Combining gold and palladium catalysis: One-pot access to pentasubstituted arenes from furan-yne and En-diyne substrates

Article abstract of DOI:10.1002/chem.201200091

A series of furan-yne systems was transformed into the corresponding tetrasubstituted annelated phenol derivatives that bear one bromo group. The two-step procedure consisted of a phenol synthesis and a subsequent electrophilic bromination with N-bromosuccinimide (NBS). The reactions can be performed in a one-pot procedure with the same precatalyst. The halogenation reaction is highly selective only in the presence of the gold catalyst. En-diyne substrates were also suitable starting materials; then the pentasubstituted aromatic core showed a completely different substitution pattern for the phenolic products. Furthermore, a one-pot protocol that consisted of a gold-catalyzed phenol synthesis, a gold-catalyzed halogenation reaction, and a palladium-catalyzed Suzuki coupling was established. The overall efficiency of this procedure was excellent and the substrate scope of the reaction was broad. Copyright

Full text of DOI:10.1002/chem.201200091

FULL PAPER
DOI: 10.1002/chem.201200091
Combining Gold and Palladium Catalysis: One-Pot Access to
Pentasubstituted Arenes from Furan–Yne and En–Diyne Substrates
A. Stephen K. Hashmi,*[a] Mohammad Ghanbari,[a, b] Matthias Rudolph,[a] and
Frank Rominger[a]
Abstract: A series of furan–yne sys-
tems was transformed into the corre-
sponding tetrasubstituted annelated
phenol derivatives that bear one
bromo group. The two-step procedure
consisted of a phenol synthesis and
a subsequent electrophilic bromination
with N-bromosuccinimide (NBS). The
reactions can be performed in a one-
pot procedure with the same precata-
lyst. The halogenation reaction is
highly selective only in the presence of
the gold catalyst. En–diyne substrates
were also suitable starting materials;
then the pentasubstituted aromatic
core showed a completely different
substitution pattern for the phenolic
products. Furthermore, a one-pot pro-
tocol that consisted of a gold-catalyzed
phenol synthesis, a gold-catalyzed halo-
genation reaction, and a palladium-cat-
alyzed Suzuki coupling was established.
The overall efficiency of this procedure
was excellent and the substrate scope
of the reaction was broad.
Keywords: arenes · furans · gold ·
one-pot reaction · palladium
Introduction
The extraordinary ability of gold to activate multiple bonds
has led to a large number of new approaches for the con-
struction of diverse carbo- and heterocyclic structures.[1]
The advantages with respect to classical routes are the
mild reaction conditions, often combined with high atom
economy,[2] and a significant increase in molecular complexi-
ty.[3] Furthermore, the functional-group tolerance and the
chemoselectivity is often amazing, which is demonstrated by
the increasing number of synthetic chemists who are using
gold-catalyzed reactions for protecting-group free access to
complex targets.[1h,4]
Scheme 1. Mechanism of the furan–yne cyclization.
Since 2000, our group[5]—and in the years that have fol-
lowed, the groups of Echavarren[6] and Shi[7]—have contrib-
uted a series of publications on a complex gold-catalyzed
(and other transition metals)[5b,6] furan–yne rearrangement
that offers a versatile tool for the synthesis of a broad range
of different heterocycles such as dihydroisoindoles, tetrahy-
droisoquinolines, dihydroisobenzofurans, isochromans, dihy-
drobenzofurans, chromanes, dihydroindoles, and tetrahydro-
quinolines (Scheme 1).
The overall regioselectivity of the reaction is determined
by the regioselectivity of the ring opening of the intermedi-
ate arene oxide 3.[5q] Thus selective reactions are obtained
from furan substrates that contain substituents that are able
to stabilize one of the two possible pentadienyl cations
formed upon ring opening of the arene oxide.
Based on this principle, furans with donor substituents in
the 3- or 5-position selectively deliver phenol derivatives in
which the phenolic hydroxyl group is located ortho to the
ring junction (Scheme 2). A loss in selectivity is observed
with 4,5-disubstituted systems or furans without any addi-
tional substituent.[5a,p] Recently, phenols with the hydroxyl
group meta to the ring junction also became accessible by
means of a tandem reaction of diynes 5.[8] In this case, the
intermediate furans bear an electron-donating substituent in
the 4-position, a substitution pattern that is not easily acces-
[a] Prof. Dr. A. S. K. Hashmi, M. Ghanbari, Dr. M. Rudolph,
Dr. F. Rominger+
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270
69120 Heidelberg (Germany)
Fax : (+49)6221-54-4205
E-mail: hashmi@hashmi.de
[b] M. Ghanbari
School of Chemistry
College of Science
University of Tehran, Tehran (Iran)
[+] This author was responsible for the crystallographic investigation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200091.
