spectroscopic spin-trapping experiments using phenyl N-tert-butylnitrone (PBN) reveal the radical nature of the reaction.

Full text of DOI:10.1021/jacs.6b05434

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Article
III
Co-Carbene Radical Approach to Substituted 1H-Indenes
Braja Gopal Das, Andrei Chirila, Moniek Tromp, Joost N. H. Reek, and Bas de Bruin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b05434 • Publication Date (Web): 24 Jun 2016
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Journal of the American Chemical Society
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CoIII-Carbene Radical Approach to Substituted 1H-Indenes
Braja Gopal Das,‡ Andrei Chirila,‡ Moniek Tromp, Joost N. H. Reek, Bas de Bruin*
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Homogeneous, Supramolecular and BioꢀInspired Catalysis (HomKat) group, Van ’t Hoff Institute for Molecular Sciences
(HIMS), University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
ABSTRACT: A new strategy for the catalytic synthesis of substituted 1Hꢀindenes via metalloradical activation of oꢀcinnamyl Nꢀ
tosyl hydrazones is presented, taking advantage of the intrinsic reactivity of a CoIII carbene radical intermediate. The reaction uses
readily available starting materials and is operationally simple, thus representing a practical method for the construction of funcꢀ
tionalized 1Hꢀindene derivatives. The cheap and easy to prepare low spin cobalt(II) complex [CoII(MeTAA)] (MeTAA = tetrameꢀ
thyltetraaza[14]annulene) proved to be the most active catalyst among those investigated, which demonstrates catalytic carbene
radical reactivity for a nonꢀporphyrin cobalt(II) complex, and for the first time catalytic activity of [CoII(MeTAA)] in general. The
methodology has been successfully applied to a broad range of substrates, producing 1Hꢀindenes in good to excellent yields. The
metalloꢀradical catalyzed indene synthesis in this paper represents a unique example of a net (formal) intramolecular carbene inserꢀ
tion reaction into a vinylic C(sp2)ꢀH bond, made possible by a controlled radical ringꢀclosure process of the carbene radical interꢀ
mediate involved. The mechanism was investigated computationally and the results were confirmed by a series of supporting experꢀ
imental reactions. DFT calculations reveal a stepwise process involving activation of the diazo compound leading to formation of a
CoIIIꢀcarbene radical, followed by radical ringꢀclosure to produce an indanyl/benzyl radical intermediate. Subsequent indene prodꢀ
uct elimination involving a 1,2ꢀhydrogen transfer step regenerates the catalyst. Trapping experiments using 2,2,6,6ꢀtetraꢀ
methylpiperidineꢀ1ꢀoxyl (TEMPO) radical or dibenzoylperoxide (DBPO) confirm the involvement of cobalt(III) carbene radical
intermediates. EPR spectroscopic spinꢀtrapping experiments using phenyl Nꢀtertꢀbutylnitrone (PBN) reveal the radical nature of the
reaction.
Substituted indenes and their closely related indane derivatives
are important structural motifs found in many natural products
such as taiwaniaquinol,1 cyanosporaside A/B,2 biological
active molecules such as endothelin receptors antagonist
enrasentan,3 an antipruritic dimetindene,4 melatonin receptor,5
antiꢀinflammatory sulindac,6 aldosterone synthase inhibitors,7
and antiꢀtubecular agents.8 Some of them are marketꢀleading
drugs and/or key intermediates for the synthesis of natural
products, pharmaceuticals and other bioꢀactive compounds, as
well as functional materials9 and metallocene complexes for
olefin polymerization.10 Because of their importance and useꢀ
fulness, construction of the indene skeleton has attracted interꢀ
est of synthetic organic and medicinal chemists for several
years. Several synthetic methodologies have been developed
over the past years, including intraꢀ and intermolecular cyꢀ
clization reactions, each with their specific advantages and
disadvantages.11 Representative intramolecular reactions inꢀ
clude ring expansion of suitably substituted cyclopropenes,12
Friedel Crafts cyclization of allyl13 and propergylic alcohol
derivatives,14 aromatic 1,3 dienes,15 and α,β unsaturated keꢀ
Figure 1. Representative natural products and drug molecules
tones.16 Other methods include oxidative cyclizations,17 pallaꢀ
containing indene moieties and some related indane derivatives.
