Efficient synthesis of tetrasubstituted furans from nitroallylic acetates and 1,3-dicarbonyl/α-activating ketones by Feist-Benary addition-elimination

Article abstract of DOI:10.1002/asia.201100988

Pure organic: The synthesis of tetrasubstituted furans often involves transition-metal catalysis or metal-halogen exchange reactions. A new approach to these heterocycles employs the Feist-Benary addition-elimination process using nitroallylic acetates an

Full text of DOI:10.1002/asia.201100988

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DOI: 10.1002/asia.201100988
Efficient Synthesis of Tetrasubstituted Furans from Nitroallylic Acetates and
1,3-Dicarbonyl/a-Activating Ketones by Feist–Bꢀnary Addition–Elimination
Wan-Yun Huang, Yi-Chieh Chen, and Kwunmin Chen*[a]
Furans represent an important subclass of five-membered
aromatic heterocycle that has been used for the synthesis of
many pharmaceutical molecules[1] and industrial materials.[2]
The functionalization of furans often allows for further
structural elaboration and adornment. As a consequence,
many valuable synthetic protocols have been devised for the
construction of polysubstituted furans, and these are based
either on introducing substituents onto the existing furan
ring or furan ring construction from acyclic precursors.[3] De-
rivatization of furans often requires the application of a
metal–halogen exchange reaction or a transition-metal-cata-
lyzed cross-coupling,[4a,b] with the halide precursor emanat-
ing from an electrophilic substitution process.[4c] On the
other hand, some excellent methods have been developed
for the build-up of functionalized furans from acyclic precur-
sors, some of which utilize alkynyl epoxides,[5a] a-alkenyl-b-
diketones,[5b] cyclopropenyl ketones,[5c] g-acyloxy butynoa-
tes,[5d] alkynyl ketones,[5e] b-acyloxy acetylenic ketones,[5f] a-
alkynyl enones,[5g–o] thioalkynone,[5p] alkynol/alkyne,[5q–s] al-
kynoate/1,3-dicarbonyls,[5t] propargylic alcohols/1,3-dicarbo-
nyls,[5u] propargylic alcohols/ketones,[5v] allenyl ketones,[5w]
propargylic esters,[5x] propargyl vinyl ethers,[5y] alkynyl cyclo-
propyl ketones,[5z–aa] alkenyl carbene/enones,[5ab] b-alkynyl
enals,[5ac] acyloxy sulfones,[5ad] enynols,[5ae–af] and various
other substrates.[5ag] The application of these methods often
requires the preparation of specially tailored starting sub-
strates utilizing transition-metal catalyzed reactions. The
Paal–Knorr reaction has proven particularly useful for furan
ring assembly.[6] The reaction of 1,3-dicarbonyl compounds
with a-haloketones (the Feist–Bꢀnary reaction) under
metal-free conditions, is another longstanding historical pro-
tocol that has provided rapid access to many different types
of substituted furans.[7]
Feist–Bꢀnary type reaction between electron-deficient nitro-
allylic acetates 1 and 1,3-dicarbonyl/a-activating ketones.
The corresponding multifunctional 3,5-alkyl/aryl-2-carboxyl-
ate-4-keto/cyano-containing tetrasubstituted furans were
typically obtained in respectable to excellent yield (52–
99%) via an interesting SN2ꢁ addition–elimination sequence
that proceeds under very mild reaction conditions [Eq. (1)].
Initially we investigated the synthesis of ring-annulated
furan 4a from nitroallylic acetate 1a[8] and cyclohexan-1,3-
diketone 2a as a model reaction. Treatment of 1a and 2a
with Et3N in CH3CN for 48 h at room temperature gave
ethyl-2-(4,5,6,7-tetrahydro-4-oxo-3-phenylbenzofuran-2-yl)a-
cetate 4a in 73% yield (Table 1, entry 1). Similar yields
were observed when the reaction was carried out in the
presence of DABCO or DBU (Table 1, entries 2–4), but
with DIPEA over 72 h, a significant jump in yield was re-
corded. We next examined the influence of different inor-
ganic bases on the reaction outcome. Yields dropped when
NaHCO3 was used as the base, while Na2CO3 led to the tet-
rasubstituted furan 4a in 80% yield (Table 1, entries 5,6).
The yield could be further improved to 94% when K2CO3
was employed as a base (Table 1, entry 7), and an almost
quantitative yield was obtained when Cs2CO3 was used in
CH3CN over 4 h (Table 1, entry 8). In an effort to further in-
crease the reaction rate, various solvents were examined in
this process. However, changes to the original solvent we
had selected failed to improve the reactivity (Table 1, en-
tries 9–11). The functionalized tetrasubstituted furan 4a was
fully characterized by IR and H1 and C13 NMR spectroscop-
ic analysis and further confirmed by single-crystal X-ray
analysis.[9]
The development of facile new methods for the efficient
ring assembly of tetrasubstituted furans remains a highly de-
sirable and challenging objective for many in the field. We
present herein a unique and generally efficient synthetic
strategy for accessing tetrasubstituted furans that exploits a
[a] W.-Y. Huang, Y.-C. Chen, K. Chen
Chemistry Department
National Taiwan Normal University
88 Sec. 4, TingChow Rd., Taipei, Taiwan 116
Fax : (+886)2-9324249
E-mail: kchen@ntnu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100988.
688
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Chem. Asian J. 2012, 7, 688 – 691

