A modular and scalable one-pot synthesis of polysubstituted furans

Article abstract of DOI:10.1002/anie.201202486

One four all: Allyl dienol carbonates can be readily converted into diversely substituted furans by a one-pot four-step sequence featuring a palladium-catalyzed decarboxylative allylic alkylation, a microwave-mediated Cope rearrangement, a nucleophilic addition, and a dehydration reaction (see scheme). The protocol is operationally simple, highly flexible, and provides di-, tri-, and tetrasubstituted furans starting from readily available materials. Copyright

Full text of DOI:10.1002/anie.201202486

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DOI: 10.1002/anie.201202486
Furan Synthesis
A Modular and Scalable One-Pot Synthesis of Polysubstituted Furans
Jeremy Fournier, Stellios Arseniyadis,* and Janine Cossy*
Functionalized furans represent an important class of five-
membered heterocycles prevalent in a number of biologically
active natural products as well as in various pharmaceuticals
and agrochemicals.[1] They are also particularly useful build-
ing blocks, finding use in fields such as synthetic organic
chemistry,[2] material science,[3] nonlinear optics,[4] and even
supramolecular chemistry.[5] As a consequence, a number of
synthetic methods have been specifically designed to access
functionalized furans.[6–10] Nonetheless, the development of
flexible and predictable de novo approaches to diversely
substituted furans starting from inexpensive and readily
available compounds still remains an area of ongoing
interest,[11] particularly since the emergence of fragment-
based drug discovery[12] for the development of small
molecules as novel potent therapeutic agents.
The palladium-catalyzed decarboxylative allylic alkyla-
tion (PDAA) reaction, most commonly referred to as the
Tsuji–Trost reaction,[13] has become a remarkably powerful
À
synthetic tool for the construction of C C bonds. This
transformation, which typically displays broad functional-
group tolerance, has been successfully applied to a wide
variety of substrates bearing either an allyl ester or an allyl
enol carbonate moiety.[14–17]
As part of an ongoing research program aimed at
developing new methods for the synthesis of functionalized
heterocycles,[18] we became particularly interested in the
Scheme 1. One-pot approach to polysubstituted furans.
outcome of the PDAA reaction when applied to a new type of
substrate, namely allyl dienol carbonates 3. Indeed, we
reasoned that by analogy with allyl vinyl carbonates, such
substrates could also undergo facile oxidative addition
followed by decarboxylation to afford the corresponding
palladium-dienolate species which, in turn, should generate
the a-allyl product 4. The latter could then be engaged in
a [3,3]-sigmatropic Cope rearrangement[19] to form the
corresponding g-allyl furanone 5, which could eventually be
treated with a variety of hard nucleophiles followed by an
acidic work-up to promote sequential functionalization and
dehydration and potentially generate the corresponding bis-,
tris- or tetrasubstituted furan 6 in an entirely tailored fashion
(Scheme 1). If successful, this reaction sequence would
represent a practical, a highly versatile, and an exceptionally
atom-economical method for accessing diversely substituted
furans starting from readily available starting materials.
Herein, we report the results of our endeavors.
To test our hypothesis, allyl dienol carbonate 3a was
chosen as a model substrate. The latter, was prepared in two
steps and 60% overall yield starting from bromo furanone 1a
through a [PdCl2(PPh3)2]-catalyzed Suzuki coupling followed
by treatment with NaHMDS and allyl chloroformate (THF,
À608C). Compound 3a was then subjected to standard PDAA
reaction conditions ([Pd(PPh3)4] (3 mol%), CDCl3, RT;
Scheme 2). In less than ten minutes, complete conversion of
the starting material was observed and, to our delight, we
were able to isolate both the a- and the g-allyl products 4a
and 5a in 76% and 18% yield, respectively. Interestingly,
after conducting a kinetic study by monitoring the reaction
1
through H NMR analysis (see the Supporting Information),
we were able to determine that the formation of the g-allyl
product 5a was solely the result of a competitive g-allylation
rather than an in situ [3,3]-sigmatropic Cope rearrangement,
which could have been triggered during the PDAA reaction.
The resulting a-allyl product 4a was eventually engaged in the
actual Cope rearrangement. After exploring various reaction
conditions, we found that microwave (MW) irradiation of
a solution of 4a in CH3CN (closed vessel, 400 W, 1808C,
1 hour) cleanly afforded the g-allyl furanone 5a in 92% yield.
