Potassium tert-butoxide mediated Heck-type cyclization/isomerization- benzofurans from organocatalytic radical cross-coupling reactions

Article abstract of DOI:10.1039/c1cc14297f

A transition metal-free Heck-type cyclization/isomerization reaction has been developed. Mediated by potassium tert-butoxide and phenanthroline a variety of benzofuran derivatives have been synthesized.

Full text of DOI:10.1039/c1cc14297f

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COMMUNICATION
Potassium tert-butoxide mediated Heck-type
cyclization/isomerization–benzofurans from organocatalytic radical
cross-coupling reactionsw
Magnus Rueping,* Matthias Leiendecker, Arindam Das, Thomas Poisson
and Lan Bui
Received 16th July 2011, Accepted 18th August 2011
DOI: 10.1039/c1cc14297f
A transition metal-free Heck-type cyclization/isomerization reaction
has been developed. Mediated by potassium tertbutoxide and phenan-
throline a variety of benzofuran derivatives have been synthesized.
are supposed to follow a homolytic radical aromatic substitution
mechanism.10,11
The goal of our research was to extend this emergent coupling
technique to intramolecular Heck-type reactions, as this would
provide a transition metal-free synthetic pathway to bicyclic
compounds.12 Although intramolecular reactions are typically
easier to perform, we were aware from the outset that the
intramolecular Heck-type reaction, in contrast to the inter-
molecular variant, cannot be easily optimized by changing the
reactant ratios and using large excess of one reactant.
To address these challenges, we chose the synthesis of
benzofuran derivatives as a first target. Herein, we show that
substituted allyl 2-iodophenyl ethers form benzofuran derivatives
in the presence of KOtBu (3 equiv.) and 1,10-phenanthroline
(0.4 equiv.) using mesitylene as a solvent (Scheme 1). To the
best of our knowledge, this is the first example for a KOtBu
mediated intramolecular reaction which connects an aromatic
carbon with a carbon atom of an alkene.
Transition-metal catalyzed reactions hold a special place in
organic synthesis due to their ability to promote C–C and
C-heteroatom bond formation.1 Despite major advances
achieved in the field, critical issues deal with the presence of
metal impurities in the final product, which may restrict their
practical applicability. Hence, alternative transition-metal-free
processes for the efficient construction of C–C and C-heteroatom
bonds are attracting attention. In this context, a series of
improved protocols for the direct C–H bond transformation,
making use of strong inorganic bases like sodium or potassium
tert-butoxide, have recently been established.
In late 2008, potassium tert-butoxide (KOtBu) was reported
to promote C–C coupling of electron-deficient nitrogen
heterocycles with haloarenes under microwave irradiation.2,3
Furthermore, in conjunction with peroxides, KOtBu was
found to assist the formation of C–C bonds between nitrogen
heteroaromatics and alkanes.4 More recently, transition metal-
free coupling reactions mediated by KOtBu and leading to biaryl
compounds were described by Shi and co-workers.5 Indepen-
dently, similar results were reported by the groups of Hayashi6a
and Kwong and Lei.6b In all cases, a catalytic system consisting
of potassium or sodium tert-butoxide and a diamine such as
DMEDA or phenanthroline promoted the reaction.5,6 Newly,
in conjunction with KOtBu, quinoline-1-amino-2-carboxylic acid
was also reported to promote the reaction between aryl halides
and arenes.7 Along the same lines, Charette et al. described the
KOtBu/pyridine mediated intramolecular arylation of various
aryl halides under microwave irradiation.8 Moreover, KOtBu
was also successfully applied in the coupling of aromatic
compounds with alkenes.9 These newly developed reactions5–7
Taking into account the recent mechanistic discussion, we
propose a homolytic radical mechanism with a single electron
RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.
E-mail: magnus.rueping@rwth-aachen.de;
Fax: +49 (0) 241-809-2665
w Electronic supplementary information (ESI) available: Extended
screening table, experimental details and characterization data. See
DOI: 10.1039/c1cc14297f
Scheme 1 A plausible reaction mechanism for the KOtBu mediated
Heck cyclization–isomerization reaction.
c
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transfer process to the aryl halide as a first step (Scheme 1).10,11
The starting compound 1 is thereby reduced to radical anion 2
by the KOtBu/diamine system.13 At this high energetic state,
iodide leaves easily the molecule and the next ring closure step
provides radical 4. The substitution pattern in the terminal
alkene is essential for the ring closure as it stabilizes both the
intermediate radical 4 and, more importantly, the double bond
in 1 and 3, which would otherwise be easily isomerized to the
vinyl ether under the reaction conditions employed.14
Table 2 Survey of temperatures, additives and concentrations
Entry T/1C Additive (equiv.) KOtBu (equiv.) Time/min Yielda (%)
1
2
3
4
5
6
7
8
80 Phen (0.4)
120 Phen (0.4)
160 Phen (0.4)
170 Phen (0.4)
160 Phen (0.2)
160 Phen (0.8)
160 Phen-Me2 (0.4)c
160 DMEDA (0.4)d
150 Phen (0.4)
150 Phen (0.4)
155e Phen (0.4)
3
3
3
3
3
3
3
3
120
120
90
120
90
90
90
90
16b
25
63
58
At this stage two different pathways can be rationalized.
