Catalytic 1,2-dihydronaphthalene and: E -aryl-diene synthesis via CoIII-Carbene radical and o -quinodimethane intermediates

Article abstract of DOI:10.1039/c7sc03909c

Catalytic synthesis of substituted 1,2-dihydronaphthalenes via metalloradical activation of o-styryl N-tosyl hydrazones ((E)-2-(prop-1-en-1-yl)benzene-N-tosyl hydrazones) is presented, taking advantage of the intrinsic reactivity of a cobalt(iii)-carbene radical intermediate. The method has been successfully applied to a broad range of substrates with various R¹ substituents at the aromatic ring, producing the desired ring products in good to excellent isolated yields for substrates with an R² = COOEt substituent at the vinylic position (～70-90%). Changing the R² moiety from an ester to other substituents has a surprisingly large influence on the (isolated) yields. This behaviour is unexpected for a radical rebound ring-closure mechanism, and points to a mechanism proceeding via ortho-quinodimethane (o-QDM) intermediates. Furthermore, substrates with an alkyl substituent on the allylic position reacted to form E-aryl-dienes in excellent yields, rather than the expected 1,2-dihydronaphthalenes. This result, combined with the outcome of supporting DFT calculations, strongly points to the release of reactive o-QDM intermediates from the metal centre in all cases, which either undergo a 6π-cyclisation step to form the 1,2-dihydronaphthalenes, or a [1,7]-hydride shift to produce the E-aryl-dienes. Trapping experiments using TEMPO confirm the involvement of cobalt(iii)-carbene radical intermediates. EPR spectroscopic spin-trapping experiments using phenyl N-tert-butylnitrone (PBN) confirm the radical nature of the catalytic reaction.

Full text of DOI:10.1039/c7sc03909c

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Catalytic 1,2-Dihydronaphthalene and E-Aryl-Diene Synthesis via
III
Co -Carbene Radical and o-Quinodimethane Intermediates
Received 00th January 20xx,
Accepted 00th January 20xx
†
†
Colet te Grotenhuis , Braja G. Das , Petrus F. Kuijpers, Wouter Hageman, Mees Trouwborst and
*
Bas de Bruin
DOI: 10.1039/x0xx00000x
Catalytic synthesis of substituted 1,2-dihydronaphthalenes via metalloradical activation of o-styryl N-tosyl hydrazones ((E)-
www.rsc.org/
2
-(prop-1-en-1-yl)benzene-N-tosyl hydrazones) is presented, taking advantage of the intrinsic reactivity of a cobalt(III)-
1
carbene radical intermediate. The method has been successfully applied to a broad range of substrates with various R
substituents at the aromatic ring, producing the desired ring products in good to excellent isolated yields for substrates
2
2
with an R = COOEt substituent at the vinylic position (~70-90% ). Changing the R moiety from an ester to other
substituents has a surprisingly large influence on the (isolated) yields. This behaviour is unexpected for a radical rebound
ring-closure mechanism, and points to a mechanism proceeding via ortho-quinodimethane (o-QDM) intermediates.
Furthermore, substrates with an alkyl substituent on the allylic position reacted to form E-aryl-dienes in excellent yields,
rather than the expected 1,2-dihydronaphthalenes. This result, combined with the outcome of supporting DFT
calculations, strongly points to the release of reactive o-QDM intermediates from the metal centre in all cases, which
either undergo a 6π-cyclisation step to form the 1,2-dihydronaphthalenes, or a [1,7]-hydride shift to produce the E-aryl-
dienes. Trapping experiments using TEMPO confirm the involvement of cobalt(III)-carbene radical intermediates. EPR
spectroscopic spin-trapping experiments using phenyl N-tert-butylnitrone (PBN) confirm the radical nature of the catalytic
reaction.
9
Hepatitis
C
NS5B polymerase inhibitors.
Recently,
Introduction
dihydronaphthalenes were found to be potent and selective
inhibitors of aldosterone
A diverse range of transition-metal complexes have been
shown to catalyse C−C coupling reactions, providing valuable
alternatives to traditional methods for carbon–carbon bond
synthase (CYP11B2) for the treatment of congestive heart
1
0
1
formation. However, the use of catalytic C
failure
and
myocardial
fibrosis
(Figure
1).
−C coupling
reactions for the synthesis of fused ring systems remains
Dihydronaphthalene derivatives are also useful starting
materials for the synthesis of several biologically active cyclic
2
challenging,
in particular those producing partially
1
1
molecules. Many strategies towards these compounds have
been published, of which dearomatization of the fully aromatic
naphthalene substrate by organometallic reagents is perhaps
unsaturated, conjugated but not fully aromatic fused
3
6
-membered ring-systems such as 1,2-dihydronaphthalenes.
