Gold catalysis: Domino reaction of En-diynes to highly substituted phenols

Article abstract of DOI:10.1002/chem.201100305

By Sonogashira coupling of 1,7-heptadiynes and 1,8-octadiynes with 2-iodoallyl alcohols, various substrates that bear a 2-alkynylallyl alcohol moiety tethered to an additional alkyne were prepared in one step. Subjection to nitrogen acyclic carbene (NAC)/gold(I) catalysts delivered highly substituted phenols in an efficient domino reaction. Furan derivatives were formed as intermediates; this was proven by in situ NMR spectroscopy. The uncommon substitution pattern of these furans opens the way for a selective formation of phenols that contain the hydroxyl group in the meta position to the ring junction, which previously was not possible by gold-catalyzed furan-yne cyclization. Furthermore, interesting mechanistic insights were obtained by products derived from secondary allyl alcohols. In this case, in addition to the phenolic compounds, a ketone is formed by 1,2-alkyl shift.

Full text of DOI:10.1002/chem.201100305

FULL PAPER
DOI: 10.1002/chem.201100305
Gold Catalysis: Domino Reaction of En-Diynes to Highly Substituted
Phenols
A. Stephen K. Hashmi,* Tobias Hꢀffner, Matthias Rudolph, and Frank Rominger[a]
Abstract: By Sonogashira coupling of
1,7-heptadiynes and 1,8-octadiynes
with 2-iodoallyl alcohols, various sub-
strates that bear a 2-alkynylallyl alco-
hol moiety tethered to an additional
alkyne were prepared in one step. Sub-
jection to nitrogen acyclic carbene
tives were formed as intermediates;
this was proven by in situ NMR spec-
troscopy. The uncommon substitution
pattern of these furans opens the way
for a selective formation of phenols
that contain the hydroxyl group in the
meta position to the ring junction,
which previously was not possible by
gold-catalyzed furan-yne cyclization.
Furthermore, interesting mechanistic
insights were obtained by products de-
rived from secondary allyl alcohols. In
this case, in addition to the phenolic
compounds, a ketone is formed by
1,2-alkyl shift.
(NAC)/gold(I)
catalysts
delivered
Keywords: alkynes · domino reac-
tions · furans · gold · phenols
highly substituted phenols in an effi-
cient domino reaction. Furan deriva-
Introduction
tion is controlled by a selective ring opening of the inter-
mediate epoxide[3] 2 to the thermodynamically favored pen-
tadienyl cation intermediate.[4] This could be proven by the
use of an electron-donating substituent in the 3-position,
then the “ortho product” was also delivered exclusively.[4]
No studies that address the selective formation of the
products with hydroxyl groups in meta position to the anel-
lation point have been published yet. Here the retrosynthet-
ic approach would be based on the use of furan-yne systems
that bear donor substituents in the 4-position of the furan
core (Scheme 2). Due to the synthetic difficulties in the at-
In the field of homogeneous catalysis with transition metals,
the role of gold catalysts has emerged from a curiosity to a
common tool, which now is used by many groups for a di-
verse field of newly developed organic transformations.[1]
Most of these reactions can be performed under remarka-
bly mild conditions and with high atom efficiency. Among
other reactions, our group contributed the furan-yne cycliza-
tion, which proved to be a versatile tool for the generation
of
a
wide array of important heterocyclic systems
(Scheme 1).[2] Until now, only heterocyclic systems with the
phenolic hydroxy group ortho to the annelated systems were
investigated. Exceptions are unsubstituted furyl groups,
which induced poor selectivity. The selectivity of the reac-
Scheme 2. Different retrosynthetic disconnections for products 4 with the
hydroxyl group in meta position to the anellation point.
Scheme 1. Synthesis of ortho-annelated products 3 by means of the furan-
yne cyclization.
tachment of 3-substituted furans to the alkyne tether, we
skipped this approach (Scheme 2, upper part). To circum-
vent these problems, we considered another disconnection,
which is based on our recently reported synthesis of highly
substituted furans from 2-alkynylallyl alcohols.[5,6]
The latter substrates should lead to the desired substitu-
tion patterns without any synthetic difficulties (Scheme 2,
lower part). Furthermore, a domino reaction could deliver
the addressed phenols with the same catalyst system.