dium catalysed intramolecular Heck type couplings,18 ringꢀ
A series of intermolecular approaches have also been develꢀ
closing metathesis,19 aromatic CꢀH bond functionalization,20
oped for indene synthesis, including [3 + 2] annulation of aryl
intramolecular Morita–Baylis–Hillman approaches,21 and
alkynes with benzyl derivatives,24 carbonyls,25 allenes and
gold22 and iodine23 catalysed rearrangements.
dienophiles,26 palladiumꢀcatalysed carbocyclization of aryl
halide/boronic acids and alkynes,27 Feꢀcatalyzed cyclization of
benzyl and substituted alkynes and allenes,28 noble metal
catalysed aromatic CꢀH bond activation cyclization,29 and
copper catalysed radical cyclizations.30 However, several of
these existing methods suffer from functional group intolerꢀ
ance, the necessity of expensive (noble) transition metal cataꢀ
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lysts, harsh reaction conditions and/or are limited to the synꢀ
thesis of specific indenes with a particular substitution pattern.
Hence, in need of a broader pallet of synthetic methodologies
the development of new, short, efficient, and broadly applicaꢀ
ble catalytic routes to expand the currently available methods
for indene synthesis from readily available starting materials is
certainly in demand, especially those employing benign, readiꢀ
ly available and inexpensive base metal catalysts.
Page 2 of 9
among those investigated. Notably, while [CoII(MeTAA)] was
already synthesized and characterized in 1976,38 it has thus far
never been used successfully as a catalyst to the best of our
knowledge. Here we report that it has a superior activity over
[Co(TPP)] in catalytic 1Hꢀindene synthesis. Furthermore, we
disclose a plausible reaction mechanism based on control
reactions, radical trapping and deuterium labeling experiꢀ
ments, EPR spectroscopy and computational studies (DFT).
1
2
3
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7
As stable metalloradicals with wellꢀdefined openꢀshell doublet
d7ꢀelectronic configuration, lowꢀspin planar cobalt(II) comꢀ
plexes have recently emerged as a new class of catalysts capaꢀ
ble of ‘carbeneꢀtransfer’ reactions proceeding via radical
mechanisms involving discrete CoIIIꢀcarbene radical intermeꢀ
diates (Figure 2). Metalloradical activation of carbene precurꢀ
sors (such as diazo compounds or Nꢀtosylhydrazones) produce
carbenoids with radicalꢀcharacter at the respective ‘carbene’
carbon, enabling catalytic radicalꢀtype organometallic transꢀ
formations.31ꢀ36 These carbeneꢀradical intermediates are best
described as oneꢀelectron reduced Fischerꢀtype carbenes, and
as a result they have characteristics of both electrophilic
Fischerꢀ and nucleophilic Schrockꢀtype carbenes; besides their
radical character they have a reduced tendency to undergo
undesirable carbene dimerization reactions.31
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RESULTS AND DISCUSSION
Our initial attempt to synthesize a substituted 1Hꢀindene inꢀ
volved reaction of oꢀcinnamyl Nꢀtosyl hydrazone (1a) in presꢀ
ence of the commercially available [CoII(TPP)] catalysts (at a
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60
°
temperature of 60 C, unless indicated otherwise). Different
bases such as LiOtBu, KOtBu, NaOtBu, K2CO3, NaOMe (Taꢀ
ble 1, entries 1ꢀ5) can be used to activate the Nꢀtosyl hydraꢀ
zone in chlorobenzene, but with LiOtBu the highest yield of
the desired 1Hꢀindene product 2a was obtained (51%; entry 1).