The 1,2-dihydronaphthalene ring system is present in various
1
2
one of the most useful and convenient methods.
natural products of therapeutic importance, including:
4
Cannabisins 48, isolated from the fruits of Cannabis sativa,
5
,7-dehydrosempervirol, isolated from the roots of Salvia
6
6
apiana and negundin B, isolated from the roots of Vitex
negundo. Nafoxidene is class of biologically active
dihydronaphthalene and its analogues can be prepared from
-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-3,4-dihydronaph-
a
1
7
thalene.
Dihydronaphthalene derivatives are used as fluorescent
8
ligands for the estrogen receptor and exhibit activity as
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Journal Name
intermediates were recently already demonstrated to be key-
intermediates in some other synthetically useful metallo-
radical catalysed reactions, including (enantioselective) alkene
1
7
18
cyclopropanation,
C
−
H functionalization,
β-ester-γ-amino
ketone synthesis, and in the regioselective synthesis of β-
1
9
2
0
21
22
lactams , 2H-chromenes and 1H-indenes.
Herein, we report the development of a cobalt-catalysed
reaction for the synthesis of substituted 1,2-
III
dihydronapthalenes involving Co -carbene radical reactivity.
Starting from safe to use and easy to prepare N-tosyl
hydrazones as carbene precursors, this reaction gives access to
a broad range of substituted products with varying functional
groups. Substrates with an alkyl substituent on the allylic
position reacted to form E-aryl dienes in excellent yields,
rather than the expected 1,2-dihydronaphthalenes.
Fig. 1 Representative natural products and drug molecules containing
1
,2-dihydronaphthalene substructures.
However, this approach requires the use of naphthalenes
containing electron-withdrawing substituents (e.g oxazolino or
imino groups) as starting materials to enhance their
electrophilicity, which limits the substrate scope.
Organometallic nucleophilic addition to electrophilic double
III
bonds
is
another
valuable
1
approach
to
the Scheme 1 Formation of Co -carbene radicals (one-electron reduced Fischer-type
2
dihydronaphthalene scaffold. Photoinitiated cyclizations to carbenes) upon activation of a carbene precursor by planar, low spin cobalt(II)
complexes.
form dihydronaphthalene have been developed by Nicolaou
and colleagues in the synthesis of biologically relevant
1
3
14
tetralins. Suzuki presented a palladium(II)-catalysed cross-
1
5
Mechanistic studies point to a metallo-radical pathway
III
involving formation of a Co -carbene radical, followed by
coupling reaction via benzylic boronates, and Yamamoto
reported the Cu(OTf) -catalyzed [4+2]-cycloaddition reaction
2
hydrogen atom transfer to give a benz-allylic radical. From
here on, ring-closure to form the dihydronapthalene product
can follow two distinct pathways, producing the same product:
of alkynyl-benzenes with alkenes.
Still, several of the abovementioned synthetic protocols suffer
from functional group intolerance, a necessity to use scarce
and expensive (noble) metal catalysts, harsh reaction
conditions, easy over-reduction/oxidation leading to loss of
the C=C double bond or full aromatization, and/or limitations
to particular substitution patterns. Hence, the development of
new, efficient, and broadly applicable catalytic routes to
complement existing methods for 1,2-dihydronaphthalene
synthesis certainly remains to be a worthwhile effort,
especially those employing readily available and inexpensive
base metal catalysts.
(
1) A direct radical-rebound step, or (2) first dissociation of an
ortho-quinodimethane fragment from the catalyst, followed
by 6 -cyclisation. Clean formation of aryl dienes when reacting
π
substrates with an alkyl substituent on the allylic position
suggests that the pathways proceeding via release of ortho-
quinodimethanes are dominant. Spin- and radical-trapping
experiments performed under catalytically relevant reaction
condition confirm the radical nature of the process.
Cobalt(II) porphyrin complexes and related low-spin planar Results and discussion
cobalt(II) complexes provide interesting opportunities in this
Initial experiments were aimed at exploring the feasibility of
,2-dihydronaphthalene synthesis from tosyl hydrazone
perspective. These stable metalloradicals, with their well-
7
defined open-shell doublet d -electronic configuration, are
1
substrate 1a, using a cobalt(II) metallo-radical approach. The
idea behind these reactions was to activate the tosyl
hydrazone moiety to generate a cobalt(III)-carbene radical
known to mediate a series of uncommon radical-type
‘
carbene-transfer’ reactions. Reaction of these cobalt(II)
complexes with carbene precursors such as N-tosylhydrazones
intermediate (Scheme
formal) carbene insertion into the allylic C
substrate via a radical-type hydrogen atom transfer (HAT) /
1
), which we anticipated to undergo net
or diazo compounds leads to formation of unusual cobalt(III)-
(
−
H bond of the
carbene radical intermediates (Scheme
1). These are best
described as one-electron reduced Fischer-type carbene
1
23
radical-rebound mechanism (Scheme 2).