Table 1. Optimization of the reaction conditions.[a]
in 52% yield. 3-Oxo-3-phenylpropanenitrile likewise served
as a good Michael donor for the desired addition–elimina-
tion process. Furans with 2-carboxylate-4-cyano-3,5-diaryl
substituents could additionally be synthesized in high to ex-
cellent yield (Scheme 1, 6a–f).
When pentane-2,4-dione was employed in this protocol,
yields were typically lower. The desired polyfunctionalized
3-aryl-2-carboxylate-4-keto-5-methyl furans were isolated in
yields that ranged from 55 to 78% (7a–c), and a further
drop in yield was noted when 1,3-diphenylpropane-1,3-dione
was employed in this process to obtain 7d. The steric hin-
drance of the aryl substituents at the C3–5 positions might
contribute significantly to the low yield observed in this
transformation. Our Michael donors also reacted satisfacto-
rily when there was an alkyl substituent in the nitroallylic
acetate component (e.g. 4i, 5h, and 6g). In yet another in-
vestigation of the scope of our method, we undertook the
Entry
Base
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
dioxane
DMSO
48
72
72
36
48
48
48
4
73
76
87
65
52
80
94
99
75
94
89
DABCO
DIPEA
DBU
NaHCO3
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
16
24
2
[a] All reactions were performed using nitroallylic acetate 1a (31.4 mg,
0.11 mmol), cyclohexan-1,3-diketone 2a (1.0 equiv), and base (1.0 equiv)
in the indicated solvent at ambient temperature. DABCO=1,4-
synthesis of some fully substituted bisACTHNUTRGNE(NUG furan) compounds.
Reaction of nitroallylic acetates with 1,3-dibenzoylacetone
proceeded slowly to give the polyfunctionalized C2 symmet-
diazabicyclo
[2.2.2]octane,
DBU=1,8-diazabicycloACTHNGUETRNNU[G 5.4.0]undec-7-ene,
DIPEA=N,N-diisopropylethylamine. [b] Yield of isolated product.
ric bisACTHNUTRGENUG(N furan) species 7e in 32% yield after 10 days.
A definitive mechanistic explanation of the furan ring as-
sembly process is unclear at the present moment, but one
possible pathway is as follows: The nucleophilic enol first
reacts with the Michael acceptor to give adduct A by an
With the optimum reaction conditions now secured, we
next studied the feasibility and scope of our new reaction
protocol. Various nitroallylic
acetates 1 and 1,3-dicarbonyls
(2)/a-activating ketones (3)
were systematically investigat-
ed. For the cyclic 1,3-diketone
substrates, various aryls and
heteroaromatic substituents in
the nitroallylic acetates were in-
vestigated and found to give
satisfactory results (Scheme 1,
4b–e). The use of 5,5-dimethyl-
cyclohexane-1,3-dione as the
Michael donor for the reaction
also gave the desired products
with excellent efficiency (4 f–h).
Encouraged by these results,
the reaction scope was further
extended to chroman-2,4-dione.
Treatment of 1a with chroman-
2,4-dione, under the optimum
conditions, gave the corre-
sponding 4H-furanoACTHNUGTRNEUNG[3,2-c]chro-
men-4-one 5a in quantitative
yield. This new furan ring con-
struction method was also toler-
ant of various aryl and hetero-
aromatic substituents in the ni-
troallylic acetates (5b–f). The
use of a less acidic b-tetralone
as the nucleophilic component
afforded
the
4,5-
dihydronaphthoACHTUNGTRENNUNG[2,1-b]furan 5g Scheme 1. The structures of the tetrasubstituted furans.
Chem. Asian J. 2012, 7, 688 – 691
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689