Upon increasing the amount of base (LiOtBu) from 1.2 to 3
equivalents the yield dropped substantially (Table 1, entries 1,
6ꢀ7). This is probably caused by decomposition or poisoning
of the catalyst in presence of excess base. To improve the
yield of the reaction different cobalt(II) sources were investiꢀ
gated. The fluorinated porphyrin and salen based cobalt cataꢀ
lysts (Table 1, entry 8, 10) did not produce the desired prodꢀ
uct, but the cheap and easy to prepare [CoII(MeTAA)] catalyst
(Figure 2) produced 1Hꢀindene 2a in excellent yield (83%)
using toluene as the solvent (Table 1, entry 9).
Table 1. Standardization of reaction conditions.
Enꢀ
try
1
2
3
Catalyst
Base
Eq
Solvent
Yielda
(%)
51
41
36
Figure 2. Formation of CoIIIꢀcarbene radicals (oneꢀelectron reꢀ
duced Fischerꢀtype carbenes) upon reacting planar, low spin
cobalt(II) complexes with carbene precursors.
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
LiOtBu
KOtBu
1.2
1.2
PhCl
PhCl
PhCl
NaOtBu 1.2
While the mechanistic details and unusual radicalꢀtype elecꢀ
tronics of the key carbene radical intermediates were only
recently disclosed,31 their unique electronic properties have
been successfully applied in a variety of interesting metalloꢀ
radical approaches of synthetic value, including enantioselecꢀ
tive alkene cyclopropanation,32 CꢀH functionalization,33 βꢀ
esterꢀ γꢀamino ketones synthesis,34 and in the regioselective
synthesis of βꢀlactams35 and 2H-chromenes.36
4
5
6
7
8
9
10
11
12
13
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
K2CO3
NaOMe
LiOtBu
LiOtBu
1.2
1.2
2
PhCl
PhCl
PhCl
PhCl
toluene
toluene
toluene
toluene
toluene
PhCl
39
27
32
0
3
[Co(TPPꢀF20)] LiOtBu
1.2
1.2
1.2
1.2
1.2
1.2
0
[Co(MeTAA)] LiOtBu
[Co(salen)]
[CuI]
83
00
27
0
LiOtBu
LiOtBu
LiOtBu
Herein, we report our efforts to develop a new metalloradical
approach for the synthesis of substituted 1Hꢀindenes, taking
advantage of the unique reactivity of CoIIIꢀcarbene radical
intermediates. The method involves a net, overall carbene
insertion into a vinylic C(sp2)ꢀH bond and uses safe and easily
accessible Nꢀtosyl hydrazones as ‘carbene’ precursors.37 This
methodology has a broad substrate scope and can be applied to
a variety of aromatic substituted Nꢀtosyl hydrazones and conꢀ
jugated vinylꢀgroups containing several different functionaliꢀ
ties. The cheap and easy to prepare low spin cobalt(II) comꢀ
[Rh2(OAc)4]
[Co(MeTAA)] LiOtBu
78
14
15
16
17
18
19
20b
[Co(MeTAA)] LiOtBu
[Co(MeTAA)] LiOtBu
[Co(MeTAA)] LiOtBu
[Co(MeTAA)] LiOtBu
[Co(MeTAA)] LiOtBu
1.2
1.2
1.2
1.2
1.2
1.2
1.2
PhH
THF
CH2Cl2
CH3CN
hexane
PhH
86
85
46
55
70
0
ꢀꢀ
LiOtBu
[Co(MeTAA)] LiOtBu
PhH
35
plex
[CoII(MeTAA)]
(MeTAA
=
tetramethylꢀ
tetraazaa[14]annulene) proved to be the most active catalyst
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Journal of the American Chemical Society
a Yields were determined by integration of the 1H NMR signals in
the presence of acenaphthene as internal standard. Reaction
carried out at room temperature.
esters are tolerated (i.e. the Etꢀ, nBuꢀ, tBuꢀ, and Phꢀesters 1a-
b
1
2
3
4
5
6
7
8
e), producing indenes 2aꢀe in good to excellent yields (78ꢀ
86%, entries 1ꢀ5) using the standardized reaction conditions
shown in Table 2. Surprisingly, α,βꢀunsaturated amide 1f
produced indene 2f in even higher yield (98%; entry 6), and
also styrene derivative 1h furnished the corresponding indene
product 2h in good yield (85%; entry 8). The α,βꢀunsaturated
nitrile substrate 1g works less well, producing indene 2g in
moderate yield (52%; entry 7).
