Organocatalytic synthesis of highly substituted furfuryl alcohols and amines

Article abstract of DOI:10.1002/anie.201207300

Top cat! Tetrahydrothiophene is an efficient organocatalyst for the synthesis of highly substituted furfuryl products from readily accessible electron-poor enynes under neutral reaction conditions. This process is applicable to a wide range of nucleophile

Full text of DOI:10.1002/anie.201207300

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Angewandte
Communications
DOI: 10.1002/anie.201207300
Organocatalysis
Organocatalytic Synthesis of Highly Substituted Furfuryl Alcohols and
Amines**
J. Stephen Clark,* Alistair Boyer, Anthony Aimon, Paloma Engel Garcꢀa, David M. Lindsay,
Andrew D. F. Symington, and Yves Danoy
Substituted furans are present in many natural products,[1]
bioactive compounds,[2] and functional materials.[3] Furans
also serve as valuable building blocks for organic synthesis.[4]
Driven by this prevalence, many methods have been devel-
oped for the synthesis of substituted furans.[5] In addition to
traditional methods,[6] metal-mediated furan syntheses are
becoming common. In particular, a variety of metals have
been used to induce intramolecular carbonyl oxycyclization
onto alkynes; electrophilic activation of alkynes has been
demonstrated by using Lewis acidic complexes of copper[7]
and zinc.[8] Additionally, gold-mediated furan syntheses have
been reported;[9] these syntheses involve both intermolecular
couplings,[10] and intramolecular cyclization of a range of 4-
and 5-oxygenated alkynyl substrates.[11] Furthermore, gold-
and silver-mediated cyclizations triggered by nucleophilic
substrate activation have been reported.[12] These metal-
mediated procedures are predated by reports of electrophilic
activation of enynones by Brønsted acid (Scheme 1a,
X = H).[13,14]
Benary synthesis,[15] but the complimentary approach, using
nucleophilic activation of conjugated alkynylcarbonyl sys-
tems, is rare. Indeed, examples are limited to catalysis by
Lewis basic phosphines. For example, Krische and co-workers
have reported the triphenylphosphine-induced reductive
condensation of g-acyloxy butynoates to give furans.[16] Addi-
tionally, Kuroda et al. have developed a furan-forming
reaction cascade that is initiated by the reaction of a stoichio-
metric amount of a phosphine with an enynone to give
a phosphorus ylide, which is trapped by an aldehyde to give an
a-alkenylfuran.[17] Inspired by this report of phosphine-based
organocatalysis, we postulated that a similar cascade could be
triggered by a thioether (Scheme 1b).[18] Sulfur-containing
compounds have been shown to act as nucleophilic cata-
lysts[19] and it seemed possible that a versatile sulfonium ylide
could be generated when a sub-stoichiometric amount of
a thioether is used.
The seminal experiment in our study involved the reaction
of enynedione 4 with a stoichiometric amount of tetrahydro-
thiophene (THT) and an excess of benzoic acid [Table 1,
Eq. (1)]. This reaction resulted in the formation of the
furfuryl benzoate 5a (Table 1, entry 1).
A screen of reaction conditions revealed that there was
50% conversion of the substrate into the benzoate 5a after
24 h (Table 1, entry 1). The reaction also proceeded with
Table 1: Preliminary optimization studies.[a]
Scheme 1. Furan synthesis from carbonyl-conjugated enynes.