6
complexes, having discrete spin density at their carbene-
carbon atom. As a result, these intermediates react via radical-
We decided to focus on the commercially available cobalt(II)-
metallo-radical catalyst [Co(TPP)]. First screening experiments
indeed revealed the feasibility of this reaction, producing
1
6-22
of interest for the development of new
protocols. Cobalt(III)-carbene radical
type pathways,
ring-closure
dihydronapthalene 2a from substrate 1a in 81% yield (Table 1,
2
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entry 1), after which we further optimized the reaction different functional groups at the aromatic ring (1a-g) and at
conditions. Different bases were tested (Table , entries 1-5), the vinylic position (1h-l). Two general routes were used to
1
t
which revealed that LiO Bu is best suited for this reaction.
arrive at substrates 1a-l, starting from 2-bromobenzaldehyde.
The first route (Scheme , top) starts with protection of the
3
aldehyde followed by converting the bromide into a new
aldehyde at the ortho position, which is then converted into an
alkene using an (E-selective) Horner-Wadsworth-Emmons
2
6
reaction. Deprotection of the aldehyde and introduction of
the tosylhydrazone results in the desired substrate.
Alternatively, the alkene can also be introduced directly
through a Heck-type reaction with 2-bromobenzaldehyde
27
Scheme 2 Anticipated steps to generate dihydronaphthalenes: HAT from the
III
H bond of a Co -carbene radical intermediate followed by a
(
Scheme 3, bottom). Substrates 1a and 1e-l were obtained as
benz-allylic C−
radical rebound ring-closure step.
pure E-isomers. For the three substrates 1b-d mixtures of the
E/Z-isomers were isolated, containing 88-94% of the major E-
isomer, which were directly used in the cobalt(II)-catalysed
ring closing-reactions.
Table 1 Standardization of reaction conditions.
a
Entry
Catalyst
Base
Eq
Solvent
PhCl
PhCl
PhCl
Yield (%)
t
1
2
3
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
LiO Bu
1.2
1.2
1.2
81
71
66
t
KO Bu
t
NaO Bu
4
5
6
7
8
9
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
[Co(TPP)]
--
K
2
CO
3
1.2
1.2
1.2
2
PhCl
PhCl
PhCH
PhCH3
PhCH
THF
69
67
95
54
0
NaOMe
LiO Bu
LiO Bu
LiO Bu
LiO Bu
LiO Bu
LiO Bu
LiO Bu
t
3
t
t
3
3
t
1.2
1.2
1.2
1.2
1.2
84
64
t
1
1
1
1
0
1
2
3
CH
3
CN
t
b
benzene 97 (89)
PhCH
benzene
Scheme 3 Substrate synthesis using either the Horner-Wadsworth-Emmons
t
3
0
94
reaction (top) or a Heck-coupling approach (bottom).
t
[Co(MeTAA)]
LiO Bu
a
1
Yields were determined by integration of the
H
NMR signals using We first tested substrates 1a-g, varying in the substitution
b
acenaphthene as internal standard. Isolated yield between brackets.
pattern of the aromatic ring (Table 2). The reaction proved to
be quite tolerant to both electron donating and electron
withdrawing substituents on the aromatic ring. Performing the
reaction on a larger scale led to similar results (entry 2). It is
clear that electron withdrawing groups at either the 6- or 7-
position have a similar effect (2b-d). An electron donating
methyl group at the 7-position (2e) results in a lower yield of
Increasing the amount of base led to a large decrease in yield
(Table 1, entries 6-8). Probably this is caused by decomposition
or poisoning of the catalyst in the presence of excess base.
Furthermore, variations in solvent revealed that in general
higher yields were obtained in non-coordinating, low-polarity
solvents like toluene or chlorobenzene. However, THF works
5
0%, but the even stronger donating methoxy-substituents at
either the 7- or 6- and 7-position restores the yields to about
0%, comparable to the electron withdrawing groups (2f-g).
rather well too (Table
1, entries 1, 6, 9-11). Finally, in the
absence of a cobalt(II) catalyst the reaction does not form the
2
7
4
desired product 2a at all.
Note that NMR spectra of the crude mixtures in most cases
reveal higher yields than isolated, thus indicating some
product loss during the purification steps using column
chromatography and rotary evaporation (see for example
We also tested the [Co(MeTAA)] catalyst for this reaction,
which was shown to have a higher activity in some related
22
,25
carbene-transfer reactions.
Co(MeTAA)] gave similar results as [Co(TPP)] (Table
3). Hence, because [Co(MeTAA)] is a quite air-sensitive
In this reaction, however,
[
1
, entry
Table
Next we tested substrates 1h-l, varying in the substitution
pattern of the allylic moiety (Table ). Surprisingly, the cobalt-
1, entry 11 and Table 3, entry 4).
