Regiodiverse three-component synthesis of arenes

Article abstract of DOI:10.1002/adsc.201000832

A ruthenium-catalyzed enyne metathesis reaction followed by a cobalt-catalyzed Diels-Alder reaction and oxidation of the dihydroaromatic intermediate generates the two regioisomeric aromatic products in good overall yields in a one-pot procedure. The regiochemistry of the cycloaddition can be controlled by the ligand choice on the cobalt catalyst to generate the product with the 1,3,5-or the 1,2,4-substitution pattern predominantly. The high functional group tolerance was used to generate bifunctionalized building blocks and finally an unprecedented regioselective Scholl reaction is described.

Full text of DOI:10.1002/adsc.201000832

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DOI: 10.1002/adsc.201000832
Regiodiverse Three-Component Synthesis of Arenes
Michael Danza and Gerhard Hilta,*
a
Fachbereich Chemie, Philipps-Universitꢀt Marburg, Hans-Meerwein-Str., 35043 Marburg, Germany
Fax : (+49)-6421-2825677; e-mail: hilt@chemie.uni-marburg.de
Received: November 8, 2010; Published online: February 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000832.
Abstract: A ruthenium-catalyzed enyne metathesis
reaction followed by a cobalt-catalyzed Diels–Alder
reaction and oxidation of the dihydroaromatic inter-
mediate generates the two regioisomeric aromatic
products in good overall yields in a one-pot proce-
dure. The regiochemistry of the cycloaddition can
be controlled by the ligand choice on the cobalt cat-
alyst to generate the product with the 1,3,5- or the
1,2,4-substitution pattern predominantly. The high
functional group tolerance was used to generate bi-
functionalized building blocks and finally an unpre-
cedented regioselective Scholl reaction is described.
Scheme 1. Intermolecular trimerization of alkynes.
An alternative to the cyclotrimerization of alkynes
is the cobalt-catalyzed Diels–Alder reaction of al-
kynes with 1,3-dienes followed by oxidation of the di-
hydroaromatic intermediate.[4]
Keywords: alkynes; arenes; cobalt; metathesis;
regioselectivity
Thereby, excellent regiocontrol can be obtained
and the dienophile is not limited to acceptor-substitut-
ed educts as in thermal Diels–Alder reactions with
normal electron demand. In the past we were able to
show that the neutral Diels–Alder reaction can be ef-
ficiently catalyzed by low valent cobalt complexes
The synthesis of highly substituted aromatic com- under ambient temperature. The products can be ob-
pounds is an issue of great interest in pharmaceutical tained in excellent yields and depending on the ligand
as well as in material science. The alternative to tradi- on the cobalt centre the 1,4- (para) or the 1,3-substi-
tional functionalizations of an already existing aro- tution (meta) regioisomer can be selectively ad-
matic backbone by cross-coupling reactions, Friedel– dressed.[5]
Crafts functionalizations and so on is the generation
To overcome the limitations of the cyclotrimeriza-
of the aromatic core by transition metal catalysis tion of three different alkynes we investigated a strat-
from functionalized alkynes or enynes. In particular, egy by which the first alkyne is converted, in the pres-
the cobalt-catalyzed cyclotrimerization of alkynes is a ence of an alkene under ruthenium-catalyzed enyne
powerful tool for this purpose.[1] Although quite a metathesis conditions, to a 1,3-diene.[6]
number of transition metal catalysts exist to realize
This intermediate is then applied in a cobalt-cata-
this transformation, to date it has not been possible to lyzed Diels–Alder reaction with the second alkyne to
perform a cyclotrimerization of three different al- generate the dihydroaromatic intermediate so that
kynes in an intermolecular fashion without tethering the desired aromatic product can be obtained after
of the starting materials to generate a single prod- oxidation with DDQ.
