Cyclization of 2-alkynylallyl alcohols to highly substituted furans by gold(I)-carbene complexes

Article abstract of DOI:10.1002/ejoc.201001479

Various 2-alkynylallyl alcohols were synthesized by a generally applicable Sonogashira coupling protocol. Subsequent gold-catalyzed transformation was investigated. The use of Au^I catalysts bearing carbene ligands, of either the N-heterocyclic carbene or nitrogen acyclic carbene type, delivered the desired products with low catalyst loadings and under very mild reaction conditions. A broad array of substrates was tested, including alkyl-, alkenyl-, and aryl-substituted alkynes, as well as substrates with two alkynyl moieties. The methodology turned out to have a broad scope. Secondary allyl alcohols were also tolerated, and the resulting trisubstituted furans could be isolated in high yields. Easily accessible 2-alkynylallyl alcohols were transformed into highly substituted furans under very mild reaction conditions by the use of gold(I)-carbene catalysts. A broad range of substrates could be transformed in high yields and within short reaction times.

Full text of DOI:10.1002/ejoc.201001479

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001479
Cyclization of 2-Alkynylallyl Alcohols to Highly Substituted Furans by
Gold(I)–Carbene Complexes
A. Stephen K. Hashmi,*[a] Tobias Häffner,[a] Matthias Rudolph,[a] and Frank Rominger[a]
Keywords: Carbene ligands / Cycloisomerization / Allylic compounds / Gold / Oxygen heterocycles
Various 2-alkynylallyl alcohols were synthesized by a gen-
erally applicable Sonogashira coupling protocol. Subsequent
gold-catalyzed transformation was investigated. The use of
AuI catalysts bearing carbene ligands, of either the N-hetero-
cyclic carbene or nitrogen acyclic carbene type, delivered the
desired products with low catalyst loadings and under very
mild reaction conditions. A broad array of substrates was
tested, including alkyl-, alkenyl-, and aryl-substituted al-
kynes, as well as substrates with two alkynyl moieties. The
methodology turned out to have a broad scope. Secondary
allyl alcohols were also tolerated, and the resulting trisubsti-
tuted furans could be isolated in high yields.
Introduction
we report on our general protocol for the gold-catalyzed[10]
version of this reaction, having the advantage of both low
catalyst loadings as well as mild reaction conditions.
Furans are among the most important five-membered
heterocycles in organic and pharmaceutical chemistry.[1]
They are not only significant as key motifs in many natural
products, but also as versatile building blocks for the con-
struction of highly complex target structures in numerous
total syntheses.[2] As an alternative to classical furan synthe-
ses, the use of transition metals as catalysts for atom-econ-
omic transformations of noncyclic substrates to furans has
Results and Discussion
The 2-alkynylallyl alcohols were prepared by Sonoga-
become a fast growing field of research in the last years.[3] shira coupling of 2-haloallyl alcohols 2 with terminal alk-
In contrast to the often harsh conditions of the classical ynes with catalyst loadings of 2.5 mol-% of (PPh3)2PdCl2/
methods, most of these reactions can be performed under CuI. Substituted 2-iodoallyl alcohols 2 were easily access-
very mild reaction conditions and within short reaction ible according to known literature procedures.[11] The re-
times.[4] In this context, the cyclization of 2-alkynylallyl sults for the Sonogashira couplings are summarized in
alcohols to highly substituted furans offers a very attractive Table 1.
synthetic tool. Besides easy access to the starting materials,
The yields of the Sonogashira coupling were good to ex-
the installation of substituents in the 3-position of the furan cellent in most cases. The scope of this coupling reaction
ring usually causes great synthetic difficulties but might be was high, which is demonstrated by the tolerance of dif-
addressed easily by this route. When we started our investi- ferent aromatic alkynes (Table 1, Entries 1–6) as well as
gation, gold as highly alkynophilic catalyst had not been alkyl-substituted alkynes (Table 1, Entries 7–9). In the case
tested for this transformation. Besides base-catalyzed cycli- of an additional double bond directly attached to the al-
zations (potassium tert-butoxide or KOH/Aliquot 336 at kyne (Table 1, Entry 10) a significantly lower yield was ob-
25–60 °C),[5] there were reports on the use of palladium served. Bifunctional alkynes could also be converted in ex-
(5 mol-% PdOAc2, 100 °C, 24 h),[6] molybdenum [15 mol-% cellent to moderate yields (Table 1, Entries 11 and 12). Vari-
Mo(CO)6, irradiation, 15 h],[7] and silver catalysts (10 mol- ation of the allyl alcohols led to a slight drop in yield for
% AgNO3 on SiO2 at room temp.,[8a,8b] 5 mol-% AgOTf,[8c] secondary alcohols (Table 1, Entries 13 and 14). In the case
80 °C). During our investigation, a AuBr3-catalyzed version of trisubstituted alkenes, no isomerization of the double
was published for the construction of fused furans.[9] Here bond was observed (Table 1, Entries 15 and 16) and yields
were also reasonable.