[CoII(MeTAA)] is the cobalt(II) complex of the tetramethylꢀ
tetraaza[14]annulene (MeTAA) ligand (Figure 3). The comꢀ
plex was first prepared in 1976,38 involving two simple steps
to obtain the complex in near quantitative yield. This is in
sharp contrast to the synthesis of porphyrin complexes, which
is in general workꢀintensive, low yielding, time consuming
and produces large amounts of unwanted side products, thus
demanding elaborate (column chromatographic) purification
steps. The MeTAA ligand has similar bonding properties as a
porphyrin, which reflects in its ability to bind a variety of
9
Table 2. Substrates scope varying functional groups at the
vinylic double bond.a
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
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,
transition metals.39 40 However, there are also some differences
which likely explain its increased reactivity as compared to
[Co(TPP)]. While porphyrins have an aromatic (4n+2) deloꢀ
calized πꢀcloud, MeTAA is Hückel antiꢀaromatic (4n), which
increases the flexibility of the ligand. Another difference beꢀ
tween these two macrocyclic structures is their ring size (14ꢀ
vs 16ꢀmembered ring). The increased flexibility and smaller
ringꢀsize of MeTAA as compared to a porphyrin leads to deviꢀ
ation from planarity, and as such [CoII(MeTAA)] adopts a
saddle shaped configuration.
Entry
1
Rꢀ
Products
Yieldb (%)
86
ꢀCOOMe (1a)
(2a)
(2b)
(2c)
(2d)
(2e)
(2f)
2
3
4
5
6
7
8
ꢀCOOEt (1b)
ꢀCOOnBu (1c)
ꢀCOOtBu (1d)
ꢀCOOPh (1e)
ꢀCONMe2 (1f)
ꢀCN (1g)
78
80
76
82
98
52
85
Figure 3. Structures of the cobalt(II) catalysts used in this study.
(2g)
(2h)
Other catalysts such as [CuI] or [Rh2(OAc)4] (Table 1, entries
11ꢀ12) proved less or not effective. Quite surprisingly the
carbene transfer catalyst [Rh2(OAc)4], which is wellꢀknown to
be operative in a variety of carbene CꢀH bond insertion reacꢀ
tions,41 produced no indene at all. In general, carbene insertion
into vinylic C(sp2)ꢀH bonds is extremely rare if not entirely
unprecedented, likely because cyclopropanation is favored for
other (nonꢀmetalloradical) carbene transfer catalysts. Notably
however, CuI did catalyze the reaction to some extend but
produced only 27% of the desired indene, with mainly the
carbeneꢀcarbene dimerized product being formed in the undeꢀ
sired side reaction.
ꢀPh (1h)
a
Reaction conditions: Nꢀtosylhydrazone (1a−h) (0.2 mmol, 1.0
equiv), LiOtBu (0.24 mmol, 1.2 equiv), [Co(MeTAA)] (5 mol%),
benzene (3 mL), 60 C, overnight. b Isolated yields after column
o
chromatography.
The substrate scope was further explored and broadened by
investigating the effect of varying the substituents on the aroꢀ
matic ring (Table 3). Substitution at the 5ꢀ or 6ꢀ position of the
aromatic ring does not affect the yield of the products 2i (Taꢀ
ble 3, entries 1ꢀ2). Electron withdrawing substituents such
as ꢀF, ꢀCl, ꢀCF3, and ꢀNO2 are all effective, affording the corꢀ
responding indenes 2iꢀl in good to excellent yields (Table 3,
entries 1−5). Reactions proceeded even better with neutral
electronꢀdonating groups on the aromatic ring such as naphꢀ
thyl (1n) and methyl (1o) groups producing the corresponding
indenes 2mꢀn in excellent yields (Table 3, entries 6−7). Subꢀ
strates 1pꢀq bearing 5ꢀmethoxy and 4,5ꢀdimethoxy substituꢀ
ents produced indenes 2oꢀp in a somewhat lower yield
(~70%).