1
complex, we decided to continue our investigations with the
commercially available, and air and moisture stable [Co(TPP)]
catalyst.
3
catalysed ring-closing protocol proved to be rather sensitive to
2
the nature of the R -substituent. While ring-closure is
2
observed for a variety of substrates with different R -
In order to investigate the scope of this new reaction, a range
of substrates (1a-l; Tables
2 and 3) was synthesized with
substituents at the vinylic position, the isolated yields are quite
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low when compared to substrates with an ester substituent at
Journal Name
2
this position. When the R -substituent is a ketone (Table 3,
1
entry 1), azine side-product formation is indicated by H NMR
spectroscopy, well-known side-reaction for diazo
compounds. A comparable, albeit slightly higher yield was
a
2
obtained with R being a more bulky limonene group (Table 3,
2
entry 2). With a phenyl-ring at the R -position the yield
increases to 50%. In this case, also 25% of the fully aromatic
naphthalene was isolated as a side-product (entry 3). When
the substituent is a methyl group, NMR characterization of the
reaction mixture reveals a crude yield of 68%, while only 21%
could be isolated. Substantial product loss during the
purification steps in this case is likely caused by the volatile
nature of product 2k. The isolated yield of the tricyclic
2
8
compound 2l is also low (entry 5).
4
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1
a
Table 2 Substrates scope varying functional groups R at the aromatic ring.
intermediate, are expected to be influenced by the nature of
2
the R substituent.
2
a
Table 3 Substrate scope varying functional groups R at the vinylic double bond.
b
Entry
Substrates
Products
Yield (%)
b
Entry
Substrates
Products
Yield (%)
1
89
1
35
(
2h)
(
2a)
(
(
1a)
1b)
(
1h)
c
d
2
3
4
76 (85 )
2
3
44
(
2b)
(
1i)
(2i)
d
74
c
50
(
2c)
(
2j)
(
1c)
(
1j)
d
65
d
(
2d)
4
5
21 (68 )
(
1d)
(
2k)
(
1k)
5
50
75
17
(
2e)
(2l)
(1l)
(
1e)
6
7
(
2f)
(
1f)
a
t
Reaction conditions: N-tosylhydrazone (1h−l) (0.1 mmol, 1.0 equiv), LiO Bu (0.12
71
o
b
mmol, 1.2 equiv), [Co(TPP)] (5 mol%), benzene (2 mL), 60 C, overnight. Isolated
(
2g)
c
(
1g)
yields after column chromatography (average of two experiments). Also 25%
d
1
a
t
naphthalene isolated. Crude yield, based on integration of the H NMR signals
using 1,3,5-trimethoxybenzene as internal standard.
Reaction conditions: N-tosylhydrazone (1a−g) (0.1 mmol, 1.0 equiv), LiO Bu (0.12
o
b
mmol, 1.2 equiv), [Co(TPP)] (5 mol%), benzene (2 mL), 60 C, overnight. Isolated
c
yields after column chromatography (average of two separate experiments).
d
Isolated yield of experiment performed with 1.0 mmol substrate. Yields of these To further investigate the difference between these two
three entries based on the major E-isomer, using an E/Z-mixture containing 6-
mechanisms we decided to test a range of substrates
1
2% of the non-productive Z-isomer.
containing
3
an alkyl substituent at the allylic position (Scheme 3, Y = -CH2R
Despite some purification issues (entry 4), the rather low yields
of the reactions described in Table as compared to those in
Table is surprising. Since the R -substituent is not in
instead of Y = H; see Table
influence on the initially anticipated radical-rebound pathway
Scheme 4a), but for the o-QDM route (Scheme 4b) this should
have a significant effect.
4). This was expected to have little
3
2
2
(
conjugation with the anticipated allyl-radical intermediate,
2
only a small influence of the R -substituent on both the HAT
and the radical-rebound steps was expected (Scheme 4a). Yet,
2
the actually observed influence of the R -group in the product
yield is substantial, suggestive of an alternative (perhaps
parallel) ring-closing mechanism involving release of a reactive
ortho-quinodimethane (o-QDM) intermediate, followed by 6π-
cyclisation to produce the 1,2-dihydronapthalene product
2
Scheme 4b). Such o-QDM pathways, with the R substituent in
(
direct conjugation with the double bond of the o-QDM
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a
Table 4 Substrates scope varying functional groups at the allylic position.
b,c
Yield
Entry
Substrates
Products
(%)
8
89 )
5
1
d
(
a
t
Reaction conditions: N-tosylhydrazone (1m−q) (0.1 mmol, 1.0 equiv), LiO Bu
o
b
(
0.12 mmol, 1.2 equiv), [Co(TPP)] (5 mol%), benzene (2 mL), 60 C, overnight.
Isolated yields after column chromatography (average of two separate
(
1m)
(3m)
c
experiments). Yields of these three entries based on the major E-isomer, using
d
an E/Z-mixture containing 11-25% of the non-productive Z-isomer. Isolated yield
e
of experiment performed at 1 mmol scale.