[a] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. T. Hꢀffner, 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
[+] Crystallographic investigation.
The structural motif of 4, with a substituent in the ortho
position of the phenolic oxygen, is an important substruc-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100305.
Chem. Eur. J. 2011, 17, 8195 – 8201
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Synthesis of 1,6-heptadiynes by means of twofold propargylation
of CH-acidic compounds.[a]
Entry
R1
R2
Base
Solvent
Yield 14/[%]
1
2
3
4
5
6
7
C(O)OMe
C(O)Me
C(O)Me
C(O)Me
CN
C(O)OMe
C(O)Me
C(O)NHPh
C(O)OEt
CN
NaH
ether
acetone
DMF
acetone
acetone
acetone
acetone
14a/94
14b/99
14c/93
14d/87
14e/40
14 f/>99
14g/87
Cs2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
C(O)Me
C(O)Me
S(O2)Ph
CN
[a] Base (3 equiv), RT, 20 h reaction time.
Scheme 3. Selected examples of natural products that contain the target
scaffold.
Table 2. Synthesis of 1,6-heptadiynes by means of twofold propargylation
of cyclic CH-acidic compounds.
ture which is found in various natural products as well as in
pharmacologically active substances. Examples (Scheme 3)
are the phenolic sesquiterpene (+)-mutisianthol (10) and re-
lated indanes that show antitumor activity;[7] w-(4-aryl-1-pi-
perazinyl)alkoxyindan 11, which possesses antianxiety activi-
ty;[8] a whole series of spiro-biindan derivatives 12 that are
HIV-1 integrase inhibitors;[9] or the recently isolated trigox-
yphin G (13).[10]
Classical routes to these targets are based on Friedel–
Crafts chemistry like the Haworth naphthalene synthesis.[11]
In these routes, the starting ortho-substituted phenols are
challenging substrates themselves, especially for larger sub-
stituents. Furthermore, for the Friedel–Crafts annellation
step, regioselectivity problems can occur. Moreover, a de-
functionalization reaction in the tether is often necessary,
which reduces the synthetic efficiency of these approaches.
Entry
Starting material
Base
Solvent
Yield 14/[%]
1
2
3
1,3-indanedione
dimedone
Meldrumꢂs acid
Cs2CO3
Cs2CO3
Cs2CO3
acetone
acetone
acetone
14h/99
14i/98
14j/78
diynes were commercially available or are well known from
the literature.[12,14]
The resulting diynes 14 were coupled with 2-iodoprop-2-
en-1-ol. All the Sonogashira coupling reactions were per-
formed with 2.5 mol% [(Ph3P)2PdCl2] and 2.5 mol% CuI at
658C (see also Scheme 4). In Table 3, it is clear that yields
were just moderate for most of the examples. This is most
probably based on the instability of the products under the
reaction conditions. Although no reaction took place at
room temperature, higher reaction temperatures could not
be employed for longer times due to product decomposition.
Interestingly, the products of a twofold Sonogashira reaction
were never observed (the starting diynes 14 were used in a
slight excess amount of 1.2–2 equiv and could be reisolated
after the reaction). A decomposition of 15 under the reac-
tion conditions chosen seems to be faster than another So-
nogashira reaction of 15. A fast and unspecific reaction of
either 15 with the vinylpalladiu-
Results and Discussion
The starting point for our study was the access to different
dialkynes 14. The latter could easily be obtained by the two-
fold propargylation of CH-acidic compounds with propargyl
bromide (Scheme 4).[12] The results of these reactions are
m(II) intermediate of the Sono-
gashira coupling or a fast reac-
tion of the product of the two-
fold Sonogashira coupling with
a species of the catalytic cycle
is conceivable.