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Table 1. Screening different conditions for the bromination of phenol 4a.
Entry
Solvent
Catalyst
Yield [%]
1
2
3
4
5
6
DCE
DCE
CH2Cl2
CH2Cl2
THF
–
59
89
61
91
87
88
5 mol% AuCl3
–
5 mol% AuCl3
5 mol% AuCl3
5 mol%
CH2Cl2
5 mol% AgSbF6
Scheme 2. Selectivity in the gold-catalyzed phenol synthesis.
Figure 1. Solid-state molecular structure of 6a.
sible by means of classical synthetic chemistry but by the
new route.
The furan–yne systems for a possible construction of pen-
tasubstituted arene systems are challenging substrates them-
selves, and as shown in Scheme 2, no selective reaction can
be expected for some of these starting materials. Inspired by
the recent reports of Wang et al. on gold-catalyzed halogen-
ation reactions with N-halosuccinimides,[9] we considered
a one-pot reaction that includes gold-catalyzed phenol syn-
thesis, gold-assisted halogenation, and subsequent palladi-
um-catalyzed cross-coupling reaction as a promising strategy
towards pentasubstituted arene systems. A possible one-pot
procedure would be attractive, as purification of the inter-
mediates could be circumvented, which not only saves time
but also greatly reduces costs for energy and production of
waste.[10] Our achievements are summarized in this contribu-
tion.
yield of the reaction was not satisfactory (59% despite
a complete conversion of the starting material), which might
indicate competitive radical-type bromination reactions at
the benzylic positions of the substrate[12] and subsequent re-
actions. If AuCl3 was added as catalyst, the yield of the reac-
tion could be significantly improved and 89% of the bromi-
nated product 6a was isolated in DCE as solvent (Table 1,
entry 2). The goldACTHNUTRGNEUNG(III) probably acts as an oxophilic Lewis
acid, coordinates to the carbonyl group of NBS, and thus en-
hances the Br+ donor activity.[13] This accelerates the elec-
trophilic bromination, which thus becomes much faster than
the competing radical processes. The solvent dependency of
the reaction turned out to be low and comparable results
were also obtained in CH2Cl2 and THF (Table 1, entries 3–
5). We also tested the gold(I)–nitrogen acyclic carbene
(NAC) complex 7,[14] which was activated by chloride ab-
straction by using silver hexafluoroantimonate (Table 1,
entry 6; the control experiment with AgSbF6 was negative).
In CH2Cl2 this catalyst showed a comparable reactivity. This
is of interest because some of the preceding reactions of po-
tential tandem sequences might only work with gold(I) pre-
catalysts.
With these promising results in hand, we turned our focus
on the evaluation of a one-pot reaction that started from the
corresponding furan–yne system 1a (Table 2). For this ap-
proach, the brominating reagent and the starting material
were mixed in CH2Cl2, and the catalyst was added at room
temperature. Unfortunately, the reaction turned out to be
unselective and only a poor yield of the desired brominated
Results and Discussion
Our initial studies concentrated on the bromination reaction
of the products of the phenol synthesis. These screenings
were performed with test substrate 4a, a substrate that can
easily be obtained by means of gold catalysis (Table 1).[5a]
To our delight, even the noncatalyzed reaction in 1,2-di-
chloroethene (DCE) showed a reaction at room tempera-
ture, and bromination was selectively observed para to the
phenolic hydroxyl group (Table 1, entry 1). The constitution
of the product could be unambiguously assigned by X-ray
crystal structure analysis (Figure 1).[11] Unfortunately, the
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Gold and Palladium Catalysis
FULL PAPER
Table 2. Gold-catalyzed reaction of furane-yne 1a and NBS.
Table 3. Cyclization–bromination sequence for furan–ynes with substitu-
ent in 5-position.