Product isolated as mixture
containing 10% cycloheptatriene product 4 (see ESI for details), which is formed
29
from the non-productive Z-isomer of 1o.
2
95
(
1n)
(3n)
Scheme 5 Ene-type [1,7]-hydride shift reaction of o-QDM intermediates leading
to formation of the E-aryl dienes shown in Table
4.
e
3
83
Surprisingly, for all such substrates tested (Table
4), the
presence of an alkyl substituent at the allylic position (Scheme
3
(
1o)
(3o)
3
2
, Y = -CH R instead of Y = H) led to a completely different
outcome of the reaction. Instead of the anticipated ring-
closure to form 1,2-dihydronapthalenes, the reaction led to
selective formation of E-aryl dienes, which could be isolated in
high yields. These products result from a net hydrogen atom
transfer not only from the allylic position, but as well from the
alkyl substituent. The reactions clearly point to dissociation of
o-QDM intermediates, which undergo an Ene-type [1,7]-
4
5
89
90
(
1p)
(3p)
(3q)
hydride shift to form the observed dienes (Scheme
5).
Entry 1 of Table 4 shows the formation of benzyl diene 3m in
high yield, also at a larger scale. When this substrate was
extended with one carbon atom the reaction still proceeded
cleanly, giving double E diene 3n in excellent isolated yield.
Also double alkyl substitution (1o) leads to selective E-aryl
(1q)
2
9
diene formation (entry 3). Next we had a look at the
influence of the electronic environment by substituting the
aromatic ring which led to similar yields (entries 4 and 5, Table
4
). Besides providing valuable mechanistic information, the
reactions in Table 4 produce interesting products with various
opportunities for further reactions or functionalization. Dienes
are for example interesting substrates for polymerization,
Diels-Alder reactions, epoxidation and [2+2] π cyclization to
3
0
give cyclobutadiene.
Mechanistic Studies
In order to shed more light on the reaction mechanism, DFT
Scheme 4 ortho-quinodimethane release followed by 6π-cyclisation (b) as an
alternative to the anticipated radical rebound mechanism (a) for 1,2-
calculations were performed. The calculated pathways for 1,2-
dihydronapyhalene formation are depicted in Scheme
catalytic cycle start with coordination of the diazo compound
a’ to the cobalt(II) porphyrin catalyst to form intermediate
6. The
dihydronaphthalene formation.
1
B.
Formation of 1a’ from the deprotonated tosylhydrazone 1a is
6
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assumed to be a non-catalysed thermal process, which is most pathway via the o-QDM intermediate
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E
has a slightly lower,
3
1
likely rate limiting (vide infra). Dinitrogen loss from diazo albeit very similar overall barrier for 1,2-dihydronaphthalene
3
2
-1
(+14.9 kcal mol ) when compared to the
adduct
B
over TS1 to form the cobalt(III)-carbene radical formation from
D
-1
-1
is a low-barrier (+10.4 kcal mol ) and exergonic direct radical-rebound path (+15.2 kcal mol ). The relative TS3
intermediate
C
process. As observed for other carbene radical species, vs. TS4 barriers are too similar to discriminate reliably between
intermediate has most of its spin density localized at the these two pathways on the basis of DFT. However, in the
carbene carbon atom’. The next step (TS2) is a HAT process presence of coordinating compounds (such as deprotonated
C
1
6
’
3
3
from the allylic C
−
H bond of
C
,
to produce the benz-allylic 1a), trapping of the [Co(por)] catalyst
This is again a low-barrier (+5.6 kcal o-QDM fragmentation pathway via
mol ) and exergonic process. Interestingly, two competing thermodynamically favoured over the radical-rebound
pathways were identified for ring-closure to form the same pathway via TS3
dihydronaphthalene product from intermediate , with very The pathway via ortho-quinodimethane
similar overall barriers. The first pathway concerns the coloured pathway) is of interest in view of the experimental
A
, after release of
E, the
3
4
radical intermediate
D
.
E
and TS4 is likely
-
1
.