Radical 4 undergoes either deprotonation to yield radical
anion 5 which reacts with the aryl halide 1 or is oxidized by
the butoxide radical formed in the first step, and subsequently
deprotonated to give 6. Base promoted isomerization leads to
the final product 7.
39b
49b
33b
40b
23b
43
9
10
11
1.5
5
3
120
120
15
46
Evaluation of various parameters revealed that only a
balanced interplay of the base, diamine, halogen and solvent
at temperatures between 150 and 170 1C results in promising
yields. As intramolecular reactions cannot be optimized
through different reactant ratios, avoiding decomposition
was an additional challenge.15 Solvent screening revealed
mesitylene, toluene, dioxane, and pyridine as potential reaction
media for the KOtBu mediated Heck cyclization. In contrast,
reactions in DMF and DMSO resulted in complete decom-
position of the starting material 9 (X = I). Decomposition was
observed also in the case of bromo- and chloro- substituted
benzene derivatives 9 (X = Br, Cl, Table 1, entries 5 and 6).
Here, a plausible explanation could be a lower compulsion of
the halide to leave the activated radical anion, which results in
side reactions of this highly active species. Sodium and lithium
tert-butoxide did not mediate the reaction (Table 1, entries 7
and 8). In these cases, the starting material was completely
recovered and we concluded that these weaker bases cannot
form the reactive radical anion.
a
b
Yield of the isolated product. Determined by 1H-NMR (internal
c
standard: 1,3,5-trimethoxybenzene). 4,7-Dimethyl-1,10-phenanthroline.
d
e
N,N0-Dimethylethylenediamine. Microwave reaction.
were obtained, supporting our proposed mechanism involving
stabilized double bonds and radicals. The ideal temperature
for this reaction was 160 1C (Table 2, entries 1–4). At higher
temperatures fast decomposition of KOtBu and aryl iodide was
observed; lower temperatures slowed down the reaction without
leading to better yields even after extended reaction times.
Decreasing the concentration of phenanthroline to 0.2 equiv.
or increasing it to 0.8 resulted in lower yields (Table 2, entries 5
and 6). The use of phenanthroline was essential,16 but it could
be replaced by 4,7-dimethyl-1,10-phenanthroline or by N,N0-
dimethylethylenediamine. However, the yields were significantly
lower in both cases (Table 2, entries 7 and 8). The same result
was observed for an increased base concentration of 5 equiv.
(Table 2, entry 10). The use of 1.5 equiv. of the base resulted in
a yield drop to 23%. Performing the reaction under microwave
irradiation17 resulted in full conversion of the starting material
and a yield of 46% after 15 minutes (Table 2, entry 11).
In previous publications on KOtBu mediated coupling
reactions, researchers have taken every conceivable step to prove
that the reactions work indeed transition metal-free.5,18 For our
study we used sublimed KOtBu from Sigma Aldrich (99.99%)
and conducted ICP-MS measurements to identify potential metal
impurities.16 As previously reported by Shi et al.,5 traces of
copper (0.34 ppm) were detected in the phenanthroline. One
key experiment to probe the role of copper traces is to determine
the yields after conducting the reaction with additional copper
salts.19 However, no effect was observed in these cases.16
With the optimized conditions in hand, we evaluated various
substrates 1a–o as cis/trans isomers in the intramolecular Heck
cyclization/isomerization reaction (Table 3). The method tolerates
various electronic and substitution patterns on the aromatic
moieties, affording benzofuran derivatives 7a–o in moderate to
good yields (Table 3).
The highest yield obtained for our initial target molecule 10
(Table 1, entry 10) was 38%. Next to the product, a considerable
amount of a by-product was formed in which the double bond
of the starting material was isomerized to the vinyl ether.
Hence, we turned our attention to substrate 1a (Table 2).
Here, yields up to 63% after column chromatography purification
Table 1 Survey of different solvents, halides and bases
Entry
Solvent
X
M
T/1C
Time/h
Yielda (%)
1
2
3
4
5
6
7
8
Toluene
DMF
DMSO
I
I
I
I
Br
Cl
I
I
I
K
K
K
K
K
K
Na
Li
K
K
K
110
110
110
110
110
110
110
110
150
150
160
14
14
14
14
14
14
14
14
14
2
28
—
—
30
—
—
—
—
29
38
21b
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Mesitylene
Mesitylene
Pyridine
The best yield was obtained in the case of substrate 1d
bearing electron donating groups on the aromatic ring directly
involved in the reaction. Bis-coupling was also achieved leading
to the corresponding product 7o in 41% yield.
9
10
11
I
I
2
a
b
Yield of the isolated product. Determined by 1H-NMR (internal
standard: 1,3,5-trimethoxybenzene).