Extended solvent screening revealed that the reaction works
best in nonꢀpolar solvents such as benzene, toluene, or hexane
(entries 9, 14, 18). Most polar solvents such as CH2Cl2 or
CH3CN (entries 16ꢀ17) led to comparatively low yields, but
THF works well as a solvent (entry 15). The reaction does not
produce 2a without a catalyst (entry 19), and the yield of the
reaction drops drastically when performing the reaction at
room temperature (entry 20). Conversion of the Nꢀtosyl hyꢀ
drazone into the corresponding diazo compound accounts for
at least part of the required activation energy.37
For most of the asymmetrically substituted substrates shown in
Table 3 (except entry 10) both possible regioꢀisomers of prodꢀ
ucts 2iꢀp are formed in a nearly 1:1 ratio. This points to alꢀ
To explore the scope of the metalloradical catalyzed indene
synthesis, several different functional groups were introduced
at the vinylic double bond (Table 2). Several α,βꢀunsaturated
3
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Page 4 of 9
lylic/benzylic double bond isomerization under the applied
8
72 c
1
2
3
4
5
6
7
8
reaction conditions, as can be expected for 1Hꢀindenes having
rather acidic allylic/benzylic protons. Substitution at the alꢀ
lylic/benzylic position has also been investigated. Interestingly
reacting Nꢀtosylhydrazone 1s results in regioꢀselective forꢀ
mation of indene product 3 in high yield (Table 3, entry 10)
with the double bond at the thermodynamically favored most
substituted position.
(1p)
(2o)
(2p)
9
70
95
(1q)
(1s)
10
Table 3. Substrates scope bearing various functional group
on aromatic ring.a
9
10
11
12
13
14
15
16
17
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19
20
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60
(3)
a
Reaction conditions: Nꢀtosylhydrazone (1a−h) (0.2 mmol, 1.0
equiv), LiOtBu (0.24 mmol, 1.2 equiv), CoMeTAA (5 mol%),
benzene (3 mL), 60 C, overnight. b Isolated yields after column
o
chromatography. c Nearly 1:1 ratio of both isomers formed.
Full statistical (thermodynamically controlled) scrambling of
the allylic and vinylic protons under the applied (alkaline)
reaction conditions was confirmed by the deuteriumꢀlabeling
experiments shown in Scheme 1. Starting either with a deuterꢀ
ium label at the azomethine position (1a-D) or at the vinylic
position (1b-D) of the carbenoid precursor leads in both cases
to a complete statistical distribution of the deuterium atoms
over the allylic/benzylic and vinylic positions, as indicated by
a 2:1 ratio of the ꢀCDHꢀ and =CD signals in the DꢀNMR specꢀ
tra of deuteriumꢀlabeled indene products 2a-D/2a’-D and 2b-
D/2b’-D (Scheme 1).
Entry
1
Substrates
Products
Yield
(%) b
87 c
(1i)
(2i)
2
85 c
(1j)
SCHEME 1. Deuterium-labeling experiments showing
complete scrambling of allylic and vinylic protons.
(2i)
(2j)
(2k)
(2l)
3
4
5
6
82 c
84 c
84 c
93 c
H
(1k)
(1l)
COOMe
NHTs
N
[Co(MeTAA)] (5 mol %)
LiOtBu (1.2 equiv)
H
D
2a-D
D
D
PhH, 60 oC
COOMe
COOMe
Overnight
1a-D (>99% D)
H
H
2a'-D
2a-D:2a'-D = 2:1
H
(1m)
COOEt
NHTs
N
[Co(MeTAA)] (5 mol %)
LiOtBu (1.2 equiv)
H
D
2b-D
D
D
PhH, 60 oC
COOEt
(1n)
(1o)
COOEt
Overnight
1b-D (>99% D)
H
H
(2m)
(2n)
2b'-D
7
88 c
2b-D:2b'-D = 2:1
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1
SCHEME 2. Proposed Mechanism of [Co(MeTAA)] Catalyzed 1H-indene Synthesis.a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
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60
a DFTꢀD3 calculated (Turbomole, BP86, def2ꢀTZVP, disp3) mechanism for [Co(MeTAA)] catalyzed 1Hꢀindene formation (free energies,
ꢁG298K°, in kcal mol−1). All energies, including the transition states, are reported with respect to species A as the reference point.