D
E (Scheme 6, blue-
2
anticipated (see also Scheme 2a) radical rebound mechanism results described in Table
Scheme , red-coloured pathway). This process involves have a large influence on the product yield. While this
attack of the terminal carbon atom of the allyl-radical moiety behaviour was unexpected in view of the anticipated radical-
on the anti-bonding orbital of the weak Co C bond in rebound mechanism (Scheme , red-coloured pathway), this
intermediate , leading to simultaneous C C bond making and makes perfect sense in view of a ring-closing mechanism
Co C bond breaking, thus forming the desired six-membered involving o-QDM intermediate
ring product with regeneration of the catalyst in one concerted in direct conjugation with the adjacent vinyl group. As such,
step (TS3). This elementary step has a quite low barrier (+15.2 and in line with the experimental results described in Table
3, showing that the R -substituents
(
6
−
6
D
−
2
−
E. After all, in E the R -moiety is
3,
-1
2
kcal mol ), albeit a bit higher than all preceding steps of the the R -substituents should have a direct influence on the
catalytic cycle. relative stabilities of species , thereby affecting both the
In view of the experimental results discussed above, bearing in thermodynamics for dissociation of as well as the barriers for
mind also the weakness of the Co C bond of , in direct -cyclisation (TS4) to form (thus explaining competing side-
E
E
−
D
6
π
F
2
conjugation with the benz-allyl radical moiety, an alternative product formation for some of the R -substituents.
pathway (See also Scheme 4b) for 1,2-dihydronaphthalene Furthermore, the influence of an alkyl substituent at the allylic
3
R instead of Y = H) proved to be
formation from
splitting of the Co
quinodimethane intermediate
TS4) to yield the same 1,2-dihydronaphthalene product
D
was considered. This involves homolytic position (Scheme
3
, Y = -CH
2
−
C bond to release the reactive ortho- even larger, leading to formation of E-aryl dienes instead of
, followed by 6 -cyclisation the expected 1,2-dihydronaphthalenes, which clearly points to
E
π
(
F
involvement of o-QDM intermediates in the reactions
1
1a
(Scheme
6, blue-coloured pathway).
described in Table 4.
While formation of o-QDM intermediate
E
from
D
is
-1
endergonic (ΔG°333K = +11.0 kcal mol ), the subsequent ring-
-1
closing barrier via TS4 is very low (+3.9 kcal mol ). As such the
a
Scheme 6 Computed mechanisms for [Co(por)]-catalysed 1,2-dihydronaphthalene formation.
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COOMe
COOMe
COOMe
base
ꢀ
II
Co
F
−60.3
1a
N
1a'
N
2
A
NHTs
=
0
COOMe
COOMe
COOMe
TS4
N2
−7.2
H
TS3
−6.9
II
Co
COOMe
Co
B
+
0.4
rebound
TS1
10.8
E
−11.1
+
COOMe
N2
COOMe
CH
III
II
Co
H
2
A
III
HAT
TS2
Co
Co
C
12.3
DFT-D3 calculated (Turbomole, BP86, def2-TZVP, disp3) mechanisms for [Co(por)]-catalysed 1,2-dihydronaphthalene formation (free energies, ΔG°333K, in kcal mol ). All energies,
D
−
6.7
−
−22.1
a
−1
including the transition states, are reported with respect to (the toluene adduct of) species A as the reference point. A cobalt-porphyrin complex without meso-substituents was
used as a simplified model of the actual [Co(TPP)] catalyst.
a
Scheme 7 Computed mechanisms for E-aryl diene formation as compared to 1,2-dihydronaphthalene formation from allyl-radical intermediate D’
.
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a
DFT-D3 calculated (Turbomole, BP86, def2-TZVP, disp3) mechanisms for [Co(por)]-catalysed 1,2-dihydronaphthalene and E-aryl diene formation from D’ (free energies, ΔG°333K, in
−
1
kcal mol ). All energies, including the transition states, are reported with respect to species D’ as the reference point. A cobalt-porphyrin complex without meso-substituents was
used as a simplified model of the actual [Co(TPP)] catalyst.
To shed more light on those reactions, we also explored the traditional closed-shell organometallic catalysis. A further
mechanism for E-aryl diene formation from allyl radical mechanistically interesting observation is that the benz-allyl
intermediate D’ (see Scheme
could in principle undergo a direct radical rebound ring-closure already quite weak Co
step (TS5, Scheme , similar to TS3 in Scheme ) to produce 3- QDM intermediates
methyl substituted 1,2-dihydronaphthalene product F’. This is uncatalysed ring closure (
7
). Allyl radical intermediate D’ radical moiety in species
D
and D’, in direct conjugation with
C bonds, triggers dissociation of o-
and E’, which either undergo an
) or Ene-type [1,7]-hydride shift (E’
a strongly exergonic (ΔG°333K = +11.0 kcal mol ) reaction step to form 1,2-dihydronaphtalenes ( ) or E-aryldienes ( ).
