Trialkylphosphine-Mediated Synthesis of 2-Acyl Furans from Ynenones

Article abstract of DOI:10.1021/acs.orglett.7b01533

A novel reaction for the synthesis of 2-acyl furans is reported. The reaction is believed to proceed by sequential addition of a trialkylphosphine to an ynenone, 5-exo-dig cyclization to form the furan, and oxidation of the resulting phosphonium ylide with molecular oxygen. Many common functional groups are tolerated during the reaction, and the products are obtained in good to excellent yield under the mild conditions. This methodology offers efficient access to biologically important compounds, including fused polycyclic compounds and furaldehydes, from simple starting materials.

Full text of DOI:10.1021/acs.orglett.7b01533

Letter
pubs.acs.org/OrgLett
Trialkylphosphine-Mediated Synthesis of 2‑Acyl Furans from
Ynenones
Chao Xu, Stephane Wittmann, Manuel Gemander, Venla Ruohonen, and J. Stephen Clark*
́
WestCHEM, School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow G12 8QQ, United
Kingdom
S
* Supporting Information
ABSTRACT: A novel reaction for the synthesis of 2-acyl furans is reported. The
reaction is believed to proceed by sequential addition of a trialkylphosphine to an
ynenone, 5-exo-dig cyclization to form the furan, and oxidation of the resulting
phosphonium ylide with molecular oxygen. Many common functional groups are
tolerated during the reaction, and the products are obtained in good to excellent
yield under the mild conditions. This methodology offers efficient access to
biologically important compounds, including fused polycyclic compounds and furaldehydes, from simple starting materials.
ubstituted furans are ubiquitous and are often found in
bioactive natural products,1 pharmaceuticals,2 and organic
Scheme 1. Syntheses of Highly Functionalized Furans from
Ynenones
S
materials.3 Furans are also valuable synthetic intermediates
because they serve as masked 1,4-dicarbonyl compounds and
can be transformed into a variety of other functional groups.4
As a consequence of the importance of furan-containing
systems, the development of new and more efficient methods
for the synthesis of furans is of general interest to organic
chemists.5 Although there are several well-established general
methods for furan synthesis,6 metal-catalyzed reactions that
employ copper,7 zinc,8 palladium,9 and gold10 complexes are
becoming increasingly popular and offer several advantages in
terms of efficiency and functional group compatibility when
compared to traditional methods. Organocatalytic processes for
the synthesis of furans have also been described, such as
Krische’s phosphine-mediated reductive condensation of γ-
acyloxy butynoates11 and Jørgensen’s synthesis of 2-hydrox-
yalkyl and 2-aminoalkyl furans,12 but these approaches have
been used less frequently.
Ynenones have emerged recently as versatile starting
materials for the synthesis of furans. For example, Kuroda
and co-workers reported an organophosphine-induced tandem
furan formation and Wittig reaction sequence (Scheme 1a).13
Additionally, our group has discovered the tetrahydro-
thiophene-catalyzed synthesis of highly substituted furfuryl
alcohols, amines from ynenones (Scheme 1b)14 and a Brønsted
acid promoted cascade reaction for the synthesis of cyclo-
propyl-substituted furans.15 Interesting examples of transition-
metal-catalyzed oxidative formation of 2-acyl furans in
moderate to good yield have been published by the groups of
Zhang,16 Liu,17 and Cui18 (Scheme 1c). On the basis of these
reports and results of prior studies concerning the synthesis of
furans from ynenones, we postulated that treatment of a simple
ynenone with a stoichiometric amount of a trialkylphosphine in
the presence of an oxidant could deliver a functionalized 2-acyl
furan (Scheme 1d).
oxygen as the oxidant (Table 1). Reaction conditions were
varied in order to minimize the reaction time and maximize the
yield. Optimization experiments revealed that the most suitable
solvents for this reaction were dichloromethane and benzene;
the desired product 2a was obtained in yields of 95% and 98%,
under standard conditions (entries 1 and 6). Solvents such as
THF, methanol, and hexane were not effective for this
transformation (entries 2−4), but DMF was suitable in some
Preliminary experiments were performed using the ynen-
dione 1a and the ynenone 1b as the model substrates with
Received: May 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01533
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditionsa
Table 2. Substrate Scope for Formation of 2-Acyl Furans
entry
substrate
solvent
initiator
conversion (%)b
95c
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1a
1b
CH2Cl2
THF
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
n-Bu3P
Ph3P
d
−
hexane
MeOH
DMF
trace
d
−
80
benzene
benzene
benzene
benzene
98c
50c
99
d
Ph3P
−
a
Reaction conditions: 1 (0.1 mmol), initiator (0.2 mmol), solvent (10
mL), at rt for 3 h under a static oxygen atmosphere unless noted
b
1
otherwise. Conversion was determined by H NMR analysis using
trimethoxybenzene as an internal standard. Isolated yield. Furan 2a/
c
d
2b was not isolated.