In summary, we have developed a transition metal-free
intramolecular Heck-type cyclization/isomerization reaction
c
10630 Chem. Commun., 2011, 47, 10629–10631
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Table
3
Scope of the KOtBu mediated Heck cyclization/
745–746; (e) T. Bunlaksananusorn and P. Knochel, J. Org. Chem.,
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S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat. Chem., 2010, 2, 1044–1049.
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7 Y. Qiu, Y. Liu, K. Yang, W. Hong, Z. Li, Z. Wang, Z. Yao and
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R. D. Stauffer, T. D. Rogerson, A. Chong and L. D. Jones,
J. Am. Chem. Soc., 1975, 97, 2507–2516. For the KOtBu-mediated
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9 E. Shirakawa, X. Zhang and T. Hayashi, Angew. Chem., Int. Ed.,
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5018–5022; (b) S. Yanagisawa and K. Itami, ChemCatChem, 2011,
3, 827–829.
11 For reviews on homolytic aromatic substitution with aryl radicals,
see: (a) R. Bolton and G. H. Williams, Chem. Soc. Rev., 1986, 15,
261–289; (b) J. Fossey, D. Lefort and J. Sorba, Free Radicals in
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Chem., 2005, 16, 27–53; (e) W. R. Bowman and J. M. D. Storey,
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12 For reports on Pd-catalyzed intramolecular Heck cyclization reac-
tions, see: (a) S. Caddick and W. Kofie, Tetrahedron Lett., 2002,
43, 9347–9350; (b) F. A. Siqueira, J. G. Taylor and C. R.
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a
Reactions were performed with 1a–o, KOtBu (3 equiv.), 1,10-phe-
nanthroline (0.4 equiv.) in mesitylene at 160 1C for 2 hours.
mediated by KOtBu.20 A variety of benzofuran derivatives are
accessible through
a reaction pathway which involves
13 Vicinal diamines are reported to form radical anions, when treated
with KOtBu: (a) G. A. Russell, R. Konaka, E. T. Strom,
W. C. Danen, K.-Y. Chang and G. Kaupp, J. Am. Chem. Soc.,
1968, 90, 4646–4653; (b) J. H. Wotiz, R. D. Kleopfer,
P. M. Barelski, C. C. Hinckley and D. F. Koster, J. Org. Chem.,
1972, 37, 1758–1763. These radical anions might act as single
electron transfer donors in the present reaction.
14 For an example, where double bond isomerization prevented the
ring closure reaction, see: R. Loska, C. M. Rao Volla and P. Vogel,
Adv. Synth. Catal., 2008, 350, 2859–2864.
15 Whereas DMF is a suitable solvent for the bimolecular Mizoroki–
Heck-type reaction mediated by potassium tert-butoxide,9 in the
present study it led to complete decomposition of the starting
materials.
16 For details, see the ESIw.
17 155 1C was the highest temperature obtained in mesitylene at
300 W.
18 N. E. Leadbeater, Nat. Chem., 2010, 2, 1007–1009.
19 S. L. Buchwald and C. Bolm, Angew. Chem., Int. Ed., 2009, 48,
5586–5587.
20 During the manuscript revision process, two publications describ-
ing further KOtBu/diamine promoted reactions appeared:
(a) C.-L. Sun, Y.-F. Gu, W.-P. Huang and Z.-J. Shi, Chem.
Commun., 2011, 47, 9813–9815; (b) C.-L. Sun, Y.-F. Gu,
B. Wang and Z.-J. Shi, Chem.–Eur. J., 2011, DOI: 10.1002/
chem.201101562.
aryl and stabilized tertiary benzhydryl radicals. Due to the
operational simplicity, the method is expected to find further
application in the synthesis of heterocyclic compounds of
interest.
Notes and references
1 (a) Metal-catalyzed Cross-Coupling Reactions, ed. A. de Meijere
and F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004;
(b) Modern Arylation Methods, ed. L. Ackermann, Wiley-VCH,
Weinheim, 2009.
2 (a) S. Yanagisawa, K. Ueda, T. Taniguchi and K. Itami, Org. Lett.,
2008, 10, 4673–4676. For LiOtBu mediated arylation of pyrrole
derivatives, see: (b) O. Vakuliuk, B. Koszarna and D. T. Gryko,
Adv. Synth. Catal., 2011, 353, 925–930.
3 KOtBu was reported to promote the arylation of amines with aryl
halides at elevated temperatures or under microwave irradiation:
(a) M. Beller, C. Breindl, T. H. Riermeier and A. Tillack, J. Org.
Chem., 2001, 66, 1403–1412; (b) L. Shi, M. Wang, C.-A. Fan,
F.-M. Zhang and Y.-Q. Tu, Org. Lett., 2003, 5, 3515–3517. These
transformations proceed through a benzyne intermediate. For
further
selected
KOtBu
catalyzed
reactions,
see:
(c) A. L. Rodriguez, T. Bunlaksananusorn and P. Knochel, Org.
Lett., 2000, 2, 3285–3287; (d) T. Bunlaksananusorn,
A. L. Rodriguez and P. Knochel, Chem. Commun., 2001,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10629–10631 10631