Entry
NBS [equiv]
Yield of 6a [%]
Yield of 4a [%]
Entry
1
Compound
Product
Yield [%]
87 (73)[a]
1
2
1
2
15
20
9
0
product 6a besides minor amounts of intermediate phenol
4a could be obtained with 1 equiv of NBS (Table 2, entry 1),
although a complete conversion of the starting material was
monitored. An excess amount of NBS suppressed the forma-
tion of the nonbrominated phenol 4a, but the yield of the
desired product 6a did not significantly improve (Table 2,
entry 2). The reason for the unselective course of the reac-
tion is based on a fast and unselective reaction of NBS with
starting material 1a. A control experiment without the gold
catalyst delivered only minor amounts of mono-bromination
at the methyl substituent besides inseparable byproducts
(Scheme 3). In this context, the formation of alkynyl bro-
mide by NBS and a gold catalyst described by Corma
et al.[15] might contribute to the formation of undesired side
products.
2
3
84
84
4
5
6
86
74
61
[a] Reaction in THF as solvent.
Scheme 3. The direct bromination of furan–yne 1a is unselective; a yield
of only 28% of 8 is obtained.
with a methyl substituent in the 3-position at the furan
(Scheme 4). As mentioned earlier, this substrate is known to
deliver the corresponding phenol with a methyl substituent
in the para position. In this case, a comparable clean reac-
To circumvent decomposition of the starting material, we
changed the protocol to a sequential one-pot procedure
(Table 3). With the furan–yne substrate 1a, a fast and clean
formation of phenol 4a took place within just a few minutes.
After the complete conversion was detected by means of
thin-layer chromatography, NBS was added. This led to
a highly selective formation of 7-bromodihydroisoindole 6a
in an excellent overall yield of 87% (Table 3, entry 1). In
THF as solvent, the reaction gave a slightly lower yield
(73%). To evaluate the general applicability of this sequen-
tial one-pot protocol, a series of furan–yne derivates were
converted under the same reaction conditions. Substrates 1b
and 1c, with additional aromatic substitutents, showed no
loss of selectivity (Table 3, entries 2 and 3). Despite the ad-
ditional aromatic moieties, no trace of dibrominated product
was observed even with 2 equiv of NBS. The bromination
selectively occurred at the electron-rich phenol ring. Sub-
strates 1d and 1e with ethyl (Table 3, entry 4) and cyclo-
propyl substituents (Table 3, entry 5) could also be convert-
ed in good overall efficiency. Changing the heteroatom in
the tether from nitrogen to oxygen slightly reduced the yield
(Table 3, entry 6), but the overall yield of this one-pot proto-
col was still satisfactory. Next we investigated furan–yne 1g
Scheme 4. Cyclization–bromination sequence for furan–yne 1g with sub-
stituent in the 3-position.
tion was observed for the one-pot sequence and the bromi-
nation in the activated ortho position to the phenolic oxygen
was highly selective. Synthetically, it is very useful that both
the ortho and the para position of the product can be bromi-
nated by starting from different substitution patterns at the
furan systems. It is noteworthy that, despite the oxygen
tether, no reduction in yield was observed for this substrate.
Finally, we tested en–diyne substrate 5 for a possible
tandem sequence as well (Scheme 5). As we reported re-
cently,[8] gold(I)–NAC complexes showed excellent perfor-
mance for this domino reaction. Thus we did not change the
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A. S. K. Hashmi et al.
Scheme 5. Cycloisomerization/bromination of en–diyne 5.
oxidation state of the catalyst and performed the bromina-
tion step with the gold(I) catalyst too. As mentioned earlier
(see Table 1), for the bromination reaction the NAC com-
Scheme 6. Suzuki coupling reaction of the brominated 6a and 6j.
plex showed similar performance as the gold
(III) salt. In-
a gold-catalyzed bromination reaction, and a palladium-cat-
alyzed Suzuki coupling starting from furan–yne systems
(Table 5).
cluding the prior gold-catalyzed en-yne cyclization, product
6h was obtained in an excellent overall yield (95% over the
two reaction steps; Scheme 5). For this substrate, a selective
bromination next to the phenolic oxygen took place. This is
extremely valuable because only terminal alkynes are suita-
ble substrates for the phenol synthesis and therefore the in-
troduction of a substituent at this position prior to the
phenol synthesis is impossible.
Table 5. Sequential one-pot sequence consisting of furan–yne cyclization,
bromination, and Suzuki coupling.