To shed more light on the catalytic reaction mechanism, we
explored the mechanism computationally. Additionally we
performed a set of trapping and control experiments, comꢀ
bined with EPR spectroscopic investigations.
radical followed by a radical rebound step could in principle
be an alternative, but all attempts to optimize such a vinyl
radical intermediate (D’ in Scheme 2) converged back to carꢀ
bene radical C, thus indicating that the route via D’ is not a
viable pathway. As such, a metalloradical pathway involving
attack of the carbene radical at the vinylic double bond to form
the cyclized γꢀradical intermediate D seems to be the most
plausible mechanism. This mechanism was fully explored for
both the [Co(MeTAA)] and [Co(TPP)] catalysts with DFTꢀD3
at the BP86, def2ꢀTZVP level, using Grimme’s version disperꢀ
sion corrections (disp3). The selected computational method is
in agreement with our previous studies involving Co(III)ꢀ
carbene radicals as intermediates in catalytic cyclizations, and
is known to provide accurate CoꢀC BDEs.42
At first sight the reaction may seem to proceed via a direct
carbene insertion into the vinylic C(sp2)ꢀH bond. However,
such reactions are unprecedented to the best of our knowledge,
and [Rh2(OAc)4] (which is wellꢀknown for its reactivity in
aromatic and aliphatic CꢀH bond functionalization by direct
carbene insertion) is not active in 1Hꢀindene formation (vide
supra). In addition, attempts to find a transition state for this
process for the [Co(MeTAA)] catalyst with DFT were unsucꢀ
cessful, and the electronic structure of a CoIIIꢀcarbene radical
in general (Figure 2) seems to be incompatible with any direct,
concerted CꢀH insertion mechanism of the carbenoid. Hydroꢀ
gen atom transfer from the vinylic CꢀH bond to the carbene
The computed mechanism for the [Co(MeTAA)] catalyst is
presented in Scheme 2. The corresponding mechanism for the
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[Co(TPP)] catalyst and the associated energy diagrams of the
reactions with both catalysts are shown in the supporting inꢀ
formation (Figure S1). All steps have accessible barriers, and
each step is exergonic.
Page 6 of 9
lation is found on the carbenoid carbon atom, in agreement
with a CoIIIꢀcarbene radical electronic structure as presented in
Figure 2. In intermediate D the largest spin population is
found at the γꢀposition, with some delocalization over the
adjacent phenyl moiety. Both structures have less than 10%
spin population at cobalt, thus showing that radicalꢀtype eleꢀ
mentary steps involving coordinated substrate radicals play a
key role in the catalytic mechanism.
1
2
3
4
5
6
7
8
The first steps of the DFT computed reaction mechanism
involve trapping and activation of the in situ generated diazo
compound by the [Co(MeTAA)] catalyst (Scheme 2). Forꢀ
mation of the CoIIꢀcatalystꢀdiazo adduct B is exergonic (ꢁG° =
ꢀ11.6 kcal molꢀ1), as is N2ꢀelimination from B to produce the
CoIIIꢀcarbene radical species C (ꢁG° = ꢀ14.7 kcal molꢀ1). The
transition state barrier for formation of C is low (TS1; ꢁG⧧ =
+7.4 kcal molꢀ1). These steps are similar to those reported
previously in the mechanisms for 2Hꢀchromene formation36
and cyclopropanation31 using CoIIꢀporphyrin catalysts.