with a very accessible transition state barrier (TS5: +15.3 kcal In an attempt to gather additional experimental mechanistic
III
−
7
6
E
E
)
-1
F
G
-1
-1
mol ; comparable to the TS3 barrier from
D: +15.2 kcal mol ). information, we performed a set of kinetic NMR studies and
However, dissociation of o-QDM E’ from D’ is only slightly radical-trapping experiments. The kinetic studies were not very
-1
endergonic (+7.0 kcal mol ), and a subsequent Ene-type [1,7]- informative though, showing zero order kinetics in the
hydride shift reaction via TS8 (Scheme , blue pathway) has a substrate as well as the catalyst (see Supporting Info). This
very low barrier (+2.0 kcal mol from E’). As such, the total TS8 points to a rate limiting thermal conversion of the poorly
7
-
1
-1
barrier from D’ of +9.0 kcal mol to form E-aryl diene product soluble substrate 1b into the soluble, reactive diazo compound
is much lower than the TS5 barrier for direct radical-rebound 1b’, and hence does not provide any information about the
ring closure to form 1,2-dihydronapthalene F’ (Scheme , top subsequent cobalt-catalysed steps. Radical trapping
red pathway). Alternative o-QDM pathways for formation of experiments proved more informative. Performing the
,2-dihydronapthalene F’, involving 6 -cyclisation of E’ or E’’ catalytic reaction of 1b in the presence of two equivalents of
over TS6 or TS7, are also higher barrier processes than 2,2,6,6-tetra-methylpiperidine-1-oxyl (TEMPO) led to
formation of over TS8 according to DFT (Scheme , bottom formation of the (over)oxidized species , isolated in 59% yield
red pathways). As such, the experimentally observed (Table (Scheme , top). Apparently it is possible to trap the cobalt(III)-
formation of E-aryl dienes for substrates containing an alkyl carbene radical intermediate
substituent at the allylic position instead of the In a separate EPR spin-trapping experiment, using phenyl N-
G
7
1
π
G
7
6
4)
8
3
7
C
with TEMPO.
3
5
thermodynamically favoured 1,2-dihydronapthalenes, must tert-butylnitrone (PBN) (
7) as the spin-trap, we first generated
be a kinetically controlled process, dictated by the very low the diazo compound 1b’ at elevated temperature, cooled
3
6
TS8 barrier.
down
Notably, the overall catalytic cycles involve the sequential the reaction mixture to room temperature, after which we
transition of (1) a diazo compound to (2) a cobalt(II) carbenoid added PBN and the catalyst to prepare the EPR sample
(
species
cobalt(III)-CH
moiety (species
B
), (3) a cobalt(III)-carbene radical (species
-aryl species containing a benz-allyl radical
and D’), thus providing an intriguing
C) and (4) a (Scheme 8, bottom).
2
D
sequence of single-electron steps uncommon
t more
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viable mechanistic possibility for ring-closure to 1,2-
dihydronaphthalenes. However, a competing pathway seems
to prevail kinetically, involving dissociation of a reactive ortho-
quinodimethane (o-QDM) intermediate from the metal,
followed by concerted, pericyclic 6π-cyclisation. The ring-
closure reaction has been successfully applied to a broad range
1
of substrates with various R substituents at the aromatic ring,
producing the desired 1,2-dihydronapthalenes in good to
2
excellent isolated yields for substrates with an R = COOEt
2
substituent at the vinylic position (~70-90% ). Changing the R
moiety from an ester to another substituent has a surprisingly
large influence on the (isolated) yields. This behaviour is
unexpected for a radical rebound ring-closure mechanism, and
points to a mechanism proceeding via o-QDM intermediates.
III
Scheme 8 Radical scavenging experiments used to trap the Co -carbene radical
intermediate.
Furthermore, substrates with an alkyl substituent at the allylic
3
R instead of Y = H) react to form E-aryl-dienes
position (Y = CH
2
in excellent yields, rather than the expected 1,2-
dihydronaphthalenes. This result, combined with the outcome
of supporting DFT calculations, strongly points to the release
of reactive o-QDM intermediates from the metal centre in all
cases. The latter either undergo a 6π-cyclisation reaction to
form 1,2-dihydronaphthalenes, or a [1,7]-hydride shift to
produce E-aryl-dienes. Both pathway are low-barrier processes
according to DFT, but the [1,7]-hydride shift outcompetes the
6π-cyclisation step for the substrates with an alkyl substituent
3
300
3320
3340
3360
3380
at the allylic position, thus producing E-aryl-dienes in
kinetically controlled reactions rather than the expected,
thermodynamically more stable 1,2-dihydronaphthalenes. Spin
trapping experiments confirm the radical nature of these
reactions. Follow-up studies in our laboratory currently focus
on exploiting metalloradical catalysed ortho-quinodimethane
B (Gauss)
Fig. 2 Isotropic X-band EPR spectrum of the PBN-trapped carbon-centred radical
T= 298 K; microwave frequency: 9.36607 GHz; power: 6.33 mW; modulation
(
amplitude: 1.0 G).
11a
formation coupled to a series of related pericyclic reactions.