uct.[2] Accordingly, the cyclotrimerization of three dif-
We envisaged that this approach could be realized
ferent alkynes in an intermolecular fashion leads to as a reaction sequence without isolation of the inter-
up to 37 isomers (Scheme 1) which are formed in a mediates by chromatography. This would be of ad-
more or less statistical mixture. In many cases only vantage because the isolation of volatile 1,3-diene in-
the regiochemistry of the products can be controlled, termediates can be circumvented and the tendency of
leading either to preference for the 1,3,5- or the 1,2,4- 1,3-dienes to polymerize when concentrated can be
substitution pattern and thereby reducing the number reduced.
of possible products.[3]
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Michael Danz and Gerhard Hilt
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In addition, flexibility is easily introduced into the all products are obtained without isolation of inter-
reaction sequence leading to 3 as two different routes mediates over three steps.
are available by simply exchanging the order at which
In entries 1–7 at least one symmetrical alkyne was
the respective alkynes 1 and 2 are applied. The two used and tri- and tetrasubstituted aromatic com-
routes exhibit different yields to generate the identi- pounds were obtained without addressing the prob-
cal product 3 (Scheme 2) and later on regioselectivi- lem of regioisomers. In the following reactions (en-
tries 8–17) two different unsymmetrical alkynes were
used and the control of the regiochemistry of the
products of type 7 was then controlled by the applica-
tion of two different cobalt catalyst systems bearing
either dppe or 8 as ligands. Catalyst system A {CoBr2
ACHUTNRGENUN[G 1,2-bis(diphenylphosphino)ethane] [=CoBr2ACHTUNGTRENN(UGN dppe)],
Zn, ZnI2} generates predominantly products
with a 1,4-substitution pattern, while catalyst system
B
{CoBr2[2,4,6-trimethyl-N-(pyridin-2-ylmethylene)-
AHCTUNGTERNNaGUN mine] [=CoBr2(8), Zn, Fe, ZnI2]} prefers to form
the regioisomeric 1,3-substituted products as de-
scribed earlier.[5c]
Utilizing these two catalysts, good to excellent re-
gioselectivities were obtained and the two regioisom-
ers were obtained in good yields (entries 8–17). The
choice of the alkyne used in the initial transformation
of the reaction sequence has a profound influence
upon the regioselectivity of the products formed in
the Diels–Alder reaction. This can be visualized par-
Scheme 2. Flexible approach to 3 by enyne metathesis,
cobalt-catalyzed Diels–Alder reaction and DDQ oxidation.
ties in the Diels–Alder reaction can be controlled ticularly well in entries 14–17. Using catalyst A the re-
when unsymmetrical starting materials are applied. gioselectivity of the sequence utilizing the two alkynes
The results for the reaction sequence are summar- 1-phenyl-1-hexyne and 4-methoxyphenylacetylene led
ized in Table 1 and we would like to emphasise that to a higher regioselectivity (78:22, entry 16) when 1-
Scheme 3. Selected follow-up reactions utilizing functionalized arene derivatives.
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Regiodiverse Three-Component Synthesis of Arenes
Table 1. Results for the enyne metathesis/Diels–Alder/oxidation reaction sequence.
Entry
Alkyne A (4)
Alkyne B (6)
Product 7
Yield[j]
1
2
70%
87%; 86%[b]
3
4
76%; 85%[c]
89%; 94%[c]
5
6
7
8
41%
80%
83%[c]
72% (96:4)
9
72% (92:8)
10
11
12
73% (91:9)
61%[d,e] (11:89)
61% (88:12)
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Michael Danz and Gerhard Hilt
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Table 1. (Continued)
Entry
Alkyne A (4)
Alkyne B (6)
Product 7
Yield[j]
13
61% (20:80)
14
15
47% (60:40)
44%[d,f] (7:93)
72%[f,g] (7:93)
16
17
80% (78:22)
7m, 7n
82%[f,h,i] (43:57)
[a]
First step: 1.0 equiv. alkyne A, 7.5 bar ethene, Grubbs II catalyst (2 mol%), CH2Cl2; second step: 1.2 equiv. alkyne B,
CoBr
CoBr
CoBr
2A
2A(dppe) (5 mol%), ZnI2 (10 mol%), Zn powder (10 mol%).