K. Chen et al.
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SN2ꢁ process (Scheme 2). This is followed by a second Mi-
chael addition from the enol oxygen atom to give the five-
membered ring (5-exo-trig addition, route a). Deprotonation
NMR spectra. Interestingly, when isobutyl-substituted nitro-
allylic acetate was used, formation of the endo addition
product 9b predominated, and the compound could be iso-
lated in 71% yield. The reversal of the preference for which
ring forms (5- vs. 6-membered) is noteworthy. This reversal
might arise from the special geometry of the resulting five-
membered keto-enol conformation.
In summary, we have developed an efficient synthesis of
tetrasubstituted furans via a Feist–Bꢀnary type reaction. The
Michael–Oxa–Michael–aromatization protocol of nitroallylic
acetates with 1,3-dicarbonyls and a-activating ketones readi-
ly gives 3,5-alkyl/aryl-2-carboxylate-4-keto/cyano functional-
ized furans in good to excellent yield. Our new method now
provides yet another powerful alternative for the synthesis
of furans having diverse substitution patterns under mild re-
action conditions. Other synthetic applications of nitroallylic
acetates are currently under investigation in our laboratory.
Experimental Section
General procedure for synthesis tetrasubstituted furans
Scheme 2. Mechanistic rationale for formation of substituted furan and
pyran rings.
(E)-Ethyl-2-acetoxy-3-nitro-4-phenylbut-3-enoate
1a
(0.11 mmol,
31.4 mg) was added to a stirred solution of 1,3-cyclohexanedione 2a
(0.11 mmol, 12.4 mg) and cesium carbonate (0.11 mmol, 36.0 mg) in
CH3CN at room temperature. The mixture was stirred until the starting
material disappeared as determined by TLC. The crude residue was puri-
fied by flash column chromatography on silica gel (hexanes/ethyl ace-
tate=3:1) to give the corresponding ethyl-2-(7-oxo-2-phenyl-4,5,6,7-tetra-
hydrobenzofuran-3-yl)acetate 4a. 1H NMR (400 MHz, CDCl3): d=7.29–
7.42 (m, 5H), 4.19 (q, 2H, J=7.2 Hz), 3.63 (s, 2H), 2.91 (t, 2H, J=
6.6 Hz), 2.49 (t, 2H, J=6.6 Hz), 2.18 (quin, 2H, J=6.6 Hz), 1.27 ppm (t,
3H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3): d=193.6, 169.2, 166.5,
144.6, 130.9, 129.6 (x2), 127.9 (x2), 127.5, 122.2, 119.7, 61.3, 38.5, 32.4,
23.6, 22.3, 14.1 ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C18H18O4Na
321.1103, found 321.1105; IR: n˜ =2945, 2871, 1735, 1679, 1576, 1447,
1370, 1340, 1189, 1008, 699 cmÀ1; m.p. 99.5–100.78C.
and elimination of HNO2 then completes the process. The
preferential formation of a five-membered ring over a six-
membered ring (except cyclopentane-1,3-dione, see below)
is consistent with Baldwinꢁs rules.[10] The energetically fa-
vored aromatization of the furan core scaffold might also be
contributing in a beneficial way.
The aforementioned addition–elimination process for the
synthesis of furans is impressive. The inherent 1,3-C,O-nu-
cleophilic nature in the donor component is essential for the
reaction. In parallel, pyran ring formation in the second Mi-
chael reaction predominated when cyclopentane-1,3-dione
was used (Scheme 2, by 6-endo-trig addition; route b). In
this particular system, treatment of the nitroallylic acetate
1a with 1,3-cyclopentanedione under the same reaction con-
ditions provided the tetrasubstituted furan 8a in only 22%
yield, with the major product being the cyclopenta[b]pyran-
2-carboxylate 9a (60%; Scheme 3).[11] The structure of the
Acknowledgements
We thank the National Science Council of the Republic of China (NSC
99-2113M-003-002-MY3 and NSC 99-2119M-003-001-MY2) and National
Taiwan Normal University (99-D and 100-D-06) for financial support of
this work.
1
cyclopenta[b]pyran was characterized by its H, 13C, and 2D
Keywords: addition · elimination · heterocycles · synthetic
methods
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Received: December 7, 2011
Published online: February 1, 2012
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