With the starting ene-diynes
Scheme 4. Synthesis of starting materials 15.
in hand, we started a screening
with the unfunctionalized sub-
summarized in Table 1. With this strategy, nearly all of the
diynes 14 could be obtained in high yields. The exception is
the malonitrile derivative 14e (Table 1, entry 5), which only
delivered a moderate yield. Thus additional functional
groups at the homopropargyl position of the tether can
easily be included. For example, ester, ketone, amide, and
nitrile moieties can be installed.
strate 15n. In a first series of experiments, with the fre-
quently used catalyst combination (IPr)AuCl/AgSbF6 in dif-
ferent solvents (Table 4), a strong dependency on the sol-
vent was observed. Whereas in most of the solvents no reac-
tions or moderate conversions were monitored (Table 4, en-
tries 2–6), we were pleased to detect complete conversion of
the starting material in dichloromethane even at room tem-
perature (entry 1). To our delight, the desired selectivity was
indeed observed and exclusively the meta-type product 16n
Cyclic CH-acidic compounds were also used, and yields
were also good to excellent (Table 2, entries 1–3).[13] Other
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Chem. Eur. J. 2011, 17, 8195 – 8201

Gold Catalysis
FULL PAPER
Table 3. Sonogashira reaction of 14 and 2-iodoprop-2-en-1-ol to ene-
diynes 15.
Table 4. Solvent screening.
Entry
Diyne
Yield 15/[%]
1
14a
15a/20
15b/61
Entry
Solvent
dichloromethane
acetone
toluene
acetonitrile
THF
Yield [%][a]
>99[b]
1
2
3
4
5
6
40
14
12
0
2
3
14b
14c
methanol
0
15c/65
15d/60
[a] NMR spectroscopic yield against BnSi
[b] Isolated yield.
ACHTUNGTRENNUNG
4
14d
Table 5. Catalyst screening.
5
6
7
14e
14 f
14g
15e/38
15 f/40
15g/39
Entry
1
Catalyst
(IPr)AuCl/AgSbF6
Yield [%][a]
>99[b]
G
2
/AgSbF6
>99
3
4
5
6
7
8
MePhosAuCl/AgSbF6
tBuNCAuCl/AgSbF6
Ph3PAuCl/AgSbF6
AuCl3
AgSbF6
pTsOH·H2O
17
0[c]
0[c]
0
0
8
14h
14i
14j
15h/46
15i/39
15j/41
0
[a] NMR spectroscopic yield against BnSi
[b] Isolated yield. [c] Decomposition.
ACHTUGNTRENUN(GN CH3)3 as internal standard.
9
performed comparably well (Table 5, entry 2),[16] whereas
Buchwald-type ligands showed only moderate conversion
(entry 3). Other gold(I) systems, namely, isonitriles or phos-
phane ligands, led to a decomposition of the starting materi-
als (entries 4 and 5). No reaction took place for AuCl3,
which is in contrast to our previously reported furan synthe-
sis and to a related protocol of Perumal et al., in which at
least moderate conversions were observed for the furan cyc-
10
11
12
13
14k
15k/43
15l/41
dipropargyl ether
1,6-heptadiyne
15m/50[a]
[5]
lization step with AuCl3. Maybe the catalyst concentration
(1 mol% AuCl3) in this case is too low for a conversion.
Control experiments with AgSbF6 and p-TsOH did also not
show any conversion.
14
1,7-octadiyne
15n/52[a]
Under the optimized conditions (1 mol% NAC 17/
1 mol% AgSbF6 in CH2Cl2), we explored the substrate
scope of the domino reaction. Table 6 shows the results of
the conversions of ene-diynes 15. In contrast to the excellent
yield for tetrahydronaphtalene 16n as mentioned above
(Table 6, entry 1), the corresponding indane derivative 15m
was formed in only moderate overall yield (entry 2). Al-
though the reactivity of the substrate was even higher (full
conversion within 1 h), competing reaction pathways seem
[a] Reaction with 2-bromallylalcohol.
was obtained. The results of an X-ray crystal structure anal-
ysis unambiguously proved the correct assignment
(Figure 1).[15]
In addition to the N-heterocyclic carbene (NHC), other li-
gands on the metal center were tested. As demonstrated in
Table 5, nitrogen acyclic carbene (NAC)/gold(I) complex 17
Chem. Eur. J. 2011, 17, 8195 – 8201
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8197

A. S. K. Hashmi et al.
exception being the tetrahydro-
naphtalene 15n, various other
solid-state
structures
were
gained from the results of an
X-ray structure analysis. A sum-
mary of the structures is also
depicted in Figure 1. For com-
pound 16m its ester derivate
16ma had to be prepared for
suitable crystals.[15] Although
NMR spectroscopic assign-
ments for the position of the re-
sulting phenolic OH group are
difficult, the results of the
X-ray structure analyses doubt-
lessly prove the constitution of
the resulting phenol derivatives
with the hydroxyl group meta
to the anellated ring.