2A(dppe) (20 mol%), ZnI2 (40 mol%), Zn powder (40 mol%).
[b]
[c]
[d]
[e]
[f]
CHTUNGTRENNUNG
CHTUNGTRENNUNG
1.5 equiv. alkyne B.
CoBr2(8) (10 mol%), ZnI2 (20 mol%), Zn powder (20 mol%), Fe powder (20 mol%).
CoBr2(8) (20 mol%), ZnI2 (40 mol%), Zn powder (40 mol%), Fe powder (40 mol%).
1.5 equiv. alkyne A, 1.0 equiv. alkyne B.
Enyne-metathesis in C6F6, Grubbs II catalyst (5 mol%).
2.0 equiv. alkyne B.
[g]
[h]
[i]
[j]
Ratio of regioisomers are given in brackets.
phenyl-1-hexyne was used first in the metathesis reac- in the synthesis of more complex aryl bromide and ar-
tion as compared to 60:40 (entry 14) when 4-methoxy- ylboronic ester derivatives. Both functionalities are
phenylacetylene was the alkyne applied first. On the well accepted and remain unaltered in the products
other hand, when catalyst B was used in the Diels– which were obtained in high yields. Electron-deficient
Alder reaction the higher regioselectivity was ob- alkynes such as propiolic esters were not utilized as
served when 4-methoxyphenylacetylene was used first starting materials in the ruthenium-catalysed enyne
in the metathesis reaction (7:93 in entry 15 versus metathesis based on the low reactivity of such educts
43:57 obtained in entry 17).
reported by Mori.[6e]
The tolerance of the reaction sequence towards
Our previous work has shown that the cobalt-based
functional groups was demonstrated in entries 6 and 7 systems show a high tolerance for a broad range of
functional groups besides the two shown in this
work.[4,5] Therefore, a bromo-functionalized building
block 7e can be generated and converted in a Sonoga-
shira reaction to the alkyne 9 in excellent yield
Scheme 5. Reaction sequence utilizing 1-hexene as alkene
component.
Scheme 4. Synthesis of bifunctionalized terphenylenes.
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Regiodiverse Three-Component Synthesis of Arenes
(Scheme 3). In addition, the boronic ester 10 was suc- Experimental Section
cessfully reacted to the phenol derivative 11 in 86%
yield by oxidation. The double Suzuki-coupling reac- Representative Procedure (Table 1, entry 2)
tion of 7f with 1,4-dibromobenzene gave the quinque-
4-Octyne (110 mg, 1.0 mmol, 1 equiv.) and Grubbs II cata-
lyst (17 mg, 0.02 mmol, 2 mol%) were dissolved in 2 mL dry
dichloromethane and were reacted in a glass autoclave with
ethene (7.5 bar) at 608C for 5 h. Then argon was bubbled
through the solution and added to a flask containing
anhydrous zinc iodide (64 mg, 0.2 mmol, 20 mol%), zinc
phenylene product 11 in 86% yield. Under the dehy-
drative conditions applied in the Scholl reaction[7] uti-
lizing FeCl3 the tribenzo[fg,ij,rst]pentaphene deriva-
tive 13 was exclusively isolated in good yield while
the corresponding tribenzoACTHNUTRGNEUGN[f,k,m]tetraphene deriva-
powder (13 mg, 0.2 mmol, 20 mol%), CoBr2ACHTUNGTRENNUNG(dppe)
tive 12 was not observed. A quantum mechanical cal-
culation of the proposed radical cation intermediate
suggested unequal orbital coefficients at the two
carbon atoms (carbon a and carbon b in 11) relevant
for the regiodivergent carbon-carbon bond formation.