Entry Catalyst Loading [mol%] Solvent (conc.) T [8C] Conv. at
24 h [%][b]
In contrast to metal-mediated processes, organocatalytic
approaches to the construction of furans are scarce. Jørgensen
and co-workers have reported an organocatalytic Feist–
1
2
3
4
5
6
7
8
THT
THT
THT
100
50
10
10
–
100
100
100
10
10
10
CDCl3 (0.1 m) 45
50
20
5
40
CDCl3 (0.1m)
CDCl3 (0.1m)
CDCl3 (1.0m)
CDCl3 (0.1m)
CDCl3 (0.1m)
CDCl3 (0.1m)
CDCl3 (0.1m)
45
45
45
45
45
45
45
THT
None
DMAP
DABCO
PBu3
THT
0
decomp.[c]
decomp.[c]
decomp.[c]
[*] Prof. Dr. J. S. Clark, Dr. A. Boyer, A. Aimon, P. Engel Garcꢀa,
Dr. D. M. Lindsay, A. D. F. Symington, Y. Danoy
School of Chemistry, University of Glasgow
9
10
11
CH2Cl2 (1.0m) reflux 60
Joseph Black Building, Glasgow G12 8QQ (UK)
E-mail: stephen.clark@glasgow.ac.uk
Homepage: http://www.chem.gla.ac.uk/staff/stephenc/
THT
THT
THF (1.0m)
reflux
5
PhMe (1.0m)
reflux 60
[a] 4 (1.0 equiv), PhCO2H (1.1 equiv). [b] Determined by 1H NMR
analysis, and rounded to the nearest 5%. [c] Substrate 4 was consumed
completely. DMAP=4-dimethylaminopyridine, DABCO=1,4-
diazabicyclo[2.2.2]octane, THT=tetrahydrothiophene.
[**] The authors gratefully acknowledge WestChem, the EPSRC (grant
EP/F031505/1), and the University of Glasgow for funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207300.
12128
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substoichiometric amounts of THT, although at a reduced
rate (Table 1, entries 2, 3). Increasing the concentration of the
reaction mixture was beneficial and the reaction proceeded at
a reasonable rate with only 10 mol% of catalyst (Table 1,
entry 4). The crucial role played by THTwas demonstrated by
the fact that the enynedione 4 failed to react in its absence
(Table 1, entry 5). The efficacy of several alternative organo-
catalysts[17,19d] was investigated but consumption of starting
material was observed without furan formation in all cases
(Table 1, entries 6–8). The reaction proceeded in a variety of
solvents and although it was low yielding when performed in
THF (Table 1, entry 10), comparable rates of reaction were
observed for reactions performed in [D]chloroform, dichloro-
methane (Table 1, entry 9), and toluene (Table 1, entry 11).
The results presented in Table 1 showed that the reaction
is robust and operates under a variety of conditions and so the
reaction was further examined to establish whether other
nucleophiles could be used (Scheme 2). Electron-rich and
electron-poor aryl carboxylic acids gave the furan products 5a
and 5b in high yield, but reactions were slow unless the
loading of THT was increased (50 mol%).
obtained even when the substrate possessed a tetrasubstituted
carbon center adjacent to the site of nucleophilic attack
(Table 2, entry 2). The sterically congested silyl-substituted
alkynes 10 and 12 also reacted to give furans (Table 2,
entries 3 and 4). However, the trimethylsilyl-substituted
enyne 10 underwent reaction to give the desilylated product
11 (Table 2, entry 3) whereas the triisopropylsilyl compound
afforded furan 13, in which the silicon substituent is retained
Table 2: Scope of electrophile.[a]
Entry
Electrophile
Product
Yield [%][b]
98
1
2
3
92
70
4
58[c]
5
89
6
97[c]
7
–(60)[c,d]
Scheme 2. Scope of nucleophile. Yields of the isolated products after
chromatography. [a] 50 mol% of THT used. [b] 3.0 equiv of nucleophile
was employed. PMB=p-methoxybenzyl; Ns=p-nitrobenzenesulfonyl.
8
>98
A highly acidic nucleophile is not necessary and when the
reaction was conducted in methanol, the methyl ether 5e was
the only product observed after 24 h. When a modest excess
of methanol (3 equiv) was used, the O-methyl furfuryl alcohol
5e was produced efficiently. The use of p-methoxybenzyl
alcohol allowed for the formation of a protected a-hydroxy-
furan 5 f in excellent yield. When bulkier tert-butyl alcohol
was used this also led to the desired furan 5g but with a lower
yield. The use of fluorinated tert-butanol as nucleophile to
give 5h was more successful, a finding that suggests the pKa of
the acid is important. Phenol was also employed as the
nucleophile in the furan-forming process (product 5i). Finally,
the use of p-nitrobenzenesulfonamide as nucleophile allowed
incorporation of a protected amine to give 5j.
9
65
10
11
63[c]
–
no reaction[c]
[a] Substrate (1.0 equiv), PhCO2H (1.1 equiv), THT (10 mol%), 1m in
CH2Cl2, reflux, 18 h. [b] The yield of the isolated product after chroma-
tography. [c] 50 mol% of THT was employed. [d] The value in brackets is
the % conversion, measured by 1H NMR spectroscopy at the time taken
for complete consumption of substrate (E)-16. Bz=benzoyl.