To obtain additional information about the mechanistic pathꢀ
way we attempted to trap intermediates with radical scavenꢀ
gers.43 In agreement with the above DFT calculations indicatꢀ
ing that CoIIIꢀcarbene radical intermediate C is the catalytic
resting state, these trapping experiments produced in all cases
products stemming from species C (Scheme 3).
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Reacting substrate 1a with [Co(MeTAA)] in the presence of
three equivalents of TEMPO under identical reaction condiꢀ
tions as used in catalytic indene synthesis led to formation of
product 5 (Scheme 3). Compound 5 was isolated, purified by
The next step involves addition of the carbene radical to the
vinylic double bond producing the cyclized γꢀradical intermeꢀ
diate D (ꢁG° = ꢀ17.7 kcal molꢀ1) via transition state TS2 (barꢀ
rier: ꢁG⧧ = +18.9 kcal molꢀ1). This appears to be the rate limitꢀ
ing step of the catalytic cycle. Indene formation from D reꢀ
quires a low barrier 1,2ꢀhydrogen atom transfer (TS3; ꢁG⧧ =
+13.8 kcal molꢀ1), relocating the radical from the γꢀ to the βꢀ
position. The thus formed cobaltꢀbound βꢀradical species is so
unstable that it spontaneously dissociates in a barrierless manꢀ
ner to form indene product E. The overall process is strongly
exergonic (ꢁG° = ꢀ58.4 kcal molꢀ1).
column chromatography and characterized by H, 13C and
1
GCMS spectroscopy (see Supporting Information). The comꢀ
pound has a TEMPO moiety attached to the carbon stemming
from the ‘carbene’, which is (over)oxidized to a carbonyl
group. The use of dibenzoylperoxide as a radicalꢀscavenger
also led to trapping of carbene radical intermediate C, in this
case leading to formation of product 7 (Scheme 3). No ringꢀ
closed intermediates could be trapped, consistent with TS2
being the rate limiting step in the DFT calculated mechanism
with all followꢀup steps after formation of D being fast
(Scheme 1). Cold spray ESIꢀHRMS experiments of the cataꢀ
lytic reaction mixture in absence of radical scavengers are in
agreement with the presence of carbenenoid species C
(Scheme 2). The detected mass m/z=576.1906 (calc.
m/z=576.1936) corresponds to [C+H]+ (C33H33CoN4O2), and
can be attributed to protonated species C.
An alternative pathway for indene formation from D is possiꢀ
ble, involving dissociation of the dearomatized (methideꢀlike
2Hꢀchromene) E’ from D, followed by 1,2 hydride shift (TS4)
to produce the 1Hꢀindene product E (Scheme 2). Dissociation
of E’ from D involving homolytic splitting of the CoꢀC bond
to produce starting complex A is endergonic by about +13 kcal
molꢀ1 according to DFT (the reverse reaction is barrierless),
but coordination of substrate 1a’ to A producing B makes the
overall process virtually thermoneutral. Subsequent converꢀ
sion of E’ to E has a low barrier transition state (TS4; ꢁG⧧ =
+10.4 kcal molꢀ1). The computed pathways for indene forꢀ
mation from D via E’ (ꢁG⧧ = +12.7 kcal molꢀ1; determined by
dissociation of E’ to form A) and the direct pathway over TS3
(ꢁG⧧ = +13.8 kcal molꢀ1) have very similar overall barriers,
and thus seem to be competing trails producing the same
product.
SCHEME 3. Radical scavenging experiments used to trap
the CoIII-carbene radical intermediate.
H
N
N
O
N
N
Ts
O
[Co(MeTAA)] (5 mol%)
LiOtBu (1.2 equiv)
+
N
Benzene, 60 o
C
COOMe
COOMe
O.