This could explain why product 13 was formed exclu-
sively. Further investigations towards regioselective
Scholl reactions are underway.[7b]
Bifunctionalized building blocks are also easily ac-
cessible. This was exemplified in the regiodiverse syn-
thesis of 14 and 15 (Scheme 4) starting from two dif-
ferent mono-functionalized alkynes and ethene utiliz-
ing either catalyst A in the Diels–Alder reaction to
predominantly generate the terphenylene regioisomer
14 (14:15=78:22) or by applying catalyst B to gener-
ate the bifunctionalized terphenylene 15 as the major
product (14:15=8:92).
(62 mg, 0.1 mmol, 10 mol%) and 4-methoxyphenylacetylene
(159 mg, 1.2 mmol, 1.2 equiv.) under an argon atmosphere.
The reaction mixture was stirred over night at ambient tem-
perature and filtered over a small plug of silica gel (eluent:
pentane/diethyl ether 1:1). The solvent was removed and
the dihydroaromatic intermediate was oxidized with DDQ
(272 mg, 1.2 mmol, 1.2 equiv.) in 15 mL toluene. After filtra-
tion over a small plug of deactivated silica gel (eluent: pen-
tane/diethyl ether 1:1) the solvent was removed and the resi-
due was purified by column chromatography on silica gel
(eluent: pentane/diethyl ether=30:1). The product 7a was
obtained as yellow solid; yield: 233 mg (0.87 mmol, 87%).
1H NMR (CDCl3, 300 MHz): d=7.57–7.51 (m, 2H), 7.38–
7.31 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.01–6.95 (m, 2H),
3.86 (s, 3H), 2.70–2.60 (m, 4H), 1.75–1.59 (m, 4H), 1.04 (t,
J=7.2 Hz, 6H); 13C NMR (CDCl3, 75 MHz): d=158.9,
140.7, 138.9, 138.2, 134.0, 129.5, 127.9, 127.5, 124.1, 114.1,
55.3, 35.0, 34.4, 24.4, 24.4, 14.3. IR: 2957, 2931, 2869, 1610,
1519, 1492, 1464, 1377, 1274, 1247, 1180, 1044, 1029, 822;
MS (EI): m/z=268 (M+, 100), 239 (89), 224 (14), 211 (16),
195 (14), 179 (11), 165 (20), 152 (16); HR-MS (EI): m/z=
268.1833, calcd. for C19H24O: m/z=268.1827.
As in the case for the synthesis of product 9 debro-
mination of 14 or 15 by the cobalt catalysts or the
zinc powder was not observed. The follow-up chemis-
try of these bifunctionalized building blocks is under
investigation.
For the expansion of the reaction sequence towards
the regiodiverse synthesis of products having three
substituents, a terminal alkene was used in place of
ethene. As the prototype reagent 1-hexene was used
in the enyne-metathesis reaction with phenylacetylene
to generate an intermediate 1,3-disubstituted 1,3-
diene (16, Scheme 5). The intermediate was then con-
verted in a regiodiverse cobalt-catalyzed Diels–Alder
reaction with trimethylsilylacetylene utilizing catalyst
A or catalyst B leading to the synthesis of the 1,2,4-
trisubstituted benzene derivative 17 or alternatively
to the 1,3,5-trisubstituted derivative 18.
Both regioisomers are addressable by the cobalt
catalysts systems A or B to predominantly generate
the desired regioisomer in good overall yields.
In conclusion, we have demonstrated that a reac-
tion sequence consisting of an enyne metathesis and a
cobalt-catalyzed Diels–Alder reaction is a versatile
tool for the synthesis of complex arene derivatives in
a modular fashion. Yields and regioselectivities are
sufficiently high to allow utilization of the reaction se-
quence in the future to address a broad range of com-
plex molecules.
Acknowledgements
This work was partly supported by the Deutsche Forschungs-
gemeinschaft.
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