The resulting EPR spectrum is depicted in Figure
2 (giso = 2.007,
N
H
A = 14.3 G, A = 2.8 G). The detected proton and nitrogen
hyperfine interactions of 2.8 G and 14.3 G, respectively, reveal
trapping of a carbon-centred radical by the PBN spin-trap. The
Conflicts of interest
most likely candidate of this PBN-trapped species is There are no conflicts to declare.
intermediate thus forming compound HR-MS
C
,
8.
spectrometry confirmed the presence of such species, with the
mass of the catalyst plus carbene-substrate plus PBN. The Funding Sources
trapping experiments are thus in agreement with the proposed
Financial support from the Netherlands Organization for
Scientific Research (NWO-CW VICI project 016.122.613) and
the University of Amsterdam (Research Priority Area
Sustainable Chemistry) is gratefully acknowledged.
metallo-radical activation steps of diazo compound 1a’ by the
cobalt(II) catalyst in order to produce carbene radical
intermediate C.
Conclusions
Acknowledgements
Metalloradical activation of substituted o-styryl N-tosyl
hydrazones provides an effective synthetic protocol for the
synthesis substituted 1,2-dihydronaphthalenes and E-aryl-
dienes, taking advantage of the intrinsic and controlled radical-
type reactivity of a cobalt(III)-carbene radical intermediate.
The cobalt-catalysed synthesis of 1,2-dihydronaphthalene
We thank Ed Zuidinga for MS measurements and Jan Meine
Ernsting for NMR advice.
Notes and references
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(a) A. de Meijere and P.J. Stang in: Metal-Catalysed Cross-
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1
0 | J. Name., 2012, 00, 1-3
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4 Uncatalysed thermal decomposition of substrate 1a is
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2
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32 Transition metal diazo adducts like B are sometimes named
‘carbenoids’. For a discussion on the naming of carbenoids and
(transition)metal carbenes (or metallocarbenes), see: (a) A.
Caballero and P.J. Pérez, Chem. Eur. J., doi:
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Journal Name
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Bartley and T. Kodadek, Science, 1992, 256, 1544.
3
3 Intramolecular HAT (via TS2) first requires rotation around the
aromatic−Cvinylic single bond of C to produce Crotated, with its allylic
hydrogen atoms closer to the carbene radical moiety. Crotated is
computed to be only +1 kcal mol less stable than C. See
supporting information.
C
-1
3
4 Unlike the copper, silver and gold systems recently reported by
Pérez and coworkers, HAT via TS2 does not involve active
participation of the gem-ester moiety: M.R. Fructos, M. Besora,
A.A.C. Braga, M.M. Díaz-Requejo, F. Maseras and P.J. Pérez,
Organometallics, 2017, 36, 172.
3
5 (a) H. Heimgartner, L. Ulrich, H.-J. Hansen and H. Schmid,
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3
6 Heating the kinetic product 3m for a prolonged period does not
lead to spontaneous ring-closure to produce the corresponding
thermodynamic 1,2-dihydronaphthalene product (2). Heating
3m in the presence of NaOMe only led to trans-esterification.
37 Trapping of the corresponding o-QDM intermediate by TEMPO
to produce compound 6 cannot be fully excluded.
1
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TOC Graphic
Catalytic synthesis of substituted 1,2-dihydronaphthalenes via
metalloradical activation of o-styryl N-tosyl hydrazones is presented, taking
advantage of the intrinsic reactivity of
a cobalt(III)-carbene radical
intermediate. Substrates with an alkyl substituent on the allylic position
reacted to form E-aryl-dienes rather than the expected 1,2-
dihydronaphthalenes.
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24 Uncatalysed thermal decomposition of substrate 1a is 36 Heating the kinetic product 3m for a prolonged period does not
unselective, producing many different products (among
which ~20% of the carbene dimerization product). Product
lead to spontaneous ring-closure to produce the corresponding
thermodynamic 1,2-dihydronaphthalene product (2). Heating
2a
was not detected in these mixtures.
5 A. Chirila, B.G. Das, N.D. Paul, and B. de Bruin,
ChemCatChem, 2017, , 1413.
3
m in the presence of NaOMe only led to trans-esterification.
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7 Trapping of the corresponding o-QDM intermediate by TEMPO
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8 Considering the results obtained in Table 4, diene formation for
substrate 1l could perhaps be expected, but was not observed.
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rotate towards the methide for the required [1,7]-hydride shift,
since it is constrained in the cyclohexyl ring (Scheme 5).
2
9 While the major E-isomer of 1o transforms selectively to the E-
aryl diene product, the non-productive Z-isomer of 1o
participates in a Buchner-type ring expansion of a benzene
solvent molecule to produce side product 4 (see ESI for
structure and characterization). As a result, product 3o was
obtained as a mixture containing ~10% of compound 4. It
proved difficult to isolate pure 3o, clean from 4.
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32 Transition metal diazo adducts like B are sometimes named
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3 Intramolecular HAT (via TS2) first requires rotation around the
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hydrogen atoms closer to the carbene radical moiety. Crotated is
-1
computed to be only +1 kcal mol less stable than C. See
supporting information.
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