[*] J. Fournier, Dr. S. Arseniyadis, Prof. Dr. J. Cossy
Laboratoire de Chimie Organique
ESPCI ParisTech, CNRS (UMR 7084)
10 rue Vauquelin 75231 Paris Cedex 05 (France)
E-mail: stellios.arseniyadis@espci.fr
janine.cossy@espci.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202486.
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Scheme 2. Sequential approach to 2,4-disubstituted furans.
DIBAL-H=diisobutylaluminum hydride.
The latter was finally treated with DIBAL-H[20] (CH2Cl2,
À788C, 30 minutes) followed by an acidic work-up (1m HCl,
RT, 12 hours) to afford the corresponding 2,4-disubstituted
furan 6a in 70% yield after purification over alumina (60%
overall yield starting from allyl dienol carbonate 3a). As
a general trend, these preliminary results showed that allyl
dienol carbonates such as 3a could be converted into the
corresponding 2,4-disubstituted furans through a simple four-
step sequence, which features a palladium-catalyzed decar-
boxylative allylic alkylation, a Cope rearrangement, a nucle-
ophilic addition, and a dehydration reaction (Scheme 2).
In the last decade, research efforts have increasingly been
dedicated to the development of more sustainable synthetic
methods, which take into account new constraints such as
atom-, step-, redox-, and pot economy.[21,22] In this context, we
aimed to conduct the entire sequence in the same flask to
avoid unnecessary and tedious purification steps and thus
offer a more straightforward and practical synthetic method.
After much experimentation, not only were we able to
perform the entire four-step sequence in toluene without
isolating any of the intermediates, but we were also able to
improve the overall yield from 60% to 80% in the case of
2,4-disubstituted furan 6a (Scheme 3).
Having identified a useful set of reaction conditions, we
next examined the scope and limitations of this transforma-
tion. To this end, several aryl- (3a–g), heteroaryl- (3h), alkyl-
(3i–k), and vinyl-substituted (3l) dienol carbonates were
synthesized and subjected to our one-pot four-step sequence.
The results are summarized in Scheme 3. As a general trend,
the expected furans 6a–k were obtained in high yields ranging
from 69 to 91%, independent of the substitution pattern on
the starting allyl dienol carbonates 3a—k; an exception was
the allyl dienol carbonate 3l (corresponding product isolated
in 39% yield) bearing a vinyl moiety, which is prone to
polymerization during the Cope rearrangement. Notably, the
isolation of furan 6j was quite challenging because of its high
volatility. In this specific case, the reaction was performed in
dichloromethane and the yield (85%) was determined by
1H NMR spectroscopy of the crude residue using
1,3,5-trimethoxybenzene as an internal reference (47% yield
upon isolation).
Scheme 3. One-pot synthesis of 2,4-disubstituted furans. [a] Yield of
product upon isolation. [b] Yield determined by H NMR spectroscopy
using 1,3,5-trimethoxy-benzene as an internal reference. [c] Reaction
sequence run in CH2Cl2 instead of toluene.
1
To introduce more structural diversity around the furan
ring, the one-pot four-step sequence was slightly modified.
Hence, after the traditional PDAA and the Cope rearrange-
ment, the nucleophilic addition was carried out using
a selection of organolithium reagents (R2Li) instead of
DIBAL-H under otherwise identical conditions (Scheme 4).
Interestingly, whether an alkyl-, an aryl-, a heteroaryl-, or
a propargyl lithium reagent was used as the nucleophile in
conjunction with the two allyl dienol carbonates tested (3b
and 3j), the corresponding 2,3,5-trisubstituted furans (6ba–be
and 6ja–jd) were obtained in good to excellent yields
(50–96% overall yield, Scheme 4).
With the aim of generating further structural diversity, we
then applied the one-pot four-step sequence to the disubsti-
tuted allyl dienol carbonate 3m. The latter was prepared in
three steps and 29% overall yield (unoptimized) starting from
dibromo furanone 1b through consecutive and regioselective
[PdCl2(PPh3)2]-catalyzed Suzuki coupling [23] and treatment of
the resulting disubstituted furanone 2 with NaHMDS and
allyl chloroformate in THF at À608C. After subjecting allyl
dienol carbonate 3m to the PDAA reaction and the
subsequent microwave-mediated Cope rearrangement, the
in situ nucleophilic addition reactions were carried out using
either DIBAL-H or an organolithium reagent, such as nBuLi,
PhLi, or 2-thienyllithium, thus affording, after acidic work-up,
the corresponding 2,3,4-trisubstituted furans 6ma and
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Scheme 4. One-pot synthesis of 2,3,5-trisubstituted furans. Yield of
isolated product is given in parentheses.