Figure 1. Solid-state molecular structures of 16n, 16ma, 16a, 16b, 16 f, 16h, 16j, and 16k as a clear proof of
the substitution pattern of the tetrasubstituted arene.
To explore the reactivity of
secondary alcohols in the
to reduce the yield (some nonisolable byproducts could be
monitored by TLC). Fortunately, the incorporation of func-
tional groups still delivered acceptable yields for most of the
examples. For the noncyclic precursors 15a–d and 15 f,
yields ranged from 42–64% (entries 3–6 and 8). Fast conver-
sions were observed no matter if ester, ketones, amides, or
sulfones were incorporated into the tether. Not unexpected-
ly, problems occurred with sub-
domino sequence, we prepared diyne 15o by Sonogashira
coupling of 2-iodo-4-methylpent-1-en-3-ol[5a] 9b and 1,7-oc-
tadiyne (36% yield). The conversion of 15o revealed a se-
lectivity pattern that was comparable to earlier studies that
concern furans with two additional substituents as nucleo-
philes in the furan-yne cyclization (Scheme 5).[4] As in the
case of 15n, the formation of six-ring annulated systems de-
strates 15e and 15g, which con-
tained stronger coordinating ni-
trile moieties (entries 7 and 9).
Whereas gold(I) catalyst 17 was
completely inhibited by both
substrates, a switch to AuCl3
(5 mol%) restored some reac-
Scheme 5. Transformation of the secondary alcohol 15o.
tivity. Interestingly, in the case
of the conversion of malonitrile
derivative 15e with gold(I) cat-
alyst 17, furan 18 was isolated in low yield in addition to re-
covered starting material (entry 7). Even the isolated furan
18 did not show any conversion to the resulting phenol with
livered considerably higher yields than five-membered de-
rivatives. Here an overall yield of 89% was obtained, which
splits up into three different products. In addition to the
phenol 16na (43%) with the common phenol substitution
pattern, ketone 19 (19%) with a quarternary carbon center
in a position to the carbonyl group was obtained as side
product. Contrary to expectations, regioisomeric phenol
16nb could not be detected. Furthermore, the intermediate
furan 5a (27%) could be isolated. The constitution of 16na
was confirmed by the NOESY NMR spectrum (NOE con-
tacts from the OH to all methyl groups and from the isopro-
pyl-methyl groups to the benzylic methylene group).
the gold
ACHTUNGTRENNUNG
only one nitrile moiety in substrate 15g. Here the goldAHCTUNGTRENNUNG
catalysis delivered phenol 16g, albeit in low yield (entry 9).
Next we investigated monocyclic precursors 15h–j (en-
tries 10–12). Whereas 15h and 15j showed moderate conver-
sions to the corresponding indanes, substrate 15i gave an
unselective reaction. This was somehow surprising as the
corresponding open-chained substrate 15b did not show
these difficulties. Finally, we tested diynes with heteroatom
incorporation. Nitrogen-containing diyne 15k delivered the
resulting isoindole 16k in moderate yield (entry 13). Un-
fortunately, the ether-bridged diyne 15l led to a significant
loss in selectivity and only 10% of the dihydroisobenzofuran
16l could be isolated (entry 14). As nearly all of the prod-
ucts of the domino reaction were crystalline solids, the only
More detailed mechanistic insights were obtained from
low-temperature
NMR
spectroscopic
experiments
(Figure 2). Although at 253 K no conversion of the starting
diyne 15m was observed, warming to 298 K initiated the
cyclization reaction. From the NMR spectra it becomes ob-
vious that first an intermediate furan is formed (characteris-
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Chem. Eur. J. 2011, 17, 8195 – 8201

Gold Catalysis
FULL PAPER
tic peaks for the furan protons at d=5.92 and 7.12 ppm),
which then further converts to the final phenolic product
within short reaction times.