4
1a
1a
5
H
N
O
Ts
O
[Co(MeTAA)] (5 mol%)
LiOtBu (1.2 equiv)
Ph
O
O
Ph
+
Ph
O
Benzene, 60 o
C
O
COOMe
COOMe
6
7
Spin trapping experiments using phenyl Nꢀtertꢀbutylnitrone
(PBN) as the spin trap support the proposed radicalꢀtype
mechanism. Heating a mixture of 1a, [Co(MeTAA)], LiOtBu
in the presence of PBN led to formation of PBNꢀtrapped carꢀ
bonꢀcentered radicals as detected with EPR spectroscopy
(Figure 5). The resulting EPR signal (g = 2.0063, AN=14.4 G,
AH=2.8 G) is strong and similar to other reported PBNꢀtrapped
carbon centered radicals.44 Heating the reaction mixture in
absence of cobalt (i.e. nonꢀcatalytic conditions, in which case
no indene formation occurs) also some PBNꢀtrapped radicals
Figure 4. (a) Spin density plots of the DFTꢀoptimized CoIIIꢀ
carbene radical species C (left) and cyclized γꢀradical intermediꢀ
ate D (right).
Spin density plots of the key intermediates C and D are preꢀ
sented in Figure 4. Most spin density is ligand centered for
both intermediates. For intermediate C the highest spin popuꢀ
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were detectable, but different ones with weaker intensity (see
supporting information).
Notes
1
2
3
4
The authors declare no competing financial interest.
Author Contributions
‡These authors contributed equally.
5
Funding Sources
6
7
8
9
Financial support from the Netherlands Organization for Scienꢀ
tific Research (NWOꢀCW VICI project 016.122.613) and the
University of Amsterdam (Research Priority Area Sustainable
Chemistry) is gratefully acknowledged.
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ACKNOWLEDGMENT
Ed Zuidinga for MS measurements, Jan Meine Ernsting for NMR
advice and Tim Storr for providing [Co(salen)].
ABBREVIATIONS
Figure 5. Isotropic Xꢀband EPR spectrum of the PBNꢀtrapped
carbonꢀcentered radical (T= 298 K; microwave frequency:
9.36607 GHz; power: 6.33 mW; modulation amplitude: 1.0 G).
ESIꢀHRMS: Electron Spray Ionization High Resolution Mass
Spectrometry; DFT: Density Functional Theory; PBN: phenyl Nꢀ
tertꢀbutylnitrone. EPR: Electron Paramagnetic Resonance, NMR:
Nuclear Magnetic Resonance.
CONCLUSIONS
REFERENCES
Metalloradical activation of a series of oꢀcinnamylꢀNꢀtosyl
hydrazones produces a variety of functionalized 1Hꢀindenes in
high yields and with a broad functional group tolerance. The
reaction uses readily available starting materials and is operaꢀ
tionally simple, thus representing a practical method for the
construction of substituted 1Hꢀindene derivatives. The cheap
and easy to prepare low spin cobalt(II) complex
[Co(MeTAA)] proved to be the most active catalyst among
those investigated, showcasing for the first time catalytic
activity of this complex in general. DFT studies reveal a stepꢀ
wise process involving activation of the diazo compound
leading formation of a CoIIIꢀcarbene radical, followed by a rate
limiting radical ringꢀclosure step to produce an indanylꢀradical
intermediate. Subsequent 1,2ꢀhydrogen atom transfer leads to
elimination of the 1H indene product and regenerates the CoIIꢀ
catalyst. The computed mechanism was confirmed by a series
of supporting radicalꢀscavenging experiments. Deuterium
labelling experiments further reveal statistical scrambling of
the allylic/benzylic and vinylic protons under the applied
reaction conditions. The metalloꢀradical catalyzed indene
synthesis in this paper represents a rare example of a net,
formal (intramolecular) carbene insertion reaction into a vinylꢀ
ic C(sp2)ꢀH bond, made possible by taking advantage of the
distinctive and controlled reactivity of the key CoIIIꢀcarbene
radical intermediates involved. Further studies aimed at exꢀ
ploring the controlled organometallic radicalꢀtype reactivity of
transition metal carbene radicals in ringꢀclosing reactions and
CꢀH bond functionalization are underway.
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ASSOCIATED CONTENT
Supporting Information
Compound characterization data (NMR, HRMS, etc.), absolute
energies (atomic units), and the coordinates of the DFTꢀoptimized
structures are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
b.debruin@uva.nl
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