Initial screening towards the optimal reaction conditions
for the gold-catalyzed transformations was performed with
[a] Organisch-Chemisches Institut, Univeristät Heidelberg,
test substrate 3a in dichloromethane (Table 2). With a load-
ing as small as 0.3 mol-% of catalyst, 100% GC yields were
detected for gold(I) complexes with carbene ligands, no
matter if an NAC[12] (nitrogen acyclic carbene; Table 2,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: +49-6221-544205
E-mail: hashmi@hashmi.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001479.
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A. S. K. Hashmi, T. Häffner, M. Rudolph, F. Rominger
SHORT COMMUNICATION
Table 1. Sonogashira coupling of 2-haloallyl alcohols 2.
Entry 1) or an NHC (N-heterocyclic carbene) ligand
Due to the superior yields for the gold(I) catalysts as well
(Table 2, Entry 2) was used. Phosphane ligands for the AuI as their reduced Lewis acidity, we examined the substrate
catalysts only delivered poor results under the same reac- scope under the optimized conditions from Table 2 (either
tion conditions (Table 2, Entries 3 and 4). The neutral Entry 1 or 2). In order to keep the reaction time short, all
gold(I) chloride or the coordinatively saturated (IPr)AuCl, substrates were converted with 1.0 mol-% of gold catalysts
without activation by a silver salt, gave no conversion under open flask conditions. All the reactions were stopped
(Table 2, Entries 5 and 6). Gold(III) sources were also effec- after 1 h, a time when complete conversion was reached for
tive (Table 2, Entries 7 and 8), but yields turned out to be all tested substrates. The results are outlined in Table 3. For
lower than those obtained with the above-mentioned sys- aromatic substrates, the reaction delivered excellent to mod-
tems.[13] The coordinatively saturated gold(III) species were erate yields, depending on the electronic properties of the
all inactive (Table 2, Entries 9–11). Control experiments systems. For comparison of the two carbene-type ligands,
with pTsOH as well as other transition metals like silver substrate 3b was converted with both types of ligands and
and copper showed no reactivity (Table 2, Entries 12–14). yields turned out to be equal (Table 3, Entry 2). Electroni-
Compound 4a could be obtained as crystals, which were cally neutral and electron-rich systems (Table 3, Entries 1
suitable for X-ray crystal structure analysis.[14] Figure 1 and 2) were excellent, whereas the increased electronic de-
shows the solid-state molecular structure of the resulting ficiency of starting materials 3c,d (Table 3, Entries 3 and 4)
1,3-disubstituted furan.
led to significantly lower yields. A slightly lower yield was
668
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Cyclization of 2-Alkynylallyl Alcohols by Gold(I)–Carbene Complexes
Table 2. Catalyst screening for model substrate 3a.
even higher for the sterically more demanding isopropyl
substituent in substrate 3n (Table 3, Entry 14). No signifi-
cant change was observed by variation of the R2 substitu-
ents of substrates 3o and 3p (Table 3, Entries 15 and 16)
and once again yields were good to excellent.
We also tested a silylated alkyne, substrate 3q, with
Cat. A; under the normal reaction conditions from Table 3,
3-methylfuran (4q) was produced in 47 and 50% yield ac-
companied by up to 21% of desilylated 3r after 1.5 and 8 h,
respectively. It seems that desilylation is an efficient process
under these conditions, and at the same time the complete
disappearance of 3r after 3 d indicated that 3r decomposed
under the reaction conditions. This was confirmed with a
sample of pure 3r (obtained by normal desilylation of 3q
with K2CO3 in methanol), which slowly decomposed but
even after 3 h did not show any trace of 4q under the same
conditions (Scheme 1).