Next we investigated whether N-chlorosuccinimide (NCS)
and N-iodosuccinimide (NIS) are also suitable for selective
halogenation reactions of the phenol substrates. These reac-
tions with standard test substrate 4a are summarized in
Table 4. In contrast to the NBS reaction, NCS turned out to
Entry
Starting
material
ArB(OH)2
Product
Yield
[%]
Table 4. Halogenation of 4a with NCS and NIS.
1
1a
1a
9a
9b
50
40
Entry
NXS
Catalyst
t [h]
Product
Yield [%]
2
3
1
2
3
4
NCS
NCS
NIS
NIS
–
24
24
1
6i
6i
6j
6j
0
AuCl3
–
AuCl3
82
63
91
1
1a
9c
34
be unreactive without the addition of the gold catalyst
(Table 4, entry 1). The gold-catalyzed process was slower
than with NBS, but yields were very good too (Table 4,
entry 2). In the case of NIS, reactivity was observed without
the catalyst, but due to the high reactivity of the NIS, the
formation of several side products was detected and the iso-
lated yield of the desired product was unsatisfactory
(Table 4, entry 3). Like in the case of NBS, with NIS and the
gold catalyst a highly selective reaction was observed
(Table 4, entry 4), and we could isolate the product of the
para-iodination reaction in excellent yield.
To evaluate the possibility of a further derivatization of
the halogenated arenes, we tested the reaction of substrates
6a and 6j with 3-methoxyphenyl boronic acid under stan-
dard Suzuki coupling conditions. Both of the reactions deliv-
ered the pentasubstituted aromatic system in good yields
within acceptable reaction times at elevated temperatures
(Scheme 6).
4
5
1b
1b
9d
9e
71
64
6
1c
9 f
60
After the evaluation of all these single reaction steps, we
finally investigated the possibility of a sequential one-pot re-
action that consisted of a gold-catalyzed phenol synthesis,
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Gold and Palladium Catalysis
Table 5. (Continued)
FULL PAPER
overall yield by about 10%. If one considers the energy
costs and the time saved, this drop in yield for the one-pot
procedure should be acceptable for most of the substrates.
Therefore, we also performed the other reactions without
changing the solvent. Switching the substituent at the boron-
ic acid to an electron-withdrawing nitro group led to a signif-
icant drop in yield (Table 4, entries 2 and 3), especially for
the nitro group in para position, which has an additionally
mesomeric effect (Table 4, entry 3). Interestingly, reactions
with substrate 1b, which contains an additional aryl moiety
in the saturated tether, delivered significantly higher overall
yields. Not only the electron-rich 3-methoxyphenyl boronic
acid delivered a remarkable overall yield of 71% (Table 4,
entry 4), but also the nitro-substituted boronic acid, which
still delivered 64% of the pentasubstituted arene over three
steps (Table 4, entry 5). Similar observations were made for
tolyl substrate 1c, which was converted to four different di-
hydroisoindoles (Table 4, entries 6–9). Yields were also up
to 70%, only the para-nitrophenyl boronic acid (Table 4,
entry 9) led to a significant drop in yield (39%). The in-
crease in yield for these substrates is based on a higher yield
for the phenol synthesis in the first reaction step. This was
underlined by performing the phenol synthesis in THF for
substrate 1c (for the single reaction step, 4c was isolated in
90% yield). Furan–ynes with alkyl groups in the saturated
tether are also suitable substrates. Compound 1d with an
ethyl substituent in the furyl position delivered an impres-
sive yield of 75% (over 90% average yield for every single
step!). Furan systems that bear an oxygen bridge also per-
formed well, and good yields were obtained not only for the
methoxyphenyl boronic acid (entry 11) but also for the elec-
tron-deficient para-fluorophenyl boronic acid (entry 12).
The overall yields for the two steps are quite good, but one
has to keep in mind that 75% overall (entry 10) corresponds
to 91% on average for each of the three steps; the minimum
overall yield from of 34% Table 5 (entry 3), still represents
71% on average for each step.