cases (entry 5). Various nucleophilic reagents were assessed for
their ability to perform 2-acyl furan formation. It was found that
tri-n-butylphosphine and triphenylphosphine both cyclized 1a
to give 2a (entries 6 and 8). However, treatment of the less
reactive ynenone 1b with tri-n-butylphosphine delivered the
desired furan product 2b in moderate yield (entry 7) and only
starting ynenone 1b was recovered when triphenylphosphine
was employed (entry 9). The crucial role played by phosphine
was demonstrated by the fact that the 2-acyl furans 2a and 2b
were not obtained when alternative reagents such as DABCO,
DMAP, or tetrahydrothiophene were employed as nucleophilic
organocatalysts.
On the basis of the results of preliminary experiments and
safety considerations, dichloromethane was identified as the
solvent of choice for the oxidative cyclization reactions.
Structurally diverse ynenones were then synthesized and
examined as substrates in the organophosphine-mediated
reaction (Table 2). In most cases, the expected 2-acyl furans
were obtained in moderate to excellent yields. The cyclization
reaction proceeded in high yield with substrates in which R3 is
electron-withdrawing (entries 1 and 3−6), irrespective of the
alkene geometry. It is notable that a reasonable yield of furan
2b was obtained from the reaction of ynenone 1b (entry 2), a
substrate that is problematic with methods described by
others.16−18 Furthermore, high yields could be obtained in
some cases where air was used as the oxidant (entry 6).
Significantly, the E and Z isomers of the phenyl-substituted
ynenone 1f both reacted under standard conditions to afford
furan 2f in good yield (entries 7 and 8). However, reduced
reactivity was observed when R3 is an aryl substituent (entry 9)
and the furan 2h was not obtained in the case where R3 is an
alkyl group; the starting ynenone 1h was recovered in this case
(entry 10). The reaction was also performed on phenyl-
substituted alkyne 1i, but the furan 2i was obtained in low yield
(entry 11). It is also noteworthy that when highly function-
alized starting material 1j was subjected to the reaction
conditions, the fused tricyclic furan 2j, corresponding to the A−
C fragment of the marine alkaloid nakadomarin A,19,20 was
a
Reaction conditions: (A) n-Bu3P (2 equiv) added to a solution of 1 in
CH2Cl2 at rt, and the mixture stirred for 3 h under a static atmosphere
of oxygen; (B) a solution of 1 in CH2Cl2 added to a solution of n-Bu3P
(1.1 equiv) in CH2Cl2 at rt, and the mixture stirred for 3 h under a
static atmosphere of air; (C) a solution of 1 in DMF added to a
solution of n-Bu3P (4 equiv) in DMF at rt, and the mixture stirred for
3−8 h under a static atmosphere of oxygen. Isolated yield. Both E
and Z isomers were consumed during the reaction. The isomers of 1g
were also cyclized individually to give 15% and 26% yields of 2g. The
ynenone 1h was recovered in 60% yield.
b
c
d
e
obtained in excellent yield (entry 12). This result demonstrates
that the reaction can be used to synthesize fused ring systems.21
B
DOI: 10.1021/acs.orglett.7b01533
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Treatment of substrate 1k, which contains a terminal alkyne
group, with tri-n-butylphosphine and oxygen in dichloro-
methane resulted in a smooth reaction to deliver the tricyclic
furaldehyde 2k in 86% yield (Scheme 2). Aldehydes of this type
and 1b with an excess of tri-n-butylphosphine in d6-benzene
under an atmosphere of argon at room temperature did not
produce spectroscopically identifiable quantities of the expected
intermediate phosphonium ylides 4a and 4b. In the case of the
diketone 1a, starting material was consumed rapidly to give a
complex mixture of unidentified products and subsequent
introduction of air did not deliver the expected product 2a. In
contrast, the less reactive ynenone 1b did not undergo reaction
in the absence of oxygen, but subsequent introduction of air
into the reaction vessel resulted in the reaction of ynenone 1b
to give the expected furan product 2b with a good level of
conversion. Based on these observations, we proposed that 1,6-
addition of the trialkyphosphine to an ynenone is favored for
reactive substrates where R3 is an electron-withdrawing group,
and that an intermediate is generated, which reacts with the
starting ynenone and/or degrades in the absence of oxygen.