Entry
Catalyst[a]
Yield (GC) [%][b]
1
2
3
4
5
cat. A/AgSbF6
(IPr)AuCl/AgSbF6
Cat. B[15]/AgSbF6
PPh3AuCl/AgSbF6
AuCl
100
100
6
2
0
6
7
(IPr)AuCl
AuCl3
0
40
8
9
10
11
12
13
14
AuBr3
73
0
0
0
NaAuCl4·2H2O
NaAuBr4
HAuCl4·xH2O
pTsOH
no conversion
no conversion
no conversion
AgSbF6
CuI
[a] Catalyst loading of 0.3 mol-%. [b] Internal standard tetradecane.
Scheme 1. Involvement of a silylated but not a terminal alkyne.
Conclusions
This gold(I)-catalyzed cyclization of easily accessible 2-
alkynylallyl alcohols is of broad scope and allows the ef-
ficient synthesis of 2,4-disubstituted and 2,3,5-trisubstituted
furans under mild conditions. The transformation of even
bifunctional substrates to the corresponding bisfurans
opens interesting aspects for synthetic chemistry. Possible
applications of this method are currently under investiga-
tion and will be reported in due course.
Figure 1. Solid-state molecular structure of compound 4a.
also monitored with phenanthrene-substituted alkyne 3e;
here the increased steric demand could be the reason. Bi-
phenyl substrate 3f showed higher reactivity again, yielding
79% of furan 4f (Table 3, Entry 6). Next we explored the
reactivity of alkyl-substituted alkynes. While complete con-
version after 1 h was also observed for these systems, only
moderate to good yields were observed (Table 3, Entries 8–
10). Surprisingly, even substrate 3j bearing an enyne moiety
could be converted; no polymerization of electron-rich styr-
ene analogue 4j was observed, once again revealing the ex-
ceptionally mild conditions of this methodology. Substrates
3k and 3l, which contain two reactive moieties, also under-
went the expected conversion, but yields differ dramatically
between the different substitution patterns (76% for sub-
strate 3k vs. 14% for 3l). Similar to other substrates the
steric influence in the β-position of the reacting alkyne car-
bon seems to play an important role. The use of secondary
alcohols as starting materials was also possible. Here no
Experimental Section
General Procedure for the Preparation of Alkynylallyl Alcohols 3:
Alkynylallyl alcohols 3 were prepared under common Sonogashira
conditions:[16] Acetylene 1 (1.2 equiv.) and vinyl iodide 2 (1 equiv.)
were dissolved in degassed NEt3 (20 mL) under nitrogen atmo-
sphere. To this solution was added Pd(PPh3)2Cl2 (2.5 mol-%). After
10 min, copper(I) iodide (2.5 mol-%) was added. The mixture was
heated at 65 °C for 16 h. After cooling to room temperature, the
solvent was removed in vacuo. The crude product was purified by
column chromatography.
General Procedure for the Gold(I)-Catalyzed Preparation of Furans
4: Alkynylallyl alcohol 3 (1 equiv.) was dissolved in dichlorometh-
ane (5 mL). To this mixture was added a solution of the gold(I)
catalyst (1 mol-%) and AgSbF6 (1 mol-%). After stirring at room
temperature for 1 h, the solvent was removed in vacuo, and the
steric limitations occurred, despite the fact that yields were crude product was purified by column chromatography.
Eur. J. Org. Chem. 2011, 667–671
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A. S. K. Hashmi, T. Häffner, M. Rudolph, F. Rominger
SHORT COMMUNICATION
Table 3. Substrate scope of the gold(I)-catalyzed cyclization of 2-alkynyl-allylalcohols.
[a] Catalyst loading of 1.0 mol-%. [b] Using IPrAuCl/AgSbF6 as catalyst system. [c] Volatile; unstable in solution.
gon, M. Tofi, G. Vassilikogiannakis, Acc. Chem. Res. 2008, 41,
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Received: October 31, 2010
Published Online: December 27, 2010
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