2,3,4,5-tetrasubstituted furans 6mb–md. As a general trend,
the desired heterocycles were obtained in particularly high
yields, ranging from 70% to 96%, yields, which compare
favorably with those of other methods reported in the
literature (Scheme 5).
Scheme 5. One-pot synthesis of 2,3,4-trisubstituted- and 2,3,4,5-tetra-
substituted furans and pyrroles. Yields represent products isolated.
Ts =p-toluenesulfonyl.
Although the feasibility of generating polysubstituted
furans in a laboratory setting on a milligram scale was
demonstrated, another important challenge was to perform
this one-pot four-step sequence on a gram scale in order to
validate the efficacy and the practicality of the method.
Unsurprisingly, the reaction proved scalable, with the use of
allyl dienol carbonate 3j giving 83% of the desired product
6ja (Scheme 6).
Scheme 6. Gram-scale synthesis of 2,3,5-trisubstituted furan 6ja.
Finally, with an efficient synthesis of polysubstituted
furans established, we turned our attention to the application
of the method to the synthesis of pyrroles, which are another
important class of heterocycle.[24,25] In the event, the N-tosyl
precursor 8 was prepared and subjected to the same reaction
conditions that were used for the synthesis of the furans. To
our delight, we were able to isolate the corresponding
2,3,4-trisubstituted pyrrole 9a and the 2,3,4,5-tetrasubstituted
pyrroles 9b–d in relatively high yield ranging from 46% to
90% (Scheme 5).
sequence represents an operationally simple, an easily
scalable and, most of all, a particularly flexible method for
constructing furans in an entirely tailored fashion. Notably,
this is probably the only method that allows access to furans of
virtually any substitution pattern. Additionally, this method
was also successfully applied to the synthesis of polysubsti-
tuted pyrroles. The implementation of the present method to
the synthesis of other key heterocycles is currently being
investigated and will be reported in due course.
In summary, we have developed an extremely mild and
efficient method for the preparation of diversely substituted
furans, including 2,4-disubstituted-, 2,3,4- and 2,3,5-trisubsti-
tuted-, and 2,3,4,5-tetrasubstituted furans, starting from
simple and readily available substrates. Overall, this reaction
Experimental Section
Typical procedure for the synthesis of 2,5-disubstituted furan 6a from
allyl dienol carbonate 3a: to a solution of allyl dienol carbonate 3a
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(50 mg, 0.17 mmol) in toluene (1 mL) at RT was added [Pd(PPh3)4]
(5.8 mg, 0.005 mmol) and the resulting reaction mixture was stirred at
the same temperature until complete conversion of the starting
material was detected; the reaction was monitored by TLC analysis
and was usually complete within 10 min. The crude reaction mixture
was then heated under microwave irradiation (closed vessel, 400 W,
1808C) for 1 h; the temperature of the reaction mixture was lowered
to À788C and then a solution of DIBAL-H (250 mL of a 1m solution in
CH2Cl2, 0.25 mmol) was added slowly to the reaction mixture. After
complete conversion of the furanone intermediate 5a, a 1m aqueous
solution of HCl was added and stirring was continued for 12 h at RT.
The organic layer was then separated and the aqueous phase was
extracted twice with EtOAc (2 mL). The combined organic layers
were then washed with brine (2 mL), dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to afford a crude
residue, which was purified by flash column chromatography over
alumina using hexane as eluent. Pure furan 6a (32 mg, 80%) was
isolated as a colorless oil.
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Received: March 30, 2012
Published online: && &&, &&&&
Keywords: allylation · furan · palladium · pyrrole · rearrangement
.
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Chemistry III, Vol. 3 (Ed.: A. R. Katritzky, C. A. Ramsden,
E. F. V. Scriven, R. J. K. Taylor), Elsevier, Oxford, 2008, pp. 45 –
268.
[25] For some recent references on the synthesis of pyrroles, see:
a) N. C. Misra, K. Panda, H. Ila, H. Junjappa, J. Org. Chem. 2007,
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Furan Synthesis
J. Fournier, S. Arseniyadis,*
J. Cossy*
&&&& — &&&&
A Modular and Scalable One-Pot
Synthesis of Polysubstituted Furans
One four all: Allyl dienol carbonates can
be readily converted into diversely sub-
stituted furans by a one-pot four-step
sequence featuring a palladium-catalyzed
decarboxylative allylic alkylation, a micro-
wave-mediated Cope rearrangement,
a nucleophilic addition, and a dehydra-
tion reaction (see scheme). The protocol
is operationally simple, highly flexible,
and provides di-, tri-, and tetrasubstituted
furans starting from readily available
materials.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!