Conjugate addition of the trialkyphosphine to the less reactive
substrate 1b is unfavorable, and oxygen is required to drive the
equilibrium toward 2-acyl furan 2b. This observation suggests
that an equilibrium is established in which the starting materials
are favored. In neither case could significant amounts of the
putative phosphonium ylide intermediate 4 or its precursor 3
be detected by 31P NMR.27
Scheme 2. Synthesis of a Polycyclic Furaldehyde
are potentially unstable, and the success of the transformation
demonstrates the mildness of the reaction conditions. This
result suggests that the reaction should be useful for the
synthesis of synthetic intermediates or bioactive natural
products that contain a sensitive 2-furaldehyde.22
A plausible reaction mechanism based on Kuroda’s13
previous report and our preliminary experimental studies is
shown in Scheme 3. In this mechansim, tri-n-butylphosphine
Scheme 3. Possible Reaction Mechanism
In order to discover whether transformation of the
phosphonium ylide 4 into the acyl furan 2 was possible
(Scheme 3), direct oxidation of a furan-containing ylide,
generated by deprotonation of a phosphonium salt, was
investigated (Scheme 5). Furfuryltriphenylphosphonium bro-
Scheme 5. Reaction of a Phosphonium Ylide with Oxygen
mide (6)28 was deprotonated with sodium hydride, and the
resulting ylide was exposed to oxygen. This reaction delivered
the alkene 729 (61% yield, 3:2 mixture of E and Z isomers)
resulting from oxidation of the ylide to give furfural followed by
Wittig reaction of the aldehyde with unoxidized ylide. The
outcome of this reaction demonstrates that a furan-containing
phosphonium ylide can be oxidized with oxygen to give the
corresponding aldehyde and provides evidence to support the
proposed reaction mechanism (Scheme 3).
In summary, we have discovered a phosphine-mediated 2-
acyl furan forming reaction that has a broad reaction scope. The
simple and mild reaction employs readily available ynenones as
substrates and offers a direct access to di- and trisubstituted
furan derivatives including fused tricyclic acyl furans and
furaldehydes.
undergoes reversible 1,6-addition to the ynenone 1 to generate
the zwitterion 3. Subsequent 5-exo-dig cyclization by
nucleophilic addition to the allene affords the phosphonium
ylide 4. Finally, the desired 2-acyl furan 2 is produced by
reaction of the ylide 4 with oxygen, possibly via the
phosphadioxetane 5. Few examples of the direct oxidation of
phosphorus ylides have been described; those would usually
involve singlet oxygen,23 a phosphite-ozone adduct,24 or an
oxaziridine.25 To the best of our knowledge there are no
literature precedents for the use of oxygen or air as the oxidant
to provide the carbonyl product from a simple phosphonium
ylide.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01533.
NMR experiments were performed on substrates 1a and 1b
in an attempt to detect and identify the intermediates involved
in the reaction (Scheme 4).26 Unfortunately, treatment of 1a
■
S
Scheme 4. Mechanistic Studies
Experimental procedures plus spectroscopic and other
data for compounds 1f−k and 2a−k (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stephen.clark@glasgow.ac.uk.
C
DOI: 10.1021/acs.orglett.7b01533
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(19) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org.
Chem. 1997, 62, 9236−9239.
J. Stephen Clark: 0000-0003-3935-0377
Notes
(20) For our previous studies concerning the total synthesis of
nakadomarin A with late-stage introduction of the furan (ring C), see:
Clark, J. S.; Xu, C. Angew. Chem., Int. Ed. 2016, 55, 4332−4335.
(21) (a) Kazem Shiroodi, R.; Rivera Vera, C. I.; Dudnik, A. S.;
Gevorgyan, V. Tetrahedron Lett. 2015, 56, 3251−3254. (b) Yao, T.;
Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679−7685.
(c) Blanc, A.; Tenbrink, K.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2009,
74, 5342−5348. (d) Schickmous, B.; Christoffers, J. Eur. J. Org. Chem.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the China Scholarship
Council, German Academic Exchange Service (DAAD), and
the University of Glasgow for funding.
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