Table 6. Substrate scope.
A sketch of the possible reaction pathway is shown in
Scheme 6. In a first rearrangement the 2-alkynylallyl alcohol
moiety delivers furan substrates 5 that bear a substituent in
the 4-position. These are most probably formed by means of
a 5-endo-dig addition of the hydroxyl group to the alkyne
followed by aromatization of the dihydrofuran part. In the
second step of the reaction cascade, a furan-yne cyclization
takes place,[4] which delivers an arene oxide I as an impor-
tant intermediate. The selectivity of the further conversion
is now determined by the substitution pattern of these arene
oxides. In cases of monosubstitution, selective ring opening
occurs and only the meta products are obtained. This is in-
duced by the stability of the pentadienyl cation II, which
can further stabilize the positive charge through hyperconju-
gation. In the case of a disubstitution, both possible epoxide
openings result in stabilized cations and indeed both open-
ing modes were observed in previous studies (III and IV).
In accordance with these, an 1,2-alkyl shift takes place for
quaternary alcohols/alcoholates, which leads to ketone 19 as
side product besides the expected phenol 16na.
Entry
1
Ene-diyne 15
16/Yield [%]
15n
16n/>99
16m/45
2
3
15m
15a
15b
16a/59
16b/42
4
5
15c
16c/47
Conclusion
6
7
8
15d
15e
15 f
16d/64
18/30[a]
16 f/49
The reported protocol is based on a Sonogashira reaction of
2-haloallyl alcohols with diynes followed by a gold-catalyzed
domino reaction. This represents a very fast entry towards
an important class of different highly substituted phenols.
With this domino process, intermediate furan derivatives
contain substitution patterns that were never applied in the
furan-yne cyclization before. Interesting mechanistic insights
can be deduced from the regioselectivity of the reaction,
which provides further proof for our overall mechanistic pic-
ture of the furan-yne cyclization. Here the importance of
the selective ring opening of the intermediate areneoxides,
which is determined by the stability of the resulting penta-
dienyl cations, is further emphasized. From the synthetic
point of view, products that contain the hydroxy group in
meta position to the ring junction of the annelated products
were for the first time accessed in a regioselective manner
by the furan-yne reaction. The resulting products represent
important substructures of many natural products, and ap-
proaches through a classical procedure often demand long
reaction sequences. Considering the molecular complexity
of the resulting products, the moderate yields for the
1,6-heptadiynes are still competitive. 1,7-Octadiynes gave
even better results. Further investigations concerning this
topic are underway.
9
15g
16g/20[b]
16h/41
10
11
12
15h
15i
15j
unselective
16j/41
13
14
15k
15l
16k/36
16l/10
[a] Plus 31% reisolated 15e. [b] 5 mol% AuCl3.
Chem. Eur. J. 2011, 17, 8195 – 8201
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8199

A. S. K. Hashmi et al.
chimica Acta 2010, 43, 27–33;
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Hashmi,
Angew.
Chem. 2010, 122, 5360–5369;
Angew. Chem. Int. Ed. 2010, 49,
5232–5241.
[2] For representative publications,
see: a) A. S. K. Hashmi, T. M.
Frost, J. W. Bats, J. Am. Chem.
Soc. 2000, 122, 11553–11554;
b) A. S. K. Hashmi, T. M. Frost,
J. W. Bats, Org. Lett. 2001, 3,
3769–3771; c) A. S. K. Hashmi,
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[3] For evidence of arene oxide inter-
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Wçlfle, W. Frey, J. W. Bats,
Angew. Chem. 2005, 117, 2858–
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[5] a) A. S. K. Hashmi, T. Hengst, M.
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Received: January 27, 2011
Revised: April 13, 2011
Published online: June 7, 2011
Chem. Eur. J. 2011, 17, 8195 – 8201
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