The scope of electrophile was also examined (Table 2).
The cyclization reaction proceeded in high yield with an aryl-
substituted alkyne (Table 2, entry 1). High yields were
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(Table 2, entry 4). The phenyl-substituted substrate 14
reacted to give the furan 15 in excellent yield (Table 2,
entry 5). The reaction was also performed on substrates in
which one of the ketone carbonyl groups was replaced with
another electron-withdrawing substituent. When the sub-
strates (E)-16, 18, 20, and 22 (Table 2, entries 6, and 8–10)
were used, the reaction afforded the corresponding furans 17,
19, 21, and 23 in good to excellent yield. It is noteworthy that
the ketoester (Z)-16 displayed reduced reactivity in compar-
ison to (E)-16 (Table 2, entries 6 and 7). At the stage where
reaction of (E)-16 was complete, only 60% conversion was
observed for (Z)-16 and isomerization of the starting material
was found. The reaction failed when substrate 24 was exposed
to the reaction conditions (Table 2, entry 11).
that an SN1 pathway is operative, releasing THT back into the
catalytic cycle.[24,25] The resulting ion D is then captured by the
nucleophile to generate the product.
The compatibility of THT with other organocatalytic
processes was investigated (Scheme 5). Most of the substrates
used herein were accessed by the Knoevenagel condensation
Treatment of substrate 25, which contains a hydroxy group
tethered to the electron-deficient enynedione, with THT
resulted in a smooth reaction to deliver the epoxyfuran 26 in
70% yield (Scheme 3). Epoxyfurans can be unstable and so
Scheme 5. Multicomponent domino synthesis of furfuryl benzoate 5a.
of a 2-alkynal, a process that is promoted by a mixture of an
alkylamine and carboxylic acid. We reasoned that the
condensation reaction would be orthogonal to the furan-
forming process and that they might be combined into a one-
pot sequence.[26] When a mixture of aldehyde 27a or 27b,
acetylacetone, and either benzoic or 4-nitrobenzoic acid was
heated with piperidine and THT, the furfuryl benzoates 5a,
5b, and 7 were isolated in yields ranging from 49–57%, which
are consistent with yields obtained when the reactions were
performed separately. A slight excess of acid is required
because it performs a dual role as a catalyst and a nucleophile.
Remarkably, the furan-forming reaction tolerates the pres-
ence of water formed during Knoevenagel condensation.
In summary, a simple organocatalytic synthesis of sub-
stituted furans has been developed. The novel features of the
procedure include the use of a simple thioether (THT) as the
organocatalyst, the formation of a furan under neutral
conditions rather than the anionic or acidic conditions
employed in conventional syntheses, and the intermediacy
of a versatile sulfonium ylide that has the potential to be
intercepted directly by a variety of electrophiles instead of
being protonated to give a sulfonium ion. The reaction
proceeds with a wide range of substrates and nucleophiles to
give highly decorated furans in good yield. The process is mild
and can lead to the formation of a fragile, biologically-
relevant epoxyfuran motif. The complementary nature of the
THT catalysis with other organocatalyzed processes has
allowed the reaction to be incorporated into a three-compo-
nent domino sequence.
Scheme 3. Synthesis of the epoxyfuran motif of lophotoxin.
the success of this reaction demonstrates the mild nature of
the reaction conditions.[20] This result suggests a potential
application of the reaction in target synthesis because the
furan 26 is analogous to a key motif found in the neurotoxin
lophotoxin and related marine furanocembranes.[21]
The proposed reaction mechanism commences with con-
jugate addition of THT to the alkyne (Scheme 4). The
resulting enolate A[22] then cyclizes to form the furan B,
bearing an adjacent sulfur ylide.[23] This ylide is sufficiently
basic to deprotonate the acid to give the corresponding
sulfonium ion C and the nucleophile. Rather than undergoing
direct SN2 reaction to form the observed product 5, it is likely
Received: September 10, 2012
Published online: October 24, 2012
Keywords: domino reactions · enynes · furans · organocatalysis ·
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thioethers
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