Entry
Starting
material
ArB(OH)2
Product
Yield
[%]
7
1c
9g
65
70
8
9
1c
9h
1c
9i
39
10
11
1d
9j
75
51
1 f
9k
12
1 f
9l
52
Last but not least, we explored the derivatization of other
positions of the arene systems (Scheme 7). By changing the
substitution pattern at the furan system (a methyl substitu-
To avoid the necessity of changing the solvent after the
first reaction step, the whole reaction cascade was per-
formed in THF. The first two reaction steps were performed
at room temperature. For the Suzuki coupling, besides the
boronic acid, the base, [PdACHTNUGTRNEUNG(PPh3)4], and water (equal
Scheme 7. Sequential one-pot transformation of furan–yne 1g.
volume to the THF) were added, and the temperature was
increased to 808C. The results for the three-step protocol
are shown in Table 4. With our standard test substrate 1a,
the three-step sequence delivered the final product 9a in an
overall yield of 50% (Table 4, entry 1). The slight drop in
yield relative to the isolated reaction steps is based on the
first reaction step. A test reaction in THF revealed a yield
of “only” 83% for this single reaction step. The overall
yield for a process that includes a change of solvent from
CH2Cl2 to THF after the first two reactions increases the
ent in the 3-position instead of the 5-position), the one-pot
procedure offers an attractive method for the introduction
of a substituent in the ortho position to the phenolic oxygen
by means of Suzuki coupling. For substrate 1g, coupling
with 3-methoxyphenyl boronic acid delivered pentasubstitut-
ed arene 9m in good overall efficiency.
En–diyne substrate 5 was also applied to the Suzuki cou-
pling protocol with 3-methoxyphenyl boronic acid
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A. S. K. Hashmi et al.
À
lyst for C C bond formation and aryl bromides are inter-
mediates. The use of the additional palladium catalyst is not
inferior, because at the same time this method for the acety-
lenic substrate uses the cheaper NBS oxidant.
Scheme 8. Sequential one-pot transformation of endiyne-yne 5.
Acknowledgements
The authors thank Umicore AG & Co. KG for the generous donation of
gold salts.
(Scheme 8). For this substrate a change of solvent after the
first two reaction steps was necessary, as the domino reac-
tion in the first step does not proceed in THF as solvent.[8]
Nevertheless, simple evaporation of the solvent, without pu-
rification, and subsequent redissolving of the residue in
a THF/H2O mixture, led to an excellent overall yield for the
sequential one-pot procedure. This sequence allows the con-
struction of pentasubstituted arene systems with the phenol-
ic oxygen meta to the ring junction, thus a completely differ-
ent substitution pattern at the resulting arene core is feasi-
ble by means of this starting material.
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This type of conversion is highly useful for the synthesis
of polyaromatic products,[16] and applications in the synthesis
of natural/bioactive compounds or the synthesis of atropoi-
someric compounds[17] are conceivable.
Conclusion
By using the same gold catalyst for two subsequent reaction
steps, which consist of a furan–yne cyclization followed by
a halogenation reaction, fivefold-substituted arenes are fea-
sible under exceptionally mild reaction conditions and in
a one-pot process. Controlled by the substituents at the
starting furan core, two entirely different substitution pat-
terns at the aromatic core can be synthesized. In addition,
even en–diyne substrates can be used as starting materials,
which enables the synthesis of another highly complex five-
fold-substituted aromatic system that cannot be easily syn-
thesized from furan precursors. The halogenation of the
phenolic systems opens the possibility of further functionali-
zation by means of palladium-catalyzed cross-coupling reac-
tions. In three-step one-pot reactions highly complex five-
fold aromatic systems can be constructed in an extremely
short reaction sequence and in remarkable overall efficiency.
This gold/palladium-catalyzed access to fivefold-substituted
arenes with diverse substitution patterns should offer a pow-
erful tool for organic chemists. Extensions of this concept to
other gold-catalyzed conversions are under investigation.
´
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Frey, Chem. Eur. J. 2006, 12, 5376–5382; h) A. S. K. Hashmi, J. P.
It is interesting to compare these results with the concept
+
À
of the C C bond formation in gold catalyis induced by F
donors like Selectfluor.[18] In both cases, an organic sub-
strate, a gold catalyst, and a boronic acid are used. In both
cases, a halogen donor is needed and the halide does not
appear in the final product. In the innovative gold-catalyzed
´
Weyrauch, E. Kurpejovic, T. M. Frost, B. Miehlich, W. Frey, J. W.
Bats, Chem. Eur. J. 2006, 12, 5806–5814; i) A. S. K. Hashmi, R. Sal-
athꢂ, W. Frey, Chem. Eur. J. 2006, 12, 6991–6996; j) A. S. K.
À
reactions of olefins with Selectfluor, C C bond formation is
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Received: January 9, 2012
Published online: May 21, 2012
Chem. Eur. J. 2012, 18, 8113 – 8119
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8119